• Chemotherapy is the drug treatment for the diseases caused by bacteria and the other pathologic

microorganisms, parasites, and tumor cells.

The objective of chemotherapy is to study and to apply the drugs that have highly selective toxicity to the
pathogenic microorganisms and have no or less toxicity to the host
• Antimicrobials - a general term for natural or synthetic compounds which at certain
concentrations inhibit growth of, or kill, micro-organisms.
– The term antimicrobials is a collective for anti-virals, anti-bacterials, anti-fungals and
anti-protozoals.
• “Antibiotic” means “against life”. Substances produced by various species of micro-organisms:
bacteria, fungi, actinomycetes— to kill or suppress the growth of other microorganisms.
• Selective toxicity- kills harmful microbes without damaging the host
• Antimicrobial spectrum : the scope that a drug kills or suppresses the growth of
microorganisms.
– Narrow-spectrum: The drugs that only act on one kind or one strain of bacteria.
(isoniazid )
– Broad-spectrum: The drugs that have a wide antimicrobial scope. (tetracycline,
chloramphenicol )
• Antimicrobial activity: the ability that a drug kills (bactericidal) or suppresses the growth
(bacteriostatic) of microorganisms.
– The minimal bactericidal concentration (MBC) the minimum amount of a drug required
to kill bacteria in vitro.
The minimal inhibitory concentration (MIC) the minimum amount of a drug required to inhibit the
growth of bacteria in vitro.
• Kill Characteristics of Bactericidal Drugs
– Concentration-Dependent Killing
• The rate & extent of killing increases as the peak drug concentration increases
e.g. Aminoglycosides, Fluoroquinolones
• These drugs exhibit a ”post-antibiotic effect” or persistent suppression of
bacterial growth after limited exposure to an antibiotic.
– Time-Dependent Killing
• Bactericidal activity continues as long as the plasma concentration is greater than
the minimum bactericidal concentration e.g. -lactams, macrolides
• The concentration of these drugs should be maintained above the MBC for the
entire time interval between repetitive doses.
• Superinfections:
– Antibacterial drugs are designed to kill bacteria, but no drug kills all bacteria
– Killing of normal flora removes the inhibitory effect of the normal flora (which produce
antibiotics & compete for essential nutrients). This allows for uninhibited growth of
potentially pathogenic bacteria & fungi

1
 • Antibiotic resistance is resistance of a microorganism to an antimicrobial drug that was
originally effective for treatment of infections caused by it.
• Pathogens resistant to multiple antibiotics are considered multidrug resistant (MDR).
Year Origin Description
John Parkington recommended using mold for treatment in his book on
1640 England
pharmacology
Sir John Scott Burdon-Sanderson observed that culture fluid covered with mould
1870 England
did not produce bacteria
Joseph Lister experimented with the antibacterial action on human tissue on what
1871 England
he called Penicillium glaucium
John Tyndall explained antibacterial action of the Penicillium fungus to the Royal
1875 England
Society
1877 France Louis Pasteur postulated that bacteria could kill other bacteria (anthrax bacilli)
Ernest Duchesne healed infected guinea pigs from typhoid using mould
1897 France
(Penicillium glaucium)
Sir Alexander Fleming discovered enzyme lysozyme and the antibiotic substance
1928 England
penicillin from the fungus Penicillium notatum
1932 Germany Gerhard Domagk discovered Sulfonamidochrysoidine (Prontosil )
During 1940's and 50's streptomycin, chloramphenicol, and tetracycline were discovered and Selman
Waksman used the term "antibiotics" to describe them (1942)

ANTIBACTERIAL DRUG ACTION

ANTIMICROBIAL RESISTANCE MECHANISMS

Four major categories
(1) Reduced Permeability
(2) Active efflux

2
(3) Antimicrobial agent modification
(4) Target modification
FACTORS INFLUENCING SELECTION OF AMA
1. Organism related factors
2. Drug related factors
3. Host factors
1. ORGANISMS RELATED FACTORS
Target organisms
a. Identification of target org. by historical data, experience, gram staining or culture
methods
Sensitivity patterns
b. Test for susceptibility, two methods
i. Diffusion method
ii. Dilution method
Antibacterial sensitivity test
• Diffusion Based Method
– Zone of inhibition (ZoI)
– Endpoints: susceptible (mild, moderate, high) or resistant (No ZoI)
• Dilution Based Method
– MIC or MBC
2. DRUG RELATED FACTORS
Spectrum of activities
a. Narrow spectrum – if the nature of org. is known
b. Broad spectrum – in life-threatening infection,empirical antimicrobial therapy, etc.

Broad Spectrum Narrow Spectrum

Ampicillin Penicillin G

Carbenicllin Streptomycin

Cephalosporins Erythromycin

Chloramphenicol Lincomycin

Tetracyclins Vancomycin

3
 Sulphonamides Polymyxin B

Type of activities
 Bactericidal – life-threatening infections, endocarditis, infections at less accessible site,
impaired host defence, etc.
 Bacteriostatic – used when host immunity is strong

Bactericidal Drugs Bacteriostatic Drugs

Penicillins Chloramphenicol

Cephalosporins Tetracyclines

Aminoglycosides Macrolides

Quinolones Sulphonamides

Vancomycin Trimethoprim

Sulphonamides + Trimethoprim Novobiocin

Combination of Antimicrobial Drugs

Bactericidal + Bactericidal = Synergistic effect
Bacteriostatic + Bacteriostatic = Additive effect
Bactericidal + Bacteriostatic = Antagonistic effect
Pharmacokinetic Profile
 Effective concentration of drug at the site of infection
 Extensively metabolised – Chloramphenicol, macrolides (not preferred for
urinary tract infection)
 Renal clearance and accumulation in urine – Nalidixic acid, nitrofurantoin (used
in UTI)
 Excellent Tissue penetration – fluoroquinolones
 Good brain penetration – sulphonamides and chloramphenicol
 Poor brain penetraiton – Penicillins and aminoglycosides
 Extensive protein binding - doxycycline
Route of administration
 Parenteral route – critically ill patients
 Oral route – long term administration & GI infections
 Depends on bioavailability by oral route
 Example; Aminoglycosides, Penicillin G, Vancomycin, etc.
5. Relative toxicity

4
  Least toxic – Penicillins
 Highly toxic – Chloramphenicol, Clindamycin
Drug Interactions – can affect
– intestinal absorption,
– enhance or slow liver metabolism,
– interfere with kidney excretion or result in competition for receptors or plasma proteins

Antimicrobial policy
 Resistance pattern in particular area
 Narrow and specific antibacterial – preferred
 Newer and broad spectrum – reserved
 Fluoroquinolones should not be used in food animals
8. Cost of therapy
 Less cost and easily available drugs - preferred
3. HOST FACTORS
Host-defence mechanisms:
 Immunocompromised animals – bactericidal drugs
 Normal immunity – bacteriostatic drugs
2. Pathological conditions:
 Renal disease – do not use aminoglycosides
 Hepatic dysfunction – do not use tetracyclins
 Meningitis – do not use penicillins (accumulate in CSF)
3. Local factors
 Pus – do not use sulphonamides & aminoglycosides
 Haematomas – Penicillins, cephalosporins and tetracyclins – bind to degraded Hb.

5
  pH – Aminoglycosides are more active in alkaline urine, methenamine& nitrofurantoin –
active in acidic urine, penicillin is inactived in acidic pH.
Age:
 Neonates: renal and hepatic elimination process – poorly developed (do not use
chloramphenicol and sulphonamides)
 Tetracyclines accumulate in bone and teeth of growing animals
 Fluoroquinolones – interfere with cartilage growth
5. Species:
 Tetracyclines – enterocolitis in horse under stress
 Oral administration of broad spectrum antibacterials – rumen metabolism get affected
 Chloramphenicol toxicity in cats – due to deficient in glucuronide conjugation
Pregnancy
 Aminoglycosides – hearing loss in neonates
 Tetracyclines – inhibit bone growth in foetus
 Anthelmintics – embryotoxic and teratogenic
7. Genetic Factors
 Acute hemolysis by sulphonamides and chloramphenicol in patients with glucose-6-
phosphate dehydrogenase deficiency
ADVERSE REACTIONS TO AMA
Antimicrobial drugs can damage the function of many organs or tissues, particularly
• kidneys (e.g., aminoglycosides, amphotericin B),
• nervous system (e.g., aminoglycosides, polymyxins),
• liver (e.g., tetracyclines, chloramphenicol),
• heart (e.g., aminoglycosides, monensin, tilmicosin, and tetracyclines),
• immune system (e.g., penicillin G),
• hematopoietic system (e.g., sulfa drugs, chloramphenicol),
• Retina and joint cartilage (e.g., fluoroquinolones)
SULPHONAMIDES, DIAMINOPYRIMIDINES AND POTENTIATED SULPHONAMIDES
• Gerhard Domagk, awarded Nobel Prize in 1939 for the discovery of the use of Prontosil, azo dye
against bacterial infections in 1935.

6
Mechanism of Action (Wood-fields Theory)
Inhibition of folic acid synthesis

7
Chemical properties and solubility
• Weak organic acids, wide range of pKa values
• Drugs with high pKa have low protein binding and low solubility and vice versa
• Varies from slightly soluble to Insoluble in water
• Sodium salt is water soluble and have high alkaline pH (except sulphacetamide)
• Sulphonamides – 2x more soluble in alkaline pH
• Sulphonamides solution - pH 9-10; highly irritant on extravascular use
• In acidic urine, N4 acetylation – decreases solubility, results in crystalluria & renal toxicity
• Solubility of sulphonamides is affected by presence of another sulphonamide – law of
independent solubility (additive effect of triple sulpha –sulphapyridine, sulphamerazine and
sulphadiazine)
Indications and microbial susceptibility
• Clinical Indications: Infections of
– Urinary System
– Respiratory System

8
 – Gastrointestinal System
– Central Nervous System
Organisms susceptible to sulphonamides are
– Bacteria (Gram +ve & Gram –ve, aerobes)
• Streptococcus, Hemophilus, Actinomyces, Bacillus, Brucella, Pasteurella,
Klebsiella, Enterobacteriaceae, Clostridium spp.
– Coccidia
– Chlamydia and
– Protozoa including Toxoplasma
Organisms resistant to sulphonamides are
– Leptospira, Pseudomonas, Mycobacterium, Mycoplasma, Rickettsia, Spirochetes
– Anaerobes
• Bacterial resistance to sulphonamides
Chromosomal mutation or transfer of plasmids
– Alteration in dihydropteroate synthase enzyme
– Decreased permeability to sulphonamides
– Increased production of PABA
Gene transfer by Plasmid
– Resistant genes – sul1, sul2, sul3 (sulphonamides), dfr (trimethoprim)
– impaired drug penetration
– the production of additional, sulfonamide-resistant, dihydropteroate synthetase enzymes
Complete cross-resistance between the sulfonamides
Steps to reduce bacterial resistance
• Therapy should be initiated in the acute stage of disease
• Therapy should be at least 3 days or more
• Loading dose and maintenance dose strategy
• Used only for sensitive organisms
• Indiscriminate use should be avoided
• Should be treated in combination with Diaminopyrimidines (Trimethoprim, Ormetoprim,
Baquiloprim)
Pharmacokinetics
• Absorption:
– Ranging from 70 -100 % upon oral administration from small intestine
– Rate of absorption
• is affected by Solubility

9
 • Presence of food in GIT
• Rapid in Dogs, Cats, Birds, intermediate in pigs and slower in cattle
– Sulphasalazine – not absorbed from GIT – gut acting sulpha drug
– Parenteral administration should be avoided as the solution of sulphonamides are strongly
alkaline
• Distribution:
– Widely distributed; incl. brain, joint and soft tissues
– Protein binding (albumin) – 15 to 90% depends on the pKa of the sulpha drugs
– High pKa, low protein binding and vice versa
– Passive diffusion in milk occurs
Sulphadiazine – pH dependent distribution in prostate gland (11% of the plasma concentration
• Metabolism:
– Herbivores metabolize sulphonamides at faster rate as compared to carnivores
– Acetylation of N4 by non-microsomal enzymes in liver – insoluble – crystalluria and
renal toxicity
– Dog – no acetylation – no renal toxicity due to acetylation
– Cattle – extensive acetylation – more toxic
– Aromatic hydroxylation
– Glucuronic acid and sulphate conjugation of the acetylated metabolites
– All metabolism pathway lead to inactivation
• Excretion:
– Renal excretion of free drug or metabolites – Major route
– Carrier mediated proximal tubular secretion
– Passive re-absorption of non-ionized drug from distal tubular fluid – low urine pH
– Small concentrations excreted in tears, feces, bile, milk and sweat.
– Alkalinization of urine – favors excretion
– Species variation in elimination t 1/2 ; e.g. Sulphadimethoxine - 12.5 h in cattle, 8.6 h in
goats, 11.3 h in horses, 15.5 h in swine, 13.2 h in dogs, and 10.2 h in cats due to
differences in protein binding and pH of the urine
– Gut acting sulphonamides – poorly absorbed from the GI tract – eliminated in feces.
Adverse effects
• Acute Toxicity
– Renal toxicity
• Precipitation of sulphonamide in glomerular filtrate
• Acidic urine – more prone to crystalluria
• Hematuria, renal tubule blockade

10
 • Sulfadiazine – least soluble
– Blood dyscrasias
• Anemia – due to decreased production of serum folate
• Thrombocytopenia – due to hypersensitivity reactions
– Hypersensitivity reactions
• Sulphadiazine – reversible immune mediated sterile polyarthritis in Doberman
breed – Type III hypersensitivity
• Idiosyncratic
• Chronic Toxicity – prolonged administration
– Keratoconjuctivitis Sicca
• Reported in dogs treated with Sulphasalazine, sulphadiazine, sulphamethoxazole
• Lacrimotoxic effect (toxic to lacrimal acinar cells)
• due to N-containing pyrimidine ring
• Schirmer Tear Test (STT) values – check for tear production regularly
• Reversal may nor may not occur
Hepatic Necrosis
– Trimethoprim-Sulphadiazine & Trimethoprim-Sulphamethoxazole
– Abnormal metabolic pathway
– Accumulation of hepatotoxic metabolites
Hypoprothrombinemia
– Dogs & Leghorn chickens – due to sulphaquinoxaline
– Induced within 24 hours – increases prothrombin time
– Inhibit Vit K epoxide reductase
Thyroid Metabolism disorders
– Sulphamethaxozole & Sulphadiazine – hypothyroidism in dogs
– Inhibits thyroid peroxidase activity
Sulphadimethoxine – goitrogenic in swine foetus (late gestation)
Acetylator Status
– In Human, slow acetylator –> leads to toxic metabolite, i.e., sulphonamide
hydroxylamine or nitroso compounds –> glutathione conjugation – > non toxic
– In Dogs, No acetylation – susceptible to adverse effects especially in Doberman Pinscher
Skin Reactions – Immune mediated response
– Stevens –Johnsons Syndrome – in human
– Toxic epidermal necrolysis / skin eruptions – in dogs
Inhibition of Carbonic anhydrous enzyme

11
 – Metabolic acidosis
– Thin egg shell in poultry
Diarrhoea
– Sulphanamides+Trimethoprim induces colitis in Horses.
Carcinogenesis
– Sulfamethazine – Thyroid hyperplasia in rats, Follicular cell adenoma of thyroid gland in
mice
• Poultry - decreased egg production and thin shelled eggs

Drug interactions
1. Sulpha drugs displaces anticoagulants and methotrexate from plasma albumin
2. Indomethacin, Probenicid, and Salicylates displaces Sulpha drug from plasma albumin
3. Sulpha drugs potentiate the action of sulphonylurea, thiazide & uricosuric agents
4. Should not be combined with Procaine Penicilline, as Procaine (PABA) antagonize the effect of
Sulpha
5. Co-administration of Folic acid, nicotinamide, glutamic acid and methionine – antagonize the
effect of Sulpha
6. Calcium and antacids – decreases the oral bioavailability of Sulpha
Classification
• Systemically Acting Sulphonamides
– Short-acting (< 12 hrs)
• Sulphadiazine, sulphafurazole, sulphamethazine, sulphachlorpyridazine,
sulphathiazole and sulphanilamide
– Intermediate acting (12 - 24 hrs)
• Sulphadimidine, sulphamethoxazole, sulphamoxole and sulphaphenazole
– Long acting (24-48 hrs)
• Sulphadimethoxine, sulphaethoxypyridazine, sulphamethoxypyridazine and
sulphabromomethazine
– Ultra long acting (> 48 hrs)
• Sulphadoxine and sulphamethopyrazine
• Locally acting Sulphonamides
– Gut acting
• Succinylsulphathiazole, phthalylsulphathiazole, phthalylsulphacetamide,
sulphaguanidine and sulphasalazine
– Topical : Silver sulphadiazine and mafenide
– Ophthalmic :Sodium sulphacetamide

12
Principles to be followed in sulphonamide
 Start therapy at early stage of infection
 Ineffective in chronic cases
 In severe infection administer by iv route
 Administer adequate quantity of drinking water during therapy
 Alkalinisation of urine prevents crystalluria
 Treatment should not exceed seven days
 If no favourable response within four to five days, discontinue the therapy
 Treatment continued 48 hours after remission to prevent recurrence for some cases
 Immune response of the host should be well maintained
Short acting
• Sulphadiazine
– Commonly used in combination with Trimethoprim
– Sparingly soluble in water, freely soluble in solutions of NaOH, KOH, ammonia in water
– Rapidly absorbed in GIT
– Excreted by kidneys in acetylated form (10-40%)
– Acetylated sulphadiazine is less soluble - crystalluria
– Less plasma protein binding (PPB) – 14%
– T1/2; cattle – 3h, pig – 4h, dog – 10h, ewes – 36h
– Attained concentration in CSF, eye and prostate on iv administration
– Used alone for the plaque and gingivitis in Beagle dogs
– Dose:
• Dogs & Cats : 50-100 mg/kg, PO or IV, BID
• Cattle : 100 mg/kg, IV
• Calves : 30 mg/kg, IV
• Pigs : 40 mg/kg, PO or 20 mg/kg, IV
• Sulphafurazole or Sulphisoxazole
– Water soluble; solubility at pH 5-7 is high
– Parent compound or N4 acetylated derivative is not deposited in kidneys – No
crystalluria even in acidic urine
– Rapidly absorbed in GIT and rapidly excreted in urine (conc. exceeds in urine than in
blood)
– Used for urinary tract infections in small animals
– Sulphafurazole is available as fixed dose combination with Phenazopyridine (10:1 ratio)
– urinary antiseptic and analgesic.

13
 – 4% solution or ointment – local application
– Dose
• Dogs & Cats : 50 mg/kg, PO, TID (q8h)
• Sulphamerazine
– Water soluble; soluble in KOH, NaOH and NH4OH
– Rapidly absorbed in GIT (sheep and swine), slowly absorbed (cattle)
– Rapidly excreted in urine
– Used alone or in combination with other sulphonamides (sulphadimidine and
sulphadiazine) or other antibiotics (tylosin)
– Dose
• Sheep : 60 -100 mg/kg, IV, & 100 mg/kg PO, TID (q8h)
• Sulphachlorpyridazine
– Highly soluble in urine pH
– Rapidly absorbed in GIT
– Rapidly excreted in urine
– T1/2 : 1.2 hours in cattle
– Used in the treatment of diarrhoea caused by E. coli in calves, colibacillosis in swine
– Dose
• Cattle : 30 mg/kg, PO, TID or 100 mg/kg, IV, OD/BID daily
• Swine : 44 – 77 mg/kg, PO, OD
• Sulphathiazole
– Less soluble in water, more toxic
– Safe when used as phthalyl derivative (phthalyl sulphathiazole)
• Can be used as gut acting sulphonamides (colitis, gastroenteritis)
– Sulphathiazole is occasionally formulated with chlortetracycline and procaine penicillin
G
– Dose
• Sheep : 36 - 72 mg/kg, IV
• Swine : 200 mg/kg, IV
Intermediate acting
• Sulphadimidine or sulphamethazine
– Intermediate to long acting
– Rapidly absorbed from GIT, slowly excreted in urine (level maintained in blood up to
24h)
– PPB: 70 %

14
 – Metabolites are highly soluble; less chance of crystalluria
– T1/2: Cattle, sheep & goat – 4 to 10 hrs, swine & horse -10-16 hrs, dogs – 16 hrs
– Metabolites :
• acetylsulphadimidine (major), sulphaguanidine (minor),
• glucuronide conjugate of sulphadimidine,
• glucuronide & sulphate conjugates of oxidative metabolites of sulphadimidine
– In cattle and swine
• Available as solution (33.3% or 20%) – for iv route, slow infusion to avoid
shock
• Bolus or sustained bolus for oral route
• Milk residue – sufficient withdrawal period
– Dose
• Cattle & Sheep : 200 mg/kg, IV as initial dose followed by 100
mg/kg OD
• Calves : 100 mg/kg, PO, once daily
• Swine : 20 - 50 mg/kg, IV or PO, OD
• Sulphamethoxazole
– Slow absorbtion from GIT, slowly excreted in urine
– Used for systemic and urinary infections
– Acetylated metabolite – relatively insoluble – crystalluria
– Sulphamethoxazole with phenazopyridine – urinary antiseptic and analgesic
– Sulphamethoxazole with trimethoprim – systemic antibacterial
– Dose
• Dogs & Cats : 100 mg/kg, PO loading dose followed by 50 mg/kg BID
• Sulphamoxole
– Close congener of sulphafurazole & sulphamethoxazole
– Soluble in water, solubility decreases with increasing in pH (unique)
– Used alone for urinary tract or respiratory infection
• Sulphamoxole
– Close congener of sulphafurazole & sulphamethoxazole
– Soluble in water, solubility decreases with increasing in pH (unique)
– Used alone for urinary tract or respiratory infection
Long acting
• General Information
– Well absorbed, slowly excreted

15
 – High PPB
– Renal tubular re-absorption
– T1/2: 24-48 hours
– Tissue accumulation – more toxic
• Sulphadimethoxine
– Less soluble in water
– Readily absorbed in sheep & swine, slowly in cattle
– PPB – 80-85%
– Metabolism – acetylation in liver
– Renal tubule – reabsorption
– T1/2; sheep -15h, swine – 14h, cattle – 12.5h, horses – 11h
– Used in respiratory, genitourinary, enteric and soft-tissue infections
• Effective against Streptococci, Staphylococci, Klebsiella, Proteus, Shigella,
E.coli, Salmonella
– In Poultry, mixed in drinking water for coccidiosis and bacterial infections
– Dose:
• Dogs & Cats : 25-50 mg/kg, PO, IV, or SC - OD
• Cattle : 50-100 mg/kg, PO, IV – OD
• Horses : 50 mg/kg, PO or IV – BID
• For coccidiosis
• Dogs & cats : 50 mg/kg PO loading dose, 25 mg/kg PO maintenance
dose for 14-20 days
• Sulphaethoxypyridazine
– Treatment of large animal infections
– Controlled release bolus – sustained plasma conc. : 2-3 days
– Dose: Cattle – 55 mg/kg, PO
– Sulphamethoxypyridazine
– Treatment of colibacillosis, respiratory infections like Pasteurellosis, foot rot and
coccidiosis
– Dose: Cattle & Sheep: 20 mg/kg, IV, SC or IM – OD
– Sulphabromomethazine
– Brominated derivative of sulphadimidine or sulphamethazine
– Soluble in water
– Single oral dose (150-200 mg/kg, PO) to treat calf diphtheria & pneumonia, metritis, foot
rot and septic mastitis in cattle
• Sulphaethoxypyridazine

16
 – Treatment of large animal infections
– Controlled release bolus – sustained plasma conc. : 2-3 days
– Dose: Cattle – 55 mg/kg, PO
Sulphamethoxypyridazine
– Treatment of colibacillosis, respiratory infections like Pasteurellosis, foot rot and
coccidiosis
– Dose: Cattle & Sheep: 20 mg/kg, IV, SC or IM – OD
Sulphabromomethazine
– Brominated derivative of sulphadimidine or sulphamethazine
– Soluble in water
– Single oral dose (150-200 mg/kg, PO) to treat calf diphtheria & pneumonia, metritis, foot
rot and septic mastitis in cattle
Ultralong acting
• Sulphadoxine
– Effect lasts for 1 week
– High PPB and slow excretion
– Attains low free plasma concentration due to high PPB
– Not useful for acute bacterial infection
– Usually combined with pyrimethamine – treatment of malaria & toxoplasmosis in human
– Severe cutaneous reactions – restricts its usage
• Sulphamethopyrazine
– Combined with pyrimethamine - antimalarial treatment
– Veterinary use is limited
Locally acting
• Gut-acting Sulphonamides
– Succinylsulphathiazole and Phthalylsulphathiazole
• Poor oral absorption
• Hydrolysed in colon to release succinic acid or phthalic acid and sulphathiazole
• Dose: Dog – 100 mg/kg PO, BID
– Phthalyl sulphacetamide
• Releases sulphacetamide in the large intestine
• Dose: Calves – 350-500 mg/kg, PO
– Sulphaguanidine
• Ionised at pH of GI contents
• Topical Sulphonamides (Ophthalmic)

17
 – Na Sulphacetamide – neutral pH and non-irritant
– Drug diffuses well throughout ocular tissues – anterior segment and aqueous humor
– Eye drops (10 – 30%) or eye ointment (6%)
• Topical Sulphonamides (Cutaneous)
– Mafenide: non-typical sulphonamide
– Not inactivated by pus or PABA
– Soluble in water
– Treatment of burns – gr+ve, gr-ve including Pseudomonas & Clostridia
– Should not be applied on raw surface – produces burning sensation and pain
– Metabolites – inhibits carbonic anhydrase enzyme – acidosis and hyperventilation
– Allergic reactions
– Adverse effects – limited its use
• Topical Sulphonamides (Cutaneous)
– Silver Sulphadiazine
• Inhibit the growth of bacteria and fungi, org. resistant to other sulpha
(Pseudomonas)
• Slowly releases silver ions – responsible for antimicrobial action
• Applied as 1% cream on burns and chronic ulcers, chronic otitis externa
• Should not be used in well established infections
• Occasionally causes burning sensation, rash and itch
• Proteases like trypsin & clostridiopeptidase in the ointment – removal of dead
skin on wounds

DIAMINOPYRIMIDINES

18
Advantages of diaminopyrimidines over sulphonamides
• Bacteriostatic effect of trimethoprim in urinary tract infections is often detectable in urine for
several days.
• Diaminopyrimidines are more widely distributed into tissues than sulfonamides.
• Most of the adverse effects of the combination are the result of the sulfonamide component.
• Cross Resistance: plasmids conferring resistance to sulfonamides often also confer resistance to
trimethoprim.
Antimicrobial activity
• Bacteriostatic
• Gram +ve and –ve aerobic organisms but not against anaerobics
• MIC < 1g/ml - susceptibility
• No activity against Mycoplasma spp., Chlamydia spp., Mycobacterium spp. and P. aeruginosa
Pharmacokinetics
• Lipid-soluble organic bases
• 60% plasma protein binding
• High tissue distribution

19
 • Highly concentrated in prostate gland (acidic environment)
• Milk to plasma concentration - 3:1 ratio
• Hepatic metabolism (oxidation followed by conjugation reactions) – principal process of
elimination
• Longer t1/2 with ormetoprim, baquiloprim as compared to trimethoprim
Adverse Effects
• Relatively non-toxic
• High doses – folic acid deficiency – care should be taken in pregnancy condition
Clinical Applications
• Currently used in combination with sulphonamides
• Treatment of prostatic infections caused by Gr-ve infection
• In combination with sulphonamides - Drug of choice for the prevention of Pneumocystis carinii
(jirovecii) pneumonia
POTENTIATED SULPHONAMIDES
• Sulphonamides + Diaminopyrimidines
• Commonly used combinations are
– Sulphamethoxazole + trimethoprim (co-trimoxazole)
– Sulphadiazine + trimethoprim (co-trimazine)
– Sulphadimethoxine + ormetoprim
– Sulphadimethoxine + baquiloprim
• Choice of combination depends on the similar PK properties
– Absorption and distribution (achievable in human)
– In animals, different PK properties with different species
– Dosage recommendation is difficult in veterinary species
Mechanisms & Advantages
– Block in the sequential stages in the synthesis of tetrahydrofolate.
– Synergistic and Bactericidal effect
– Results in the reduction of doses of sulphonamides – reduces the adverse effects
– Broadens the anti-bacterial spectrum
– Reduces the chances of bacterial resistance to drugs
Sulphamethoxazole + trimethoprim (co-trimoxazole)
– Widely used in human and veterinary practices
– 5 parts of sulphamethoxazole and 1 part of trimethoprim results in 20:1 ratio of
sulphamethaxozole and trimethoprim in plasma
– Antibacterial spectrum – broad

20
 • Gr +ve (strepto, staphylo, Nocardia, etc.), Gr –ve (Enterobacteriaceae, resistant
org. – Pseudomonas aeruginosa)
• Protozoa – coccidia and toxoplasma
– Slow development of resistance as compared to individual drugs
• Plasmid that codes for dfr
– Pharmacokinetics
• Absorption is rapid on oral route, slow on sc route
• Tmax 1-4 hours
• Ruminants –trimethoprim trapped in rumen-reticulum – degradation
• Metabolism: Trimethoprim undergo oxidation and conjugation, Sulphonamides
undergo acetylation and conjugation with glucuronic acid.
• Both get excreted in urine.
• T1/2 : dogs – 2-5hr, horses – 2-5hr, cattle 1.5 hr
– Adverse Effects/Toxicity
• Well tolerated in the recommended doses
• TMP tend to increase GI and hemolytic effects, skin toxicity of sulphonamides
• Dogs – KCS, hepatitis, vomiting, diarrhoaea, anorexia, hemolytic anaesmia &
fever, Type I and III hypersensitivity reactions
– Doberman – transient arthritis
• Cats – salivation, frothing, anorexia and anaemia
• Horses – transient pruritus
• Human – kernicterus (displacement of bilirubin from albumin)
• Cleft palate reported in rats – due to reduced production of folate
– Contraindication and Precautions
• Contraindicated to animal hypersensitive to sulpha drugs, renal insufficiency,
hepatopathies, blood dyscrasias
• Should not be used in pregnant animals
• Milk withdrawal of 7 days is required
• Thyroid function test in dogs treated for longer duration
• Excess water should be provided to enhance the excretion of sulphonamides
– Clinical uses
• Upper and lower respiratory tract infection
• Renal and urinary tract infection
• GIT
• Skin and wound infection
• Septicaemia

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 • Coccidiosis in small animals
– Doses
• Dogs & Cats : 30 mg/kg, PO or IV/SC –BID
• Cattle, Sheep & Goats, swine : 25-50 mg/kg, IV, IM – OD or BID
• Horses : 15 mg/kg, IV, BID
• Birds : 50 – 100 mg/kg, PO (oral suspension), BID
– Commonly used combination in veterinary practice
– Doses
• Dogs & Cats : 30 mg/kg, PO or SC –BID
• Cattle, Sheep, Horses & Swine : 20 mg/kg, PO – OD
: 15 - 25 mg/kg, IM, slow IV, OD
• Poultry : 15 mg/kg, drinking water
: 300 g/tonn feed
Sulphadoxine + trimethoprim
- Longer duration of action
- Doses
• Dogs & Cats : 15 - 20 mg/kg, PO or SC –OD or alternate days
• Cattle, & Swine : 15 mg/kg, IM (preferred), slow IV - OD or alternate
days
• Horses : 15 mg/kg, IM, slow IV (preferred)
Ormetoprim + Sulphadimethoxine (1:5)
– Longer duration of action as compared to co-trimoxazole – therapeutic level maintained
over 24 hours
– Used for skin and soft tissue infections (Staph & E. Coli) in dogs
– Treatment and prophylaxis of coccidiosis in small animals and poultry
– Doses
• Dogs : 50 mg/kg, PO followed by 25 mg/kg OD
Baquiloprim + Sulphadimethoxine
- recommended for dogs and cats due to PK properties similarities in these species
- Doses
• Dogs : 30 mg/kg, PO alternate days
: 12 mg/kg, SC - OD
• Cats : 20 -40 mg/kg, PO –OD, 20 mg/kg , SC followed by PO -OD
• Cattle & Swine : 10 mg/kg, IM - OD
Baquiloprim + Sulphadimidine (1:5)

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 - bacterial infections in cattle and swine
- t1/2 of baquiloprim is similar to sulphadimidine
- Doses
• Cattle : 10 mg/kg, SC or IM - OD
: 40 -80 mg/kg, PO – repeated after 2 days, if required
• Pigs : 10 mg/kg, SC or 30 mg/kg on alternate days

CLINICAL APPLICATION OF SULPHONAMIDES

• Cattle, Sheep and Goat
– Best to give in combination with Trimethoprim
– Used to treat bovine interdigital necrobacillosis and coccidiosis
– Sulphadimethoxine – only approved for use in dairy cows
– To treat Toxoplasma abortion in sheep – sustained release oral Sulphamethazine +
Pyrimethamine (0.5 mg/kg)
– Sulphonamides + Chlortetracyclins – to prevent clostridial enterotoxemias in lambs
• Swine
– To promote growth and to control group E streptococcal infections and atrophic rhinitis
– Sulphomethazine + Chlortetracyclins
Horses
– Equine protozoal myeloencephalitis
• Sulphadiazine (20 mg/kg, PO, SID or BID, for up to 12 weeks or longer)
combined with Pyrimethamine (1 mg/kg PO, SID for up to 120 days
– Pneumocystis carinii pneumonia in foal
• Dapsone – 3mg/kg, po, SID
• Dogs and Cats – used in the treatment as below
– Sulfizoxazole – urinary tract infections in dogs
– Silver sulphadiazine cream – chronic otitis externa, burn wounds
– Sulfasalazine (salicylsulfapyridine) 25 mg/kg, PO, TID – chronic colitis in dogs (3-4
weeks)

23
 • Hydrolysed by colonic bacteria to yield – sulfapyridine and 5-aminosalicylate
(anti-inflammatory effect)
• Can be combined with low dose of corticosteroid – reduce overall duration of
therapy
• Should not be extended beyond 4 weeks – chance of KCS
• Same dose may induce salicylate poisoning in cats
– Dapsone – treatment of dermatitis herpetiformis
• Poultry
– Prevention and treatment of coccidiosis, infectious coryza, pullorum disease/fowl typhoid
-LACTAM ANTIBIOTICS
PENICILLINS
• History:
– Sir Alexander Fleming, 1928 discovered Penicillin from the Mold Penicillium notatum
• In 1940, Howard Florey and Ernst Chain — isolated and purified Penicillin
• In 1945, Alexander Fleming, Howard Florey and Ernst Chain — shared Nobel Prize for the
discovery and use of Penicillin
• Chemistry:
– Basic structure
• 5 member thiazolidine ring connected to a Beta lactam ring having a secondary
anime group (-NH) to form 6-aminopenicillanic acid (6-APA)
– Structure activity relationship (SAR)
• -lactam ring – key feature
• Cleavage of -lactam ring - destroys activity
• Penicillinase or -lactamase secreted by bacteria – cleaves -lactam ring –
• Resistance due to ABA modification
• Chemical alteration in 6-APA – loss of activity
• Side chain (– R) – determines individual penicillin activities
• -COOH – site of salt formation (Na, K, Procaine)
• Salt esters – stabilizes, affects solubility and PK
• Properties and Solubility:
– Poorly soluble, weak acid
– Sensitive to heat, light, extremes in pH, heavy metals, strong alcohols, oxidising and
reducing agents.
– Optimal pH 6-6.5 for stability
– Reconstitute before administration (hydrolysis on storage with water)
– Gastric acid hydrolyse amide side chain

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 – Penicillanase cleaves -lactam ring produce penicilloic acid
– Alkaline Na salt of sulphonamides inactivates penicillins
– Na & K salts of penicillin – water soluble – parenteral route
– Trihydrate forms – both oral and parenteral route
MECHANISM OF ACTION
• Inhibit cell wall synthesis by interfering with the Peptidoglycan synthesis.
• Inhibit the activity of the transpeptidase and carboxypeptidases which catalyze cross-linkage of
the glycopeptide polymer units that form the cell wall.
• Results in lysis of cell wall – in cells which are actively synthesizing cell wall.
• Transpeptidases and carboxypeptidases are also called as Penicillin Binding Proteins (PBPs).
• PBPs are both membrane bound or cytoplasmic proteins
• Variations in the action of different beta-lactam antibiotics depends on the differences in affinity
for PBPs
Factors Affecting Activity of -lactams
• Active during the Log phase of bacterial growth
• Efficacy is time-dependent (conc.>MIC )
• Efficacy is more in isotonic environment (isotonic to host and hypotonic to the org.)
• Efficacy decrease in chronic infection – due to slow growth of org.
• Do not produce significant post-antibiotic effect (PAE)
• Inactive against org. which do not possess cell wall such as Mycobacterium, fungi, protozoa and
viruses.
Resistance to -lactams
• -lactamases: > 190 proteins, classified as
– Gr+ve, Gr-ve specific
– Transmission – plasmid or chromosomal coded
– Inducible or constitutive
– Amber Class – A, B, C & D type (Class A – Veterinary medicine)
• Staphylococcal  lactamases – do not inactivate cephalosporins and anti-
staphylococcal pencillins, can be inactivated by  lactamase inhibitors
(clavulanic acid and sulbactam)
• Gram –ve  lactamases - most diverse, penicillinase, cephalosporinase or both,
not inhibited by  lactamase inhibitors, ESBLs (Extended spectrum 
lactamases) inducible – difficult to treat
– Resistance to Drug Access to Binding Sites
• Gr-ve org– impenetrable porins
• Altered Penicillin-binding proteins
– Example, methicillin resistant Staphylococcus aureus

25
 Quiescent organisms
– Org. do not grow and unaffected by antibiotic
Tolerant organisms
– Org. undergo inhibition of growth when treated with lactams
Pharmacokinetics of -lactams
• Absorption:
– Weak acids – favours oral absorption
– Many types of penicillin – destroyed by gastric acid
– Tmax – 2 hrs (oral), 15-30 min (IM or SC)
– Depot preparation – procaine and benzathine Penicillin G
• Distribution:
– Widely distributed to body fluids and tissues
– Do not penetrate brain, bone, cartilage, cornea & bronchial secretions – unless inflamed
– Penicillins do not penetrate phagocytic cells
– PPB 20-80%
• Metabolism:
– Generally excreted unchanged
– < 20% biotransformation of aminopenicillins & G in renal impaired condition
– Penicilloic acid - allergenic
• Excretion:
– Excreted in urine
– 20% by glomerular filtration, 80% by tubular secretion
– Tubular secretions can be inhibited by probenicid – prolong the penicillin level in
circulation
– Biliary route – common for semisynthetic penicilliln
– T1/2 30-120 min
• Adverse Effects of -lactams
Hypersensitivity
– Metabolite Penicilloic acid act as hapten – immune reaction
– Maculopapular rash to angioneurotic edema
• Cattle –rash, urticaria, drug fever, angioedema, serum sickness, vasculitis and
anaphylaxis (rare)
– Cross allergenic reaction between penicillins
• GI disturbances
– Diarrhoea and superinfection

26
 • Thrombocytopenia
• Organ toxicity
– Neurotoxic -Epileptic patients are at risk, Ataxia in dogs
– Interstitial nephritis (high conc. in renal tissues)
Contraindications
– Patients hypersensitive to penicillins
– High doses of Na or K pencillins – avoid in renal diseases, CHF, or electrolyte
abnormalities cases
– Oral administration to be avoided in serious systemic infection and shock
– Avoid in pregnant animals
Drug Interactions
– Salicylates, phenylbutazone and sulphonamides displace penicillins from plasma protein
binding
– Probenicid, weak acid drugs inhibit tubular secretion
– Combination with aminoglycosides – synergistic or additive effect
– Combination with bacteriostatic drugs like chloramphenicol, tetracyclines, erythromycin
– antagonistic effect
– Chemical interaction – carbenicillin & ticarcillin with aminoglycosides, hence should not
be mixed in vials or in syringes
– Penicillins should not be given with anticoagulants
– Acid susceptible Penicillin G should not be mixed in normal saline or other parenteral
fluids to avoid inactivation at acidic pH.
Classification of Penicillins
I. Narrow Spectrum
1. -lactamase sensitive
a. Acid susceptible penicillin – Penicillin G & Penamicillin
b. Acid resistant penicillin – Penicillin V & Pheneticillin
2. -lactamase resistant
a. Isoxazolyl penicillins – oxacillin, cloxacillin, dicloxacillin & flucloxacillin
b. Non-isoxazolyl penicillins – meticillin, nafcillin & temocillin
II. Broad Spectrum
1. Aminopenicillins – ampicillin, amoxycillin & epicillin
2. Ampicillin precursors – hetacillin, bacampicillin, metampicillin, pivampicillin &
telampicillin
3. Other penicillins – mecillinam, pivmecillinam & sulbenicillin
III. Extended Spectrum / Anti-Pseudomonal Penicillins

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 1. Carboxypenicillins – carbenicillin, carindacillin & ticarcillin
2. Ureidopenicillins – mezlocillin & azlocillin
3. Piperazine penicillin – piperacillin
IV. Potentiated Penicillins
1. Amoxicillin – clavulanic acid
2. Ampicillin – sulbactam
3. Ticarcillin – clavulanic acid
4. Ampicillin – flucloxacillin
5. Piperacillin - tazobactam
NARROW SPECTRUM -LACTAMASE SENSITIVE
Acid susceptible or Natural Penicillins
– Penicillin G or Benzylpenicillin
• Obtained from Penicillium chrysogenum
• Most potent penicillin
• Available as Na, K, Procaine or Benzathine salt
• Na & K salts are water soluble
• Procaine & Benzathine salts are – less water soluble
– Depot preparation – slow release
Unitage of Natural Penicillin G
– Penicillin G is still measured in terms of units rather than weight (units / kg body weight)
– One International Unit (I.U.) of Penicillin G sodium salt represents the specific activity
in 0.6 g of sodium penicillin
– 1 mg of penicillin G Na salt = 1667 units of penicillin
– 1 mg of Penicillin G K salt = 1595 units of penicillin
– 1 mg of Procaine Penicillin G = 1050 units of penicillin
– 1 mg of Benzathine Penicillin G = 1272 units of penicillin
– Dosage of semisynthetic penicillins are expressed in weight (mg / kg)
Antibacterial Spectrum - Penicillin G
– Penicillin G is a narrow spectrum; Gr +ve and few Gr –ve
• Actinomyces spp. – Lumpy jaw, mastitis
• Bacillus anthracis – Anthrax
• Clostridium spp. – Black quarter, botulism, braxy, lamb dysentery, pulpy kidney,
tetanus
• Corynebacterium spp. – Bronchopneumonia, mastitis, polynephritis, cystitis
• Leptospira spp. – Abortion, nephritis

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 • Staphylococcus spp. – Mastitis, Metritis, enteritis, otitis, conjuctivitis
• Streptococcus spp. – Mastitis, endocarditis, strangles, septicemia, otitis, metritis,
tonsilitis
– Penicillin is not effective against Rickettsia, Mycobacterium, fungi, virus and protozoa
Pharmacokinetics of Penicillin G
– Penicillin G is erratically absorbed (15-30%) from GIT
• Destroyed by gastric acid
– IM/SC – high peak plasma conc. within 20 to 30 min
– IV – in life-threatening infections – slow IV (Na and K salts only)
– Depot (procaine and benzathine) IM only
• Hydrolysed to parent compound, plasma conc. within 2-3h
• Procaine penicillin – blood level observed up to 24 hrs
– should not be given IV - adverse effect on cardiac conduction
• Benzathine penicillin – blood level observed up to 7 days
– Well distributed in tissues except CSF, brain, milk and joints
– PPB 50-60%
– Excreted unchanged in urine
• glomerular filtration and active tubular secretion
– T1/2 0.5 to 1 hour

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Clinical Use of Penicillin G
– Penicillin G is the drug of choice for many gram +ve infections
– Used alone or in combination with Streptomycin, dihydrostreptomycin, novobiocin
• Injectable
• intramammary
– Used prophylactically before procedures like surgery, endoscopy and catheterization
– Dose for Na or K Penicillin G
• Cattle: up to 300,000 units/quarter TID
• Dog: 20,000 units/kg q4-6h
• Horse: 25,000 – 50,000 units/kg q6h

30
 • Sheep & Goat: 20,000 – 45,000 units/kg q6h
– Dose for Procaine Penicillin G
• Dogs & Cats: 20,000 units /kg IM - OD or BID
• Ruminants, Horse, Swine, Camelids – 40,000 units/kg, IM, BID
– Dose for Benzathine Penicillin G
• Dogs & Cats 40,000 – 50,000 units/kg, IM q5d
• Cattle & Horses - 50,000 units /kg, IM, q3d
• Swine – 10,000 -40,000 units/kg, IM q3d
2. Acid resistant Penicillins
– Penicillin V
• Oral absorption –acid resistant – unpredictable
• Veterinary medicine
– Treatment of GI infection, mild & moderate systemic infection
– Not suitable for severe infection due to high MBC
– Used as potassium salt and benzathine salt
• Expressed in weight or can be used as unit
– 1 mg of Penicillin V = 1380 -1610 units (USP)
• Dose
– Dogs & Cats : 5-10 mg/kg, PO, TID
– Horses : 40 -60 mg/kg, PO, TID
– Swine : 200 g/tonne feed
NARROW SPECTRUM -LACTAMASE RESISTANT
I. Isoxazolyl Penicillins
– Active against penicillinase producing organism, Staphylococcus org.
– Examples; oxacillin, cloxacillin, dicloxacillin, flucloxacillin
II. Cloxacillin
– Acid resistant, penicillinase resistant, freely water soluble
– Cloxacillin benzathine – less water soluble
– Antibacterial spectrum
I. Antistaphylococcal penicillins (narrow spectrum)
– Pharmacokinetics
I. F = 30-60% on PO, absorption decreases with food
II. PPB >90%
III. Metabolized to active and inactive metabolites

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 IV. Excretion – kidney (major), bile (minor)
V. T1/2 – 30 min. in dogs
– Clinical use
I. Treatment of skin, bone and soft tissue infection, septicaemia (dogs – 20-40
mg/kg on empty stomach, TID or 10-15 mg/kg, IM, q6h)
II. Ophthalmic infection
III. Bovine mastitis – 200 mg/quarter (lactating period)
• Dry period – cloxacillin-benzathine intramammary – 500mg/quarter
. Oxacillin
– Intramammary and Ophthalmic infection
– Resistant strain called Oxacillin – resistant Staph aureus (ORSA)
– Dogs & Cats: 20-40 mg/kg, PO, TID
– Horses: 20-50 mg/kg, IM or IV, TID, QD, daily
III. Dicloxacillin
 more active against -lactamase resistant Staphylococcal than oxacillin & cloxacillin
 Acid stable
 Dogs & Cats : 10-25 mg/kg, PO, IM, or IV, TID
IV. Flucloxacillin
 Similar to Dicloxacillin
 Higher incidence of hepatic dysfunction but lower renal adverse effects
 Dogs & Cats: 15 mg/kg, PO; QD
. Non - Isoxazolyl Penicillins
 Meticillin (Methicillin)
 Now Staphylococcus aureus has become resistant – called as Methicillin
Resistant Staphylococcus aureus (MRSA)
 MRSA- not due to penicillinase but due to altered PBPs
 MRSA strain is used to determine the antibiotic sensitivity of Staphylococcus
aureus to other -lactamase resistant penicillins
 MRSA strains are susceptible to Vancomycin / fluroquinolones
 Meticillin – inactive orally , IM – Tmax – 30 min
 Achieve therapeutic conc. in CNS
 Excreted in urine (major route), seen in bile and other secretions
 Dose: Dogs & Cats 10 mg/kg, PO, IM q6h
. Non - Isoxazolyl Penicillins
 Nafcillin
 Inactivated by gastric acid

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  Produce therapeutic conc. In CNS
 Intramammary preparation for treatment of mastitis
 Dose: Dogs & Cats 10 mg/kg, PO, IM q6h
 Temocillin
 Active only against Gram –ve bacteria, Enterobacteriaceae
BROAD SPECTRUM PENICILLINS
1. Aminopenicillins
a) Ampicillin: semi-synthetic
• Only difference is the presence of amino group in Penicillin G which help to
penetrate the Gr-ve bacteria
• Antibacterial spectrum – active against Streptococcus, non-penicillinase
producing Staphylococcus, Corynebacterium, Clostridium, E. Coli, Proteus,
Haemophilus, Salmonella, Brucella, Klebsiella and Pasteurella spp.
• Organisms not susceptible – Pseudomonas, Serratia, Enterobacter &
Acinetobacter
• PK:
– stable in gastric acid, oral absorption affected by the presence of food
– No CNS entry
– PPB – 20%
– Metabolised to penicilloic acid in liver
– Excreted unchanged in urine
– T1/2 dogs & cats- 45-80 min, swine – 60 min
• Dose: 5-10 mg/kg, IM BID or TID, oral 10-20 mg/kg, q8h
1. Aminopenicillins
b) Amoxicillin: semi-synthetic
• Similar to Ampicillin
• PK:
– Twice well absorbed on PO, not affected by food as compared to
Ampicillin
– Widely distributed, penetrates purulent & mucoid bronchial secretions
– Excreted unchanged in urine & bile
– T1/2 dogs, cat & cattle- 60-90 min
• Susceptible to -lactamase, hence combined with clavulanic acid (a -lactamase
inhibitor)
• Dose:
– Dogs & Cats : 10-20 mg/kg, PO, BID, 15 mg/kg, SC or IM (depot) –
q2d

33
 – Cattle & sheep: 5-10 mg/kg, IM OD
– Calves: 8-10 mg/kg PO, BID
– Horses: 20 mg/kg, IM, BID
– Poultry: 10-20 mg/kg, PO by adding to drinking water
Ampicillin Precursors / Prodrugs
– Hetacillin
• Prepared by the reaction with acetone and ampicillin
• Orally absorbed converted to ampicillin in vivo
• Hetacillin potassium – IM/IV
• Dose: Dogs & Cats -10 -40 mg/kg, PO, BID or TID
– Bacampicillin
• Contains an ethoxycarbonyloxyethyl group
• Rapidly absorbed orally and converted to ampicillin in vivo
• Produces high plasma conc.
• Dose: Horse – 25 mg/kg, PO, BID
– Other prodrugs
• Pivampicillin, Telampicillin, Metampicillin
– Improved oral absorption
– Hydrolysed in vivo to produce ampicillin
Other Antibiotics
– Mecillinam
• Binds to PBP2
• Less active against gr+ve than gr-ve (E. Coli, Salmonella, Klebsiella and
Enterobacter but not Pseudomonas)
• Susceptible to -lactamase
• Treatment of urinary tract infections
– Pivmecillinam
• Orally active pro-drug of mecillinam
• Treatment of urinary tract infections
• Adverse effect – depletion of carnitine levels in body due to pivalate by forming
a conjugate with carnitine
EXTENDED SPECTRUM / ANTI-PSEUDOMONAL PENICILLINS
• Effective against many bacterial including Pseudomonas aeruginosa those are resistant to
Ampicillin and Amoxicillin
• Ineffective against Staphylococcus aureus and -lactamase

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I. CaboxyPenicillin
1. Carbenicillin
– Acid labile, not absorbed orally
– Given IV, requires high conc. in blood for antipseudomonal action (probenecid will help
to achieve the same)
– T1/2 – 1 hour
– Used for the treatment of serious Pseudomonas or Proteus infection like burns, urinary
tract infections and septicemia
– Low therapeutic index – neurotoxicity
– CHF due to high Na load, Hypokalemia, interfere with platelet function
– Carbenicillin used in combination with Gentamicin or Tobramycin (should not be mixed
in same syringe – in vitro interaction)
– Dogs & Cats : 50 mg/kg, IM, SC, IV, q6/8h
– Birds: 200 mg/kg, PO, BID; 100-200 mg/kg, IM or IV – q6-12h
2. Carindacillin
– Acid stable ester of carbenicillin
– Hydrolysed in vivo to active drug carbenicillin
– F- 40%, Tmax – 1 h
– Achieve high concentration in urine, for the treatment of urinary tract Pseudomonas or
Proteus infection
– Dogs & Cats : 15-50 mg/kg, PO, q6/8h
3. Ticarcillin
– 2 to 4 times more active against Pseudomonas
– Synergistic effect when combined with aminoglycosides
– Acid labile
– Intrauterine use in horse – treatment of metritis
– Combined with clavulanic acid
– Dogs & Cats : 50 -75 mg/kg, IM, SC, IV TID
– Horse, Swine: 40 -50 mg/kg, IM or IV, BID or TID
– Birds: 200 mg/kg, IV or IM, TID
. Ureido-Penicillin / Acyl-ureido pencillins
Mezlocillin
– Active against Pseudomonas, Klebsiella – superior to that of carbenicillin
– Gr-ve org. – Enterobacter, Bacteroides, Proteus, Serratia and Neisseria spp.
– Susceptible to -lactamases
– Treatment of enteric bacilli – parenterally administered

35
 – Combined with aminoglycosides
– Excreted by liver – useful for biliary tract infections – ascending colangitis
– Costly antibiotic – limits its use in veterinary medicine
. Piperazine Penicillin – Piperacillin
– Active against Pseudomonas, Klebsiella, Enterobacteriaceae, Bacterioides
– Not absorbed orally
– Combined with aminoglycosides – synergistic effect
– Useful in neutropenic or immunocompromised patients
– Combined with tazobactam – gr+ve and gr-ve pathogens, anaerobes
– Dogs & Cats: 25 -50mg/kg, IM, IV, SC – TID; Birds : 100 -200 mg/kg IM, IV, TID
POTENTIATED PENICILLINS /  - LACTAMASE PROTECTED PENICILLINS
1. Amoxicillin-Clavulanic acid (Co-Amoxiclav)
– 4:1 ratio, Clavulanic acid is an irreversible inhibitor of -lactamases – ‘suicide inhibitor’
– Clavulanic acid is produced by fermentation of Streptomyces clavuligerus
– Amox-Clav – not destroyed by gastric acid
– Antibacterial activity – Staph aureus, E. coli, Proteus, Klebsiella, Salmonella, Shigella
– Not effective against MRSA and Pseudomonas infection
– PK:
• Well absorbed orally, distributed to body tissues and fluids
• Clavulanic acid is metabolised before excretion
– In the treatment of skin, soft tissues infections, urinary, biliary and respiratory tract
infections
– Small animals : periodontitis and kennel cough
– Calves: enteritis, naval ill
– Cattle: Respiratory tract infection, soft tissue infection, metritis and mastitis (in
combination with prednisolone - intramammary infusion)
– Swine: RTI, Colibacillosis, mastitis, metritis, agalactia
– Dose: Dogs & Cats- 10-20 mg/kg, PO, BID, TID,
– Cattle: 7 mg/kg IM or SC, OD
– Sheep & Goats: 20 mg/kg, IM or IV, TID
– Birds: 50-100 mg/kg, PO, TID
2. Ampicillin – Sulbactam
– Active against Pasteurella, Staphylococcus aureus, Haemophilus, gr-ve aerobes &
anaerobes
– Used for intra-abdominal, surgical and skin and soft tissues infections

36
 – Pain at injection site, thrombophlebitis
– Dogs & Cats: 20-50 mg/kg IM or IV, TID
– Cattle: 10 mg/kg, IM, OD
3. Ticarcillin-Clavulanic acid
– Dogs & Cats: 15-25 mg/kg IV infusion, TID, 40-75 mg/kg, IV, TID
– Horses: 50 mg/kg, IV TID
CEPHALOSPORINS
• Most frequently used antibiotics
• Cephalosporins are bactericidal, inhibit enzymes in the cell wall synthesis of susceptible bacteria.
• Cephalosporins are semi-synthetic and derived from ‘Cephalosporin-C’ derived from fungus
Cephalosporium acremonium (Acremonium strictum).
• Other natural cephalosporins are P and N in addition to C, isolated by Italian scientist “Giuseppe
Brotzu” in 1948.
Properties and Solubility
• Water soluble and acid stable as compared to Penicillins
• Stable to temperature and pH changes
• May or may not susceptible to -lactamases
• Free base form for oral administration
• Sodium salt in aqueous form for parenteral administration
• Antibiotics such as aminoglycosides inactivate cephalosporins when mixed in vitro
Classification of Cephalosporins
• Classified based on the chronology of development and antimicrobial properties
• 5 Generations
– I Generation (highly active against Gr+ve , less active against Gr-ve, susceptible to
cephalosporinases)
Cefalotin, cefazolin, cefalexin, cefadroxil, cefapirin, cefaloridine, cefalonium, cefradine,
cefacetrile and cefaloglycin,
– II Generation (highly active against Gr-ve, less active against Gr+ve, resistant to β-
lactamase)
Cefuroxime (axetil), cefaclor, cefamandole, cefonicid, ceforanide, cefotiam and cefprozil
– III Generation (highly active against Gr-ve, including Pseudomonas, less active against
Gr+ve, org. produce Extended Spectrum β-lactamase - ESBL)
Cefotaxime, ceftiofur, ceftriaxone, ceftazidime, cefoperazone, cefovecin, cefixime, cefpodoxime
and ceftizoxime
– IV Generation (Broad spectrum, incl. Pseudomonas, resistant to β-lactamase, ESBL)
Cefepime, cefpirome and cefquinome
– V Generation (newer generation, broad spectrum)

37
 Ceftobiprole and ceftaroline

Bacterial Resistance to Cephalosporins

• Secretion of β-lactamases (cephalosporinases)
• Target modification
• Decreased permeability
Pharmacokinetics of Cephalosporins
• Limited animal data, PK extrapolated from human data
• Absorption:
– Few acid stable – oral route, F =75-90%
– Others parenteral – IM (Tmax – 30 min) or IV
Distribution:
– Widely distributed – lungs, kidneys, bone, placenta, soft tissues, pleural, pericardial and
joint fluids
– III gen (cefoperazone) – crosses BBB
– Poor penetration into prostate, aqueous & vitreous humours and milk
– PPB – 20-80%
Metabolism
– Most of them are not metabolised and excreted unchanged in urine
– Some (cefalotin, cefotaxime) –deacetylated – inactive or mildly active metabolite
Excretion
– By kidney (tubualar secretion mainly, glomerular filtration)
– III Gen (cefoperazone) – excreted in bile

38
 – T1/2: 30-120 min (effective blood level 6 to 8 hours)
– Probenicid increases the t1/2 of cephalosporins
Adverse Effects
• Relatively non-toxic
• Hypersensitivity is possible, cross-reactivity – 10% of penicillin sensitive
• GI disturbances , superinfection (SI), pain at IM injection and lethargy
• Prolonged treatment in human – interstitial nephritis, hepatitis, thrombocytopenia and
neutropenia
Contraindications
• Contraindicated in patients hypersensitive to cephalosporins and pencillins
• Prolonged treatment in animals should be avoided esp. cats – anemia or SI
• Avoided in pregnant animals
• Dosage should be adjusted in renal insufficiency
Drug Interactions
• Concomitant use of aminoglycosides and loop diuretics – potentiate the nephrotoxic effects of
cephalosporins
• Bacteriostatic (chloramphenicol) should not be comibined with cephalosporins
• Probenicid prolongs plasma levels by competitively inhibit tubular secretion
Clinical Uses of Cephalosporins
• First generation
– Skin, soft tissues, urinary and respiratory infections
– Canine S. intermedius skin infections and UTI
– Bovine S. aureus and streptococcal mastitis.
• Second and third generation
– Used to treat infections resistant to I generation cephalosporins
– Gram-negative aerobes, e.g. E. coli, Pasteurella and Salmonella infections, respiratory
infections
– Anaerobic infections
– Cefovecin – susceptible infections in dogs & cats
– Cefoxitin – mixed aerobic and anaerobic infections
– Anti-pseudomonal cephalosporins - Cefoperazone, cefovecin, cefsulodin and ceftazidime
• Fourth and Fifth Generation
– Generally reserved for human infections
First Generation Cephalosporins
• Active against Gram +ve infections, penicillinase resistant, methicillin-susceptible Staphylococci
and Streptococci,

39
• Few Gram –ve PEcK infections
– Proteus mirabilis
– Escherichia coli
– Klebsiella pneumoniae
• First alternative to Penicillins – gr+ve aerobes
• Bone and soft tissue infections of all species
• Antibiotic prophylaxis – due to its ability to penetrate tissues and body fluids
• Cefalotin Cefazolin Cefalexin
• Cefadroxil Cefapirin Cefaloridin
• Cefradine Cefalonium
• Cefalotin
– Injectable, marketed first as cefalotin sodium, water soluble
– ABSpec:
• Gr +ve aerobes
• Penicillin G sensitive Strep and Staph, Clostridium and Proteus sp.
• Anaerobes are susceptible
• Resistant to staphylococcal -lactamase
– Not absorbed orally, IM injection – painful
– Metabolised by liver and kidney; deacetylation – desacetylcefalotin
– Excreted by kidneys unchanged (60-80%) and as desacetyl metabolite
– T1/2; dogs – 40-50min, horses – 15-50min.
– Dose:
• Dogs & cats : 10 – 30 mg/kg, IM, IV, SC – TID
• Cattle : 55 mg/kg, SC, QID
• Horses : 10 -20 mg/kg, IM, IV, QID
• Birds : 100 mg/kg, IM, QID
• Cefazolin
– Injectable, marketed as cefazolin sodium, water soluble
– ABSpec: similar to cefalotin
• More active against Klebsiella and E. coli
• Sensitive to -lactamase than cefalotin
• More active against gr-ve Enterobacteriaceae (resembles II generation)
– Not absorbed orally, administered by IM or IV injection only
– Tmax – 30 min after IM injection in dogs

40
 – Excreted by kidneys unchanged mainly via glomerular filtration
– T1/2; dogs –50 min, horses – 40-90 min, cattle – 50 -100 min
– Used for surgical prophylaxis, preferred I gen antibitoic due to better t 1/2
– Dose:
• Dogs & cats : 10 – 30 mg/kg, IM, IV, SC – TID
1.3 mg/kg loading dose, followed by 1.2 mg/kg/hr IV infusion
• Cattle & sheep : 15 -20 mg/kg, IM, IV, SC – BID or TID
• Horses : 10 -25 mg/kg, IM, IV - BID or TID
• Birds : 25-50 mg/kg, IM, IV
• For surgical prophylaxis (for soft tissues)
– Dogs : 20 mg/kg, IV before and every 2.5 hours during surgery
• Cefalexin
– Orally active
– ABSpec: similar to cefalotin
• Less active against -lactamase producing Staphylococci
– Almost completely absorbed after oral administration
– Attains high conc. in blood and bile
– Excreted by kidneys unchanged
– T1/2; dogs & cats –1 to 2 hrs
– AE: may cause salivation, tachypnoea and excitability in dogs, emesis and fever in cats
– Dose:
• Dogs & cats : 10 – 15 mg/kg, PO - BID
10 mg/kg, IM, or SC - SID
• Cattle : 7 mg/kg, IM - SID
• Horses : 25 mg/kg PO - QID
• Sheep & pigs : 10 mg/kg, IM, SID
• Birds : 35-50 mg/kg, IM - SID
• Cefadroxil
• Orally active similar to cefalexin, mainly approved for small animals
• ABSpec: similar to cefalexin
• Skin, soft-tissues and genitourinary tract infections in dogs
• Well absorbed after oral administration, Tmax -1 to 2 hr, dogs
• Good tissue distribution and exerts sustainable action
• Excreted by kidneys unchanged

41
 • T1/2; dogs - 2 hrs, cats – 3 hrs
• Dose:
• Dogs : 10 mg/kg, PO – BID, administered along with feed if vomiting
occurs
• Cats : 20 mg/kg, PO – SID or BID (for acute or severe infections)
• Foals : 30 mg/kg PO - BID
• Calves : 25 mg/kg, PO - BID
• Cefapirin
• Injectable, available as Cefapirin Na, Cefapirin benzathine
• ABSpec: similar to cefalotin
• Cattle: for mastitis, intramammary - cefapirin Na during lactation, cefapirin
benzathine in dry cows
• Well absorbed after IM injection, F>95%
• Excreted by kidneys unchanged
• T1/2; dogs - 25 min, cattle – 1 hr, horses – 40-50 min
• Dose:
• Dogs &Cats : 10 -30 mg/kg, IM, IV, SC – TID or QID

• Horses : 20 mg/kg, IM – BID or TID

• For mastitis
• Lactating cows : 200 mg/quarter, intramammary – BID
• Dry cows : 300 mg/quarter, intramammary
• Cefaloridine
• Nephrotoxic cephalosporin
• ABSpec: similar to cefalotin
• Dose:
• Dogs &Cats : 10 mg/kg, IM, SC – BID or TID
Cefalonium
• Derivative of cefaloridine – for intramammary use, low solubility in water
• Dose
• Dry cow : 250 mg/quarter
Cefradine
• Both oral and injectable
• ABSpec: similar to cefalexin
• Oral administration causes diarrhoea

42
 • Dose:
• Dogs : 10 – 25 mg/kg, PO– TID or QID
• Foals : 25 mg/kg, PO, TID or QID
Second Generation Cephalosporins
• Effective against few Gram +ve HEN org. and more Gram –ve org. including PEcK org.
– HEN stands for Haemophilus influenzae, Enterobacter aerogenes and Neisseria
• Broader spectrum than First generation, including few anaerobes
• Ineffective against Pseudomonas, Enterococcus, Actinobacter sp
• Relatively resistant to -lactamases
• Cefuroxime
• Cefuroxime axetil
• Cefaclor
• Cefamandole
• Cefuroxime
– Less effective orally, well tolerated IM or IV injection
– ABSpec:
• Enterobacter, indole positive Proteus, Klebsiella, Actinobacillus and
Haemophilus spp.
• Stable to -lactamases produced by Staph and Gr-ve org
– Well distributed, attains good conc. in CSF
– Primarily used in humans for the treatment of meningitis caused by H.influenza,
meningococci and pneumococci
– Better absorbed with food
– Intramammary formulations are available
– Dose
• Dogs & Cats : 10 mg/kg, IV - BID or TID
20 – 50 mg/kg, IM or SC – BID or TID
• Cefuroxime axetil (L-acetyloxyethyl ester of Cefuroxime)
– Orally active, hydrolysis of ester in vivo to release cefuroxime
– ABSpec: similar to cefuroxime
– Oral F = 30-50%
– Dose
• Dogs & Cats : 10 -30 mg/kg, PO – BID
• Cefaclor
– Orally active

43
 – ABSpec:
• E.coli, Haemophilus, Proteus and Morexella
• Not active against -lactamase producing bacteria
– Dose
• Dogs & Cats : 4-20 mg/kg, PO, TID under fasted condition
• Cefuroxime axetil (L-acetyloxyethyl ester of Cefuroxime)
– Orally active, hydrolysis of ester in vivo to release cefuroxime
– ABSpec: similar to cefuroxime
– Oral F = 30-50%
– Dose
• Dogs & Cats : 10 -30 mg/kg, PO – BID
• Cefamandole
– Injectable
– ABSpec: similar to cefuroxime
– It contains methyl tetrazole thiomethyl (MTT) group at R1 associated with
• Hypothrombinemia, inhibition of vitamin K activation, disulfiram like reactions
– T1/2 in human – 45 min
– Dose
• Dogs & Cats : 6 -40 mg/kg, IM, IV – TID or QID
• Other II generation Cephalosporins
– Cefonicid, Ceforanide, Cefotiam, Cefmatazole, Cefbuperazone, Cefminox, Cefprozil and
Cefuzonam
– Available for human treatment
– Veterinary use information is lacking
Third Generation Cephalosporins
• Introduced in 1980s
• Extended spectrum against Gr-ve including Pseudomonas, Enterobacter and Proteus spp.
• Poor activity against Staphylococcus
• Reach CNS
• Mostly Parenteral administration
• Cefotaxime
• Ceftiofur
• Ceftazidime
• Cefoperazone
• Cefovecin

44
• Cefixime
• Cefpodoxime
• Cefotaxime
• ABSpec:
• Effective against Gr+ve cocci except Enterococci, active against penicillin
resistant strains of Streptococcus pneumoniae
• Not active against anaerobes esp. Bacterioides, Pseudomonas and Staph
• Resistant to many -lactamases
• Parenteral administration – IM or SC (F>90%)
• Well distributed
• Metabolised to desacetylcefotaxime – less active – metabolised further
• Excreted in urine, T1/2; 45-60 min in dogs and cats
• Clinical use: RTI, Skin, bones, joints, urogenital, meningitis & septicemia
• Gram –ve meningitis in small animals
• Dose
• Dogs & Cats : 25- 50 mg/kg, IM, IV or SC – BID or TID
• Dogs : 3.2 mg/kg, loading dose, followed by 5 mg/kg/hr, IV
• Foals : 20-30 mg/kg, IV – QID
• Birds : 75 -100 mg/kg, IM or IV, TID or QID
• Ceftiofur
• Available as Na and HCl salts, most potent III gen Cephalosporin
• ABSpec: similar to Cefotaxime
• Metabolised to active desfuroylceftiofur – longer duration of action
• T1/2: Cattle 9-12 hrs
• Clinical use:
• Respiratory infections in ruminants, swine and horses
• Intradigital necrobacillus (foot rot) and metritis in cattle
• Early mortality infections in day-old chicks & turkey poults
• UTI in dogs
• AE: anaemia and thrombocytopenia if dose is exceeded
• Dose:
• Dogs : 4 mg/kg, SC, OD or BID (2.2 mg/kg, SC – OD or BID for UTI)
• Horses & Camelids : 2.2 to 4.4 mg/kg, IM – OD
• Swine : 3 mg/kg, IM –OD, 3-5 days
• Ruminants : 1.1 to 2.2 mg/kg, IM – OD

45
 • Poultry (Chicks) : 0.08 – 0.2 mg/chick, SC
• Ceftriaxone
• Broad spectrum, equivalent to Cefotaxime in efficacy and safety
• Parenteral administration, distribute widely incl. CSF
• Excreted by both renal and non-renal (bile), t1/2 – 6-11 hrs in animals
• Clinical use: to treat Enterobacteriaceae, Lyme’s disease, Borrelia sp.
• Dose:
• Dogs & Cats: 15-50 mg/kg, IM or IV – BID
• Horses : 25 -50 mg/kg, IV or IM – BID
• Ceftazidime
• Broad spectrum, high activity against Pseudomonas & Enterobacteriaceae
• Less active against Gr+ve cocci and anaerobes, Bacterioides fragilis
• Unmetabolised and excreted in urine
• T1/2 man – 1.5 h
• Dose:
• Dogs &Cats:15-30 mg/kg, IM, SC or IV – BID to QID or 1.2 mg/kg IV followed
by 1.5 mg/kg/hr IV infusion delivered in parenteral fluid
• Horses: 20 mg/kg IV or IM, TID
• Cefoperazone
• Not orally absorbed
• Susceptible to -lactamases
• Does not penetrate CNS unless meningitis is present
• Excreted mainly in bile unlike other cephalosporins, Heptaic or biliary obstruction –
require dosage adjustment
• Safe drug but diarrhoea due to changes in gut microflora
• Cefoparazone contains N-methylthiotetrazole side chain – coagulation abnormalities
• Oily preparation for intramammary use
• Dose:
• Dogs & cats : 22 mg/kg, IV or IM – TID or QID
• Horses : 30 -50 mg/kg, IV or IM – BID or TID
• Cefovecin
• Developed for Veterinary use only
• ABSpec:
• Active against Staph, Strep, E. coli, P. multocida, Klebsiella, Proteus
• Not active against Pseudomonas, Enterococcus sp.

46
 • Treatment of gingivitis, superficial and deep pyoderma, cellulitis & abscesses caused by
Gr-ve and Gr+ve bacteria
• T1/2 Cats 6.9 days
• Dose:
• Cats : 8 mg/kg, SC – q2w – 3 doses
• Cefixime
• Orally active
• ABSpec:
• Less active against gr+ve cocci
• More active against streptococci, Enterobacteriaceae & -lactamase producing H.
influenza
• Poor activity against Staph aureus and Pseudomonas aeruginosa
• Clinical use:
• RTI, UTI and biliary infection
• Diarrhoea – side effect
• Dose:
• Dogs & Cats : 5-10 mg/kg, PO – OD or BID
• Cefpodoxime
• Orally active, prodrug – cefpodoxime proxetil – improved oral absorption
• Oral F = 60% in dogs, t1/2 dog -6 hrs, horses – 7 hrs
• ABSpec: similar to cefixime
• Clinical use:
• Skin and other soft tissue infections in dogs
• Dose:
• Dogs : 5-10 mg/kg, PO – OD or BID
Fourth Generation Cephalosporins
• Antipseudomonal cephalosporins
• ABSpec of III generation and highly resistant to -lactamases
• IV gen ceph are zwitter ions, penetrate outer membrane of Gr-ve
• Cefepime:
– Developed in 1994
– Broad spectrum – Gr+ve, Gr-ve, Pseudomonas
– Not active against MRSA, Enterococoi, B. fragilis, L. monocytogenes
– Excellent penetration in CSF
– Administered by IV route only, less reported in veterinary use

47
 – Dose:
• Dogs : 40 mg/kg, IV, QID
: 1.4 mg/kg (loading dose) followed by 1.1 mg/kg/hr IV infusion
• Foals : 11 mg/kg, IV, TID
• Cefquinome
• Developed for use in animals, analogue of Cefpirome
• Higher affinity to PBPs
• Clinical use:
• Mastitis and Bovine pneumonia pathogens
• Dose:
• Cattle : 1 mg/kg, IM, OD
• Calves : 2 mg/kg, IM, OD
• Cefpirome
• Eliminated by kidney 80-90%
• Used in patients with severe or life-threatening infections, bactremia, neutropenic
patients, skin & soft tissue infection, UTI & nosocomial pneumonia
• Other IV gen: cefozopran, cefclidine, cefluprenam and cefoselis
Fifth Generation Cephalosporins
• Recently introduced, not universally accepted
• Antipseudomonal and less susceptible to resistance
• Ceftobiprole:
– Active against MRSA, Penicllin resistant Streptococcus pneumoniae, Pseudomonas
aeruginosa and Enterococci.
– Resistant to staphylococcal -lactamases
– Administered by IV route
Ceftaroline fosamil
– Prodrug - converted to active metabolite Ceftaroline and inactive metabolite Ceftaroline
M1
– Approved for the treatment of community-acquired bacterial pneumonia and acute
bacterial skin infections
CEPHAMYCINS
• 7-methoxy analogues of cephalosporins
• Often classified as cephalosporins due to similar pharmacological properties and clinical use
• Cephamycins are produced by actinomycetes Streptomyces
• Unlike cephalosporins, cephamycins very effective against anaerobic microbes
• Cefoxitin

48
 • Hygroscopic powder or granules – water soluble
• Often classified in second generation cephalosporins
• ABSpec: similar to II gen ceph, highly resistant to -lactamases of Gr-ve org.
• PK:
• IM route – achieve therapeutic conc.
• Distributed widely
• Excreted in urine unchanged
• T1/2 Horse-45 min, Cattle -70-80 min, Probenecid enhances t1/2
• Clinical use
• Treatment of anaerobic infection
• In dogs & cats, abdominal infection, soft tissue wounds and prior to surgery
• Dose
• Dogs & Cats : 20-30 mg/kg, IM, SC or IV – TID or QID
• Horses : 20 mg/kg, IV, q4-6h
• Cefotetan
• ABSpec: similar to cefoxitin and more active against Gr-ve aerobes
• Contains N-methylthiotetrazole sidechain – causes hypoprothrombinaemia
• Dose
• Dogs & Cats : 30 mg/kg, IV or SC, TID
• Cefmetazole – similar to cefotetan
CARBACPHAMS
• Carbacephems are similar to cephems but with a carbon substituted for the sulphur, only member
of this group is Loracarbef
• Loracarbef structurally resembles cefaclor
• Its use is discontinued due to frequent GI and other adverse effects
OXACEPAMS
• Oxygen substituted for the sulphur
• Latamoxef and Flomoxef
• Latamoxef (Moxalactam):
– Often described in III generation cephalosporins
– Achieves CNS concentration
– Contains N-methylthiotetrazole side chain
• Causes hypoprothrombinaemia – with prolonged bleeding time and coagulopathy
CARBAPENEMS
• New class of beta-lactams, broad spectrum and resistant to -lactamases

49
• Derived from Streptomyces sp.
• MoA:
– Binds to PBP1 and PBP2 – bactericidal
– Longer post-antibiotic effect
• ABSpec:
– Aerobic, anaerobic gram +ve incl. Enterobacteriaceae, Pseudomonas & Listeria
– MRSA – less susceptible
– Resistant to -lactamases
– Allows penetration through porin channels
• Imipenem, Meropenem and Ertapenem
• Imipenem
– Marketed in combination with Cilastatin – inhibitor of renal tubular dipeptidase
– Derived semi-synthetically from Thienamycin produced by Streptomyces cattleya
– ABSpec:
• Aerobic and anaerobic gram +ve and –ve bacteria
• Not active against MRSA, and resistant strain of Enterococcus faecium
• Resistant to -lactamases, now org code for imipenem hydrolysing -lactamases
– PK:
• Only parenteral administration, IM F> 95%
• Widely distributed, except CSF
• Hydrolysed by dipeptidase enzyme in brush border of the proximal renal tubule
results in low urinary drug level, hence Cilastatin is combined with imipenem
• Cilastatin – increases urinary conc of imipenem and prevents proximal tubular
necrosis when imipenem is used alone
• Eliminated by both renal (75%) and non-renal (25%), t1/2 -1-3 h
– Side effects / Contraindications
• Higher incidences of GI disturbances
• CNS toxicity (tremors, seizures) in renal insufficiency patients
• Hypersensitivity - Cross reaction with Penicillins
– Drug Interactions
• Aminoglycosides – results in additive and synergistic effect
• Should not be administered with other beta-lactam antibiotics
• Probenecid does not affect the excretion
– Clinical Uses
• Genito-urinary and lower respiratory tract infections

50
 • May be used in small animals or equines
• Expensive and only parenteral administration
– Dose
• Dogs & Cats : 2-5 mg/kg, slow IV (may be added to IV fluids) – TID, QID
: 5-10 mg/kg, deep IM, q6-8h
• Horses : 15 mg/kg, slow IV – q4-6h
• Meropenem
– ABSpec
• Extremely broad spectrum
• No need to Co-administer with Cilastatin – not hydrolysed by dipeptidase
enzyme
• Less active against gr+ve org
– Well distributed, incl. CSF, bile, heart valves, lung and peritoneal fluid
– More soluble than imipenem, Lower incidences of seizures
– Subcutaneous injection – slight hair loss at the site of injection
– Dose
• Dogs & Cats : 8 mg/kg, SC – BID
: 24 mg/kg, IV – BID
• Ertapenem
– ABSpec: similar to meropenem
• Active against Gr-ve bacilli incl. Enterobacteriaceae, Gr+ve , except MRSA,
MREnterococcus, Pseudomonas (can be treated with Doripenem)
– Dose
• Dogs & Cats :15 mg/kg, IV or SC - BID
MONOBACTAMS
• -lactam ring is alone – monocyclic
• Active against Gram -ve aerobic with NO action against Gr+ve or anaerobes
• ABSpec similar to aminoglycosides
• Resistant to -lactamases
• Only one drug Aztreonam available for Clinical use
• Aztreonam
– Isolated from Chromobacterium violaceum
– Binds with PBP-3 – induces formation of long filamentous bacteria
– ABSpec:
• Effective against Gr-ve at low conc, Pseudomonas at moderate conc

51
 • Inactivated by ESBL
– Only parenteral administration (IM o/r IV)
– Plasma t1/2 - 2 hours in humans
– No cross reactivity with Penicillin or Cephalosporins, hence can be used in penicillin
sensitive patients
– No data on domestic animals
-LACTAMASE INHIBITORS
• Clavulanic Acid, Sulbactam and Tazobactam
• Clavulanic Acid
– Contains -lactam ring, isolated from Streptomyces clavuligens
– No antibacterial action, binds to -lactamase due to similarity with penicillin
– ‘Suicide inhibitor’ due to irreversible, progressive inhibitor
– PK:
• Well absorbed from GIT and parenteral injection sie
• Metabolised and excreted in urine through glomerular filtration and not affected
by probenicid
• T1/2 in human
• Sulbactam
– 2 to 3x less potent than clavulanic acid, does not induce chromosomal BL
– Only parenteral, Ampicillin-sulbactam, cefoperazone – sulbactam
– Tazobactam
– Combined with Piperacillin – broadest antibacterial spectrum
AMINOGLYCOSIDES
History:
 Streptomycin – first member of aminoglycosides antibiotics discovered in 1944 by Waksman and
co-workers from Streptomyces griseus, a soil bacteria
 Neomycin – 1949
 Kanamycin – 1957
 Gentamicin – 1963
Chemistry:
 Aminoglycosides consists of two or more amino sugars joined in glycosidic linkages to a hexose
(aminocyclitol) nucleus

52
  All aminoglycosides are produced by the soil actinomycetes
 Streptomyces sp. derived aminoglycoside carry suffix –mycin e.g. streptomycin
 Microsmonospora sp. derived aminoglycosides carry suffix – micin, e.g. gentamicin
General properties of aminoglycosides
1. Water soluble, polar compound, ionise in solution, used as sulphate salts, highly water
soluble, stable for months
2. Not absorbed orally, distribute only extracellularly, not metabolised, excreted unchanged
in urine
3. Act by inhibition of protein synthesis
4. Bactericidal, active against Gr-ve bacilli (newer agent – broad spectrum)
5. Poor penetration in to the mammalian cell – not effective against intracellular bacteria
6. More active in alkaline pH
7. Ototoxicity (8th Cranial nerve damage), nephrotoxicity and Neuro-muscular block
8. Narrow margin of safety
9. Resistance develop rapidly, however it is partial resistance
10. Synergistic antibacterial effect with beta-lactam antibiotics
CLASSIFICATION
Narrow Spectrum
 Streptomycin and Dihydrostreptomycin

53
 Broad Spectrum
 Neomycin, Framycetin, Kanamycin, Paromomycin and Arbekacin
Extended Spectrum
 Gentamicin, Amikacin, Tobramycin, Sisomicin and Netilmicin
MECHANISM OF ACTION
 Bactericidal by inhibiting the protein synthesis
 Concentration dependent bactericidal effect
 Efficacy depends on the high oxygen tension in the environment
 Action of Aminoglycosides broadly divided in to two processes
I. Entry in to bacterial cells
II. Binding to bacterial ribosomes
 Entry into Bacterial Cell
I. Passage across the cell wall: diffuses through the porin channels of Gram –ve org in to
the periplasmic space
II. Passage across the cell membrane: Occurs via oxygen dependent process, which is linked
to the electron transport chain
 Phase I: Ionic aminoglycosides interact with anionic component of cell
membrane in a conc. dependent manner. Cations like Mg2+ and Ca2+ retard the
interaction
 Phase II: Transported actively across cell membrane –Oxygen dependent active
transport (anaerobic bacteria are therefore resistant to AGs) slow energy-
dependent phase (EDP-I) that transports the drug into the bacterial cytosol.
Binding to Bacterial Ribosomes
 Aminoglycosides bind with 30S ribosomes stronger than 50S ribosomes
 Interference with formation of the initiation complex of protein synthesis
 Distortion of m-RNA codon resulting in misreading of the codon – synthesis of
abnormal proteins
 Promotion of premature termination of translation – incompletely synthesised
protein
 Inhibit ribosomal translocation, where the peptidyl-t-RNA moves from the A site
to the P site.
 Binding to 30S-50S ribosome juncture – responsible for bactericidal effect
 Affects the integrity of the cell membrane
 Changes induced during the energy-dependent transportation of AG
 Incorporation of the defective proteins in the membrane
Antimicrobial Features of Aminoglycosides
1. Bactericidal action is concentration dependent

54
 • should be given in single large dose instead of divided doses
2. Most effective against rapidly multiplying bacteria
3. Shows a Post-antibiotic effect (PAE) due to strong irreversible binding to ribosomes
• Single daily dose is effective though the half-life is shorter
4. Synergistic with beta-lactam antibiotics – cell wall damage by beta lactam facilitates increased
uptake of aminoglycosides
Mechanism of Resistance to Aminoglycosides
1. Decreased permeability
2. Production of Aminoglycosides Modifying Enzymes
3. Alteration at the Ribosomal Binding Site
Pharmacokinetics of Aminoglycosides
Absorption:
• Poorly absorbed from GIT (F <10%), oral route is only for GI infections
• Bacterial cleansing of intestine prior to surgery of GIT
• Absorption from IM injection is >90%, Tmax 30-45 min, SC route – slow
• IV and IP routes should be avoided- high conc. lead to toxicities
Distribution:
• Extensively distributed in ECF only
• Do not enter in to the brain, CSF, eye and most tissues except kidneys and inner ear, where it
accumulates in high concentration – toxicity
• Crosses placental barrier – deafness in young ones
• PPB < 20%
• Vd  volume of ECF
Metabolism:
• Not metabolised
Excretion:
• Excreted unchanged in urine by glomerular filtration
• T1/2 – 2-4 hours in normal renal function, 24-48hrs in renal insufficiency
• Renal clearances depends on the Vd
• Neonates – high ECF, low blood level, low renal clearance
• Dehydration – reduced ECF, increased renal clearance
Aminoglycosides Toxicity
Nephrotoxicity:
• 40 to 50x accumulation in proximal tubular cells
• Positively charged AG is attracted to the negatively charged phospholipids (phosphatidyl inositol)
which is high in renal cortex and cochlear tissues.

55
 • Transported inside the cell by pinocytosis
• Interaction of AG with membrane is enhanced by the acidic pH
• Interaction can be inhibited by Ca++ and Mg++
• AG inhibit various enzymes such as
• Phospholipases -  PG, IP3 & DAG
• Sphingomyelinases
• ATPases
• Neomycin is most nephrotoxic followed by Tobramycin and Gentamicin
• Dihydrostreptomycin is least nephrotoxic
Ototoxicity:
• Vestibular and auditory dysfunctions
• AG accumulates into Perilymph and Endolymph of the inner ear in a dose and time dependent
manner
• Elimination is slow
• Irreversible damage of vestibular or cochlear sensory cells
• Streptomycin is most vestibulotoxic followed by Gentamicin
• Neomycin is most Ototoxic followed by Kanamycin and Amikacin
• Cats are most susceptible to Ototoxic effect of AG
Neuromuscular blockade
• Interference of Ach release from motor nerve endings by antagonism of Ca++
• Decrease in sensitivity to the Ach in the post-synaptic site
• Muscular weakness, apnoea, respiratory arrest – very high doses of AG
• Neomycin, Streptomycin – high propensity for NM blockade followed by Kanamycin, amikacin
and gentamicin
• Tobramycin is least toxic
• Neuromuscular blockade may be treated with IV administration of calcium salts or neostigmine

Contraindicated in:
• Patients with renal disease, neonatal or geriatric animals
• Animals with myasthenia gravis
• Working dogs due to adverse effect on hearing ability
• Pregnancy
Drug Interactions
• Concurrent use of loop diuretics (furosemide) and osmotic diuretic (mannitol) aggravates
nephrotoxic and ototoxicity

56
 • Respiratory paralysis when used with inhalant anaesthetics or NM blocker (d-tubocurarine)
• Synergistic antibacterial effect with beta-lactam
• AG with cephalosporins are controversial due to additive nephrotoxic effect
Clinical Use
• Mostly Gram –ve infections
• GI tract, urinary tract, respiratory tract and Skin infections
• Effective against Septicaemia, Osteoarthritis, Mastitis and Wounds
• Intrauterine – to treat metritis
• Intramammary – to treat mastitis
• Topical in eyes and ears (provided tympanic membrane is intact)
Narrow Spectrum Aminoglycosides
• Streptomycin
• Oldest AG obtained from Streptomyces griseus
• Water soluble, used in combination with penicillins
• ABSpec: against aerobic Gr-ve bacillli
• E. coli, Salmonella, Klebsiella, Pasteurella, Brucella, Campylobacter foetus and
Leptospira
• Mycobacterium tuberculosis
• PK
• Ionised, not absorbed from GIT
• IM –Tmax 60-90 min, distributed in ECF, unmetabolised, excreted unchanged in
urine
• T1/2 – 3 to 4 hours
• Clinical Use
• In combination with Penicillin for the treatment of shipping fever, foot rot,
mastitis
• Used to control algae in ornamental ponds and aqua
• Dose
• For enteric infections : Dogs & Cats – 15 mg/kg, PO – OD
• For systemic infections: All species – 5-10 mg/kg, IM – OD
• For mastits : Lactating cows – 100 mg/quarter, Dry cows – 500 mg/quarter
Broad Spectrum Aminoglycosides
• Neomycin
• Obtained from Streptomyces fradiae, highly stable antibiotic
• Complex of three compounds – neomycin A(neamine), B (framycetin) and C

57
 • Framycetin and Neomycin C are active, Neomycin A is inactive
• ABSpec: against aerobic Gr-ve bacillli and Gr+ve org
• PK
• IM –Tmax 60 min, unmetabolised, excreted unchanged in urine
• Adverse Effects
• Highly ototoxic and nephrotoxic
• Prolonged usage lead to Intestinal malabsoption syndrome, flattening of villi
• Bacterial or fungal superinfection on chronic use
• Clinical Use
• Oral – enteric infections or sterilise colon prior to surgery, enema form –
to decrease ammonia producing bacteria in the treatment of hepatic
encephalopathy
• Topical – skin, eye or ear infections
• Intramammary – treatment of mastitis
• Not used in parenteral route – due to toxicity
• Dose for enteric infections :
• Dogs & Cats – 10 mg/kg, PO in divided doses (DD),
• Cattle : 10 -20 mg/kg, PO-BID, Horses: 5-15 mg/kg, PO – OD, Sheep – 22
mg/kg, PO, DD – 14days
• Pigs: 230 g/ tonnes feed or 12.5 g/100 liter drinking water
• Poultry: 10 mg/kg, PO, or 230 g/tonne feed
• Framycetin or Neomycin B
• Oral and topical routes – enteritis, skin, eye or ear infections
• For acute masitis with systemic involvement – I/M route: 5 mg/kg –BID
• Combined with other antibacterial drugs and corticosteroids for topical infections
• Kanamycin
• Produced by Streptomyces kanamyceticus
• Three components Kanamycin A (major), B & C (minor)
• Chemically and pharmacologically related to neomycin
• Used topically and oral route for enteric infections
• Parenterally for treatment of soft tissues, respiratory and urinary tract infections
• Toxicity – damage to the eighth cranial nerve and kidney
• Dose
• Dogs and Cats: 10 mg/kg, PO – QID, 5-7.5 mg/kg, IM or SC – BID or TID
• Birds : 10 -20 mg/kg, IM -BID

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 • Paromomycin
• Isolated from Streptomyces rimosus var. paromomycinus, S. catenulae or S.
chrestomyceticus
• Wide spectrum – Gr+ve, Gr-ve, tapeworm, GI protozoan – Entamoeba histolytica and
Giardia
• Used in enteric infections
• Arbekacin
• Stable in the presence of aminoglycoside-inactivating enzymes produced by MRSA
• Used for the short term treatment of MRSA infection
Extended Spectrum Aminoglycosides
• Gentamicin
• Isolated from Micromonospora purpurea , a soil bacteria
• Complex of three compounds – Gentamicin C1, C1a and C2
• ABSpec: against aerobic Gr-ve and Gr+ve org including Pseudomonas
• Many bacteria resistant to other AG sensitive to gentamicin
• PK
• IM –Tmax 30-40 min, F > 90%, unmetabolised, excreted unchanged in
urine, t1/2; 1 to 3 h
• Clinical Use
• Low cost and extended spectrum – widely used in veterinary medicine
• Respiratory tract, Urinary tract, GI tract, bones, soft tissues and skin
infections
• Topical – skin, eye or ear infections
• Intramammary and intrauterine – treatment of mastitis and metritis
respectively
• Heat stable (autoclavable) antibiotic – used in preparation of
microbiological growth media
• Dose :
• Dogs & Cats – 5 mg/kg, IM or SC – BID on first day followed by SID
• Cattle , Horses: 2.5 – 5 mg/kg, IM-BID or TID
• Pigs for colibacillosis: 1.1 to 2.2 mg/kg/day in drinking water for 3 days
• Birds: 5-10 mg/kg, IM – BID or TID
• For Metritis: Cows & Mares : 200-250 ml of 2% solution in sterile water, IU, OD
– 3 days
• Amikacin
• Semisynthetic, acetylated derivative of Kanamycin A
• ABSpec: Broadest, effective against org resistant to Gentamicin and Tobramycin

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 • Resistant to AG inactivating enzymes
• PK
• IM - unmetabolised, excreted unchanged in urine, t1/2; 0.5 to 1.5 h in
dogs & cats, 1-2 h in horses, 2-3 in cattle
• Dose :
• Dogs & Cats – 5-10 mg/kg, IM or SC – BID or TID
• Cattle – 10 mg/kg, IM – TID
• Horses: 6.6 mg/kg, IM or IV- TID or QID
• Camelids: 18-21 mg/kg, IM, IV or SC – OD
• Birds: 15 mg/kg, IM, SC – BID
• For Metritis: Mares : 200-250 ml of 2% solution in normal saline, IU, OD – 3
days
• Tobramycin
• Isolated from Streptomyces tenebrarius
• ABSpec: serious Gr-ve infections, effective against org resistant to Gentamicin,
• Resistant to AG inactivating enzymes
• PK similar to gentamicin
• Dose :
• Dogs & Cats – 4 -6 mg/kg, IM or SC or slow IV– BID or TID
• Horses: 1 – 1.5 mg/kg, IM or slow IV- TID
• Birds: 2.5 - 5 mg/kg, IM – BID
• Sisomicin and Netilmicin
• Sisomicin is derived from Micromonospora inyoensis and Netilmicin is semi-
synthetic derivative of sisomicin
• Broader spectrum of activity than gentamicin
• Resistant to AG inactivating enzymes
• Under clinical trials for use in vet practice
TETRACYCLINES
 Streptomyces aureofaciens in 1948, followed by oxytetracycline and tetacycline by removing the
chlorine atom in 1952.
 Semisynthetic tetracyclines are Metacyclines, Doxycyclines and Rolitetracycline
In 2005, Tigecycline was introduced active against org. which are resistant to other tetracycline
Chemistry:
 Tetracyclines are 4 ringed amphoteric compounds
 Acidic and hygroscopic, in aqueous solution form salts with both acids and bases
 Fluoresce when exposed to UV light

60
  HCl salts of tetracyclines are used in clinics except Doxycyclines as hyclate salt.
 Tetracyclines form insoluble chelate with Ca++, Mg++, Fe+++ and Al+++
 Tetracyclines are stable as powder (yellow crystalline) but not aqueous solutions, hence they are
formulated in propylene glycol, polyvinyl pyrrolidine and stabilizers
Classification of Tetracyclines
I. Short acting tetracyclines (t1/2 =< 8hrs)
e.g. Oxytetracyline, Tetracycline and Chlortetracycline
II. Intermediate acting tetracyclines (t1/2 = 8-16 hrs)
e.g. Demeclocycline and Metacycline
III. Long-acting tetracyclines (t1/2 = > 16 hrs)
e.g., Doxycycline, Minocycline and Tigecycline
Mechanism of Action of Tetracyclines
 Inhibit Protein synthesis, Bacteriostatic
 Two processes
I. Passage of tetracyclines into bacterial cell
II. Interaction of tetracylines with bacterial ribosomes
I. Passage of Tetracyclines into bacterial cell
 Two transport mechanisms
a. Passive diffusion through porin channels or by lipid bilayer (lipophilic doxy and minocycline)
b. Active carrier transport mechanism – energy dependent
II. Interaction of Tetracyclines with bacterial ribosomes
 Bind to 30S ribosomal subunit
 Prevent binding of aminoacyl t-RNA to the A-site on the m-RNA complex
 Inhibition of protein elongation or synthesis – incomplete peptide chain
Antimicrobial Spectrum of Tetracyclines
 Broad Spectrum antibiotic
 Also active against Mycoplasma, Rickettsia, Chlamydia and some Protozoa like Anaplasma,
Haemobartonella and amoebae.
 Resistant org. to tetracyclines are Pseudomonas, Proteus, Serratia, Klebsiella, Salmonella,
Staphylococcus and Corynebacterium spp.
 Ineffective against Virus and Fungi
Microbial Resistance to Tetracyclines
 Three mechanisms
 Decreased penetration into cells or energy dependent efflux
 Enzymatic inactivation and
 Ribosomal protection

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  Development of Resistance through
 Plasmid mediated – transmitted through transduction or conjugation
 Cross resistance (org. resistant to one tetracycline usually resistant to other members of the
group)
 Partial cross-resistance between tetracyclines and chloramphenicol in some org.
Pharmacokinetics of Tetracyclines
 Absorption:
 Older tetracyclines – less oral bioavailable
 New lipophilic tetracyclines, e.g. minocycline and doxycycline – 100% BA on oral
administration
 Absorption decreases in the presence of polyvalent cations, (e.g. Ca++, Mg++ and Fe++
+) present in milk and milk products
 Cause irritation on parenteral administration hence formulated with procaine
 Distribution:
 Widely distributed incl. kidneys, liver, lungs, bile and bones
 Do not penetrate brain and CSF except doxy and minocyclines
 Stored in RE cells of liver, spleen and bone marrow
 Incorporated in forming bone, enamel due to the chelating action with Ca
 Crosses placenta and amniotic fluid
 Metabolism:
 Not metabolised except the lipid soluble tetracyclines (doxy and mino)
 Excretion:
 In urine (~ 60%) via glomerular filtration
 In faeces (~ 40%) via biliary excretion
 Undergo enterohepatic circulation – increase the duration of action
Adverse Effects of Tetracyclines
 Gastrointestinal :
 GI irritation, Anorexia, abdominal pain, diarrhoea, nausea and vomiting
 Superinfection – candidiasis, enterocolitis or pseudomembranous colitis
 Fatal diarrhoea in horses
 Indigestion due to deleterious effect on rumen microbes in ruminants
 Effect on bones/teeth:
 Tetracycline deposits in growing teeth and bones due to chelating effect with calcium –
form tetracycline-calcium orthophosphate complex – inhibits calcification – results in
permanent discoloration

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  Tetracyclines can interfere with the calcium deposition in bones and delay fracture
healing
 Suppress of bone growth in foetus
 Hepatotoxicity :
 Fatty infiltration of liver and jaundice
Nephrotoxicity
 Impair urinary concentrating ability
 Acute tubular nephrosis
 Inhibition of mammalian protein synthesis – increase in BUN level
Hypersensitivity
 Rarely produce skin rashes, urticaria, pruritus and exfoliative dermatitis
 Minocycline – more likely to cause allergic drug reactions
 Cardiovascular Effects
 Rapid IV – hypotension, collapse and sudden death in animals due to rapid chelation of
blood calcium
 Pretreatment with calcium borogluconate and slow IV infusion suggested
 Other effects
 Irritation on parenteral injection
 Prolong blood coagulation due to chelation of calcium
 Drug fever in cats, photoallergy in human
Contraindications of Tetracyclines
 Contraindicated in hepatic insufficiency, renal diseases and hypersensitive patients
 Oral administration in ruminants and horses – inhibit bacterial fermentation of plant fibers
 Should not be used in last trimester of pregnancy and up to 4 weeks in neonates
 Tetracycline preparations should not be used after expiry – cause proximal tubular damage due to
degradation product – anhydro-4-epitetracycline results in Fanconi syndrome
 Fanconi syndrome –glucose, amino acids, uric acid, phosphate and bicarbonate – passed in to
urine
 Should not be given with food, may form insoluble chelation with cations except doxycycline and
minocycline
Drug Interactions of Tetracyclines
 Antacids, iron preparations, saline purgatives, kaolin, pectin and NaHCO 3 – decrease the
absorption of tetracyclines
 Concurrent administration of nephrotoxic drugs like methoxyflurane
 Tetracycline interfere with bactericidal activity of penicillins, cephalosporins and
aminoglycosides
 Tetracyclines and oral anticoagulants – aggravates bleeding

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  Microsomal enzyme inducers – decrease t 1/2 of lipid soluble tetracyclines (doxycycline and
minocycline)
 Should not be mixed in IV fluids like ringers lactate and calcium preparation
Clinical Uses of Tetracyclines
 Treatment of infections – bacteria, mycoplasma, chlamydiae and rickettsiae, anaplasma,
hemobartonella, ehrilichia and borrelia
 Birds – psittacosis
 Bronchopneumonia, UTI, metritis, mastitis, prostatitis, cholangitis and pyodermatitis
 Actinomycosis and actinobacillosis
 As a growth promoters in food producing animals
 Oral, Parenteral, Topical or intramammary route
 IM route is not recommended for tetracyclines - excessive tissue irritation
 Ophthalmic solution – conjuctivitis
Short Acting Tetracyclines
Oxytetracycline
 It is obtained from streptomyces rimosus
 Oxytetracycline HCl injection prepared in propylene glycol or povidone base
 Oral F = 60-80%, Tmax 0.5-2 h, long acting products – slow absorption
 Widely distributed except in CSF and brain, excretion unchanged
 T1/2 in dogs and cats = 4-6 h, cattle= 4-10 h, horses = 8-10 h, swine = 6-7 h and sheep = 3.5 h
 Depot preparation – maintain plasma conc. = 72-96 h
 Treat infections of respiratory and urinary tract, skin, ear and eye
 Causes irritation on injection, available with piroxicam
 Drug withdrawal period 14-22 days in food producing animals
 Doses
 Most of the species – 5-20 mg/kg, IM or slow IV – BID
 Poultry – 10-25 g/100 liters of drinking water
Tetracycline
 It is obtained from streptomyces aureofaciens or derived semi-synthetically from oxytetracycline
 Oral F = 60-80%, T1/2 in dogs and cats = 5-6 h
 ABSpec similar to oxytetracycline
 Doses
 Dogs & Cats – 20 mg/kg, PO – TID, 7 mg/kg IM or slow IV – BID
 Cattle & Sheep – 10 mg/kg – BID, up to 5 days
 Horse – 5-7.5 mg/kg, IV –BID

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  Pigs – 40 mg/kg, PO – SID addition to drinking water
 Poultry – 60 mg/kg SID to drinking water
Chlortetracycline
 It is obtained from streptomyces aureofaciens
 Fairly soluble in water, strong bitter taste
 Oral F = 30%, only given by oral route, as IM route is highly painful
 ABSpec similar to oxytetracycline
 Used as growth promoter in food producing animals
 Drug withdrawal time – 10 days (cattle), 1-7 days (pigs)
 Doses
 Dogs & Cats – 20 mg/kg, PO – TID
 Cattle – 10 -20 mg/kg PO– BID
 Sheep – 80 mg/animal/day in feed
 Pigs – 20-50 mg/kg, PO – OD, 400 -600 g/tonne feed
 Poultry – 20-50 mg/kg, PO – OD, 300 – 400 g/tonne feed
 Turkey & ducks – 10-30 mg/kg, PO - OD
Intermediate Acting Tetracyclines
Demeclocycline
 It is obtained from streptomyces aureofaciens, chlortetracycline without methyl group
 More stable and more active than chlortetracycline
 Rapidly absorbed by oral route and well distributed, slowly excreted, t1/2-10-18hrs but not used
in vet practice as the lipid soluble drugs are available
 It inhibits ADH, hence can be used in the treatment of hyponatremia and excessive water
retention due to the syndrome of inappropriate ADH (SIADH) by blocking the ADH to its
receptor
Metacycline
 Semi-synthetic derivative of oxytetracycline
 Efficacy is comparable to oxytetracycle, t1/2-14-16 h
 Less used in veterinary practice
 Used as a precursor in the synthesis of doxycycline hyclate
Long Acting Tetracyclines
Doxycycline
 Semi-synthetic derivative of oxytetracycline or metacycline, lipophilic
 Longer duration of action, available as hyclate, calcium or monohydrate salts
 Hyclate – oral or injectable, calcium and monohydrate salts – oral
 ABSpec –

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  similar to oxytetracycline
 better penetration in to bacterial cell,
 effective against Staphylococcus than other Tetracyclines
 PK
 Oral F = 90-100%, absorption less affected by food, milk or calcium salts
 Well distributed incl. lungs, brain, CSF, PPB~90%
 Metabolised to inactive metabolite (40%) –eliminated in feces
 Insignificant effect on lower intestinal microflora
 Does not accumulate in patients with renal dysfunction
 T1/2 16 to 20 hours
 Adverse effects
 Less GI irritation or superinfection
 Less vulnerable to chelation with cations
 Evidence of inducing collapse on IV in horse, hence should not be used in horse –IV
 Dogs & Cats – nausea and vomiting observed, hence administered with food
 Likely to produce photosensitivity, hepatotoxicity and nephrotoxicity
 Clinical Use
 Ehrlichiosis in dogs, psittacosis in birds, anaplasmosis in calves
 Prophylaxis and treatment of anthrax
 Useful in patients with azotemia
 Dose
 Dogs & Cats : 5 -10 mg/kg, PO or IV – OD
 Horse & Swine : 10 mg/kg, PO – BID
 Birds : 15 -25 mg/kg, PO –BID or 130 mg/litre of drinking water
Minocycline
 Semi-synthetic derivative of oxytetracycline, lipophilic
 Oral F = 95-100%, well distributed, higher PPB, Enterohepatic recirculation, inactive metabolite
in feces, t1/2 dog – 7h, man 15-20h
 Decreases the absorption in presence of food, milk and cations but not to greater extent
 Spectrum of activity: Bacteria, protozoa, Rickettsiae and Ehrlichiae
 Dose: Dogs – 12.5 to 25 mg/kg, PO-BID, Cats – 5 to 15 mg/kg, PO-BID or TID
Tigecycline
 Newly introduced tetracyclines called glycylcycline antibiotics, derived from minocycline
 ABSpec: Gr+ve, Gr –ve, MRSA, MDR strain of Acinetobacter baumannii
 No activity against Pseudomonas and Proteus

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  Licensed for human use for the treatment of skin and soft tissue infections
Other Tetracyclines
Clomocycline, Lymecycline, Meclocycline and Rolitetracycline
• Lymecycline is 5000x more soluble than tetracycline
• Unique – absorbed only by active transport in intestine
• Meclocycline – only topical application for skin infection
• Totally insoluble in water, may cause liver and kidney damage if given systemically
AMPHENICOLS
Broad spectrum, Bacteriostatic antibiotic
• Chloramphenicol, its congeners Thiamphenicol, Florfenicol and Azidamfenicol
Chloramphenicol
 Obtained from Streptomyces venezuelae in 1947, but now manufactured synthetically
 Highly effective against anaerobic bacteria
Properties
 Highly lipid soluble, freely soluble in alcohol and acetone, less soluble in water
 Aqueous solution – neutral and stable, should be protected from light
 Chloramphenicol palmitate ester is insoluble in water – oral
 Chloramphenicol succinate ester soluble in water – parenteral
 Ester salts are hydrolysed in vivo to release chloramphenicol
Chemistry
 Exists in 4 stereoisomers, only D-threo form has antibacterial activity
 P-nitro group is not essential for antibacterial activity
 The p-nitro group is responsible for irreversible suppression of bone marrow
Mechanism of action
 Inhibit protein synthesis
 Penetrate bacterial cell by passive and facilitated diffusion
 Binds to 50S ribosomal subunit and prevents the activity of peptidyl transferase
 Interferes with transfer of elongating polypeptide chain in the newly attached aminoacyl t-RNA at
ribosome mRNA complex
Antimicrobial spectrum
 Gr+ve, Gr-ve, aerobic and anaerobic bacteria
 Active against Nocardia, Rickettsia, Chlamydia and Mycoplasma
 No activity against Pseudomonas, Proteus, Mycobacterium, protozoa, fungi and virus
Bacterial Resistance
 Slow and graded manner

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  Through multidrug resistance plasmid – also codes resistant for tetracyclines, erythromycin,
streptomycin, ampicillin, etc.
 Three mechanisms
 Chloramphenicol acetyltransferase – inactivating enzyme (gr-ve; constitutive and gr+ve;
inducible)
 Reduced membrane permeability
 Mutation of the 50S ribosomal subunit
Pharmacokinetics
 Highly lipid soluble, absorbed rapidly and efficiently after oral dosing
 Tmax = 30 min (oral), delayed in case of palmitate ester, needs intestinal lipases to release the
drug.
 Rumen microflora inactivates chloramphenicol
 Highly distributed including brain, CSF, aqueous humor, placenta and synovial fluid
 Plasma therapeutic range is 5-15 g/ml, PPB 30-60%
 Metabolism by glucuronide conjugation – inactive metabolite
 Cats are deficient in glucuronide conjugation, hence the elimination in cat is slower
 Parent drug (15-20%) and inactive metabolite excrete in urine through glomerular filtration and
tubular secretion
 Biliary route of excretion is possible, but enterohepatic recirculation happens
 T1/2 dogs -1-5 h, cats 4-5h and ponies <1 h (unsuitable in equines – very low t1/2)
Adverse Effects
 Low order of toxicity when used in recommended dose
 Bone marrow depression
 Dose-dependent (reversible) and dose-independent (irreversible)
 Reversible – inhibition of mammalian mitochondrial protein synthesis
 Vacuolation of myeloid and erythroid series, lymphopenia and neutropenia
 Irreversible – formation of toxic intermediates with para-nitro group – damage the stem
cells
 Aplastic anemia and peripheral blood pancytopenia
 GI effects – vomiting, diarrhoea and anorexia
 CVS effects –rapid IV infusion with propylene glycol formulation – collapse, hemolysis and
death in large animals
 Hypersensitivity reactions
 Other effects:
 Human – Gray-baby syndrome characterised by vomiting, hypothermia, ashen grey
cyanosis, CVS collapse and death

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  Due to accumulation of unconjugatied chloramphenicol and blocks electron
transport in liver, myocardium and skeletal muscle.
Contraindication
 Hypersensitive patients and pre-existing hematological disorders
 Impaired hepatic and renal functions
 Avoided in neonates and nursing bitches and queens
Drug Interactions
 Potent inhibitors of CYP 3A4, 2C19 – prolong t1/2 of antidepressants, antiepileptics, proton pump
inhibitors, calcium channel blockers, etc.
 Phenobarbital and rifampicin – shortens the t1/2 of chloramphenicol
 Cyclophosphamide and chloramphenicol – severe bone marrow depression
 Macrolide binds at 50S ribosome – competition for the same binding site
 Should not be combined with bactericidal drugs
 Impairs immune function, hence vaccination is not advised in animals receiving chloramphenicol
Clinical Use
 Used in wide range of susceptible microbial infections esp. anaerobic infections such as
salmonellosis and bacteroides sepsis.
 Chronic respiratory infections, otitis externa
 Should not be used in food producing animals due to development of resistance
 Topical – ointments, eye drops – bacterial conjuctivitis
Dose
 Dogs : 40-50 mg/kg, PO, IM or slow IV – BID
 Cats :12.5 -20 mg/kg, PO, IV or IM – BID
 Horses: 50 mg/kg, PO, TID, QID, 20-50 mg/kg, IV – q2-4h
 Birds: 30-50 mg/kg, PO – TID or QID
THIAMPHNICOL
 Semisynthetic derivative of chloramphenicol, p-nitro group is replaced with sulphomethyl group
(CH3 SO2)
 Less lipid soluble and less potent, similar AbSpec as chloramphenicol
 Not metabolised, excreted unchanged in urine, T1/2 is 2 h in dogs
 Less toxic – abolishes the occurrence of idiosyncratic aplastic anemia
 Reversible dose dependent bone marrow depression is possible
 Common veterinary antibiotic
 Dose:
 Cattle & swine: 10-30 mg/kg, IM –OD
 Calves & lambs: 30 mg/kg, PO, BID or OD

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  Swine : 50-200 ppm in feed
 Poultry: 100-500 ppm in feed
FLORFENICOL
 Fluorinated analogue of thiamphenicol
 Less susceptible to microbial inactivation, abolishes the irreversible aplastic anemia
 ABSpec similar to chloramphenicol, more active than chloramphenicol and thiamphenicol
 Well absorbed after oral and parenteral administration
 Widely distributed including brain and CSF, metabolised in liver (35%), t 1/2 IV route 2-5 h, IM -
18 h in cattle
 Safe at recommended dose, Reversible bone marrow depression is possible
 Cattle – BRD, interdigital phlegmon, Swine – swine respiratory disease
 Dose:
 Dogs & Cats : 20 mg/kg, PO –IM, QID or TID
 Cattle & sheep: 20 mg/kg, IM –q2d, 40 mg/kg, SC– q3d or q4d
 Camelids: 20 mg/kg, IM or SC –q2d
 Swine : 100 ppm in drinking water for 5 days
Azidamfenicol
 Only topical – eye drops or ointment – susceptible bacterial infection
MACROLIDES
Introduction:
 Macrolides or macrocyclic lactones consists of large lactone ring, 14-16 atoms attached to one or
more deoxy sugars (cladinose or desosamine) by glycosidic linkages
Obtained from various species of Streptomyces, some are prepared semi-synthetically
Properties of Macrolides
 Weak base pKa 6 to 9
 ‘Ion trapping’ in acidic fluids like milk and prostatic fluid
 Poorly soluble in water, soluble in organic solvents
 Inactivated in basic (pH>10) and acidic (pH<4) environments with maximum activity between
pH 7.8 to 8
Classification of Macrolides
I. Macrolide antibiotics
1. Older macrolide antibiotics, E.g. Erythromycin, Tylosin, Tilmicosin, Spiramycin,
Oleandomycin and Troleandomycin
2. Newer macrolide antibiotics, E.g. Clarithromycin and Roxithromycin
II. Azalide antibiotics, e.g. Azithromycin and Tulathromycin
III. Ketolide antibiotics, e.g. Telithromycin

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Mechanism of Action – Macrolides
 Protein synthesis inhibitors – binds to 50S ribosomes
 Bacteriostatic at low dose, bactericidal at high dose
 Action of Macrolides – two processes
1. Passage of macrolides into bacterial cells
• Active transport mechanism
• Gr+ve org. accumulate 100 times more than Gr-ve org.
• Non-ionised form is more permeable – more active at alkaline pH
2. Interaction with bacterial ribosomes
• Binds to 50S ribosome and block translocation of peptidyl-tRNA from A site to P
site
Antimicrobial Spectrum- Macrolides
 Effective against aerobic and anaerobic gr+ve bacteria
 Similar or slightly wider spectrum than Penicillins
 Alternative to penicillins to those patients with penicillin allergy
 Active against -hemolytic streptococci, pneumococci, staphylococci and enterococci
 Not active against Gr-ve except Pasteurella, Haemophilus and Neisseria spp.
 Active against Mycobacterium, Mycoplasma, Chlamydia and Rickettsia spp.
 Ineffective against protozoa, virus and fungi
Bacterial Resistance – Macrolides
 Changes in ribosomal structure
 Decreased permeability
 Efflux pump
 Increased production of inactivating enzyme
• Plasmid mediated transfer
• Cross-resistance with other lincosamides and chloramphenicol – due to their similar binding site
Pharmacokinetics – Macrolides
 Absorption:
 Lipid soluble – rapidly absorbed through GIT
 Enteric coated to prevent gastric acid inactivation or esters salt can be used
 Food interferes with the GI absorption
 Oral Tmax = 1-2 h, IM or SC injection – rapid absorption
 Distribution:
 Widely distributed, accumulate in macrophages and leukocytes – ion trapping
 Crosses placenta, but not BBB and blood-CSF barrier

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  Conc in milk is several times higher than the plasma
 PPB = 70-80%, bound to 1-acid glycoprotein, not to albumin
 Metabolism:
 Extensively metabolised (~80%) in liver
 Excretion:
 Excreted in bile (>60%), enterohepatic cycling (EHC)
 Renal excretion is minor, but higher in parenteral administration
 T1/2 – 1 to 3 h, due to EHC, conc. maintained up to 6 h on oral and 12 to 24h on IM
injection
Adverse Effects – Macrolides
 Do not produce serious adverse effects
 GI disturbances: Horses are more susceptible – serious and fatal, erythromycin estolate salt –
hepatotoxicity and cholestasis
 Hypersensitivity
 Other effects
 Tylosin and tilmicosin – CVS toxicity
 Erythromycin and Clarithromycin – QT prolongation – Torsade de pointes
Contraindicated in
 Hypersensitive patients
 Liver dysfunction
 Horses and rabbits
 Lactating animals (as it concentrates in milk)
 Avoid in pregnancy
Drug Interactions
 Should not be used with chloramphenicol or lincosamides – 50S ribosome
 Erythromycin and troleandamycin inhibit microsomal enzymes
 Activity decreases in acidic environment
Clinical Use- Macrolides
 As Penicillin substitute
 Upper respiratory tract infections
 Bronchopneumonia
 Enteritis
 Metritis
 UTI
 Mastitis

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  Arthritis
MACROLIDE ANTIBIOTICS – OLDER
 Erythromycin
 Isolated from Streptomyces erythreus in 1952
 Narrow spectrum – gram +ve and few gram –ve org.
 Penicillin substitute
 Should be given enteric coated or more stable salts or esters such as ethylsuccinate,
esolate
 IM or SC, F= 40-60%, other PK properties are as discussed before
 Metabolised by CYP3A, t1/2 = 3 cattle, dogs & cats = 1 -1.5 h
 Prokinetic effect – increases intestinal motility, binding to motilin receptor
 Diarrhoea is self-limiting in most species, except in horses, rats, rabbits
 Rectal oedema and partial anal prolapse – swine
 Drug of choice for Campylobacter and Rhodococcus equi in foals
 Dose:
 Dogs & Cats : 2-10 mg/kg, PO –TID, Foals : 25 mg/kg, PO or IM -TID
 Cattle: 8-15 mg/kg, IM, OD or BID, Sheep & swine: 2-6 mg/kg, IM – OD
 Poultry: 25 g /100 lit of drinking water
 Tylosin
 Isolated from Streptomyces fradie
 Similar antimicrobial spectrum as erythromycin
 Development of resistance is low
 Like Erythromycin, Tylosin is not recommended in adult horses due to fatal diarrhoea
 Indicated for pleuropneumonia, foot rot, metritis in cattle, upper respiratory tract
infection, leptospirosis in dogs, chronic respiratory disease in poultry
 Dose:
 Dogs & Cats : 40 mg/kg, PO – divided doses, Dogs & Cats : 4-10 mg/kg, IM OD
 Cattle: 10-20 mg/kg, IM, OD or BID,
 Swine: 10 mg/kg, IM – OD or 25 g /100 lit of drinking water
 Poultry: 50 g /100 lit of drinking water
 Tilmicosin
 Semi-synthetic
 Good efficacy against Mycoplasma, high affinity for lung tissue
 Potentially toxic antibiotic – CVS – tachycardia, arrhythmia
 Contraindicated in Horses, swine (IM – cause death) and non-human primates

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  Not indicated in dairy cattle – present in milk up to 42 days
 Treatment of Actinobacillus pleuropneumoniae, Mycoplasma hypopneumoniae and
Pasteurella multocida in swine, ovine mastitis, prophylactic treatment of calves entering
feedlots
 Dose:
 Cattle: 10 mg/kg, SC, q72h
 Swine: 200 – 400 g/tonne
 Spiramycin
 Effective against Mycoplasma gallisepticum, added in drinking water – poultry
 Oleandomycin and Troleandomycin -Used as feed additive – growth promoter in food animals
MACROLIDE ANTIBIOTICS – NEWER
 Clarithromycin
 Semi-synthetic derivative of erythromycin
 Similar antimicrobial spectrum as erythromycin
 Effective against Helicobacter pylori
 Better absorbed, longer t1/2, increased intracellular uptake
 Active metabolite – prolong the action – PAE, excretion by bile and urine
 Drug of choice for Rhodococcus equi in foals in combination with rifampin
 In combination with H2 blocker and Bismuth for H. pylori treatment in human
 Dose:
 Dogs & Cats : 5-10 mg/kg, PO –BID,
 Foals : 7.5 mg/kg, PO BID in combination with rifampin (10 mg/kg)
 Roxithromycin
 Semi-synthetic, Longer acting and more stable than erythromycin
 Dose:Dogs: 15 mg/kg, PO – OD
AZALIDE ANTIBIOTICS
 Contains ‘N’ in macrolide ring, semi-synthetically derived to overcome the limitations of
erythromycin
 Gastric liability, short t1/2, and narrow ABspec
 Azithromycin
 More effective against Gr-ve bacteria, Haemophilus influenzae , intracellular org.
Chlamydia and Toxoplasma, Mycoplasma and Mycobacteria.
 Absorption is better on empty stomach
 Concentrates 100- 200 times in respiratory tract, leucocytes, macrophages
 T1/2 – horse -18h, dogs – 30 h, Cats – 35 h
 Eliminated in bile – unchanged form

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  Indicated for RTI, genital tract, skin and soft tissues
 Dose:
 Dogs & Cats : 5-10 mg/kg, PO –OD
 Foals :10 mg/kg, PO –OD – followed by alternate days
 Calves: 30 mg/kg, PO – OD for 7 days
 Tulathromycin
 Approved for Veterinary practice only
 Indicated in Pasteurella multocida, Manheimia haemolytica
 Long t1/2 = 96 h in cattle, withdrawal period for milk – 2 months
 Recommended for BRD and swine RD
 Dose:
 Cattle & Pigs – 2.5 mg/kg, single injection in neck
KETOLIDE ANTIBIOTICS
 Telithromycin
 Semi-synthetic ketolide derived from erythromycin
 Binds to both 50S and 30S ribosomes
 Acid stable, fairly rapidly absorbed, conc. in tissues much higher than blood
 Metabolised in liver and excreted in bile
 T1/2 – human -10h, used in the treatment of upper and lower RTI
 Adverse effects – GI disturbances, blurred vision, palpitation, rashes and damage to liver
LINCOSAMIDES
Introduction:
 Monoglycoside antibiotics containing amino acid like side chain.
 Resemble macrolides in several aspects
 Clindamycin, lincomycin and pirlimycin
Properties:
 Monobasic compounds derivative of amino acid and a sulphur containing octose
 More stable in salt form
 Basic compound, hence concentrated in acidic fluid
 First lincosamide, lincosamine isolated from Streptomyces lincolnensis
 Lincosamine is superseded by Clindamycin – improved antibacterial activity
Mechanism of Action
 Bacteriostatic
 Binds to 50S ribosome, premature dissociation of peptidyl-tRNA from ribosome
 More active at alkaline pH similar to macrolides

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  May be bactericidal at higher concentration for the susceptible organism
Antimicrobial spectrum:
 More active againt Gr +ve anaerobes than aerobes and Gr-ve
 Clindamycin is broad spectrum, effective against Gr-ve anaerobes
Bacterial Resistance
 Alteration of 50S ribosomal subunit
 Transfer of resistance through plasmid
 Show cross-resistance to other macrolides
Pharmacokinetics
 Oral F = 60-90%, IM absorption is rapid and good
 Widely distributed, bones and soft tissues, do not cross BBB but cross placenta
 Metabolised to active and inactive metabolites – excreted in bile and urine
 Excreted in milk – require prolonged withdrawal time
Adverse Effects:
 GI disturbances, pseudomembranous colitis in ruminants, horses (highly susceptible), rodents and
humans
 Due to suppression of gut microorganism and overgrowth of Clostridium difficile –
endotoxin – necrotising effect on colonic mucosa
 Induce ketosis in cattle
 Inhibit Neuromuscular transmission – skeletal muscle paralysis
 Hypersensitivity and pain at injection site
Contraindicated in
 ruminants and horses – fatal colitis
 Hypersensitive animals
 Liver disease animals, neonates – due to impaired biotransformation
 Lactating animals –accumulate in milk
Drug Interactions
 Increases the neuromuscular blocking effects of general anaesthetics and skeletal muscle relaxant
 Should not be used with chloramphenicol and macrolides – reduces the efficacy
 GI adsorbents (e.g. Kaolin and Pectin) reduce intestinal absorption of lincosamides
Lincomycin
 Naturally occurring antibiotic isolated from Streptomyces lincolnensis, 1962
 ABSpec:
 Gr+ve anaerobes and Mycoplasma, little effect on Gr-ve org.
 PK:

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  Oral F = 60%, presence of food delays absorption, Tmax 2-4 h after oral dosing
 IM – Tmax 1-2 h, widely distributed except CNS, crosses placenta and in milk
 Metabolised (~50%) and excreted as parent and metabolite in bile and urine
 T1/2 : 3-4 h in small animals
 Not recommended for ruminants (severe enteritis), horses, rabbits and rodents
 Clinical Use
 Swine dysentry, staphylococci, streptococci, Erysipelothrix and Mycoplasma
 Infections of bone, respiratory and skin
 Growth promoter in poultry
 Dose
 Dogs & Cats: 20 mg/kg, PO-BID, IM-OD
 Pigs: 10 mg/kg, IM – OD, or 110 g/tonne feed or 3.3 g/100 litres of water
 Birds : 100 -200 mg/l in drinking water
Clindamycin
 Semi-synthetic derivative of Lincomycin
 More potent, better absorbed and less toxic than lincomycin
 ABSpec: similar to lincomycin
 PK:
 Oral F = 90%, presence of food delays absorption, Tmax 1-2 h after oral dosing
 IM – Tmax 45-60min, widely distributed in skeletal and soft tissue except CNS
 Accumulates in neutrophils and macrophages – up to 50x of plasma conc., PPB – 90%
 Metabolised (80-90%) and excreted as parent and metabolite in bile and urine
 T1/2 : 3-5 h oral, 10-12h after SC
 Not recommended for ruminants, horses, rabbits and rodents
 Clinical Use
 Anaerobic infections, periodontal disease, osteomyelitis, dermatitis, and deep tissue
infections caused by Staphylococcus aureus
 Toxoplasmosis in dogs
 Dose
 Dogs & Cats: 5-10 mg/kg, PO-BID, 10 mg/kg, IM – BID
QUINOLONES
 Synthetic antibacterial having 4-quinolone structure
 Nalidixic acid – I member of the family introduced in 1964, usefulness limited to urinary and GIT
infections
 Congeners of Nalidixic acid, viz., oxolinic acid and rosoxacin in 1970s as first generation

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  II generation quinolones called fluoroquinolones in 1980s
Chemistry and SAR:
 Basic structure is 4-quinolone, with carboxylic acid at 3rd position
 Structure Activity Relationship (SAR)
 Carboxyl group at position 3 and ketone group at position 4 –essential for antibacterial
activity
 Substitution at postion 6 with fluorine called fluoroquinolines (FQ) – enhance the activity
aginst Gr-ve, Gr+ve, mycoplasma and chlamydia.
 Addition of piperazine ring at position 7 on FQ – increases the tissue and bacterial
penetration and improves spectrum including Pseudomonas. E.g. Cipro and Enrofloxacin
 Substitution of ‘O’ at position 8 – improves activity against Gr+ve and anaerobic org.
without affecting the bactericidal profile.
Properties:
 Amphoteric, pKa 6-6.5 for carboxyl group and 7.5 -8 for nitrogen of piperazine group – exists as
zwitter ion at physiological pH
 Highly lipophilic and poor water solubility at pH 6 and 8
 In concentrated acidic urine, some quinolones form needle-shaped crystals
 Quinolones are available in water soluble-salts or free bases as parenteral and oral formulations
Classification:
 First-generation quinolones
e.g. nalidixic acid,
oxolinic acid, flumequine, cinoxacin, pipemidic acid, piromidic acid and rosoxacin
 Second-generation quinolones
e.g. enrofloxacin,
difloxacin, ciprofloxacin, orbifloxacin, danofloxacin, marbofloxacin, norfloxacin, ofloxacin, pefloxacin,
sarafloxacin, lomefloxacin and enoxacin
 Third-generation quinolones
e.g. pradofloxacin,
ibafloxacin, levofloxacin, grepafloxacin, sparfloxacin, balofloxacin, pazufloxacin, temafloxacin and
tosufloxacin
 Fourth-generation quinolones
e.g. moxifloxacin,
gatifloxacin, besifloxacin, clinafloxacin, garenofloxacin, gemifloxacin, sitafloxacin, trovafloxacin and
prulifloxacin
Mechanism of Action:
 Bactericidal, inhibits the replication of bacterial DNA by interfering with action of DNA gyrase
(topoisomerase II)
 Quinolones enter the organism through porin channels – passive diffusion
Selectivity in the Mechanism of Action:

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  Bacterial DNA gyrase is susceptible to fluroquinolones at 0.1 to 10 g/ml
 Mammalian topoisomerase enzymes are different though they perform similar function as
bacterial DNA gyrase
 Affinity of the mammalian topoisomerase of quinolone is very low (0.001x) than the bacterial
DNA gyrase
Concentration below MIC range and very high conc are less active
 Biphasic pattern is due to inhibition of RNA and protein synthesis at high conc. –
reducing the bactericial activity
Antibacterial Spectrum
• I generation : Gr-ve, less systemic distribution
• II generation : Gr –ve (aerobic), atypical pathogens and limited Gr+ve activity
• III generation: expanded Gr –ve, atypical intracellular activity and improved Gr+ve coverage
• IV generation: similar to III gen, but gain anaerobic coverage
 Concentration dependent bactericidal effect (Tmax > MIC)
 Post-antibiotic effect (PAE) – do not overdose the patient
 Less active in anaerobic and acidic (e.g., abscesses) environments
Bacterial Resistance
• Staphylococcus aureus, Enterococci and Streptococcus pyogenes – exhibit resistance worldwide
• Chromosomal mutation - producing altered DNA gyrase
• Plasmid mediated resistance is rare – due to its mechanism of action
• Cross resistance among closely related FQ
• Ban on using the quinolones as food additives
Pharmacokinetics
• Absorption:
– F > 80% in monogastric species by oral route,
– Tmax: 0.5 – 2h, food delays rate of absorption, IM or SC – rapid absorption
– quinolones chelates Al, Mg, Ca, Fe, Zn
Distribution
– Wide distribution incl. CNS, bone and prostate.
– Tissue penetration is higher than in plasma, stool, bile, prostate or lung tissue
– Accumulate in macrophage and PMN leucocytes – intracellular infections
– PPB varies from ~10% (norfloxacin) to > 90% for nalidixic acid
Metabolism
– Varies – i.e. not metabolised (ofloxacin), partially metabolised (ciprofloxacin) and
completely metabolised (pefloxacin)
– Metabolic activation – Enrofloxacin to Ciprofloxacin

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 Excretion
– Major route – renal, some FQ – both renal and hepatic clearance, also present in milk
– Alkaline urine- reabsorption – increased t1/2
– T1/2 – 3 to 6 h with PAE, - dosing interval – 12 – 24h
Adverse Effects
 Hypersensitivity
 Lower threshold to seizure – chance of convulsions at high dose
 Crystalluria in dogs due to their low solubility in acidic urine
 Cartilage deformities, chondro destruction and joint growth disorders – young dogs and foals
 Due to chelation of Mg++ in cartilage
 Haemolytic anaemia
 Blindness – retinotoxicity in cats at high doses
 Foetal toxicity
 QTc interval prolongation and cardiac arrhythmia in humans
Contraindications
 Not recommended in growing dogs under 12 (small breed) and 18 (large breeds) months of age
 Avoid in pregnant and animals with seizure disorders
 Due to the crystalluria property, animal should not be dehydrated
Drug Interactions
 As a potent chelator of divalent and trivalent cations – should not be administered with antacids,
multimineral supplements – up to 4 hrs
 Probenicid block tubular secretion of quinolones
 FQ inhibit the biotransformation of theophylline
 FQ + NSAID – lowers the seizure threshold
 FQ + Corticosteroid – tendon rupture
 Synergistic effect with beta-lactam, aminoglycosides, clindamycin or metronidazole
First Generation Quinolones
Nalidixic Acid:
 Non-fluorinated
 Used primarily as a urinary antiseptic
 Active against gram-negative bacteria esp. E. coli, Proteus, Klebsiella, Enterobacter and Shigella
 Oral F>90%, PPB>95%, metabolized in liver, excreted in urine (20-50x than the plasma conc.)
 Photosensitivity, urticaria, CNS effect, therapy longer than 2 weeks – affect liver function
 Dose for urinary tract infection
 Dogs & cats: 3 mg/kg, PO, 4 times daily

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Oxolinic acid
 Used in fish infections
Second Generation Quinolones
Enrofloxacin:
 Exclusively for use in animals
 ABSpec: Gr+ve, Gr-ve, including Pseudomonas, Brucella, Chlamydia and Mycobacterium
species
 Long ‘concentration dependent’ post-antibiotic effect of 5 to 8 hours
 PK:
 Oral F>80% in dogs, 60% in adult horses and 40% in foals, Tmax – 1h
 Widely distributed including bone, synovial fluid, prostate, aqueous humor and pleural
fluid, accumulated in WBCs.
 Eliminated in urine as metabolised to ciprofloxacin (25%) and unchanged (75%)
 T1/2 in 4-5 h in dogs, 6 h in cats
 Clinical uses:
 infections of skin, urinary tract and soft tissues in dogs and cats
 Respiratory disease in cattle, enzootic pneumonia in pigs
 Recommended in infections in exotic species
 Dose: 2.5 to 5 mg/kg PO- OD or BID to most of the species
Difloxacin:
 Its efficacy is not as good as enrofloxacin
 PK:
 Well absorbed from GIT, Tmax – 3h, PPB 20-50%, hepatic metabolism in to active
metabolite, Sarafloxacin, excreted mainly in feces, enterohepatic cycling, t1/2 -9h
 Dose: 5 to 10 mg/kg,PO –OD in dogs, horses and poultry
Ciprofloxacin:
 Most widely used FQ in human medicine
 Oral F -40% in dogs, 50% in calves, 2-12% in ponies, PPB – 25% (pigs) to 70% (calves), t 1/2 – 2-
5h in dogs and 2.5 h in pigs and cattle
 Clinical use: bone and joint, skin and soft tissues, endocarditis, gastroenteritis, UTI, Prostatitis,
cellulitis, cystitis and anthrax
 Dose: 5 – 15 mg/kg, PO, bid
Orbifloxacin:
 Activity similar to enrofloxacin
 PK:
 PPB 8% in dogs, 50% of drug excreted unchanged in urine, t1/2 -6h in dogs & cats

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  Clinical use: skin, soft tissues and UTI
 Dose: 2.5 to 7.5 mg/kg, PO –OD in dogs & cats, horses, sheep and swine
Danofloxacin:
 Used for the respiratory infections in chickens, cattle and pigs
 Dose: 1.25 mg/kg, IV, OD
Marbofloxacin:
 Long t1/2 – 10 h, used for the infections of skin, respiratory system and mammary gland
 Dose:2-5 mg/kg, PO -OD
Norfloxacin:
 UTI, Genital and GIT infections
 Dose: 20 mg/kg,PO –BID in dogs & cats
Ofloxacin:
 Mixture of 50% levofloxacin and 50% dextrofloxacin
 Lipid soluble, no food interaction
Pefloxacin:
 Methyl derivative of norfloxacin
 Lipid soluble, complete absorption orally, extensively metabolised
 Used in human medicine
Third Generation Quinolones
Pradofloxacin:
 Developed exclusively for use in veterinary medicine
 Enhanced activity against Gr+ve and anaerobes
 Recommended in dogs & cats for the treatment of
 Respiratory tract, urinary tract, wound, abscesses, periodontal therapy
Ibafloxacin
 Developed exclusively for veterinary use
 For the treatment of infections of the skin and soft tissues, urinary tract and respiratory tract,
superficial or deep pyoderma
 Adverse effects – transient mild diarrhoea, vomiting, lethargy and anorexia
 Dose: Dogs & cats – 2-5 mg/kg, PO –OD
Levofloxacin
 Laevo-isomer of ofloxacin, improved activity against Strep. pneumonia, other Gr+ve and Gr-ve
org.
 Its use in RTI, UTI, Skin and Soft tissues, anthrax, endocarditis, meningitis, etc
 Its clinical use in animals is limited

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  IV generation FQ act on both DNA gyrase and Topoisomerase IV
 Slows the development of resistance
 Sparfloxacin, trovafloxacin – discontinued from clinical use due to phototoxicity, QTc
prolongation, thrombocytopenia, nephritis and hepatotoxicity
Moxifloxacin
 ABSpec – Gr+ve, Gr-ve and anaerobes
 Potent effect against Mycobacterium tuberculosis
 Drug of last resort, however not good for UTI
 Dose: Horse– 5 mg/kg, PO –OD
Gatifloxacin
 Systemic use is banned due to increased incidence of serious hyperglycemia
 Topical formulation – ophthalmic use – considered safe
OTHER ANTIBACERIALS
I. Natural and Semi-synthetic antibacterials
1. Polypeptide antibiotics: Polymyxin B and colistin, Bacitracins, thiostrepton, gramicidin
and tyrothricin
2. Glycopeptide antibiotics: Vancomycin, Teicoplanin, Telavancin and Dalbavancin
3. Aminocyclitol antibiotics: Spectinomycin and Apramycin
4. Rifamycins: Rifamycin SV, rifampicin, rifabutine, rifaximin and rifapentine
5. Pleuromutilins : Tiamulin, Valnemulin and Retapamulin
6. Streptogramins: Stretogramin, Virginiamycin, Pristinamycin, Quinupristin
7. Amonocoumarins: Novobiocin, Coumermycin and Clorobiocin
8. Miscellaneous Antibiotics: Fusidic acid, Mupirocin, Daptomycin, Fosfomycin and
Cycloserine
. Synthetic antibacterials
1. Nitrofurans : nitrofurantoin, furazolidone, nitrofurazone, nifuraldezone, furaltadone,
nifuroxime and nifurprazine
2. Nitroimidazoles: metronidazole and dimetridazole
3. Oxazolidone: linezolid, torezolid and eperezolid
4. Arsenicals: arsanilic acid and sodium arsanilate
5. Hydroxyquinolines: Clioquinol and diiodohydroxyquin
Polypeptide Antibiotics
I. Polymyxins – bactericidal
 Polymyxins – A, B, C, D, E and M ; polymyxin B and E (colistin) – useful
 Polymyxin B
 Obtained from Bacillus polymyxa

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  Used only for topical and oral administration
 Parenteral administration – leads to toxicity
 MoA: detergent like action on bacterial cell membrane – positively charged
cyclic peptide interacts with negatively charged LPS of Gr-ve org.
 Active against gram negative bacteria
 Activity reduced by serum, tissue fluids, soap, Mg, Co, Fe and Mn
 Development of resistance is slow and is chromosome dependent
 PK: not absorbed on topical or from GIT, Parenteral - low blood level,
metabolised and excreted in urine, t1/2 – 3-4 h
 Adverse effects: on parenteral – nephrotoxicity and neurotoxicity
 Clinical use: Gr-ve infections of skin, eye and ear(otitis externa), bovine mastitis
caused Pseudomonas and Klebsiella
 Dose : All species – 20000Units/kg, PO –BID, cattle -50,000 – 100,000 Units –
intramammary and intrauterine
 10,000 Units of polymyxin B = 1 mg of pure antibiotic
II. Polymyxins – bactericidal
 Polymyxins – E (colistin)
 Oral use –colistin sulphate, Parenteral use – colistin sodium methanesulphonate
 ABSpec similar to Polymyxin B, more potent against Pseudomonas, Shigella and
Salmonella
 Adverse effect is similar to Polymyxin B, in addition – periperal neuritis, nystagmus,
transient deafness and leucopenia
Bacitracin – bactericidal
 Isolated from Bacillus subtilis, mixture of 5-10 separate
components, of which
Bacitracin A is most active and major component
 MoA: inhibit the cell wall synthesis – by inhibiting the peptioglycan synthesis
 Zn enhances the effect of bacitracin
 ABSpec: narrow, Gr+ve org, effective against penicillinase producing Staphylcoccus
aureus
 Antibacterial activity is not affected by blood or tissue debris
 Resistance is rare
 Not absorbed from GIT
 Adverse effect – Nephrotoxicity on parenteral administration
 Clinical use – skin, eye, ear infections
 In combination with polymyxin – widen the spectrum of activity
 As zinc or magnesium salt – swine and poultry ration – growth promoter

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  Alternative treatment to vancomycin in the treatment of pseudomembranous
colitis caused by Clostridium difficile endotoxin
Thiostrepton – cyclic oligopeptide antibiotic containing sulphur
 Isolated from Streptomyces aureus
 Stable in gastric and intestinal juices and urine
 ABSpec: effective against Gr+ve org, few Gr-ve org.
 Not absorbed from GIT and primarily used for topical infections
 Used in ointments in combination with nystatin and neomycin and/or glucocorticoids
 Used in mastitis caused by Gr-ve org.
Gramicidin – heterogenous mixture of antibiotic - bactericidal
 Isolated from Bacillus brevis
 MoA: increase the permeability of Na+ & K+ ion by acting as channel
 ABSpec: effective against Gr+ve org except for Gr+ve bacilli, few Gr-ve org such as
Neisseria
 Toxic internally – cause hemolysis
 Only used as topical antibiotic
Tyrothricin – cyclic polypeptide antibiotic
 Mixture of tyrocidin and gramicidin obtained from Bacillus brevis
 Act against Gr+ve, and few gr-ve
 MoA: leakage of ions and uncoupler of oxidative phosphorylation
 Not absorbed orally, only topical use
Glycopeptide Antibiotics
Glycosylated cyclic or polycyclic non-ribosomal peptides
 MoA: inhibits cell wall synthesis by inhibiting the peptidoglycan synthesis
 Vancomycin, Teicoplanin, Telavancin, Dalbavancin, etc.
Vancomycin
 Obtained from Streptococcus orientalis, freely soluble in water
 MoA: inhibit the formation of peptidoglycan strands in the cell wall
 ABSpec: Gr+ve org – Staph, Strep, Enterococcus, Clostri, Coryne sps.
 PK: not absorbed orally, IV admin – widely distributed except CNS, excreted unchanged
in urine, t1/2 – 2-3 hours
 Adverse effects: parenteral – ototoxicity and nephrotoxicity, rapid IV injection cause –
intense flushing (Red man syndrome) in human
 Clinical use: reserve antibiotic for MRSA, oral – to treat antibiotic induced enterocolitis
esp. by Clostridium difficile
 Dose: Dogs -3 mg/kg, PO –BID or TID, 10 – 20 mg/kg IV, TID-QID

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Teicoplanin
 Isolated from Actinoplanes teichomyceticus
 Mixture of 5 major (A2-1 to 5) and 4 minor (Rs-1 to 4)
 MoA is similar to vancomycin but less toxic than vancomycin
 Useful against Vancomycin resistant org., MRSA, penicilllin-resistant enterococcal inf.
 Substitute for penicillin in allergic patients
 Oral – for the treatment of pseudomembranous colitis and Clostridium diffficile
associated diarrhoea
Telavancin and Dalbavancin
 Bactericial lipoglycopeptide – semi-synthetically derived from vancomycin
 Used in MRSA or other gr+ve org.
 Adverse effects – similar to vancomycin - nephrotoxicity
 Bacteriostatic, chemically related to aminoglycosides but do not contain amino sugars but the
amino group attached to cyclitol ring
 Spectinomycin and Apramycin
Spectinomycin
 Obtained from Streptomyces spectabilis
 MoA – binds to 30S and inhibit protein synthesis, does not cause misreading mRNA –
bacteriostatic
 Resistance – mutation in ribosomal subunits, inactivating enzyme
 PK: oral F <10%, IM or SC – widely distributed in ECF, unmetabolised, excreted unchanged in
urine
 Adverse effects: No nephro and ototoxicity, but produce NM block at high dose
 DI: concurrent use with chloramphenicol or tetracyclines – antagonistic effect
 Clinical use : Enteric and respiratory infections
 Dose:
 Dogs – 20 mg/kg, PO-BID, 5-10 mg/kg, IM-BID
 Cattle- 8-12 mg/kg, IM- TID, Calves- 20-30 mg/kg, IM –OD
 Horse – 20 mg/kg, IM- TID; Pigs – 10 mg/kg, PO-BID
Apramycin or Nebramycin II
 Obtained from Streptomyces tenebrasius
 Bactericidal against gram negative bacteria
 PK: oral F <10%, parenteral – 90%, t1/2 – 2 -4 hours
 Clinical use : colibacillosis and salmonellosis in calves and pigs
 Dose:
 Calves- 20-40 mg/kg, PO –OD by addition to milk, milk replacer or drinking water

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  Lambs – 10 mg/kg, PO –OD
 Pigs – 5 g/100litres of drinking water
 Piglets – 10 -20 mg/kg, PO – OD
 Poultry – 25 – 50 g/100 litres drinking water
Rifamycins
• Macrocyclic antibiotic produced by Streptomyces mediterranei
• Effective against Gr+ve and very effective against Mycobacterium – used to treat TB, leprosy,
mycobacterium avian complex (MAC) in human
• Also posses antiviral activity
• Natural rifamycins are B, O, S, SV and X
• Semi-synthetic – rifampicin, rifabutin, rifaximin and rifapentine
Rifamycin SV
 Seldom used as an intramammary and parenteral antibiotic
 Excreted in bile
 Parenteral administration – used in cholecystitis
Rifampicin
 Semi-synthetic derivative of Rifamycin B
 Zwitter ion, Pkas -1.9 and 7.9, lipophilic, intensely red solid in colour
 MoA: inhibit DNA-dependent RNA polymerase - bactericidal
 Halts initiation of mRNA transcription
 Rifampicin cannot stop elongation of mRNA once polymerase binds to DNA
 Inhibits only prokaryotic (gram +ve and mycobacterium)org
 High concentration – inhibits viral DNA-dependent RNA polymerase and reverse
transcriptase
 Antimicrobial spectrum
 Gr+ve and Mycobacterium, Clostridium and Bacteroides, Brucella (gr-ve)
 Some activity against yeast and fungi when combined with amphotericin B
 Bacterial resistance
 Resistance develops quickly if used as sole antibiotic
 Should be used in combination with erythromycin, -lactam and selected
aminoglycosides
 Alteration in DNA-dependent RNA polymerase (target modification)
 Pharmacokinetics
 Oral F – 40-70%, Tmax – 2-4 h PO, presence of food delays Tmax, IM inj- absorption
rapid
 Rapid distributed incl. CSF, lipophilic, penetrates abscesses and caseous, PPB – 75-80%

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  Metabolised to deacetylrifampicin – active, unmetabolised drug –EHC
 Excreted in bile, red colour of the drug impart red-orange colour to excreta and saliva,
T1/2 – 8h dog, 6.8h horse, 3.5h sheep.
 Half-life shortens by 40% during first 2 weeks of treatment – inducer of microsomal
enzymes
 Adverse effects
 Hepatotoxicity, IV in horse – CNS depression, sweating, hemolysis and anorexia
 Partial , reversible immunosuppression, GI disturbances, hypersensitivity
 Contraindicated in hyper sensitive patients, pre-existing hepatic dysfunction and should be
avoided in pregnant animals
 Drug Interactions
 CYP2C9 and CYP3A4 inducer – metabolise many drugs
 Synergism between rifampicin and amphotericin B – fungal infection, due to better
penetration of rifampicin across the cell wall
 Clinical use
 In animals: used in combination with erythromycin for the treatment of pneumonic
infections in foals caused by Rhodococcus equi
 Used in combination with amphotericin B – treatment of CNS fungal infections like
asperigillosis or histoplamosis
 In human: treatment of tuberculosis
 Dose
 Foals : 5 mg/kg, PO –BID with erythromycin 25 mg/kg PO-TID
 Dogs & Cats, Birds : 10-20 mg/kg, PO –OD or BID
 For CNS fungal infections; dogs & cats- 10-20 mg/kg PO-TID in combination with
amphotericin B and flucytosine.
Rifabutin
 Semi-synthetic derivative of rifamycin S
 MoA as rifampicin
 Effective against Gr+ve and few Gr-ve org
 Used in the treatment of TB particularly in HIV patients due to less interaction with
antiretroviral org.
Rifaximin
 Semi-synthetic rifamycin, poorly absorbed from GIT
 Treatment of traveler’s diarrhoea, hepatic encephalopathy (orphan drug)
Pleuromutilins
Tiamulin
 Semi-synthetic derivative of pleuromutilin obtained from Pleurotus mutilis

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  Available as hydrogen fumarate salt for oral use, oily inj. 250 mg/ml
 MoA: inhibit protein synthesis by binding to 50S ribosome – break in peptide chain –
bacteriostatic, at higher conc. Bactericidal
 Broad spectrum; Gr+ve, mycoplasma, anaerobes incl. Treponema hyodysenteriae, Gr-ve
org such as Haemophilus, Bordetella, E. coli, Pasteurella and Actinobacillus
 Growth promoting effect
 Resistance by modification of ribosome (target modification)
 PK: Oral F>90%, Tmax: 2-4 h, high conc. found in lungs, extensively metabolised to 20
metabolites – excreted in bile (major) and urine
 Adverse effects:
 Pigs – GI disturbances and CNS depression
 Cause growth retardation when given with ionophores – monensin and
salinomycin
 Inhalation cause nose, throat, respiratory tract irritation
 Contraindicated in animal having access to feed mixed with ionophores – monensin and
salinomycin
 DI occurs by interference of tiamulin in the metabolisms of polyether
ionophores- toxic
 Clinical use in pigs
 Treatment of enzootic pneumonia
 Dose: 15 mg/kg, IM – OD for 3 days, 30-40 g/tonne feed, - 2 months
(prophylaxis)
 Swine dysentry
 Dose: 8.8 mg/kg, PO (60 g /litre drinking water) for 3-5 days
 5 mg/kg, PO (or 100 g/ tonne feed) for 7-10 days)
 Mycoplasmal arthritis
 Tiamulin is used as feed additive for growth promoting properties in swine
Valnemulin
 For animal use only
 Treatment of swine dysentery, ileitis, colitis, pneumonia
 Treatment of Mycoplasma bovis in the lungs of calves
 Adverse effect- perianal erythema, concurrent administration with ionophore antibiotics –
severe growth depression, ataxia, paralysis, death
 Dose:
 Swine dysentery – 3-4 mg/kg daily or 75 g/tonne in feed
 Swine enzootic pneumonia – 10-12 mg/kg b.wt. or 200 g/tonne in feed
Ritapamulin

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  Effective against MRSA
 Topical use
Streptogramins
Streptogramin
 Isolated from Streptomyces virginae
 Two distinct groups – A and B (individually bacteriostatic, combination – bactericidal)
 MoA:
 Streptogramin A binds to Peptidyl transferase domain of 50S ribosome
 Configuration change results in increase the binding activity of Streptogramin B
to 100 fold
 Both streptogramin A and B bind to ribosome – form a stable ternary complex –
inhibition of protein synthesis and bactericidal effect
 A and B in 7:3 ratio
 IV – to treat vancomycin resistant Enterococcus faecium
 Rarely used due to the availability of linezolid
Virginiamycin
 Isolated from Streptomyces virginae
 Virginiamycin S and M in the ratio of 1:4 (individually bacteriostatic, combination –
bactericidal)
 Growth promoter and production enhancer in swine and poultry
Pristinamycin
 Isolated form Streptomyces pristinaespiralism
 Pristinamycine 1A and IIA (individually bacteriostatic, combination – bactericidal)
 Treatment of MRSA and erythromycin resistant Streptococci and Staphylococci
Quinupristin-Dalfopristin
 Derived from Pristinamycin 1A and IIA respectively (30% +70%)
 Treatment of Gr+ve, MRSA, vancomycin resistant E. faecalis
Aminocoumarins
 Inhibit DNA gyrase – novobiocin, coumermycin, clorobiocin
 Novobiocin
 Isolated from Streptomyces niveus and S. spheroides
 Compete with ATP for binding to the B subunit of bacterial DNA gyrase – inhibit the
ATP dependent DNA supercoiling catalysed by gyrase
 Affinity for gyrase is higher than the fluroquinolones
 Interferes with bacterial cell wall and cell membrane synthesis
 ABSpec – Gr+ve, Gr-ve (Haemophilus, Proteus, Neisseria and Brucella)

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  Novobiocin
 Novobiocin is combined with tetracycline – broaden spectrum, decrease resistance
 PK: orally absorbed, Tmax 1-4h, PPB – 90%, mainly excreted in bile & feces
 Adverse effects: GI disturbances, blood dyscrasias
 Clinical use: used in combination with Penicillin G – mastitis, in combination with
tetracycline for oral use in dogs, feed additive in poultry
 Dose: dogs – 10 -20 mg/kg, PO – BID-TID
Miscellaneous Antibiotics
 Fusidic acid
 Narrow spectrum, steroidal antibiotic isolated from Fusidium coccineum
 Inhibit protein synthesis by preventing binding of aminoacyl t-RNA to ribosome
 Effective against gr+ve, MRSA
 Fusidic acid + quinolones = antagonistic
 Fusidic acid +rifampicin = additive or synergistic
 Topical – cutaneous infection, eye drops
 Mupirocin (Pseudomonic acid)
 Obtained from Pseudomonas fluorescens.
 Blocks isoleucyl synthetase that adds isoleucine to peptide chain
 Gr +ve and Mycoplasma
 Bacteriostatic at low conc. and bactericidal at high conc.
 Topical use in dogs and cats – skin and soft tissue infections
 Daptomycin
 Novel lipopeptide obtained from Streptomyces roseosporus
 Bind to membrane cause rapid depolarisation – loss of membrane potential leading to
inhibition of protein, DNA and RNA synthesis - bactericidal
 Effective against gr+ve only
 Topical – cutaneous infection
 Fosfomycin
 Broad spectrum, obtained from Streptomyces.
 Inhibit cell wall synthesis
 Treatment of urinary tract infections in human, where it is usually administered as a
single oral megadose
Synthetic Antibacterials
 Nitrofurans
 Furazolidone, furaltadone, nifuraldezone and nifurprazine
 MoA: Bactericidal

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  Prodrug – reduced by bacterial nitrofuran reductase – reactive intermediates
 Inhibit carbohydrate metabolism – by blocking oxidative
decarboxylation of pyruvate to acetyl CoA
 Inhibit mRNA translation, ribosomal protein, DNA
 More active in acidic environment
 AMSpec: Gr-ve (mainly) and Gr+ve, coccidia, trichomonads, amoeba and giardia
 Resistance: limited and develops slowly
 Chromosomal mutation
 Cross resistance among nitrofurans but not with other antibacterial agent
 PK: vary with individual nitrofurans
 No absorption from GIT or absorbed drug is eliminated rapidly – no systemic
conc. except urine
 Feed promotes absorption, acidic urine-reabsorption in the renal tubule
 Adverse Effects:
 GI disturbances,
 CNS signs – excitation, tremors, convulsions and peripheral neuritis
 Depression of spermatogenesis
 Carcinogenic in laboratory animals
 Drug interactions:
 Nitrofurans inhibit MAO – should not be used with sympathomimetics
 Alcohol with nitrofurans – disulfiram – like reaction
 Clinical use
 Topical for cutaneous infections
 Urinary antiseptic
 PK: rapidly absorbed from GIT and rapidly excreted in urine within 30 min
 Macrocrystalline form – slow absorption
 Contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency – risk of
extravascular hemolysis
 Dogs & Cats: 4 mg/kg, PO – TID
 Horse: 2.5 -4.5 mg/kg, PO – TID
 Nitrofurans - Furazolidone
 Used for enteric infections
 Clostridium, Salmonella, Shigella, Staphylococcus, Streptococcus, E.coli
 Giardia, Trichomonas, Coccidia and Histomonas
 Poorly absorbed, distributed to CSF
 Inhibits MAO, should not be administered with antidepressants

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  For enteric infections
 Dogs : 2.2 mg/kg, PO –TID for 7 days
 Cats and Horse: 4 mg/kg, PO – BID or TID, Birds – 100 – 200 mg/l drinking
water
 For coccidiosis
 Dogs & cats: 8-20 mg/kg PO, TID for 7 days
 Nitrofurans - Nitrofurazone
 Topical and enteric infections due to poor oral absorption
 For topical infections
 All species : 0.2% in ointments, cream, solutions and wound dressings
 For enteric infections
 Dogs & Cats: 22 mg/kg, PO – BID
 Piglets: 100 mg (total) PO – OD, Pigs: 50 g/tonne feed for 7 days
Nifuraldezone
 Bacterial enteritis in calves
Furaltadone
 Enteric infections and mastitis
 Absorbed orally – produce systemic adverse effects
 Nitroimidazoles – antiprotozoal and antibacterial
 Metronidazole:
 Treatment of trichomoniasis, giardiasis and amoebiasis
 Bactericidal – gr+ve, gr-ve anaerobic, no activity against aerobic
 MoA – disrupt DNA synthesis (cytotoxic metabolite requires low redox potential
– available in anaerobic conditions)
 Anaerobic infections – pelvic, genitourinary tract, RTI, gingivitis, brain
abscesses in dogs, cats and horses
 Used in the treatment of Pseudomembranous colitis due to Clostridium
 Peptic ulcer due to Helicobacter pylori
 Oxazolidones
 Most important class for the treatment of MRSA
 Linezolid. Torezolid, eperezolid, posizolid, radezolid (under clinical trials)
 Linezolid:
 Only marketed oxazolidones
 MoA: protein synthesis inhibitor – prevents the formation of initiation complex
by binding to 23S portion of the 50S subunit
 Cross resistance between other protein inhibitors – nonexistent

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  ABSpec: gr+ve incl. vancomycin resistant streptococci, MRSA. Listeria,
corynebacterium spp.
 Bacteriostatic but with PAE for 1-4 h
 Resistance by mutation in 23S rRNA, efflux pump
 PK: Oral F ~100%, Tmax 1-2h, distribution - low resp. tract,
 Slow diffusion –BBB, metabolised in liver by non-CYP,
 Excretion by non-renal (65%) and renal, t1/2 – 4-5h
 Linezolid: relatively safe drug
 Adverse effects: GI disturbances, cause Clostridium difficile associated diarrhoea
(CDAD) and pseudomembranous colitis, bone marrow supression
 Drug Interaction: weak monoamine oxidase inhibitor – should not be used with
sympathomimetic and serotonergic drugs
 Clinical uses: severe infections by Gr+ve – skin and soft tissue and pneumonia
 “Reserve antibacterial”
 High cost limits use in veterinary practice
 Dogs & Cats: 10mg/kg, PO or IV, BID or TID depending on the severity of infection
 Arsenicals
 Organic salts of arsenic – arsanilic acid and sodium arsanilate – antibacterial activity –
used as feed additives
 Arsanilic acid:
 Mild to moderate antibacterial activity
 Slightly soluble in cold water and alcohol, soluble in hot water
 Treatment for coliform septicaemia in poultry and pigs
 Added to feed as growth promoter
 High dose - arsenic poisoning
 For enteric infections
 Pigs & poultry :250 mg/kg feed for up to 2-3 weeks and 5 to6 days
respectively
 As growth promoter : pigs -100 mg/kg feed
 Hydroxyquinolines
 Antibacterial, antifungal and antiprotozoal activity
 To treat intestinal infections caused by bacteria and protozoa
 Topical for cutaneous infections caused by bacteria and fungi
 Example: Clioquinol, diiodohydroxyquin, broxyquinoline and hydroxyquinoline
URINARY ANTISEPTICS
 Antibacterial concentration achieved in urinary tract, bladder or renal pelvis infections

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 Nalidixic acid, Nitrofurantoin and Methenamine
 Methenamine:
 Other uses – in adhesive and sealing compounds, preservation of hides, corrosion
inhibitors for steel, stabiliser for lubricating and insulating oils
 Medicinal use – methenamine maleate, methenamine hippurate
 MoA : release formaldehyde gas in water
C6H12N4 + 6H2O + 4H+ -> 6HCHO + 4NH4+
 Degree of hydrolysis and its antibacterial efficacy – pH dependent
 At pH7.4, no decomposition occurs
 At pH 6 about 6% formaldehyde is released
 At pH 5 about 20% formaldehyde is released
 Hydrolysis is slow, requires 3 h to reach 90% completion
 Addition of mandelic acid or hippuric acid helps to acidify the urine
 Methenamine has no antimicrobial activity in blood and tissues
 Methenamine:
 ABSpec: bacteriostatic but bactericidal in acidic urine, gr+ve, gr-ve and fungal infections
 Resistance: urea splitting org. - Proteus spp. may inhibit the release of formaldehyde in
acidic urine
 PK: rapidly absorbed oral, 10-30 % degraded in stomach – hence enteric coated tablet
 Excreted unchanged in urine, Peak formaldehyde conc. 2 h after oral dosing, 3-8
h after enteric coated tablets
 Adverse events :
 gastritis due to release of HCHO in stomach
 Painful and frequent micturition, albuminuria, haematuria, cystitis – high dose
 Carcinogenic effect
 It is not a primary agent for acute urinary tract infections
 Dose:
 Methenamine hippurate :Dogs: 500 mg (total), PO, BID, Cats: 250 mg (total),
PO-BID
 Methenamine mandelate: Dogs: 10 -20 mg/kg,PO –OD or BID

CHAPTER-24: ANTI FUNGAL AGENTS – INTRODUCTION

 Fungi are eukaryotes with membrane bound organelles and have common cellular characteristics
with mammalian cell. Hence it is difficult to target the fungus specifically without host toxicity.
 In vitro antifungal susceptibility testing differ from that of bacteria because fungi may be in the
form of yeast or filamentous fungi
 Yeast – Candida, Cryptococcus neoformans, Malassazia
 Filaments – Aspergillus, Fusarium, Rhizopus, Microsporum, Trichophyton

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  Mycelial form – Sporothrix
 Dimorphic fungi – Blastomyces, Coccidioides, Histoplasma

Drug resistance

 Drug resistance- Inherent or Acquired – Mutation

 Decrease the uptake of drug, Efflux, reduced affinity of target enzymes
 Combination - Reduce the resistance

Topical and systemic fungal infections

 Topical infections caused by a variety of fungi

 Dermatophytes establish on the skin
 The yeast or opportunistic pathogens also invade the external auditory canal and cornea
 Systemic infections are life threatening like a)Aspergillosis – Brooder pneumonia and mycotic
abortion b)Blastomycosis – Lungs c)Histoplasmosis – Invade macrophages of host and
disseminate to lungs d)Cryptococcosis – Granuloma of alveoli and urinary tract

ANTIFUNGAL CHEMOTHERAPY

Sites of action of antifungal drugs

 Cell wall - Ecchinocandins - Caspofungin

 Cell membrane
o Polyenes - Amphotericin B; Nystatin; Natamycin
o Azoles - Imidazole - Ketoconazole, Miconazole, Enilconazole, clotrimazole, Triazole -
Fluconazole, Itraconazole, Voriconazole
o Allylamines - Terbinafine , Naftidine
 Nucleic acid synthesis - 5 - Flucytosine
 Others -Griseofulvin ->inhibit mitosis ->interfere with polymerisation of microtubule and
disorganise the spindle formation

ANTIFUNGAL AGENTS

 Locally active antifungal drugs are used to treat topical infections.

 The antifungal agents are

Iodine preparations Tincture iodine, Potassium iodide

(Iodophores)
Copper preparations CuSO4, Cuprimycin
Phenols Thymol, Hexachlorphene
Fatty acids and salts Propionates, Undecylenates
Organic acids Benzoic acid, Salicylic acid
Dyes Gentian violet, Carbofuschin

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 Hydroxyquinolones Iodochlorhydroxyquin, Nitrofurans
Imidazole Miconazole, Clotrimazole,
Thiabendazole
Polyene antibiotics Amphotericin B, Nystatin, Natamycin
Miscellaneous Tolnaftate, Haloprogin, Dichlorofen and
Monosulfiram

Benzoic acid

 Bacterostatic and fungistatic organic acid used as food preservative

 This is effective against trichophyton infection in cattle and man.

Salicylic acid

 Antipyretic agent
 It is having Keratolytic and some fungistatic effect
 It softens the crust and acts on the organism thus exposed
 It is suitable for topical ringworm infection. Used as Whitfield’s ointment.

Undecylenic acid

 Topical fungistatic effective against Microsporum sp.

 At higher concentration it is an irritant. Hence used in combination with zinc or copper salts to
minimise the irritation.
 Copper is also an antifungal agent
 It is ringworm fungicidal, because of its astringent and caustic nature.

CELL WALL SYNTHESIS INHIBITOR

 Cell wall of fungi is made up of glucosamine polymer and chitin ,a layer of manno protein
(heavily glycosylated at the outside), a layer of b -1, 3-glucan and b -1, 6 - glucan and a layer of
chitin
 Echinocandins are novel lipopeptide antifungal agents which are b -(1,3)- glucan synthase
inhibitor, preventing formation of b -(1,3)-glucan (polypeptide) in the cell wall.
o Caspofungin -> first commercially available.
o Micafungin
o Anidulafungin

Spectrum

 Active against candida including isolates resistant to azoles and amphotericin B.

o Highly active against Aspergillus sp.
o Active against Pneumocystis carnie
o Limited -> C.neoformens, B.dermatitidis, Fusarium np. C.immitis

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PK

 Only IV-Caspofungin
o Elimination ->Urine and faeces as metabolites

Toxicity

 Phlebitis at infusion site. Fever, nausea well tolerated

Clinical application

 Invasive aspergillosis unresponsive to others.

 Candidiasis ->Similar efficacy like amphotericin B or fluconazole.

CELL MEMBRANE SYNTHESIS

 Cell membrane of fungi contain ergosterol instead of cholesterol in mammalian cell

 Drugs that interfere with ergosterol biosynthesis -> Allylamines, Azoles
 Drugs that bind to ergosterol -> Polyene antibiotics

POLYENE ANTIBIOTICS

Amphotericin B

 Heptane product of Streptomyces nodosus

Chemistry

 It is an amphoteric polyene macrolide, poorly soluble in water and unstable at 37 ° C.

 Antifungal activity are maximal between pH 6.0 and 7.5 and decrease at low pH.

I/V

 Amphotericin B sodium deoxycholate compound with phosphate buffer is more water soluble.
 Lipid formulations or liposomal drugs are less toxic [costly].

MOA

 Binds to ergosterol, the principal sterol of fungal cell membrane , cause leakage of cell content.
H+ influx and K+ efflux -> internal acidification ->fungicidal effect.

Spectrum

 Broad spectrum antifungal antibiotic – fungicidal. Active against blastomycosis, Histoplasmosis,

coccidiomycosis, candidiasis, cryptococcosis and sporotrichosis.
 Not effective against ringworm

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PK

 It is not absorbed on oral administration . The half life is more than 20hrs; binds to plasma protein
and cellular lipoprotein and released slowly from these sites. Only a small portion is excreted in
urine. Penetration into CSF is poor. Absorption from lungs following aerosol administration,
hence useful in pulmonary aspergillosis.
 Lipid based formulation are taken by the RES. Interaction of amphotericin B with mammalian
cell -> reduced toxicity. Lipid complex concentrate in lung tissue -> fungal pneumonia.

Drug interaction:

 Combined with other drugs for synergistic effect and reduced the toxicity.
 With Flucytosine -> additive / Synergistic ; In Candida Cryptococcus infections
 Reduces the dose of amphoteicin B and reduces the nephrotoxicity
 In human used for Cryptococcal meningitis
 With Azoles -> theoretically antagonism
 Candidiasis – Fluconazole + Amphotericin ; Better than monotherapy
 Systemic mycoses in dogs - Can be administered wih ketoconazole

Toxicity:

 Renal toxicity-> acute tubular necrosis

 Thrombophlebitis at injection site, Hypokalemia, cardiac arrhythmia, nausea , malaise and
depression. In dogs and cats nephrotoxicity develops within 3-4 weeks of starting treatment. BUN
and creatinine should be monitored to know the extent of renal damage.
 Lipid based formulations are less toxic.

Administration:

 Two basic regimens have been suggested for treatment of systemic mycoses in dogs.
 For healthy dogs 0.5mg/kg , I/V every 48h with BUN monitoring. On the first day the total dose
is diluted in 20ml of 5% Dextrose and 5ml is given ; if no anaphylactic reaction is observed
within a minute the remainder is given over 45 seconds.
 Thereafter the total dose is given over 1 minute in 20ml of 5% dextrose; Continued for 6-12
weeks.
 If BUN exceeds 60mg/dl, dose is discontinued or reduced 25 to 50% of total dose until BUN falls
below 40mg/dl. Slow I/V infusion, in 1litre of 5% dextrose over 5hrs - less renal damage.

II regimen

 In debilitated animals an initial dosage is 0.2mg/kg I/V,increasing by 0.1 mg/kg daily until day
4(0.5mg/kg), then use the maintenance dose (0.25mg/kg) every other day.

Application

 Inspite of toxicity it is the drug of choice for systemic mycoses caused by dimorphic fungi in
immune compromised host.

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  In non compromised host the less toxic ketoconazole and necurtriazoles are preferred though they
are fungistatic.
 Horses -> Localised cutaneous phycomycoses for 6 weeks.
 Pulmonary cryptococcosis -0.5mg/kg infusion for a month.
 Not suitable for local application in mycotic keratitis.

Natamycin: S.natalensis

 Effective against a wide range of filamentous and dimorphic fungi and yeasts.
 Used for local application against ringworm, in the udder for mastitis and on eyes for mycotic
keratitis. Not effective against deep mycotic infections of eye because of poor penetration.
 Candida mastitis - 20ml of 2.5% solution (or) 10ml of 5% solution ->I/mammary OID for 3days
 Horses -> Filamentous fungal keratitis one drop of 5% suspension every 1 or 2hrs, decreasing to
6 or 8 times daily after a few days
 Can be used Nasal aspergillosis in horses
 Toxic by oral route.

Nystatin : S.nouresii

 Disorganises the membrane of fungi by occupying ergosterol binding site. It is effective against
candid , Malassia, Cryptococcus and some Dermatophytes. Some Candida are resistant and in
dogs to treat Malassia infections of outer ear and in horses to treat candid metritis.
 Can be given orally, poor absorption , hence useful in treating GI candidiasis

ALLYLAMINES

 Terbinafine - Demarophytes, Malassezia, Sporothrix, Candida, Dimorphic and filamentous fungi

 (oral and topical use)
 Naftifine (topical) - Dermatophytic infection
 More effective in systemic treatment of intractable and persistent dermatophyte infection. More
effective than azoles and griseofulvin.

MOA

 Inhibit squalene epoxidase -> prevents the conversion of squalene to ergosterol.

 Squalene -> alters membrane permeability -> cell death.

Antifungal activity

 Dermatophyte, Aspergillus, Sporothrix, Candida, Malassezia, Sporothrix, Dimorphic fungi.

Resistance

 Rare. Resistance development is through mutation and efflux of the drug.

PK

 Lipophilic, well absorbed, binds strongly to plasma protein.

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  Penetrates keratinized tissues, enters the stratum corneum and sebum by direct diffusion through
the dermis and living epidermis.
 Stays in the skin and hair for long time.
 Excretion through urine (80%) and faeces (20%)

Drug Interaction

 Inhibitor of Cytochrome P450

 Synergistic with Azole -> act at different point
 + Triazole -> in the treatment of resistant organisms of Candida and Aspergillus

Toxicity

 Well tolerated
 Adverse effects in GI system and skin
 Abnormalities in liver enzymes and hematological parameters .

Clinical Application

 High efficacy, low incidence of adverse reaction , short course -> choice for dermatomycosis.
 Terbinafine + Triazole -> to treat resistant candida
 Length of therapy ->33 to 63 days.
 More active than Griseofulvin against Trichophyton and Microsporum.

AZOLES

 Imidazole - Ketoconazole - Oral(O), or Topical(T) , Enilconazole (T), Miconazole (T),

Clotrimazole (T);
 Triazole - Fluconazole (O, I/V,T), Itraconazole (O,I/V), Voriconazole (O,I/V)
 Azoles are fungistatic with long t 1/2, increased bio availability following oral administration , low
toxicity and enhanced activity.

MOA

 Inhibit the Cytochrome P450 dependent ergosterol synthesis, leading to disruption of fungal
membranes and membrane bound enzymes. They are fungistatic but cidal at high concentration.
 Because of static effect treatment should be prolonged in immuno compromised host.

Ketoconazole

Chemistry

 Poorly water soluble, highly lipophilic, weak dibasic compound that requires an acid pH for
dissolution-> hence absorbed form stomach.

Antimicrobial activity

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  Broad spectrum -> Yeast, Dimorphic fungi, filamentous fungi including Dermatophytes
 G+ve bacteria, Leishmania, plasmodium and other protozoa.

Pharmacokinetics

 Well absorbed after oral administration, given with food metabolised in the liver and excreted in
bile with little active drug in urine.
 Limited distribution.

Drug Interaction

 Enzyme inhibitor
 +Flucytosine->Cryptococcal infection

Toxicity and adverse effects

 Nausea,vomiting,dizzineers,itching, increase in liver enzyme especially in human.

 Dogs -> Inappetance, pruritus, alopecia,reversible lightening of hair. Long term treatment
(13.6M)- Cataracts, severe hepatitis.
 Man ->Inhibits mammation P450 responsible for cholesterol, cortisol and testosterone synthesis
leading to Gynecomastia
 Teratogenic and embryotoxic
 Administration
 Ringworm->5/10 mg/kg Po daily for 4-6wks
 Systemic fungal infection in dogs and cats -> 10mg/kg 12h

Clinical Application

 Triazoles are preferred than ketoconzole.

 Alternative to amphotericin B in the treatment of systemic mycotic infection (Dimorphic fungi,
Candidiasis, Cryptococcosis) in immunocompetent animals.
 Systemic treatment of Malassezia infection , Soft tissue sporotrichosis in humans.
 Griseofulvin is preferred over ketoconazole in treatment of ringworm.
 Activity against Aspergillus is questionable

Itraconazole

 Less toxic, broad spectrum including aspergillus, available for PO and I/V administration.
 Horses -> Keratomycosis, mycotic rhinitis.
 + Enilconazole -> guttural pouch mycosis.

Fluconazole

 Inhibits lanosterol 14 a - demethylase, which prevents the formation of ergosterol.

 Squalene -> lanosterol-> zymosterol-> -> Ergosterol

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  Water soluble, weakly protein bound, well distributed, useful in treatment of yeast infections in
CSF.
 With Amphotericin B - Oral and systemic treatment of candidiasis in human
 Cryptococcal meningitis in AIDS patients.
 Dogs -> Candida , Coccidioides, Cryptococcus
 Limited efficiency against Blastomycosis,Aspergillosis.

Voriconazole ->2 nd generation triazole

 Very broad spectrum, available in oral and I/V formulation, extensively metabolised in liver, high
volume of distribution and excellent tissue penetration.
 Dose related visual disturbance in 20 to 40% of the human patients.
 Effective in invasive Aspergillosis, Fusarium and flu resistant candida infections
 Animal studies are limited.

Topical azoles

 Ketoconazole, miconazole, Clotrimazole, Enilconazole, Itraconazole, ketoconazole, miconazole

Clotrimazole

 Clotrimazole is broad spectrum topical antifungal agent.

 Horses -> Local application in mycotic keratitis, Metritis
 1% Solution -> Aspergillus infection of cornea
 Dogs ->Nasal aspergillosis -> intranasal treatment
 Human -> candida vaginitis
 Cow -> Mycotic endometritis, infusions of 400-600mg in saline every other day for 12 days.
 Yeast mastitis ->100-200mg / quarter / day of 1% solution as single daily dose on 4 occassions.

Miconazole ->similar to clotrimazole

 Topical treatment of Dermatophyte, Candida, Aspergillius and Malassezia

 Miconazole + Chlorhexidine -> Shampoo more effective than selenium sulphide for the treatment
of seborrhic dermatitis in dogs caused by Malassezia

FLUCYTOSINE

Flucytosine or 5-Fluorocytosine

 Antimetabolite - Pyrimidine synthesis inhibitor

 Fluorinated pyrimidine, low molecular weight, slightly soluble in water but readily soluble in
alcohol.

MOA

 After permease mediated entry into fungal cell flucytosine deaminated to 5-fluorouracil which is
incorporated to mRNA and results in faulty protein syntesis.

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  On the other hand 5-fluorouracil is also converted to 5-fluorodeoxy uridine monophosphate that
inhibit thymilate synthase which is involved in the fungal DNA synthesis and nuclear division.

Anti fungal activity

 Narrow spectrum -> Candida, C.neoformans, few Aspergillus are susceptible; others are resistant.
 Development of resistance is common , hence used in combination along with Azole /
amphotericin B -> Crytococcus

Kinetics

 Well absorbed from intestine after oral administration in humans. Excellent tissue penetration,
including CSF. Excreted unchanged in the urine.

Toxicity

 Well tolerated. Occasional side effects -> Reversible anorexia, Nausea, vomiting, diarrhoea, mild
elevation of liver enzymes, bone marrow depression
 ->leucopenia

Reversible

 Skin eruptions characterized by depigmentation, followed by ulceration, exudation & crust

formation.

Clinical application

 Cryptococcal infection in cats + Azoles / Amphotericin B

GRISEOFULVIN

Griseofulvin: P.griseofulvum

 Benzo furan cyclohexane antibiotic, poorly soluble in water.

MOA

 Fungistat - inhibits mitosis by interfering with the polymerization of microtubule protein and
disorganise the spindle microtubules
 Also affects cytoplasmic microtubules

Antifungal activity: all dermatophytes

PK

 Absorption after oral administration depends on particle size. Enhanced by high fat meal.
 Metabolised in the liver & eliminated in the faeces.

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  Deposits in the newly formed keratin of hairs, nails and skin and gradually moves to the site of
infection in the superficial keratinized epithelium, where keratinised cells mature and are
progressively desquamated.
 Actively growing fungus are killed whereas dormant cells are only inhibited, so that cure occurs
only when infected keratinized cells are shed. Hence, treatment is prolonged.

Toxicity

 Prolonged mediaction – mild & transient side effects such as mild CNS effects, Photosensitivity,
GI Disturbances; Teratogenic; Dogs and cats vomit if given in empty stomach.

Administration

 Drug should be given one or 2 weeks beyond clinical or mycological cure.

 Single daily dose of 50mg / kg , reduced to 25 mg /kg once clinical response occurs.
Ring worm infected cattle -> as 10% mycelial mixture, 7.5 – 10 mg /kg for 1-3 weeks

Clinical Application

 Dermatophytic infection – ring worm -> PO - 3 - 6 weeks in dogs and cats.230917

MISCELLANEOUS ANTIFUNGAL AGENTS

Iodides

 MOA is poorly understood, probably by enhancement of the inmmune response of the host or by
spurring the halide peroxide killing system of phagocytic cells.
 Amphotericin B and Imidazoles also affect the immune system
 Sodium iodide and Ketoconazole - Additive effect
 Nasal aspergillosis, ringworm, Sporotrichosis,

Thiabendazole

 Useful in topical ringworm infection when dissolved in alcohol. Orally as an adjunct in the
treatment of nasal aspergillosis in dogs.

Monosulfiram

 Insecticide and included in some preparation when fungicidal and miticidal activity is required.

Dichlorofen

 Taeniacide and fungicide. Available as 2% ointment or alcoholic solution.

 Effective against Trichophyton and Microsporum. It is also bactericidal.

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 CHAPTER-25: ANTIVIRAL CHEMOTHERAPY - INTRODUCTION

 About 69 percent illness is due to viruses. The conventional approach is to develop effective
vaccines. So far only around 16 anti viral drugs for animals and human. Their uses in Veterinary
practice are questionable, because of difference in virus and virus induced replication.
 Virus: Obligate intracellular parasites, need host genetic machinery for replication, narrow
therapeutic index, lack enzymes that function in energy metabolism.
 Protein synthesis and cell dependant replication. Hence they multiply only within the cells.
 Animal viruses may be single stranded or double stranded RNA or DNA viruses

DNA RNA
Pox Rubella
Herpes Rhabdo virus (Rabies) Picorno
Adeno Orthomyxo
Hepadna Paramyxo
Papilloma Parainfluenza
Parvo Corona

REASON FOR FAILURE OF ANTIVIRAL THERAPY

 Drugs that target viral process must penetrate the host cell.
 Lack of broad spectrum antiviral drugs
 Lack of in vitro susceptibility testing procedures
 Narrow spectrum. Drugs target specific enzymes – Polymerase transcriptase involved in viral
nucleic acid synthesis. Hence development of resistance is easier ( point mutation – substitution
of single important nucleic acid )
 Inhibits only actively replicating virus, unable to eliminate non replicating/latent viral infection
 Mostly virustatic, hence success depends on hosts immune response
 The most successful use of antiviral drugs is synthetic nucleosides that either inhibit DNA/RNA
polymerase or act as chain terminators after incorporation into nucleic acids
 They are effective prophylactically and in early stage. Rapid and early diagnosis is important.

VIRAL REPLICATION

 RNA virus: direct, need virion enzyme (viral RNA polymerase) to synthesize mRNA or viral
RNA serve as mRNA
 DNA virus: indirect, viral DNA transcribed to host mRNA by host cell RNA polymerase
 Retro virus: unique, make a copy of DNA from viral RNA with the help of reverse transcriptase
 DNA gets incorporated into host genome mRNA viral proteins

SPECIFIC ANTIVIRAL AGENTS

 Agents preventing attachment and penetration: Immunoglobulin, Interferon

 Agents preventing entry: Amantidine
 Nucleoside analogues: Idoxuridine, Trifluridine (PYRIMIDINE) and Vidarabine (PURINE)
 Inhibitor of reverse transcription: Zidovudine (AZT), Acyclovir, Gancyclovir, Ribavirin
 Inhibitor of mRNA translation: Antisense oligopeptides
 Maturation: Methisazone, 2`Diodyl-d-Glucose
 Improving host resistance: Interferons, Gamma globulins

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  Improving host immunomodulation: Inosiplex, levamisole, Poly I, Poly C

AMATINIDE

 Amantidine and its derivative Rimantidine are synthetic tricyclic amine

 They lead to inhibition or delay of the uncoating process and also interfere with early stage of
viral mRNA transcription
 At usual concentration inhibit replication of different strains of Influenza virus
 It is used as chemo prophylactic agent
 Almost completely absorbed from GIT and 90% is excreted unchanged in urine
 It produces fever, side effects related to CNS. Aerosol administration reduces the toxicity
 Veterinary uses: Prophylaxis in Equine Influenza

IODXURIDINE, VIDARABINE AND TRIFLURIDINE

 Potent inhibitors of DNA synthesis of Herpes virus . Inhibition takes place during synthesis of
DNA strand. These drugs are incorporated into the growing chain of viral DNA, resulting in
misinterpretation of genetic code.
 Inhibit DNA polymerase
 Defective viral protein
 Toxicity- Anemia, neutropenia, loss of hair etc.; Because of toxicity reserved for topical
application.
 Idoxuridine, Trifluridine - analog of thymidine; Trifluridine is less toxic and better penetration
than Idoxuridine
 Vidarabine- analog of adenosine; Acts on Herpes, Pox, Rhabdo, Vaccinia viruses
 Deaminated to Hypoxanthine arabinoside and 50% excreted in urine
 Used for the treatment of Herpes simplex, Keratitis, Encephalitis, Mucocutaneous infection and
Cytomegalo viral infection
 Used with Acyclovir in Acyclovir resistant patients
 Veterinary use: Feline herpes Keratitis, Bovine Vulvovaginitis and Kerato Conjunctivitis, local
herpes infection
 Vidarabine: Local bovine herpes, Vaccinia teat lesions.

ACYCLOVIR and GANCYCLOVIR

 Synthetic acyclic purine nucleoside analogue of 2`deoxy guanosine. It is selective for viral rather
than normal cells.
 Less cytotoxic, breakthrough in antiviral chemotherapy.
 Acyclovir is not phosphorylated in normal cell because of lack of viral thymidine kinase, non
toxic to uninfected cell.
 Valacyclovir, Desiclovir are prodrugs developed because of 90% of acyclovir is excreted in urine
intact
 Human - Herpes simplex 1 and 2, Varicella Zoster virus – chicken pox
 Veterinary Use - Equine herpes in foals
 Topical - Local herpes, Bovine herpes mammillitis, Equine coital exanthema, Feline
rhinotracheitis, Viral Kerato conjunctivitis

Gancyclovir

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  Guanosine analog, more active against Cytomegalo herpes virus than Acyclovir in immune
compromised patients.
 Administration through I/V.
 Neutropenia and thrombocytopenia are adverse effects.
 Veterinary use: Cytomegalovirus infection

RIBAVIRIN AND AZIDOTHYMIDINE/ZIDOVUDINE

Ribavirin

 Guanosine analog
 It is activated by viral phosphorylation and subsequently prevents the formation of mRNA and
translation of viral genome. Broad antiviral activity against many RNA & DNA virus. Resistance
is rare.
 Aerosol- Respiratory syncytial virus broncholitis influenza
 Veterinary use: Influenza, Parainfluenza, Bovine herpes virus, Canine distemper, Blue tongue,
Marek's, Feline calcivirus
 Topical: Local herpes infection (not feline), Vaccinia teat lesions.
 Inhibitor of Reverse Transcription

Azidothymidine/Zidovudine

 Suppress only active viral replication; already infected patients cannot be treated
 Administration only through I/V
 Toxicity- Granulocytopenia and Anemia
 Veterinary Use: Retrovirus, FeLV, FIV, Equine infectious anemia (EIA)
 In HIV patients - prolongs survival, decrease opportunistic infection, and increases the immune
function, decrease HIV antigens and RNA (when combined with Didanosine)
 Inhibitors of mRNA translation

ANTISENSE Oligonucleotide

 The sequence of a nucleotide chain containing information for protein synthesis is called sense
sequence. The complementary strand is antisense sequence.
 Antisense drugs recognize and bind to sense sequence of specific mRNA
 Prevent synthesis of specific proteins

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  Destruction of mRNA by ribonuclease in cell
 Viral genome V mRNA sense strand mRNA drug
 Inhibit viral mRNA translation

IMMUNIZATION AND INTERFERONS

Immunization

 Passive immunization by im, iv or sc injection with Immunoglobulin can prevent entry of virus
into cells
 The proteolytic effect lasts for several weeks but may not be complete. This is useful to control
CD, Rabies, TVT and Gastroenteritis in swine, Infectious hepatitis, Measles, Poliomyelitis,
Chicken pox. If hyper immune serum is not available pooled sera from the recovered or
vaccinated animals may be used. To avoid anaphylactic shock only one injection should be given.

Interferons

 These are cytokines or interrelated group of proteins released by cells infected by virus.
Interfrons(IFN) possess antiviral, immune-modulatory and antiproliferative effects. They are
highly species specific. Three types are recognized
 INF-α - Leucocytes
 INF-β - Fibroblasts antiviral action in response to viral infection especially RNA virus
 INF-Ý or lymphokines - Lymphocytes à antigen/mitogen stimulation, immuno modulation
 They inhibit all the steps in viral multiplication. Bind to specific cell surface receptors and inhibit
viral penetration, uncoating, synthesis of mRNA, translation, assembly and release. It can be
administered s/c, i/m, i/v or locally. It is an important part of defense mechanism.
 IFN production by Tissue culture is costly
 Bovine IFN α, γ produced by Genetic engineering

Interferons inducers/ Host modulators

 Some fungal metabolites have this activity

 Induce production of its own interferon
 High molecular substances like Poly-I, Poly-C, a synthetic poly ribonucleotide also induce
interferon
 Partially effective in dogs against viral hepatitis
 action of interferon

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110
 CHAPTER-26: ANTINEOPLASTIC GRUGS

Learning objectives

 After completion of this chapter, the student/learner should know

o Importance of oncogenesis
o Recent approaches for the treatment of neoplasam
o Mechanism of action of newer antineoplastic drugs

INTRODUCTION AND HISTORY

 Chemotherapy is the use of chemical substance to treat the disease. In modern days it refers to
cytotoxic drugs used to treat cancer.

History

 First drug for cancer chemotherapy was not originally intended for that purpose.
 Mustard gas was as a chemical warfare during World War I and further studied during World
War II. During World War I people accidentally exposed to mustard gas were later found to have
low WBC count.
 It was reasoned that an agent that damaged the rapidly growing WBC might have similar effect
on cancer. In 1940, lymphoma patients were given mustard gas by vein and noticed remarkable
improvement, which in turn lead to drug discovery and development.
 At present chemotherapy has advanced to targeted therapy resulting in better resolution and least
side effects.

DEFINITION AND CELL CYCLE

Neoplasm

 Uncontrolled growth of cells coupled with malignant behavior, invasion and metastasis.

Antineoplastic drugs / cytotoxic drugs

 It must possess selective toxicity to malignant cells at normal dose than the host cells. They react
with important substrates of enzymes that are related to DNA or RNA synthesis or function.
Hence they are selectively toxic to cells that are rapidly dividing or those with high mitotic index.
 Neoplastic cells may be actively proliferating or temporarily quiescent. It is possible for tumor
cells to reach end stage of cell division when they will no longer divide.
 Since, Chemo therapeutic drugs are highly active against proliferating cells
 It is essential to understand cell cycle. The various stages of cell cycle are:

Cell cycle

G1 phase

 Pre replicative period / Pre synthetic period.

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  It lasts for 7-170 hrs where in cell sends growth signals / Mitogens start the process of cell
division – Protein synthesis and RNA transcription occurs during this stage.

S phase

 DNA synthesis period for chromosome doubling.

 It lasts for 8-30 hrs in preparation for mitosis and is the target for many antineoplastic drugs

G2 phase

 DNA Synthesis period; cell activity increases.

 The duration is 1- 4 hrs during which RNA and protein are synthesized in preparation for cell
division.

M phase

 Mitosis / cell division stage

 The duration is very short < 1 hr

Go Phase

 Non proliferative period. Antineoplastic drugs are rarely effective in this stage.
 Cells like myocytes and neurons enter Go and rarely / never cycle again
 possible cell cycle check points

CLASSIFICATION OF ANTINEOPLASTIC AGENTS

 Alkylating agent
 Antimetabolites
 Naturally occurring compounds
 Hormones and antihormones
 Miscellaneous

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Alkylating agents

 Nitrogen mustard: Mechlorethamine, Cyclophosphamide ,Melphalan, Uracil, Mustard &

Chlorambucil
 Alkyl Sulfonates: Busulfan
 Nitrosoureas: Carmustine, Lomustine, Semustine, Streprozocin.
 Triazene: Dacarbazine
 These compounds are highly reactive intermediates that are able to transfer alkyl group to DNA.
 Mono functional alkylating agent Transfer single alkyl group to DNA Miscoding of DNA -
Strand leakage or disruption-> Cell death / Mutagenesis/ carcinogenesis
 Polyfunctional – Cell death
 Cross resistance between alkylating agent exists.

Antimetabolites

 Folic acid analogues: Methotrexate

 Pyrimidine analogues: Fluoruracil, Cytarabine -> Cytosine arabinoside.
 Purine analogues: 6 mercaptopurine, 6 thioguanine.
 Resemble normal cellular metabolites and subvert normal metabolic pathways in a toxic manner.
Tetrahydrofolate deficiency blocks reaction requiring folate coenzymes and so disrupt DNA and
RNA synthesis

Natural products:

 Vinca alkaloids: Vinblastine, Vincristine - M stage

 Antibiotics:
 Dactinomycin [Actinomycin D] - Cell cycle Non specific
 Arthracychine antibiotics – Daunorubicin, Doxarubicin – Non specific but maximal effect at S
phase.
 Glycopeptides – Bleomycin (G2, M phase) , Mitomycin C
 Enzymes : L-asparaginase obtained from E coli (G1 phase)

Hormones and their antagonists

 Adrenocorticosteroids - Glucocorticoid - Non specific

 Progestin
 Estrogen
 Anti estrogen
 Androgen

Miscellaneous

 Cisplatin
 Mitotane
 Hydroxyurea
 Proacarbazine
 Glutathiamine

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 CLASSIFICATION OF ANTINEOPLASTIC

Cycle specific drug

 This group act at a certain phase of the cell cycle, usually at S or M phase. The effect of the drug
is more when the cells are actively proliferating.

Example

 Methotrexate
 Pyrimidine and purine Analogues
 Hydroxyurea
 Vinca alkaloids.
 Cells in the Go phase are troublesome because they are not susceptible to cytotoxic drugs and
start proliferating once the treatment has been stopped.

Cycle non specific drugs

 This group act at all stages except Go phase. Increased drug level kills the cells.
 These drugs are given in large doses for a short period but capable of causing bone marrow
suppression.

Example

 Alkylating agents
 Some antineoplastic antibiotics

Chemotherapy in veterinary practice

 Cancer chemotherapy can be of most value in three conditions.

 Lymphosarcoma, Leukemia and Solid tumors where in bulk of tumor has been destroyed by
surgery, cryosurgery or radiation but the risk of metastasis is high.
 Considerable care should be taken before starting chemotherapy since they are highly toxic

POSSIBLE SITE AND MECHANISM OF ACTION

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 GUIDELINES TREATMENT AND SCHEMES

 A detailed clinical and radiological examination should be made and the tumor should be
clinically staged.
 A histological examination is required and prognosis obtained.
 Full co-operation of the owner is essential
 Acquire adequate background knowledge before therapy.

Treatment schemes

 Chemotherapy may be given with a curative intent or it may aim to prolong the life or to palliate
symptoms.

Combined modality chemotherapy/Combination therapy

 Surgery / Radiation + Chemotherapy - number of different drugs are given simultaneously.

 Cell cycle specific drugs are given initially followed by cell cycle non specific drugs inorder to
minimize the chances of resistance and toxicity.

Neoadjuvant chemotherapy (Preoperative treatment)

 Aimed for shrinking the primary tumor, thereby rendering local therapy like surgery /
radiotherapy more effective.

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Adjuvant chemotherapy (Postoperative treatment)

 Used when there is little evidence of cancer, but risk of recurrence is more. It is useful in killing
cancer cells that has spread to other parts and also highly effective in newly growing tumors,
Since they are fast dividing.

Palliative chemotherapy - given without curative intent, but simply to decrease tumor load and increase
life expectancy

TOXICITY AND RESISTANCE

Toxicity

 All the actively multiplying cells are affected by these cytotoxic drugs. The common side effects
are
 Bone marrow suppression, resulting in leucopenia, increased incidence of infection,
thrombocytopenia and uncontrolled bleeding.
 GI disturbances including anorexia, nausea, vomiting, diarrhea, stomatitis and ulcerative
enteritis. Antiemetics can be administered before the commencement of treatment.
 Suppression of immune response
 Alopecia
 Secondary malignancy due to the use of antineoplastic agent
 Impairment of reproductive function
 Tissue necrosis at the site of injection

Resistance:

 Resistance occurrence may be due to

 Pharmacokinetic factors inability to attain effective concentration of a drugs for a sufficient
period of time.
 Cytokinetic factor – includes growth rate and growth fraction of tumor cells.
 Biochemical factors include
 Defective transport into cell -> Chemotherapeutic agent often does not reach the core of the
tumor (solid tumor) where in cells have ceased dividing. P- glycoproteins present in the cell act as
efflux pump.
 Impaired drug activation within the cell
 Increased drug inactivation
 Increased intracellular nucleopeptide pools
 Altered patterns of DNA repair
 Gene amplification and increased RNA coding for necessary enzymes
 Altered or diminished active sites on target protein
 Changes in proliferation rate

DOSE

 The dose is calculated based on body surface area and expressed as m 2. Since chemotherapeutic
agents are highly toxic to other normal cells and certain parameters like BMR, blood volume,
cardiac output and renal function were found to correlate better with BSA (body surface area)
than body weight, the dose for CTA is expressed in m2.

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  SA in m2 = Km x 102/3/104
 Km factor based on metabolic rate of each species
 Dog 10.1
 Cat 10.0
 W B. wt in grams

CHAPTER-27: ANTINEOPLASTIC DRUGS

Learning objectives

 After completion of this chapter, the student/learner should have clear idea about alkylating
agents, different mustards,antimetabolites,and their effects and side effects
 Purine and pyrimidine analogues and their role in neoplastic arrest.
 Role of hormones and their analogues, natural products as antineoplastic agents
 Student should know the importance of developing importance of cacer chemotherapy.

AKYLATING AGENTS

 These compounds are highly reactive intermediates that are able to transfer alkyl group to DNA.
They add alkyl / methyl group to DNA.

Monofunctional Alkylating agent

 Transfer single alkyl group (7-N guanine residue)

 Inhibit correct utilization of base pair instead of AT CG
 Guanine pairs with Thymine
 Miscoding of DNA
 Strand breakage or disruption
 Cell death/ mutagenesis/ carcinogenesis

Polyfunctional alkylating agents

 Alkyl group is added to both the strands of DNA

 Cross linking of DNA strand à prevents uncoiling
 Inhibition of cell growth, apoptosis - cell death
 Alkylating agents are activated by CYP 450 and resistance to one alkylating agent induces
resistance to others.
 Though not cell cycle specific rapidly dividing cells are more affected.

Resistance

 Increased ability to repair DNA lesions

 Decreased permeability to the drug
 Increased production of glutathione /Glutathione-s -transferase , which catalyse the conjugation
of drug to glutathione.

Side effect

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  Myelosuppression
 Nausea and vomiting
 Some degree of GI toxicity
 Reversible hair loss

NITROGEN MUSTARD

 Limited use in combination with other agents for Hodgkin’s disease, non-Hodgkin’s lymphoma,
lymphoreticular neoplasia, pleural and peritoneal effusions, mast cell tumor.
 Extremely short duration of action since it undergoes rapid chemical transformation in water or
body fluids. It is a severe vesicant hence should be given carefully through I/V. GI toxicity is
prominent unlike other alkylating agents.
 Dogs and cats: 5 mg/M2 as a single treatment or 2-4 divided doses on successive days.

Cyclophosphamide

 A broad spectrum anticancer drug given alone or in combination and is widely used in veterinary
medicine.
 Indication: Non Hodgkin’s lymphoma, Lymphoreticular neoplasm, sarcomas, carcinoma of lung,
ovary, mammary gland and multiple myeloma.
 Can be given orally or parenterally. At normal dose it is cell cycle specific and at high dose – Cell
cycle non specific
 Toxicity - Damages the bladder, Necrotising haemorrhagic cystitis (bleeding)

To overcome the toxicity

 Withdrawal of therapy

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  Administer free radical scavenger Acetyl cysteine and MESNA (Sodium salt of methyl ethyl
sulfonate)
 Concurrent administration of prednisolone

Melphalan

 Phenylalanine derivative of Mechlorethamine. Recommended for oral administration before food.

 Widely used for Mammary carcinoma, Malignant melanoma, Multiple myeloma, Ovarian
carcinoma, Testicular seminoma

Side effect

 Anorexia
 Nausea and vomition
 Dose limiting Myelosuppression
 Necrotising haemorrhagic cystitis (bleeding)

Chlorambucil

 Slowest acting and least toxic

 Substitute for cyclophosphamide when haemorrhagic cystitis is exhibited
 Indications – Chronic lymphoreticular tumors, Ovarian carcinoma

AKYL SULFONES,NITROSOUREAS AND TRIAZENE

 Indcation – Chronic granulocytic leukaemia

 Well absorbed orally and then be given through intravenously
 Patients should be premedicated with phenytoin. Since it crosses BBB and induces seizures

Nitrosoureas

Carmustine or BCNU (IV)

 Lomustine or CCNU Oral administration – Dog - 100 mg/m2 – Single dose every 6 week
 Need biotransformation, Highly lipid soluble and crosses the BBB
 Indication
 Brain tumours and metastases, Hodgkin’s disease, Cancer of lung, Stomach and Colon.
 Streptozocin: Malignant pancreatic insulinoma

Triazene

Dacarbazine

 Indication: Malignant melanoma, Soft tissue carcinoma

 Not much used in veterinary
 With Doxorubin – treatment of relapsed lymphoma. Given through IV
 Side effect : Alopaecia, flu like symptom, malaise and myalgia

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 ANTIMETABOLITIES

 Resemble normal cellular metabolites and inturn subvert normal metabolic pathways in a toxic
manner
 Tetrahydro folate deficiency blocks reaction requiring folate coenzymes and inturn disrupt DNA
and RNA synthesis
 It is cell cycle specific - S phase is most sensitive
 Side effect: Bone marrow suppression, Severe GI toxicity
 Possible site and mechanism of action

FOLIC ACID AND ANALOGUE

 Folic acid analog used against a variety of neoplasms

 Inhibits DHFR and prevent the formation of tetrahydro folate and thereby the purine and
pyrimidine nucleotides
 It needs intracellular activation to polyglutamate derivation which is selectively retained within
cancer cells.
 Administration– Parenteral or intrathecal in CNS neoplasia
 Excreted in urine and at high dose precipitate in renal tubules.
 Side Effect: Bone marrow suppression following high dose
 Treatment: Administration of leucovorin after high dose rescues the cells.

Resistance

 Cellular uptake due to activity of P-glycoprotein

 Polyglutamate formation
 Synthetic of DHFR through gene amplification
 Altered DHFR with reduced affinity for the drug
 antifolate possible site

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 PYRIMIDINE ANALOGUE

 It is converted to active phosphate form and inhibits thymidylate synthase and inturn DNA and
RNA synthesis.
 Indication: GI, liver skin and mammary carcinomas
 Administration: IV as well as topical, Metabolized in the liver and enters into the CSF
 Side Effect: CNS disturbance -> neurological signs -> seizures and death
 GI disturbance and oral ulceration.
 Mild Myelosuppression
 Contraindicated in cats unprovoked rage, extreme dementia and sudden death.

Cytarabine/Cytosine arabinoside

 Analogue of deoxycytidine and must be activated by conversion to monophosphate nucleotide

Cytarabine
 Administration -> IV / SC
 Indication: Canine and feline lymphomas, Leukemia of both lymphoid and non lymphoid type
 Toxicity: Leucopenia with megaloblastic changes, GI disturbance.
 With Doxorubicin used in the treatment of leukemia.
 pyrimidine analogue

PURINE ANALOGUE

 Sulphydryl Substituted analogue of hypoxanthine

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  Needs intracellular activation and inhibits a number of enzymes of purine nucleotide inter
conversion leading to inhibition of DNA and RNA synthesis
 Administration oral, IV. Undergoes rapid degradation and some renal excretion
 Side Effect: Bone marrow suppression, Nausea and Vomition.

Indication:

 Acute lymphocytic leukemia,

 Granulocytic leukemia

Thioguanine

 Similar to 6 – Mercaptopurine
 Inhibits several enzymes in Purine Nucleotide pathway, inhibition of nucleotide interconversion,
decreased intracellular guanine and interference with DNA and RNA synthesis.
 Indication: Acute nonlymphocytic leukemia
 Adult acute leukemia (synergistic with Cytarabine)
 examples such as

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 NATURAL PRODUCTS

Natural Products

Vince alkaloids

 mitotic inhibitiors
 These are large and complex molecules derived from periwinkle plant, Vinca rosea.
 Vincristine formyl side chain active only in M phase
 Vinblastine methyl side chain also blocks cells utilization of glutamic acid, inhibit purine
synthesis (active in other phases also – S phase)
 Bind to the tubulin and interfere with mitotic spindle formation and thus segregation of
chromosomes in metaphase is arrested.
 Administration: IV, metabolised in the liver, partially excreted unchanged in urine.
 Indication: TVT (Vincristine), Lymphoreticular neoplasm
 Soft tissue sarcoma - Vincristine + Doxorubicin + Cyclophosphamide
 Vinblastine – used as a substitute for vincristine when the vincristine-induced neuropathy is noted
(Slowly reversible sensory motor peripheral neuropathy & muscle weakness)
 Dose: Vincristine - 0.5 to 0.75 mg/m2 IV once weekly.

Antibiotics

 Dactinomycin / Actinomycin D fungal product of Streptomyces. Cell cycle non specific

 Binds with the double stranded DNA – intercalate and blocks the actions of RNA polymerase
prevent transcription.
 Administration: IV
 Indication: Lymphoreticular neoplasm, Testicular carcinoma, Rhabdomyo sarcoma, Alternative
to methotrexate resistant Choriocarcinoma
 Highly toxic Potentiates the effect of radiation therapy - radiation recall effect.

Anthracycline antibiotics:

 Doxorubicin / Adiramyan
 Daunorubicin / Daunomycin

MOA

 Blocks DNA and RNA synthesis, strand break

 Inhibits topoisomerase II
 High affinity binding to DNA through intercalation
 Blockade of DNA and RNA synthesis, DNA strand scission.
 Alteration in cell membranes transport.
 Generation of semiquinone and oxygen free radicals that cause DNA strand breaks.

Doxorubicin

 solid tumors – breast cancer and hematologic malignancies

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Daunorubinin

 Acute myelocytic leukemia.

 Cell cycle non specific, Maximum effect during S phase
 Side effect: Myelosuppression, cardio toxicity and serve vesicant and cause phlebitis and urticaria
(Should be premediacatd with corticosteroids and antihistamines.)

Glycopeptide

 Bleomycin
 Cell cycle specific (G2 & M phase)
 MOA – intercalate into DNA, cause chain scission and fragmentation. Also inhibit DNA repair
enzyme
 Indication – Testicular tumors, squamous cell carcinoma, lymphoma and seminoma
 Side Effect – Lung toxicity, Little myelosuppression hence can be combined with other and
myelosuppresive drugs.

Enzymes

 L-asparaginase enzyme derived from E-coli

 G1 phase specific
 Normal cells synthesize asparagine internally which is utilized for protein synthesis.
 Leukemia cells cannot synthesize and utilize externally supplied asparagines leading to cell death.
 L- asparaginase
 Asparagine Aspartic acid

Indication

 Lymphoreticular neoplasm

HORMONES AND THEIR ANTAGONISTS

 Glucocorticoids -> Cell cycle non specific and often used following induction by another agent.
 Prednisone and prednisolone -> Lymphoreticular neoplasm in combination with other
chemotherapeutic agent.
 Dexamethasone, prednisone & prednisolone -> Leukemia and lymphoma of the CNS.
 Estrogens (Diethyl stilbesterol, Oestradiol): Prostatic hyperplasia, Peri anal glandular neoplasm
 Complications: Life threatening bone marrow suppression and aplastic anemia, Feminization and
fluid retention.

Tamoxifen

 Antiestrogen
 Occupies the estrogen receptor of estrogen sensitize tumors and block the stimulatory activity of
hormone in these cells.
 Indication: Early stage and metastatic breast cancer
 Chemopreventive agent in women at high risk of breast cancer, Endometrial cancer.

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Progestins ( Megestrol, Medroxy Progesterone)

 Oppose the effects of hormones in endometrial, prostatic, breast, renal cell and ovarian carcinoma
 Androgens: Breast carcinoma, hypernephroma
 Antiandrogen (Cyproterone): Prostatic tumor

MISCELLANEOUS AGENTS

Carboplatin

 It’s a derivative of platinum, causes inter and intra strand DNA alkylation
 Cell cycle non specific drug administered iv with mannitol to promote diuresis, since it is
extremely nephrotoxic
 Carboplatin is less nephrotoxic and has prolonged half life.

Mitotane

 Derivative of DDT and DDD

 Causes selective destruction of neoplastic adrenal cortical cells. It may act by inhibiting ACTH
steroid production and causes atrophy of inner zones of adrenal cortex.

Hydroxyurea

 Inhibits ribonucleotide reductase, leading to depletion of essential DNA precursors, cells

accumulate in S phase of cell cycle.
 Indication: Granulocytic leukemia.
 Palliative treatment of chronic myelogenous leukemia, management of polycythemia Vera in
dogs and cats.

NEWER APROACHES

 Hematopoietic stem cell transplant for hematologic malignancies like myeloma, lymphoma and
leukemia.
 Isolated infusion approaches to overcome toxicity but not useful in metastasis
 Isolated limb perfusion
 Isolated infusion into lung and liver for solid tumors

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  Specially targeted drug delivery - vehicle specific and target tumor cells.
 Nonoparticles - useful vehicle for poorly soluble agents such as Paclitaxel
 Minicells - bacterially derived minicells of 400nm particles for encapsulation and cancer cell
targeting of chemotherapeutics and is taken up by endocytosis.
 High dose of CTA can be administered by these methods and even resistant tumor cells can be
destroyed.
 possible signal transduction

other

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127
 CHAPTER-28: ANTHELMINTICS

Learning objectives

 After completion of this chapter, the student/learner should know about the mechanism of action
useful anthelmintics, antitramatodal and cestodal
 student/learner should aware of spastic and flacid paralysis and mechanism of action of different
anthelmintics
 idea about the spectram of activity and species difference in case of levamisole and certain unique
drugs

INTRODUCTION

 Antiparasitics are drugs that reduce the parasitic burden by killing (vermicide) or inhibiting their
growth (vermifuge).
 Anthelmintics are drugs or agents that eliminate the worms from gastrointestinal tract.
 Helminths have a complex body structure and are classified into 3 groups,
o Trematodes / flukes - Indirect life Cycle
o Cestodes / tapeworms - Indirect life Cycle
o Nematodes / round worms - Direct life cycle

CHARACTERISTICS OF AN IDEAL ANTHELMINTIC

Broad spectrum of activity

 Should be active against a large variety of helminths in all animals. Effective against mature and
immature worms, larval stages.
o Antinematodal - Effective against hypotactic and migrating larva.
o Fasciolicide - should kill immature flukes.
o Anticestodal - should be able to remove the scoleces and not just the strobilae.
 An ideal Broad Spectrrum anthelmintic should be active against all the three categories. Eg.
Albendazole, closantel, Netobomin.

Wide therapeutic index: A safety margin of at least six fold is expected for modern anthelmintics

Short residence time

 The drug should not have a tendency to accumulate in tissue or secreted in milk.
 The withdrawal period should be minimal and those drugs are safer. However in non-food
animals prolonged persistence may be beneficial by providing extended period of protection
against reinfection.

Easy to administer: should be effective on a single dose.

Economical: Easily available, cheap and stable under normal storage conditions.

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 MECHANISM OF ANTHELMINTIC ACTION

 The mode of action of anthelmintics can be broadly categorised into two types:
o Interference with parasite energy metabolism
o Neuro muscular paralysis of the worm.

Drugs affecting energy metabolism

 The normal metabolic process is affected.

Inhibition of fumarate reductase in mitochondria

 Fumarate -> Succinate

 Failure to synthesise ATP. In the absence of energy the worms die. Eg Benzimidazoles
and its pro drugs.

Inhibition of tubulin polymerisation

 Binding of drugs with tubulin block polymerisation and microtubule formation. As a

result inhibition of mitosis, embryonation, egg hatching, secretory function etc.
 Eg. Benzimidazole (Primary target).

Inhibition of mitochondrial phosphorylation/uncoupling of oxidative phosphorylation

 These act as protonophores, allowing hydrogen ions to leak through the inner
mitochondrial membrane and interfere with ATP synthesis eg. Salicylanilide’s and
substituted phenols which are mainly flukicides.

Inhibition of glycolysis

 Glycolytic enzymes phosphoglycerate kinase and mutase are selectively inhibited leading
to depletion of energy eg. Clorsulon (flukicide) and Thiacetarsamide (heart worm).

Drugs causing paralysis/Neuro muscular incoordination

 Interfere with the normal Neuro muscular function of worms and induce spastic or flaccid
paralysis, the parasites are dislodged from the host and expelled out. The killing is generally
rapid.
 The drug categories are:

Cholinesterase inhibitors

 Increased concentration of Ach at neuromuscular junction leads to spastic paralysis eg.

OPC -> coumaphos crufomate, dichlorovos. Trichlorofon, Haloxon etc.
 [ OPC inhibits AchE by phosphorylating the esteratic site ]

Cholinergic agonist

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  Act as agonist at nicotinic Ach receptor of nematode à ganglionic stimulation causes
sustained muscle contraction initially followed by depolarising neuro muscular blockade
which in turn leads to spastic paralysis.
 Eg. Imidazothiazole -> levamisole, Butamisole
 Tetrahydropyrimidines -> Pyrantel, Morantel

Muscle hyperpolarization

 Block neuro muscular transmission in parasite by hyperpolarising the nerve membrane

leading to flaccid paralysis and expelled by peristalsis eg. Piperazine. It also blocks
succinate production by the worm. It may also act through GABA.

Potentiation of inhibitory transmitters / GABA agonists

 Act as agonist at GABA receptor -> Opens chloride channel -> flaccid paralysis.
 Eg. Piperazine
 Ivermectin -> Macrocyclic lactones – paralyse the pharynx (unable to feed), the body
wall and uterine muscles of nematodes.
 [Glutamate gated chloride channel in arthropod and nematode nerve cell]. It is not active
against cestodes / trematodes since they do not have receptor at glutamate gated chloride
channel.

OTHER MECHANISMS

 Affecting the permeability of the cell and vacuolation of tegument eg. Praziquantal -> Increases
the permeability of trematode tegument to calcium and result in spastic contraction of muscle. Eg.
Diamphenethide
 Disruption of tegument -> Eg. Bunamidine, Espirantel, Praziquantal.
 Inhibit glucose metabolism of Fasciola – Diamphenethide, Clorsulon
 Interferes with Arachidonic acid metabolism of filarial parasite – DEC.
 Opsonize the parasite for destruction by host immune system.

ANTHELMINTIC REESISTANCE

 It is commonly seen in Haemonchus species, Trichostroglyus, Ostertagia, Nematodirus and

Oesophagastomum.
 Cross resistance is common between members of the same group.
 The predisposing factors for development of anthelmintic drug resistance by parasites are
o Use of drug below the therapeutic / recommended dose.
o Containues use of particular group for a long period.
o Overuse / unwarranted use
o Extensive use of anthelmintic with long withdrawal period.
o Poor management practices
 Measures to overcome resistance:
o Rotational use of anthelmintics
o Avoid Indiscriminate use, follow the dosing schedule
o Narrow spectrum compound suitable for parasitic stage should be used.

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 CLASSIFICATION OF ANTHELMINTIC DRUGS AND ITS SPECTRUM

Group Drug Anthelmintic activity

Benzimidazoles Thiabendazole Nematodes
Parbendazole Nematodes
Oxibendazole Nematodes
Flubendazole Nematodes (Pigs)
Canbendazole Nematodes and cestodes
Fenbendazole Nematodes and cestodes
Mebendazole Nematodes and cestodes
Oxfendazole Nematodes and cestodes
Luxabendazole Nematodes and Flukes
(sheep)
Triclabendazole Trematodes
Albendazole Adult nematodes and their
larva, Cestodes, mature
flukes
Benzimidazole Pro- drugs Febantel Nematodes
(Fenbendazole)
Thiophanate Nematodes
(Lobendzole)
Netobimon
(Albendazole)
Imidazothiazoles Levamisole
Butamisole Nematodes
Tetramisole
Salicylanilides Closantel Broad spectrum
Niclosamide Cestodes and Intestinal
Trematode
Oxyclozanide Mature flukes
Rafoxanide Trematode and some
nematodes.
Substituted phenols Diamfanetide N,T,C
Niclofolan Trematode

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 Bithionol C&T
Nitroxymil N&T
Nitroscanate N & Cestodes (dogs)
Disophenol Hookworm in dogs &cats
Clorsulon Adult & immature flukes.
Tetra hydro pyrimidines Pyrantel Nematode & Horse tape
worm
Morantel Nematodes
Oxantel Nematodes
Macro cyclic lactones Ivermectin
(Avermectins)
Doramectin Nematodes & ectoparasites
Moxidectin
Milbemyin D
Milbemycin oxime
Heterocyclic compounds Piperazine Nematodes
Diethyl carbamazine Nematodes (dogs) ,Heart
citrate (DEC) Worm, Microfilaria
Pyrazinoisoquinolones Praziquantal Trematode & cestode
Benzazepines Espirantel cestodes
Miscellaneous Phenothiazine Nematodes
Arecoline Cestodes (dogs)
Bunamidine Cestodes
CCl4 Trematodes

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 CHAPTER-29: ANTIPROTOZOAL DRUGS

Learning objectives

 After completion of this chapter, the learner/student should have an idea about the protozoal
infections.
 pharmacodynamic intervention of drugs at various stages.

INTRODUCTION

 Parasitic protozoa are responsible for a wide range of diseases in both animals and man, diseases
which are of world importance but are difficult to eliminate as they are frequently transmitted by
ticks and fleas.

Important protozoan diseases and drugs used

Disease Therapeutic drug

Anaplasmosis Imidocarb, tetracyclines
Babesiosis Trypan blue, Acriflavin, Diminazene, Amicarbalide Imidocarb,
Phenamidine
Theileriosis Parvaquone, Buparvaqone, Tetracycline,
Trypnasomiasis Suramin, Trypan blue, Diminazine, Quinapyramine
Rickettsiae Tetracycline

QUINAPYRAMINE COMPOUNDS

Quinapyramine chloride and sulphate

 There are two quinapyramine compounds of use – the sulphate which is rapidly absorbed and
mainly trypanocidal with low prophylactic value and the chloride which is more slowly absorbed
and has a strong prophylactic effect
 Combined as Antrycide prosalt or Pro-salt R.F.(10% sulphate and 6.67% chloride) and is
administered by subcutaneous injection at the rate of 0.025ml/Kg body weight.
 Toxicity is not so important, except in young stock where overdosage may cause trembling,
sweating and salivation, followed in severe cases, by and increase in respiration, heart rate,
collapse and death. In normal dosage, symptoms when they occur are only of a mild and
transitory nature.

Suramin

 This is a complex aromatic organic compound.

 It has marked curative and less useful prophylactic properties against T. evansi in horse, camels,
cattle and dogs; against T.brucei in horse and dogs and sometimes cattle and against T.equinum.

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 Suramin is potentially toxic, because the therapeutic index is very narrow. Horse and donkeys are
very susceptible, but camels are quite resistant. Symptoms are those associated with liver, kidney,
spleen and adrenal gland damage.

AMICARBALIDE ISETHIONATE

 This compound is a complex urea compound

 It is active against Babesia divergens, B. bovis, B. bigemina, B. argentina and B. caballi. It is
used mainly to create premunity by controlling the clinical symptoms but not eradicating the
infection.
 Administered through subcutaneous, intramuscular or intravenous route preferably at high fever.
It can also be added to citrated blood used for transfusion.

IMIDOCARB DIPROPIONATE

 It is known chemically ad 3,3-bis (2- imidazolin – 2ly) carbanilidipropionate

 Mechanism of action: Vacuolization of the cytoplasm and alteration in size of the neucleus.
 Well absorbed and distributed through out the body
 Bound to plasma protein and detectable amounts were found in all major tissues up to 4 weeks
after intramuscular administration.
 Excreted unchanged. Major route – urine, 10% in faeces.
 Recommended for the treatment and prophylaxis of babesiosis and anaplasmosis.
 Administered through subcutaneous and intramuscular route but not through intravenous route.
 Dose:

Babesiosis Cattle 1.2 mg /Kg body weight

Horse 2.4 mg /Kg body weight
Dog 6 mg /Kg body weight
Anaplasmosis Cattle 3 mg /Kg body weight

 Narrow margin of safety. 10 mg / Kg body weight in cattle, imidocarb can cause death.

QUINURONIUM SULPHATE

 The drug is used against babesiosis

 If it is used in early febrile stages of the disease, clinical cure (not eradicate the infection)
achieved in 24-48 hours, though a second injection may be needed on the next day or the one
after.
 The course of treatment should not be repeated for a period of at least 2 weeks, preferably 3
months; this is due to occasional development of sensitization, which may result in severe shock
and death when treatment is repeated.
 This drug only clinically cures the animals but not eradicate the infection. So on recovery, these
animals retain a number of organisms in their system which maintains the resistance of the animal
to reinfection. This phenomenon is known as premunition.

TRYPAN BLUE

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  This one of the azo dyes and is therefore related distantly to the sufonamides
 It was one of the earlier agents used against babesiosis, but ineffective against B. equi, B. bovis
and B. gibsoni.
 The drug is relatively non-toxic but stains tissues and secretions, including milk, a blue green
colour which may persist for several weeks.

HYDROXY NAPTHOQUINNOLONES

 These drugs are used against Theileriosis

 Causes marked degeneration of micro schizonts and suppression of parasitemia.

Parvaquone

 Most cost effective compound in the series of hydroxynapthoquinnolones.

Buparvaquone

 A parvaquone analogue in which cyclohexyl moiety is substituted by an alkyl group, this

substitution slows down the metabolic degradation of parent compound.
 Most effective in the hydroxynapthoquinnolone group as active during incubation period and also
after the out break of bovine theileriosis ( in advaced stage).
 Pre slaughter withdrawal period for milk and edible tissue is 2 and 42 days respectively.

CHAPTER-30: ANTICOCCIDIAL CHEMOTHERAPY

Learning objectives

 After completion of the class student should have idea about the life cycle of coccidia and
intervention of drugs at various stages
 Pharmacodynamic aspect of different drugs
 Shuttle programme of useage

INTRODUCTION

 Coccidiosis was a dreadful disease in 1940`s in the broiler industry leading to bloody diarrhea
and heavy mortality.
 It also affects cattle, sheep, goat, pigs, dogs and cats.
 Two intestinal protozoan parasites of coccidian namely Eimeria and Isospora with numerous
species have been identified.
 In broiler E.tenella and E.necatrix are the most commonly encountered protozoans.
 Solid immunity develops following exposure and it is species and strain specific.
 Control is possible by continuously feeding a coccidiostat for a prolonged period throughout the
period with a zero withdrawal drug.
 In layer immunization procedure would be most suitable eg., administration of coccivac
containing 7 species of protozoan oocyst.
 Preventive anticoccidial may be given for 6-22 weeks
 Such continuous feeding of a static drug has led to the developed starting from Sulphonamides in
1940 to Ionophores inearlier to overcome resistance.
 Two programmes are followed.

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 o Shuttle programme– Use of two or more drugs subsequently during the early growth
period of birds
o Rotation programme– Use of Pharmacologically different anticoccidials in relation one
after another in succeeding crops of birds

LIFE CYCLE OF COCCIDIA

 Sporulated Oocyst thus gets out from the host in feces hatched out into Sporozoites. From
sporozoites, tropozoites are formed. This further leads to the formation of 1 st generation Schizont.
From this merozoites and further tropozoites are formed.
 2nd generation Schizonts are formed from which male and female gametocytes are formed. Fusion
of male and female gametes leads to the formation of Sporulating Oocyst which then enters the
host.
 In the life cycle of coccidian, upto the formation of Merozoites from Oocyst belongs to 1 st asxual
cycle and again the formation of one merozoite to other merozoite is 2 nd asexual cycle and the
formation of gametocytes from Merozoites is sexual reproduction.
 Most of the drugs show the greatest activity during 1 st or 2nd asexual cycle and some inhibit the
sexual stage.
o 1st asexual cycle: Clopidol, Quinolones, Monensin, Robenidine, Amprolium
o 2nd asexual cycle: Zoalene, Nicarbazine, Sulfonamide, Dinitolmide

ANTI COCCIDIAL DRUGS

Clopidol

 It is a pyridine derivative active only against the sporozoites of Eimeria. Hence it is not effective
if given after the day of exposure of coccidial oocyst. It is a coccidiostat and does not allow
natural immunity to develop.
 Clopidol 100ppm + 8.35ppm Methylbenzoquate à continuously in chicken and turkey.
 Withdrawal period is about 5 days and not to be mixed with other coccidiostats.

Quinolones

 Act on Sporozoite stage and selectively inhibit electron transport and thus respiration in coccidial
mitochondria, not in the host
 They are insoluble in water, poorly absorbed hence non-toxic
 Rapid development of resistance hence used in combination with Clopidol
 Eg., Decoquinate – not suitable for laying and breeding birds but suitable for calves
 Methyl benzoate – most potent Quinolones

Ionophores (Polyethyl antibiotics)

 Most effective and widely used anticoccidials (growth promoter)

 They interfere with the transport of ions through membranes, causing an influx of positively
charged ions. This upsets the osmotic balanceof the cell. Mainly active towards Sporozoites and
1st generation Schizonts and Merozoites. Hence it should be fed continuously and not
recommended for established infection

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Monensin

 Source: S.cinnamonensis
 Complex with Na and K ions, affects permeability of membrane
 Low therapeutic index
 Highly effective against all species
 Not recommended for laying hens, equines
 Withdrawal period is 3 days.

Laslocid

 Source: S.lasaliensis
 Not recommended for other birds and animals except broilers and replacement layers
 Least toxic at normal dosage but net litter may be a problem because

Narasin

 Source: S.aurefaciens
 Effective against intestinal and caecal coccidian in broiler if administered continuously
 Not for layers and other animals

Salinomycin

 Source: S.albus
 Similar to Narasin
 Prophylaxis in broiler

Maduramycin

 Source: Actinomadura fumaense

 Most potent iionophore for broilers.
 All have a withdrawal period of 5 days

Robenidine

 A guanidine derivative inhibits oxidative phosphorylation, primarily coccidiostat against parasite

up to almost mature first generation schizont and some coccidiocidal effect against second
generation schizont.
 Recommended for broiler, turkey and rabbit continuously in feed.
 Contraindicated in laying hens and not to be combined with other anticoccidials.
 Withdrawal period: 5 days.
 Side effect: Unpleasant taste of meat and egg.

Amprolium

 It is a thiamine antagonist introduced in 1960. Acts on the early first generation schizonts and
merozoites.

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  It is used prophylactically in combination with Ethopabate and Sulphaquinoxaline against E.
Brunetti and E. Maxima inorder to increase the spectrum.
 It has good activity against E. tenella and E. acervulina.
 It is used for the treatment of coccidiosis in chicken, turkey and ruminants.
 The major advantage of this drug is slow development of resistance.
 Method of administration
 Broiler and Layer: Continuously in feed.
 Cattle: Prophylactic / therapy.
 Layers: contraindicated
 Withdrawal period: 3 days.

Dinitolmide

 It is a Dinitrobenzamide with greatest activity against asexual stage of coccidia, the merozoites
 Prolonged treatment induces coccidiociddal effect
 It is highly active against E. tenella and E. necatrix
 It is also used for treating birds during periods of low exposure risk to coccidian
 It is contraindicated in layers.
 Withdrawal period: 3 days.

Nicarbazin

 It is a carbanilide, predominantly coccidiocidal, suppressing second generation schizonts

 It is also used for prevention rather than treatment. Owing to its slow development of resistance it
is still used in shuttle programme.
 It can be used to overcome heat stress in broilers if fed during hot climate
 Contraindicated in layers and with other anticoccidials
 Withdrawal period is about 7 days 9after egg production and hatchability)

Sulfonamide

 More effective against intestinal then caecal species of coccidian

 They are effective against 2nd generation schizonts. Hence it is effective when clinical signs of
outbreak are noticed.
 2nd generation schizonts are important for developing immunity, hence natural immunity develops
in chicken on sulphonamides prophylactic program
 Sulphaquinoxaline is used for treatment alone and with amprolium in turkey, chicken and rabbit
also as prevention in cattle.
 Sulfaquinoxaline + Pyrimethamine + Ormetoprim
 Contraindicated in replacement layer birds, stopped before 28 days of coming to lay, withdrawal
period is about 5 days

Arprinocid

 It is a purine analog converted to an acetic 1-N-oxide metabolite.

 Highly active against the early invasive and intracellular stages of Eimeria and also affects
sporulation of oocyst
 Inhibit microsomal metabolism of DNA synthesis in coccidian.
 Parent compound inhibits hypoxanthine-guanosine transport of E.tenella in vitro.

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  Coccidiocidal on prolonged medication effective against all species of chicken and turkey
coccidian.
 Rapid development of resistance and hence confined to shuttle programme.

Halofuginone

 It is extracted from plant Hydrangea family

 Highly toxic to all coccidian of chicken and turkey at just 3ppm
 It is both static and cidal with activity against early developing stages (asexual)
 Contraindicated in layers
 Withdrawal period is about 7 days.

Toltrazuril

 Potent coccidiocidal, active against schizogony and gametogany stage especially developing
aporozoites can be used with interrupted treatment programme of 2-3 days in water rather than
continuous feeding hence allows strong immunity development.
 Recommended for Monensin resistant strains. Needs extended withdrawal period.
 Other species: Sulphonamides, Amprolium and Ionophores are generally used.

Diclazuril

 Benzeneacetonitrile derivative, safe and potent coccidiocidal drug compatible with all drugs and
feed additives and has a zero withdrawal period. Effective against both schizonts and gametocytes
 Of Eimeria tenella, gametocyte of E.brunetti etc. The stage against which it is active is species
specific. Recommended at the rate of 1ppm in feed for broiler, turkey and rabbit.

Halofuginone are static as well as cidal others are static

CHAPTER-31: EXTERNAL ANTIPARASITICS

INTRODUCTION

 Insecticides are used on animals to control mites, fleas,ticks and flies

Factors affecting the action of insecticides

 Individual variations in response to insecticides

 Young animals are most susceptible
 Stress can increase susceptibility
 Species variation - horses tend to develop uricaria and hyperthermia
 Cats are very susceptible to cholinergic stimulants
 Avoid applications in extremely hot and humid weather

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organophosphates(OPC)

 Thio compounds include coumaphos, fenthion,diazinon, ethion, famphur.

 Oxy compounds include dicholorovos and tetrachlovinphos

Mechanism of action

 The OPC insecticides inhibit Ach breakdown by inhibiting ChE irreversibly.

 Compounds are lipophilic, well absorbed through the skin
 Metabolism of OPC occurs mainly in the liver. compounds pose no residue problem.
 Applied to animals topically

Adverse effects

 Clinical sign include salivation, lacrimation, urination, defecation, fasiculation ataxia and
convulsion
 Chronic toxicity or delayed toxicity seen with some OPC compounds with a delayed onset of
paralysis due to progressive demylination of motor nerons.
 Treatment involves decontamination and administration of atropine sulfate and pralidoxime.

CARBAMATES and CHLORINATED HYDROCARBONS

Carbamates

 Carbaryl and propoxur. They are used in the treatment of ectoparasites in small animals as
powder, shampoo and collar formulations.
 Mechanism of action - inhibites ACh esterase via carbamylation. Their effects are more reversible
than those of OPC since the binding between carbamates and cholinesterase is noncovalent.
 Adverse effects similar to OPC poisoning. Atropine sulfate is an effective antidote.
 2-Pam should not be used to treat carbamate poisoning
o Carbamate binding to cholinesterase is reversible
o 2-PAM itself inhibits cholinesterase in a reversible manner.

Chlorinated hydrocarbons

 Cholrinated ethane derivatives - DDT, methoxychlor are very effective synthetic insecticides.
Enviornmental Protection Agency banned these compounds

Mechanism of action

 These insecticides increase intracellular sodium and calcium of exictable cells via two
mechanisms
 High sodium cause depolarization and calcium will overstimulate neurotransmission, which
paralyze the insects.
 They prevent the closure of sodium channels, leading to an increase in intracellular sodium
concentration
 They increase calcium by inhibiting the uptake of calcium into the endoplasmic reticulum

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Pharmacokinetic properties

 Highly lipophilic, fat in feed promotes absorption however, obese animals are more resistant to
insecticide toxicity, because fat adsorbs lipophilic chemicals.
 DDT is metabolized into DDD and DDE which is water soluble and is excreted in the urine.
 DDE is permanently stored in the adipose tissue of animals, causing residue problems

Adverse effects

 CNS stimulation which may lead to convulsion, cardiac arrhythmia may be induced .
Phenobarbital to control convulsions.
 Egg shell thinning results from the ability of DDT to block estrogen receptors that mediate the
deposition of calcium into the egg shell

Lindane

 It increases excitability of excitable cells by blocking GABA gated chloride channels to induce
depolarization.
 Lindane is more toxic than DDT. Young animals, especially, calves and toy breed dogs are
sensitive to poisoning.

PYRETHROIDS AND OTHER ECTOPARASITICIDES

Pyrethroids

 Allethrin, cypermethrin, fenvalerate,permethrin

 They are alkaloids of pyrethrum which increases excitability of ectoparasite neurons by
prolonging the opening of sodium channels, therby causing arthropod paralysis. They are
generally safe but may cause local irritation hypersalivation and vomition
 Pyrethroids should not be used in cats

Other ectoparasiticides

Amitraz

 It is a formamidine insecticide for use in dogs, pigs and cattle

 It activates octopamine receptors in arthropods, which inhibits neurotransmission, resulting in
flaccid paralysis
 Amitraz should not be applied to swine before 3 days of slaughter.

INSECT DEVELOPMENT INHIBITORS (IDIS)

Diflubenzuron

 This drug inhibit chitin synthesis in larvae and eggs of insects. They have no effects on adult
insects. chitin is an important constituent of exoskelton and egg shell.

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Insect growth regulators

 cyromazine, Pyriproxyfen : They mimic the actions of the juvenile hormones of insects. They
interfere with reproductive organ differentiation cyromazine is administered orally for 4-6 wks to
control fecal maggots in poultry. It is also used as a spray on to surface of manure.

Rotenone

 It is an alkaloid derived from the root of the Derris plant.

 It inhibits cellular respiratory metabolism by blocking the electron generation results in reduced
nerve conduction.

RESISTANCE TO ECTOPARSITICIDES

 Some arthropodes are resistant to the lethal effects of drugs following continous exposure to
them.

Mechanism of resistance

Behavioral resistance

 After exposing to a particular ectoparasiticide, the pests would develop the behaviour to avoid the
agent

Physiological resistance

 Decreased penetration into target organism

 Increased metabolism of ectoparasiticides
 Decreased sensitivity of the target site.

Strategies

 Appropriate selection of ectoparasiticides

 Reduction in the number of treatments
 Use of ectoparasiticide rotations and mixtures
 Limited interactions with agronomical pesticides
 Resistance monitering

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 CHAPTER-32: ANTISEPTICS AND DISINFECTANTS

DEFINITIONS

Sterilization

 The act or process, physical or chemical, that destroys or eliminates all forms of life, especially
microorganisms.

Disinfection

 The killing of pathogenic organisms by direct application of physical or chemical agents.

Disinfection processes lack the margin of safety achieved by sterilization procedures, particularly
concerning their lack of sporicidal activity.

Disinfectant

 An agent, usually chemical, that frees from infection by destroying the disease causing
microorganism. This refers to substances applied to inanimate objects.
 High – level disinfectant: active against bacterial endospores.
 Intermediate-level disinfectant: inactivate tubercle bacilli but not bacterial spores.
 Low – level disinfectant: rapidly kills vegetative form of bacteria and fungi but not tubercle
bacilli, endospores and small non lipid viruses.

Antiseptics

 A substance that prevents or arrests the growth or action of micro organism on living tissue either
by inhibiting their activity or by destroying them.

Germicide

 An agent that destroys micro organisms, especially pathogenic organisms.

 Most disinfectants rapidly kill bacteria (with minutes), whereas antibiotics though effective at
lower concentration may be only bacteriostatic or kill only after several hours after exposure.
 Antibiotics are used systemically, locally or topically, but antiseptics are intended for use on skin
or mucous membrane.

IDEAL PROPERTIES OF ANTISEPTIC

 It should have a broad spectrum of activity, including bacteria, fungi and virus.
 It should be rapidly effective and should be germicidal.
 It should not allow the emergence of resistant pathogens.

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  It should not be inactivated by protein or organic matter or tissue debris.
 It should be minimally toxic.
 It should be non-staining, non irritant and non-corrosive or non toxic.
 It should be odorless and deodorizing.
 It should have detergent property
 It should have residual action after rinsing.
 It should be simple, easily available, stable and economical to use.

FACTORS AFFECTING THE ACTION OF DISINFECTANTS

 Type of disinfectant and its concentration.

 Type of organism, their number, presence of spores and capsules
 Temperature and pH of solution
 Presence of organic matter
 Length of exposure
 Temperature of room and pressure applied (gaseous disinfectants)

CLASSIFICATION OF DISINFECTANTS

 Oxidizing agents
o The peroxides – H2O2, KMno4
o The halogens – Chlorine, Iodine
 Reducing agents - Formaldehyde, Glutaraldehyde, Sulphur dioxide
 Acids and Alkalis - H2SO4, NaOH, Boric acid, Na2Co3, Benzoic acid, Quick lime, Salicylic Acid
 Alcohols - Ethyl alcohol, Isopropyl alcohol
 Phenols and cresols
 Chloroxy phenols - P- Chlorometa xylenol PCMX, Dichlorometa xylenol
 Dyes - Acriflavine, Gentian violet
 Detergents
o Anionic - soap
 Sodium lauryl sulphate
 Ca and Ammonium mandelate
o Cationic - Quarternary ammonium compounds
 Cetrimide
 Benzalkonium chloride
o Amphoteric - Ampholytic surfactant
 Biocides
 Chlorhexidine hydrochloride
 EDTA

OXIDIZING AGENTS

 Two types of oxidising agents are

o Those which release gaseous oxygen – Hydrogen peroxide
o Those which cause oxidation without the release of oxygen –KMnO4, The halogens

Solution of Hydrogen peroxide (3%) -> Intermediate Level Disinfectant

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  Produces nascent oxygen in contact with organic mater, which is partly due to the enzyme
catalase
 In turn is responsible for oxidizing effect.
 Organic matter affects the action
 Generally available as 20 volume solution .

Benzoyl peroxide

 Slowly release oxygen, Oxidizing antiseptic, keratolytic and antiseborrheic – useful in pyoderma
in dogs.
 Skin irritation limits its use.

Sodium perborate

 White crystalline powder, decompose in solution to give sodium metaborate and Hydrogen
peroxide which inturn release nascent oxygen.

Potassium permanganate

 Dark purple crystals with metallic luster forming pink or deep purple solutions in water.
 Astringent and antiseptic.
 1 in 1000 solution is used to clean the wound and as mouth lotion (antiseptic and deodorizer)
 5% solution is astringent, reduce excess granulation
 Once the solution turns brown it is inactive.
 Stains the tissues ( Destainer - Oxalic and sulphurous acid).

The Halogens

 Antiseptic halogens

Chlorine

 Inexpensive, easily available, bactericidal and broad spectrum.

 Strong oxidizing agent, Oxidation of peptide links and denaturation of protein.
 It accumulation inhibits essential enzyme system.
 It is inactivated in the presence of organic matter.
 Two derivatives of chlorine are
o Inorganic compound
 Eg. Na hypochlorite – Dakin’s Solution ( 0.4 % available chlorine )
 It is unstable and releases Cl slowly when exposed to the atmosphere or organic
material.
 It can be used as Teat dip at a concentration of 4% available chlorine.
o Organic derivatives
 Eg. Chloramines T and Chlorinated lime (Bleaching powder)
 Chloramines T - slowly release oxygen, disinfection of udder and sanitation of
dairy utensils.

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  Chloramines releases Cl and HoCl which acts as oxidizing agent. They are also
used to treat swimming pool and drinking water.
 Chlorinated lime (Bleaching powder)
 Mixture of calcium hypochlorite and CaCl 2 yields 30 % chlorine and is used for
disinfection of water supply, live-stock premises, disposal of carcasses etc.

Iodine

 Antiseptic wound dressing, but is an irritant and retards wound healing.

 Interacts with proteins of cytoplasmic membrane.
 Two forms
o Those releasing free iodine
 Lugol’s Iodine
 Tincture iodine - Weak and Strong
o Antiseptic and mild irritant action – weak tincture Iodine (25%)
o Iodophors - Complex between iodine and a carrier polyvinyl pyrrolidone – povidone
iodine
 Increases the solubility of iodine
 Sustained release
 Improves the activity of Iodine
 Use
o Skin scrub, low Iodine concentration prevent staining hence used in mastitis control as
teat dip (0.5 % available Iodine)
 Toxicity: Cutaneous and systemic absorption leads to iodism
 Resistance is rare.

REDUCING AGENT / ALDEHYDES

 Formaldehyde
 Glutaraldehyde
 Sulphur dioxide

Formaldehyde

 Highly bactercidal and action is not affected by organic matter

 Formalin – strongly astringent and antiseptic, precipitates protein on the skin and hardens it.
 Foot bath 1 in 10 to give 4 % formaldehyde
 Fumigation:
 10% formaldehyde solution is used for room disinfection followed by closing the room for 24 hrs
 In combination with KMno4 (3:5 ) or boiling formaldehyde alone
 It is an irritant and has corrosive action on the skin. The irritant vapours can be neutralised with
ammonia solution

Glutaraldehyde

 Chemo sterilizing agent, less irritant and active against bacteria, fungi, virus, spores and biofilms.
 MOA – Denaturation of protein and is an alkylating agent

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  Contact time: 10 – 30 mts for High Level Disinfection and 6 – 10 hrs for s terilization,
 Use: Disinfection for lensed clinical equipment (endoscope or cryoscope) and treatment of blood
products. It is more active at alkaline pH- 7.5 to 8.5.

Sulphur dioxide

 Liberates gas when sulphur is ignited, 0.5 kg should be burned / 100 sq.ft. and atmosphere should
be moist and ventilation should be sealed.

ACIDS AND ALKALIES

 Release H+ and OH- ion and denature protein, potent bactericides except mycobacteria.

Acids

Boric acid

 Mild germicidal activity

 Does not irritate the skin or tissues
 2% solution is used as collyrium and mouth wash
 Borax glycerine (12% W/v borax with glycerine) and boro glycerine (31% boric acid in
glycerine) is used for treating wound lesions.
 Boric acid (2.5 g) with Salicylic acid (1.5 g) and talc (upto 50 g) is used as dusting
powder.

Benzoic acid

 Along with Salicylic acid as Witfield's ointment it acts as a fungicide on skin

Acetic acid

 2-5 % solution is used as antiseptic wound dressing and possess bacteriostatic property.

Alkalies

Sodium carbonate (Washing soda)

 4% solution is used as antiseptic cleansing for wound.

Calcium oxide (Lime)

 It is used as general disinfectant in farm yard by scattering in the drains or by sweeping

on the floors.

Calcium hydroxide (Milk of lime)

 For disinfecting the areas contaminated with excreta

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 ALCOHOLS

Ethyl alcohol

 70% is used as skin antiseptic at injection site and as preoperative skin swab. It is virucidal and
less toxic.

Isopropyl alcohol

 50% possess bactericidal action and is used as skin antiseptics.

Uses

 Intermediate level disinfectant

 Alcohol acts by denaturing the protein and i nhibition of cell metabolites

 It is used alone or in combination with Iodine, Phenol, Chlorhexidine

 Not active in the presence of physical dirt and not recommended for surgical instruments (not
sporicidal)
 Immersion of hand in 65.5 % ethanol for 1mt is as effective as scrubbing for 4 – 7 mts.

PHENOL AND CRESOL

Phenols

 First disinfectant and antiseptic used by Joseph Lister in 1867.

 Intermediate Level Disinfectant
 It is coal tar derivative.
 It acts by denaturing the bacterial protein. It acts as a protoplasmic poison when applied to tissues
and may even cause necrosis.
 Act on cytoplasmic membrane and cause leakage.
 It is mainly used as a general disinfectant(1-2% solution) and chemical sterilizer (5%)
 Phenol is used as a standard to measure the effectiveness of other disinfectants and antiseptics in
terms of phenol coefficient.

Cresol

 Impure mixture of ortho, meta and para metyl deriatives of phenol and is obtained from coal tar
distillation
 It is a better disinfectant and less toxic than phenol
 2% solution of cresol with soap is commercially available as Lysol and is used as disinfectant

Toxicity

o Both phenol and cresol are toxic to dogs and cats hence should not be used to disinfect
the kennels or cat cages.
o Cats and dogs should not be bathed with soaps containing carbolic acid.
o Toxic signs include convulsion, coma and death due to respiratory and cardiac failure.

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Detergents

 These are surface active agents, reduce surface and interfacial tension and act as cleansing -
emulsifying agents with antibacterial property. They are also called as surfactants and are of two
types:
o Ionic - Anionic and Cationic
o Nonionic - not antibacterial
 Detergent antiseptics are non irritant and non toxic at the recommended concentration.
 Their activity is reduced in the presence of organic matter, and have no effect on spores, virus and
fungi.

Anionic Detergents

 Active in mild acid solution and include soaps, calcium mandelate, ammonium mandelate and
sodium lauryl sulphate.
 Active only against G+ve organisms
 Soap emulsifies the grease and cause loosening of keratin, dirt and debris.
 It is combined with agents such as Phenol, Chlorhexidine, Potassium Iodide and
Hexachlorophene to increase the antibacterial activity.
 Hard Soap is o btained by reaction of vegetable oil with Sodium hydroxide and is used as
emulsifying and dispersing agent in liniment, lubricant enema/ rectal suppository.

Cationic Detergents

 Active in alkaline medium and include quartenary ammonium compounds and dyes.
 Active against G+ve (high cone) and G-ve bacteria, ineffective against spores, virus and fungi
 Bind irreversibly to phospholipids and proteins of cytoplasmic membrane and impair
permeability and cause bactericidal effect .
 Primarily used to disinfect floor, wall and equipment surface
 It forms a flim on the skin which is strongly antiseptic externally but unreactive internally

Cetrimide

o It acts as a foaming agent

o 1% solution is used for skin cleansing and wound dressing
o 0.1% solution is used to disinfect dairy equipments, utensils, clothes and hands
o 0.5% cream is used as a prophylactic agent against mastitis
o 1% solution containing 0.2% sodium nitrite is used as antirust agent.

Benzalkonium chloride

o 0.1% alcoholic solution is used for skin sterilisation

o 0.01-0.05% solution is used on mucous membrane and to clean deep wounds

OTHERS

Amphoteric compounds

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  Amphoteric surfactant biocides have one anionic and one cationic group
 Anionic at pH above the isoelectric point and cationic at pH below the isoelectric point. They are
called as Zwitter ions.
 Shampoos- equal anions and cations, hence they are balanced

Chlorhexidine hydrochloride

 Intermediate Level Disinfectant

 Its a potent bactericidal agent and acts by disrupting the bacterial cell wall
 Active against both G+ve and G-ve organisms
 Incompatible with soap and anionic detergents
 Ineffective against fungi, virus and spores
 0.5% alcoholic or 1% aqueous solution is used as skin antiseptic
 1 :5000 solution is used for dairy and 1:1000 is used as eye lotion
 1g pessary is effective against metritis
 1% aqueous solution is used as antiseptic teat dip
 Toxicity is low and irritation is uncommon
 Useful in prophylaxis and treatment of oral diseases.

EDTA

 Tris EDTA acts on cell wall and alter the cell membrane permeability
 Active against G-ve organisms
 Potentiates action of chlorhexidine in lavage solution
 Used as an irrigant in combination with antibiotics in otitis externa, bacterial rhinitis and multiple
fistula in dogs.

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 CHAPTER-33: INDIGENOUS PLANTS

INTRODUCTION

 Indigenous drugs refer to pharmacologically active principles primarily obtained from the
medicinal plants with proven therapeutic value.
 A large number of medicinal plants have been recognized to possess therapeutic value in the
treatment of a variety of diseases.
 The medicinal plants contain pharmacologically active principles such as alkaloids, glycosides,
resins, tannins, fixed oils, volatile oils etc.

MEDICINAL PLANTS AND ITS PHARMACOLOGICAL ACTIONS

Rauwolfia serpentine
Active principle Reserpine
Pharmacological action Tranqulizer and Antihypertensive
Vinca rosea
Active principle Vincristine and Vinblastine
Pharmacological action Anticancer drug – common used for the treatment of transveneral tumour in dogs.
Withania somnifera
Active principle Somniferine
Pharmacological action General tonic and Immunostimulant
Laptadenia reticulate
Active pricinple Laptadine
Pharmacological action Galactagogue
Gingiber officinalis
Active principle Gingerol
Pharmacological action Carminative and Stomachic
Ricinus communis
Active principle Ricin
Pharmacological action Purgative

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INDIGENOUS ANTIBACTERIAL/ANTISEPTIC AGENTS

 Curcuma longa
 Azadirachta indica
 Allium sativum
 Ocimum sanctum
 Zingiber officinalis

INDIGENOUS ANTIFUNGAL AGENTS

 Curcuma longa
 Pongamia glabra
 Azadirachta indica
 Cassia alata

INDIGENOUS ANTHELMINTIC

 Areca catechu
 Azardirachta indica
 Carica papaya
 Punica grantum

INDIGENOUS ARTHROPODE REPELLANTS/ INSECTICIDAL AGENTS

Acorus calamus Repellant of Ixodid ticks

Azadirachta indica wide range insecticidal
Curcuma longa Against ticks and mites
Chrysanthemum indicum Against scabies
Pongamia glabra Against sarcoptic mange
Ricinus communis Against mites
Tinospora cardifolia Against scabies

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