Drug Evaluation

Drugs 39 (2): 264-307, 1990

0012-6667/90/0002-0264/$22.00/0
© ADiS Press Limited
All rights reserved.
DREND290

Amoxicillin/Clavulanic Acid
An Update of its Antibacterial Activity, Pharmacokinetic
Properties and Therapeutic Use

Peter A. Todd and Paul Benfield

ADIS Drug Information Services, Auckland, New Zealand

Various sections of the manuscript reviewed by: K.E. Aldridge, Louisiana State Univer-
sity Medical Center, New Orleans, Louisiana, USA; S.c. Aronoff, Section of Immuno-
logic and Infectious Diseases, Rainbow Babies and Children's Hospital, Cleveland, Ohio,
USA; B.!. Davies, Streeklaboratorium voor de Volksgeszondheid, De Wever-Ziekenhuis,
Heerlen, The Netherlands; V. Fainstein, Infectious Diseases Associates of Houston, Hous-
ton, Texas, USA; D. Felmingham, Department of Clinical Microbiology, University Col-
lege Hospital, London, England; R. Fujii, Research Institute of Chemotherapy for Mother
and Child, Tokyo, Japan; K. [shibiki, School of Medicine, Keio University, Tokyo, Ja-
pan; R.N. Jones, The Clinical Microbiology Institute, Tualatin, Oregon, USA; J. Ku-
mazawa, Department of Urology, Kyushu University, Fukuoka, Japan; H.C. Neu, Co-
lumbia-Presbyterian Medical Center, New York, New York, USA; D.S. Reeves, Department
of Medical Microbiology, Southmead Hospital, Bristol, England; H.W. Van Landuyt, A.Z.
St-Jan, Ruddershove, Brugge, Belgium; L. Weinstein, Brigham and Women's Hospital,
Boston, Massachusetts, USA.

Contents Summary ................................................................................................................................... 265

1. Chemistry and Mechanism of Action ................................................................................ 268
2. Antibacterial Activity .......................................................................................................... 268
2.1 Inhibitory Activity In Vitro .......................................................................................... 269
2.2 Bactericidal Activity In Vitro ....................................................................................... 271
2.3 Factors Affecting In Vitro Activity .............................................................................. 272
2.4 Activity In Vivo ............................................................................................................. 272
2.5 Development of Resistance .......................................................................................... 272
3. Pharmacokinetic Properties ................................................................................................ 273
3.1 Absorption and Plasma Concentrations ...................................................................... 273
3.2 Distribution .................................................................................................................... 274
3.3 Metabolism and Excretion ........................................................................................... 275
3.4 Effects of Disease and Age on Pharmacokinetics ....................................................... 278
3.4.1 Renal Insufficiency ............................................................................................... 278
3.4.2 Gastrointestinal Disease ....................................................................................... 278
3.4.3 Age ......................................................................................................................... 279
4. Therapeutic Trials ................................................................................................................ 279
4.1 Urinary Tract Infections ............................................................................................... 279
4.1.1 Noncomparative and Dose-Finding Studies ...................................................... 279
4.1.2 Comparative Studies ............ :: .............................................................................. 281
4.2 Respiratory Tract Infections ......................................................................................... 283
4.2.1 Noncomparative and Dose-Finding Studies ...................................................... 283
AmoxiciIlin/Clavulanic Acid: An Update 265

4.2.2 Comparative Studies ............................................................................................ 284

4.3 Otorhinolaryngological Infections ................................................................................ 284
4.3.1 Noncomparative Studies ...................................................................................... 284
4.3.2 Comparative Studies ............................................................................................ 285
4.4 Skin and Soft Tissue Infections ................................................................................... 285
4.4.1 Noncomparative Studies ........................ .............................................................. 285
4.4.2 Comparative Studies ............................................................................................ 286
4.5 Sexually Transmissible Diseases .................................................................................. 287
4.5.1 Gonorrhoea ........................................................................................................... 287
4.5.2 Other Sexually Transmissible Diseases .............................................................. 288
4.6 Obstetric and Gynaecological Infections .............................. .................................. ..... 288
4.7 Prophylactic Treatment ................................................................................................ 291
4.8 Miscellaneous Studies ........................................................................................ ........... 293
4.9 General Practice Studies ............................................................................................... 294
5. Adverse Effects ................................................. ... ................................................................. 295
6. Dosage and Administration ................................................................................................ 295
7. Place of Amoxicillin/Clavulanic Acid in Therapy ............................................................ 296

Summary
Synopsis Clavulanic acid enhances the antibacterial spectrum oj amoxicillin by rendering most
fI-lactamase-producing isolates susceptible to the drug. In clinical trials amoxicillin/cla-
vulanic acid is clinically and bacteriologically superior to amoxicillin alone and at least
as effective as numerous other comparative agents. such as orally administered cephalo-
sporins. cotrimoxazole. doxycycline and bacampicillin. in the treatment oj adults and
children with the most common jorms oj injection encountered in general practice. i.e.
urinary tract injections. upper and lower respiratory tract injections. otorhinolaryngolog-
ical injections. and skin and soft tissue injections. It may also provide effective treatment
jor uncomplicated gonorrhoea. chancroid and gynaecological injections as well as acting
as a prophylactic agent against surgical injection.
Thus. in general practice environments where fI-lactamase production has restricted
the effectiveness oj amoxicillin. the combination oj clavulanic acid with amoxicillin has
clearly extended the usejulness oj a tried and proven first-line antibacterial agent.

Antibacterial Activity C1avulanic acid is an irreversible 'suicide' inhibitor of intracellular and extracellular
{3-lactamases, effective against a wide variety of these enzymes including those of Rich-
mond and Sykes classes II to V (but not class I cephalosporinases), staphylococcal {3-
lactamase, and /3-lactamase produced by Bacteroides jragilis. C1avulanic acid, therefore,
protects amoxicillin from inactivation by many /3-lactamases. As a consequence the anti-
bacterial activity of amoxicillin has been restored at a time when the spread of resistance
due to /3-lactamase production severely threatened its usefulness.
Clavulanic <!cid alone possesses only weak antibacterial activity, except against Le-
gionella spp., and certain strains of Branhamella catarrhalis. B. jragilis and Neisseria
gonorrhoeae. However, the addition of clavulanic acid to amoxicillin increases the sus-
ceptibility to amoxicillin of amoxicillin-resistant strains of Gram-negative and Gram-
positive aerobic and anaerobic bacteria where resistance is caused by /3-lactamase pro-
duction. These include Staphylococcus aureus (but not methicillin-resistant strains), Hae-
mophilus spp., Branhamella catarrhalis. Neisseria gonorrhoeae. Escherichia coli. Proteus
spp., Klebsiella pneumoniae. Citrobacter diversus. Salmonella and Shigella spp., Cam-
py/obacter jejuni. Bacteroides spp., and Mycobacterium spp. The susceptibility of amox-
icillin-sensitive strains is not generally affected by the addition of clavulanic acid.
Amoxicillin/clavulanic acid is bactericidal in vitro. usually at concentrations no more
266 Drugs 39 (2) 1990

than one dilution higher than in vitro inhibitory concentrations. The in vitro synergy of
c1avulanic acid combined with amoxicillin has been confirmed in vivo in numerous ex-
perimental infections in animals. The combination of amoxicilIin with c1avulanic acid
appears to suppress the development of resistance under experimental conditions.

Pharmacokinetic Properties Combining c1avulanic acid with amoxicillin causes no appreciable alteration of the
pharmacokinetics of either drug compared with their separate administration. After oral
administration, both components achieve maximum plasma concentrations in about I
hour and these concentrations show a direct relationship to the dose administered. The
absolute bioavailability of c1avulanic acid is about 60%. Absorption is unaffected by
concomitant administration of food, milk, ranitidine or pirenzepine and little affected
by antacid administration, but cimetidine may increase the rate of absorption of both
components. Probenecid increases the plasma concentration of amoxicillin but not c1a-
vulanic acid.
Clavulanic acid has a volume of distribution of about 25% of bodyweight and is about
22% protein bound in vitro. The tissue and body fluid distribution of both components
is generally adequate to achieve antibacterial levels, although concentrations may be
somewhat low in bronchial secretions and cerebrospinal fluid. Both components transfer
across the placenta but only very small quantities transfer into breast milk.
Both c1avulanic acid and amoxicillin possess a mean elimination half-life of about I
hour and a mean total clearance of about 25 L/h in healthy subjects. The main route of
elimination is via the urine, and 6-hour urinary recovery of intact drug after oral admin-
istration is about 60 to 80% for amoxicilIin and 30 to 50% for c1avulanic acid. Glavulanic
acid is excreted mainly by glomerular filtration and amoxicillin by tubular secretion; thus,
probenecid delays the excretion of amoxicillin but not c1avulanic acid. While amoxicillin
is mainly excreted unchanged, c1avulanic acid is subject to hydrolysis and subsequent
decarboxylation. . .
Gastrointestinal disease may slow the rate of absorption of amoxicillin and c1avulanic
acid. The pharmacokinetic profile in children administered bodyweight adjusted dosages
paralleled that in adults. Renal impairment decreases the clearance of amoxiciUin and
less markedly c1avulanic acid: dosage reductions or increasing the dose interval are thus
required. Both components are removed by haemodialysis and appropriate dose supple-
mentation is therefore necessary at the end of a haemodialysis session.

Therapeutic 1:rials Amoxicillin/c1avulanic acid has usually been administered empirically to patients with
symptoms suggestive of bacterial infection without selection of patients according to the
resistance or susceptibility of the pathogen. Dosages of amoxicillin/c1avulanic acid were
usually in the range 250/125 to 875/125mg 2 or 3 times daily iii adults and bodyweight
adjusted dosages were administered to children.
In adult patients with complicated or uncomplicated urinary tract infection, amoxi-
cillin/c1avulanic acid was clinically and bacteriologically superior at a statistically sig-
nificant level compared with amoxicillin alone and cefatrizine propylene glycol, and bac-
teriologically superior compared with cotrimoxazole. In addition, it was at least as effective
as cefaclor, cefalexin and pivmecillinam/pivampicillin.
In adult patients with upper or lower respiratory tract infections, amoxicillin/c1avu-
lanic acid was clinically more effective than amoxicillin alone or josamycin at a statis-
tically significant level. Clinically and bacteriologically it was at least as effective as ba-
campicillin, pivmecillinam/pivampicillin, doxycycline, erythromycin, cefuroxime axetil,
cefixime and cefaclor.
Amoxicillin/c1avulanic acid has been shown to be clinically more effective at a sta-
tistically significant level than amoxicillin alone in the treatment of acute otitis media
in adults, but statistically significant differences were not identified in comparisons with
amoxicillin in children with otitis media or maxillary sinusitis. Some studies have shown
statistically significant superiority of amoxicillin/c1avulanic acid over cefaclor or myrin-
gotomy both clinically and bacteriologically in children with acute otitis media.
Amoxicillin/Clavulanic Acid: An Update 267

In skin and soft tissue infection amoxicillin/clavulanic acid produced a statistically

significant higher bacteriological response rate and a tendency towards a higher clinical
response rate compared with amoxicillin in adults with wound infection and children
with non bullous impetigo. In addition, in adults with wound infection amoxicillin/cla-
vulanic acid was equivalent to cefuroxime axeti!. In adults and children with skin and
soft tissue infection, amoxicillin/clavulanic acid and cefaclor achieved similar clinical
and bacteriological responses.
In uncomplicated gonorrhoea, administration of 2 doses of amoxicillin/clavulanic
acid 3000/125 or 3000/250mg 4 to 6 hours apart or a single dose concomitantly with
probenecid Ig proved the most satisfactory and convenient regimens, with antibacterial
activity extended to cover penicillinase-producing Neisseria gonorrhoeae. Amoxicillin/
clavulanic acid 500/250mg 3 times daily for 3 days appears to provide an excellent treat-
ment for chancroid.
Amoxicillin/clavulanic acid may provide an effective and more manageable regimen
than the standard triple combination of a f:J-lactam/an aminoglycoside/an imidazole in
the treatment of obstetric and gynaecological infections but more study is required in
this area before any definitive conclusions may be drawn. Amoxicillin/clavulanic acid
has shown excellent results compared with other prophylactic regimens such ascepha-
losporins or aminoglycosides, and was superior to metronidazole at a statistically sig-
nificant level, in the prevention of postoperative infectious complications following gyn-
aecological, abdominal and vascular surgery.

Adverse Effects About 13% of patients report adverse effects with amoxicillin/clavulanic acid, re-
quiring withdrawal of treatment in less than 3% of patients. The adverse effects are pri-
marily mild gastrointestinal disturbances, including diarrhoea, nausea, vomiting and in-
digestion. Rash, and Candida vaginitis or stomatitis each occur in about I% of patients.
There have been isolated reports of urticaria, anaphylaxis, behavioural changes, and la-
boratory test abnormalities.
Gastrointestinal adverse effects may be reduced by taking the drug with food. Their
frequency may· be related to the dose of clavulanic acid and they may also occur con-
siderably more frequently in children. Compared with other antibacterial agents, amox-
icillin/clavulanic acid has usually been at least as well tolerated, although some orally
administered cephalosporins (e.g. cefaclor) caused fewer gastrointestinal effects.

Dosage and Administration The usual dosage for routine oral use in adult infections is 250/125mg or 500/125mg
3 times daily, although in Italy the usual dose is 875/125mg twice or 3 times daily,
depending on the severity of infection. A number of parenteral preparations are available
which may be administered intravenously in cases of severe infection or as a prophylactic
in patients undergoing surgery. The recommended daily dose in children is 20 to 40mg/
kg, based on the amoxicillin component. Doses towards the lower end of this range
should be adequate in mild to moderate infections while higher doses may be used against
more severe infections. Dosage reductions are necessary in patients with renal failure.
Amoxicillin/clavulanic acid should be administered with food and is contraindicated in
patients with a known history of f:J-lactam hypersensitivity.

The orally administered antimicrobial combin- of the wealth of data published since these reviews,
ation of amoxicillin/clavulanic acid has been pre- and because of the increased importance and use
viously reviewed in the Journal (Brogden et al. of amoxicillin/clavulanic acid in clinical practice,
1981), and during the interval since then other re- a reappraisal of the drug is timely.
views have been published (Smith & LeFrock 1985; Coverage. of this update is restricted to data
Stein & Gurwith 1984; Weber et al. 1984). In view published since the review of Brogden et al. (1981).
268 Drugs 39 (2) 1990

The reader is referred to the latter for information

on those aspects of amoxicillin/clavulanic acid that
were well established by the time of its publication.
Thus, the antimicrobial activity of amoxicillin/cla-
vulanic acid is overviewed in this update. Signifi-
cant new data concerning the pharmacokinetic
properties of amoxicillin/clavulanic acid have be- Amoxicillin
come available since the previous review, partic-
ularly with respect to tissue distribution. Greater
attention has been given to new data on the clinical
efficacy and tolerability of amoxicillin/clavulanic
acid, especially in comparison with other antimi-
crobial agents, to provide a more precise definition
of the drug's place in therapy.
Clavulanic acid
This review concentrates on the pharmacology
of clavulanic acid alone and in combination with Fig. 1. Structural formulae of amoxicillin and c1avulanic acid.

amoxicillin. A complete review of amoxicillin alone

The binding of (3-lactamases with clavulanic acid
is provided by Neu (1979). In the commercially
is a complex physicochemical process. In general,
available formulations, clavulanic acid is present
a reversible complex is formed initially but cova-
as the potassium salt. Several nonclinical studies
lent bonding rapidly leads to irreversible inacti-
have also used the sodium salt. However, through-
vation of the (3-lactamase and clavulanic acid. Cla-
out this review all doses are expressed in terms of
vulanic acid has thus been termed a 'suicide'
clavulanic acid.
inhibitor of (3-lactamases (Rolinson 1984). As a re-
sult of this inhibition, compounds such as amox-
1. Chemistry and Mechanism of Action
icillin, which would normally have been hydro-
lysed and bound by the J3-lactamase, are spared.
Clavulanic acid is a naturally occurring J3-lac-
Thus, certain amoxicillin-resistant isolates may be
tam produced by Streptomyces clavuligerus. It is
rendered susceptible to amoxicillin through the
structurally similar to the penicillin nucleus but is
protective effect of clavulanic acid. As amoxicillin
devoid of the acylamino side chain, the sulphur
and clavulanic acid are both absorbed after oral
atom is replaced by oxygen, and it contains an hy-
administration and possess similar pharmacokin-
droxyethylidene substituent in the oxazolidine ring
etic properties, they offer a rational antimicrobial
(fig. I). Like other J3-lactams, clavulanic acid pen-
combination. The spectrum of activity of amoxi-
etrates through the bacterial cell wall but it gen-
cillin is thus extended to cover many J3-lactamase-
erally possesses poor intrinsic antimicrobial activ-
producing strains, overcoming some of the prob-
ity. However, it binds to intracellular and
lems of resistance to amoxicillin that have increas-
extracellular J3-lactamases including those of Rich-
ingly limited the usefulness of t~is drug in certain
mond and Sykes classes II to V (but not class I
environments over the last few decades.
cephalosporinases), staphylococcal J3-lactamase, and
the (3-lactamase of Bacteroides fragilis (Fuchs et al.
1983; Neu 1984; Neu & Fu 1984; Reading et al. 2. Antibacterial Activity
1983; Rolinson 1984). Clavulanic acid is generally
a more potent inhibitor of cell-free (3-lactamases The antibacterial activity of amoxiciIIin/clavu-
except class I enzymes, against which sulbactam is lanic acid has been well established, and the amount
usually more active (Campoli-Richards & Brogden of literature published in this area is voluminous.
1987; also see Masters et al. 1989). This is partly because amoxicillin/clavulanic acid
AmoxicilIin/Clavulanic Acid: An Update 269

is being used as a standard reference drug with 20mm susceptibility. In some European countries
which other orally administered antibacterial agents discs containing amoxicillin 2~g and c1avulanic acid
are compared. As the antibacterial activity has been I~g are available for testing highly susceptible
previously described by others (Brogden et al. 1981; organisms such as Neisseria gonorrhoea, Haemo-
Smith & LeFrock 1985; Stein & Gurwith 1984), philus injluenzae, Branhamella catarrhalis and
this reappraisal provides only an overview based Staphylococcus aureus.
on selected references, generally those evaluating The following description of the in vitro activity
large numbers of isolates or unusual bacterial spe- of amoxicillin/c1avulanic acid against the more
cies or covering points of special interest. common bacterial species is primarily based on
Most studies have used a 2 : I 'ratio of amoxi- general references (Fuchs et al. 1983; Neu & Fu
cillin to c1avulanic acid, which is the ratio most 1984). A typical example of the antibacterial spec-
commonly used in marketed formulations of the trum and potency of amoxicillin/c1avulanic acid
drug. Nevertheless, other ratios have been inves- compared with c1avulanic acid separately is pro-
tigated, in particular a 4 : I ratio as well as a 7: I vided by Fuchs et al. (1983) [table I]. Low concen-
ratio. Both are available as marketed formulations, trations of clavulanic acid alone have good activity
the latter only in Italy. Unless otherwise stated in against Legionella pneumophila and when com-
this section, it may be assumed that a 2 : I ratio bined with amoxicillin various Legionella species
was used and, for convenience, only the dose of (including L. pneumophila, L. micdadei and L.
amoxicillin is given. bozemanii) are extremely susceptible (Gomez-Lus
et a11987; Jones & Thornsberry 1984; Stokes et al.
2.1 Inhibitory Activity In Vitro 1989a). Some strains of Branhamella catarrhalis,
Bacteroides jragilis and Neisseria gonorrhoeae are
The guidelines of the National Committee for
also susceptible to low concentrations of c1avulanic
Clinical Laboratory Standards in the US have been
acid alone (Hunter et al. 1980). Otherwise, c1avu-
used in this review. Thus, MICs of amoxicillin/
lanic acid alone has little intrinsic antibacterial ac-
c1avulanic acid ~ 8/4, 16/8 or ;:;. 32/16 mg/L in-
tivity.
dicate susceptible, moderately susceptible or re-
Generally, amoxicillin-susceptible bacteria which
sistant, respectively, for species other than Sta-
are {1-lactamase-negative, anaerobic Gram-positive
phylococcus and Haemophilus. For both of these
cocci, and Gardnerella vaginalis are not influenced
species an MIC of ~ 4/2 mg/L indicates susceptible
by the addition of c1avulanic acid to amoxicillin.
and values of;:;. 8/4 or;:;' 8/16 mg/L are considered The primary rationale for the use of clavulanic acid
to reflect resistance of Staphyloccoccus or Hae- in combination with amoxicillin is that it extends
mophilus species, respectively. It should be noted the spectrum of antibacterial activity of amoxicil-
that some {1-lactamase-producing Gram-negative lin to include strains which produce {1-lactamase,
strains (e.g. Escherichia coli, and species of Kleb- with the notable exception of those that produce
siella, Proteus and Citrobacter) may not be suscep- class I {1-lactamase.
tible at concentrations of amoxicillin and c1avu- The addition of c1avulanic acid to amoxicillin
lanic acid achieved in plasma after oral enhances the activity of the latter against {1-lacta-
administration but are susceptible at achievable ur- rnase-producing Gram-positive strains. Thus, many
inary concentrations. {1-lactamase-positive strains of Staphylococcus au-
For disc testing, standard discs containing reus and coagulase-negative Staphylococcus species
amoxicillin 20~g and c1avulanic acid I O~g have are rendered susceptible, while methicillin-resist-
been used: inhibition zone diameters ~ 13mm in- ant strains generally remain resistant. Listeria
dicate resistance, 14 to 17mm intermediate sus- monocytogenes (Bille et al. 1987) and Streptococcus
ceptibility, and;:;' 18mm susceptibility. Different species are usually susceptible to amoxicillin alone.
values are again accepted for Haemophilus and Many species of Mycobacterium are resistant to
Staphylococcus species: ~ 19mm resistance and ;:;. amoxicillin alone because of {1-lactamase produc-
270 Drugs 39 (2) 1990

Table I. In vitro activity of clavulanic acid and amoxicillin/cla· in the Corynebacterium 02 group are resistant to
vulanic acid (after Fuchs et al. 1983) amoxicillin/clavulanic acid (Soriano et al. 1987).
Organism (no. of strains) MICgO (mg/L)
Although the fJ-lactamase enzymes produced by
the Bacteroides group resemble class I fJ-lacta-
clavulanic amoxicillin + mases, they are usually inhibited by clavulanic acid
acid clavulanic
acid
(Reading & Farmer 1981). Clavulanic acid thus
renders most amoxicillin-resistant strains of B. fra-
Escherichia coli (30) > 16 32 gitis, B. distasonis, B. bivius, B. ,ovatus, B. thetaio-
Klebsiella pneumoniae (30) > 16 8
taomicron, B. vulgatus, B. melaninogenicus and B.
Enterobacter cloacae (22) > 66 > 64
Enterobacter aerogenes (22) > 16 64
oratis susceptible (Barry et al. 1986; Bourgault &
Enterobacter agglomerans (10) > 16 > 64 Lamothe 1986; Brown 1984; Burnat et al 1989;
Enterobacter gergoviae (2) > 16 > 64 Garcia-Rodriguez et al. 1989; Lacroix et al. 1984;
Serratia marcescens (29) > 16 >64 Lamothe et al. 1984; Wust & Wilkins 1978). Many
Citrobacter diversus (11) > 16 2.0
amoxicillin-resistant strains of other anaerobic
Citrobacter freundii (12) > 16 64
Morganella morganii (11) > 16 > 64 genera may also be made susceptible by the addi-
Proteus mirabilis (30) > 16 1.0 tion of clavulanic acid, including various species
Proteus vulgaris (12) > 16 8.0 of Clostridium, Fusobacterium, Peptococcus and
Providentia rettgeri (12) > 16 > 64 Peptostreptococcus (Brazier et al. 1985; Oeforges et
Providentia stuartii (24) > 16 > 64 al. 1984; Oerriennic et al. 1987; Goldstein & Citron
Acinetobacter calcoaceticus > 16 64
vaLanitratus (18)
1986; Rodloff et al. 1984). Amoxicillin/clavulanic
Pseudomonas aeruginosa (30) > 16 > 64 acid did not totally inhibit the growth of Chla-
Pseudomonas spp.a (38) > 16 > 64 mydia trachomatis strains in vitro although there
Streptococcus pyogenes (20) > 16 0.03 was a reduction in the number of viable organisms
Streptococcus pneumoniae (20) > 16 0.25
(Bowie 1986).
Streptococcus faecalis (30) > 16 1.0
Methicillin-resistant > 16 32
Clavulanic acid enhances the activity of amox-
Staphylococcus aureus (12) icillin against many Gram-negative bacteria where
Methicillin-sensitive > 16 8.0 resistance is caused by fJ-lactamase production.
Staphylococcus aureus (57) These species commonly include: E. coli, Proteus
Ampicillin-sensitive Haemophilus 0.25
mirabilis, Klebsiella pneumoniae, Citrobacter di-
influenzae (24)
Ampicillin"resistant HFfemophilus 2.0
versus, Proteus vulgaris, various species of Salmon-
influenzae (24) ella and Shigella (Megraud & Gavinet 1987), Yer-
Neisseria meningitidis (25) 1.0 0.12 sinia enterocolitica (Megraud & Gavinet 1987),
a Including P. acidovorans (4), P. cepacia (5), P. fluorescens
Haemophilus injluenzae(Jorgensen et al. 1988; La-
(7), P. maltophila (4), P. putida (6) and P. stutzeri (12). pointe & Lavallee 1987; Yoger et al. 1981), Hae-
mophilus ducreyi (Girouard et al. 1981; Sanson-Le
Pors et al. 1983), Branhamella catarrhatis (Ahmad
tion but with the addition of clavulanic acid many et al. 1984; Alvarez et al. 1985; Fernfmdez-Roblas
strains of M. tuberculosis, M. fortuitum, M. bovis et al. 1988), Neisseria gonorrhoeae (Goh et al. 1985;
and M. kanasaii are susceptible, although M. che- Obaseiki-Ebor et al. 1985; Tapsall et al. 1987; Tsuji
lonei remains resistant (Casal et al. 1986; Cyna- et al. 1986; Van Klingeren & Van Wijngaarden
mon & Palmer 1983; Santos et al. 1987; Swenson 1981; Waghorn et al. 1986), different species of
et al. 1985; Wong et al. 1988). fJ-Lactamase pro- Campylobacter (c. jejuni and C. coli) [Gaudreau
duction is also a major mechanism of resistance to et al. 1987; Lambert et al. 1986; Van der Auwera
amoxicillin for Nocardia brasiliensis, but such & Sconeaux 1985], and Aeromonas (A. caviae, A.
strains become susceptible with the addition of cla- hydrophila and A. sobria) [San Joaquin et al. 1986].
vulanic acid (Wallace et al. 1987). Some bacteria It has also recently been shown that clavulanic acid
Amoxicillin/C1avulanic Acid: An Update 271

renders Pseudomonas pseudo mallei susceptible to hours) and significantly more rapid than cefotax-
amoxicillin; this species is generally resistant to ime against various species of Enterobacteriaceae
amoxicillin because of i1-lactamase production (Wilson & Hunter 1986). As with all i1-lactams the
(Chau et al. 1986;' Leelarasamee et al. 1988). In the bactericidal effect was due to the formation of non-
latter study a 4: I ratio of amoxicillin/clavulanic acid viable spheroplasts (e.g. Yourassowsky et al. 1987).
was used. Comparisons of MIC and MBC (minimum bac-
It should be pointed out that the resistance of tericidal concentration) values for amoxicillin/cla-
many Gram-negative bacteria to amoxicillin is un- vulanic acid have shown that MBC values were
affected by the addition of clavulanic acid includ- often the same as MIC values, usually within I di-
ing Enterobacter species, Serratia marcescens, Ci- lution and only rarely up to 2 dilutions higher for
trobacter freundii , Morganella morganii, various isolates, including Haemophilus spp. (Jor-
Providencia species, Acinetobacter species, and gensen et al. 1986; Lapointe & Lavallee 1987), Bac-
Pseudomonas species (with the notable exception teroides spp. (Bourgault & Lamothe 1986; Garcia-
of P. pseudo mallei). Rodriguez et al. 1989) and M. tuberculosis (Cy-
The susceptibility of organisms to amoxicillin/ namon & Palmer 1983). The bactericidal effects of
clavulanic acid has also been examined in many amoxicillin/clavulanic acid observed against both
studies involving up to tens of thousands of clinical extracellular and intracellular cultures of L. pneu-
isolates from general practice and hospital patients mophila (Stokes et al. 1989b) warrant further in-
(e.g. Beale & Sutherland 1989; De Mouy et a11989; vestigation.
Focht et al. 1988; Nunes da Costa & Goncalves Thomas et al. (1985) studied the bacteriostatic
1989; Verbist 1983). In general, just over 90% of and bactericidal titres of serum from 7 healthy sub-
clinical isolates (including Gram-negative, Gram- jects given amoxicillin/clavulanic acid 500/125mg
positive aerobic and anaerobic strains) were sus- or flucloxacillin 500mg each given 3 times daily.
ceptible to amoxicillin/clavulanic acid compared Bacteriostatic and bactericidal titres were similar
with about 60 to 70% of isolates susceptible to at both peak and trough concentrations against i1-
amoxicillin or ampicillin alone. When compared lactamase-producing S. aureus, and the antistaph-
with other reference antibacterial agents (trimetho- ylococcal activity of amoxicillin/clavulanic acid was
prim, cotrimoxazole, sulphonamides, nalidixic acid, significantly higher than that of flucloxacillin. Bin-
nitrofurantoin), amoxicillin/clavulanic acid gave the gen et al. (1987) studied the serum bactericidal ac-
highest percentage of susceptible isolates. tivity of 20 neonates with E. coli sepsis treated with
intravenously administered amoxicillin/clavulanic
2.2 Bactericidal Activity In Vitro acid 100/10 mg/kg or cefotaxime 100 mg/kg daily,
both regimens in combination with netilmicin 4
The bactericidal effects of amoxicillin/clavu- mg/kg/day. While serum bactericidal activity was
lanic acid have been studied in in vitro models, similar with both regimens, the mean minimum
many of which were designed to mimic in vivo bactericidal time was longer in the patients receiv-
serum, urine or blister fluid pharmacokinetics. ing amoxicillin/clavulanic acid (3.9 vs 1.2 hours;
These studies have confirmed that amoxicillin/cla- p < 0.01). Decazes et al. (1987) determined the
vulanic acid exerts bactericidal effects at clinically bactericidal activity of cerebrospinal fluid of
achievable concentrations against i1-lactamase-pro- patients with purulent meningitis given intraven-
ducing strains of B. catarrhalis, E. coli, K. pneu- ous amoxicillin/clavulanic acid 200/20 mg/kg/day
moniae and S. aureus (Boon et al. 1982b; Griffin against a i1-lactamase-producing strain of H. influ-
et al. 1989; White et al. 1982, 1985; Wilson & enzae. 10 of 12 tested samples lacked bactericidal
Hunter 1986; Yourassowsky et al. 1987, 1988). activity in vitro, and this was found to be caused
These studies have also shown that the bactericidal by poor penetration of clavulanic acid into cere-
effects are particularly rapid (usually within a few brospinal fluid at the doses used in this study.
272 Drugs 39 (2) 1990

2.3 Factors Affecting In Vitro Activity bacteraemia due to H. influenzae type b; pneu-
monia due to K. pneumoniae; endocarditis due to
Measurement of in vitro susceptibility by the S. aureus; and intraperitoneal infection due to S.
agar plate dilution method is not generally affected aureus, E. coli, E. aerogenes, K. pneumoniae, P.
by culture media, pH from 6 to 8, and addition of mirabilis, P. vulgaris, C. freundii and M. morganii.
50% human serum (Comber et al. 1980; Hunter et There have been several studies comparing the
al. 1980). However, the activity of clavulanic acid activity of amoxicillin/clavulanic acid with other
may be reduced by the presence of supplements antimicrobial agents in experimental animal infec-
used to support the growth of fastidious organisms tions. In subcutaneous abscesses due to B. fragilis,
such as H. influenzae, N. gonorrhoeae and B. ca- amoxicillin/clavulanic acid was as effective as
tarhalis (Fernimdez-Roblas et al. 1988; White et al. metronidazole, as effective or more effective than
1983). The rapid determination of susceptibility clindamycin, and more effective than cefoxitin
using standard discs of amoxicillin 20~g and cla- (Boon et al. 1982a; Brown & Ribeiro 1982). In ad-
vulanic acid lO~g gives a good approximation of dition, amoxicillin/clavulanic acid was more·effec-
susceptibility (Comber et al. 1980), although this tive than cefuroxime, metronidazole or combina-
disc does not accurately predict the susceptibility tions of metronidazole with cefuroxime or
of some N. gonorrhoeae strains (Kumamoto 1982). ampicillin in the treatment of mixed E.coli and B.
For highly susceptible organisms 3~g discs are fragilis subcutaneous infection (Beale et al. 1989).
available (see section 2.1). In addition, disc testing Amoxicillin/clavulanic acid was also as effective as
using Oxoid Diagnostic Sensitivity Test Agar gives vancomycin and more effective than cloxacillin or
smaller inhibitory zones and a falsely low index of flucloxacillin in experimental endocarditis due to
susceptibility compared with Mueller-Hinton Agar S. aureus (Cantoni et al 1989; Catherall et al. 1989).
(Brown & Ribeiro 1982). Increasing inoculum size However, in pneumonia produced by K. pneu-
from 102 or 10 3 to 106 cfu (colony-forming units)/ moniae amoxicillin/clavulanic acid was less effec-
ml increases the MIC value about2-fold for H. in- tive than either ceftazidime, cefotiam or kanamy-
fluenzae, E. coli and Klebsiella spp., and increasing cin (McColm et al. 1986).
the inoculum from 10 3 to 106 cfu/ml may increase Clavulanic acid has proved effective in protect-
the MIC value by 10 to 100 fold for penicillin-re- ing amoxicillin from degradation by iJ-Iactamase-
sistant S. aureus (Comber et al. 1980; Hunter et al. producing bacteria in animal models of peritonitis
1980: Van Klingeren & Dressens-Kroon 1979). and subcutaneous infection (Boon et aI, 1982a;
Catherall & Mizen 1984) and in the human bladder
2.4 Activity In Vivo (Goldstein et al. 1979; Lindeque 1982).

2.5 Development of Resistance

Since publication of the previous review in the
Journal, many additional studies in mice and rats Lim et al. (1989) showed that regular prescrip-
have confirmed that amoxicillin/clavulanic acid is tion of amoxicillin/clavulanic acid for 6 years in a
more effective than amoxicillin alone in various rural region of the Netherlands produced no change
experimental infections caused by iJ-Iactamase- in the resistance pattern of clinical isolates of E.
producing organisms (Aronoff et al. 1986; Beale et coli and P. mirabilis. Further retrospective studies
al. 1989; Boon et al. 1982b; Brown & Ribeiro 1982; are required to confirm that no change in resist-
Catherall & Mizen 1984; Catherall et al. 1989; ance has occurred in clinical isolates.
McColm et al. 1986; Roholt & Keiding 1987; Yoger Labia et al. (1982) applied the Szybalski tech-
et al. 1981). Such infections have included: pye- nique with an amoxicillin/clavulanic acid gradient
lonephritis due to E. coli and M. morganii; sub- to produce a strain of E. coli that was resistant to
cutaneous abscesses due to S. aureus, K. pneumon- the combination. The mechanism of resistance was
iae, and a mixture of E. coli and B. fragilis; caused by the hyperproduction of the Amp C-type
Amoxicillin/Clavulanic Acid: An Update 273

chromosomal cephalosporinase which is present in Reading 1982; Haginaka et al. 1981b, 1986; Uno
all strains of E. coli. However, using the same tech- et al. 1982]. There is good correlation between
nique with another strain of E. coli, which pro- HPLC and microbiological assays (Foulstone &
duces a penicillinase-type ~-lactamase that was re- Reading 1982).
sistant to amoxicillin but susceptible to amoxicillin/ Clavulanic acid is degraded in serum at a rate
clavulanic acid, it was not possible to isolate re- of 4.2 %/h at room temperature and 11.2 %/h at
sistant variants. This was only possible by applying 3rC (Munch et aI. 1981). Thus, clavulanic acid
chemical mutagenesis. From these results the auth- concentrations determined in body fluids and tis-
ors anticipated that the combination of amoxicil- sues may be considerably underestimated due to
lin/clavulanic acid would exert a lower selective degradation, which may partly explain the differ-
pressure on bacteria than amoxicillin alone. ences between some studies. This is exemplified by
Martinez et al. (1987) have reported an increase the approximately 3-fold difference in clavulanic
in the rate of amoxicillin/clavulanic acid-resistant acid sputum concentration depending on storage
E. coli in 2 hospitals in Madrid. The resistance was conditions in the study by Gould et al. (1988). Also,
caused by overproduction of a plasmid-mediated the half-life of clavulanic acid in urine at 37°C var-
TEM-I ~-lactamase. Williams et al. (1988) subse- ied between 1.3 and 9.2 hours depending on pH
quently confirmed a similar pattern of resistance (English et al. 1978). No degradation occurred dur-
during an outbreak of multiresistant E. coli in a ing storage at -55°C for 2 weeks (Yokota et al.
London hospital. These reports of resistance ap- 1982).
peared to arise from single clones. French and Ling
(1988) have reported a high rate of amoxicillin/ 3.1 Absorption and Plasma Concentrations
clavulanic acid-resistant E. coli in hospitals in Hong
Kong. The isolates did not arise from a single clone; Combining clavulanic acid with amoxicillin does
the mechanism of resistance was not investigated. not influence the absorption or other pharmaco-
Whether these 'pockets' of resistance signal a fu- kinetic variables of either drug after the oral
ture trend which may limit the usefulness of amox- administration of single doses to healthy subjects
iciIIin/clavulanic acid against E. coli infections re- (Adam et ai. 1982; Haginaka et ai. 1981a; Hoflken
mains to be seen. et aI. 1981; Nakagawa et ai. 1982; Uno et ai. 1982).
Table II gives examples of mean Cmax (maximum
3. Pharmacokinetic Properties plasma concentration) values for amoxiciIIin and
clavulanic acid following the oral administration of
At the time of the previous review on amoxi- single doses alone and in combination to healthy
ciIIin/clavulanic acid in the Journal, only the rel- subjects. Mean Cmax values were directly related
atively basic pharmacokinetic properties of the drug to the dose administered (Jackson et al. 1982).
combination had been established. Since then, While some authors have found considerable inter-
many studies have been published which give a individual variation in absorption and peak plasma
much more detailed pharmacokinetic profile. concentrations of clavulanic acid (Homer & Dal-
Various microbiological assays have been used hoff 1980; Munch et al. 1980) others did not (Adam
to measure amoxicillin and clavulanic acid con- et al. 1982; Hoflken et al. 1981; Saito 1981). Mean
centrations in body fluids and tissues (Adam et al. t max (time to Cmax ) values were about 1 hour for
1982; Reading & Cole 1977; Yokota et al. 1982). both amoxicillin and clavulanic acid (e.g. Jackson
An enzymatic technique has also been described et ai. 1982; Nakagawa et al. 1982). No accumula-
(Cull mann & Dick 1985), but more accurate meas- tion of amoxicillin or clavulanic acid appears to
urements of amoxiciIlin, clavulanic acid and their occur after repeated dose administration in healthy
breakdown products are obtained by high perform- subjects (Nakagawa et al. 1982; Wise et al. 1984).
ance liquid chromatography (HPLC) [Foulstone & Nilsson-Ehle et al. (1985) found the mean ab-
274 Drugs 39 (2) 1990

Table II. Mean peak plasma concentrations of amoxicillin and a 30-minute infusion of amoxicillin/clavulanic acid
clavulanic aci.d after oral administration of single doses alone 2000/200mg in healthy subjects, mean Cm ax values
and in combination to healthy subjects
were 108.3 and 13.9 mg/L, respectively (Staniforth
Dose (mg) Mean Cmax (mg/L) References et a1. 1984).
Coadministration of amoxicillin/clavulanic acid
amoxi- clavulanic amoxicillin clavulanic
cillin acid acid
with food, milk, antacids, cimetidine, ranitidine or
pirenzepine did not lead to any pharmacokinetic
125 2.6 3 interaction in healthy subjects which would be likely
250 4.0-5.3 3,8,9
to be of any significance during clinical usage. No
500 5.9-10.8 1,3,4,5,9,11,12
1000 10.2-19.7 3-5,11
statistically significant effect OIl' absorption was
125 2.3-3.3 1,8 noted during coadministration with food (Eshel-
250 1.9-4.3 5,7 man & Spyker 1978; Jackson et a1. 1982; Naka-
125 62.5 2.3 1.3 10 gawa et a1. 1982; Staniforth et a1. 1982, 1985), milk
250 125 3.1-4.4 2.1-3.0 2,8,10
(Staniforth et a1. 1985), pirenzepine or ranitidine
500 125 8.0-9.7 3.5-3.9 1,5
500 250 5.5-10.0 1.1-5.2 2,5,6,8,10,12,13
(Deppermann et a1. 1988). Coadministration with
750 375 5.6 5.4 8 magnesium hydroxide and/or aluminiumhydrox-
1000 250 13.6 5.6 5 ide antacids caused a minor but statistically sig-
References: 1 Adam et al. (1982); 2 Ball et al. (1980);
nificant decrease in t max and increase in Cmax val-
3 Croydon & Sutherland (1970); 4 Gordon et al. (1972); ues for amoxicillin but not clavulanic acid; areas
5 Jackson et al. (1982); 6 Kosmidis et al. (1981); 7 Munch under the plasma concentration versus time curves
et al. (1981); 8 Nakagawa et al. (1982); 9 Neu & Winshell (1970); (AUC) were not affected (Deppermann et al. 1988;
10 Saito (1981); 11 Spyker et al. (1977); 12 Staniforth et al.
Staniforth et al. 1985). Coadministration .wi,th ci-
(1983); 13 Wise et al. (1984).
metidine produced statistically significant in-
creases in C max and area under the plasma con-
centration-time curve (AUC) values (about 15 to
solute bioavailability for clavulanic acid was 60% 30%) for both amoxicillin andclavulanic acid, an
when comparing oral with intravenous adminis- effect which was not seen if amoxicillin/clavulanic
tration of amoxicillin/clavulanic acid SOO/12Smg acid was administered intravenously (Staniforth et
in healthy subjects. There was wide interindividuaf a1. 1985). These authors postulated that cimetidine
variation (31.4 to 98.8%), indicating highly vari- may increase intraluminal pH and therefore the
able absorption from the gastrointestinal tract. solubility of amoxicillin and clavulanic acid. Coad-
Jackson et a1. (1982) found similar plasma con- ministration of amoxicillin/clavulanic acid with
centration profiles for amoxicillin and clavulanic probenecid produced a statistically and clinically
acid after the oral administration of amoxicillin/ significant increase in plasma amoxicillin concen-
clavulanic acid 500/125mgas either film-coated tration, but did not affect that of clavulanic acid
tablets, dispersible tablets or a syrup to healthy (Staniforth et al. 1983, 1984).
subjects. The same was also found following oral
administration of a single dose of amoxicillin/cla- 3.2 Distribution
vulanic acid 2S0/62:Smg as 2 paediatric syrup
formulations and as a dispersible tablet. Clavulanic acid is less lipid soluble than amox-
Croydon et al. (1981) found mean Cmax values icillin and has a volume of distribution (V d) of
of 105.4 and 28.S mg/L, respectively, following t~e about 2S% of bodyweight (e.g. Bennett et al. 1983;
bolus injection of amoxicillin/clavulanic acid 1000/ Nakagawa et al. 1982; Nilsson-Ehle et al. 1985). In
200mg in healthy subjects. Under the same con- vitro, clavulanic acid is 22% bound to serum pro-
ditions, Staniforth et al. (1984) reported values of teins at concentrations from 1 to 100 mg/L (Hunter
about 90 and 45 mg/L, respectively. At the end of et a1. 1980). Amoxicillin alone or in combination
Amoxicillin/Ciavulanic Acid: An Update 275

with clavulanic acid does not displace bilirubin 3.3 Metabolism and Excretion
from cord serum in vitro until the concentration is
about 10 times higher than normal therapeutic The mean elimination half-lives of amoxicillin
concentrations. Therefore, the drug is unlikely to and clavulanic acid are both about 1 hour after the
displace bilirubin from albumin when admini- oral administration of various single doses alone
stered to jaundiced human neonates (Davies 1985). or in combination to healthy subjects (e.g. Adam
The distribution of amoxicillin and clavulanic et al. 1982; Hoffken et al. 1982; Jackson et al. 1982;
acid into human body tissues and fluids after their Nakagawa et al. 1982; Nilsson-Ehle et al. 1985; Wise
concomitant administration has been well studied et al. 1984).
and the results are summarised in table III. In gen- Nakagawa et al. (1982) found a mean total
eral, adequate antibacterial concentrations were clearance of about 25 L/h for both amoxicillin and
achieved in most tissues and fluids, as well as in clavulanic acid after the oral administration of
urine, which is the major route of elimination (see various single doses either alone or in combination
section 3.3). Particularly low concentrations of cla- to healthy subjects. After the intravenous admin-
vulanic acid were found in some studies for spu- istration of a single dose of amoxicillin/clavulanic
tum and tonsil tissue, as well as for CSF from acid 500jl25mg to healthy subjects, Nilsson-Ehle
patients with bacterial meningitis. These may have et al. (1985) determined mean plasma and renal
been the result of a low dosage administered and/ clearance for clavulanic acid at 14.9 and 6.3 L/h/
or inadequate protection of samples against deg- 1. 73m 2, respectively, and the mean renal clearance
radation (see beginning of section 3). Yamaguchi of clavulanic acid was 6.9 L/h/1.73m 2 after oral
et al. (1982) have found that, despite the low con- administration of the same dose. Staniforth et al.
centration of clavulanic acid measured in sputum, (1983) found a mean renal clearance of 5.3 L/h for
coadministration of clavulanic acid with amoxicil- clavulanic acid after the oral administration of a
lin was justified in patients with respiratory tract single dose of amoxicillin/clavulanic acid 500/
infection due to /3-lactamase-producing organisms, 250mg to healthy subjects.
as sufficient protection against degradation of After oral administration of various single doses
amoxicillin occurred to significantly increase spu- of amoxicillin and clavulanic acid alone or in com-
tum amoxicillin concentrations compared with the bination to healthy subjects, amoxicillin is ex-
administration of amoxicillin alone. The penetra- creted largely unchanged in urine with a mean 6-
tion of amoxicillin/clavulanic acid into CSF after hour recovery of intact drug of about 60 to 80%,
administration of maximum recommended doses while clavulanic acid is more extensively metab-
would appear insufficient for adequate treatment, olised and mean 6-hour urinary recovery of intact
as CSF lacked consistent bactericidal activity drug is about 30 to 50% (e.g. Adam et al. 1982;
against /3-lactamase-producing organisms in vitro Jackson et al. 1982; Nakagawa et al. 1982; Nilsson-
(Decazes et al. 1987). Ehle et al. 1985; Wise et al. 1984). Nilsson-Ehle et
Following administration of a single oral dose al. (1985) found that mean 12-hour urinary recov-
of amoxicillin/clavulanic acid 250/125mg, both ery of clavulanic acid was higher (49%) after intra-
components cross the placenta to achieve peak venous administration compared with oral admin-
concentrations of up to about 50% of correspond- istration (36%) after a single dose of amoxicillin/
ing maternal serum samples in umbilical cord clavulanic acid 500/125mg in healthy subjects. Wise
serum and amniotic fluid (Matsuda et al. 1982; et al. (1984) found a mean 8-hour urinary recovery
Takase et al. 1982). From the limited available data of 66% and 27%, respectively, after a single oral
it appears that amoxicillin and clavulanic acid en- dose of amoxicillin/clavulanic acid 500/250mg in
ter breast milk in only very small quantities (Mat- healthy subjects, but after repeating the dose 3 times
suda 1982; Takase et al. 1982; von Kobyletzki & daily for 4 days recovery was reduced with mean
Primavesi 1987). 24-hour values of 46% and 10%, respectively. How-
276 Drugs 39 (2) 1990

Table III. Concentrations of amoxicillin and clavulanic acid in various body tissues and fluids after their combined administration

Tissue/fluid Status of Dose (amoxicillin/ Time Peak tissue or fluid Tissue or fluid/ Reference
subjects clavulanic acid in mg) after concentration serum concentration
[no. of sUbjects]8 doseb (mg/kg or mg/L)c ratio ("!o)

amoxicillin clavulanic amoxicillin clavulanic

acid acid

Blister fluid Healthy 500/250 [6] 3h 3.8 2.0 72 55 23

RTI 875/125 [6] 2.3-2.5h 6.31 3.23 112 87 28
Bile T-tube 250/125 [4] 4h 1.1 0.2 18
drainage
Peritoneal Abdominal 1000/200 IV [30] 2h >5 > 1 84 66 22
fluid surgery
Elective 1000/200 IV [6] 30-75 14.6 3.6 65 86 12
laparoscopy min
Synovial fluid Hip 1000/200 IV [7] 20-165 19.9 3.8 104 81 9
replacement min
Joint effusion 1000/200 IV [15] 30 min 41 5 100 100 17
Non-infected Cirrhotic 1000/200 IV qid [6] 2h 18.0d 1.75d 8
ascites
CSF: non- Diagnostic 500/250 [4] 4h 0.34 0.19 8 22 16
inflamed
meninges
CSF: inflamed Bacterial 2000/200 IV [21] 2h 2.25 0.25 5.8 8.4 2
meninges meningitis 200/20 per kg [11] 1-2h 3.83 0.32 17.9 20.9 4
Fat Vascular 1000/200 IV [15] 30 min 5.1 0.7 12.8 7.5 6
surgery
Vein Vascular 1000/200 IV [15] 30 min 7.5 1.2 18.8 12.9 6
surgery
Artery Vascular 1000/200 IV [15] 30 min 4.8 1.6 12.0 17.2 6
surgery
Bone Hip 2000/200 IV [14] 30-60 6.4 0.7 7.2 13.1 5
replacement min
Hip 2000/200 IV qid [9] 31 min 3.6 0.5 7.1 5.9 9
replacement
Hip 2000/200 IV [7] 35-55 26.0/ 2.32/1.6e 26
replacement min 18.22e
Perianal Surgery 1000/200 IV [17] 1.7-2.6h 8.9-9.7 0.01-2.1
abscess pus
Prostate Surgery 2000/200 IV [10] 15-120 26.4 0.6 73 39 14
min
Surgery 875/125 [31] 3h 0.77 0.15 19
Female genital Gynae- 1000/200 IV [18] 1h 11.3 0.4 32 10 21
tissue' cological 1000/200 IV tid [15] 1h 14.1 0.4 56 16 21
surgery 500/250 [10] 126-200 1.2-1.7 0.4-0.7 47-59 26-45 3
min
Ovary Gynae- 1000/200 IV [18] 1h 16.3 0.5 46 14 21
cological 1000/200 IV qid [15] 1h 17.6 0.7 69 26 21
surgery
Middle ear Surgery 875f125 [23] 3h 0.4 19
mucosa
Amoxicillin/Clavulanic Acid: An Update 277

Table III. Contd

Tissue/fluid Status of Dose (amoxicillin/ Time Peak tissue or fluid Tissue or fluid/ Reference
subjects clavulanic acid in mg) after concentration serum concentration
[no. of subjects]a dose b (mg/kg or mg/L)C ratio (%)

amoxicillin clavulanic amoxicillin clavulanic

acid acid

Gingiva Oral surgery 250/125 [6] 60-90 0.9 0.6 54 19 20

min
500/250 [6] 60-90 0.7 0.7 28 21 20
min
Maxillary ENT infection 250/125 [4] 2h 0.3 0.2 10 11 13
sinus
mucous
membrane
Tonsil ENT infection 250/125 [4] 2h 0.4 0.2 14 12 13
ENT infection 500/250 [3] lh 1.0 0.5 31 15 10
Surgery 875/125 [22] 4h 0.87 0.17 19
Sputum Bronchitis 500/250 bid [14] NR 0.31 0.25 7
Bronchitis 500/250 [3] lh 0.44 0.92 8.3 18 16
Bronchitis 875/125 [10] 2-4h 1.31 0.79 19
Bronchitis 1000/250 [10] 0-8h 0.92 0.16 16.8 8.2 25
RTI 250/125 [3] 3-4h < 0.02 ()9 24
RTI 500/250 [3] 3-4h 0.1 09 24
RTI 500/250 tid [13] lh 0.26 0.23 6.7 8.8 11
Saliva RTI 500/250 tid [13] lh 0.12 0.44 3.1 17.0 11
Bronchial Carcinoma 1000/200 IV [12] NR 1.78 0.35 7
mucus diagnosis
Bronchial Carcinoma 1000/200 IV [12] NR 0.45 0.1 7
washings diagnosis
Pulmonary Surgery 875/125 [32] 3h 2.56 0.56 19
Surgery 2000/200 [10] 54 min 34.1 2.3 40 23 27
Pleural fluid Pulmonary 1000/250 [13] 4h 6.9 3.1 75 139 15
surgery
Pleuritic fluid Pleurisy 500/250 [4] 4h 5.0 2.4 119 282 16

a Oral administration unless stated otherwise.

b Time may be approximate, or a range of sampling times may be given.
c May represent the greatest reported mean concentration rather than the actual peak.
d Estimated values.
e Cortical/cancellous bone.
f Including OViduct, ovarium, perimetrium, endometrium, myometrium,cervix, portiO vaginalis and fallopian tube.
g Recorded as 'hardly detected'.
Abbreviations: NR = not recorded; IV = intravenous; CSF = cerebrospinal fluid; RTI = respiratory tract infection; ENT = ear-nose-
throat; tid = 3 times daily; qid = 4 times daily.
References: 1 Ambrose et al. (1988); 2 Bakken et al. (1986); 3 Cho et al. (1983); 4 Decazes et al. (1987); 5 Duben et al. (1986);
6 Earnshaw et al. (1987); 7 Gould et al. (1988); 8 Grange et al. (1989); 9 Grimer et al. (1986); 10 Hatano et al. (1982); 11 Havard et
al. (1982); 12 Houang et al. (1985); 13 Iwasawa (1982); 14 Jurincic et al. (1987); 15 Kitzis et al. (1982); 16 Kosmidis et al. (1981);
17 Morgan et al. (1986); 18 Sakai et al. (1982); 19 Scaglione et al. (1988): 20 Tsutsou et al. (1982); 21 von Kobyletzki (1987); 22 Wise
et al. (1983); 23 Wise et al. (1984); 24 Yamaguchi et al. (1982); 25 Maesen et al. (1987); 26 Welsmeier et al. (1989); 27 Cox et
al. (1989); 28 Novelli et al. (1987).
278 Drugs 39 (2) 1990

ever, Nakagawa et al. (1982) found no change after et al. 1984; Usuda et al. 1982). The effects are well
the oral administration of amoxicillin/clavulanic exemplified by Horber et al. (1986) who studied
acid 250/ 125mg 3 times daily for 1 week in healthy the disposition after single doses of amoxicillin/
subjects. clavulanic acid 500/1 25mg orally and 1000/200mg
Clavulanic acid appears in urine faster than intravenously. The volume of distribution and the
amoxicillin and is excreted by glomerular filtra- systemic availability were independent of renal
tion; its excretion is therefore unaffected by pro- function, while total body, renal and nonrenal
benecid. Amoxicillin, however, is excreted mainly clearance of amoxicillin and clavulanic acid de-
by tubular secretion; concomitant probenecid creased with increasing renal impairment. As the
administration therefore delays excretion and in- decrease in total body clearance was more pro-
creases plasma concentrations of amoxicillin (Stan- nounced for amoxicillin than for clavulanic acid,
iforth et al. 1983, 1984). there was an increase in the amoxicil-
The majority of amoxicillin is excreted un- lin: clavulanic acid AUC ratio from 4.9 for a glo-
changed, although some hydrolysis of the j3-lactam merular filtration rate (GFR) > 75 ml/min/1.73m2
ring occurs giving rise to penicilloic and pena- to 14.7 for patients undergoing haemodialysis.
maldic acids as major metabolites, which are also Dosage recommendations were formulated based
excreted in urine (Haginaka et al. 198Ia). As men- on the standard doses of amoxicillin/clavulanic acid
tioned at the beginning of section 3, clavulanic acid 500/125mg orally and 1000/200mg intravenously
is extensively degraded in biological material at which would prevent undue accumulation of
normal body temperature. The fate of clavulanic amoxicillin while maintaining adequate plasma
acid has, however, been little studied in humans. clavulanic acid concentrations. After an initial
Administration of radiolabelled clavulanic acid to loading dose, repeated doses shOuld be admini-
animals showed that approximately equal propor- stered every 4 hours to patients with normal renal
tions of the radiolabel are recovered in urine, faeces function (GFR > 75 ml/min/1.73m2), every 8 hours
and respired air, while only about 1% was excreted for those with a GFR from 35 to 75 ml/min/
via bile (Jackson et al. 1982). These authors pos- 1.73m2, and every 12 hours for those with a GFR
tulated that the j3-lactam ring of clavulanic acid was from 10 to 35 ml/min/1.73m2.
hydfOlysed with subsequent decarboxylation, Studies in patients with chronic renal failure
yielding l-amino-4-hydroxybutan-2-one as a major have shown that clinically significant extraction of
metabolite. both amoxicillin and clavulanic acid occurs during
haemodialysis (Dalet et al. 1984; Davies et al. 1988;
3.4 Effects of Disease and Age on Horber et al. 1986; Slaughter et al. 1984; Usuda et
Pharmacokinetics al. 1982). Dosage supplementation would appear
necessary at the end of a haemodialysis session but
Studies have reported the effects of renal im- specific guidelines are difficult to define, as these
pairment (section 3.4.1) and gastrointestinal dis- would depend on both the duration of haemodi-
ease (section 3.4.2) on the pharmacokinetics of alysis and its timing after the administration of
amoxicillin/clavulanic acid. In addition, disposi- amoxicillin/clavulanic acid.
tion has been studied using paediatric formulations
(section 3.4.3). 3.4.2 Gastrointestinal Disease
Gastrointestinal disorders may change the phar-
3.4.1 Renal Insufficiency macokinetics of both amoxicillin and clavulanic
Several studies have indicated that the phar- acid. Celiac disease has been reported to decrease
macokinetics of amoxicillin/clavulanic acid are the absorption of amoxicillin (Neu 1979). The ab-
progressively affected by increasing renal impair- sorption of amoxicillin, when given alone or in
ment (Dalet et al. 1984; Horber et al. 1986; Jackson combination with clavulanic acid, was delayed and
Amoxicillin/Clavulanic Acid: An Update 279

t max was prolonged in patients who have under- enrolled patients who were unselected with respect
gone vagotomy and pyloroplasty. However, AUC to the susceptibility or resistance of the infecting
remained unchanged (Farrell et al. 1981). pathogen. Treatment was thus usually admini-
stered empirically, closely paralleling the clinical
3.4.3 Age picture as presents in general practice.
Many studies have examined the pharmacoki- In most trials, amoxicillin/clavulanic acid was
netic disposition of amoxicillin/clavulanic acid ad- administered orally. Those studies using other
ministered either orally or intravenously as a paed- routes of administration are specified. Whenever
iatric formulation in children with proven or possible the dosages of amoxicillin/clavulanic acid
suspected bacterial infections. Several Japanese are each specified, e.g. 250/125mg refers to the dose
studies have examined a granule formulation of of amoxicillin and clavulanic acid, respectively.
amoxicillin/clavulanic acid in a 2 : 1 ratio follow-
ing oral administration of total single doses ranging 4.l Urinary Tract Infections
from 7.5 to 20 mg/kg (Haruta et al. 1985; Motohiro
et al. 1985a; Nakazawa et al. 1985; Nishimura et Probably the most extensive clinical experience
al. 1985; Sato et al. 1985). Other studies have ex- with amoxicillin/clavulanic acid has been gained
amined liquid or syrup formulations of a 4 : 1 ratio in the treatment of urinary tract infections, and a
of amoxicillin/clavulanic acid after single or re- recent review specifically addresses this application
peated doses of 6.6/1.7 to 20/5 mg/kg (Begue et al. (Gasser et al. 1987).
1982; Nelson et al. 1982; Schaad et al. 1986; Van
Nierkerk et al. 1985), while Schaad et al. (1983) 4.1.1 Noncomparative and DosecFinding
studied disposition after intravenous administra- Studies
tion of a single dose of 20/5 mg/kg. Since the previous review on amoxicillin/cla-
In general, the pharmacokinetic profile of vulanic acid in the Journal, numerous noncom-
amoxicillin and clavulanic acid in children paral- parative and dose-finding studies have been pub-
leled that in adults. Mean pharmacokinetic vari- lished in paediatric (AI Roomi et al. 1984; Fink &
ables were the same as in adults, indicating similar Swoboda 1982; Kattamis et al. 1982; Principi et al.
patterns of absorption and excretion. Some of the 1988; Roca et al 1989; Ruberto et al 1989) and
lower doses gave relatively low plasma concentra- adult patients (Abbas et al. 1984; Agrawal et al.
tions of amoxicillin and clavulanic acid, which 1987; Brumfitt & Hamilton-Miller 1984; Crokaert
might prove therapeutically inadequate (e.g. Nel- et al. 1982; Dalet & Del Rio 1984; Derluyn 1982;
son et al. 1982). Adequate plasma drug concentra- Dickie & Lang 1986; Iravani & Richard 1982; Kar-
tions were attained with minimum doses of either achalios & Georgiopoulos 1984; Leng 1982; Matos-
10/2.5 or 10/5 mg/kg, depending on the formula- Ferreira & Corte Real 1988; Mayer et al. 1982;
tion ratio, and maintained with these doses re- Nakazawa et al. 1983; Stein et al. 1982; Umbach
peated at 6- to 8-hour intervals. et al. 1982; Van Erps et al. 1982; Viniaker et al
1989).
4. Therapeutic Trials In unselected patients, cure rates were about 95%
and 60 to 80% in patients with uncomplicated and
Numerous clinical trials have been published complicated urinary tract infection, respectively.
since the earlier review in the Journal. Many were Similar cure rates were also seen in studies which
comparative studies and these allow a better def- specifically studied infections caused by amoxicil-
inition of the place of amoxicillin/clavulanic acid lin-resistant or t1-lactamase-producing bacteria (e.g.
in the treatment of different types of infections. Abbas et al. 1984; Crokaert et al. 1982; Dalet &
Unless otherwise specified, clinical trials of Del Rio 1984; Leng 1982). Amoxicillin/clavulanic
amoxicillin/clavulanic acid have almost invariably acid was most effective in eradicating E. coli, Kleb-
280 Drugs 39 (2) 1990

Table IV. Summary of major clinical trials comparing amoxicillin/clavulanic acid (AMX/CA) with other antibacterial agents in urinary
tract infections

Reference Design Patient Dosage [no. of Duration Results (% responding)b

typeS pts evaluated] (days)
clinical bacteriological

Amoxicillin (AMX)
Gallacher et r,db Complicated, AMX/CA 250/125mg tid [28] 5 87 90
al. (1986) unselected AMX 250mg tid [24] 43 33
Martinelli et al. r,db Uncomplicated, AMX/CA 250/125mg tid [13] 9
85~ P
25 < 0.05
(1981) selected C AMX 250mg tid [8]
Ohkawa et al.
(1983)
r,db Complicated,
unselected
AMX/CA 1000/500mg daily [114]
AMX 1000mg daily [120]
5
75
43 tP < 0.01
71
34

Cotrimoxazole (SXT)
Ancill et al.
(1987)
r,sb Uncomplicated,
unselected
AMX/CA 250/125mg tid [27]
SXTf [28]
7
96t
64 P < 0.06

Bailey et al. r,nb Uncomplicated, AMX/CA 250/125mg tid [24] 4-9

(1983) selected d SXT 160/800mg bid [28] 100 ~ P
83 = 0.039
Brumfitt & r,nb Recurrent, AMX/CA 250/125mg tid [44] 7
84f
97 P < 0.05
Hamilton- uncomplicated, SXT 160/800mg bid [38]
Miller (1985) selected e
Flavell Matts
et al. (1985)
r,sb Mixed,
unselected
AMX/CA 250/125mg tid [26]
SXT 160/800mg bid [26]
7 96
85
100
88
tP = 0.08
Karachalios r,nb Uncomplicated, AMX/CA 250/125mg tid [54] 10 100
95
83 ~ P < 0.001
(1985a) unselected SXT 160/800mg bid [50] 100

Cefaclor (CEC)
Gurwith et al. r,sb Uncomplicated, AMX/CA 250/125mg tid [30] 10 87
(1983) unselected CEC 250mg tid [36] 72
Iravani & r,db Uncomplicated, AMX/CA 250/125mg tid [51] 10 96
Richard (1986) unselected CEC 250mg tid [53] 92

Cefuroxime axetil (CXM)

Williams et al. r,nb Uncomplicated, AMX/CA 250/125mg tid [89] 5 97 70
(1987) unselected CXM 250mg bid [140] 97 72

Cefalexin (CN)
Pedler & Bint r,nb Bacteriuria in AMX/CA 250/125mg tid [31] 7 76 77
(1985) pregnancy, CN 250mg tid [27] 60 74
unselected

Cefatrizine propylene glycol (CFT)

Kawada et al. r,db Complicated, AMX/CA 250/125mg tid [147] 5
58
37 ~ P < 0.01 79~ P
61 < 0.01
(1983) unselected CFT 250mg qid [150]

Pivmecillinam/pivampicillin (PVM/PVA)
O'Dowd et al. r,nb Uncomplicated, AMX/CA 250/125mg tid [28] 5 72 75
(1984) unselected PVMWVA 200/250mg [29] 57 85

a Unselected = no selection of patients according to resistance or susceptibility of pathogens.

b Methods of calculating response rates varied widely between studies.
c Amoxicillin-resistant pathogens only included.
d Resistance to test drug reason for,exclusion (similar on both drugs).
e Resistance or hypersensitivity to test drug reason for exclusion (53% excluded from SXT vs 6% on AMX/CA).
Dosage not stated.
Abbreviations: bid = twice daily; tid = 3 times daily; qid = 4 times daily; r = randomised; nb = nonblind (or not stated); sb = single-
blind; db = double-blind.
Amoxicillin/ Clavulanic Acid: An Update 281

siella spp., Citrobacter spp., P. mirabilis, S. epi- who had a pathogen resistant to the combination)
dermidis, S. aureus and S. faecalis , and less effec- in the majority of studies.
tive against infections caused by Enterobacter and Amoxicillin/c1avulanic acid was clearly superior
Pseudomonas spp. Not unexpectedly, Pseudo- to amoxicillin alone, although it tended to produce
monas was a frequent source of reinfection in more adverse effects. Most studies showed that
patients with complicated infection and reduced amoxicillin/c1avulanic acid was statistically supe-
efficacy was associated with the pres~nce of an in- rior to cotrimoxazole both clinically and bacteri-
dwelling catheter or multiple pathogens in such ologically. Also, cure was faster in those patients
patients. who did respond on amoxicillin/c1avulanic acid
Amoxicillin/c1avulanic acid was usually admin- compared with cotrimoxazole (mean 3.2 vs 4.8 days,
istered 8-hourly for 7 to 10 days using either a 2 : I p = 0.004) [Flavell Matts et al. 1985]. However,
or 4 : I formulation; single doses of 250/125, 500/ some studies showed that cotrimoxazole was su-
125 and 500/250mg being most commonly used in perior at a statistically significant level (Bailey et
adults, with bodyweight-adjusted doses used in al. 1983; Brumfitt & Hamilton-Miller 1985). The
children. A regimen of 875/125mg twice daily has reason was clear for the latter study: the selected
also been used. While increasing the dose did not nature of the patient population, which excluded
appear to improve the cure rate in uncomplicated 53% of enrolled patients on cotrimoxazole com-
infection, the higher doses appeared more effective pared with only 6% on amoxicillin/c1avulanic acid
in patients with complicated infection. In a pilot because of pathogen resistance or known hyper-
study Dickie and Lang (1986) found that a single sensitivity to the drug. Amoxicillin/c1avulanic acid
dose of amoxicillin/c1avulanic acid 3000/250mg was as well tolerated as cotrimoxazole.
was effective in the treatment of uncomplicated Amoxicillin/c1avulanic acid was clinically and
cystitis, but the high dosage proved unpalatable and bacteriologically at least as effective as cefaclor, ce-
produced a high incidence of gastrointestinal ad- furoxime axetil, cefalexin and pivmecillinamjpiv-
verse effects. ampicillin, but was statistically superior to cefatri-
Mayer et al. (1982) found that amoxicillin/c1a- zine propylene glycol. With respect to tolerability,
vulanic acid was effective in the treatment of ur- amoxicillin/c1avulanic acid was usually equivalent
inary tract infection in pregnant women and was to these comparative agents, although it produced
well tolerated by the mother and fetus. more adverse effects and hepatic enzyme test ab-
normalities compared with cefaclor in the study by
4.1.2 Comparative Studies Iravani and Richard (1986). However, this study
The results of major comparative clinical trials also showed that reinfection, relapse and superin~
of amoxicillin/c1avulanic acid are summarised in fection were more frequent with cefaclor.
table IV. Treatment with amoxicillin/c1avulanic There have been several other comparative
acid, usually at a dosage of250/125mg 3 times daily studies not included in table IV because of inad-
for 4 to 10 days, produced clinical and bacterio- equate reporting, limited numbers of patients or
logical response rates of about 70 to 100%, the re- their retrospective nature which has limited their
sponse being dependent on the severity of infec- value. Begue et al. (1987) reported that intravenous
tion, complications, and method and timing of followed by oral amoxicillin/c1avulanic acid was as
assessment. More favourable response rates were effective as intravenous followed by oral amoxi-
achieved with uncomplicated infection and where cillin plus intramuscular netilmicin in infants and
assessment was made immediately at the end of children with acute pyelonephritis. Knothe et a1.
therapy without an adequate follow-up to deter- (1985) found that ofloxacin was more effective than
mine relapses and reinfections. It should be em- amoxicillin/c1avulanic acid in patients with lower
phasised that amoxicillin/c1avulanic acid was ad- and upper urinary tract infection. In a retrospec-
ministered 'blind' (i.e. without withdrawing patients tive analysis of their clinical experience, Sabbour
282 Drugs 39 (2) 1990

Table V. Summary of major clinical trials comparing amoxicillin/clavulanic acid (AMX/CA) with other antimicrobial agents in
respiratory tract infections

Reference Design Patient type a Dosage [no. of Duration Aesults (% responding)b

pts evaluated] (days)
clinical bacteriological

Amoxicillin (AMX)
Benard et al. r,db Mainly acute on AMX/CA 1000/250mg bid [34] 8
88f
62 P = 0.03
(1982) chronic bronchitis AMX 1000mg tid [16]
Jensen et al. r,sb Children with chronic AMX/CA 50/12.5 mg/kg/day 14 57 70
(1988) obstructive pulmonary tid plus probenecid 250-750
disease plus mg/day [30]
ampicillin-sensitive AMX SO mg/kg/day tid plus 59 57
H influenzae probenecid 250-7S0 mg/day [36]
Miki et al. r,db Mostly chronic AMX/CA 250/125 mg qid [148] 14 67
83~ P < 0.05
72
(1983) AMX 259mg qid [127] 58

Phenoxymethylpenicillin (PV)
Kaplan & r,nb Children with group A AMX/CA 40 mg/kg/day [21] 10 90
87f P < 0.01
31
Johnson Streptococcus acute PVc [24] 29
(1988) infection failed on PV

Bacampicillin (BAC)
Renton et al. r,nb Acute bronchitis AMX/CA 250/125mg tid [31] 7 90
(1984) BAC 800mg bid [28] 71

Pivmecillinam/pivampicillin (PVM/PVA)
Beumer & r,nb Acute on chronic AMX/CA 500/125mg tid [18] 10 28 83
Sips (1984) bronchitis PVM/PVA 200/250mg bid [19] 26 58
PVM/PVA 400/500mg bid [19] 37 74
McGhie et al. r,sb Acute and acute on AMX/CA 250/125mg tid [193] 7-10 94
(1986) chronic bronchitis PVM/PVA 200/250mg bid [195] 94

Doxycycline (DO)
Ulmer & r,nb Acute on chronic AMX/CA 250/125mg bid [15] 10 60
Zimmermann bronchitis DO 200mg then 100mg od [15] 26
(1981)

Oxytetracycline (OT)
Boston et al. r,sb Various upper and AMX/CA 250/125mg tid [379] 7 88
(1986) lower infections OT 250mg qid [369] 84

Josamycin (JM)
Gaillat et a!. r,nb Chronic AMX/CA 400/100mg tid [16] 10-15 100~ P < 0.01
75
(1987) JM 500mg tid [16]

Erythromycin (E)
Pariente r,nb Chronic AMX/CA 1600/400 mg/day [79] 10 87
(1987) E 2000 mg/day [86] 76

Ciprofloxacin (CPO)
Schmidt et al. r,nb Acute on chronic AMX/CA 1000/250mg tid [20] 10-12 70
(1989) bronchitis CPO 500mg bid [20] 70

Cefuroxime axetil (CXM)

Hebblethwaite r,nb Acute upper infection AMX/CA 250/125mg tid [188] 5 98 72
et al. (1987) CXM 250mg bid [175] 97 73
Mayhew r,sb Lower infections AMX/CA 250/125mg tid [323] 7 93 90
(1987) CXM 500mg bid [331] 94 90
Amoxicillin/Clavulanic Acid: An Update 283

Table V. Contd

Reference Design Patient type a Dosage [no. of Duration Results (% responding)b

pts evaluated] (days)
clinical bacteriological

Cefixime (CFM)
Beumer (1989) r,nb Lower infections AMX/CA 500/125mg tid [30] 14 74 52
CFM 200mg bid [30] 71 54

Cefaclor (CEC)
Penn et al. r,nb Acute on chronic AMX/CA 500/125mg tid [21] > 5 86
(1983) CEC 500mg tid [20] 80

Cefuroxlme (CXM) followed by cefalexin (CN)

O'Donovan et r,nb Chronic lower AMX/CA 1000/200mg tid IV for 7 100
al. (1987) infection 2 days then orally [106] 93! P < 0.05
CXM 750mg tid IV for 2 days 80 91
then CNc orally [68]

a All patients were unselected with respect to pathogen resistance, except for those in the study of Kaplan & Johnson (1988).
b Response rates usually calculated immediately at end of therapy and clinical response usually defined as cure or improvement.
c Dosage not stated.
Abbreviations: od = once daily; bid = twice daily; tid = 3 times daily; qid = 4 times daily; r = randomised; nb = nonblind (or not
stated); sb = single-blind; db = double-blind.

and Osman (1988) found very similar clinical and 250/125mg 3 times daily or ciprofloxacin 250mg
bacteriological success rates in patients with recur- twice daily for 5 days, respectively.
rent upper urinary tract infection treated with 1 of
the following regimens: oral amoxicillin/clavulanic 4.2 Respiratory Tract Infections
acid 250/125mg 3 times daily for 10 days; oral rif-
ampicin 600mg plus trimethoprim 160mg once 4.2.1 Noncomparative and Dose-Finding
daily for 10 days; intramuscular sulbactam 500mg Studies
plus ampicillin Ig twice daily for 5 days; and oral Most of the noncomparative studies published
'pivampicillin 125mg plus pivmecillinam 100mg 3 over the past decade included only limited num-
times daily for 7 days. Hart et al. (l981) studied bers of patients (Aigner et al. 1984; Beeuwkes &
56 patients with mostly complicated urinary tract Rutgers 1981; Bisetti et al 1987; Bonsignore et al
infection, caused by gentamicin-resistant Klebsi- 1989; Borgo et al 1989; Bruna et al 1989; D' Adda
ella. They noted similar rates of cure and recurr- et al 1989; Fink & Swoboda 1982; Galleri et al 1988;
ence with the following regimens: amoxicillin/cla- Gooch et al. 1985; Havard et al. 1982; Karachalios
vulanic acid 250/125mg orally 3 times daily for 5 1985b; Maesen et al. 1987; Micillo et al 1987;
days; cefradine 500mg orally 4 times daily with and Mouzinho et al 1989; Palermo et al 1987; Saroglou
without mecillinam 400mg orally 3 times daily for et al. 1982; Thomley et al. 1986; Wallace et al. 1985;
7 days: cefuroxime 750mg intramuscularly 3 times Yamaguchi et al. 1982). Clinical success rates were
daily for 5 days; and amikacin 7.5 mg/kg twice daily usually about 80 to 90%. With the exception of
intravenously or intramuscularly for 5 days. Re- Italian studies, which employed a treatment regi-
cently, Abbas et al. (1988) reported clinical re- men of 875/125mg twice daily, dosages of 250/
sponse rates of 85.1% and 91.6% in over 250 gen- 125mg 3 times daily were routinely used in less
eral practice patients with acute urinary tract severe infections, increasing to 500/250mg 3 times
infection treated with amoxicillin/clavulanic acid daily in patients with more severe, recurrent or l
284 Drugs 39 (2) 1990

chronic lower respiratory tract infection. Also, in (1988) found similar rates of cure with amoxicillin
the latter more severe infections some studies used alone or combined with clavulanic acid in children
parenteral administration of amoxicillin/clavu- with chronic obstructive pulmonary disease plus
lanic acid during the first 2 or 3 days of treatment ampicillin-sensitive H. injluenzae: the bacteriolog-
followed by oral administration (e.g. Aigner et al. ical cure rate for H. injluenzae tended to be higher
1984; Maesen et al. 1987). In children, lower dos- with amoxicillin/clavulanic acid, and when poly-
ages were used in accordance with the manufac- microbial infections were present amoxicillin/cla-
turers' recommendations (e.g. Fink & Swoboda vulanic acid produced a significantly superior bac-
1982; Gooch et al. 1985). When isolated, the most teriological response rate (86% vs 47%, p < 0.05).
frequently occurring pathogens were H. injluenzae, Amoxicillin/clavulanic acid was superior to josa-
B. catarrhalis, S. pneumoniae and K. pneumoniae, mycin (Gaillat et al. 1987) and cefuroxime fol-
which were eradicated with similar success rates. lowed by cefalexin (O'Donovan et al. 1987). Also,
However, one study which performed a follow-up in comparison with oxytetracycline in general
examination one week after treatment reported re- practice patients (Boston et al. 1986), it produced
lapse of infection in 14 of 20 patients; /3-lactamase- a higher rate of 'good' responses (64% vs 51 %, p <
producing B. catarrhalis was the infecting organ- 0.001). In other comparisons, amoxicillin/clavu-
ism in 5 of these patients (Maesen et al. 1987). lanic acid was at least as effective as bacampicillin,
pivmecillinam/pivampicillin, doxycycline, erythro-
4.2.2 Comparative Studies mycin, ciprofloxacin, cefuroxime axetil, cefixime
Amoxicillin/clavulanic acid has been compared and cefaclor.
with many other antimicrobial agents in patients In children with acute group A streptococcal in-
with respiratory tract infections (table V). The fection who had previously failed with phenoxy-
patients in these trials were almost invariably methylpenicillin, amoxicillin/clavulanic acid pro-
treated 'blind', i.e. they were not selected with re- duced a more favourable clinical response and a
spect to resistance of the pathogen to amoxicillin/ statistically significantly greater bacteriological re-
clavu1anic acid or the comparative agent. Bacter- sponse rate than phenoxymethy1penicillin (Kaplan
iological response rates were frequently not deter- & Johnson 1988).
mined because of the methodological difficulties In general, amoxicillin/clavulanic acid appeared
involved in isolating the causative bacteria. to be at least as well tolerated as the other agents
The clinical response rate (usually defined as with which it was compared.
cure or improvement at the end of treatment) with
amoxicillin/clavu1anic acid was generally 80 to 4.3 Otorhinolaryngological Infections
100%. Higher response rates (usually cures) were
found fot the less severe infections, i.e. acute upper 4.3.1 Noncomparative Studies
respiratory tract infection in outpatients, usually Studies have been conducted in paediatric and
after treatment with the lower dosage of 250/125mg adult patients with otorhinolaryngological infec-
3 times daily. Patients with more severe infection, tions, including tonsillitis, otitis, pharyngitis,
e.g. chronic infection of the lower respiratory tract sinusitis, laryngitis etc. (e.g. Amendola et al. 1989;
in compromised inpatients, received high dosages Catalano et al. 1988; Cohen et al. 1989; Esposito
of up to 3000/600mg daily and clinical response et al. 1989; Fior et al. 1989; Gehanno & Simonet
was more frequently determined as improvement 1989; Hatano et al. 1982; Iwasawa 1982; Kawa-
rather than cure. mura et al. 1983; Le Clech & Bourdiniere 1987;,
The clinical response to amoxicillin/clavulanic Motta et a1 1989; Ottaviani et al. 1988; Solbiati et
acid was superior to amoxicillin alone at a statis- al. 1988; Thomassin & Pech 1986). These studies
tically significant level in 2 studies (Benard et al. have essentially confirmed previous findings where
1982; Miki et al. 1983). However, Jensen et al.' clinical response rates usually exceeded 90% in un-
Amoxicillin/C1avulanic Acid: An Update 285

selected patients. The most frequent infecting vs 19%, p < 0.0 I). The particularly low rates of
organisms were S. aureus, H. injluenzae, S. pneu- bacteriological response are explained by high rates
moniae and B. catarrhalis. of recurrence and persistence at follow-up. Other
A recent double-blind placebo-controlled study studies determined the bacteriological response
examined the efficacy of amoxicillin/c1avulanic acid immediately at the end of therapy; these also found
administered for I month to over 100 children with somewhat high rates of relapse during follow-up
secretory otitis media. By means oftympanometry regardless of treatment.
it was shown that active treatment reversed the Recently, Engelhard and colleagues (1989) re-
disease in 61 % of patients compared with 30% in ported that 10 days' treatment with bodyweight-
a similar number of patients given placebo. In- adjusted doses of amoxicillin/c1avulanic acid was
deed, significantly superior tympanometric results more effective than myringotomy in infants with
were recorded in the amoxicillin/c1avulanic acid acute otitis media. Recovery, assessed otoscopi-
group for up to 8 months after the end of treatment cally, occurred in 60% of patients treated with
(Thomsen et al. 1989). amoxicillin/c1avulanic acid alone or in combina-
tion with myringotomy compared with 23% of
4.3.2 Comparative Studies patients treated with myringotomy plus placebo (p
The results of studies comparing amoxicillin/ < 0.01; n = 30/treatment group). These results were
c1avulanic acid with either amoxicillin alone or ce- associated with persistent ear infections in 70% of
faclor are summarised in table VI. In children and patients treated with myringotomy and placebo
adults with acute otitis media amoxicillin/c1avu- versus rates of 7 and 17% in the groups treated with
lanic acid tended to produce superior clinical and amoxicillin/c1avulanic acid alone or amoxicillin/
bacteriological response rates compared with c1avulanic acid plus myringotomy, respectively (p
amoxicillin alone, with the result being statistically < 0.001).
significant for clinical response in the study by Baba
et al. (1983). Amoxicillin/c1avulanic acid and 4.4 Skin and Soft Tissue Infections
amoxicillin alone proved similarly effective in
children with acute maxillary sinusitis. Amoxicil- In the subsequent studies on skin and soft tissue
lin/c1avulanic acid was comparable (Kaprio et al. infections patients were included with various con-
1988) or superior to cefaclor in the treatment of ditions such as wound infection, abscess, cellulitis,
paediatric otitis media; statistically significant re- furunculosis, impetigo etc. These conditions are
sults in favour of amoxicillin/c1avulanic acid were characterised by a wide range of Gram-negative and
found for clinical and bacteriological effects in the Gram-positive, aerobic and anaerobic pathogens,
studies by Odio et al. (1985) and Marchant et al. and often mixed infections. Uncommon pathogens
(1986), respectively. While amoxicillin/clavulanic may be present, but most frequently include S. au-
acid and amoxicillin alone showed similar tolera- reus, S. pyogenes, Bacteroides spp., Fusobacterium
bility, amoxicillin/clavulanic acid was not as well spp., E. coli and Klebsiella spp. Amoxicillin/cla-
tolerated as cefaclor. Amoxicillin/clavulanic acid vulanic acid proved effective against a wide range
produced significantly more minor gastrointestinal of pathogens, although the few infections caused by
side effects compared with cefaclor. Proteus, Pseudomonas or Enterobacter did not usu-
Jacobsson et al. (1988) compared amoxicillin/ ally respond.
c1avulanic acid 40/10 mg/kg/day and cefaclor 20
mg/kg/day in over 100 children with otitis media 4.4.1 Noncomparative Studies
that was either recurrent or resistant to penicillin. Noncomparative studies in adult and paediatric
A clinical response greater than 90% was found with patients with skin and soft tissue infections have
each treatment, while the bacteriological response generally shown that amoxicillin/clavulanic acid
was higher with amoxicillin/c1avulanic acid (33% produced clinical and bacteriological response rates
286 Drugs 39 (2) 1990

Table VI. Summary of clinical trials comparing amoxicillin/clavulanic acid (AMX/CA) with other antimicrobial agents in otorhino-
laryngological infections

Reference Study Patient type a Dosage [no. of Duration Results (% responding)b

design pts evaluated] (days)
clinical bacteriological

Amoxicillin (AMX)
Saba et al. (1983) r,db Adults, acute AMX/CA 250/125mg tid [83] 7 60
63~ P
47 < 0.05
exacerbation of AMX 250mg tid [99] 50
chronic otitiS
media
Chan et al. (1988) r,db Children, otitiS AMX/CA 40/10 mg/kg/day [56] 10 52
media with AMX 40 mg/kg/day [50] 32
effusion
Wald et al. (1986) r,nb Children, acute AMX/CA 40/10 mg/kg/day [28] 10 75
maxillary AMX 40 mg/kg/day [30] 83
sinusitis Placebo [35] 60

Cefaclor (CEC)
Kaleida et al. r,nb Children, acute AMX/CA 40/10 mg/kg/day [64] 10 98
(1987) otitis media CEC 40 mg/kg/day [69] 96
Kaprio et al. r,sb Children, acute AMX/CA 20 mg/kg/day [127] 7 94
(1988) otitis media CEC 40 mg/kg/day [115] 92
Marchant et al.
(1986)
r,nb Children, acute
otitis media
AMX/CA 40/10 mg/kg/day [55]
CEC 40 mg/kg/day [59]
10 89
91
97 t
75 P = 0.028

Odio et al. (1985) r,nb Children, acute AMX/CA 40/10 mg/kg/day [70] 10 100~ P = 0.019
92
otitis media with CEC 40 mg/kg/day [60]
effusion

a All patients were unselected with respect to pathogen resistance.

b Response rates usually determined immediately at the end of therapy and clinical response usually defined as cure or improve-
ment.
Abbreviations: tid = 3 times daily; r = randomised, nb = nonblind (or not stated); db = double-blind.

in excess of 90% (Garrel et al. 1982; Motohiro et biological response rates which were at least as
al. 1985b; Sakai et al. 1982). Similar results have effective as cefuroxime axetil in adults with wound
been achieved in odontogenic infections (Gerlach infections and as cefaclor in adults or children with
et al. 1989; Tsutou et al. 1982). various skin and soft tissue infections. Amoxicil-
lin/clavulanic acid tended to be clinically more ef-
4.4.2 Comparative Studies fective than amoxicillin alone in adult patients with
Huizinga et al. (1986) compared amoxicillin/ wound infection and produced a superior bacter-
clavulanic acid 250/ 125mg 3 times daily with pla- iological response rate at a statistically significant
cebo for 5 days in a randomised double-blind study level. After to days' treatment of children with
in over 70 adult patients with wound infections. nonbullous impetigo there were no new lesions in
Microbiological cure, although low, was signifi- a group administered amoxicillin/c1avulanic acid
cantly higher for patients receiving amoxicillin/cla- whereas 5 of 25 patients given amoxicillin alone
vulanic acid (16% vs 0%, p < 0.05). had developed new lesions. In a study not reported
The results of some major studies comparing in table VII (because dosages were not stated)
amoxicillin/c1avulanic acid with other antimicrob- amoxicillin/clavulanic acid appeared as effective
ial agents are summarised in table VII. Amoxicil- as penicillin ± dicloxaciUin in adult patients with
lin/clavulanic acid produced clinical and micro- bite wounds (Goldstein et al. 1987b).
Amoxicillin/Clavulanic Acid: An Update 287

In the comparison with cefaclor by Jaffe et al. 4.5 Sexually Transmissible Diseases
(1985), amoxicillin/clavulanic acid produced a
lower rate of persistence in children with S. aureus 4.5.1 Gonorrhoea
infection (14% vs 67%) and a lower rate of super- The increasing incidence of penicillinase-pro-
infection (0% vs 16%). ducing N. gonorrhoeae (PPNG) has decreased the
In comparisons with other agents, amoxicillin/ usefulness of the once highly effective first-line
clavulanic acid was generally as well tolerated, al- treatments of uncomplicated gonorrhoea with pro-
though Pien (1983) and Fleisher et al. (1983) noted caine penicillin, and ampicillin or amoxicillin with
a significantly higher rate of mild gastrointestinal probenecid. An increasing incidence of spectino-
effects compared with cefaclor. mycin resistance is also decreasing the effective-

Table VII. Summary of clinical trials comparing amoxicillin/clavulanic acid (AMX/CA) with other antimicrobial agents in skin and soft
tissue infections

Reference Design Patient type a Dosage [no. of pts Duration Results (% responding)b
evaluated] (days)
clinical bacteriological

Amoxicillin (AMX)

~l
Dagan & Bar- r,db Children, non- AMX/CA 40/10mg/kg/day tid 10 96
David (1989) bullous impetigo [24] p < 0,01
. AMX 40 mg/kg/day tid [25] 80 76c
Umemura et al. r,db Adults, wound AMX/CA 250/125mg tid [92) 7 76
(1983) infection AMX 250mg tid [97) 63
85t
71 P < 0.05
Cefuroxime axetll (CXM)
Watts et al. (1987) r,nb Adults, wound AMX/CA 250/125mg tid [56J 5 98 83
infection CXM 250mg bid [58) 97 63
CXM 500mg bid [57] 96 67

Cefaclor (CEC)
Fleisher et al. r,nb Children, various AMX/CA 20/5 mg/kg/day 5-10 86 100
(1983) skin and soft tid [21)
tissue infection CEC 20 mg/kg/day tid (20) 90 90
Jaffe et al. (1985) r,db Children, various AMX/CA 20/5 mg/kg/day tid 10 82 95
skin and soft [22)
tissue infection CEC 20 mg/kg/day tid [21) 81 65
Parish & Aten r,db Adults, various AMX/CA 500/125mg tid [21) 5-10 81 80
(1984) skin and soft CEC 500mg tid [17) 88 89
tissue infection
Pien (1983) r,db Adults, various AMX/CA 250 or 500/125mg tid 5-10 100 75 or 100d
skin and soft [1)
tissue infection CEC 250 or SOOmg bid [43) 100 63 or 70d
Risser et al. r.db Children, various AMX/CA 20/5 mg/kg/day tid 10 97 100
(1985) skin and soft [37J
tissue infection CEC 20 mg/kg/day tid (27) 100 100

a All patients were un selected with respect to pathogen resistance.

b Response rates usually determined immediately at the end of therapy and clinical response usually defined as cure or improve-
ment.
c Response after 5 days.
d Bacteriological response rates given for respective dosages; the higher dosage was administered for more severe infections.
Abbreviations: bid = twice daily; tid = 3 times daily; r = randomised; nb = nonblind (or not stated); db = double-blind.
288 Drugs 39 (2) 1990

ness of this drug. First-line treatment failures may effective (p < 0.05) than a single intramuscular in-
always be effectively treated with alternative agents jection of kanamycin 2000mg. Single oral doses of
such as parenteral cephalosporins. However, much amoxicillin/clavulanic acid 3000/250mg and ce-
effort has been directed towards finding a suitable furoxime axetil 1500mg, both in combination with
first-line agent that equals the original efficacy of probenecid Ig, were similarly effective.
earlier treatments by covering PPNG and spec-
tinomycin-resistant strains. Additionally, the ideal 4.5.2 Other Sex ually Transmissible Diseases
drug should be simple to administer as a single oral Fast et al. (1982) studied the efficacy of amox-
dose and inexpensive, particularly important con- icillin 500mg, and amoxicillin/clavulanic acid 500/
siderations in developing countries. 125mg and 500/250mg, all administered 3 times
Numerous recently published noncomparative daily for 7 days, in 64 patients infected with {3~
(table VIII) and comparative (table IX) studies have lactamase-producing strains of H. ducreyi. Whereas
allowed a more definitive conclusion concerning all amoxicillin-treated patients failed to respond,
the place of amoxicillin/clavulanic acid in the all but 2 treated with amoxicillin/clavulanic acid
treatment of uncomplicated gonorrhoea. were cured Clinically and bacteriologically. In an-
Administration of a single oral dose of amoxi- other study (Ndinya-Achola et al. 1986), admin-
cillin/clavulanic acid 3000/125 or 250mg did not istration of a single dose of amoxicillin/clavulanic
provide adequate cure rates in patients with PPNG acid 3000/250mg or 2 doses 24 hours apart proved
infections. However, administration of 2 doses 4 ineffective in the treatment of chancroid caused by
to 6 hours apart or a single dose with concomitant H. ducreyi. However, administration of 500/250mg
administration of probenecid Ig usually achieved 3 times daily for 3 days cured 42 of 44 patients
satisfactory cure rates including coverage ofPPNG with chancroid.
strains. Also, administration of repeated doses for Symonds and Biswas (1986) have reported that
several days or a single dose in combination with amoxicillin/clavulanic acid was 100% effective in
procaine penicillin G proved extremely effective treating 6 patients with vaginosis caused by Gard-
regimens with cure rates approaching 100%. Thus, nerella vagina/is. Clearly, data from larger num-
administration of 2 oral doses of amoxicillin/cla- bers of patients are required before any conclu-
vulanic acid 3000/250mg at a 4- to 6-hour interval sions can be drawn.
would appear to provide the most practical of the Van der Meijden et al. (1987), in a preliminary
regimens investigated, although administration of study in a limited number of patients, found that
a single dose in combination with probenecid Ig amoxicillin/clavulanic acid was less effective than
would appear almost as effective and probably more metronidazole in patients with clue cell-positive
practical when patient compliance might be a discharge. They considered amoxicillin/clavulanic
problem. It should be noted that the 3000/125mg acid should be reserved for pregnant women and
and 3000/250mg formulations of amoxicillin/cla- those showing metronidazole intolerance, until re-
vulanic acid are under clinical evaluation and not sults from larger studies are available.
yet generally available.
In comparative studies clavulanic acid im- 4.6 Obstetric and Gynaecological Infections
proved the cure rate of amoxicillin, when admin-
istered in combination with probenecid, by ex- In an early study, Mayer et al. (1982) reported
tending the antibacterial activity to PPNG strains. 100% clinical success (76% complete, 24% partial)
A single oral dose of amoxicillin/clavulanic acid in 37 women with pelvic inflammatory disease
3000/250mg was significantly (p = 0.01) more ef- caused by in vitro susceptible organisms after oral
fective than a single intramuscular injection of pro- treatment with amoxicillin/clavulanic acid 500/
caine penicillin G 2.4 x 106 U, and 2 doses of 125mg 3 times daily for 9 to 36 days. Similar re-
amoxicillin/clavulanic acid 4 hours apart were more sults were seen in Japanese studies involving small
Amoxicillin/Clavulanic Acid: An Update 289

Table VIII. Summary of noncomparative studies investigating amoxicillin/clavulanic acid (AMX/CA) in the treatment of uncomplicated
gonorrhoea

Reference Patient Treatment Cure rate in assessable patients

type
total PPNG non-PPNG

Bee & Phang 5 genital AMX/CA 3000/250mg 2 oral doses 69/69 (100%) 27/27 (100%) 42/42 (100%)
(1985) 6 hours apart
De Silva et al. 5 or 2 AMX/CA 3000/250mg single oral 109/110 (99%) Only 1 PPNG
(1984) anogenital dose strain (cured)
Kim et al. 5 genital (a) AMX/CA 3000/250mg + 48/50 (96%) 23/25 (92%) 25/25 (100%)
(1987) probenecid 1000mg single oral dose
(b) AMX/CA 250/125mg tid orally for 51/51 (100%) 20/20 (100%) 31/31 (100%)
5 days
Lawrence & 5 or 2 (a) AMX/CA 3000/125mg + 97/100 (97%) 11/13 (85%) 86/84 (98%)
Shan son anogenital probenecid 1000mg single oral dose
(1985) (b) AMX/CA 3000/250mg + 140/144 (97%) 5/7 (71%) 134/136 (99%)
probenecid 1000mg single oral dose
Lim et al. 5 genital AMX/CA 3000/125mg single oral 31/35 (89%) 11/15 (73%) 20/20 (100%)
(1982) dose
Lim et al. 5 + 2 genital (a) AMX/CA 3000/125mg single oral 64/74 (86%) 8/11 (73%) 56/63 (89%)
(1986) dose
(b) AMX/CA 3000/250mg single oral 70/79 (89%) 10/14 (71%) 60/65 (92%)
dose
(e) AMX/CA 3000/250mg + 87/90 (97%) 20/23 (87%) 67/67 (100%)
probenecid 1000mg single oral dose
(d) AMX/CA 3000/250mg 2 oral 93/97 (96%) 28/29 (97%) 65/68 (96%)
doses 4 hours apart
(e) AMX/CA 250f125mg + 87/88 (99%) 28/29 (97%) 59/59 (100%)
probenecid 1000mg single oral dose
+ procaine penicillin G 4.5 x 106 U
1M
(f) AMX/CA 500/250mg + 57/58 (98%) 19/20 (95%) 38/38 (100%)
probenecid 1000mg single oral dose
+ procaine penicillin G 4.5 x 106 U
1M
Munday et al. 5 or 2 AMX/CA 3000/250mg single oral 144/161 (89%) 5/8 (62%) 139/153 (91%)
(1985) anogenital dose
Osato et al. 5 or 2 PPNG AMX/CA 500/250mg tid orally for 121/121 (100%)
(1986) genital 2-5 days
Osoba et al. 5 genital AMX/CA 3000/250mg + probenecid 92/92 (100%) 73/73 (100%) 21/21 (100%)
(1986) 1000mg single oral dose

Abbreviations: tid = 3 times daily; 1M = intramuscularly; PPNG = penicillinase-producing N. gonorrhoeae.

numbers of patients (Cho et al. 1983; Takase et al. 95 were clinically cured, 3 markedly improved, and
1982). Obwegeser et al. (1989) more recently re- 2 failed. After 2 weeks' follow-up 71/79 assessable
ported the results of treatment of 100 unselected patients were cured while 3 had a relapse or infec-
consecutive patients with salpingitis using amoxi- tion. Other recent studies in patients with pelvic
cillin/clavulanic acid 1000/200mg 6-hourly for 3 inflammatory disease have indicated that addition
days parenterally followed by 1000/250mg 8-hourly of doxycycline to amoxicillin/clavulanic acid im-
for a further 6 days orally. At the end of therapy proved efficacy by extending the antibacterial ac-
290 Drugs 39 (2) 1990

Table IX. Summary of studies comparing amoxicillin/clavulanic acid (AMX/CA) with other antimicrobial agents in uncomplicated
gonorrhoea

Reference Patient type Dosage Cure rate in assessable patients

(study design)
total PPNG non-PPNG

Amoxicillin (AMX)
Key et al.
(1985)
<3 or 'I anopharyngo-
genital (r.db)
AMX/CA 3000/125mg +
probenecid l000mg single
101/108
(94%) 8110
(80%) j 95/98
(97%)
oral dose p < 0.01
AMX 3000mg + probenecid 97/112 0/13 97/99
l000mg single oral dose (87%) (0%) (98%)

.
Procaine penicillin G (P)

~IM l
Latif et al. <3 genital (nr.nb) AMX/CA 3000/250mg single
(1984) oral dose (91%)= 0.01
P 2.4 x 106 U 1M 42/57 P
(74%)

Kanamycin (K)

93ml
Lim et al. <3 genital (nr.nb) AMX/CA 3000/250mg 2 oral 28/29 65/68
(1984) doses 4 hours apart (96%) 005 (99%) (96%)
K 2000mg 1M 83/95 P < . 20/24 63/71
(87%) (83%) (89%)

Cefuroxlme axetil (CXM)

Schift et al. <3 or 'I genital (r.nb) AMX/CA 3000/250mg + 185/191 7/11 178/180
(1986) probenecid 1000mg single (97%) (64%) (99%)
oral dose
CXM 1500mg + probenecid 184/185 10/10 174/175
1000mg single oral dose (99%) (100%) (99%)

Abbreviations: r = randomised; nr = not stated as being randomised ; db = double-blind; nb = nonblind; 1M = intramuscularly;

PPNG = penicillinase-producing N. gonorrhoeae.

tivity to include C. trachomatis infection (Henry- 3 or 4 times daily or triple therapy (amoxicillin or
Suchet & Douyeb 1987; W01ner et al. 1988). ampicillin 3000 to 4000 mg/day plus 1 of genta-
In 3 brief reports, amoxicillin/clavulanic acid micin 160mg, dibekacin 150mg or tobramycin
has been stated to be at least as effective as a stand- 150mg daily plus metronidazole 1500 mg/day)
ard triple combination of ampicillin/an aminogly- intravenously. Oral administration of amoxicillinj
coside/metronidazole in patients with postpartum clavulanic acid 2000/500 to 3000j750mg daily or
infection (Fernandez-Roblas et al. 1988), pelvic in- amoxicillin or ampicillin 2000 to 3000mg daily plus
flammatory disease or septic abortion (Green- metronidazole 1500mg daily commenced once an
Thompson et al. 1988), and salpingitis (Leng et al. adequate response was obtained. Tetracycline was
1988). These reports did not provide sufficient in- also given to patients with confirmed C. tracho-
formation to allow appropriate interpretation. matis infection. Clinical results were similar in both
However, other comparative studies have been treatment groups with 90% or more of patients
more adequately reported. Ciraru-Vigneron et al. achieving an 'excellent' or 'favourable' response.
(1989) compared amoxicillin/clavulanic acid with Similar results have been reported by Kervasdoue
a standard triple regimen in 152 patients with sev- (1987) and Tison et al (1988).
ere pelvic inflammatory disease. Initially, patients Houang et al. (1987) compared amoxicillin/cla-
were given amoxicillin/clavulanic acid 1000/200mg vulanic acid 500/250mg 3 times daily orally with
 Amoxicillin/Ciavulanic Acid: An Update 291

ampicillin SOOmg 4 times daily orally plus metro- lin/clavulanic acid. Bernard et al. (1989) observed
nidazole 400mg 3 times daily parenterally, each twice the rate of wound infection in patients sub-,
regimen administered for 7 days, in 60 patients with jected to colorectal surgery in conjunction with cef-
postoperative infections after gynaecological sur- oxitin prophylaxis compared with a group given
gery. The patients with abdominal wound infection amoxicillin/clavulanic acid: In a population of
achieved a better response to amoxicillin/clavu- paediatric patients; 6% of those given amoxicillin/
lanic acid, while the 2 regimens were comparable clavulanic acid developed postoperative wound in-
in patients with pelvic infection or persistent pyr- fections whereas the incidence rates in groups of
exia. patients administered metronidazole ,plus genta-
More comparative studies are required involv- micin or not given prophylactic therapy was 28%
ing large numbers of patients with gynaecological in each (Brereton et al. 1989). Chest infection oc~­
infection before any conclusion can be made con- cutired more frequently in biliary surgery patients
cerning the place of amoxicillin/clavulanic acid in given amoxicillin/clavulanic acid compared with
treatment. others on ceftriaxone prophylaxis, but the differ-
ence was not statistically significant (EI-Mufti et al.
1989).
4.7 Prophylactic Treatment Besides the above mentioned studies, there have
been a number of noncomparative and placebo-
controlled trials. Jurincic et at. (1987) administ~red
The results of studies comparing amoxicillin/
amoxicillin/clavulanic acid 2000/200mg intraven-
clavulanic acid with other antimicrobial agents as
ously as a single dose beforepi':ostate surgery in 30
prophylactic therapy are summarised in table X.
patients; no postoperative infectious complications
In general, amoxicillin/clavulanic acid was at least
were noted. Holl and Konradt (1988) 'administered
as effective as prophylactic regimens consisting of
2 intravenous prophylactic doses of amoxicillin/
a cephalosporin either alone (e.g. EI Mufti et al.
clavulanic acid 2000/200mg in 60 patients under-
1989; Playforth et al. 1987) or in combination with
going colon surgery; treatment was totally effective
·metronidazole (e.g. Friese et al. 1989; Tehan &
in 55 patients. Kuhn (1986) reported the results of
Whittaker 1989). Amoxicillin/clavulanic acid was
clearly superior to benzylpenicillin in prophylaxis prophylactic treatment with intravenous amoxicil-
against wound sepsis following limb amputation lin/clavulanic acid 1000 or 2000/200mg with vari-
because of sepsis (Huizinga et al. 1983) Most ofthe ous numbers of doses in 802 patients undergoing
studies summarised in table X involved patients different surgical procedures; treatment was suc-
undergoing various forms of abdominal surgery. cessful in 9S.S% of cases.
There were few statistically significant differences Raine et al. (1984) randomised 32 patients
between the prophylactic effects of amoxicillin/cla- undergoing major head and neck surgery to receive
vulanic acid and alternative agents on the inci- intravenous amoxicillin/clavulanic acid 1000/
dence of postoperative wound infections. Brown et 200mg at 4-hourly intervals for 12 doses or no
al. (1988) reported statistically significant results in treatment; the postoperative wound infection rate
favour of amoxicillin/clavulanic acid for operative was significantly lower in actively treated patients
site, abdominal and respiratory tract infections, (25% vs 75%, p < 0.025). Evans et at. (1988) ran-
duration of hospital stay, number of postoperative domised 46 renal failure patients undergoing major
antibiotic courses and surgical interventions for surgery to receive 2 intravenous doses of amoxi-
operative site infections. Metronidazole "alone did cillin/clavulanic acid 1000/200mg or no treatment;
not provide an adequate enough spectrum to cover no patients receiving amoxicillin/clavulanic acid
infections caused by Gram-negative bacteria, which developed a wound infection compared with 27%
mainly explains the superior result with amoxicil- of untreated patients (p < O.OS). Brackenbury and
292 Drugs 39 (2) 1990

Table X. Summary of randomised studies comparing amoxicillin/clavulanic acid (AMX/CA) with other antimicrobial agents in
prophylactic therapy

Reference Patient type Drug (doses) Results (% of patients developing infections)

[no. of pts assessed]

Abri et al. (1989) Colorectal surgery AMX/CA 2000/200mg IV x 1

42.3! 11.S~wound
[76] UTI
MZ SOOOmg IV + MTR SOOmg IV 27.1 lS.3~ infection
+ 1 [84]
Ashall et al. General surgery AMX/CA doses nr [128] 8.7 ~ wound
(198S) CZ + MTR doseshr [126] 7.8 infection 5
Bernard et al. Colorectal surgery AMX/CA 2000/200mg IV x 2
6.21 wound
(1989) [32]
13.8 infection (p < O.OS)
FOX 2000mg IV x 2 [29]
Bey tout et al. Gastrointestinal AMX/CA 1000/200mg x 3 [47]a 10 ~ major infectious
(1987) surgery GM 80mg + ORN 800mg x 2 14 complications 5
[43]a
Brereton et al. Abdominal AMX/CA 30 mg/kg IV x 7 [47]b
61 wound
(1989) surgery MTR 7.S mg/kg IV + GM 2 mgt 28 infection
(paediatrics) kg IV x 7 [36]e (p < O.OS, AMX/CA
No prophylaxis [32] 28 vs other groups)
AMX/CA 2000/200mg IV x 3
Brown et al.
(1988)
Hysterectomy
(mainly [138]
14 ~ overall infectious
abdominal) MTR 1000mg supp. x 3 [142]
33 ~ morbidity (p < 0.001)
Dieterich et al. Vascular surgery AMX/CA 2000/200mg IV x 2
wound o ~ other
(1989) [72]
FOX 200mg IV x 2 [69]
OJ
o infection 2.9 ~ infections
Dombrovicz & Hysterectomy AMX/CA 2000/200mg IV x 1[34] S. ~ O.Ol pelvic
UTI
Foidart (1988) CXM lS00g IV + MTR SOOmg IV 13.9S 2.7 S infection
Xl [36]
Drumm et al.
(198S)
Appendectomy AMX/CA 1000/200mg IV x 1
[11S]
11 ~ wound

MTR SOOmg IV x 1 [116] 18 ~ infection

EI Mufti &
Glessa (1988)
Cholecystectomy AMX/CA 1000/200 mg IV x 1
[SO] 26 ~ wound 2 ~ chest
CTX 2000mg IV X 3 [SO]
~ infection 4 ~ infection
EI-Mufti et al. Biliary surgery AMX/CA 1000/200mg IV Xl d
~chest

!
41 wound 12
(1989) (mainly [100]
cholecystectomy) CRO 2000mg IV x 1 [100]
4 infection 3 ~ infection
Friese et al. Gynaecological AMX/CA 2000/200mg IV x 1
4.0 O.Sl wound
(1989) surgery [199] UTI
infection
CXM lS00mg IV + MTR SOOmg 4.1 O.S
IV x 1 [196]
Hall et al. (1989) Colorectal surgery AMX/CA 1000/200mg IV x 2
[182]
GM 120mg IV x 2 + MTR
23

18
1 . overall In ectious
morbidity
f

lS00mg IV x 1 [177]
Huizinga et al. Limb amputation AMX/CA SOO/2S0mg oral x 7
9.7 ~wound
(1983) (due to sepsis) [31]
P O.S x 106 U oral x 9 [13] 69.3~sepsis (p < 0.001)
Amoxicillin/Clavulanic Acid: An Update 293

Table X. Contd

Reference Patient type Drug (doses) Results (% of patients developing infections)

[no. of pts assessed]

Menzies et al. 'Clean/potentially AMX/CA 1000/200mg x 1 [62]a 3 11

(1989) contaminated' MZ 5000mg x 1 [67]a 7 13
abdominal wound other infective
surgery8 infection complications
'Contaminated' AMX/CA 1000/200mg x 3 [63]a 16 27
abdominal MZ 5000mg x 3 [66]a 8 18
surgery!
Playforth et al. Abdominal AMX/CA 1000/200mg IV x 1 3.1! major 9.6! minor

I
(1987) surgery [353] infectious infectious
MOX 1000mg IV x 1 [186] 3.2 complications 8.6 complications
Tehan & Various AMX/CA 1000/200mg IV x 3
wound
Whittaker (1989) (gynaecological, [593] 88 infection
abdominal, CED 1000mg 1M + MTR 1000mg
vascular surgery) supp. x 3 [294]

a Route of administration not stated.

b Infants < 2 weeks old received 5 doses.
c Infants < 2 weeks old received 5 doses of gentamicin.
d Four patients undergoing laparotomy and biopsy received 2 additional doses at 6-hour intervals.
e Included cholecystectomy, gastrotomy and nephrectomy (noninfected).
Included gastrectomy, exploration of common bile duct, bowel resection and appendicectomy.
Abbreviations: CED = cefradine; CRO = ceftriaxone; CXM = cefuroxime; CTX = cefotaxime; CZ = cefazolin; FOX = cefoxitin;
GM = gentamicin; 1M = intramuscular; IV = intravenous; MOX = latamoxef (moxalactam); MTR = metronidazole; MZ = mezlocillin;
nr = not reported; ORN = ornidazole; P = benzylpenicillin; supp. = suppository; UTI = urinary tract infection.

Adams (1989) found that amoxicillin/clavulanic 4.8 Miscellaneous Studies

acid significantly decreased the rate of wound in-
fection compared with placebo in a double-blind There have been a number of studies of amox-
study involving 185 patients with animal bites. icillin/clavulanic acid besides those previously
Most studies of the prophylactic use of amoxi- mentioned in section 4. In general, these studies
cillin/clavulanic acid employed 1 or 2 intravenous did not provide sufficient information to evaluate
doses of 1000/200mg or 2000/200mg. Pollock et al. the drug's place in the treatment of these infec-
(1989) have recently reported the prophylactic ef- tions.
ficacy of amoxicillin/clavulanic acid administered Preliminary studies in patients with cystic fi-
either intravenously or subcutaneously at the site brosis indicate that amoxicillin/clavulanic acid may
of the proposed incision in patients undergoing ab- be effective in controlling S. aureus (Kiosz & Heil-
dominal surgery. Two groups, each of approxi- mann 1988) and H. in./luenzae infections (Penketh
mately 300 patients, received a single dose by I of et al. 1984).
the 2 routes. There were significantly fewer wound Yoshioka et al. (1987) compared amoxicillin/
infections in the group given amoxicillin/clavu- clavulanic acid and ciprofloxacin, both in combin-
lanic acid at the site of the incision (8.4%) com- ation with metronidazole, in a randomised trial in-
pared with patients who received the drug intra- volving 56 patients with intra-abdominal sepsis.
venously (15.9%). Other infective or noninfective The regimens were initially administered paren-
postoperative complications occurred to similar terally and then orally. 96.1% of patients receiving
extents in both groups. ciprofloxacin were cured or improved compared
294 Drugs 39 (2) 1990

with 89.3% receiving amoxicillin/c1avulanic acid. volving large numbers of patients with various
Parenteral followed by oral administration of infections, including those of the urinary tract, lower
amoxicillin/clavulanic acid was of similar clinical and upper respiratory tract, and skin and soft tis-
efficacy to a combination of penicillin G, netil- sue, i.e. the types of infections most frequently en-
micin and an imidazole in a study involving 64 countered by the general practitioner. Amoxicillin/
children with appendicular peritonitis. Recovery clavulanic acid produced clinical and bacteriolog-
rates were 86% with the former treatment and 97% ical response rates in excess of 70% depending on
with the latter (Schmitt et al. 1989). the nature and severity of the infection, and i,t was
Lippert (1982) showed that oral long term treat- significantly more effective than amoxicillin alone.
ment with amoxicillin/clavulanic acid 500/125mg Since that review there have been several general
twice daily improved all 10 patients with post-trau- practice studies which are worth mentioning.
matic wound infections. Jeffries et al. (1983) reported on 385 children
Bingen et al. (1987) found that serum bacteri- with a wide range of infections commonly encoun-
cidal drug concentrations in neonates with E. coli tered in general practice (mainly otitis media, ton-
septicaemia were achieved more rapidly with a sillitis, pharyngitis and bronchitis) who were treated
parenteral combination of cefotaxime plus netil- for 7 days with bodyweight adjusted · doses of
micin compared with amoxicillin/c1avulanic acid amoxicillin/c1avulanic acid. A successful clinical
plus netilmicin. response was achieved in 95% of the children. Bac-
Promising results were obtained in a small group teriological cure was documented in 67 of79 (84%)
of patients with chronic bone and joint infecrions cases where bacteria were isolated, and this in-
(3 months to 30 years duration) treated with amox- cluded 13 of 18 (72%) infections caused by ampi-
icillin/c1avulanic acid alone (n=6) or in a combin- cillin-resistant organisms. 60 patients (15.6%) re-
ation with other agents (n= 13) for a mean duration ported possible adverse effects, mainly mild
of 4.8 months. 16 patients remained cured after gastrointestinal disturbances; 10 patients (2.6%) had
long term follow-up, while 2 had reinfection and to be withdrawn from treatment because of ad-
persistence of Enterococcus faecalis infection oc- verse effects. The authors concluded that amoxi-
curred in another patient (Desplaces et al. 1989). cillin/clavulanic acid appeared suitable for paedi-
In a randomised study in 40 patients with non- atric infections in general practice.
puerperal breast abscesses (Casey & Walther 1983) Another general practice study involved 694
oral amoxicillin/clavulanic acid 500/1 25mg 3 times adults with upper or lower respiratory tract, urin-
daily and oral amoxicillin 750mg plus c1indamycin ary tract, and skin and soft tissue infections (Dav-
300mg 4 times daily, each administered for 10 days, ies et al. 1982). The patients were randomised un-
proved similarly effective, providing 95% and 100% der observer-blind conditions to receive amoxi-
success rates, respectively. cillin/clavulanic acid 250/125mg 3 times daily or
Studies in very limited numbers of patients have cotrimoxazole (trimethoprim l60mg + sulfame-
indicated that amoxicillin/clavulanic acid may have thoxazole 800mg) twice daily each for I week. The
potential in the treatment of Yersinia enterocolitica overall clinical response rate was similar in both
infection in thalassaemic patients (Kattamis et al. groups: 68.0% on amoxicillin/clavulanic acid ver-
1984) and in immunocompromised patients with sus 67.6% on cotrimoxazole. However, the clinical
Nocardia asteroides infection when combined with and bacteriological response rates tended to favour
amikacin (Goldstein et al. 1987a). amoxicillin/clavulanic acid when patients with pa-
4.9 General Practice Studies thogenic organisms isolated were analysed alone.
Adverse effects were reported in similar percent-
At the time of the previous review on amoxi- ages of patients (around 25%), and while amoxi-
cilIin/clavulanic acid in the Journal, several multi- cillin/c1avulanic acid caused significantly more
centre general practice studies were reported in- diarrhoea, cotrimoxazole caused more · nausea.
Amoxicillin/C1avulanic Acid: An Update 295

Thus, amoxicillin/clavulanic acid was as effective ciated with amoxicillin/clavulanic acid have been
and well tolerated as cotrimoxazole in adult gen- recently reported (Schneider et al. 1989; Van den
eral practice patients. Broek et al. 1988). There have been isolated re-
Amoxicillin/clavulanic acid 500/125mg twice ports of increases in blood urea nitrogen or serum
daily displayed similar efficacy to cefuroxime ax- transaminase, eosinophilia and leucopenia (Des-
etil 250mg twice daily when 488 general practice grandchamps & Schnyder 1987; Dubs 1985; Ellis-
patients with tonsillitis, bronchitis, otitis media or Pegler et al. 1982; Weber et al. 1984). A retrospec-
sinusitis were treated for 7 to 10 days. Clinical cure tive survey of reports submitted to the manufac-
or improvement was achieved in over 95% of turer or the US Food and Drug Administration over
patients with both treatments. Tolerability was also a 3-year period has identified 18 cases of hepatic
comparable with 6.5 to 7% of patients in each group dysfunction causally related to amoxicillin/clavu-
experiencing mainly gastrointestinal adverse ef- lanic acid. Seven of these patients had a predom-
fects (Stahl & Pappo 1989). inantly cholestatic syndrome. In 6 patients the con-
dition was classified as mixed cholestatic-
5. Adverse Effects hepatocellular and as hepatocellular in another 4.
The nature of hepatic injury was undefined in the
Croydon (1989) summarised the safety profile remaining patient. Following withdrawal of treat-
of amoxicillin/ciavulanic acid in clinical trials in- ment all patients recovered without complications
volving 9700 patients worldwide. Adverse effects (Reddy et al. 1989). Rahman (1987) suggested a
occurred in 13.1 % of patients and they primarily possible causal relationship between hyperkalae-
included gastrointestinal disturbances: diarrhoea mia and administration of amoxicillin/clavulanic
(4.1%), nausea (3.0%), vomiting (1.8%) and indi-
acid in a patient, although this was considered un-
gestion (1.6%). Hypersensitivity reactions in-
likely by Robinson (1988) and more probably
cluded: rash (1.1 %), 9 cases of urticaria and I case
caused by haemolysis of blood samples.
of anaphylaxis. Candida vaginitis and stomatitis
Macknin (1987) reported behavioural changes
occurred in I% of cases. In general, these effects
(increased irritability and aggression) in 4 paedi-
were mild and transient,and treatment discon-
atric patients receiving amoxicillin/clavulanic acid.
tinuation was infrequent (less than 3% of patients).
A number of studies have examined the effects
Data from clinical trials (section 4) have shown
that amoxicillin/clavulanic acid is as well tolerated of amoxicillin/clavulanic acid administration on
as other antimicrobial agents with which it has been faecal flora, and the development of resistance and
compared, although gastrointestinal effects may be superinfection, in healthy subjects and patients
more frequent with amoxicillin/clavulanic acid (Brumfitt et al. 1986; Borderon et al. 1985; Mit-
compared with orally administered cephalosporins termayer 1982; Motohiro et al. 1985c; Sunakawa
(sections 4.1.2 and 4.3.2). The frequency of gas- et al. 1985; Vlaspolder et al. 1987). In general, the
trointestinal adverse effects appears related to the administration of amoxicillin/clavulanic acid fa-
dosage of clavulanic acid administered (Crokaert voured colonisation by Enterobacteriaceae resist-
et al. 1982) and may occur more often in children ant to amoxicillin/clavulanic acid, staphylococci
(Simon 1985). Coadministration of food with were decreased, and there were no consistent
amoxicillin/clavulanic acid may decrease the in- changes in counts of Bacteroides spp., Pseudo-
cidence and severity of gastrointestinal adverse ef- monas spp., or yeast. Clostridium difficile was not
fects (Staniforth et al. 1982). detected. Vlaspolder et al. (1987), however, found
There have been infrequent reports of mild ele- yeast colonisation in 50% of patients receiving the
vations of serum transaminase levels in patients high prophylactic dosage of parenteral amoxicillin/
receiving amoxicillin/clavulanic acid (Ohkawa et clavulanic acid 1000/200mg 4 times daily for 10
al. 1983). Two cases of cholestatic hepatitis asso- days.
296 Drugs 39 (2) 1990

6. Dosage and Administration Amoxicillin/clavulanic acid might therefore be ex-

pected to find a similar therapeutic niche to that
Numerous formulations of amoxicillin/clavu- once held by amoxicillin, i.e. a broad spectrum
lanic acid are available worldwide. The usual dos- orally active agent which is particularly useful in
age for routine oral use in adult infections is 250/ general practice where antibacterial agents are fre-
125mg or 500/125mg 3 times daily, although in quently prescribed empirically.
Italy a dose of 875/125mg is administered twice or Clinical trials have shown that amoxicillin/cla-
3 times daily, depending on the severity of the in- vulanic acid is clinically and bacteriologically su-
fection. A number of parenteral preparations are perior to amoxicillin and at least as effective as
available which may be used to treat serious in- numerous other comparative agents (e.g. oral
fections or prophylactically (l or 2 doses) in patients cephalosporins, cotrimoxazole, doxycycline, ba-
undergoing surgery. Administration may be campiciIlin) in adults and children with the most
changed to the oral route after sufficient improve- common infections encountered in general prac-
ment has occurred in patients with serious infec- tice, i.e. urinary tract infections, upper and lower
tions initially treated intravenously. respiratory tract infections, otorhinolaryngological
A number of suspensions and syrups are avail- infections, and skin and soft tissue infections.
able for oral administration in paediatric patients. Amoxicillin/clavulanic acid appears to provide an
The recommended daily dose in children is in the excellent treatment for chancroid and is suitable
range 20 to 40 mg/kg, based on the amoxicillin for use in uncomplicated gonorrhoea, in particular
component. Doses towards the lower end of this providing activity against penicillinase-producing
range should be adequate in mild to moderate in- strains. Because of its broad spectrum of antibac-
fections while higher doses may be used against terial activity it is also appropriate for surgical pro-
more severe infections. phylaxis, comparing most favourably with a num-
In patients with renal failure the daily dosage ber of other frequently used regimens. It may
should be reduced or the interval between doses provide a more convenient treatment than some
increased (see section 3.4.1). triple regimens for obstetric and gynaecological in-
Amoxicillin/clavulanic acid should be admini- fections, but this requires further study.
stered together with food which does not alter bio- While it is clear that amoxicillin/clavulanic acid
availability but may decrease the incidence of gas- offers a therapeutic advantage over amoxicillin
trointestinal adverse effects. It should not be alone where there is a high prevalence of {3-lacta-
administered to patients with a known history of rnase-producing strains, in environments where
{3-lactam hypersensitivity, and if such reactions do these strains are not yet a major problem it may
occur during therapy the drug should be immedi- be more appropriate to continue with the use of
ately withdrawn and appropriate therapy insti- amoxicillin alone. This is particularly relevant
tuted. where cost may be a prime consideration. In ad-
dition, the gastrointestinal tolerability of amoxicil-
7. Place of Amoxicillin/Clavulanic Acid lin may be considerably reduced by the addition
in Therapy of clavulanic acid and some studies have shown
that children may exhibit very high rates of gas-
Clavulanic acid broadens the antibacterial spec- trointestinal intolerance. This may limit the use-
trum of amoxiciIIin by rendering {3-lactamase-pro- fulness of amoxicillin/clavulanic acid and needs to
ducing strains susceptible to amoxicillin. Thus, a be addressed in special studies. However, should
tried and proven antibacterial agent, whose use- its tolerability prove to be comparable to that of
fulness has tended to be compromised by the grow- amoxicillin alone and if {3-lactamase resistance
ing incidence of {3-lactamase resistance, is re-estab- continues to spread, as would be expected, amox-
lished for effective use in clinical practice. icillin/clavulanic acid will probably become in-
Amoxicillin/Clavulanic Acid: An Update 297

al. Comparison of Augmentin with co-trimoxazole for treat-

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Amoxicillin/Clavulanic Acid: An Update 299

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