PHARMACOLOGY – Infectious & Parasitic Disease Module

PENICILLINS
BETA-LACTAM ANTIBIOTICS
• Antibiotics having a four-membered β-lactam ring, which is essential to their
activity – Hydrolysis of the β-lactam ring by bacterial β-lactamases can lead
to inactivation.
• All β-lactam antibiotics interfere with the synthesis of the bacterial cell wall
peptidoglycan.
• Examples of beta-lactam antibiotics are;
o PENICILLINS
o CEPHALOSPORINS
o CARBAPENEMS
o MONOBACTAMS

Penicillins – Mechanism of Action

• Penicillins act by inhibiting the transpeptidase action of penicillin-binding proteins (PBPs) involved in the
cross-linking of the peptidoglycan layer of the cell wall.
o The polysaccharide in peptidoglycan contains alternating amino sugars, N-acetylglucosamine and N-
acetylmuramic acid.
o A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar, which terminates in D-alanine.
o Penicillin-binding protein removes the terminal D-alanine and the energy so released is utilized for
establishment of cross linkages between peptide chains.
o Cross-links give the cell wall its rigidity.
• Beta-lactam antibiotics are structural analogs of the natural D-Alanine substrate, thus covalently bind to the
transpeptidase site of PBPs.
• Bactericidal – Bacterial cell death occurs due to;
o Osmotic rupture
o Destruction of the cell wall by autolysins – Bacteria produce degradative enzymes (autolysins) that
participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin, the
degradative action of the autolysins occurs even in the absence of cell wall synthesis. Penicillin also leads
to inactivation of an inhibitor of autolytic enzymes in the cell wall.
• Penicillins are ineffective against,
o Resting organisms which are not making new cell wall.
o Organisms without cell wall – Eg: Mycoplasma, Mycobacteria, Protozoa, Fungi, Viruses.
o Human cells – Hence, has a high therapeutic index.
• Penicillins act in a time-dependent fashion.
• Penicillins are effective against many gram-positive, gram-negative bacteria, aerobes as well as anaerobes.
❖ In gram-positive bacteria, the cell wall is almost entirely made of peptidoglycan that are extensively
cross linked, and their cell walls are easily traversed by penicillins. In gram-negative bacteria, the
cell wall consists of alternating layers of lipoprotein and peptidoglycan. Also, the lipopolysaccharide
membrane presents a barrier to the water-soluble penicillins. Therefore, gram-positive bacteria
have a higher susceptibility to penicillin.
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Penicillins – Classification
• Narrow spectrum penicillin –
o Benzylpenicillin sodium (penicillin G)
Natural Penicillin
o Phenoxymethylpenicillin (penicillin V)
o Repository forms – Benzathine benzylpenicillin, Procaine benzylpenicillin
o Anti-staphylococcal penicillins – Methicillin, Cloxacillin, Flucloxacillin, Nafcillin, Oxacillin
❖ Anti-staphylococcal penicillins are semisynthetic penicillins active against Staphylococci and
Streptococci. They are resistant to staphylococcal β-lactamases (Penicillinase resistant).
• Broad spectrum (Extended-spectrum) penicillin –
o Aminopenicillins – Amoxicillin, Ampicillin, Co-amoxiclav (Amoxicillin with clavulanic acid)
o Anti-psuedomonal penicillin – Only parenteral forms are available; High cost.
❖ Antipseudomonal penicillins include ureidopenicillin (Eg: Piperacillin) and
Carboxypenicillins (Eg: Ticarcillin) that are active against Pseudomonas.

Penicillins – Pharmacokinetics
❖ Absorption
• Penicillin G – Destroyed by acid gastric juice at pH=2. Hence, need parenteral therapy.
• Penicillin V – Resistant to gastric acid. But food decreases the absorption, better absorbed on an
empty stomach.
• Anti-staphylococcal penicillins – Food decreases the absorption of all the penicillinase-resistant
penicillins because as gastric emptying time increases, the drugs are destroyed by stomach acid.
• Aminopenicillin –
o Amoxicillin – Rapidly and completely absorbed even if taken with food.
o Ampicillin – Absorption affected by food. Available as parenteral therapy.
❖ Distribution
• About 60% is plasma protein bound.
• Distributed mainly in the extracellular fluids – Therapeutic concentration is achieved in joint fluid,
pleural, pericardial fluid, bile, middle ear in the presence of inflammation. Blood, pus, and tissue
fluids do not interfere with the action.
• Penetration into eyes, central nervous system, bone and prostate is poor. Levels in prostate are
insufficient to treat prostate infection.
• Crosses the blood brain barrier only if the meninges are inflamed(meningitis) and therapeutic
concentrations are achieved.
• Crosses the placenta; Hence, effective in certain intrauterine infections. No teratogenicity.
• Found in breast milk – may produce diarrhoea, rash and candidiasis in the baby.
❖ Metabolism
• Metabolism is usually insignificant because of rapid excretion.
• Exceptions – No dosage adjustment is required for these drugs in patients in renal failure.
o Nafcillin and oxacillin are primarily metabolized in the liver.
o Ampicillin, Amoxicillin and Cloxacillin is eliminated by both the renal and biliary excretion.
o Some metabolism of penicillin G may occur in patients with impaired renal function.
❖ Elimination
• Elimination is mainly by kidneys – Tubular secretion (90%), Glomerular filtration (10%).
• Probenecid inhibits the tubular secretion of penicillins by competing for organic acid transporters.
• Dose adjustment are required only in severe renal failure (due to wide therapeutic index) and in
neonates and premature babies.
• Plasma elimination half-life is short (about 30 – 90 minutes). Ampicillin and other extended-
spectrum penicillins are secreted more slowly than penicillin G.
• Piperacillin exhibit saturation (zero-order) kinetics; it is about 25% excreted in bile.
• Large doses are recommended 6 – 8 hourly.
• Broad spectrum penicillins cause failure of oral contraception –By inhibiting colonic bacteria, it
interferes with deconjugation and enterohepatic circulation of oral contraceptives.
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Penicillins – Adverse Reactions
• HYPERSENSITIVITY REACTIONS: Type I and IV (Most commonly type I reactions) – Ranging from mild
(rash, urticaria, fever, bronchospasm) to severe (anaphylactic reaction, Steven Johnson syndrome,
hemolytic anemias, vasculitis).
• ANAPHYLAXIS – Anaphylaxis is common with parenteral forms. Metabolic opening of the β-lactam ring
creates a highly reactive penicilloyl group, which polymerizes and binds with tissue proteins to form the
major antigenic determinant.
o 50% occur immediately, 85% within 15 minutes and all anaphylaxis reactions occur within 1 hour.
o Penicillins become more allergenic if left to stand in solution. Therefore, need to inject immediately.
o Allergy can be avoided by,
1) A reliable history of a previous adverse response to penicillin.
2) Observation for immediate-type reactions.
3) Since alternative drugs are available, avoid penicillin if there is suspicion of allergy.
4) Evaluating type I hypersensitivity with penicillin intra-dermal testing.
• CROSS ALLERGY – Seen between penicillins (less commonly with carbapenems and monobactams) and
partial cross-allergy exists between penicillins and cephalosporin.
• CATION TOXICITY – Penicillins contains high amounts of Na+ or K + as the cations.
❖ Caution in heart failure and chronic kidney disease.
• NEUROTOXICITY – Dose related ADRs (Uncommon; seen with high IV doses or intrathecal administration)
(Penicillins can provoke encephalopathy, coma, convulsions due to GABA inhibition).
• DIARRHOEA and other GI disturbances – Common with oral penicillins (particularly broad-spectrum type),
They alter the bacterial flora in the gut. Can be associated with supra-infection such as pseudomembranous
colitis (caused by Clostridium difficile and most commonly seen with ampicillin and amoxicillin [more with
ampicillin than amoxicillin]).
• Specific reactions to individual penicillins –
o SUPER-INFECTION caused by broad spectrum penicillins (Eg: Oral candidiasis)
o CHOLESTATIC JAUNDICE with cloxacillin, flucloxacillin and co-amoxiclav.
o MACULAR PAPULAR RASH with aminopenicillins in the setting of viral illnesses (such as infectious
mononucleosis in Epstein-Barr virus infection), glandular fever and lymphocytic leukaemias.
o Antibiotic associated fever
o Very rarely – Blood disorders (Cytopenias – with high doses for > 10 days), Coagulation disorders,
Interstitial nephritis, Hepatitis

Penicillins – Antibacterial spectrum

Benzylpenicillin (Penicillin G)
• Drug of choice for the treatment of gas gangrene (Clostridium perfringens)
and syphilis (Treponema pallidum), in leptospirosis and actinomycosis.
o Most sensitive to Neisseria meningitidis (Meningococcus) and
Streptococcus pyogenes (Group A, β-haemolytic streptococci).
o Moderately sensitive to Streptococcus pneumoniae, viridans
streptococci and other gram-negative cocci.
o Least sensitive to Enterococcus. Faecalis (Group D streptococci).
• Staphylococcus aureus and Neisseria gonorrhoea (Gonococcus) is
resistant to benzylpenicillin.

Phenoxymethylpenicillin (Penicillin V)
• Spectrum is identical to Penicillin G, but it is only about 1/5th as active
against Neisseria, other gram negative bacteria and anaerobes.
• Indicated only in minor infections because of its relatively poor
bioavailability, the need for dosing multiple times a day, and its relatively narrow antibacterial spectrum.
• Used only for streptococcal pharyngitis, sinusitis, otitis media and for prophylaxis of rheumatic fever (when
an oral drug has to be used).

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Anti-staphylococcal Penicillins
• Non-penicillinase producing organisms are less sensitive to these drugs than to penicillin G. Have minimal to
no activity against gram-negative infections.
• Use is restricted only to the treatment of infections caused by penicillinase-producing Staphylococci,
including methicillin-sensitive Staphylococcus aureus (MSSA).
❖ However, due to its toxicity (interstitial nephritis), methicillin is not used clinically and used only in
sensitivity test to identify Methicillin resistant Staphylococcus aureus (MRSA).

Aminopenicillins
• Have an antibacterial spectrum similar to that of penicillin.
o But less active than benzylpenicillin against Gram-positive cocci, but more active than the anti-
staphylococcal penicillins.
o More active against Listeria monocytogenes and enterococcal species.
• Active against gram-negative bacilli – Haemophillus influenzae, Escherichia coli, Proteus mirabilis,
Salmonella species, Shigella and, Helicobacter pylori.
❖ However, 60% of E. coli and 20% of Haemophillus influenzae are resistant to treatment.
• Not active against Klebsiella and Pseudomonas spp.
• Amoxicillin and ampicillin are inactivated by penicillinase – All Staphylococcus spp. are resistant.
• Both ampicillin and amoxicillin are indicated in exacerbations of chronic bronchitis, sinusitis, community
acquired mild pneumonia, otitis media, oral infections, and UTI.
• Amoxicillin is administered with clavulanic acid (Co-amoxiclav) as oral or IV dosage forms.
o Clavulanic acid is a beta-lactamase inhibitor; has no antibacterial activity. It binds irreversibly to β-
lactamases, and competitively protects the penicillin against bacterial β-lactamases.
o The combination is effective for beta lactamase producing bacteria including anaerobes (Eg:
Bacteroides sp.) which are resistant to amoxicillin, and thereby extends their antimicrobial spectra.
o Indications – Infections of respiratory tract, bone and joint, genito-urinary tract, severe dental
infections, abdominal infections, cellulitis, animal bites.
o CHOLESTATIC JAUNDICE can occur during or after treatment. High risk in those above 65 years of
age and with prolonged therapy; should not be given for > 14 days.

Anti-pseudomonal penicillins
• Have the same antibacterial spectrum as ampicillin (and are susceptible to β-lactamases).
❖ But less active than aminopenicillins against Gram-positive bacteria.
• Have the additional capacity to destroy Pseudomonas aeruginosa, indole-positive Proteus spp. and
Enterobacter species. Piperacillin is active against Klebsiella pneumoniae as well.
o Ticarcillin is available in combination with clavulanic acid to provide greater activity against
penicillinase–producing organisms.
o Piperacillin is available as a combination with the β-lactamase inhibitor tazobactam.

Repository forms
• These are insoluble salts of penicillin G, which must be given by deep intramuscular injection. They release
penicillin G slowly at the site of injection to yield low, but prolonged drug levels..

Procaine Penicillin Benzathine benzylpenicillin

• It has 300 mg of procaine penicillin and 60 mg of • Consists of two molecules of benzylpenicillin and
benzylpenicillin. one molecule of ammonium base.
• Procaine is an anaesthetic – Pain free injection. • Slowly released from the site of injection. Low
• Used to treat syphilis – once a day injection. blood levels are present for 3 weeks.
(12–24 hourly as aqueous suspension) • Used to prevent infection with beta haemolytic
streptococcal pharyngitis to prevent rheumatic
fever – once in 3 weeks (as aqueous suspension)

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Penicillins – Resistance to penicillin
• Acquired resistance to penicillins and other β-lactams is due to one of four general mechanisms;
1. Inactivation of antibiotic by β-lactamase – The most common mechanism of resistance.
o β-lactamases hydrolyze the cyclic amide bond of the β-lactam ring, which results in loss of
bactericidal activity – mainly seen in gram-positives and in small amounts in gram-negatives.
o Gram-positive organisms secrete β-lactamases extracellularly. Gram-negative bacteria inactivate β-
lactams in the periplasmic space (i.e. between the lipoprotein and peptidoglycan layers of cell wall).
2. Modification of target PBPs – Leads to methicillin resistance in Staphylococci and penicillin
resistance in Pneumococci and most resistant Enterococci.
o These resistant organisms produce PBPs that have low affinity for binding β-lactam
antibiotics. They are not inhibited except at relatively high, often clinically unachievable,
drug concentrations.
3. Impaired penetration of drug to target PBPs – Only in Gram-negative species
o The outer membrane of their cell wall is impermeable to beta-lactams, and it requires outer
membrane protein channels called porins for them to enter into the organism.
o Absence of the proper channel or down-regulation of its production can impair drug entry
into the cell.
4. Antibiotic efflux – In gram negatives (Eg: Klebsiella pneumoniae); reduce the amount of
intracellular drug.

CEPHALOSPORINS
Cephalosporins – Introduction
• Cephalosporins are β-lactam antibiotics, closely related both structurally and functionally to the pencillins.
• Cephalosporins have the same mode of action as penicillins – impair bacterial cell wall synthesis and hence
are bactericidal; They also exhibit time-dependent killing.
❖ However, they bind to different enzymes than those which bind penicillin (PBP-1 and PBP-3). This
explains difference in spectrum, potency and lack of resistance.
• Cephalosporins have a broad spectrum of activity – improved activity against Gram-negative organisms, but
less anti–Gram-positive activity.
• They are affected by the same resistance mechanisms as penicillins. However, they tend to be more resistant
than the penicillins to certain β-lactamases.
• Most cephalosporins are produced semi-synthetically by the chemical attachment of side chains to 7-
aminocephalosporanic acid (cephalosporin-C).
• Oral and parenteral preparations are available – Treats ‘day to day’ as well as ‘serious infections’
• High safety profile – Wide therapeutic index.

Cephalosporins – Limitations
• Emerging resistance patterns.
• Some III and IV generation cephalosporins are available only as parenteral formulations.
• Cross allergy with penicillins.
• Insensitivity to – Listeria monocytogenes, Atypical organisms (including Mycoplasma and Chlamydia),
Clostridium difficile, Methicillin resistant Staphylococcus aureus (Except 5th generation), Enterococci

Cephalosporins – Classification
• Cephalosporins divided into generations based on;
o Antimicrobial and pharmacokinetic properties,
o Chronological sequence of development, and,
o Resistance to β-lactamases.

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First Generation Second Generation Third Generation Fourth Generation Fifth Generation
“FA/PHA” “Everything Else” “ONE/TEN/IME” “PI” “ROL”
Cefixime
Cephalexin Cefuroxime axetil Cefpodoxime proxetil
Oral Cefadroxil Cefaclor Ceftibuten
Cephradine Cefprozil Cefdinir
Examples Cefditoren
Cefotaxime
Cefuroxime
Cefazolin Ceftazidime Cefepime Ceftobiprole
Parenteral Cefotetan
Cephalothin Ceftriaxone Cefpirome Ceftaroline
Cefoxitin
Ceftizoxime
Gram-
+++ ++ + ++ +++
Positives
Gram-
+ ++ +++ +++ +++
Negatives
• Weaker than the first • Highly augmented • Highly active against • Active against, gram
• Act as penicillin G
generation against gram activity against gram- gram negative bacteria. positive cocci especially
substitutes.
positive cocci and bacilli. negative organisms. • Good Gram-positive Methicillin resistant
• Good activity against
• Increased activity against (Eg: Enterobacteriaceae) coverage as well Staphylococcus aureus
gram-positive bacteria
gram negative organisms • Less active than first (balanced spectrum). (MRSA) and penicillin
(Streptococci,
such as H. influenzae, generation agents against • Modest activity for resistant Streptococcus
Pneumococci, MSSA)
Enterobacter aerogenes, gram positive cocci anaerobes. Effective pneumoniae.
Antibacterial • Modest activity against
and some Neisseria spp. (including pneumococci, against infections • Bind to altered PBPs
Spectrum gram negative bacteria
(but less than third MSSA) and anaerobes. resistant to earlier drugs. expressed in these
(E. coli, K. pneumoniae
Specific generation agents). • Ceftazidime has good • Active against bacteria – PBP-2A (in
and Proteus mirabilis).
• Anaerobic coverage – activity against Pseudomonas. MRSA), for PBP2B and
• Most oral anaerobes are
some like cefoxitin has Pseudomonas. PBP2X (in penicillin
sensitive, but Bacteroides
coverage against resistant Streptococcus
fragilis is resistant.
Bacteroides fragilis). pneumoniae).
• Not effective against –
• Not effective against –
Pseudomonas, Penicillin
Pseudomonas
resistant Streptococci,
Staphylococcus
epidermidis

Resistance to beta-lactamase Low or absent + ++ +++ Highest

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Absorption Oral forms are generally well absorbed. • Given by IM or IV routes. • Given by IV route.
• All are distributed well
• Protein binding is only
into body compartments.
• Good distribution to 20%.
• Poor protein binding. • Ceftriaxone differs from
Distribution most tissues. • Widely distributed in
others by its high protein
tissues and body fluids.
binding.
Inadequate penetration into the CNS. Adequate levels in CSF regardless of inflammation.
• Cefuroxime axetil is an • Not significant.
ester prodrug hydrolyzed • Cefotaxime deacetylated
PK during drug passage in the body; active
Metabolism • Not significant.
through the gut mucosa. metabolite exerts
Free cefuroxime enters synergistic action with
the systemic circulation. the parent drug.
• Primarily excreted • Most are renally cleared.
• Renally cleared.
through kidneys. • Cefoperazone and
• All are renally cleared. • Plasma half-life is only
• Probenecid increases ceftriaxone excreted
Elimination 2 hours.
plasma half-life. through bile.
Dose adjustments must be made in severe renal impairment.
General have a plasma half-life of 1 – 4 hours, but ceftriaxone has a half-life of 7 – 8 hours (permitting once daily dosing, or at the most twice).

• UTI’s
• Minor staphylococcal • Cefaclor – URTI’s
infections • Cefuroxime – Community • Gonorrhoea • Infections caused by
• Cellulitis or soft tissue acquired pneumonia, • Pseudomonas infection MRSA.
abscess gonorrhoea • Same as third generation.
(Ceftazidime with an • Complicated skin and
• Cefazolin used in surgical • Cefoxitin, Cefotetan – • Serious hospital
aminoglycoside) skin structure infections.
Therapeutic Uses prophylaxis before Peritonitis and acquired infections
• Community Acquired • Resistant and hospital
cardiac surgery and diverticulitis and some resistant to commonly
Pneumonia acquired infections.
orthopedic prosthesis gynecological infections used antibiotics.
• Complicated UTI/Sepsis • Community-acquired
procedures (has better (anaerobic infection) • Enteric fever pneumonia.
penetration to tissues)

Ineffective in meningitis.

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Third Generation Cephalosporins
• Ceftriaxone
o Very effective in treating meningitis caused by N. meningitidis, Pneumococci, H. influenza and
susceptible enteric gram-negative rods, but NOT by Listeria monocytogenes.
o A single intramuscular dose is effective in treating gonorrhoae. An alternative drug for syphilis.
o Excellent for treatment of community acquired pneumonia caused by Pneumococci, H. influenza
and Staphylococcus aureus, Lyme disease caused by Borrelia burgdorferi, complicated UTIs,
abdominal sepsis and septicaemias, and, also for multi resistant typhoid fever (with high doses).
• Cefotaxime
o Like ceftriaxone, has been utilized effectively for treating meningitis and community acquired
pneumonia, and a single intramuscular dose is effective in treating gonorrhoae.
o Has been used in respiratory, genitourinary, abdominal infections, septicaemia, anaerobic and
hospital acquired infections.
• Ceftazidime
o Has excellent activity against Pseudomonas and other gram-negative bacilli – Ceftazidime with
aminoglycosides is the treatment of choice for pseudomonal meningitis.
o Also useful for nosocomial infections and in neutropenic, febrile, immunocompromised patients.
• Cefixime
o Cefixime is used to treat respiratory, urinary and biliary infections.
o In a single oral dose, it provides effective treatment of uncomplicated gonorrhoea.
o Not effective against Staphylococcus aureus and Pseudomonas.

Cephalosporins – Adverse Effects

• HYPERSENSITIVITY REACTIONS – Identical to penicillins, but incidence is lower; Determined by similarity
in side chain, not β-lactam structure.
o If allergic to penicillins, could be allergic to cephalosporins (Cross-reactivity) – around 3% to 5%.
o If a patient has had a severe or immediate allergic reaction or if serum or skin testing for penicillin
allergy is positive, then a cephalosporin should not be used.
o Highest rate of allergic cross-sensitivity is between penicillin and first-generation cephalosporins.
o Rashes are frequent. Anaphylaxis, Angioedema, Asthma, Urticaria have also occurred.
• Local irritations – THROMBOPHLEBITIS (after intravenous injection), PAIN (after parenteral injection).
• DIARRHOEA – Due to alteration of gut microbiome or due to irritation.
• NEPHROTOXICITY – Interstitial nephritis and tubular necrosis
• NEUTROPENIA, THROMBOCYTOPENIA, HAEMOLYTIC ANAEMIA
• BLEEDING MANIFESTATIONS (by the same mechanism as warfarin) – By cephalosporins with a
methylthiotetrazole group (cefoperazone, ceftriaxone)

Cephalosporins – Interactions
• The risk of nephrotoxicity increases when administered with aminoglycosides.
• The risk for bleeding increases when taken with oral anticoagulants.
• DISULFIRAM-LIKE REACTION may occur if alcohol is consumed within 72 hours after cephalosporin
administration – Flushing, Throbbing in the head and neck, Respiratory difficulty, Vomiting, Sweating, Chest
pain, Hypotension.
• Reduced absorption by antacids, Inactivation of oral typhoid vaccine.

Cephalosporins – Prescribing in Special Groups

• Pregnancy – Safe in pregnancy.
• Breast-feeding – Present in breast milk in low concentration, but appropriate to use in breast feeding (But
may cause loose motion in the child).
• Caution in renal failure.
• Certain cephalosporins are excreted through bile. Caution in liver failure.
• Safe in children.

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AMINOGLYCOSIDES
Aminoglycosides – Nomenclature
• “–MYCIN” – Derived from bacteria of the Streptomyces genus – Eg: Streptomycin, Neomycin, Kanamycin
• “–MICIN” – Derived from Micromonospora – Eg: Gentamicin, Netilmicin
• “–CIN” – Developed through chemical modifications of existing aminoglycoside scaffolds – Eg: Amikacin

Aminoglycosides – Mechanism of Action

• Transport of aminoglycoside into the bacterial cell – They passively diffuse across the outer coat of gram-
negative bacteria through porin channels. Entry across the cell membrane is by carrier mediated active
transport, which is an oxygen-dependent process and is linked to the electron transport chain.
❖ Antibiotics affecting bacterial cell wall synthesis (β-lactams, vancomycin) enhance entry of
aminoglycosides into the cell and exhibit SYNERGISM.
Eg: In the treatment of infective endocarditis
• Irreversible inhibitors of protein synthesis – Bind with high affinity to the A site of 30S ribosomal subunit,
leading to its conformation changes,
(1) interfering with assembly of the functional ribosomal apparatus and initiation of protein synthesis,
(2) misreading of the genetic code and inhibition of translocation,
(3) preventing polysome formation and promoting their disaggregation to nonfunctional monosomes.
• Incorrect amino acid sequences are entered into peptide chains and/or peptides of abnormal lengths are
produced and results in a nonfunctional protein.
• Aminoglycosides are bactericidal and exhibit concentration-dependent killing.
o Higher concentrations relative to the organism's minimum inhibitory concentration (MIC) induces
more rapid, and complete, killing of the pathogen.
o For aminoglycosides, the target maximum concentration is 8 – 10 times the MIC.
• Aminoglycosides also exhibit POST-ANTIBIOTIC EFFECT (PAE) – Persistent suppression of bacterial growth
after the drug concentration has fallen below the MIC.
o PAE is approximately 3 hours (1 – 7.5 hours).
o PAE is longer for gram-negative organisms than gram-positive organisms.
o The larger the dose, the longer the PAE.

Aminoglycosides – Pharmacokinetics
❖ Absorption
• They are polycations and therefore highly ionized – Not absorbed after oral administration.
• Usually given intramuscular or intravenous injections.
◼ Neomycin is NOT given parenterally due to severe nephrotoxicity and ototoxicity. It is given
topically (for skin infections) or orally (for bowel preparation prior to colorectal surgery).
• Absorption from intramuscular injection site is rapid; peak plasma levels are attained in 30 – 60
minutes.
❖ Distribution
• Aminoglycosides are water-soluble and do not readily cross cell membranes.
• Distribute mainly to the extracellular fluid – volume of distribution is nearly equal to the
extracellular fluid volume (𝐕𝒅 ~ 0.2 – 0.4 L/kg).
o But plazomicin has a higher volume of distribution – 13.3 to 18.5 L (52.9 L in speticemia).
• Volume of distribution is increased with ascites, burns, pregnancy, critical illnesses etc.
• Transfer to the cerebrospinal fluid is poor, even when the meninges are inflamed.
◼ Intrathecal or intraventricular injection is required for high levels in cerebrospinal fluid.
• All aminoglycosides cross the placenta and may accumulate in fetal plasma and amniotic fluid.
• Low concentrations are attained in serous fluids like synovial, pleural and peritoneal, but these levels can be
significantly increased with repeated dosing.
• Poor penetration into the biliary tree and bronchial secretions.
❖ Metabolism – Not metabolized in the body,

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❖ Elimination
• Eliminated 99% unchanged by kidneys – Mainly by glomerular filtration, and attain high
concentrations in the urine (25 – 100-fold compared to serum).
• The plasma half-life is 1.5 – 3.5 hours. About 50% – 60% of a dose is excreted unchanged within 24 hours.
• If renal function is impaired, accumulation occurs rapidly with a resultant increase in toxic effects.
• Significant accumulation occurs in the renal cortex – About 5 – 10% taken up by cells in the PCT;
Readily bind to anion phospholipids in plasma membrane of the PTC (saturable) and endocytosed.
• Reduction in dose or increase in dose-interval is essential in renal failure, in elderly and in neonates.
• Partially and irregularly removed by hemodialysis and peritoneal dialysis.

Aminoglycosides – Adverse Effects

• NEPHROTOXICITY – Dose-related. Ranging from mild, reversible renal impairment to severe, potentially
irreversible, acute tubular necrosis.
o Accumulate in subcellular organelles and inhibit their functions by disrupting calcium-mediated
transport processes. As the elimination of these drugs is almost entirely renal, this nephrotoxic action can
impair their own excretion and a vicious cycle may develop.
o Nephrotoxicity is more likely to occur when,
▪ therapy is continued for more than 5 days or at higher doses,
▪ in patients with pre-existing renal disease or in conditions in which urine volume is reduced,
▪ concomitant use of other nephrotoxic agents such as loop diuretics and other nephrotoxic
antimicrobial agents (Eg: first-generation cephalosporins, vancomycin, amphotericin)
o Measures to minimize nephrotoxicity
1. Select the least toxic aminoglycoside.
2. Correcting hypokalemia and hypomagnesemia prior to administration.
3. Avoiding in patients with reduced effective arterial volume or with low blood pressure.
4. Adjusting the dose for kidney function.
5. Limiting the duration of therapy to 7 – 10 days.
6. Minimizing concomitant nephrotoxic medications.
7. Monitoring blood levels and adjusting the dose accordingly – In traditional dosing, blood
level should be monitored 30 – 60 minutes after a dose, and just before the next dose.
8. Prompt discontinuation of the drug as soon as renal toxicity is detected or suspected.
9. Once-daily dosing regimen – where possible.
• OTOTOXICITY – Vestibular or cochlear damage; Can be transient or irreversible.
o Directly related to high peak plasma levels and the duration of treatment. Susceptibility to ototoxicity is
genetically determined via mitochondrial DNA.
o May manifest as;
▪ vertigo, disequilibrium, lightheadedness, nausea, vomiting and ataxia in vestibular damage,
▪ tinnitus, high-frequency hearing loss initially or deafness in cochlear damage.
o Measures to minimize ototoxicity
1. Serum drug concentration monitoring.
2. Prevention of concomitant ototoxic drugs (Eg: cisplatin, loop diuretics).
3. Co-administration of protective agents (Eg: N-acetylcysteine, salicylate).
4. Audiology should be performed at the start of and during therapy, particularly if prolonged.

Ototoxicity
Aminoglycoside Nephrotoxicity
Vestibular Cochlear
Streptomycin +++ + +
Neomycin +++ ++++
Gentamicin +++ + +++++
Amikacin + +++ +++
Tobramycin +++ ++ ++++

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• NEUROMUSCULAR BLOCKADE – Inhibition of the Ca2+ uptake necessary for the exocytotic release of acetylcholine
or decreasing the sensitivity of the muscle end-plates to acetylcholine; Can result in respiratory paralysis.
o Seen in patients with myasthenia gravis, a rapid increase in concentrations or concurrent administration with
neuromuscular blockers (Eg: Curare).
o Usually reversible by prompt administration of calcium gluconate or neostigmine.
• HYPERSENSITIVITY (rarely) – Eg: Contact dermatitis with topically applied neomycin.

Contra-indications: Medicine interactions:

1. Previous aminoglycoside toxicity 1. Increased toxicity – Potent diuretics, Other
2. Hypersensitivity nephrotoxic and ototoxic drugs
3. Myasthenia gravis 2. Increased effects
• Atracurium, Rocuronium etc.
Cautions: • Quinidine – Increases levels and effect of
1. Renal impairment gentamicin.
2. Elderly 3. Aminoglycosides antagonize the effects of
3. Once daily, high dose regimen should be neostigmine and pyridostigmine.
avoided in endocarditis and burns of more 4. Gentamicin increases plasma concentrations
than 20% of the total surface area. of digoxin.

Aminoglycosides – Antibacterial spectrum

• Aerobic gram-negative and gram-positive organisms – Including multidrug resistant organisms, such as
Enterobacteriaceae, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp, and
Haemophilus influenza, Listeria spp. – But NOT active ALONE against Streptococci and Enterococci.
• Against mycobacteria – Streptomycin, tobramycin, and amikacin.
• NOT adequate therapy as monotherapy for serious infections caused by Staphylococcus aureus.
• Anaerobic bacteria are intrinsically resistant to aminoglycosides – Due to the absence of the oxygen
dependent active transport process.

Aminoglycosides – Indications
• Important as a second agent in treatment of serious infections.
o In combination for Gram-negative bacillary infection – Septicaemia, Nosocomial respiratory tract
infections, Complicated UTI, Complicated intra-abdominal infections, and osteomyelitis.
o Antimycobacterial therapy – Multi-drug resistant TB (MDR-TB), and 2nd line anti-tuberculosis
therapy (ATT).
o Bacterial endocarditis – Usually gentamicin as a part of the antimicrobial combination for
enterococcal or streptococcal infection of the heart valves.
o Monotherapy – Tularemia, Plague
o Neonatal infections (such as neonatal bacterial meningitis)
o Topical – ocular, ear, skin infections

Aminoglycosides – Dosing and Administration

Traditional dosing Extended-interval therapy
• A weight-based dose – Divided 2 – 3 times daily. • Higher weight-based dose.
• Dose adjustments must be made to prevent • Administered at an extended interval – Every 24
toxicity in patients with renal insufficiency – hours if renal function is normal; Longer if with
Either the dose is reduced and/or the interval renal dysfunction.
between doses is increased.

Extended-interval therapy – Advantages

• Higher plasma concentrations attained after the single daily dose will be equally or more effective than the
divided doses – Due to concentration-dependent bactericidal action and concentration dependent post-
antibiotic effect.
• With the single daily dose, the plasma concentration will remain subthreshold for ototoxicity and
nephrotoxicity for a longer period each day.
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Aminoglycosides – Special Groups
• Neonates and children – Monitor serum concentrations.
• Pregnancy and breastfeeding – Not usually used, unless there is no safer alternative.
• Elderly – Caution due to increased risk of toxicity.
• Renal impairment – Dose adjustment needed.

TETRACYCLINES
Tetracyclines – Introduction
• Tetracyclines are a class of antibiotics having a nucleus of four cyclic rings – obtained from soil
actinomycetes.
Eg: ◼ Conventional tetracyclines – Doxycycline, Minocycline, Tetracycline
◼ Glycylcycline – Tigecycline
◼ Newer agents – Extended spectrum (approved > 2018) – Eravacycline, Omadacycline

Tetracyclines – Mechanism of Action

• Tetracyclines enter the cells via a similar pathway to aminoglycosides (passive diffusion and an energy-
dependent active transport protein mechanism) – concentrate intracellularly in susceptible organisms.
• Reversible inhibitors of protein synthesis – Bind reversibly to the 30S subunit of the bacterial ribosome.
This action prevents binding of aminoacyl–tRNA to the mRNA–ribosome complex, thereby inhibiting
addition of new amino acids to the growing peptide.
• Tetracyclines are bacteriostatic and its efficacy is associated with AUC/MIC ratio.

Tetracyclines – Pharmacokinetics
❖ Absorption –
• Absorption occurs mainly in the stomach and the proximal small intestine.
• Absorption and bioavailability are variable.
o Doxycycline and minocycline are completely absorbed irrespective of food.
o Absorption after oral administration is affected by food intake for tetracycline, and is
approximately 50%; Absorption is better if taken in empty stomach.
o Tigecycline is poorly absorbed orally and must be administered intravenously
• A portion of an orally administered dose of tetracycline remains in the gut lumen, alters intestinal
flora and cause diarrhoea, and, is excreted in the feces.
❖ Distribution –
• Widely distributed in the body – Penetrate into tissues and body fluids well.
• Also, bind to tissues undergoing calcification (such as teeth and bones) or to tumors that have a high
calcium content.
• Cross the placenta and concentrate in fetal bones and teeth, and are also excreted in breast milk.
• Only minocycline and doxycycline achieve therapeutic levels in the cerebrospinal fluid.
• Lipid solubility – Minocycline > Doxycycline > Tetracycline.
❖ Metabolism –
• Tetracycline and doxycycline – Hepatic metabolism is negligible.
• Minocycline – undergoes hepatic metabolism. Some degree of enterohepatic circulation occurs.
❖ Elimination –
• Tetracycline is primarily eliminated unchanged in the urine via by glomerular filtration – Require
dose adjustments in renal failure.
• Minocycline is eliminated to a lesser extent via the kidney. Doxycycline and tigecycline are
eliminated primarily via the bile into the feces and do not accumulate significantly in renal failure,
requiring no dosage adjustment in renal failure.
• Minimally removed by hemodialysis, peritoneal dialysis, or hemofiltration.
• Classified based on the plasma elimination half-life as short-acting (tetracycline; 6 – 8 hours), or
long-acting (doxycycline and minocycline; 16 – 18 hours). Tigecycline has a half-life of 36 hours.
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Tetracyclines – Antibacterial spectrum
• Broad spectrum – Effective against many gram-positive and gram-negative bacteria, protozoa, spirochetes,
non-tuberculous mycobacteria, and atypical species.
◼ All gram-positive and gram-negative cocci – Streptococcus pneumoniae, Streptococcus pyogenes,
Staphylococcus aureus (including MRSA) and enterococci.
❖ Minocycline is also effective against Neisseria gonorrhoeae and Neisseria meningitidis and
has been used to eradicate meningococci from the nasopharynx of carriers.
◼ Most gram-positive bacilli – Clostridia and other anaerobes, Listeria monocytogenes,
Propionibacterium acnes (used in the treatment of acne), non-tuberculous mycobacteria (eg,
Mycobacterium marinum and leprae), Helicobacter pylori.
◼ Some gram-negative bacilli – Vibrio cholerae, Yersinia pestis, Brucella spp.
❖ NOT active against Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae,
Salmonella typhi and many Bacteroides fragilis.
◼ Spirochetes – Borrelia burgdorferi and recurrentis, Leptospira interrogans, Treponema pallidum.
◼ All rickettsiae
◼ Atypical organisms – Chlamydia spp., Mycoplasma spp., Actinomyces.
◼ Protozoa – Entamoeba histolytica, Plasmodia spp..
• Generally, the same for all tetracyclines; However, minocycline is the most active due to its slight increase in
lipid solubility, than doxycycline.

Tetracyclines – Uses
◼ Meningococcal prophylaxis (Minocycline) ◼ Leptospirosis treatment and prophylaxis
◼ Acne (Doxycycline)
◼ Atypical mycobacterial infections (Eg: ◼ Syphilis
Mycobacterium marinum) ◼ Rickettsial infections
◼ Whipple's disease ◼ Chlamydial infections
◼ Brucellosis ◼ Legionnaire's disease
◼ Traveler's diarrhea ◼ Mycoplasma pneumonia
◼ Pelvic Inflammatory Disease ◼ Nocardiosis
◼ Melioidosis ◼ Actinomycosis
◼ Tularemia ◼ Amoebiasis
◼ Early Lyme disease ◼ Chloroquine-resistant malaria

Tetracyclines – Adverse Effects

• Generally safe.
• GASTROINTESTINAL SYMPTOMS (Dose-related) – Nausea, Vomiting, Oesophageal irritation, Abdominal
discomfort, Epigastric pain, Anorexia, Bulky stools, Diarrhoea, Pseudomembranous colitis.
❖ Due to the risk of oesophageal ulceration, patients are advised to take the capsule with plenty of
water while standing or sitting, and to remain upright for at least 30 minutes after each dose.
• Allergic and skin reactions (rare) – PHOTOSENSITIVITY
• HEPATOTOXICITY (rare) – Tetracycline, Minocycline (> Doxycycline)
• RENAL TOXICITY – Exacerbate pre-existing renal failure (Due to anti-anabolic effects – Inhibition of protein
synthesis in host cells causing blood urea to rise), Nephrogenic diabetes insipidus (Demeclocycline)
• HEMATOLOGICAL DISORDERS – Increased PT, APTT, and low platelets.
• JARISCH-HERXHEIMER TYPE REACTION (JHR) in spirochetal infections.
• STAINING – Of teeth and nails, and sometimes dental hypoplasia and bone deformities.
• VESTIBULAR DYSFUNCTION – Vertigo (also Drug induced lupus, Pericardial effusions) with Minocycline.
• Increased intra-cranial pressure

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Tetracyclines – Drug Interaction
• Absorption is impaired by multivalent cations (i.e. Ca2+ , Mg 2+ , Fe2+ , Al3+ ), by dairy products including milk,
antacids and alkaline pH – Formation of insoluble and unabsorbable complexes due to chelating property.
• Oral isotretinoin – Contraindicated due to risk of intracranial hypertension.
• Reduced effect of beta-lactams – Injectable tetracyclines should NOT be mixed with penicillin.
• Carbamazepine, phenytoin, barbiturates and chronic alcohol congestion – Induces the hepatic metabolism of
doxycycline and shorten its half-life.

Tetracyclines – Contraindications
• Young children (under 12 years of age) – Permanent tooth discoloration in children with repeated or
prolonged use. Minimal risk with doxycycline short courses.
• Pregnant or breastfeeding women – Minimal risk with doxycycline short courses.
o Crosses the placenta and accumulates in foetal bone and teeth.
o Increased risk of hepatotoxicity in the mother.
• End-stage renal failure (except doxycycline).

Tetracyclines – Administration
• Commonly administered as oral capsules – Tetracycline should be taken 1 hour before or 2 hours after food.
• Usually taken 6 hourly or twice daily.
• The almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily
dosing as well for certain indications.
• Should NOT be injected intramuscular or intrathecally – Due to causing pain.

MACROLIDES
Macrolides – Introduction
• The macrolides are antibiotics with a broad spectrum of activity against many gram-positive bacteria.
• They are primarily bacteriostatic, may be bactericidal at higher doses and exhibit time-dependent killing.
• The most commonly used macrolide antibiotics are – Erythromycin, Clarithromycin and Azithromycin.

Macrolides – Mechanism of Action

• Irreversible inhibition of bacterial protein synthesis – Macrolides irreversibly bind to bacterial 50s
ribosomal subunit.
o Once bound, the drug prevents the translation of mRNA, specifically
the growing peptide chain, by preventing the addition of the next
amino acid by the tRNA.
o The binding site is near the peptidyl transferase site, thus peptide
chain elongation (i.e., transpeptidation) is prevented by blocking of
the polypeptide exit tunnel and inhibiting translocation steps.
o Since the bacterial ribosomal structure is highly conserved across
most, if not all bacterial species, it is considered to be broad-
spectrum.
• In addition to anti-microbial properties, macrolides (especially
azithromycin) non-antibacterial immunomodulatory actions (i.e. anti-
inflammatory and anti-secretory actions) as well.
o Used in the treatment of CoVID 19 in the initial days of the
pandemic.
o Used in respiratory tract infections and chronic airway
inflammatory conditions (such as azithromycin prophylaxis in
bronchiectasis, COPD, cystic fibrosis etc.).

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Macrolides – Pharmacokinetics
❖ Absorption –
• In acidic aqueous media, erythromycin is rapidly degraded via intramolecular dehydration – must be
administered with enteric coating or as esterified forms.
• Clarithromycin and azithromycin are stable at gastric pH – Their bioavailability is better than that of
erythromycin base (25%), and enteric coating is not required.
• Food interferes with the absorption of erythromycin and azithromycin by retarding gastric
emptying, but food can delay, but increase the absorption of clarithromycin.
❖ Distribution –
• Widely distributed in the body – except to the brain and cerebrospinal fluid and synovial fluid.
❖ Erythromycin is one of the few antibiotics that diffuses into prostatic fluid.
• Distribution – Azithromycin > Clarithromycin > Erythromycin
• Because these antibiotics also concentrate in tissues, epithelial lining fluid and alveolar macrophage
concentrations are usually higher than plasma levels.
• High levels of azithromycin persist in tissues for extended periods, which is beneficial for dosing
regimens and adherence, but may facilitate selection for the resistance seen with the agent.
❖ Metabolism –
• Azithromycin and erythromycin remain largely unmetabolized and is excreted in the bile and faeces
in the active form. Partial reabsorption occurs through the enterohepatic circulation.
❖ Should be avoided in severe hepatic impairment.
• Clarithromycin is metabolized in the liver (60%), by the cytochrome P450 enzyme system –
Metabolism exhibits saturation kinetics.
• Clarithromycin undergoes hepatic first pass metabolism – The major metabolite is microbiologically
active and it is more active than the parent compound against some species.
❖ Elimination –
• 20 to 30% of clarithromycin and also its active metabolite is excreted unchanged in the urine.
❖ Dose modification is needed in severe renal impairment.
• Due to concentrating in tissues and slow release from there, azithromycin has the longest plasma
elimination half-life (50 hours). Erythromycin has the shortest plasma half-life (90 min).

Macrolides – Drug Interactions

• Erythromycin and Clarithromycin inhibits hepatic cytochrome P450 enzymes interfering with the
metabolism of many drugs, leading to an increase in their plasma levels.
• Azithromycin does NOT inactivate cytochrome P450 enzymes and, therefore, is free of drug interactions.
Inhibition of metabolism of
Inhibition of CYP450 Additive pharmacologic effects.
macrolides
Warfarin, Statins, Cyclosporin, Azole antifungal agents,
Drugs that prolong QT interval
Carbamazepine, Tacrolimus, Some calcium channel blockers
Drugs (Eg: Clarithromycin with
Digoxin, Theophylline, CCBs, Anti-HIV protease inhibitors
cetirizine)
Terfenadine, Ergot alkaloids (Eg: Ritonavir)

• Concomitant therapy may

increase the risk of statin-
associated rhabdomyolysis. Prolongation of the QT interval
• Reduced inactivation of
due to an effect on potassium
terfenadine may lead to Increases macrolide
Effects ion channels – can lead to the
serious cardiac arrhythmias, concentration.
torsades de pointes
and of ergot alkaloids may
cause ergotism. arrhythmia.
• Increased risk of sudden
cardiac death.
❖ In addition, macrolides eliminate a species of intestinal flora that ordinarily inactivates digoxin, thus leading to
greater reabsorption of the drug from the enterohepatic circulation and increases bioavailability of digoxin.

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Macrolides – Antibacterial spectrum
• Antimicrobial spectrum of erythromycin is very similar to that of penicillin, and is a safe and effective
alternative for penicillin-allergic patients – Especially for,
o Gram-positive cocci – Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae
o Spirochaetes – Treponema pallidum.
o Intracellular-organisms – Chlamydia spp., Mycoplasma pneumoniae, Ureaplasma urealyticum,
Legionella pneumophila, Moraxella catarrhalis, Campylobacter jejuni and Helicobacter pylori.
• Also, effective against penicillin-resistant strains.
• Macrolides have NO coverage for anaerobic organisms, Pseudomonas and Enterobacteriaceae (such as
Escherichia coli, Salmonella spp. etc.).

Clarithromycin Azithromycin
Erythromycin
Have a broader spectrum than erythromycin.
• Gram-positive cocci.
• Gram-positive bacilli – Corynebacterium Less active than erythromycin.
diphtheriae, Bacillus anthracis, Listeria Similar to erythromycin.
monocytogenes, Clostridium tetani.
• Spirochaetes. Similar to erythromycin.
More active than erythromycin. Highest activity.
• Intracellular organisms.
Including Toxoplasma
Toxoplasma gondii
• Less active against most gram-negative More active than erythromycin –
More active than erythromycin –
organisms – Neisseria gonorrhoeae, Also, Haemophilus influenzae
Also, Haemophilus influenzae.
Bordetella pertussis. and Moraxella catarrhalis.

Many mycobacteria – Including Mycobacterium leprae,

• Some mycobacteria.
Mycobacterium avium complex and Mycobacterium kanasii.

Macrolides – Uses
• Commonly used to treat respiratory tract infections like pneumonia, sinusitis, pharyngitis, and tonsillitis.
o Primary drugs used to treat atypical pneumonia, usually caused by organisms like Mycoplasma
pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae.
o COPD exacerbations – Because of the anti-inflammatory and immunomodulating characteristics.
• Penicillin allergy patients – In post-rheumatic fever patients and for endocarditis prophylaxis.
• Erythromycin –
o Diphtheria, pertussis and for some chlamydial infections.
o Used off-label for treating gastroparesis. (Erythromycin stimulates motilin receptors in the GIT – thereby
inducing gastric contractions, gastric emptying and intestinal motility without significant effect on colon.)
• Clarithromycin
o Standard triple therapy protocol against Helicobacter pylori infection.
o Second-line anti-tuberculosis treatment.
• Azithromycin – Sexually transmitted infections such as gonococcal and chlamydial infections.

Macrolides – Adverse Effects

• GASTROINTESTINAL SYMPTOMS – Common (more with erythromycin); Nausea, vomiting, abdominal pain,
anorexia and diarrhoea.
• DYSGEUSIA (Altered taste sensation) – with clarithromycin (rarely with azithromycin).
• PSEUDOMEMBRANOUS COLITIS
• PROLONGATION OF THE QT INTERVAL in the ECG (erythromycin > clarithromycin > azithromycin)
• SENSORINEURAL HEARING LOSS – Majority reversible with cessation of the drug.
• HEPATOTOXICITY (cholestatic jaundice) in pregnant women – Due to ester forms of erythromycin; as a
HYPERSENSITIVITY reaction.
• Increase the chances of pyloric stenosis in newborns.
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Macrolides – Contraindications
• Hypersensitivity
• QT prolongation
• Patients taking Class Ia and Class III antiarrhythmic agents.
• Pregnancy (relative) – Erythromycin can be safely given; but avoid other macrolides unless potential benefit
outweighs risk.

Other newer macrolides

Erythromycin
(Clarithromycin, Azithromycin)
• Natural. • Semi-synthetic.
• Low oral bioavailability. • Rapid absorption and better bioavailability.
• Acid labile. • Acid resistant.

• Relatively narrower spectrum of activity. • Broader spectrum than erythromycin.

• Short half-life. • Longer half-life.

• Require multiple doses (every 6 hourly). • Twice-daily or once-daily adminitration.

administration.

• Poor tissue penetration. • Better tissue penetration

penetrat ion

• Poor GI tolerance. • Better GI tolerance.

• Higher hepatic CYP450 enzyme inhibition. • Comparatively lower level of inhibition
inhibition.

• Higher risk of QT prolongation. • Lower risk of QT prolongation

prolongation.

SULPHONAMIDES
Sulphonamides – Introduction
• Sulfonamide is a functional group that is the basis of several groups of drugs, which are called
sulphonamides or sulfa drugs.
• Some sulfonamides are devoid of antibacterial activity – sulfonylureas and thiazide diuretics are newer drug
groups based upon the antibacterial sulfonamides.
• In recent times, use of sulphonamides has become limited because of rapid emergence of bacterial
resistance, higher adverse drug reactions and the availability of many safer and more effective antibiotics.
• Currently certain sulfonamides (sulfadiazine or sulfamethoxazole) are used only as co-trimoxazole, in
combination with trimethoprim, which acts against dihydrofolate reductase.

Sulphonamides – Pharmacokinetics
❖ Absorption – Well and rapidly absorbed from the stomach and small intestine (except sulfasalazine).
❖ Distribution –
• Widely distributed in the body – Including the cerebrospinal fluid and prostatic fluid.
• Can also cross the placenta and enter the fetus and may be excreted in breast milk.
• Extent of plasma protein binding is variable – depends on the ionization constant (pK 𝑎 ) of the drug.
❖ Metabolism –
• Metabolized in the liver – by acetylation and conjugation; the major acetylated product is inactive.
• The capacity to acetylate is genetically determined in a bimodal form, i.e. there are slow and fast
acetylators.
❖ Elimination –
• Kidney is the principal route of elimination – unchanged sulfonamides and inactive metabolites are
excreted in the urine, mainly by glomerular filtration.
❖ Dose adjustments are required in patients with severe renal failure.
• Less soluble in acidic urine – Precipitation causes crystalluria and, potential damage to the kidney.
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Sulphonamides – Mechanism of Action
• Most bacteria do not use preformed exogenous folate as humans, but
must synthesize it from PABA (p-aminobenzoic acid).
• The sulfonamides are structural analogues of PABA, and thus compete
with it for DHP synthase. Folate is essential for production of purines,
that is required for the synthesis of DNA and RNA in bacteria, and thus
sulphonamides ultimately impair nucleic acid formation.
• Humans derive DHF from dietary folate which protects their cells from
the metabolic effect of sulfonamides.
• Trimethoprim acts at the subsequent step by inhibiting DHF
reductase, which converts DHF to THF. Trimethoprim is relatively safe
because bacterial DHF reductase is much more sensitive to
trimethoprim than is the human form of the enzyme.
• Both sulfonamides and trimethoprim are bacteriostatic.

Sulphonamides – Classification
• Short- and intermediate-acting agents
• Long-acting agents Used to treat parasitic diseases
• Agents that are limited to the bowel lumen – Eg: sulfasalazine
• Topical agents

Sulphonamides – Examples
• Sulfamethoxazole – Intermediate-acting sulfonamide available in a
fixed combination with trimethoprim as co-trimoxazole for numerous
indications.
• Sulfadiazine – Another intermediate-acting sulfonamide, used with
pyrimethamine in the treatment of toxoplasmosis.
• Sulfadoxine – A long-acting sulfonamide, available in a fixed
combination with pyrimethamine for the treatment of malaria.
• Silver sulfadiazine – Used topically for prophylaxis and treatment of infected burns, leg ulcers and pressure
sores because of its wide antibacterial spectrum (which includes Pseudomonas).
• Sulfasalazine – Poorly absorbed in the gastrointestinal tract, used to treat ulcerative colitis and Crohn’s
disease.

Sulphonamides – Antibacterial spectrum

• Effective against Gram-positive as well as Gram-negative bacteria – including Streptococcus pyogenes,
Haemophilus influenzae, Vibrio cholerae, Calymmatobacterium granulomatis, Haemophilus ducreyi,
Chlamydia spp, Actinomyces, Nocardia, Toxoplasma.
• Anaerobic bacteria are NOT susceptible.
• Many pathogens are typically resistant –
o Pseudomonas aeruginosa o Most anaerobes – E. coli, Shigella spp. etc.).
o Meningococci, Streptococci, o Mycobacterium tuberculosis
Staphylococci and Gonococci. o Treponema pallidum
o Penicillin-resistant Streptococcus o Campylobacter jejuni
pneumoniae o Rickettsiae

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CO-TRIMOXAZOLE
• Combination of sulfamethoxazole and trimethoprim (with a 5 : 1 ratio to reach the optimal peak plasma
concentration in the ratio of 20 : 1).
• Causes a sequential block in folate metabolism – DHP synthetase and DHF reductase.
• Both compounds have a similar half-life (~10 hours) and about 80% excreted in urine.
• Trimethoprim is less plasma protein bound and more lipid soluble; enters many tissues and has a larger
volume of distribution.
• Individually they both are bacteriostatic but the combination is bactericidal – The combination has a wider
antibacterial spectrum and the MIC of each component can be reduced 3 – 6 times.
• Delays the development of bacterial resistance – Synergism between trimethoprim and the sulfonamide
results in up to 40% of bacteria that are resistant to one component, being susceptible to the combination.
• When sulfonamides are combined with pyrimethamine they have greater antiprotozoal activity.

Co-trimoxazole – Indications
• Prevention and treatment of pneumonia due to Pneumocystis carinii in immunosuppressed patients.
• Prevention and treatment of toxoplasmosis, and treatment of Nocardia and melioidosis.
• Bacterial Diarrhoea with Dysentery/Acute gastroenteritis/Traveler’s Diarrhoea.
• Nocardia infections – Drug of choice for pulmonary lesions or brain abscesses due to Nocardia.
• Urinary tract infections.

Sulphonamides – Adverse Effects

• Generally, well tolerated.
• Adverse reaction rate is as high as 25 to 50% in patients with HIV, with many of the reactions being severe.
• Adverse effects from co-trimoxazole can usually be managed by stopping the drug – For conditions in which
co-trimoxazole is considered first-line therapy (Eg: Pneumocystis jirovecii pneumonia in HIV patients)
continued treatment may be indicated in the setting of non-life threatening adverse reactions.
• CRYSTALLURIA and renal toxicity.
• HYPERSENSITIVITY REACTIONS – common; Fever, exfoliative dermatitis, photosensitivity, urticaria etc.
• RASHES – especially at mucocutaneous junctions.
• STEVEN’S JOHNSON’S SYNDROME, Erythema multiforme, Polyarteritis nodosa, Eosinophilia
• HEMOLYSIS in G6PD deficiency
• BONE MARROW SUPPRESSION – Neutropenia, Agranulocytosis and Thrombocytopenia
• KERNICTERUS in neonates (Due to displacing bilirubin from protein binding site).
• Nausea, Vomiting, Epigastric Pain, Hepatitis
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Sulphonamides – Contraindications
• Pregnancy
o Avoided in the first trimester since trimethoprim may interfere with folate metabolism and increase
the risk of neural tube defects.
o Should also be avoided, if possible, in the last month of pregnancy, due to the ability of sulfonamides
to displace bilirubin bound to serum albumin, thereby increasing free unconjugated bilirubin levels
that could increase the risk of kernicterus in the neonate. Also, can cause neonatal haemolysis and
methaemoglobinaemia.
• Newborns and infants less than 2 months of age
• Uraemia in renal disease
• Allergy
• Acute porphyria

CHLORAMPHENICOL
Chloramphenicol – Mechanism of Action
• Broad spectrum of activity.
• Primarily bacteriostatic (bactericidal in high concentrations and against
Haemophilus influenzae, Neisseria meningitidis and Streptococcus
pneumoniae).
Inhibits bacterial protein synthesis by reversibly binding to the 50s
ribosomal subunit at the peptidyl transferase reaction – Inhibits transfer
of the elongating peptide chain to the newly attached aminoacyl-tRNA.
❖ In contrast to clindamycin, which acts on the A and P sites, and
macrolides which block the exit tunnel.

Chloramphenicol – Pharmacokinetics
❖ Absorption
• Rapidly and completely absorbed when given orally.
• Administered intravenously as a pro-drug (chloramphenicol
succinate).
❖ Distribution –
• Chloramphenicol is an extremely lipid-soluble small molecule
that remains relatively unbound to plasma proteins.
• Large volume of distribution – penetrates effectively into all
tissues of the body, including the brain.
• The concentration achieved in brain and CSF increases to as high
as 89% when the meninges are inflamed.
• Secreted into breast milk and should be avoided in breastfeeding mothers.
❖ Metabolism –
• The pro-drug is hydrolyzed to active chloramphenicol and there is much individual variation in the
capacity to perform this reaction.
• Metabolized primarily in the liver to an inactive glucuronide by conjugation with glucuronic acid.
❖ Dose reductions are necessary in patients with liver dysfunction or cirrhosis.
• In the neonate, the process of glucuronidation is slow, and plasma concentrations are extremely
variable, especially in premature neonates.
❖ Elimination –
• About 10% of chloramphenicol and its metabolite is eliminated in the urine by tubular secretion.
• A small amount of active drug is excreted into bile and feces.
• Its plasma elimination half-life is about 5 hours in adults.

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Chloramphenicol – Antibacterial spectrum
• Has a broad spectrum of activity against a number of bacteria including gram-negative and gram-positive
organisms and rickettsiae – Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli,
Haemophilus Influenza, Neisseria meningitidis, Salmonella typhi.
• It is NOT effective against Pseudomonas aeruginosa.

Chloramphenicol – Indications
• Superficial eye infections (bacterial conjunctivitis, blepharitis etc.)
• Otitis externa
• Meningitis
• Typhoid fever and gastroenteritis
• Serious rickettsial infections such as scrub typhus and Rocky Mountain spotted fever.
• Brucellosis
• Cholera
❖ However, despite these indications, chloramphenicol should only be initiated if there is known
susceptibility to the drug, and when other less dangerous antimicrobials are ineffective, not
tolerated or contraindicated.

Chloramphenicol – Adverse Effects

• APLASTIC ANAEMIA – Can cause in two ways,
1) (Commoner) – Predictable, dose-related, and reversible mild anemia, with thrombocytopenia and
neutropenia.
2) Type B adverse drug reaction – Idiosyncratic reaction (unpredictable, irreversible, and dose-
independent) – later onset, fatal after pancytopenia develops.
❖ Due to shared ribosomal structures between bacteria and mitochondria, protein and ATP
synthesis in mammalian mitochondria may be inhibited leading to depleted ferritin
concentrations in the mitochondria.
• The ‘GREY BABY’ SYNDROME in neonates – Circulatory collapse in which the skin develops a cyanotic grey
colour. It is caused by failure of the liver to conjugate, and of the kidney to excrete the drug.
• HYPERSENSITIVITY
• OTOTOXICITY (with topical ear drops), OPTIC NEURITIS, Neurotoxicity
• GASTROINTESTINAL REACTIONS – Oesophagitis with oral use, GI disturbances secondary to alteration of
the intestinal microbial flora.
• Severe metabolic acidosis
• Drug interactions – Chloramphenicol inhibits some hepatic oxidases and, thus, blocks the metabolism of
drugs such as warfarin and phenytoin.

Chloramphenicol – Contraindications
• Acute porphyria
• Known hypersensitivity to chloramphenicol
• Neonates less than one week old, especially preterm infants
• Pregnancy (category C)

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QUINOLONES
Quinolones – Introduction
• Quinolones are synthetic antimicrobials – Nalidixic acid is the predecessor to all quinolones.
• Fluorination of the quinolone structure of nalidixic acid – fluoroquinolones;
o Higher efficacy and potency,
o More expanded spectrum,
o Slower development of resistance,
o Better tissue penetration, and,
o Better safety profile and tolerability.
• Quinolones are categorized into four generations;
1st Generation – Nalidixic acid
2nd Generation – Ciprofloxacin, Norfloxacin, Ofloxacin
3rd Generation – Levofloxacin, Gatifloxacin, Sparfloxacin
4th Generation – Moxifloxacin, Trovafloxacin
❖ Ciprofloxacin is considered as the prototype fluoroquinolone.

Quinolones – Mechanism of Action

• Inhibit bacterial DNA gyrase (Topoisomerase II) and topoisomerase IV (but NOT human topoisomerases) –
o Prevent the supercoiling of DNA, which is necessary for compacting chromosomes into the bacterial
cell, thereby promoting DNA strand breakage.
o Inhibition of topoisomerase IV impacts chromosomal stabilization during cell division, thus
interfering with DNA synthesis (the separation of newly replicated DNA).
• Bactericidal and exhibit concentration-dependent killing.

Quinolones – Pharmacokinetics
❖ Absorption –
• Well-absorbed after oral administration – Oral bioavailability of levofloxacin is almost 100%.
But Norfloxacin is poorly absorbed orally and has a low oral bioavailability.
• Absorption is interfered by divalent and trivalent cations – In antacids (with Al or Mg), Dietary
supplements (with Zn or Fe), Calcium (in milk), Sucralfate.
• Food does not impair oral absorption, but may delay the time to peak serum concentrations.
❖ Distribution –
• Widely distributed into all tissues and body fluids – levels are high in bone, urine, kidneys and lungs.
• Penetration into cerebrospinal fluid is relatively low except for ofloxacin.
• All quinolones are concentrated in macrophages and polymorphonuclear leukocytes, thus having
activity against intracellular organisms.
❖ Metabolism –
• Moxifloxacin is excreted primarily by the liver – No dose adjustment is required for renal
impairment, but should be used with caution in patients with hepatic failure
• Ciprofloxacin and norfloxacin are partly eliminated by hepatic cytochrome P450 enzymes – Which
are inhibited by them, thereby increasing the concentration of other drugs such as theophylline and
warfarin.
❖ Elimination –
• Excreted primarily in urine – both glomerular filtration and tubular secretion; except moxifloxacin.
• Dose adjustments are required in patients with renal impairment.
• There is substantial excretion and re-absorption via the colonic mucosa, and patients with intestinal
malfunction, (Eg: paralytic ileus), are prone to accumulate quinolones.

Quinolones – Bacterial spectrum

• Extremely active against Gram-negative organisms – Eg: Enterobacteriacea, Haemophilus influenzae, and
Neisseria spp.
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• Most have useful activity against Pseudomonas aeruginosa, some mycobacteria (including Mycobacterium
tuberculosis) and atypical organisms (Eg: Chlamydia spp., Mycoplasma spp., Legionella pneumophila).
• Most earlier agents are less active against Gram-positive organisms (resistance commonly emerges).
• But the newer agents have good activity against some Gram-positive organisms – Eg: Streptococcus
pneumoniae; Typically, NOT used for the treatment of Staphylococcus aureus (especially MRSA) or
enterococcal infections due to emergence of resistance.
• Activity against some anaerobes – Most are NOT effective against anaerobes (except 4th generation).

1st Generation 2nd Generation 3rd Generation 4th Generation

Nalidixic acid Ciprofloxacin Levofloxacin Moxifloxacin
Extended Gram-negative activity.
Gram-negative activity
Some Gram-positive and Extended Gram-positive and atypical coverage.
Except Pseudomonas
Atypical coverage. Anaerobic coverage.

Ciprofloxacin – Indications
• Activity against many systemic infections – urinary, gastrointestinal and respiratory tract infections,
gonorrhoea and septicaemia.
• Used for resistant tuberculosis – reserved as a 2nd line anti-tuberculosis drug.
❖ Should NOT be used as first line treatment for lower respiratory tract infections – to prevent
resistance in mycobacteria.
• Oral therapy of chronic Gram-negative infections such as osteomyelitis, soft tissues, and joints and intra-
abdominal infections.
• Prophylaxis and therapy of anthrax, including cases resulting from bioterrorism.
❖ Highly susceptible organisms – E. coli, Klebsiella pneumoniae, Salmonella typhi, Proteus mirabilis,
Haemophilus influenzae, Neisseria gonorrhoeae, Vibrio cholerae, Campylobacter jejuni.
❖ Moderately susceptible organisms – Pseudomonas aeruginosa, Staphylococcus aureus,
Mycobacterium tuberculosis.

Ciprofloxacin – Adverse Effects

• Well tolerated.
• GIT DISTURBANCES (most common) – Nausea, Vomiting, Diarrhoea caused by Clostridium difficile.
• CNS EFFECTS – Headache, Dizziness or light-headedness, CONVULSIONS.
• Rashes including PHOTOSENSITIVE REACTIONS
• Tendon damage including ACHILLES TENDON RUPTURE and tendinitis (rarely) – Risk is higher in elderly
and by the concomitant use of corticosteroids.
o May occur within 48 hours of starting or several months after stopping.
o Avoid in patients with a history of tendon disorders related to quinolones.
o If tendinitis is suspected, the quinolone should be discontinued immediately.
• PROLONGATION OF QT INTERVAL (especially by Moxifloxacin)
• ARTHROPATHY – Articular cartilage erosion in weight bearing joints.
• Less frequent side-effects include dyspepsia, abdominal pain, anorexia, sleep disturbances, asthenia,
confusion, anxiety, depression, hallucinations, tremor, blood disorders (including eosinophilia, leucopenia,
thrombocytopenia), arthralgia, myalgia.

Ciprofloxacin – Cautions
• In patients with a history of epilepsy.
• In G6PD deficiency and myasthenia gravis.
• Exposure to excessive sunlight should be avoided (discontinue if photosensitivity occurs).
• Can prolong the QT interval – risk of arrhythmias.

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Ciprofloxacin – Contraindications
• Pregnancy
• Breastfeeding
• In children under 12 years – Due to risk of arthropathy.
• Known hypersensitivity and past history of tendon disorders related to quinolones.

Quinolones – Other examples

• Nalidixic acid – Now used mainly for the prevention of UTI. May cause haemolysis in G6PD deficient
subjects, and also benign intracranial hypertension. It is contraindicated in infants.
• Norfloxacin – Due to poor oral bioavailability and short half-life, used for acute or chronic recurrent UTI.
• Ofloxacin – Has modestly greater Gram-positive activity, but less Gram-negative activity than ciprofloxacin.
Used for UTI, respiratory tract infections, gonorrhoea and topically for eye infection.
• Levofloxacin – Greater activity against Streptococcus pneumoniae than ciprofloxacin. Used for UTI and RTI.
• Moxifloxacin – Has strong anti-Gram-positive activity and is also effective against many anaerobes. But it has
poor activity against Pseudomonas aeruginosa.

Urinary Antiseptics – Introduction

• Oral antimicrobial agents, which are restricted for lower urinary tract infections – such as Nalidixic acid,
Nitrofurantoin and Methenamine.
• They are concentrated in urine, but do NOT achieve sufficient antibacterial levels in the circulation –
Therefore cannot be used for upper UTI.

(01) Nitrofurantoin
• Narrow spectrum antibiotic that has toxic effects on sensitive bacteria – rapid intracellular conversion of
nitrofurantoin to highly reactive intermediates, that inhibits various enzymes, damage DNA, disrupt
metabolic processes and the synthesis of proteins, RNA, and DNA.
• Primarily bacteriostatic, but may be bactericidal at higher concentrations and in acidic urine, because its
activity is enhanced at lower pH.
• Effective against many gram-negative bacteria especially Escherichia coli – but except Pseudomonas
aeruginosa, Proteus spp. and other resistant gram-negative bacteria.
• Gram-positive cocci are also susceptible.
• Development of resistance to nitrofurantoin during continued therapy is less, and there is no cross-
resistance with other antimicrobial agents.
• Used in the;
o Treatment of UTI – Uncomplicated lower UTI (not associated with prostatitis), Catheter associated UTI.
o Prophylaxis of UTI.
◼ Recurrent attacks of UTI.
◼ Acute exacerbation of UTI, when eradication is not possible.
◼ Anatomical defects in the urinary system with recurrent UTI.

Nitrofurantoin – Pharmacokinetics
❖ Absorption – Well-absorbed after oral administration.
❖ Metabolism – Rapidly metabolized in the liver and other tissues.
❖ Elimination –
• Remaining drug is excreted unchanged, primarily in urine – both glomerular filtration and tubular
secretion.
• Elimination is so rapid that no systemic antibacterial concentrations are NOT attained in blood or
tissues – NOT to be used in pyelonephritis or in sepsis.
• In renal failure and in azotaemia, urine concentrations are insufficient for antibacterial action, but
high blood levels may cause toxicity.
❖ Contraindicated in severe renal insufficiency (creatinine clearance < 60 mL/min).

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Nitrofurantoin – Adverse Effects
• GIT DISTURBANCE (frequent) – nausea, vomiting and diarrhea
• PULMONARY TOXICITY – Acute pneumonitis and other pulmonary effects (Eg: Pulmonary fibrosis) – In
patients chronically treated for prophylaxis of UTI.
• NEUROLOGICAL PROBLEMS – Headache, Nystagmus, Polyneuropathies.
• HEMOLYTIC ANEMIA – contraindicated in patients with G6PD deficiency.
• HYPERSENSITIVITY reactions

Nitrofurantoin – Contraindications
• Renal impairment (creatinine clearance < 60 mL/min).
• Patients with G6PD deficiency
• Pregnancy – especially women who are 38 weeks or more pregnant, and Neonates.

(02) Metronidazole
• Metronidazole belongs to the nitroimidazole class.
• It inhibits nucleic acid synthesis by forming nitroso radicals, which disrupt the DNA of microbial cells –
occurs when metronidazole is partially reduced, and because this reduction usually happens only in
anaerobic bacteria and protozoans, it has relatively little effect on human cells or aerobic bacteria.

Metronidazole – Pharmacokinetics
❖ Absorption – Well-absorbed after oral administration – Oral bioavailability is approximately 80%; Food may
slow down absorption.
❖ Distribution –
• Widely distributed in the body – including cerebrospinal fluid and into abscess cavities.
• Cross the placenta and excreted into breastmilk.
• About 20% is bound to plasma proteins.
❖ Metabolism –
• About 60% undergoes hepatic metabolism by oxidation followed by glucuronidation.
• The metabolites are active – show antibiotic and antiprotozoal activity in vitro.
❖ Elimination – Unchanged metronidazole and its metabolites are mainly excreted via the kidneys and to a
lesser extent with faeces.

Metronidazole – Indications
• Protozoal infections – Amoebiasis, Giardiasis, Trichomoniasis.
• Vaginitis – Bacterial vaginosis and trichomoniasis.
• Diseases caused by anaerobic cocci and anaerobic gram-negative bacilli
o Drug of choice for the treatment of pseudomembranous colitis caused by Clostridium difficile.
o Intra-abdominal infections, Pelvic inflammatory disease, aspiration pneumonia, rosacea (topical),
fungating wounds (topical), Lung abscess, Periodontitis, Oral infections.
o Infections caused by other susceptible anaerobic organisms such as Bacteroides, Fusobacterium,
Clostridium, Peptostreptococcus, and Prevotella species.
• In triple therapy to eradicate Helicobacter pylori (along with omeprazole and clarythromycin).
• To prevent infection in people recovering from surgery.
• Acute necrotizing ulcerative gingivitis

Metronidazole – Adverse Effects

• DISULFIRAM-LIKE REACTION – Patients are advised not to drink alcohol during systemic metronidazole
therapy and for at least 48 hours after completion of treatment.
• GI DISTURBANCES – METALLIC TASTE, Nausea, Vomiting, Diarrhoea, Weight loss, Abdominal pain etc.
• NEUROTOXICITY – Headache, Dizziness, increased risk of peripheral neuropathy and seizures.
• HYPERSENSITIVITY – Thrombophlebitis (after intravenous administration), rash, itch, flushing, fever,
glossitis, stomatitis, leucopenia, neutropenia etc.

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ANTI-HELMINTHICS AND ANTI-FILARIALS

Anti-Helminthics – Introduction
• Anti-helminthics are medicines that either kill or expel infecting helminths.
◼ Benzimidazoles – Mebendazole, Thiabendazole, Albendazole
◼ Piperazines – Diethylcarbamazine citrate (DEC), Piperazine citrate
◼ Praziquantel
◼ Levamisole
◼ Ivermectin
• They were previously called vermicides (kills worms) or vermifuges (promotes worm expulsion).
• Anti-helminthics act by,
o Paralyzing the parasite (Eg:. by preventing muscular contraction).
o Damaging the worm such that host immune system can eliminate it.
o Altering parasite metabolism – However, metabolic requirements of helminths vary greatly and
drugs effective for one species may be ineffective against others.

Challenges in Preventing/Treating Helminthics

• Infections are most common in resource poor-developing countries.
• They are larger and more complex than bacteria with a eukaryotic cell structure similar to that of human
cells – Drug should penetrate the tough exterior cuticle of the worm or gain access to its alimentary tract.
• Many helminths have active drug efflux pumps that reduce the concentration of the drug in the parasite.
❖ Development of resistance has NOT been a problem in the clinical use of anthelmintics so far.
• Several anti-helminthic drugs were originally developed for veterinary use.
• Limited introduction of new drugs.
• No effective vaccines available (But low cost, effective public health interventions are available).

Principles of management of helminthic infestations

• Drug used depends on the type of helminth, co-infection with other helminths and the site where helminth is
situated in the body – In addition, lack of side effects/toxicity, ease of administration (preferably single
dose) and low cost also should be considered.
• Repeated periodic chemotherapy is required in certain helminths – continued exposure to risk factors.
• Treatment should be combined with strategies for prevention of transmission depending on the spread.
• During treatment, release of antigens of killed organisms can induce immune response and cause clinical
deterioration.
• Mass drug administration program carried out in regions with high prevalence of infection.

(01) Benzimidazoles – Mebendazole, Thiabendazole, Albendazole

Benzimidazoles – Mode of Action
• Broad-spectrum anthelminthic – Active against both larval and adult stages of nematodes; Also, ovicidal in
against some nematodes (Eg: Ascaris and Trichuris spp.).
• Inhibits microtubule polymerization of helminth by binding to beta tubulin in parasite – Interfere with
microtubule dependent metabolic functions such as glucose uptake.
• Selective inhibitory action of helminths due to higher affinity for parasitic β–tubulin.
• Effect takes time to develop and the worms may not be expelled from the gut for several days.

Benzimidazoles – Adverse Effects

• Benzimidazoles have a good safety profile and well tolerated even by patients in poor health.
• GI DISTURBANCE (more with thiabendazole).
• Headache, Dizziness and Drowsiness.
• ALLERGIC REACTIONS (fever, rashes, alopecia, BONE MARROW SUPPRESSION)
• Thiabendazole can cause LIVER FAILURE and STEVEN JOHNSON SYNDROME. Resistance to β-lactamases.

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Mebendazole (IMPORTANT) Albendazole Thiabendazole

Poorly soluble in aqueous solution.

Fatty meals and bile salt increases absorption.

• Rapidly absorbed from GI tract.
Absorption
• Low systemic bioavailability – Due to low • Can also be absorbed from skin.
• Poorly absorbed from GI tract – Absorption
absorption (5 – 10%) and extensive first
is variable and erratical.
pass metabolism.
• Albendazole sulfoxide is highly plasma
PK protein bound (70%).
Distribution • Highly plasma protein bound (about 95%).
• Albendazole sulfoxide is widely distributed
in tissue, bile, CSF and also hydatid cysts.
Rapidly metabolized by the liver (undergoes extensive first pass metabolism). • Very rapidly metabolized by the liver.
Metabolism
• Inactive metabolites. • Active sulfoxide and sulfone metabolites. • Inactive metabolites.
• Metabolites excreted in urine and bile within • Excreted in urine (90%) in 48 hours, as the
Elimination • Metabolites excreted in urine
24 – 48 hours. glucuronide or sulfonate conjugate.
• More specific and selective effect against • More effective against tissue helminths – High
intestinal nematodes and for multiple bioavailability and activity of the metabolites. • Effective in strongyloidiasis, hook worm and
infestations than other benzimidazoles. • Also has larvicidal effect (ascariasis, hydatid, roundworm.
• Effective for hook worm, round worm, cysticercosis, hookworm), ovicidal effect • Use declined due to toxicity compared to
Anti-helminthic action
enterobiasis (pin worm) and trichuriasis (ascariasis, ancylostomiasis, trichuriasis). other drugs.
(whip worm) – larvicidal as well as ovicidal. • Effective in hook worms, round worms, • Current use is for cutaneous larva migrans –
• Can cause expulsion of worms (Especially trichuriasis, enterobiasis, hydatid disease, topical application of thiabendazole cream.
Ascaris) from mouth or nose. cysticercosis, lymphatic filariasis.
• Contraindicated in pregnancy, liver and renal
Special situations Safety not established in pregnancy and children less than 2 years.
diseases.
• Take on empty stomach when used for
• Can be taken before or after meals. intestinal helminths.
• Tablet should be chewed before swallowing. • Take with fatty meal when used for tissue • Should be given after meals.
Advices
helminths. • Tablets should be chewed before swallowing.

Dose and duration of treatment is the same for children above 2 years as for adults.

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Praziquantel Levamisole Pyrantel pamoate

• Broad spectrum antihelminthic. • Nicotine like action – stimulating and • Broad-spectrum anti-helminthic.
• Disrupts calcium homeostasis – Binds to a subsequently blocking the ganglia • Depolarizing agent that inhibits
voltage gated calcium channel and induce an neuromuscular junction. cholinesterase.
influx of calcium, causing rapid and • Paralyzed worms are expelled in faeces. ❖ Stimulate nicotinic receptor present at
Mechanism of Action prolonged contraction of musculature and • Interference with carbohydrate metabolism the NMJ of nematode → Depolarization
eventual paralysis and death of worm. (inhibition of fumarate reductase) may also → Contraction of the muscle → Spastic
• Disrupts tegument of parasite, unmasking be contributing. paralysis → Worm detachment and
novel antigens and making it more • Ova are not killed. natural expulsion of the worm.
susceptible for host’s immune response.
Absorption Well and rapidly absorbed in GI tract. • Poorly absorbed from the GI tract.
• Effective against luminal organisms, but not
Distribution Widely distributed – Distributes into the cerebrospinal fluid also. against the migratory forms or ova.
• Metabolized to inactive metabolites on first
PK Metabolism • Metabolized in liver to inactive metabolites.
pass metabolism by the liver.
• Metabolites are excreted in urine • • Excreted in kidney • • Less than 15% excreted in urine.
Elimination • Major proportion of administered dose is
• Plasma half-life is 60 – 90 minutes. • Plasma half life – 4 hours recovered in faeces.
• Use with caution in pregnant women and
• Safe in pregnancy, lactation and children – children < 12 months old.
Special situations
used in national disease control program. • Safe to be used in breast feeding mothers.
• Reduce the dose in liver disease.
• Drug of choice for schistosomiasis - Both • Effective against roundworms and
• Effective against hookworm, enterobiasis,
adult schistosomes and immature forms and hookworms.
Anti-helminthic roundworm.
cercariae. • Immunomodulatory effects are present –
action • Ineffective against trichuriasis or
• Effective in cysticercosis, other treamatodes restores depressed T cell function.
strongyloidiasis.
and cestodes. (used in nephrotic syndrome).
• Side effects are minimal in therapeutic doses.
• More marked in patients with heavy worm • GI disturbances
Adverse Effects loads due to products released from dead • CNS disturbances • Mild GI symptoms, Headache and Dizziness
worms – Contraindicated for the treatment • Agranulocytosis
of ocular cysticercosis.
• Should be taken with or after meals.
• Should be swallowed without chewing • Antagonistic property to piperazine and
Advices
because of bitter taste and can induce should not be used concomitantly.
retching and vomiting.
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❖ Anti-filarial medicines are Diethylcarbamazine (DEC), Ivermectin and Albendazole.

(02) Piperazines – Diethylcarbamazine citrate (DEC), Piperazine citrate

Piperazines – Mode of Action (Anti-helminthic action)
• Reversibly inhibits neuromuscular transmission in the worm – Via a GABA agonist action at GABA gated
chloride channels and increase Cl− conductance in nematode muscle and causing hyperpolarization and
depresses responsiveness to contractile action of acetylcholine.
• Paralyzed worms are expelled alive by peristalsis. Therefore, usually co-administered with a stimulant
laxative (such as senna) to facilitate the expulsion of the worms.
• Effective against ascariasis (roundworm) and enterobiasis (threadworm) with cure rates over 90%, but it is
not recommended for other helminth infections.
• NOT given in pregnancy; Cautions in hepatic or renal impairment, cardiac disorders and other severe acute
diseases.

DIETHYLCARBAMAZINE CITRATE (DEC) – IMPORTANT

Diethylcarbamazine Citrate – Mode of Action (Anti-Filarial action)
• The mechanism is not well understood; The proposed mechanism(s) of action are,
o Alteration of helminthic surface membranes resulting in enhanced killing by the host immune
system and inflammatory response.
o Alteration of organelle membranes, promoting apoptosis.
o Disruption of microtubule formation.
o Immobilization – Due to inhibition of parasite cholinergic muscle receptors.
o Interfere with the helminth arachidonate metabolism.
• DEC is primarily microfilaricidal – Rapidly removes the microfilariae from the blood circulation (but does
NOT kill microfilariae in nodules that contain the adult worms and also in transudates [such as hydrocoeles]).
• Also, has some activity adult worms as well – slow acting macrofilaricidal.

Diethylcarbamazine Citrate – Indications

• Preferred drug for Wuchereria bancrofti, Brugia malayi and Loa loa.
❖ NOT used in treatment of acute filariasis as the immune response against killed worms can worsen
the acute attack.
❖ Elephantiasis due to chronic lymphatic obstruction is NOT affected by DEC, because of the fibrosis of
lymphatics being irreversible.
❖ Used in the treatment of Tropical Pulmonary Eosinophilia (TPE).

Diethylcarbamazine Citrate – Pharmacokinetics

❖ Absorption – Rapidly absorbed when given orally (but NOT completely).
❖ Distribution – Widely distributed throughout the cells and tissues of the body – except adipose tissue.
❖ Metabolism – Partly metabolized in the liver.
❖ Elimination –
• Unchanged drug and the metabolites are eliminated via kidneys (more than 50% in acidic urine;
Decreases when urine becomes alkaline).
• Dose adjustments are required in renal failure and people with sustained alkaline urine.

Diethylcarbamazine Citrate – Adverse Effects

• GI disturbances
• Dizziness, Arthralgia, Headache, Paraesthesia, Vertigo, Incoordination, may precipitate epilepsy
• ALLERGIC REACTIONS DUE TO PRODUCTS OF DYING FILARIA – higher with high microfilarial loads.
o Febrile reaction – with skin reactions (urticaria), bronchospasms, lymphadenopathy, hypotension,
tachycardia, dizziness, GI and respiratory disturbances, cough etc.
o Start during the first day of treatment and lasts till day 3 – 7.
o When these symptoms disappear, even larger doses can be given.
o NOT used in patients with onchocerciasis as DEC can accelerate blindness – Ivermectin is used.

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o Antihistamines can be given for the first few days of therapy to limit allergic reactions;
corticosteroids should be started and doses of DEC lowered or interrupted if severe reactions occur.

(03) Ivermectin
Ivermectin – Mode of Action
• A semisynthetic drug derived from an Actinomycete organism – Broad spectrum antiparasitic.
• Causes motor paralysis, either by,
o Binding to GABA receptors – Increase Cl− conductance and Hyperpolarization; same as DEC,
o Binding to novel allosteric site on nicotinic acetylcholine receptor and increase the transmission.

Ivermectin – Pharmacokinetics
❖ Absorption – Available only for oral administration – Rapidly absorbed within 4 – 5 hours.
❖ Distribution –
• Highly protein bound and highest tissue concentration in liver and fat.
• Widely distributed throughout the body – except in brain due p-glycoprotein efflux pump in blood
brain barrier preventing ivermectin from entering CNS.
❖ Metabolism – Metabolized in the liver by the cytochrome P450 enzymes.
❖ Elimination –
• Excretion of the drug and its metabolites is almost exclusively in the feces.
• Long half-life (about 16 hours) due to low clearance and large volume of distribution.

Ivermectin – Indications
• Drug of choice for Onchocerciasis and strongyloidiasis.
• Effective against Wuchereria bancrofti, Brugia malayi and Onchocerca volvulus – Microfilaricidal;
Effectively kills microfilariae but does NOT kill adult worms.
❖ Synergistic activity against lymphatic filariasis, when used with DEC or albendazole.
• Strongyloidiasis, round worms, trichuriasis, enterobiasis – NOT active against hookworms.
• Certain insects – Scabies and Lice.

Ivermectin – Adverse Effects and Contraindications

• Usually well tolerated.
• Due to REACTIONS FROM DYING MICROFILARIAE – itching, tender lymph nodes, joint pain.
Less severe than compared to DEC
• Contraindicated in conditions with impaired blood brain barrier (meningitis, African trypanosomiasis) – can
act on GABA receptors in CNS.
• Should NOT be used during pregnancy and safety not established in children < 5 years.

Mass Drug Administration (MDA)

• Distribution of drugs to entire populations, regardless of ascertainment of disease or infection status, based on
prevalence of the disease in the area – To prevent/cure symptoms and morbidity and to reduce transmission
within the community.
• Safe and inexpensive medicines used.
• Diseases controlled using MDA are – Chlamydia trachomatis, Onchocerciasis, Lymphatic filariasis, Schistosomiasis,
Soil transmitted helminths.
• Mass Drug Administration for Filariasis
o Annual dosing of (1) Diethylcarbamazine with ivermectin, or, (2) Albendazole with ivermectin, or,
(3) Diethylcarbamazine with albendazole for 4 – 6 years.
o In Sri Lanka, Diethylcarbamazine (6 mg/kg body weight) and Albendazole (400 mg) were used for
mass drug treatment from 2002 to 2006 in all endemic districts.
o MDA given to all except children < 2 years, pregnant women and very sick people in the community.
o In May 2016, Sri Lanka and Maldives became the first countries in the WHO South-East Asia Region
to be officially declared ‘filariasis free’.

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ANTI-MALARIAL MEDICINES
Life Cycle of the Malaria Parasite and the Site of Action of Anti-malarial Drugs

Destroys the sporozoites.

Sporontocidal No drug satisfactorily destroys the sporozoites. Therefore, parasite can

always enter the liver and multiply.
❖ Drugs will act only after the parasite enters the liver.
Tissue schizonticide Destroys asexual parasites in tissues (i.e. in liver – exo-erythrocytic cycle).

Blood schizonticide Destroys asexual parasites in blood (erythrocytic cycle).

Gametocytocide Destroys gametocytes in the blood.

Objectives of Treatment – Current Guidelines

• Primary objective of treatment – To ensure rapid and complete elimination of the Plasmodium parasite from the
patient’s blood in order to prevent progression of uncomplicated malaria to severe disease or death.
• From a public health perspective – To reduce transmission of the infection to others by reducing the infectious
reservoir and to prevent the emergence and spread of resistance to anti-malarial medicines.
• In every suspected case of malaria, laboratory confirmation by microscopic examination of blood smears and/or
Rapid Diagnostic Test (RDT) is mandatory prior to initiation of anti-malarial treatment.
❖ Treating malaria based on clinical suspicion without laboratory confirmation should be avoided.
• All confirmed malaria patients should be admitted to a medical institution for a minimum of 3 days to be
managed under supervision. To monitor parasitological response to AMM, blood smear should be examined daily
during the 3 days that the patient is admitted.
• If parasitaemia persists more than 3 days, the practice should continue until parasitaemia clears.
• If facilities are available, a test for G6PD deficiency should be carried out prior to giving primaquine.

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Anti-malarial Medicines (AMM) and Indications
Indications Site of Action Medicines

Treatment of an acute attack of Chloroquine

uncomplicated malaria. Quinine
01. (Short term treatment to kill the asexual A RBC cycle (asexual). Artemisinin-based
parasites, responsible for the morbidity Combination Therapy
and mortality.) Artesunate
Prevention of relapse (Radical cure).
Hypnozytes
02. [Plasmodium vivax and ovale only.] B Primaquine
(Persisting hepatic forms)
(Follows after treating the acute attack.)
Primaquine
Causal prophylaxis. Initial hepatic forms.
Prophylaxis Chloroquine
03. (mainly, given in a
weekly basis.) Suppressive Quinine
C Early destruction of RBC forms.
prophylaxis. Mefloquine, Proguanil,
Pyrimethamine
Primaquine
Quinine
04. Prevention of transmission of parasites. D Gametocytes (sexual forms). Artesunate
Mefloquine, Proguanil,
Pyrimethamine

01 AMMs for Uncomplicated, Mono-infection with Plasmodium falciparum

• Six doses of Artemisinin based combination Therapy (ACT) over a 3-day period.
• Brand of ACT used in Sri Lanka (Coartem®) contain 20mg of artemether and 120mg of lumefantrine.
• Dose is according to patient’s weight – Coartem® tablets are packed in four colour coded blister packs; The
colour of the blister pack and the number of tablets given is selected based on the weight of patient.
• This regime will NOT be suitable for,
o Infants less than 5 kg and Pregnant women in first trimester (ACT is contra-indicated), and,
o Severe complicated malaria (because ACT is NOT available as an injectable preparation).
• ACT should be taken immediately after a meal or drink containing at least 1.2 g of fat (a glass of milk).
• A single dose of primaquine should be administered on day 3 or prior to discharge from hospital to destroy
gametocytes (prevent transmission).
❖ Primaquine is contraindicated in PREGNANCY, LACTATION, INFANTS UNDER THE AGE OF 1 YEAR,
and SEVERE G6PD DEFICIENCY.

02 AMMs for other types of acute attacks

Uncomplicated, Mono-infection with

Oral Quinine sulfate (8 hourly) as Primaquine is contraindicated,
01 Plasmodium falciparum in Pregnancy
and, Clindamycin* (twice a day) for 7 days.
(only for the first trimester)
• IV Artesunate (on admission, then at 12 hour and 24 hours,
and then once a day until the patient is able to take oral
medication; If IV not possible, IM acceptable).
02 Severe Plasmodium falciparum malaria
• Single dose of Primaquine
When IV artesunate is not available; Quinine dihydrochloride
slow IV infusion (loading dose on admission, then every 8 hours)
• Chloroquine (over three days)
03 Mono-infection with Plasmodium vivax
• Primaquine for 14 days

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* Clindamycin is a slow acting erythrocytic schizontocidal against all species of plasmodia including multidrug
resistant Plasmodium falciparum and chloroquine resistant Plasmodium vivax; Potentiates the antimalarial activity of
quinine and artemisinin, and is used in combination with one of these. Liver stages and gametocytes are NOT affected.

02 AMMs for Radical Cure of Plasmodium vivax and Plasmodium ovale

• Primaquine (with chloroquine) – Given orally for 14 days at the end of acute treatment.
❖ Patients should be warned about haemolysis in G6PD deficiency.
• When Primaquine is contraindicated;
o Pregnant or breast feeding – Weekly Chloroquine (chemoprophylaxis) until pregnancy and breast
feeding is completed, and then, depending on G6PD status, Primaquine to prevent future relapses.
o Infants – No data available about safety of primaquine. WHO suggest giving primaquine for infants of
6 – 12 months of age. For infants under 6 months – case by case recommendations.
o G6PD deficiency:
◼ If mild to moderate – Primaquine over an extended period (once a week for 8 weeks)
◼ If severe or in situations where G6PD levels cannot be measured – Case by case considering
many factors such as access to health care facilities in case of a bleed, etc.

03 AMMs for Prophylaxis

• Can be achieved by way of giving AMM to,
o Inhibit the pre-erythrocytic development (causal prophylaxis) – can be stopped soon after leaving
the endemic area,
o Kill the asexual blood stages (suppressive prophylaxis) – must be taken for at least 4 weeks after
leaving the area, to eliminate asexual parasites emerging from the liver weeks after exposure.
• Types of chemoprophylaxis of malaria are,
1) Intermittent preventive treatment of malaria in pregnancy.
2) Intermittent preventive treatment of malaria in infants.
3) Seasonal malaria chemoprevention.
4) Travelers to endemic areas – Prophylactics are started before entering the endemic area,
▪ To establish tolerability, and,
▪ for AMM with long plasma elimination half-life to reach the steady state.
• AMMs that can be used in chemoprophylaxis are,
o Causal prophylaxis – Primaquine (NOT clinically used because of its toxic potential), Chloroquine,
Proguanil, Atovaquone
o Suppressive prophylaxis – Primaquine, Chloroquine, Doxycycline, Mefloquine, Proguanil, Tafenoquine
o Intermittent preventive treatment of malaria in pregnancy – Pyrimethamine (+ Sulfadoxine)

04 AMMs for Prevention of Transmission

• For Plasmodium falciparum malaria – Single dose of Primaquine
• For Plasmodium vivax and ovale malaria – NOT required since the radical cure kills gametocytes as well.

(01) Artemisinin-based Combination Therapy – Artemether, Artesunate

• Both are soluble derivatives of Artemisinin (which is poorly soluble in water as well as in oil).
o Artemether is lipid soluble – given as oil-based IM injection or orally (mostly as FDCs).
o Artesunate is water soluble, Available for IV, IM, rectal and oral administration (mostly as FDCs).
• To prevent the development of resistance, these agents are NOT used alone. They are used as FDCs.
1) Artemether is usually combined with lumefantrine.
2) Artesunate can be combined with pyrimethamine–sulfadoxine, mefloquine,
clindamycin, etc.

Artemisinin Derivatives – Mode of Action

• Mechanism is not well defined – Involves cation-mediated generation of reactive
intermediates by reduction of the peroxide bridge by heme iron in the parasite food
vacuole, and thus interfering with the conversion of haem to non-toxic haemozoin.

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• Rapidly effective against blood stages of the parasite from ring stage to early schizonts stage – NOT active
against sporozoites and extra erythrocytic stages (liver schizonts, hypnozoites, merozoites).
• Reduces early gametocytes (but not against the fully mature gametocyte) limiting transmission of parasite
from a treated infective patient.

Artemisinin Derivatives – Pharmacokinetics

❖ Distribution –
• Widely distributed throughout the body.
• Highly plasma protein bound (Artemether 95% bound; Dihydroartemisinin 93% bound).
❖ Metabolism – Converted to the active metabolite dihydroartemisinin (arterimol) in the liver by cytochrome
enzymes.
❖ After oral administration, dihydroartemisinin is responsible for most of the antimalarial action, but
after IM (artemether) or IV administration (artesunate), the non-metabolized medicines also
contribute for the anti-malarial activity.
❖ With repeated dosing, artesunate causes auto-induction of its own metabolism.
❖ Elimination –
• Both artemether and artesunate have short elimination half-lives.
• Dihydroartemisinin is metabolized in the gut and liver and excreted in urine.

Artemisinin Derivatives – Indications

ARTEMETHER ARTESUNATE
• Treatment of uncomplicated malaria caused by • IV or IM artesunate is indicated for initial
Plasmodium falciparum and vivax. treatment of severe malaria.
❖ NOT indicated for prophylaxis. (Due to • Rectal artesunate is indicated for pre-referral
the risk of increasing resistance, and treatment of severe malaria.
short elimination half-life) • FDC with other AMM indicated for treatment of
• Follow on treatment of severe malaria caused uncomplicated malaria.
by Plasmodium falciparum, when patient is
well enough to take oral medication.

Artemisinin Derivatives – Adverse Effects

ARTEMETHER ARTESUNATE
• Hypersensitivity reactions, gastro-intestinal • Mostly, similar to artemether.
symptoms, dizziness, increased liver enzymes, • Significant – Dose-dependent haemolysis even
neutropenia, reticulocytopenia, bradycardia, weeks after treatment.
prolongation of PR and QT intervals. • Cautions are – Renal and hepatic failure, Children
• Cautions are – Renal failure, Chronic cardiac with anaemia (low plasma concentration of
disease patients, Meningitis (higher concentration artesunate is reported).
of artemether is documented in CSF).

Artemisinin Derivatives – Safety

• Artemether-Lumefantrine FDC – Considered to have a wide therapeutic index.
o Pregnancy – Experience is limited in humans. Teratogenicity was reported in animal studies if given
in first trimester.
◼ First trimester – Avoid for uncomplicated malaria; For severe malaria, IV artesunate can be
given as benefits (life-saving) outweigh the risk.
◼ During second and third trimester, lactation – Can be given for all types of malaria including
uncomplicated malaria.
o Safety not studied in infants < 5 kg and elderly > 65 years (Hence, avoid preferably).
o Avoid in patients with prolonged QT intervals, family history of sudden deaths/prolonged QT
intervals, anti-arrhythmics etc. – as lumefantrine also causes minimal prolongation of QT interval.

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• Cautions in electrolyte disturbances and patients unable to take food should be monitored. Also, use with
caution in hepatic and renal impairments with close monitoring, especially of ECG.
• Drug interactions – Should NOT be given with drugs metabolized by the cytochrome P450 isoenzyme
(CYP2D6) (Eg: metoprolol, neuroleptics, tricyclic antidepressants, etc.), as the isoenzyme CYP2D6 is inhibited
by lumefantrine.

LUMEFANTRINE
• Active against the erythrocytic forms of all Plasmodium species, especially falciparum and viva.
• Only available as a fixed drug combination with artemether – using lumefantrine alone increases the
chances of parasite developing resistance.
• Variable bioavailability – Absorption is substantially increased by fatty meals or milk with plasma levels
peaking about 10 hours after oral intake; Failure to take it with fat rich food may result in recrudescence.

(02) Chloroquine
• It is a synthetic 4–Aminoquinoline derivative.
• Very potent against blood schizonts of all four species – Hence, used mainly to treat an acute attack.
• NOT effective against sporozoites or hypnozoites – Cannot be used for radical cure; or against gametocytes.
• Widely used in 1960 – 2010 or so, but NOT used for Plasmodium falciparum infections now, because of
wide spread resistance.

Chloroquine – Mode of Action

• Mechanism is not well understood – Concentrates within acidic food vacuoles of the parasites, primarily by
ion trapping. Then it interferes with digestion of haemoglobin by the parasite and reduce the supply of
amino acids for its viability.

• Also forms complexes with parasitic DNA in high concentration – but unlikely to be related to its antimalarial activity.

Chloroquine – Pharmacokinetics
❖ Absorption – Well absorbed when given orally.
❖ Distribution – Widely distributed throughout the body – concentrated in many tissued including spleen,
liver, heart, kidney, cornea and retina etc. Concentrates within parasitized red blood cells.
❖ Metabolism – About 30% is metabolized in the liver (dealkylated by the hepatic oxidases, and some metabolic
products retain antimalarial activity).
❖ Elimination –
• Major portion (about 70%) is excreted unchanged in urine.
• Has a long plasma elimination half-life (early plasma t½ about 7 days; terminal t½ about 50 days)
because it is released slowly from the concentrated tissues – Requires a loading dose (in order to
achieve adequate free plasma concentration).

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Chloroquine – Clinical Uses
• Malaria (for radical cure of mono-infection with Plasmodium vivax; for Plasmodium malariae and ovale.)
• Disease-modifying anti-rheumatoid drug for rheumatoid arthritis (RA)
• Systemic Lupus Erythematosus (SLE)
• Extraintestinal amoebiasis

Chloroquine – Adverse Effects

• Adverse effects are minimal in doses normally used for malaria, but seen when high doses are used (as for
RA and SLE).
• Immediately - GIT symptoms, Headache, Blurred vision, PRURITUS, Dizziness, Restlessness, Hypotension.

❖ These immediate adverse effects can be managed by,

1) Taking the tablets with meals to reduce gastrointestinal disturbances.
2) Correcting the dehydration and reducing the fever.
3) Repeating the same dose, if the tablets are vomited within 1 hour of ingestion.
• Precipitation of an acute attack of PORPHYRIA in susceptible people.
• If used IV bolus doses or IM injections (Acute overdose can be rapidly fatal)– ARRHYTHMIAS,
HYPOTENSION, Respiratory and Cardiac arrest, Seizures, Neurotoxicity and Ototoxicity.
• Long term use (Eg: RA and SLE) – Corneal deposits (reversible), RETINAL TOXICITY (irreversible), Bone
marrow suppression, Depigmentation or loss of hair

Chloroquine – Cautions and Contraindications

• Contraindicated in;
o patients with history of generalized seizures or psoriasis.
o patients who develop retinal or visual field changes attributable to chloroquine, and in patients with
known hypersensitivity.
• Cautions in;
o Renal impairment
o Pregnancy (For malaria, benefits outweigh the risks)
• If used for long term – retinal examination should be done 6 monthly.
• Chloroquine can cross the placenta, but it is safe to be used in pregnancy and also in breast-feeding.

(03) Primaquine
• It is an 8–Aminoquinoline derivative.
• Primaquine is effective against the hepatic forms including the hypnozoites – clinically useful in radical cure
of Plasmodium vivax and ovale, and gametocytes of all four species – prevents transmission.
• Unlike other antimalarial drugs, primaquine is NOT effective against erythrocytic schizonts.
• Resistance to primaquine is rare – Almost invariably used with another drug, usually ACT as per current
guidelines.
• Mechanism of action is not well understood – Reactive intermediate metabolites of primaquine are thought
to disrupt the electron transport chain and interferes with mitochondrial function.

Primaquine – Pharmacokinetics
❖ Absorption – Well absorbed when given orally.
❖ Distribution – Moderately concentrated in tissues.
❖ Metabolism – Rapidly metabolized by the liver, with a plasma elimination half-life of 6 hours and eliminated
within 24 hours in urine.

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Primaquine – Adverse Effects
• Dose related GIT symptoms
• HAEMOLYSIS IN G6PD DEFICIENCY
• METHAEMOGLOBINAEMIA
• Leucopaenia

(04) Quinine
• Quinine is an alkaloid of cinchona bark.
• Effective against erythrocytic forms of all four species and gametocidal
against Plasmodium vivax, malariae and ovale, but NOT falciparum.
• It is NOT effective against other pre-erythrocytic forms and on hypnozoites.
• Less effective and more toxic than chloroquine, and may not prevent
recrudescence – Doxycycline or Clindamycin is mostly added to it for
complete parasite clearance.
• Mode of action is similar to chloroquine – Interferes with haem utilization
of the parasite. But it is NOT concentrated in tissues like Chloroquine.
• Well absorbed when given orally. But in severe malaria, given as an IV infusion (a loading dose is required).

Quinine – Clinical Uses

• Severe Plasmodium falciparum malaria, when IV artesunate is not available.
• Uncomplicated, Mono-infection with Plasmodium falciparum in Pregnancy (only for the first trimester).
❖ Cautions and Contraindications are; Haemoglobinuria, Myasthenia gravis, Cardiac arrhythmia
(caution), Diabetes (caution) and PREGNANCY (caution).

Quinine – Adverse Effects

• GIT ADVERSE EFFECTS – nausea, vomiting, gastric irritation, diarrhoea, abdominal pain, anorexia.
• IDIOSYNCRATIC REACTIONS – urticaria, asthma, oedema of eyelids, thrombocytopaenia, fever.
• Quinine toxicity (with plasma level > 5 mg/L)
o “CINCHONISM” – nausea, headache, tinnitus, dizziness, blurred vision, transient hearing loss,
giddiness, ECG changes (delayed AV conduction, bradycardia)
o HYPOGLYCAEMIA
• Quinine toxicity (with plasma level > 20 mg/L) – hypotension, cardiac arrhythmias, delirium, coma
• BLACK WATER FEVER – very rare, severe, usually fatal condition associated with acute haemolytic anaemia
and renal failure when quinine is given in cerebral malaria.

ANTI-MALARIAL RESISTANCE
• Antimalarial resistance is defined as the ability of a parasite strain to survive and/or multiply despite the
administration and absorption of a drug given in doses equal to or higher than those usually recommended, but
within tolerance of the subject.
• Multidrug resistance (MDR) is defined as resistance to more than two antimalarial compounds of different
chemical classes.
• Facilitators of emergence of resistance to anti-malarials are;
1) Parasite mutation rate
2) Overall parasite load
3) Strength of drug selected
4) Poor patient compliance
5) Poor adherence to malaria treatment guidelines.
6) Improper dosing, timing, storage, etc.
7) Ignoring pharmacokinetic properties
8) Fake drugs lead to inadequate drug exposure on parasites.
9) Poor-quality antimalarials
▪ Falsified antimalarial without active pharmaceutical ingredient.
▪ Wrong active pharmaceutical ingredients (APIs) (Eg: use of halofantrine instead of artemisinin).

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ANTI-VIRAL
Viruses and Anti-Virals – Introduction
• Viruses are not considered living things, because they cannot reproduce on their own. They must invade the
cells of other living beings and take over the cells' machinery to replicate – obligate intracellular parasitism.
• Developing antiviral medicines has been difficult, because most drugs that kill viruses also damage the
host's cells, where the viruses hide. However, since 1980s, when AIDS virus began to receive attention,
encouraging progress has been made.
• Antiviral drugs cure or control virus infections. But, unlike antibacterial drugs, narrow in spectrum, and
have limited efficacy.
• Antivirals are most effective when the viruses are replicating. Therefore, the earlier the treatment is given,
better the response – i.e. therapy has to be started in the incubation period (prophylactic or pre-emptive).
❖ However, the anti-viral therapy is further complicated due to the clinical symptoms appearing late in
the course of the disease, by when most of the virus particles have replicated.
• Antiviral drugs are virustatic – active only against replicating viruses and do NOT affect latent virus.
• Some viral infections require monotherapy for brief periods of time (Eg: HSV, influenza), while others
require multiple drug therapy for indefinite periods (Eg: HIV).
• Viral replication requires several steps and anti-viral agents can potentially target any of these steps.

• Antiviral drugs can be classified into two broad groups.

1. Anti-Retroviral Drugs (Majority of the drugs)
2. Other Anti-Viral (Non-Retroviral) Drugs

01 Anti-Retroviral Drugs
• Treat infections caused by retroviruses (Primarily HIV) – No cure, slows or reduce disease progression and
increase life expectancy. Also, they reduce risk of transmission to sexual partners and fetus.
• Combination therapy – Reduce the risk of emergence of resistance. But associated with serious side effects.
❖ The most effective combination – HAART (Highly Active Anti-Retroviral Therapy); Produces intense
suppression of viral replication.
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• Different classes of anti-retroviral drugs act at different stages of the HIV life cycle.

• There are two main classes of anti-retroviral drugs.

1. Reverse transcriptase inhibitors – Nucleoside analogues/Non-Nucleoside analogues
2. Protease inhibitors
• Other classes of anti-retroviral drugs are,
3. Fusion inhibitors
4. Integrase inhibitors
5. Entry inhibitors (CCR5 chemokine receptor antagonists)
6. Pharmacokinetic enhancers

(01) Reverse Transcriptase Inhibitors

• HIV replicates by converting viral ssRNA to dsDNA, which then gets incorporated to host DNA. This crucial
conversion is catalyzed by reverse transcriptase. RTI inhibit construction Viral DNA.

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• Reverse transcriptase inhibitors (RTIs) target construction of viral DNA by inhibiting activity of reverse
transcriptase.
• There are two subtypes of reverse transcriptase inhibitors.
Nucleoside-analogue RTIs Non-nucleoside-analogue RTIs
• Highly selective, noncompetitive inhibitors of HIV-1
• Act by competitive inhibition of HIV-1 reverse
reverse transcriptase.
transcriptase.
• Bind directly to HIV-1 reverse transcriptase (but not
• First phosphorylated to the corresponding nucleotides
HIV-2) near the catalytic site and inducing a
and can then act as false substrates; Incorporated into
conformational change, inactivate it.
the growing DNA chain, but due to the lack of a 3′-
• Results in inhibition of RNA and DNA dependent DNA-
hydroxyl group, causes chain termination.
polymerase activity.
• Do NOT require activation by host cellular enzymes.
• Require activation by host cell enzymes –
• Have considerably longer half-lives than nucleoside-
phosphorylation into the corresponding triphosphate.
analogue RTIs.
Unwanted Effects Unwanted Effects
• γ-DNA polymerase in the host cell mitochondria is • Cross-resistance with other non-nucleoside-analogue
also susceptible to inhibition at therapeutic RTIs.
concentrations. • Drug interactions – inducers, substrates or inhibitors,
• Mammalian α-DNA polymerase is relatively resistant of the liver cytochrome P450 enzymes.
but effects may be seen at high doses and may be the • High incidence of hypersensitivity reactions
basis of some unwanted effects. (including rash and gastrointestinal intolerance).
Zidovudine, Lamivudine, Stavudine,
Didanosine, Abacavir, Emtricitabine Nevirapine, Efavirenz, Etravirine, Rilpivirine
Tenofovir (a neucleotide-analogue)

(02) Protease Inhibitors – Indinavir, Ritonavir

• In the process of its replication, HIV produces protein and also the protease enzyme – cleaves precursor
protein into various structural and functional component parts, that are later assemble to viral parts.
• Protease inhibiters target viral assembly by reversible inhibition of protease – prevent the processing of
viral proteins into functional conformations, resulting in immature, noninfectious viral particles.
• ALL are metabolized by cytochrome P450 enzymes and most protease inhibitors inhibit cytochrome P450.

❖ Other classes of anti-retroviral drugs are;

• Bind to the gp41subunit of the viral envelope glycoprotein and
Fusion inhibitors block the conformational changes necessary to induce fusion of Enfuvirtide
the viral particle with the host cell membrane.
Dolutegravir,
• Inhibit the HIV viral enzyme integrase, which is responsible for
Integrase inhibitors Elvitegravir,
integration of viral DNA into the DNA of the infected cell.
Raltegravir
• Bind to the CCR5 chemokine coreceptor on host cells – Induce a
Entry inhibitors conformational change, that impedes CCR5 interaction with HIV Maraviroc
glycoprotein gp120, preventing HIV entry into host.
• No antiviral activity – Prolongs action of protease inhibitors
Cobicistat
Pharmacokinetic enhancers atazanavir and darunavir by inhibiting CYP3A4 enzyme and thus
Low dose ritonavir
boosting their concentration.

• The decision to begin antiretroviral therapy in HIV is based on,

o The CD4+ cell count (< 200 cells per μL)
o Plasma viral load (100,000 viral genome copies per mL)
o In pregnancy – to reduce risk of vertical transmission.
o Those with an AIDS diagnosis (Eg: Kaposi sarcoma), or hepatitis B and HIV co-infection.

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HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) [Portmanteau inhibitors]
• A new way to combat HIV through the meaning of combining two antiviral agents into one drug, achieving
optimal effect than when two or more drug are taken separately.
• Currently two types of antiretroviral combinations (with at least three anti-HIV drugs, belonging to at least
two different classes) are recommended for first-line treatments.
1. Boosted protease inhibitor OR integrase inhibitor + Two
nucleoside-analogue RTIs
Eg: ◼ Dolutegravir + Tenofovir + Lamivudine
◼ Dolutegravir + Tenofovir + Emtricitabine
2. A non-nucleoside RTI + Two nucleoside-analogue RTIs
Eg: ◼ Efavirenz + Tenofovir + Lamivudine/Emtricitabine
◼ Efavirenz/Nevirapine + Zidovudine + Lamivudine

Antiretroviral drugs – Adverse Effects

❖ Vary by drug, by ethnicity, and by individual, and by interaction with other drugs, including alcohol.
• HYPERSENSITIVITY
• GI DISTURBANCES – nausea, vomiting, dyspepsia, diarrhoea, bloating, pancreatitis or hepatitis etc.
• NERVOUS SYSTEM EFFECTS – insomnia dizziness, headache, vivid dreams and psychotic symptoms,
peripheral neuropathy, paresthesias etc.
• MUSCLE DAMAGE – Toxic myopathy, Rhabdomyolysis, Elevated serum creatinine kinase.
• BLOOD DISORDERS – sometimes anaemia or neutropenia
• LIPODYSTROPHY SYNDROME – Redistribution of body fat in some patients, Buffalo hump.
• IMMUNE RECONSTITUTION SYNDROME – Improvement of immune function with antiretroviral treatment
may provoke a marked inflammatory reaction against residual opportunistic organisms.
o Usually occur within first few weeks or months of treatment.
o Autoimmune diseases such as Graves’ disease has also been reported.
• OSTEONECROSIS – Reported after long term exposure to antiretroviral drugs.

Antiretroviral drugs – In Pregnancy

• Anti-retroviral therapy should be started in all adults (including pregnant and breast-feeding women),
adolescents as well as children as soon as possible after diagnosis of HIV infection is confirmed.
• All pregnant women with HIV should take HIV medicines as soon as possible, throughout pregnancy for
their own health and to prevent perinatal transmission of HIV – Most HIV medicines are safe to use during
pregnancy, and HIV medicines do not increase the risk of birth defects.
❖ Pregnant women with HIV can use the same treatment regimens recommended for non-pregnant
adults; unless the risk of any known side effects to a pregnant woman or her baby outweighs the
benefits of a treatment regimen.
❖ Women who are already on an effective HIV treatment regimen when they become pregnant should
continue using the same regimen throughout their pregnancies.

02 Other Anti-viral Drugs (Non-Retroviral)

• Antivirals are NOT curative, and must be used prophylactically or early in the development of an infection.
❖ Antiviral therapy must normally be initiated within 48 hours of the onset of an infection to provide
any benefit.
• Their mechanism of action is typically to inactivate the enzymes needed for viral replication – reduce the
rate of viral growth, but will NOT inactive the virus already present.
• Recommended dosage of the anti-viral drugs varies with the drug, patient’s age, the condition, the route of
administration and other factors.

• Viruses can be classified as DNA viruses and RNA viruses.

o DNA viruses – Hepatitis B, Herpesviruses (HSV-1, HSV-2, Varicella zoster, Epstein-barre virus,
Cytomegalovirus), Poxviruses (smallpox, Molluscum), Adenoviruses (sore throat, conjunctivitis),
Papillomaviruses (warts)
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o RNA viruses – Orthomyxoviruses (influenza), Hepatitis A, C, D and E, Paramyxoviruses (measles,
mumps, respiratory tract infections), Rubella, Rhabdoviruses (rabies), Picornaviruses (colds, meningitis,
poliomyelitis), Arboviruses (arthropod-borne diseases, Eg: Japanese encephalitis, dengue, yellow fever).

Drug classes/Mechanisms Anti-DNA Viral Drugs Anti-RNA Viral Drugs

Inhibitors of viral penetration Palivizumab
Docosanol Adamantane antivirals
Inhibitors of viral uncoating
(Amantadine, Rimantadine)
Acyclovir, Valacyclovir, Ganciclovir,
DNA Polymerase Inhibitors
Famciclovir, Cidofovir, Foscarnet
mRNA Inhibitors Fomivirsen Ribavirin
Release inhibitors
Oseltamivir, Zanamivir
(Neuraminidase inhibitors)
Imiquimod, Interferons and Interferons and Pegylated
Immunomodulators
Pegylated interferons interferons

Anti-DNA Viral Drugs

(01) ACYCLOVIR – IMPORTANT
• Available in oral, IV and topical forms. (oral and topical given 5 times a day – oral dose 400 mg or 800 mg)
• Mechanism of action –
o A structural analog of guanine which is activated only after mono-
phosphorylation by virus-specific thymidine kinase (Hence, has a
wide therapeutic index). Inhibits viral DNA synthesis by,
◼ Competition with deoxyGTP for the viral DNA polymerase, and
binding to the DNA template as an irreversible complex, and,
◼ Chain termination following incorporation into the viral DNA.
o Should be administered as early as possible for successful treatment.
But will NOT eradicate the persistent viruses, because viral DNA is
integrated in the host genome.
• Pharmacokinetics –
❖ Absorption – Oral bioavailability is about 20% and it decreases with
increasing dose; it is sufficient to exert its effect in systemic infections.
❖ Distribution – Widely distributed, including the CSF (However,
require a higher dose in treating viral encephalitis – should be
administered IV).
❖ Elimination – Excreted unchanged by kidneys in urine – glomerular
filtration and tubular secretion.
• Adverse effects – Remarkably few; Well tolerated. Safe in pregnancy and
breast feeding, and thus can be used if benefits outweigh the risks.
o GI effects, Headache, Neuro-psychiatric reactions with systemic use.
o Severe local inflammation, if extravasated in IV administration.
o Crystal-uria (Patient should be advised to drink more water).
o Cautions in renal impairment and elderly (due to increased risk of
neurological adverse effects).
• Indications –
o Herpes simplex (skin and mucous membrane infections, ocular
keratitis, encephalitis)
o Varicella zoster (chickenpox) – Orally in immune-competent patients,
IV in immune-compromised and even immunocompetent with
pneumonia or hepatitis (IV dose – 200 mg three times per day).
o Shingles – for best response, start within 48 hours of onset of rash; little
benefit if treatment is delayed beyond 72 hours.

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Treatment of Viral Infections – Varicella Zoster
• Acyclovir, Famciclovir, Valacyclovir (DNA polymerase inhibitors) – These drugs are NOT curative, but
may reduce the pain of a herpes outbreak and shorten the period of viral shedding.
• Treatment varies with age and other special situations.
o Neonates with chickenpox – Parenteral treatment indicated. Oral therapy not recommended since
absorption can be variable.
o Children (Between 1 month and 12 years) – Disease mild. Antiviral treatment NOT recommended.
o Adolescents and adults – Antiviral treatment should be started within 24 hours of symptoms;
severity and duration can get reduced.
o Immuno-compromised – Given for 10 days, with 7 days as IV drugs.
o Pregnancy – Seek specialist advice. Acyclovir is not known to be harmful; can be used if benefits
outweigh the risks.
o Breastfeeding – caution.

NOTE – The rest of the lecture has been included as additional information; Therefore, the following is added to the
note only for the sake of completeness.

(02) IMMUNOMODULATORS – Interferons, Pooled immunoglobulins, Monoclonal antibodies

• INTERFERONS –
o Can be used on both DNA and RNA viruses.
Indications
o Inhibit multiple steps in the viral replication
pathway – Penetration, Uncoating, mRNA Interferon α-2A Interferon α-2B
synthesis, Assembly and Release. • Chronic Hepatitis B • Chronic Hepatitis B
o Interferons act: • Chronic Hepatitis C • Hepatitis C
▪ directly on uninfected cells to induce
• Kaposi’s sarcomas • Condyloma acuminata
enzymes that inhibit viral RNA
translation, leading to the degradation of viral mRNA and tRNA.
▪ indirectly by stimulating the immune system.
o NOT active orally; may be administered intralesional, subcutaneous or intravenously. Metabolized in
the kidney and liver.
o In “pegylated” formulations, a polyethylene glycol has been covalently attached to the interferon to
increase the molecular size. The larger molecular size delays absorption from the injection site,
lengthens the duration of action, and also decreases its clearance.
o Adverse effects are,
◼ Flu-like symptoms (mediated by cytokine release) – fever, myalgia, rash, lassitude, headache
◼ Alopecia (loss of hair)
◼ Bone marrow suppression; if used for a longer duration
• POOLED IMMUNOGLOBULINS –
o Contain antibodies against various viruses present in the population.
o Antibodies are directed against virus envelope; neutralize and prevent their attachment to host cells.
o Used in rubella, rabies, or poliomyelitis – If used before onset of symptoms, may attenuate or prevent.
• HYPER-IMMUNE GLOBULINS – Specific against particular viruses (Hepatitis B, Varicella zoster and Rabies).
• PALIVIZUMAB –
o Humanized monoclonal antibody directed against a glycoprotein on the respiratory syncytial virus.
o Indicated for prevention of RSV infections in children at high risk. NOT indicated for adults.
o Used as an intramuscular injection.
o Adverse effects – Fever, Rash, Rhinitis, Diarrhoea.
• INOSINE PRANOBEX –
o Interfere with viral nucleic acid synthesis, but also has immuno-potentiating actions on the host.
o Indicated for herpes infections of mucosal tissues or skin.

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(03) GANCICLOVIR • It is a synthetic guanosine analogue, that inhibits RNA
• Available as intravenous injections, oral capsules, and intra- polymerase and interferes with the synthesis of viral mRNA.
occular inserts. • Rarely, can lead to deterioration of respiratory function in
❖ The capsules should be reserved for prophylactic use in infants. Careful monitoring is essential for safe use.
organ transplant patients, or for HIV infected patients
who cannot be treated with the intravenous drug. (02) AMANTADINE
• Mechanism of action – Similar to acyclovir. • An anti-influenza drug – Inhibit viral capsule disassembly by
• Adverse Effects – inhibiting the viral membrane protein M2.
o Dose-dependent granulocytopenia, anemia and • Cross the BBB – also used for treatment of Parkinsonism.
thrombocytopenia when administered systemically. • Generally well tolerated – may show more frequent CNS
◼ Should NOT be used with other drugs which effects, including dizziness, ataxia, hallucinations and seizures.
cause hematologic toxicity. • Pregnancy is a caution (category C).
o Pregnancy is a caution (category C – has caused
significant foetal abnormalities in animal studies Treatment of Viral Infections
including cleft palate and organ defects). 01 Cytomegalovirus (CMV)
o Breast feeding is NOT recommended. • DNA polymerase inhibitors – Ganciclovir, Valganciclovir (oral),
• Indications – Foscarnet (IV), Cidofovir (IV) is used to treat in CMV retinitis.
o CMV infections in immune-compromised. • Anti-cytomegaloviral drugs must routinely be used for
o CMV prophylaxis for transplant recipients. secondary prophylaxis (maintenance therapy following an
initial response) to prevent reinfection in
(04) VALACYCLOVIR immunocompromised patients (primarily HIV-positive
• The valyl ester of acyclovir – has greater oral bioavailability patients and transplant recipients).
than acyclovir; rapidly hydrolyzed to acyclovir and achieves
levels comparable to those of acyclovir after IV administration. 02 Hepatitis
• Mode of action and adverse effects are similar to acyclovir. • Acute viral hepatitis – Mainly requires symptomatic treatment.
• Generally well tolerated – nausea and headache are common. • Acute hepatitis C – Early treatment with interferon alfa may
• Famciclovir is also similar in actions and the adverse effects. reduce the risk of chronic hepatitis.
• Active and passive immunization can be done against hepatitis
A and B.
(05) CIDOFOVIR
• Chronic hepatitis B
• Used for CMV retinitis in immune-compromised patients.
o Entecavir and tenofovir are options for initial treatment.
• Adverse Effects –
o Peginterferon alfa is an option for initial treatment and
o Renal toxicity (53%) – Patients should be well
is preferable to interferon alfa. However, it is
hydrated, and renal function should be checked
contraindicated in decompensated liver disease.
regularly.
o Lamivudine, telbivudine, adeforvir, entecavir and
◼ Should NOT be used with other drugs that
tenofovir (Nucleoside-analogue inhibitors of viral RT
may cause kidney damage.
[HBV DNA polymerase]) used for long term treatment.
o Nausea and vomiting, Asthenia, Headache and diarrhea.
• Chronic hepatitis C – Before starting therapy, genotype of the
o Pregnancy is a caution (category C – has caused
infecting hepatitis C virus should be determined and viral load
significant foetal abnormalities in animal studies)
measured as this affects the choice and duration of treatment.
o Breast feeding is NOT recommended.
o A combination of ribavirin (mRNA inhibitors) and
peginterferon alfa is used.
(06) FOSCARNET o HCV inhibitors – Elbasvir with grazoprevir; reduce viral
• Used in treatment of immunocompromised patients with CMV load by inhibiting hepatitis C virus RNA.
infections and in acyclovir-resistant herpes simplex virus. o Non-structural protein 5A inhibitors – Daclatasvir,
• Adverse Effects – ombitasvir (with paritaprevir and ritonavir).
o Renal toxicity o Nucleoside analogues – Ribavirin; Nucleotide analogues
o Alterations in electrolyte levels may cause seizures and – Sofosbuvir; Protease inhibitor – Simeprevir; Other –
arrhythmias. Dasabuvir.
o Pregnancy is a caution (category C – has caused skeletal
abnormalities in developing foetus). 03 Influenza
o Not known whether foscarnet is excreted in breast milk. • Oseltamivir, Zanamivir, Peramivir (Neuraminidase inhibitors)
(However, the drug does appear in breast milk in – most effective if started within few hours of onset of
animal studies.) symptoms; Indicated for post-exposure prophylaxis as well.
❖ Reduces severity and duration of symptoms caused by
Anti-RNA Viral Drugs influenza A and B in adults and children, if commenced
(01) RIBAVIRIN within 36 hours of onset of symptoms.
• Broad spectrum antiviral – against many DNA and RNA viruses. ▪ Pregnancy – can use during pandemic, if potential
o used by aerosol for treatment of hospitalized infants benefits outweigh the risk.
and young children with severe lower respiratory tract ▪ Breast feeding – Oseltamivir can be used.
infections due to respiratory syncytial virus (RSV). • Amantadine, Rimantadine (Inhibitors of viral uncoating) – for
o used orally in adults to treat other viral diseases prophylaxis and treatment of influenza A, but is NO longer
including acute and chronic hepatitis, herpes genitalis, recommended due to widespread resistance.
measles, and Lassa fever. • Ribavirin (mRNA inhibitors) – for respiratory syncytial virus.
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ANTI-FUNGALS
Classification of Anti-Fungals
ANTI–FUNGAL DRUGS

Antibiotics Azoles Flucytosine Allylamines

Terbinafine
Polyene Amphotericin B Imidazoles Triazoles
Antibiotics Nystatin Ketoconazole
Fluconazole
Heterocyclic Miconazole
Griseofulvin Itraconazole
benzofuran Clotrimazole
Caspofungin
Echinocandins Micafungin
Anidulafungin

• Fungal infections can be;

1) Superficial – Affects the skin and mucous membranes, or,
2) Systemic – Affects deeper tissues such as heart, lungs, brain etc.
• Therefore, antifungals can also be classified as;
1) Antifungals for superficial fungal infections –
o Nystatin
o Griseofulvin
o Azoles
o Terbinafine.
Whitfield’s ointment (for dermatophytes) – NOT in use now.
Salicylic acid 3%; Benzoic acid 6% and Emulsifying ointment 91%.

2) Antifungals for systemic fungal infections –

o Amphotericin B
o Azoles (Fluconazole, Itraconazole, Voriconazole [broad spectrum])
o Flucytosine
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Drug Mechanism of Action Indications Important PK Preparations Adverse Effects

Disruption of fungal cell membrane Superficial Infections • High systemic toxicity – • Mouth washes
• Binds to ergosterol, and changes • ONLY for candidiasis only used locally. • Mouth paints.
• Nausea
the membrane permeability – the (oropharyngeal thrush, • it is not absorbed when • Oral tablets,
Nystatin • Vomiting
hydrophilic core of polyene vaginal candidiasis etc.). given orally, or, through Lozenges
• Diarrhoea
structure creates a • ONLY for topical use – mucous membranes or • Creams, Ointment
Polyene skin. • Severe skin rashes
transmembrane ion channel. skin and mucosal lesions. or Powder
Antibiotics
• Gross disturbances in ion balance (mouth, intestine, vaginal) • Vaginal pessaries
(contains
many double – Leads to leakage of ions and • Absorbed negligibly
enzymes from fungal cells. Systemic Infections • Lozenges – • Mild GI disturbances
bonds) from the gut and must
• Causes cell death of fungi – • Drug of choice for most oropharyngeal • Fever, chills
be given by IV infusion
Fungicidal. systemic fungal infections. candidiasis Anorexia, nausea,
Amphotericin B for systemic infections.
❖ Ergosterol is specific to fungal Eg: severe invasive • Lipid formulations vomiting.
• Should be protected
membranes, and NOT found in candidiasis, Invasive less toxic (but, • Renal impairment
from light during IV
mammalian cell membranes. aspergillosis. expensive) • Hypokalaemia
administration.
Superficial Infections
Topical agents – Miconazole, Clotrimazole
• Dermatophytes – Tinea capitis, Tinea corporis, Tinea • Creams
paedis, Tinea unguium and tinea cruris. • Ointments
• Tinea versicolor – caused by Malassezia furfur. • Dusting powders
• Candidiasis • Shampoos
Topical and shampoo forms of ketoconazole are also
• Inhibit the fungal cytochrome available – for seborrheic dermatitis and tinea versicolor.
P450 enzyme, lanosine 14α-
demethylase, and inhibits Systemic fungal infections
conversion of lanosterol to • Oral preparations
ergosterol – It alters the fluidity of • Metabolized in the liver and excreted in are NOT • Hepatotoxicity
the membrane, thus disrupts the bile. recommended to • Drug interactions
membrane structure and • It is a hepatic microsomal enzyme treat fungal • Adrenal insufficiency
Azoles Ketoconazole
function, and, inhibits fungal cell inhibitor – Inhibits metabolism of infections. and gynaecomastia
growth. warfarin, phenytoin sodium and
• Primarily fungistatic. cyclosporin.
• Interferes with fungal oxidative • Well absorbed after oral administration.
enzymes causing lethal • Water soluble.
accumulation of hydrogen Fluconazole • Good penetration into CSF – Effective in Oral or intravenous • Hepatotoxicity is less.
peroxide. fungal meningitis.
• And for Candida albicans.
• Hepatotoxicity
• Negative inotropic –
• Improved absorption with food, reduced • Oral capsule
Itraconazole Caution in heart
absorption with fatty meals. • Oral solution
failure with prolonged
use or IV use.

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Superficial Infections
• Interferes with ergosterol • A newer antifungal agent • 5% absorbed through the
biosynthesis, by inhibiting for superficial infections. skin. Avoid application • GI disturbances
• Oral tablets (for
conversion of squalene to • Superficial candidiasis on the chest in breast • Headache
nail infections)
Terbinafine ergosterol, and thereby inhibits • Tinea versicolor feeding mothers. • Skin rash and pruritus
• Topical forms
the formation of fungal cell • Dermatophyte • Has an extensive first • Liver toxicity
(creams and gells)
membrane. onychomycoses (of nails) pass metabolism when • Blood dyscrasias
• Fungicidal. and other dermatophyte given orally.
infection.
• Poorly soluble in water –
better absorbed with • Oral tablets (for • Contraindicated in
• Interferes with mitosis by binding fatty food. hair, skin and nail pregnancy and
to fungal microtubules and • Causes liver enzyme infections) porphyria.
disrupting assembly of mitotic induction. • Topical – Metered • Avoid pregnancy for
• Dermatophytes
Griseofulvin spindle. • Taken up selectively by dose spray one month after
• May produce defective DNA keratin as it is being ❖ Prolonged treatment.
preventing cell replication. formed in the cells of the treatment required • Men should not father
• Fungistatic. nail bed, hair follicles and until infected children within 6
skin – Prevents infection keratin is shed. months of treatment.
of new keratin.
• Systemic yeast and other
• Converted to a pyrimidine
fungal infections (Narrow • Agranulocytosis
analogue and inhibits thymidylate • Usually given IV.
Flucytosine spectrum). • Aplastic anaemia
synthetase and thus DNA • Oral
• Often given in combination • Alopecia
synthesis.
with amphotericin B.

Principals of Antifungal Treatment

• Identify whether the infection is superficial or deep.
❖ If superficial infection – topical therapy is sufficient, but in severe infections oral therapy may be required. Do NOT use oral drugs for trivial (minor)
infections.
❖ If deep, systemic therapy (oral/other) is required.
• Look for risk factors and correct them.
o Diabetes mellitus
o Use of broad-spectrum antibiotics or cytotoxics (anti-cancer drugs) (especially oral candidiasis).
o Immune deficiency – congenital, acquired, drug induced (steroids) or due to malignancy.
o Repeated trauma, foreign bodies, IV lines etc.
o Prolonged immersion in water
o Infancy, old age, pregnancy
• Look for an animal source for dermatophyte infections.

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• Toxicity is less with topical azoles.
• Azoles are toxic to liver when given orally, and hence monitor the liver functions. Blood counts may also be
needed to be monitored when giving some antifungals (such as amphotericin B, griseofulvin etc.)
• Prolonged treatment is necessary for infections affecting the stratum corneum.
• Most systemic antifungals – caution in pregnancy; avoid, unless benefit outweighs the risks.

Anti-Fungal drugs – Patient Advices

• What are antifungal medicines and whether drugs should be taken orally or administered topically.
❖ If topical, clear instructions on administering the preparation prescribed should be given (Eg:
vaginal pessary, oral gel or paint, cream, shampoo etc.).
❖ If orally, whether before, after or with a meal, and how to take it should be instructed (Eg: Nystatin
oral liquid should be swished around the mouth before swallowing).
• Duration of treatment and importance of proper adherence throughout the complete duration.
(Eg: vaginal candidiasis – duration can be a few days, several weeks or months)
• Possible adverse effects (especially when administered orally or by injections).
• Use in special situations – Pregnancy
o Topical treatments are suitable.
o Oral fluconazole, itraconazole should be used with caution since concerns regarding risk of
miscarriage and foetal birth defects when used in first trimester.
o Nystatin is safe to be used in pregnancy. Amphotericin B is not known to be harmful, but avoid
unless potential benefits outweighs the risk.

ANTI-MICROBIAL CHEMOPROPHYLAXIS
Anti-Microbial Chemoprophylaxis – Introduction
• Antimicrobial chemoprophylaxis is the administration of antimicrobial agents (AMA) with the aim of
preventing infectious diseases or suppressing contacted infection before it clinically manifests.
• However, antimicrobial agents are intended to treat an apparent disease, and therefore using antimicrobial
agents to prevent infections is generally NOT recommended except in few specific indications.
• Antimicrobial chemoprophylaxis should be used in circumstances in which efficacy has been demonstrated,
and benefits and the cost effectiveness outweigh the risks of prophylaxis.

Types of antimicrobial chemoprophylaxis

1 Primary Chemoprophylaxis Secondary Chemoprophylaxis
Prevention of an initial infection. Prevent recurrence of an infection.
1. Post splenectomy
2. Infective endocarditis
1. Rheumatic fever
3. Bacterial meningitis
2. Recurrent cellulitis
4. Cirrhotic patients with gastrointestinal bleeding
3. Recurrent UTI
5. Spontaneous bacterial peritonitis
4. Opportunistic infections in AIDs
6. Post-transplantation/chemotherapy
7. Early-onset neonatal infection
8. Opportunistic infections in AIDS
2 True Chemoprophylaxis Pre-Emptive Suppression Therapy
Using an AMA for a person who is not infected, to
Using an AMA for an already infected person to
prevent infection by one organism of virtually
prevent clinical features or to reduce severity.
uniform susceptibility.
1. HIV – post-exposure 1. Malaria
1. Meningococcal meningitis 2. Tuberculosis
2. Chicken pox 3. CMV infection or chicken pox in
3. Post–sexual assault antimicrobial prophylaxis immunosuppressed/post-transplant patients

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3 Surgical Chemoprophylaxis Non-surgical Chemoprophylaxis
Using an AMA to prevent infections not related to a
surgery (Eg: Trauma, Rheumatic fever etc.).
Using an AMA to prevent surgical wound infections. 1. Prevention of infections of animal/human bites
2. Head and neck trauma
3. Penetrating abdominal trauma

Factors to be considered (risks and benefits) of antimicrobial chemoprophylaxis

▪ Preferably a single pathogen

▪ Immunosuppressed/immunodeficient ▪ Known AMA sensitivity patterns.
(Eg: Opportunistic infections) ▪ To contain epidemics and pandemics
▪ At risk of serious complications. caused by pathogen.
▪ For successful surgeries in patient. Host Microbe ▪ Developing antibacterial Resistance.

Target
AMAs
disease
▪ To Prevent major, life-threatening ▪ Narrow antimicrobial spectrum.
infections. (Eg: Infective endocarditis) ▪ Efficacious.
▪ To Prevent minor infections which ▪▪ No serious
Narrow side effects.spectrum.
antimicrobial
have major complications. Benefits Risks ▪▪ Cost-effective.
Efficacious.
(Eg: Streptococcal sore throats) ▪ Cost of therapy
▪ To prevent repeated infections. ▪ Adverse effects of AMAs.
(Eg: UTI) ▪ Promotes irrational use of AMAs.

Anti-Microbial Chemoprophylaxis – Requirements

• Should know the organism (preferably single) causing infection.
• Should know local resistance pattern.
• Should know period of time for which the patient is at risk – Administered only during the period of risk
(ideally for a few minutes before until a few hours after the risk period).
• A narrow spectrum AMA is preferred – to prevent development of resistance.
• Much easier to achieve chemoprophylaxis for short term exposures (Eg: surgical operations) than for long
term and less well-defined risk.

Anti-Microbial Chemoprophylaxis – Principles

• Indications for antimicrobial chemoprophylaxis are well documented.
• If indicated, AMAs can be given either before a potential exposure or after a known exposure.
• Irrational use of AMAs for the purpose of prophylaxis should be avoided – because the antimicrobial
prophylaxis in these situations may be hazardous; Also, infections by resistant organisms, fungal and other
superinfections can occur.
Eg: ◼ In viral infections to prevent secondary bacterial infections (Eg: after RTI, measles etc.).
◼ In patients with long term urinary catheters.
◼ In newborns, especially after prolonged or instrumental delivery.
◼ To prevent postpartum infections in the mother after a normal delivery.
◼ To prevent respiratory tract infections in unconscious patients or in those on respirators.
• Potential benefit must be always weighed against the potential risks.
• Needs to start only few minutes before the exposure and the duration should be kept short.
• A single effective AMA with favorable therapeutic index is recommended.
• Dose of AMA for true chemoprophylaxis is generally lower than the therapeutic dose (this dose will be
inadequate for therapy).

01 Antimicrobial Chemoprophylaxis in Surgery

• Before contamination by surgical incision occurs, with the aim of reducing the incidence of surgical site
infection (SSI), when;
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o The risk of infection is high because of presence of large numbers of bacteria at the operative site
(Eg: in operations on the large bowel),
o Even if the risk of infection is low, consequences of infections would be dangerous (Eg: infection of
prosthetic heart valve or prosthetic joints, or to prevent infections in abnormal heart valve following
transient bacteriaemia of dentistry),
o Even if the risk of infection is low, randomized controlled trials have shown the benefits of prophylaxis to
outweigh the risks (Eg: single-dose antistaphylococcal prophylaxis for uncomplicated hernia/breast surgery).

Anti-Microbial Chemoprophylaxis in Surgery – Principles

1. Indicated in some clean and all clean-contaminated surgeries, especially involving,
o Introduction of prosthetic material,
o Surgeries where consequences of infection would be catastrophic (Eg: neurosurgery, open heart
surgery, orthopedic surgery or ophthalmic surgery etc.), or,
o With impaired host defenses.
Wound Classification
Uninfected operative wounds. No inflammation. Wound is closed primarily. By
Clean wounds definition, a viscus (respiratory, alimentary, genital, or urinary tract) is not entered
during a clean procedure.

Operative wounds in which a viscus is entered under controlled conditions and

Clean-contaminated wounds without unusual contamination – minimal spillage, no contact with infected material
or minor break in technique.

Open, fresh accidental penetrating wounds/operations with major breaks in sterile

Contaminated wounds
technique/grafting on chronic open wound/gross spillage from a viscus.

Old traumatic wounds with retained devitalized tissue, foreign bodies, or faecal
Dirty wounds
contamination/wounds that involve existing clinical infection or perforated viscus.

2. When selecting the antibiotics, the following should be considered,

o Patient risk factors – Pre-existing infection, Recent antimicrobial use, Known colonization with
multidrug-resistant organisms, Prolonged hospitalization, or the Presence of prostheses.
o Environmental factors – Institutional prevalence, Patterns of antibiotic susceptibility, etc.
3. Pharmacokinetics of ABA should be considered – Optimal time within the 30 minutes before surgical
incision (except for vancomycin, ciprofloxacin, gentamicin etc.).
4. A single dose is enough for majority of procedures.
5. A repeat intra-operative dose is required if,
o the procedure is prolonged (lasting more than 2 hours) and the drug has a short half-life, or also,
o if there is an excessive blood loss during the procedure.
❖ Interval between pre- and intraoperative doses should equal to approximately two half-lives of the drug.
6. Postoperative doses of IV antibiotics (up to 24 hours) are only required in defined circumstances (Eg: some
cardiac and vascular surgeries, lower limb amputation).
❖ It should NOT be extended beyond 24 hours, regardless of the surgical procedure. (Extended
prophylaxis → Increased risk of adverse effects.)
7. Non-ABA measures also should be adopted (such as optimal preparation of the patient, hygienic practices).
8. Avoid using broad-spectrum antibiotics.
9. Vancomycin should not be used for prophylaxis (except penicillin hypersensitivity or risk of MRSA is high).
10. Route is parenteral in majority of instances.
11. Nasal screening and decolonization for Staphylococcus aureus is recommended for cardiac, orthopaedic
and neurosurgical procedures with implants.
12. Infections due to lapses in surgical technique, operating theatre procedures, aseptic technique during and
after operation CANNOT be prevented by use of prophylactic antibiotics.

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02 Infective Endocarditis
• Antibiotic prophylaxis should be considered for patients at highest risk for infective endocarditis,
(1) Patients with any prosthetic valve, including a transcatheter valve, or those in whom any prosthetic
material was used for cardiac valve repair.
(2) Patients with a previous episode of infective endocarditis,
(3) Acquired valvular heart disease with stenosis or regurgitation,
(4) Hypertrophic cardiomyopathy
(5) Patients with congenital heart disease (CHD);
o Any time of CHD,
o Any type of CHD repaired with a prosthetic material, whether placed surgically or by
percutaneous techniques, up to 6 months after the procedure, or life-long if residual shunt or
valvular regurgitation remains.
❖ Antibiotic prophylaxis is NOT recommended in other forms of valvular diseases or CHD.
• If patients at risk of endocarditis are undergoing a gastrointestinal or genitourinary tract procedure at a site
where infection is suspected, they should receive appropriate ABA therapy that includes cover against
organisms that cause infective endocarditis.
• Patients at risk of IE should be advised,
o Antibiotics needs to be administered 30 – 60 min prior to the procedure.
o To maintain good oral hygiene (Low-grade, repeated bacteraemia occurs more frequently during
daily routine activities such as toothbrushing, flossing or chewing).
o To seek urgent medical attention if they detect possible symptoms of endocarditis, such as
unexplained fever.
• Since 2002, many international guidelines have significantly reduced the number of indications for ABA
prophylaxis for endocarditis. ABA prophylaxis is NOT routinely recommended for prevention of infective
endocarditis in patients undergoing following procedures.
o Dental procedures (No association between invasive dental procedures and IE in most cases).
o Upper and lower gastrointestinal tract.
o Genitourinary tract; includes urological, gynaecological and obstetric procedures, childbirth.
o Upper and lower respiratory tract; this includes ear, nose and throat procedures and bronchoscopy.
o Dermatological procedures.
• Antibiotic administration carries a small risk of anaphylaxis and increased risk of anti-microbial resistance.

03 Rheumatic Fever
• Can occur after tonsilo-pharyngitis or scarlet fever – caused by Group A Streptococci.
• Some people have genetic predisposition to get several attacks after the first attack of Rheumatic fever.
• Recurrent attacks are more severe than first one. So, prevention of a second attack is needed (secondary
prophylaxis).
Previous attack of acute Prevent colonization of
rheumatic fever (RF) or the upper respiratory Prevent pharyngitis Prevent development of
a well-documented tract with Group A caused by Group A recurrent attacks of RF.
rheumatic heart disease. Streptococci. Streptococci. Secondary Prophylaxis

❖ Secondary prophylaxis is mandatory for all patients who have had an attack of RF, whether or not they have
the residual rheumatic valvular heart disease.
• Penicillin is the antibiotic of choice.
o Benzathine benzylpenicillin (IM) [repository form] – Every 3 - 4 weeks.
o Phenoxymethylpenicillin – If patients refuse benzathine benzylpenicillin.
◼ 250 mg orally (for all ages), 12-hourly, Daily.
◼ Poor adherence and doubtful systemic bioavailability are the issues.
• If the patient is proven to be/suspected to be allergic to penicillin – Erythromycin (orally; 12-hourly),
Azithromycin (unlicensed).

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Factors influencing the risk of RF recurrence
• Age
• Presence of rheumatic heart disease
• The time elapsed from the last attack
• The number of previous attacks
• Socio economic, educational background, degree of crowding in the family, family history of ARF/RHD,
occupation and place of employment
• Adherence to medicines and follow up

Duration of secondary prophylaxis

• Duration depends on patient factors (Eg: social circumstances, clinical features, and the likelihood of
ongoing exposure to Streptococcus pyogenes, further episodes of ARF)
o Patients without proven carditis - 5 years after last attack or until 18 years of age.
o Patients with carditis (mild mitral regurgitation or healed carditis) – 10 years after the last attack or
until 25 years of age (whichever is longer).
o Patients with more severe valvular disease and patients after valve surgery – Until 40 years of age or
sometimes life-long.

04 High-risk Needle Puncture Injuries

• Post-exposure Procedure
o Encourage the wound to bleed, ideally by holding it under running water.
o Wash the wound using running water and plenty of soap.
o Do not scrub the wound, while you're washing it.
o Do not suck/squeeze the wound.
o Dry the wound and cover it with a waterproof plaster or dressing.
o Contact the infectious control unit.
• Post-exposure Procedure for HIV risk – if there is exposure to blood, visibly bloody fluids or other potentially
infectious material from HIV-infected or HIV-unknown sources;
❖ Three drug regime (Tenofovir, Emtricitabine, Lopinavir/Atazanavir [TDF, FTC, LPV/ATV]) for 28 days.
❖ Start as soon as possible, ideally within 2 hours.
Possible exposures
1) Break in the skin by a sharp object that is contaminated.
2) Bitten by a person with visible bleeding in the mouth.
3) Splash on to a mucosal surface (mouth, nose, or eyes).
4) A non-intact skin (Eg: dermatitis, chapped skin, abrasion or open wound) exposure.

05 Recurrent Cellulitis
• Patients with lymphedema or severe venous insufficiency of their extremities (Eg: Filariasis) and also those with
oedema (because of heart failure, nephrotic syndrome, CKD, cirrhosis etc.) are of increased risk of recurrent
cellulitis – Typically, to initiate chemoprophylaxis, more than 2 or 3 episodes per year should happen.
• Treating the underlying causative factor for oedema is more effective than prevention of recurrent Cellulitis.
• First choice – Penicillin V (phenoxy methyl penicillin); Monthly administration of IM benzathine penicillin is
recommended as an alternative to oral penicillin V.
• Given until the underlying cause is cured and oedema goes off.

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ANTI-BACTERIAL COMBINATIONS AND OTHER

ANTI-BACTERIALS
01 Anti-Bacterial Combinations
Anti-Bacterial Combinations – Introduction
• It is therapeutically advisable to treat patients with single agent that is most specific for the infective
organism, as this principle reduces – Super-infections, Emergence of resistant bacteria and Harmful effects.
• But there are some rational indications to use combinations of anti-bacterials.
❖ Considerable likelihood that using combinations of anti-bacterials will have a beneficial effect or the
anticipated benefit is worth (more than) the potential harm or the cost of the medicine.

Basis for using several antibacterial agents together - Categories

(01). A severe infection, without specific diagnosis, which requires immediate therapy in serious infections for
empirical therapy to cover the most probable organisms (Eg: Bacterial meningitis, Infective endocarditis),
or, unknown source of infection in critically ill patients (Eg: Sepsis).
(02). An infection caused by mixed bacterial flora (Eg: Pelvic Inflammatory Disease where Neisseria
gonorrhoeae, Chlamydia trachomatis, anaerobes, and gram-negative bacteria are often concomitantly
cultured), or, Multiple infections in the same patient caused by different bacteria (Eg: As in a nursing home
patient who has concomitant pneumonia, UTI, and infected bed ulcers).
(03). Prevention of toxic effects of an antibacterial.
(04). Prevention of development of drug resistance (Eg: Tuberculosis, Helicobacter pylori)
(05). Achievement of antibacterial synergism to take advantage of synergism that exists between certain ABAs in
treating very virulent organisms (Eg: Use of penicillin with aminoglycosides to treat Enterococcus
endocarditis), or, to treat bacteria which has multiple features (Eg: In treating TB existing as active
multipliers, dormant stage, living within macrophages and living within cavities and caseation; So need
more than one antibacterial).

Anti-Bacterial Combinations – Disadvantages

• Tendency of fixed, "packaged" combinations to encourage inadequate therapy.
• Possible increase in hypersensitivity and/or toxicity to one or more of the agents (Eg: Nephrotoxicity and
Ototoxicity etc.).
• Probable emergence of bacterial resistance to either or both of the ABAs in a mixture.
• Super-infection by originally resistant organisms not affected by the therapy (Eg: Pseudomembranous
colitis by Clostridium difficile).
• Accumulation of antibacterial-resistant organisms within hospitals or other semi-closed communities.
• Possibility of interference of one antibacterial with the operation of another in a given combination.
• More harmful effects including ADRs and drug interactions.
• Compliance may be reduced (more tablets, more timings, night dose, etc)
• Cost – for drug acquisition, preparation and administration.

Anti-Bacterial Combinations – Administration

• Several ABAs in combination can be administered,
o As individual medicines (most common method that you see in the ward) – They can be in different
dosage forms (Eg: tablet and injection), and the dose vary for individual patients, duration vary for
individual ABAs, etc.
o Fixed Dose Combination (FDC) – A combination of two or more actives in a fixed ratio of doses.
◼ This term is used generically to mean a particular combination of actives irrespective of the
formulation or brand.
◼ It may be administered as single entity products given concurrently, or as a finished
pharmaceutical product (FDC–FPP).

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FDC-FPP – Examples
• Some anti-bacterial agents (Co-amoxiclav → Amoxicillin + Clavulanic acid; Co-trimoxazole →
Sulfamethoxazole + Trimethoprim)
• Anti-malarials (ACT → Artemether + Lumefantrine)
• Anti-TB medicines (RHZE → Rifampin + Ethambutol + Pyrazinamide + Isoniazid)
• Anti-HIV therapy (Atripla → Efavirenz + Emtricitabine + Tenofovir)

FDC-FPP – Advantages
• Has a greater efficacy than any of the component actives given alone at the same dose.
• Reduced incidence of adverse drug reactions (ADR of one drug could be reduced by the other).
• Reduced incidence of resistance.
• Therapy is simplified, thus improving adherence.
• Convenience for prescribers and patients.
• Simplified logistics of procurement and distribution.
• Lower cost (But in certain instances, cost is higher as well).

FDC-FPP – Disadvantages
• Dose reduction/ adjustment for one of the components is impossible.
• Sometimes incidence of ADRs and drug interactions is higher.
• The product (tablets or capsules), is so large that patients find it difficult to swallow.
• It is difficult to identify which medicine in the FDCs has caused an adverse effect.
• Incompatible pharmacodynamics.
• Titration of dose of medicine to suit individual patients is not possible.
• The incidence of adverse effects increases.
• In FDCs, there is always a chance that individual medicines may not be present in adequate amounts.
• FDCs increase the price of the medication, if unnecessary drugs are included.
• One of the drugs in the combination may be unnecessary or wasteful (Eg: vitamins + iron).

02 Other Anti-Bacterials of importance in Sri Lanka

◼ Glycopeptides (Vancomycin, Teicoplanin)
◼ Carbapenems (Imipenem, Meropenem)
◼ Lincosamides (Clindamycin, Lincomycin)
◼ Monobactams (Aztreonam, Carumonam)
◼ Oxazolidinones (Linezolid, Eperezolid)
◼ Colistin

Need for new Anti-Bacterials

• Pharmaceutical industries are not interested in developing new ABAs as market is limited and short lasting.
• If the current “newer” ABAs are not used rationally, there will be no ABAs to kill resistant bacteria in future.

Cefepime – 4th Generation Cephalosporin

• Has a balanced spectrum – gram-negative coverage comparable to ceftazidime but better gram-positive
coverage (comparable to ceftriaxone); Highly resistant to β-lactamases.
• Best beta-lactam for IM administration.
• Minimal hepatic metabolism. Plasma elimination half-life is 2 hours.
• WHO – A last resort antibacterial.
• For pneumonia, pyelonephritis, intra-abdominal infections, bacteraemia and septicaemia etc.

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Vancomycin Meropenem/Imipenem Clindamycin Linezolid Colistin

Drug Class Glycopeptides Carbapenems – β Lactams Lincosamides Oxazolidinones Polymyxins
• Inhibits bacterial cell wall • Inhibits protein synthesis • Inhibits protein synthesis • Cationic polypeptides with
synthesis. • Inhibits bacterial cell wall by binding to 50s ribosomal by binding to 23s ribosomal detergent activity. They
• Blocks peptidoglycan synthesis same as subunit – Competes with RNA of the 50s subunit and bind to membrane
Pharmacodynamics polymerization by binding penicillins. chloramphenicol and prevents the formation of a phospholipids and disrupt
to D-alanyl-D-alanine. macrolides for the binding. 70S initiation complex. bacterial cell membranes.
Bactericidal Bactericidal
Bacteriostatic
Time dependent Time dependent
• Oral absorption poor. • Rapidly absorbed when • Well absorbed when given
Absorption • IV administration is • IV administration. given orally. orally; bioavailability • Available as a prodrug,
recommended. • Oral or IV administration.approximately 100%. which is administered IV or
• Widely distributed except inhaled via a nebulizer.
• Widely distributed, • Widely distributed, • Distributed to well-
in CSF. About 20 – 30% of • Little or no absorption
Distribution including the CSF when the including bone, except into perfused tissues.
PK plasma level is reached in occurs from oral route.
meninges are inflamed. the CSF. • Protein binding low.
CSF in inflamed meninges.
• Imipenem undergoes rapid • Rapidly converted to an • Hepatic metabolism into
Metabolism metabolism by renal active metabolite by the
inactive metabolites.
enzyme dehydropeptidase. liver.
Elimination • Unchanged in urine. • Eliminated by the kidney. • Primarily via bile and urine. • Excreted in urine. • Excreted in urine.
• Broadest spectrum of
activity and greatest
potency against many
aerobic and anaerobic gram
• Only gram positives –
positive and negative
Staphylococci, Streptococci,
bacteria. • Most gram-positive cocci
Enterococci, Listeria, • Directed primarily against
• Meropenem has slightly (including most species of • Gram-negative bacteria
Lactobacillus, Actinomyces, gram-positive organisms,
superior activity against Streptococci and including Pseudomonas
Clostridium etc. such as staphylococci
Spectrum Gram-negatives such as Staphylococci including aeruginosa, but except
• Gram-negatives, fungi and (including MRSA),
Pseudomonas aeruginosa MRSA) and many anaerobic Proteus spp., Neisseria spp.,
mycobacteria are resistant. streptococci, and
and Enterobacteriaceae, organisms (such as and Serratia spp.
• Active against MRSA. enterococci.
whereas Imipenem is Bacteroides fragilis).
• Given orally to treat
slightly more active against
Clostridium difficile.
Gram-positives such as
enterococci, Acinetobacter,
and some staphylococci
(except MRSA).
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• Usually as a second line • Should be used as “last-line

antibacterial or for resistant agents” or “antibacterials of • Serious infections by
last resort” but this does not
bacteria. susceptible strains of
happen in real time • Topically – In combination
• Potentially life-threatening practice, irrationally used staphylococci, streptococci
with other antimicrobials
infections that cannot be in many infections. and anaerobic bacteria in
• Gram-positive infections for skin infections, burns,
treated with other effective, • Emergence of multidrug- conditions such as LRT
such as treatment of otitis externa, corneal
less toxic antimicrobials, resistant (MDR) pathogens infections, skin and skin
bacterial pneumonia, skin ulcers and conjunctivitis
including penicillins and seriously threatens this structure infections,
and skin structure caused by gram-negative
cephalosporins – such as class of lifesaving drugs. gynecological infections,
Indications infections, and vancomycin- bacteria including
Endocarditis, Osteomyelitis, • Imipenem is converted to intra-abdominal infections,
resistant enterococcal Pseudomonas.
Pneumonia, Septicaemia, an inactive metabolite by septicemia, and bone and
(VRE) infections. • Orally – Gram-negative
Skin and skin structure dehydropeptidase that is joint infections.
• Alternative to vancomycin bacillary (E. coli,
infections, Enterocolitis etc. potentially nephrotoxic. • Acne vulgaris (topical use).
in hospitalized patients. Salmonella, Shigella etc.)
• Usually combined with Hence, combining it with • Bacterial vaginosis (vaginal
diarrhoeas, especially in
another antibacterial to cilastatin inhibits the use) in non-pregnant
infants and children.
expand the coverage (such metabolism and, thus, women and second or third
as aminoglycoside, prevents the formation of trimester pregnant women.
cephalosporin). the toxic metabolite.
• Red man syndrome – Rapid
• Gastrointestinal – Nausea,
infusion may cause flushing • Hypersensitivity reactions
vomiting and diarrhea, • Cross resistance is unlikely
of the upper body (“red – cross reaction with
Abdominal pain, due to the unique
neck”) or pain and muscle penicillin, cephalosporin.
Pseudomembranous colitis, mechanism of action. • Significant toxicity with
spasm of chest and back. • Seizures
Oesophagitis. • Haematological – Anaemia, systemic administration.
• Anaphylaxis and phlebitis • Pseudomembranous colitis
Adverse Effects • Hypersensitivity Reactions Thrombocytopaenia, • Nephrotoxicity
• Nephrotoxicity • Nausea, vomiting
• Pruritus, vaginitis, and rare Neutropaenia. • Neurological symptoms
• Sensorineural deafness • Meropenem has a slightly
instances of exfoliative • Gastrointestinal – nausea, • Neuromuscular blockade
• Hypotension, tachycardia, lower rate of ADRs than
dermatitis. diarrhea, headache, and
etc. with rapid infusion due imipenem.
• Jaundice and abnormalities rash.
to histamine release.
in liver function tests
• Blood dyscrasias
• Administer in a dilute
solution for a prolonged • Hepatotoxicity – Monitor • Renal Impairment/Hepatic • Renal function should be
period and/or pretreat hepatic function. impairment – Serum half- • No dose adjustments are monitored daily and the
Special situations with anti-histamines to • Renal toxicity – Reduce dose life is slightly increased. required for renal or dose reduced in patients
avoid flushing. in moderate renal Dosage adjustment is NOT hepatic dysfunction. with low creatinine
• Caution – renal impairment impairment. usually needed. clearance.
and hearing disorders.

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AWaRe Classification

RESERVE GROUP (Last Resort) ANTIBIOTICS

• Monobactams Eg: Aztreonam, Carumonam • Tigecycline
• Fosfomycin • Polymyxins Eg: polymyxin B, colistin
• 3rd generation cephalosporins Eg: ceftazidime • Daptomycin
• 4th generation cephalosporins Eg: cefepime • Carbapenems Eg: Meropenem, Imipenem
• 5th generation cephalosporins Eg: ceftaroline • Minocycline
• Oxazolidinones Eg: linezolid

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