clavulanic acid. An update of its antibacterial activity, pharmacokinetic properties and therapeutic use.

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 University Medical Center, New Orleans, Louisiana, USA; S.c. Aronoff, Section of Immunologic 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, Houston, Texas, USA; D. Felmingham, Department of Clinical Microbiology, University College Hospital, London, England; R. Fujii, Research Institute of Chemotherapy for Mother and Child, Tokyo, Japan; K. [shibiki, School of Medicine, Keio University, Tokyo, Japan; R.N. Jones, The Clinical Microbiology Institute, Tualatin, Oregon, USA; J. Kumazawa, Department of Urology, Kyushu University, Fukuoka, Japan; H.C. Neu, Columbia-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/clavulanic acid is clinically and bacteriologically superior to amoxicillin alone and at least as effective as numerous other comparative agents. such as orally administered cephalosporins. 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. otorhinolaryngological 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 Richmond and Sykes classes II to V (but not class I cephalosporinases), staphylococcal {3lactamase, and /3-lactamase produced by Bacteroides jragilis. C1avulanic acid, therefore, protects amoxicillin from inactivation by many /3-lactamases. As a consequence the antibacterial activity of amoxicillin has been restored at a time when the spread of resistance due to /3-lactamase production severely threatened its usefulness. Clavulanic 16 > 16 > 66 > 16 > 16

32

> 16

> 16

> 64 > 64

> 16 > 16 > 16 > 16 > 16 > 16 > 16 > 16

>64 2.0 64 > 64 1.0 8.0 > 64 > 64 64

+

8

> 64 64

vaLanitratus (18) Pseudomonas aeruginosa (30) Pseudomonas spp.a (38) Streptococcus pyogenes (20) Streptococcus pneumoniae (20) Streptococcus faecalis (30) Methicillin-resistant Staphylococcus aureus (12) Methicillin-sensitive Staphylococcus aureus (57) Ampicillin-sensitive Haemophilus influenzae (24) Ampicillin"resistant HFfemophilus influenzae (24) Neisseria meningitidis (25)

a

> 16

> 16 > 16

> 16 > 16 > 16

> 16

> 64 > 64 0.03 0.25 1.0 32

8.0

0.25 2.0 1.0

0.12

Including P. acidovorans (4), P. cepacia (5), P. fluorescens (7), P. maltophila (4), P. putida (6) and P. stutzeri (12).

tion but with the addition of clavulanic acid many strains of M. tuberculosis, M. fortuitum, M. bovis and M. kanasaii are susceptible, although M. chelonei remains resistant (Casal et al. 1986; Cynamon & Palmer 1983; Santos et al. 1987; Swenson et al. 1985; Wong et al. 1988). fJ-Lactamase production is also a major mechanism of resistance to amoxicillin for Nocardia brasiliensis, but such strains become susceptible with the addition of clavulanic acid (Wallace et al. 1987). Some bacteria

in the Corynebacterium 02 group are resistant to amoxicillin/clavulanic acid (Soriano et al. 1987). Although the fJ-lactamase enzymes produced by the Bacteroides group resemble class I fJ-lactamases, they are usually inhibited by clavulanic acid (Reading & Farmer 1981). Clavulanic acid thus renders most amoxicillin-resistant strains of B. fragitis, B. distasonis, B. bivius, B. ,ovatus, B. thetaiotaomicron, B. vulgatus, B. melaninogenicus and B. oratis susceptible (Barry et al. 1986; Bourgault & Lamothe 1986; Brown 1984; Burnat et al 1989; Garcia-Rodriguez et al. 1989; Lacroix et al. 1984; Lamothe et al. 1984; Wust & Wilkins 1978). Many amoxicillin-resistant strains of other anaerobic genera may also be made susceptible by the addition of clavulanic acid, including various species of Clostridium, Fusobacterium, Peptococcus and Peptostreptococcus (Brazier et al. 1985; Oeforges et al. 1984; Oerriennic et al. 1987; Goldstein & Citron 1986; Rodloff et al. 1984). Amoxicillin/clavulanic acid did not totally inhibit the growth of Chlamydia trachomatis strains in vitro although there was a reduction in the number of viable organisms (Bowie 1986). Clavulanic acid enhances the activity of amoxicillin against many Gram-negative bacteria where resistance is caused by fJ-lactamase production. These species commonly include: E. coli, Proteus mirabilis, Klebsiella pneumoniae, Citrobacter diversus, Proteus vulgaris, various species of Salmonella and Shigella (Megraud & Gavinet 1987), Yersinia enterocolitica (Megraud & Gavinet 1987), Haemophilus injluenzae(Jorgensen et al. 1988; Lapointe & Lavallee 1987; Yoger et al. 1981), Haemophilus ducreyi (Girouard et al. 1981; Sanson-Le Pors et al. 1983), Branhamella catarrhatis (Ahmad et al. 1984; Alvarez et al. 1985; Fernfmdez-Roblas et al. 1988), Neisseria gonorrhoeae (Goh et al. 1985; Obaseiki-Ebor et al. 1985; Tapsall et al. 1987; Tsuji et al. 1986; Van Klingeren & Van Wijngaarden 1981; Waghorn et al. 1986), different species of Campylobacter (c. jejuni and C. coli) [Gaudreau et al. 1987; Lambert et al. 1986; Van der Auwera & Sconeaux 1985], and Aeromonas (A. caviae, A. hydrophila and A. sobria) [San Joaquin et al. 1986]. It has also recently been shown that clavulanic acid

Amoxicillin/C1avulanic Acid: An Update

renders Pseudomonas pseudo mallei susceptible to amoxicillin; this species is generally resistant to amoxicillin because of i1-lactamase production (Chau et al. 1986;' Leelarasamee et al. 1988). In the latter study a 4: I ratio of amoxicillin/clavulanic acid was used. It should be pointed out that the resistance of many Gram-negative bacteria to amoxicillin is unaffected by the addition of clavulanic acid including Enterobacter species, Serratia marcescens, Ci-

trobacter freundii , Morganella morganii, Providencia species, Acinetobacter species, and Pseudomonas species (with the notable exception of P. pseudo mallei). The susceptibility of organisms to amoxicillin/ clavulanic acid has also been examined in many studies involving up to tens of thousands of clinical isolates from general practice and hospital patients (e.g. Beale & Sutherland 1989; De Mouy et a11989; Focht et al. 1988; Nunes da Costa & Goncalves 1989; Verbist 1983). In general, just over 90% of clinical isolates (including Gram-negative, Grampositive aerobic and anaerobic strains) were susceptible to amoxicillin/clavulanic acid compared with about 60 to 70% of isolates susceptible to amoxicillin or ampicillin alone. When compared with other reference antibacterial agents (trimethoprim, cotrimoxazole, sulphonamides, nalidixic acid, nitrofurantoin), amoxicillin/clavulanic acid gave the highest percentage of susceptible isolates. 2.2 Bactericidal Activity In Vitro The bactericidal effects of amoxicillin/clavulanic acid have been studied in in vitro models, many of which were designed to mimic in vivo serum, urine or blister fluid pharmacokinetics. These studies have confirmed that amoxicillin/clavulanic acid exerts bactericidal effects at clinically achievable concentrations against i1-lactamase-producing strains of B. catarrhalis, E. coli, K. pneumoniae and S. aureus (Boon et al. 1982b; Griffin et al. 1989; White et al. 1982, 1985; Wilson & Hunter 1986; Yourassowsky et al. 1987, 1988). These studies have also shown that the bactericidal effects are particularly rapid (usually within a few

271

hours) and significantly more rapid than cefotaxime against various species of Enterobacteriaceae (Wilson & Hunter 1986). As with all i1-lactams the bactericidal effect was due to the formation of nonviable spheroplasts (e.g. Yourassowsky et al. 1987). Comparisons of MIC and MBC (minimum bactericidal concentration) values for amoxicillin/clavulanic acid have shown that MBC values were often the same as MIC values, usually within I dilution and only rarely up to 2 dilutions higher for various isolates, including Haemophilus spp. (Jorgensen et al. 1986; Lapointe & Lavallee 1987), Bacteroides spp. (Bourgault & Lamothe 1986; GarciaRodriguez et al. 1989) and M. tuberculosis (Cynamon & Palmer 1983). The bactericidal effects of amoxicillin/clavulanic acid observed against both extracellular and intracellular cultures of L. pneumophila (Stokes et al. 1989b) warrant further investigation. Thomas et al. (1985) studied the bacteriostatic and bactericidal titres of serum from 7 healthy subjects given amoxicillin/clavulanic acid 500/125mg or flucloxacillin 500mg each given 3 times daily. Bacteriostatic and bactericidal titres were similar at both peak and trough concentrations against i1lactamase-producing S. aureus, and the antistaphylococcal activity of amoxicillin/clavulanic acid was significantly higher than that of flucloxacillin. Bingen et al. (1987) studied the serum bactericidal activity of 20 neonates with E. coli sepsis treated with intravenously administered amoxicillin/clavulanic acid 100/10 mg/kg or cefotaxime 100 mg/kg daily, both regimens in combination with netilmicin 4 mg/kg/day. While serum bactericidal activity was similar with both regimens, the mean minimum bactericidal time was longer in the patients receiving amoxicillin/clavulanic acid (3.9 vs 1.2 hours; p < 0.01). Decazes et al. (1987) determined the bactericidal activity of cerebrospinal fluid of patients with purulent meningitis given intravenous amoxicillin/clavulanic acid 200/20 mg/kg/day against a i1-lactamase-producing strain of H. influenzae. 10 of 12 tested samples lacked bactericidal activity in vitro, and this was found to be caused by poor penetration of clavulanic acid into cerebrospinal fluid at the doses used in this study.

272

2.3 Factors Affecting In Vitro Activity Measurement of in vitro susceptibility by the agar plate dilution method is not generally affected by culture media, pH from 6 to 8, and addition of 50% human serum (Comber et al. 1980; Hunter et al. 1980). However, the activity of clavulanic acid may be reduced by the presence of supplements used to support the growth of fastidious organisms such as H. influenzae, N. gonorrhoeae and B. catarhalis (Fernimdez-Roblas et al. 1988; White et al. 1983). The rapid determination of susceptibility using standard discs of amoxicillin 20~g and clavulanic acid lO~g gives a good approximation of susceptibility (Comber et al. 1980), although this disc does not accurately predict the susceptibility of some N. gonorrhoeae strains (Kumamoto 1982). For highly susceptible organisms 3~g discs are available (see section 2.1). In addition, disc testing using Oxoid Diagnostic Sensitivity Test Agar gives smaller inhibitory zones and a falsely low index of susceptibility compared with Mueller-Hinton Agar (Brown & Ribeiro 1982). Increasing inoculum size from 102 or 10 3 to 106 cfu (colony-forming units)/ ml increases the MIC value about2-fold for H. influenzae, E. coli and Klebsiella spp., and increasing the inoculum from 10 3 to 106 cfu/ml may increase the MIC value by 10 to 100 fold for penicillin-resistant S. aureus (Comber et al. 1980; Hunter et al. 1980: Van Klingeren & Dressens-Kroon 1979). 2.4 Activity In Vivo Since publication of the previous review in the Journal, many additional studies in mice and rats have confirmed that amoxicillin/clavulanic acid is more effective than amoxicillin alone in various experimental infections caused by iJ-Iactamaseproducing organisms (Aronoff et al. 1986; Beale et al. 1989; Boon et al. 1982b; Brown & Ribeiro 1982; Catherall & Mizen 1984; Catherall et al. 1989; McColm et al. 1986; Roholt & Keiding 1987; Yoger et al. 1981). Such infections have included: pyelonephritis due to E. coli and M. morganii; subcutaneous abscesses due to S. aureus, K. pneumoniae, and a mixture of E. coli and B. fragilis;

Drugs 39 (2) 1990

bacteraemia due to H. influenzae type b; pneumonia due to K. pneumoniae; endocarditis due to S. aureus; and intraperitoneal infection due to S. aureus, E. coli, E. aerogenes, K. pneumoniae, P. mirabilis, P. vulgaris, C. freundii and M. morganii. There have been several studies comparing the activity of amoxicillin/clavulanic acid with other antimicrobial agents in experimental animal infections. In subcutaneous abscesses due to B. fragilis, amoxicillin/clavulanic acid was as effective as metronidazole, as effective or more effective than clindamycin, and more effective than cefoxitin (Boon et al. 1982a; Brown & Ribeiro 1982). In addition, amoxicillin/clavulanic acid was more·effective than cefuroxime, metronidazole or combinations of metronidazole with cefuroxime or ampicillin in the treatment of mixed E.coli and B. fragilis subcutaneous infection (Beale et al. 1989). Amoxicillin/clavulanic acid was also as effective as vancomycin and more effective than cloxacillin or flucloxacillin in experimental endocarditis due to S. aureus (Cantoni et al 1989; Catherall et al. 1989). However, in pneumonia produced by K. pneumoniae amoxicillin/clavulanic acid was less effective than either ceftazidime, cefotiam or kanamycin (McColm et al. 1986). Clavulanic acid has proved effective in protecting amoxicillin from degradation by iJ-Iactamaseproducing bacteria in animal models of peritonitis and subcutaneous infection (Boon et aI, 1982a; Catherall & Mizen 1984) and in the human bladder (Goldstein et al. 1979; Lindeque 1982). 2.5 Development of Resistance Lim et al. (1989) showed that regular prescription of amoxicillin/clavulanic acid for 6 years in a rural region of the Netherlands produced no change in the resistance pattern of clinical isolates of E. coli and P. mirabilis. Further retrospective studies are required to confirm that no change in resistance has occurred in clinical isolates. Labia et al. (1982) applied the Szybalski technique with an amoxicillin/clavulanic acid gradient to produce a strain of E. coli that was resistant to the combination. The mechanism of resistance was caused by the hyperproduction of the Amp C-type

273

Amoxicillin/Clavulanic Acid: An Update

chromosomal cephalosporinase which is present in all strains of E. coli. However, using the same technique with another strain of E. coli, which produces a penicillinase-type ~-lactamase that was resistant to amoxicillin but susceptible to amoxicillin/ clavulanic acid, it was not possible to isolate resistant variants. This was only possible by applying chemical mutagenesis. From these results the authors anticipated that the combination of amoxicillin/clavulanic acid would exert a lower selective pressure on bacteria than amoxicillin alone. Martinez et al. (1987) have reported an increase in the rate of amoxicillin/clavulanic acid-resistant E. coli in 2 hospitals in Madrid. The resistance was caused by overproduction of a plasmid-mediated TEM-I ~-lactamase. Williams et al. (1988) subsequently confirmed a similar pattern of resistance during an outbreak of multiresistant E. coli in a London hospital. These reports of resistance appeared to arise from single clones. French and Ling (1988) have reported a high rate of amoxicillin/ clavulanic acid-resistant E. coli in hospitals in Hong Kong. The isolates did not arise from a single clone; the mechanism of resistance was not investigated. Whether these 'pockets' of resistance signal a future trend which may limit the usefulness of amoxiciIIin/clavulanic acid against E. coli infections remains to be seen.

3. Pharmacokinetic Properties At the time of the previous review on amoxiciIIin/clavulanic acid in the Journal, only the relatively basic pharmacokinetic properties of the drug combination had been established. Since then, many studies have been published which give a much more detailed pharmacokinetic profile. Various microbiological assays have been used to measure amoxicillin and clavulanic acid concentrations in body fluids and tissues (Adam et al. 1982; Reading & Cole 1977; Yokota et al. 1982). An enzymatic technique has also been described (Cull mann & Dick 1985), but more accurate measurements of amoxiciIlin, clavulanic acid and their breakdown products are obtained by high performance liquid chromatography (HPLC) [Foulstone &

Reading 1982; Haginaka et al. 1981b, 1986; Uno et al. 1982]. There is good correlation between HPLC and microbiological assays (Foulstone & Reading 1982). Clavulanic acid is degraded in serum at a rate of 4.2 %/h at room temperature and 11.2 %/h at 3rC (Munch et aI. 1981). Thus, clavulanic acid concentrations determined in body fluids and tissues may be considerably underestimated due to degradation, which may partly explain the differences between some studies. This is exemplified by the approximately 3-fold difference in clavulanic acid sputum concentration depending on storage conditions in the study by Gould et al. (1988). Also, the half-life of clavulanic acid in urine at 37°C varied between 1.3 and 9.2 hours depending on pH (English et al. 1978). No degradation occurred during storage at -55°C for 2 weeks (Yokota et al. 1982). 3.1 Absorption and Plasma Concentrations Combining clavulanic acid with amoxicillin does not influence the absorption or other pharmacokinetic variables of either drug after the oral administration of single doses to healthy subjects (Adam et ai. 1982; Haginaka et ai. 1981a; Hoflken et aI. 1981; Nakagawa et ai. 1982; Uno et ai. 1982). Table II gives examples of mean Cmax (maximum plasma concentration) values for amoxiciIIin and clavulanic acid following the oral administration of single doses alone and in combination to healthy subjects. Mean Cmax values were directly related to the dose administered (Jackson et al. 1982). While some authors have found considerable interindividual variation in absorption and peak plasma concentrations of clavulanic acid (Homer & Dalhoff 1980; Munch et al. 1980) others did not (Adam et al. 1982; Hoflken et al. 1981; Saito 1981). Mean t max (time to Cmax ) values were about 1 hour for both amoxicillin and clavulanic acid (e.g. Jackson et ai. 1982; Nakagawa et al. 1982). No accumulation of amoxicillin or clavulanic acid appears to occur after repeated dose administration in healthy subjects (Nakagawa et al. 1982; Wise et al. 1984). Nilsson-Ehle et al. (1985) found the mean ab-

Drugs 39 (2) 1990

274

Table II. Mean peak plasma concentrations of amoxicillin and clavulanic aci.d after oral administration of single doses alone and in combination to healthy subjects Dose (mg) amoxicillin

clavulanic

amoxicillin

acid

125 250 62.5 125 125 250 375 250

References

clavulanic acid

2.6 4.0-5.3 5.9-10.8 10.2-19.7

125 250 500 1000

125 250 500 500 750 1000

Mean Cmax (mg/L)

2.3 3.1-4.4 8.0-9.7 5.5-10.0 5.6 13.6

2.3-3.3 1.9-4.3 1.3 2.1-3.0 3.5-3.9 1.1-5.2 5.4 5.6

3 3,8,9 1,3,4,5,9,11,12 3-5,11 1,8 5,7 10 2,8,10 1,5 2,5,6,8,10,12,13 8 5

References: 1 Adam et al. (1982); 2 Ball et al. (1980); 3 Croydon & Sutherland (1970); 4 Gordon et al. (1972); 5 Jackson et al. (1982); 6 Kosmidis et al. (1981); 7 Munch et al. (1981); 8 Nakagawa et al. (1982); 9 Neu & Winshell (1970); 10 Saito (1981); 11 Spyker et al. (1977); 12 Staniforth et al. (1983); 13 Wise et al. (1984).

solute bioavailability for clavulanic acid was 60% when comparing oral with intravenous administration of amoxicillin/clavulanic acid SOO/12Smg in healthy subjects. There was wide interindividuaf variation (31.4 to 98.8%), indicating highly variable absorption from the gastrointestinal tract. Jackson et a1. (1982) found similar plasma concentration profiles for amoxicillin and clavulanic acid after the oral administration of amoxicillin/ clavulanic acid 500/125mgas either film-coated tablets, dispersible tablets or a syrup to healthy subjects. The same was also found following oral administration of a single dose of amoxicillin/clavulanic acid 2S0/62:Smg as 2 paediatric syrup formulations and as a dispersible tablet. Croydon et al. (1981) found mean Cmax values of 105.4 and 28.S mg/L, respectively, following t~e bolus injection of amoxicillin/clavulanic acid 1000/ 200mg in healthy subjects. Under the same conditions, Staniforth et al. (1984) reported values of about 90 and 45 mg/L, respectively. At the end of

a 30-minute infusion of amoxicillin/clavulanic acid 2000/200mg in healthy subjects, mean Cm ax values were 108.3 and 13.9 mg/L, respectively (Staniforth et a1. 1984). Coadministration of amoxicillin/clavulanic acid with food, milk, antacids, cimetidine, ranitidine or pirenzepine did not lead to any pharmacokinetic interaction in healthy subjects which would be likely to be of any significance during clinical usage. No statistically significant effect OIl' absorption was noted during coadministration with food (Eshelman & Spyker 1978; Jackson et a1. 1982; Nakagawa et a1. 1982; Staniforth et a1. 1982, 1985), milk (Staniforth et a1. 1985), pirenzepine or ranitidine (Deppermann et a1. 1988). Coadministration with magnesium hydroxide and/or aluminiumhydroxide antacids caused a minor but statistically significant decrease in t max and increase in Cmax values for amoxicillin but not clavulanic acid; areas under the plasma concentration versus time curves (AUC) were not affected (Deppermann et al. 1988; Staniforth et al. 1985). Coadministration .wi,th cimetidine produced statistically significant increases in C max and area under the plasma concentration-time curve (AUC) values (about 15 to 30%) for both amoxicillin andclavulanic acid, an effect which was not seen if amoxicillin/clavulanic acid was administered intravenously (Staniforth et a1. 1985). These authors postulated that cimetidine may increase intraluminal pH and therefore the solubility of amoxicillin and clavulanic acid. Coadministration of amoxicillin/clavulanic acid with probenecid produced a statistically and clinically significant increase in plasma amoxicillin concentration, but did not affect that of clavulanic acid (Staniforth et al. 1983, 1984). 3.2 Distribution Clavulanic acid is less lipid soluble than amoxicillin and has a volume of distribution (V d) of about 2S% of bodyweight (e.g. Bennett et al. 1983; Nakagawa et al. 1982; Nilsson-Ehle et al. 1985). In vitro, clavulanic acid is 22% bound to serum proteins at concentrations from 1 to 100 mg/L (Hunter et a1. 1980). Amoxicillin alone or in combination

275

Amoxicillin/Ciavulanic Acid: An Update

with clavulanic acid does not displace bilirubin from cord serum in vitro until the concentration is about 10 times higher than normal therapeutic concentrations. Therefore, the drug is unlikely to displace bilirubin from albumin when administered to jaundiced human neonates (Davies 1985). The distribution of amoxicillin and clavulanic acid into human body tissues and fluids after their concomitant administration has been well studied and the results are summarised in table III. In general, adequate antibacterial concentrations were achieved in most tissues and fluids, as well as in urine, which is the major route of elimination (see section 3.3). Particularly low concentrations of clavulanic acid were found in some studies for sputum and tonsil tissue, as well as for CSF from patients with bacterial meningitis. These may have been the result of a low dosage administered and/ or inadequate protection of samples against degradation (see beginning of section 3). Yamaguchi et al. (1982) have found that, despite the low concentration of clavulanic acid measured in sputum, coadministration of clavulanic acid with amoxicillin was justified in patients with respiratory tract infection due to /3-lactamase-producing organisms, as sufficient protection against degradation of amoxicillin occurred to significantly increase sputum amoxicillin concentrations compared with the administration of amoxicillin alone. The penetration of amoxicillin/clavulanic acid into CSF after administration of maximum recommended doses would appear insufficient for adequate treatment, as CSF lacked consistent bactericidal activity against /3-lactamase-producing organisms in vitro (Decazes et al. 1987). Following administration of a single oral dose of amoxicillin/clavulanic acid 250/125mg, both components cross the placenta to achieve peak concentrations of up to about 50% of corresponding maternal serum samples in umbilical cord serum and amniotic fluid (Matsuda et al. 1982; Takase et al. 1982). From the limited available data it appears that amoxicillin and clavulanic acid enter breast milk in only very small quantities (Matsuda 1982; Takase et al. 1982; von Kobyletzki & Primavesi 1987).

3.3 Metabolism and Excretion The mean elimination half-lives of amoxicillin and clavulanic acid are both about 1 hour after the oral administration of various single doses alone or in combination to healthy subjects (e.g. Adam et al. 1982; Hoffken et al. 1982; Jackson et al. 1982; Nakagawa et al. 1982; Nilsson-Ehle et al. 1985; Wise et al. 1984). Nakagawa et al. (1982) found a mean total clearance of about 25 L/h for both amoxicillin and clavulanic acid after the oral administration of various single doses either alone or in combination to healthy subjects. After the intravenous administration of a single dose of amoxicillin/clavulanic acid 500jl25mg to healthy subjects, Nilsson-Ehle et al. (1985) determined mean plasma and renal clearance for clavulanic acid at 14.9 and 6.3 L/h/ 1. 73m 2, respectively, and the mean renal clearance of clavulanic acid was 6.9 L/h/1.73m 2 after oral administration of the same dose. Staniforth et al. (1983) found a mean renal clearance of 5.3 L/h for clavulanic acid after the oral administration of a single dose of amoxicillin/clavulanic acid 500/ 250mg to healthy subjects. After oral administration of various single doses of amoxicillin and clavulanic acid alone or in combination to healthy subjects, amoxicillin is excreted largely unchanged in urine with a mean 6hour recovery of intact drug of about 60 to 80%, while clavulanic acid is more extensively metabolised and mean 6-hour urinary recovery of intact drug is about 30 to 50% (e.g. Adam et al. 1982; Jackson et al. 1982; Nakagawa et al. 1982; NilssonEhle et al. 1985; Wise et al. 1984). Nilsson-Ehle et al. (1985) found that mean 12-hour urinary recovery of clavulanic acid was higher (49%) after intravenous administration compared with oral administration (36%) after a single dose of amoxicillin/ clavulanic acid 500/125mg in healthy subjects. Wise et al. (1984) found a mean 8-hour urinary recovery of 66% and 27%, respectively, after a single oral dose of amoxicillin/clavulanic acid 500/250mg in healthy subjects, but after repeating the dose 3 times daily for 4 days recovery was reduced with mean 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

Blister fluid Bile Peritoneal fluid

Synovial fluid

Non-infected ascites CSF: noninflamed meninges CSF: inflamed meninges Fat Vein Artery Bone

Status of subjects

Dose (amoxicillin/ clavulanic acid in mg) [no. of sUbjects]8

Time after doseb

amoxicillin

clavulanic acid

amoxicillin

clavulanic acid

Reference

500/250 [6] 875/125 [6] 250/125 [4]

3h 2.3-2.5h 4h

3.8 6.31 1.1

2.0 3.23 0.2

72 112

55 87

23 28 18

1000/200 IV [30]

2h

>5

> 1

84

66

22

1000/200 IV [6]

14.6

3.6

65

86

12

19.9

3.8

104

81

9

41 18.0d

5 1.75d

100

100

1000/200 IV qid [6]

30-75 min 20-165 min 30 min 2h

Diagnostic

500/250 [4]

4h

0.34

0.19

8

22

16

Bacterial meningitis Vascular surgery Vascular surgery Vascular surgery Hip replacement Hip replacement Hip replacement Surgery

2000/200 IV [21] 200/20 per kg [11] 1000/200 IV [15]

2h 1-2h 30 min

2.25 3.83 5.1

0.25 0.32 0.7

5.8 17.9 12.8

8.4 20.9 7.5

2 4 6

1000/200 IV [15]

30 min

7.5

1.2

18.8

12.9

6

1000/200 IV [15]

30 min

4.8

1.6

12.0

17.2

6

2000/200 IV [14]

30-60 min 31 min

6.4

0.7

7.2

13.1

5

3.6

0.5

7.1

5.9

9

35-55 min 1.7-2.6h

26.0/ 18.22e 8.9-9.7

2.32/1.6e 0.01-2.1

26.4

0.6

73

39

14

0.77 11.3 14.1 1.2-1.7

0.15 0.4 0.4 0.4-0.7

32 56 47-59

10 16 26-45

19 21 21 3

16.3 17.6

0.5

46 69

14 26

21

1000/200 IV [7] 1000/200 IV [15]

2000/200 IV qid [9] 2000/200 IV [7]

2000/200 IV [10]

Surgery Female genital Gynaecological tissue' surgery

875/125 [31] 1000/200 IV [18] 1000/200 IV tid [15] 500/250 [10]

Ovary

1000/200 IV [18] 1000/200 IV qid [15]

15-120 min 3h 1h 1h 126-200 min 1h 1h

875f125 [23]

3h

mucosa

Tissue or fluid/ serum concentration ratio ("!o)

Healthy RTI T-tube drainage Abdominal surgery Elective laparoscopy Hip replacement Joint effusion Cirrhotic

Perianal abscess pus Prostate Surgery

Middle ear

Peak tissue or fluid concentration (mg/kg or mg/L)c

Gynaecological surgery Surgery

1000/200 IV [17]

0.7 0.4

17 8

26

21

19

277


Table III. Contd

Tissue/fluid

Gingiva

Status of subjects

Dose (amoxicillin/ clavulanic acid in mg) [no. of subjects]a

Sputum

Saliva Bronchial mucus Bronchial washings Pulmonary Pleural fluid Pleuritic fluid

Reference

Peak tissue or fluid concentration (mg/kg or mg/L)C

Tissue or fluid/ serum concentration ratio (%)

amoxicillin

clavulanic acid

amoxicillin

clavulanic acid

0.9

0.6

54

19

20

ENT infection

250/125 [4]

60-90 min 60-90 min 2h

ENT infection ENT infection Surgery Bronchitis Bronchitis Bronchitis Bronchitis RTI RTI RTI RTI Carcinoma diagnosis Carcinoma diagnosis Surgery Surgery Pulmonary surgery Pleurisy

250/125 [4] 500/250 [3] 875/125 [22] 500/250 bid [14] 500/250 [3] 875/125 [10] 1000/250 [10] 250/125 [3] 500/250 [3] 500/250 tid [13] 500/250 tid [13] 1000/200 IV [12]

2h lh 4h NR lh 2-4h 0-8h 3-4h 3-4h lh lh NR

0.4 1.0 0.87 0.31 0.44 1.31 0.92 < 0.02 0.1 0.26 0.12 1.78

1000/200 IV [12]

NR

0.45

0.1

875/125 [32] 2000/200 [10] 1000/250 [13]

3h 54 min 4h

2.56 34.1 6.9

0.56 2.3 3.1

40 75

23 139

19 27 15

500/250 [4]

4h

5.0

2.4

119

282

16

Oral surgery

250/125 [6] 500/250 [6]

Maxillary sinus mucous membrane Tonsil

Time after dose b

0.7

0.7

28

21

20

0.3

0.2

10

11

13

0.2 0.5 0.17 0.25 0.92 0.79 0.16

14 31

12 15

8.3

18

16.8

8.2

6.7 3.1

8.8 17.0

13 10 19 7 16 19 25 24 24 11 11 7

()9

09 0.23 0.44 0.35

7

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-nosethroat; 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

ever, Nakagawa et al. (1982) found no change after the oral administration of amoxicillin/clavulanic acid 250/ 125mg 3 times daily for 1 week in healthy subjects. Clavulanic acid appears in urine faster than amoxicillin and is excreted by glomerular filtration; its excretion is therefore unaffected by probenecid. Amoxicillin, however, is excreted mainly by tubular secretion; concomitant probenecid administration therefore delays excretion and increases plasma concentrations of amoxicillin (Staniforth et al. 1983, 1984). The majority of amoxicillin is excreted unchanged, although some hydrolysis of the j3-lactam ring occurs giving rise to penicilloic and penamaldic acids as major metabolites, which are also excreted in urine (Haginaka et al. 198Ia). As mentioned at the beginning of section 3, clavulanic acid is extensively degraded in biological material at normal body temperature. The fate of clavulanic acid has, however, been little studied in humans. Administration of radiolabelled clavulanic acid to animals showed that approximately equal proportions of the radiolabel are recovered in urine, faeces and respired air, while only about 1% was excreted via bile (Jackson et al. 1982). These authors postulated that the j3-lactam ring of clavulanic acid was hydfOlysed with subsequent decarboxylation, yielding l-amino-4-hydroxybutan-2-one as a major metabolite. 3.4 Effects of Disease and Age on Pharmacokinetics Studies have reported the effects of renal impairment (section 3.4.1) and gastrointestinal disease (section 3.4.2) on the pharmacokinetics of amoxicillin/clavulanic acid. In addition, disposition has been studied using paediatric formulations (section 3.4.3). 3.4.1 Renal Insufficiency Several studies have indicated that the pharmacokinetics of amoxicillin/clavulanic acid are progressively affected by increasing renal impairment (Dalet et al. 1984; Horber et al. 1986; Jackson

Drugs 39 (2) 1990

et al. 1984; Usuda et al. 1982). The effects are well exemplified by Horber et al. (1986) who studied the disposition after single doses of amoxicillin/ clavulanic acid 500/1 25mg orally and 1000/200mg intravenously. The volume of distribution and the systemic availability were independent of renal function, while total body, renal and nonrenal clearance of amoxicillin and clavulanic acid decreased with increasing renal impairment. As the decrease in total body clearance was more pronounced for amoxicillin than for clavulanic acid, there was an increase in the amoxicillin: clavulanic acid AUC ratio from 4.9 for a glomerular filtration rate (GFR) > 75 ml/min/1.73m2 to 14.7 for patients undergoing haemodialysis. Dosage recommendations were formulated based on the standard doses of amoxicillin/clavulanic acid 500/125mg orally and 1000/200mg intravenously which would prevent undue accumulation of amoxicillin while maintaining adequate plasma clavulanic acid concentrations. After an initial loading dose, repeated doses shOuld be administered every 4 hours to patients with normal renal function (GFR > 75 ml/min/1.73m2), every 8 hours for those with a GFR from 35 to 75 ml/min/ 1.73m2, and every 12 hours for those with a GFR from 10 to 35 ml/min/1.73m2. Studies in patients with chronic renal failure have shown that clinically significant extraction of both amoxicillin and clavulanic acid occurs during haemodialysis (Dalet et al. 1984; Davies et al. 1988; Horber et al. 1986; Slaughter et al. 1984; Usuda et al. 1982). Dosage supplementation would appear necessary at the end of a haemodialysis session but specific guidelines are difficult to define, as these would depend on both the duration of haemodialysis and its timing after the administration of amoxicillin/clavulanic acid. 3.4.2 Gastrointestinal Disease Gastrointestinal disorders may change the pharmacokinetics of both amoxicillin and clavulanic acid. Celiac disease has been reported to decrease the absorption of amoxicillin (Neu 1979). The absorption of amoxicillin, when given alone or in combination with clavulanic acid, was delayed and

279


t max was prolonged in patients who have undergone vagotomy and pyloroplasty. However, AUC remained unchanged (Farrell et al. 1981).

3.4.3 Age Many studies have examined the pharmacokinetic disposition of amoxicillin/clavulanic acid administered either orally or intravenously as a paediatric formulation in children with proven or suspected bacterial infections. Several Japanese studies have examined a granule formulation of amoxicillin/clavulanic acid in a 2 : 1 ratio following oral administration of total single doses ranging from 7.5 to 20 mg/kg (Haruta et al. 1985; Motohiro et al. 1985a; Nakazawa et al. 1985; Nishimura et al. 1985; Sato et al. 1985). Other studies have examined liquid or syrup formulations of a 4 : 1 ratio of amoxicillin/clavulanic acid after single or repeated doses of 6.6/1.7 to 20/5 mg/kg (Begue et al. 1982; Nelson et al. 1982; Schaad et al. 1986; Van Nierkerk et al. 1985), while Schaad et al. (1983) studied disposition after intravenous administration of a single dose of 20/5 mg/kg. In general, the pharmacokinetic profile of amoxicillin and clavulanic acid in children paralleled that in adults. Mean pharmacokinetic variables were the same as in adults, indicating similar patterns of absorption and excretion. Some of the lower doses gave relatively low plasma concentrations of amoxicillin and clavulanic acid, which might prove therapeutically inadequate (e.g. Nelson et al. 1982). Adequate plasma drug concentrations were attained with minimum doses of either 10/2.5 or 10/5 mg/kg, depending on the formulation ratio, and maintained with these doses repeated at 6- to 8-hour intervals.

4. Therapeutic Trials Numerous clinical trials have been published since the earlier review in the Journal. Many were comparative studies and these allow a better definition of the place of amoxicillin/clavulanic acid in the treatment of different types of infections. Unless otherwise specified, clinical trials of amoxicillin/clavulanic acid have almost invariably

enrolled patients who were unselected with respect to the susceptibility or resistance of the infecting pathogen. Treatment was thus usually administered empirically, closely paralleling the clinical picture as presents in general practice. In most trials, amoxicillin/clavulanic acid was administered orally. Those studies using other routes of administration are specified. Whenever possible the dosages of amoxicillin/clavulanic acid are each specified, e.g. 250/125mg refers to the dose of amoxicillin and clavulanic acid, respectively. 4.l Urinary Tract Infections Probably the most extensive clinical experience with amoxicillin/clavulanic acid has been gained in the treatment of urinary tract infections, and a recent review specifically addresses this application (Gasser et al. 1987). 4.1.1 Noncomparative and DosecFinding Studies Since the previous review on amoxicillin/clavulanic acid in the Journal, numerous noncomparative and dose-finding studies have been published in paediatric (AI Roomi et al. 1984; Fink & Swoboda 1982; Kattamis et al. 1982; Principi et al. 1988; Roca et al 1989; Ruberto et al 1989) and adult patients (Abbas et al. 1984; Agrawal et al. 1987; Brumfitt & Hamilton-Miller 1984; Crokaert et al. 1982; Dalet & Del Rio 1984; Derluyn 1982; Dickie & Lang 1986; Iravani & Richard 1982; Karachalios & Georgiopoulos 1984; Leng 1982; MatosFerreira & Corte Real 1988; Mayer et al. 1982; Nakazawa et al. 1983; Stein et al. 1982; Umbach et al. 1982; Van Erps et al. 1982; Viniaker et al 1989). In unselected patients, cure rates were about 95% and 60 to 80% in patients with uncomplicated and complicated urinary tract infection, respectively. Similar cure rates were also seen in studies which specifically studied infections caused by amoxicillin-resistant or t1-lactamase-producing bacteria (e.g. Abbas et al. 1984; Crokaert et al. 1982; Dalet & Del Rio 1984; Leng 1982). Amoxicillin/clavulanic 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 Patient typeS

Dosage [no. of pts evaluated]

Duration (days)

Complicated,

AMX/CA 250/125mg tid [28] AMX 250mg tid [24]

5

unselected

Martinelli et al. r,db

Uncomplicated,

AMX/CA 250/125mg tid [13]

9

(1981) Ohkawa et al.

selected C Complicated,

AMX 250mg tid [8] AMX/CA 1000/500mg daily [114]

5

unselected

AMX 1000mg daily [120]

AMX/CA 250/125mg tid [27] SXTf [28]

7

AMX/CA 250/125mg tid [24] SXT 160/800mg bid [28] AMX/CA 250/125mg tid [44] SXT 160/800mg bid [38]

4-9

r,sb

Uncomplicated, unselected Uncomplicated, selected d Recurrent, uncomplicated, selected e Mixed,

r,nb

unselected Uncomplicated,

Reference

Design

Results (% responding)b clinical

bacteriological

87

90

43

33

Amoxicillin (AMX) Gallacher et al. (1986)

r,db

r,db

(1983) Cotrimoxazole Ancill et al. (1987) Bailey et al. (1983) Brumfitt & HamiltonMiller (1985) Flavell Matts et al. (1985) Karachalios

(SXT) r,sb r,nb r,nb

75 43

t

P

85~ P 25 < 0.01

34

96t 64 P < 0.06 83 100 ~ P

7

84f 97 P

AMX/CA 250/125mg tid [26] SXT 160/800mg bid [26]

7

96

AMX/CA 250/125mg tid [54]

10

85 100

100 88

95 83

(1985a)

unselected

SXT 160/800mg bid [50]

Cefaclor (CEC) r,sb Gurwith et al. (1983) Iravani & r,db Richard (1986)

Uncomplicated, unselected Uncomplicated,

AMX/CA 250/125mg tid [30] CEC 250mg tid [36]

10


10

Cefuroxime axetil (CXM) Williams et al. r,nb Uncomplicated, (1987) unselected

AMX/CA 250/125mg tid [89] CXM 250mg bid [140]

5

97 97

70 72

Cefalexin (CN) Pedler & Bint r,nb (1985)

AMX/CA 250/125mg tid [31] CN 250mg tid [27]

7

76 60

74

Cefatrizine propylene glycol (CFT) Kawada et al. r,db Complicated, (1983) unselected

AMX/CA 250/125mg tid [147] CFT 250mg qid [150]

5

Pivmecillinam/pivampicillin (PVM/PVA) O'Dowd et al. r,nb Uncomplicated, (1984) unselected

AMX/CA 250/125mg tid [28] PVMWVA 200/250mg [29]

5

a b c d e

unselected

Bacteriuria in pregnancy, unselected

100

= 3 times daily; qid = 4 times daily; r = randomised;

t

= 0.039

< 0.05

P

= 0.08

~ P < 0.001

87 72 96 92

58 37

72 57

77

~ P < 0.01

79~ P 61

nb

< 0.01

75 85

Unselected = no selection of patients according to resistance or susceptibility of pathogens. Methods of calculating response rates varied widely between studies. Amoxicillin-resistant pathogens only included. Resistance to test drug reason for,exclusion (similar on both drugs). 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 blind; db = double-blind.

< 0.05

71

= nonblind (or not stated); sb = single-

Amoxicillin/ Clavulanic Acid: An Update

siella spp., Citrobacter spp., P. mirabilis, S. epidermidis, S. aureus and S. faecalis , and less effective against infections caused by Enterobacter and Pseudomonas spp. Not unexpectedly, Pseudomonas was a frequent source of reinfection in patients with complicated infection and reduced efficacy was associated with the pres~nce of an indwelling catheter or multiple pathogens in such patients. Amoxicillin/c1avulanic acid was usually administered 8-hourly for 7 to 10 days using either a 2 : I or 4 : I formulation; single doses of 250/125, 500/ 125 and 500/250mg being most commonly used in adults, with bodyweight-adjusted doses used in children. A regimen of 875/125mg twice daily has also been used. While increasing the dose did not appear to improve the cure rate in uncomplicated infection, the higher doses appeared more effective in patients with complicated infection. In a pilot study Dickie and Lang (1986) found that a single dose of amoxicillin/c1avulanic acid 3000/250mg was effective in the treatment of uncomplicated cystitis, but the high dosage proved unpalatable and produced a high incidence of gastrointestinal adverse effects. Mayer et al. (1982) found that amoxicillin/c1avulanic acid was effective in the treatment of urinary tract infection in pregnant women and was well tolerated by the mother and fetus. 4.1.2 Comparative Studies The results of major comparative clinical trials of amoxicillin/c1avulanic acid are summarised in table IV. Treatment with amoxicillin/c1avulanic acid, usually at a dosage of250/125mg 3 times daily for 4 to 10 days, produced clinical and bacteriological response rates of about 70 to 100%, the response being dependent on the severity of infection, complications, and method and timing of assessment. More favourable response rates were achieved with uncomplicated infection and where assessment was made immediately at the end of therapy without an adequate follow-up to determine relapses and reinfections. It should be emphasised that amoxicillin/c1avulanic acid was administered 'blind' (i.e. without withdrawing patients

281

who had a pathogen resistant to the combination) in the majority of studies. Amoxicillin/c1avulanic acid was clearly superior to amoxicillin alone, although it tended to produce more adverse effects. Most studies showed that amoxicillin/c1avulanic acid was statistically superior to cotrimoxazole both clinically and bacteriologically. Also, cure was faster in those patients who did respond on amoxicillin/c1avulanic acid compared with cotrimoxazole (mean 3.2 vs 4.8 days, p = 0.004) [Flavell Matts et al. 1985]. However, some studies showed that cotrimoxazole was superior at a statistically significant level (Bailey et al. 1983; Brumfitt & Hamilton-Miller 1985). The reason was clear for the latter study: the selected nature of the patient population, which excluded 53% of enrolled patients on cotrimoxazole compared with only 6% on amoxicillin/c1avulanic acid because of pathogen resistance or known hypersensitivity to the drug. Amoxicillin/c1avulanic acid was as well tolerated as cotrimoxazole. Amoxicillin/c1avulanic acid was clinically and bacteriologically at least as effective as cefaclor, cefuroxime axetil, cefalexin and pivmecillinamjpivampicillin, but was statistically superior to cefatrizine propylene glycol. With respect to tolerability, amoxicillin/c1avulanic acid was usually equivalent to these comparative agents, although it produced more adverse effects and hepatic enzyme test abnormalities compared with cefaclor in the study by Iravani and Richard (1986). However, this study also showed that reinfection, relapse and superin~ fection were more frequent with cefaclor. There have been several other comparative studies not included in table IV because of inadequate reporting, limited numbers of patients or their retrospective nature which has limited their value. Begue et al. (1987) reported that intravenous followed by oral amoxicillin/c1avulanic acid was as effective as intravenous followed by oral amoxicillin plus intramuscular netilmicin in infants and children with acute pyelonephritis. Knothe et a1. (1985) found that ofloxacin was more effective than amoxicillin/c1avulanic acid in patients with lower and upper urinary tract infection. In a retrospective 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

Amoxicillin (AMX) Benard et al. r,db (1982) r,sb Jensen et al. (1988)

Patient type a


Duration Aesults (% responding)b (days) clinical bacteriological

Mainly acute on chronic bronchitis Children with chronic obstructive pulmonary disease plus ampicillin-sensitive H influenzae Mostly chronic

AMX/CA 1000/250mg bid [34] AMX 1000mg tid [16] AMX/CA 50/12.5 mg/kg/day tid plus probenecid 250-750 mg/day [30] AMX SO mg/kg/day tid plus probenecid 250-7S0 mg/day [36] AMX/CA 250/125 mg qid [148] AMX 259mg qid [127]

8

= 0.03

57

70

59

57

14

83~ P < 0.05 72

67 58

10

90 29

87f P < 0.01 31

AMX/CA 250/125mg tid [31] BAC 800mg bid [28]

7

90 71

10

Acute and acute on chronic bronchitis

AMX/CA 500/125mg tid [18] PVM/PVA 200/250mg bid [19] PVM/PVA 400/500mg bid [19] AMX/CA 250/125mg tid [193] PVM/PVA 200/250mg bid [195]

28 26 37 94 94

Acute on chronic bronchitis

AMX/CA 250/125mg bid [15] DO 200mg then 100mg od [15]

10

60 26

Various upper and lower infections

AMX/CA 250/125mg tid [379] OT 250mg qid [369]

7

88 84

Josamycin (JM) r,nb Gaillat et a!. (1987)

Chronic

AMX/CA 400/100mg tid [16] JM 500mg tid [16]

10-15

100~ P < 0.01 75

Erythromycin (E) Pariente r,nb (1987)

Chronic

AMX/CA 1600/400 mg/day [79] E 2000 mg/day [86]

10

87 76

Acute on chronic bronchitis

AMX/CA 1000/250mg tid [20] CPO 500mg bid [20]

10-12

70 70

Acute upper infection

AMX/CA 250/125mg tid [188] CXM 250mg bid [175] AMX/CA 250/125mg tid [323] CXM 500mg bid [331]

5

98 97 93 94

Miki et al. (1983)

r,db

Phenoxymethylpenicillin (PV) Kaplan & r,nb Children with group A AMX/CA 40 mg/kg/day [21] PVc [24] Johnson Streptococcus acute (1988) infection failed on PV Bacampicillin (BAC) Renton et al. r,nb (1984)

Acute bronchitis

Pivmecillinam/pivampicillin (PVM/PVA) r,nb Acute on chronic Beumer & bronchitis Sips (1984) McGhie et al. (1986)

r,sb

Doxycycline (DO) Ulmer & r,nb Zimmermann (1981) Oxytetracycline (OT) Boston et al. r,sb (1986)

Ciprofloxacin (CPO) Schmidt et al. r,nb (1989) Cefuroxime axetil (CXM) Hebblethwaite r,nb et al. (1987) Mayhew r,sb (1987)

Lower infections

14

88f 62 P

7-10

7

83 58 74

72 73 90 90

283


Table V. Contd Reference

Design

Cefixime (CFM) Beumer (1989) r,nb

Cefaclor (CEC) r,nb Penn et al. (1983)

Patient type a

Lower infections

Acute on chronic

Cefuroxlme (CXM) followed by cefalexin (CN) Chronic lower O'Donovan et r,nb al. (1987)

infection

Duration Results (% responding)b


(days)

AMX/CA 500/125mg tid [30] CFM 200mg bid [30]

14


> 5

AMX/CA 1000/200mg tid IV for 2 days then orally [106]

7

CXM 750mg tid IV for 2 days

clinical

bacteriological

74

52 54

71

86 80

100

93! P < 0.05 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 stated); sb

= twice daily; tid = 3 times daily; = single-blind; db = double-blind.

and Osman (1988) found very similar clinical and bacteriological success rates in patients with recurrent upper urinary tract infection treated with 1 of the following regimens: oral amoxicillin/clavulanic acid 250/125mg 3 times daily for 10 days; oral rifampicin 600mg plus trimethoprim 160mg once daily for 10 days; intramuscular sulbactam 500mg plus ampicillin Ig twice daily for 5 days; and oral 'pivampicillin 125mg plus pivmecillinam 100mg 3 times daily for 7 days. Hart et al. (l981) studied 56 patients with mostly complicated urinary tract infection, caused by gentamicin-resistant Klebsiella. They noted similar rates of cure and recurrence with the following regimens: amoxicillin/clavulanic acid 250/125mg orally 3 times daily for 5 days; cefradine 500mg orally 4 times daily with and without mecillinam 400mg orally 3 times daily for 7 days: cefuroxime 750mg intramuscularly 3 times daily for 5 days; and amikacin 7.5 mg/kg twice daily intravenously or intramuscularly for 5 days. Recently, Abbas et al. (1988) reported clinical response rates of 85.1% and 91.6% in over 250 general practice patients with acute urinary tract infection treated with amoxicillin/clavulanic acid

qid

= 4 times daily; r = randomised;

nb

= nonblind (or not

250/125mg 3 times daily or ciprofloxacin 250mg twice daily for 5 days, respectively. 4.2 Respiratory Tract Infections 4.2.1 Noncomparative and Dose-Finding Studies Most of the noncomparative studies published over the past decade included only limited numbers of patients (Aigner et al. 1984; Beeuwkes & Rutgers 1981; Bisetti et al 1987; Bonsignore et al 1989; Borgo et al 1989; Bruna et al 1989; D' Adda et al 1989; Fink & Swoboda 1982; Galleri et al 1988; Gooch et al. 1985; Havard et al. 1982; Karachalios 1985b; Maesen et al. 1987; Micillo et al 1987; Mouzinho et al 1989; Palermo et al 1987; Saroglou et al. 1982; Thomley et al. 1986; Wallace et al. 1985; Yamaguchi et al. 1982). Clinical success rates were usually about 80 to 90%. With the exception of Italian studies, which employed a treatment regimen of 875/125mg twice daily, dosages of 250/ 125mg 3 times daily were routinely used in less severe infections, increasing to 500/250mg 3 times daily in patients with more severe, recurrent or l

284

chronic lower respiratory tract infection. Also, in the latter more severe infections some studies used parenteral administration of amoxicillin/clavulanic acid during the first 2 or 3 days of treatment followed by oral administration (e.g. Aigner et al. 1984; Maesen et al. 1987). In children, lower dosages were used in accordance with the manufacturers' recommendations (e.g. Fink & Swoboda 1982; Gooch et al. 1985). When isolated, the most frequently occurring pathogens were H. injluenzae, B. catarrhalis, S. pneumoniae and K. pneumoniae, which were eradicated with similar success rates. However, one study which performed a follow-up examination one week after treatment reported relapse of infection in 14 of 20 patients; /3-lactamaseproducing B. catarrhalis was the infecting organism in 5 of these patients (Maesen et al. 1987).

4.2.2 Comparative Studies Amoxicillin/clavulanic acid has been compared with many other antimicrobial agents in patients with respiratory tract infections (table V). The patients in these trials were almost invariably treated 'blind', i.e. they were not selected with respect to resistance of the pathogen to amoxicillin/ clavu1anic acid or the comparative agent. Bacteriological response rates were frequently not determined because of the methodological difficulties involved in isolating the causative bacteria. The clinical response rate (usually defined as cure or improvement at the end of treatment) with amoxicillin/clavu1anic acid was generally 80 to 100%. Higher response rates (usually cures) were found fot the less severe infections, i.e. acute upper respiratory tract infection in outpatients, usually after treatment with the lower dosage of 250/125mg 3 times daily. Patients with more severe infection, e.g. chronic infection of the lower respiratory tract in compromised inpatients, received high dosages of up to 3000/600mg daily and clinical response was more frequently determined as improvement rather than cure. The clinical response to amoxicillin/clavulanic acid was superior to amoxicillin alone at a statistically significant level in 2 studies (Benard et al. 1982; Miki et al. 1983). However, Jensen et al.'

Drugs 39 (2) 1990

(1988) found similar rates of cure with amoxicillin alone or combined with clavulanic acid in children with chronic obstructive pulmonary disease plus ampicillin-sensitive H. injluenzae: the bacteriological cure rate for H. injluenzae tended to be higher with amoxicillin/clavulanic acid, and when polymicrobial infections were present amoxicillin/clavulanic acid produced a significantly superior bacteriological response rate (86% vs 47%, p < 0.05). Amoxicillin/clavulanic acid was superior to josamycin (Gaillat et al. 1987) and cefuroxime followed by cefalexin (O'Donovan et al. 1987). Also, in comparison with oxytetracycline in general practice patients (Boston et al. 1986), it produced a higher rate of 'good' responses (64% vs 51 %, p < 0.001). In other comparisons, amoxicillin/clavulanic acid was at least as effective as bacampicillin, pivmecillinam/pivampicillin, doxycycline, erythromycin, ciprofloxacin, cefuroxime axetil, cefixime and cefaclor. In children with acute group A streptococcal infection who had previously failed with phenoxymethylpenicillin, amoxicillin/clavulanic acid produced a more favourable clinical response and a statistically significantly greater bacteriological response rate than phenoxymethy1penicillin (Kaplan & Johnson 1988). In general, amoxicillin/clavulanic acid appeared to be at least as well tolerated as the other agents with which it was compared. 4.3 Otorhinolaryngological Infections

4.3.1 Noncomparative Studies Studies have been conducted in paediatric and adult patients with otorhinolaryngological infections, including tonsillitis, otitis, pharyngitis, sinusitis, laryngitis etc. (e.g. Amendola et al. 1989; Catalano et al. 1988; Cohen et al. 1989; Esposito et al. 1989; Fior et al. 1989; Gehanno & Simonet 1989; Hatano et al. 1982; Iwasawa 1982; Kawamura et al. 1983; Le Clech & Bourdiniere 1987;, Motta et a1 1989; Ottaviani et al. 1988; Solbiati et al. 1988; Thomassin & Pech 1986). These studies have essentially confirmed previous findings where clinical response rates usually exceeded 90% in un-

285

Amoxicillin/C1avulanic Acid: An Update

selected patients. The most frequent infecting organisms were S. aureus, H. injluenzae, S. pneumoniae and B. catarrhalis. A recent double-blind placebo-controlled study examined the efficacy of amoxicillin/c1avulanic acid administered for I month to over 100 children with secretory otitis media. By means oftympanometry it was shown that active treatment reversed the disease in 61 % of patients compared with 30% in a similar number of patients given placebo. Indeed, significantly superior tympanometric results were recorded in the amoxicillin/c1avulanic acid group for up to 8 months after the end of treatment (Thomsen et al. 1989).

4.3.2 Comparative Studies The results of studies comparing amoxicillin/ c1avulanic acid with either amoxicillin alone or cefaclor are summarised in table VI. In children and adults with acute otitis media amoxicillin/c1avulanic acid tended to produce superior clinical and bacteriological response rates compared with amoxicillin alone, with the result being statistically significant for clinical response in the study by Baba et al. (1983). Amoxicillin/c1avulanic acid and amoxicillin alone proved similarly effective in children with acute maxillary sinusitis. Amoxicillin/c1avulanic acid was comparable (Kaprio et al. 1988) or superior to cefaclor in the treatment of paediatric otitis media; statistically significant results in favour of amoxicillin/c1avulanic acid were found for clinical and bacteriological effects in the studies by Odio et al. (1985) and Marchant et al. (1986), respectively. While amoxicillin/clavulanic acid and amoxicillin alone showed similar tolerability, amoxicillin/clavulanic acid was not as well tolerated as cefaclor. Amoxicillin/clavulanic acid produced significantly more minor gastrointestinal side effects compared with cefaclor. Jacobsson et al. (1988) compared amoxicillin/ c1avulanic acid 40/10 mg/kg/day and cefaclor 20 mg/kg/day in over 100 children with otitis media that was either recurrent or resistant to penicillin. A clinical response greater than 90% was found with each treatment, while the bacteriological response was higher with amoxicillin/c1avulanic acid (33%

vs 19%, p < 0.0 I). The particularly low rates of bacteriological response are explained by high rates of recurrence and persistence at follow-up. Other studies determined the bacteriological response immediately at the end of therapy; these also found somewhat high rates of relapse during follow-up regardless of treatment. Recently, Engelhard and colleagues (1989) reported that 10 days' treatment with bodyweightadjusted doses of amoxicillin/c1avulanic acid was more effective than myringotomy in infants with acute otitis media. Recovery, assessed otoscopically, occurred in 60% of patients treated with amoxicillin/c1avulanic acid alone or in combination with myringotomy compared with 23% of patients treated with myringotomy plus placebo (p < 0.01; n = 30/treatment group). These results were associated with persistent ear infections in 70% of patients treated with myringotomy and placebo versus rates of 7 and 17% in the groups treated with amoxicillin/c1avulanic acid alone or amoxicillin/ c1avulanic acid plus myringotomy, respectively (p < 0.001). 4.4 Skin and Soft Tissue Infections In the subsequent studies on skin and soft tissue infections patients were included with various conditions such as wound infection, abscess, cellulitis, furunculosis, impetigo etc. These conditions are characterised by a wide range of Gram-negative and Gram-positive, aerobic and anaerobic pathogens, and often mixed infections. Uncommon pathogens may be present, but most frequently include S. aureus, S. pyogenes, Bacteroides spp., Fusobacterium spp., E. coli and Klebsiella spp. Amoxicillin/clavulanic acid proved effective against a wide range of pathogens, although the few infections caused by Proteus, Pseudomonas or Enterobacter did not usually respond.

4.4.1 Noncomparative Studies Noncomparative studies in adult and paediatric patients with skin and soft tissue infections have generally shown that amoxicillin/clavulanic acid 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 otorhinolaryngological infections Study design

Patient type a

Amoxicillin (AMX) Saba et al. (1983)

r,db

Chan et al. (1988)

r,db

Wald et al. (1986)

r,nb

Reference

Cefaclor (CEC) Kaleida et al. (1987) Kaprio et al. (1988) Marchant et al. (1986) Odio et al. (1985)

r,nb r,sb r,nb r,nb

Results (% responding)b


Duration (days)

Adults, acute exacerbation of chronic otitiS media Children, otitiS media with effusion Children, acute maxillary sinusitis

AMX/CA 250/125mg tid [83] AMX 250mg tid [99]

7

63~ P 47

AMX/CA 40/10 mg/kg/day [56] AMX 40 mg/kg/day [50]

10

52 32

AMX/CA 40/10 mg/kg/day [28] AMX 40 mg/kg/day [30] Placebo [35]

10

75 83 60

Children, acute otitis media Children, acute otitis media Children, acute otitis media Children, acute otitis media with effusion

AMX/CA 40/10 mg/kg/day [64] CEC 40 mg/kg/day [69] AMX/CA 20 mg/kg/day [127] CEC 40 mg/kg/day [115] AMX/CA 40/10 mg/kg/day [55] CEC 40 mg/kg/day [59] AMX/CA 40/10 mg/kg/day [70] CEC 40 mg/kg/day [60]

10

98 96 94 92 89 91

7 10 10

bacteriological

clinical

< 0.05

60 50

t

97 75 P = 0.028

100~ P = 0.019 92

a b

All patients were unselected with respect to pathogen resistance. Response rates usually determined immediately at the end of therapy and clinical response usually defined as cure or improvement. 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 al. 1985b; Sakai et al. 1982). Similar results have been achieved in odontogenic infections (Gerlach et al. 1989; Tsutou et al. 1982). 4.4.2 Comparative Studies Huizinga et al. (1986) compared amoxicillin/ clavulanic acid 250/ 125mg 3 times daily with placebo for 5 days in a randomised double-blind study in over 70 adult patients with wound infections. Microbiological cure, although low, was significantly higher for patients receiving amoxicillin/clavulanic acid (16% vs 0%, p < 0.05). The results of some major studies comparing amoxicillin/c1avulanic acid with other antimicrobial agents are summarised in table VII. Amoxicillin/clavulanic acid produced clinical and micro-

biological response rates which were at least as effective as cefuroxime axetil in adults with wound infections and as cefaclor in adults or children with various skin and soft tissue infections. Amoxicillin/clavulanic acid tended to be clinically more effective than amoxicillin alone in adult patients with wound infection and produced a superior bacteriological response rate at a statistically significant level. After to days' treatment of children with nonbullous impetigo there were no new lesions in a group administered amoxicillin/c1avulanic acid whereas 5 of 25 patients given amoxicillin alone had developed new lesions. In a study not reported in table VII (because dosages were not stated) amoxicillin/clavulanic acid appeared as effective as penicillin ± dicloxaciUin in adult patients with bite wounds (Goldstein et al. 1987b).

287


In the comparison with cefaclor by Jaffe et al. (1985), amoxicillin/clavulanic acid produced a lower rate of persistence in children with S. aureus infection (14% vs 67%) and a lower rate of superinfection (0% vs 16%). In comparisons with other agents, amoxicillin/ clavulanic acid was generally as well tolerated, although Pien (1983) and Fleisher et al. (1983) noted a significantly higher rate of mild gastrointestinal effects compared with cefaclor.

4.5 Sexually Transmissible Diseases

4.5.1 Gonorrhoea The increasing incidence of penicillinase-producing N. gonorrhoeae (PPNG) has decreased the usefulness of the once highly effective first-line treatments of uncomplicated gonorrhoea with procaine penicillin, and ampicillin or amoxicillin with probenecid. An increasing incidence of spectinomycin 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

Results (% responding)b


Duration (days)

AMX/CA 40/10mg/kg/day tid [24]

10

96

7

80 76

clinical

bacteriological

Amoxicillin (AMX) Dagan & Bar-

r,db

Umemura et al. (1983)

Children, nonbullous impetigo

David (1989) r,db

Cefuroxime axetll (CXM) Watts et al. (1987) r,nb

Cefaclor (CEC) Fleisher et al. (1983)

r,nb

Jaffe et al. (1985)

r,db

Parish & Aten

r,db

(1984) Pien (1983)

r,db

Risser et al. (1985)

r.db

Adults, wound infection

. AMX 40 mg/kg/day tid [25] AMX/CA 250/125mg tid [92) AMX 250mg tid [97)

63

~l

85t 71 P

Adults, wound infection

AMX/CA 250/125mg tid [56J CXM 250mg bid [58) CXM 500mg bid [57]

5

98 97 96

83 63 67

Children, various skin and soft tissue infection Children, various skin and soft tissue infection Adults, various skin and soft tissue infection Adults, various skin and soft tissue infection Children, various skin and soft tissue infection

AMX/CA 20/5 mg/kg/day tid [21)

5-10

86

100

10

90 82

90 95

5-10

81 81

65 80

88

89

CEC 20 mg/kg/day tid (20) AMX/CA 20/5 mg/kg/day tid [22) CEC 20 mg/kg/day tid [21) AMX/CA 500/125mg tid [21) CEC 500mg tid [17)

p

76c

< 0,01

< 0.05

AMX/CA 250 or 500/125mg tid [1) CEC 250 or SOOmg bid [43)

5-10

100

75 or 100d

AMX/CA 20/5 mg/kg/day tid [37J CEC 20 mg/kg/day tid (27)

10

100 97

63 or 70d 100

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 improvement. Response after 5 days.

c d

Bacteriological response rates given for respective dosages; the higher dosage was administered for more severe infections. = twice daily; tid = 3 times daily; r = randomised; nb = nonblind (or not stated); db = double-blind.

Abbreviations: bid

288

ness of this drug. First-line treatment failures may always be effectively treated with alternative agents such as parenteral cephalosporins. However, much effort has been directed towards finding a suitable first-line agent that equals the original efficacy of earlier treatments by covering PPNG and spectinomycin-resistant strains. Additionally, the ideal drug should be simple to administer as a single oral dose and inexpensive, particularly important considerations in developing countries. Numerous recently published noncomparative (table VIII) and comparative (table IX) studies have allowed a more definitive conclusion concerning the place of amoxicillin/clavulanic acid in the treatment of uncomplicated gonorrhoea. Administration of a single oral dose of amoxicillin/clavulanic acid 3000/125 or 250mg did not provide adequate cure rates in patients with PPNG infections. However, administration of 2 doses 4 to 6 hours apart or a single dose with concomitant administration of probenecid Ig usually achieved satisfactory cure rates including coverage ofPPNG strains. Also, administration of repeated doses for several days or a single dose in combination with procaine penicillin G proved extremely effective regimens with cure rates approaching 100%. Thus, administration of 2 oral doses of amoxicillin/clavulanic acid 3000/250mg at a 4- to 6-hour interval would appear to provide the most practical of the regimens investigated, although administration of a single dose in combination with probenecid Ig would appear almost as effective and probably more practical when patient compliance might be a problem. It should be noted that the 3000/125mg and 3000/250mg formulations of amoxicillin/clavulanic acid are under clinical evaluation and not yet generally available. In comparative studies clavulanic acid improved the cure rate of amoxicillin, when administered in combination with probenecid, by extending the antibacterial activity to PPNG strains. A single oral dose of amoxicillin/clavulanic acid 3000/250mg was significantly (p = 0.01) more effective than a single intramuscular injection of procaine penicillin G 2.4 x 106 U, and 2 doses of amoxicillin/clavulanic acid 4 hours apart were more

Drugs 39 (2) 1990

effective (p < 0.05) than a single intramuscular injection of kanamycin 2000mg. Single oral doses of amoxicillin/clavulanic acid 3000/250mg and cefuroxime axetil 1500mg, both in combination with probenecid Ig, were similarly effective. 4.5.2 Other Sex ually Transmissible Diseases Fast et al. (1982) studied the efficacy of amoxicillin 500mg, and amoxicillin/clavulanic acid 500/ 125mg and 500/250mg, all administered 3 times daily for 7 days, in 64 patients infected with {3~ lactamase-producing strains of H. ducreyi. Whereas all amoxicillin-treated patients failed to respond, all but 2 treated with amoxicillin/clavulanic acid were cured Clinically and bacteriologically. In another study (Ndinya-Achola et al. 1986), administration of a single dose of amoxicillin/clavulanic acid 3000/250mg or 2 doses 24 hours apart proved ineffective in the treatment of chancroid caused by H. ducreyi. However, administration of 500/250mg 3 times daily for 3 days cured 42 of 44 patients with chancroid. Symonds and Biswas (1986) have reported that amoxicillin/clavulanic acid was 100% effective in treating 6 patients with vaginosis caused by Gardnerella vagina/is. Clearly, data from larger numbers of patients are required before any conclusions can be drawn. Van der Meijden et al. (1987), in a preliminary study in a limited number of patients, found that amoxicillin/clavulanic acid was less effective than metronidazole in patients with clue cell-positive discharge. They considered amoxicillin/clavulanic acid should be reserved for pregnant women and those showing metronidazole intolerance, until results from larger studies are available.

4.6 Obstetric and Gynaecological Infections In an early study, Mayer et al. (1982) reported 100% clinical success (76% complete, 24% partial) in 37 women with pelvic inflammatory disease caused by in vitro susceptible organisms after oral treatment with amoxicillin/clavulanic acid 500/ 125mg 3 times daily for 9 to 36 days. Similar results were seen in Japanese studies involving small

289


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

gonorrhoea Reference

Bee & Phang

Patient type 5 genital

Kim et al. (1987)

total AMX/CA 3000/250mg 2 oral doses

5 or 2

AMX/CA 3000/250mg single oral

anogenital 5 genital

dose (a) AMX/CA 3000/250mg + probenecid 1000mg single oral dose (b) AMX/CA 250/125mg tid orally for

Lawrence & Shan son (1985)

5 or 2 anogenital

Lim et al. (1982) Lim et al. (1986)

5 genital 5

+ 2 genital

5 days (a) AMX/CA 3000/125mg + probenecid 1000mg single oral dose (b) AMX/CA 3000/250mg + probenecid 1000mg single oral dose AMX/CA 3000/125mg single oral

(1986) Osoba et al. (1986)

non-PPNG 42/42 (100%)

69/69 (100%)

27/27 (100%)

109/110 (99%)

Only 1 PPNG strain (cured)

48/50 (96%)

23/25 (92%)

25/25 (100%)

51/51 (100%)

20/20 (100%)

31/31 (100%)

97/100 (97%)

11/13 (85%)

86/84 (98%)

140/144 (97%)

5/7 (71%)

134/136 (99%)

31/35 (89%)

11/15 (73%)

20/20 (100%)

dose (a) AMX/CA 3000/125mg single oral

64/74 (86%)

8/11 (73%)

56/63 (89%)

dose (b) AMX/CA 3000/250mg single oral

70/79 (89%)

10/14 (71%)

60/65 (92%)

87/90 (97%)

20/23 (87%)

67/67 (100%)

(d) AMX/CA 3000/250mg 2 oral doses 4 hours apart

93/97 (96%)

28/29 (97%)

65/68 (96%)

(e) AMX/CA 250f125mg + probenecid 1000mg single oral dose + procaine penicillin G 4.5 x 106 U 1M (f) AMX/CA 500/250mg + probenecid 1000mg single oral dose + procaine penicillin G 4.5 x 106 U 1M AMX/CA 3000/250mg single oral dose AMX/CA 500/250mg tid orally for 2-5 days AMX/CA 3000/250mg + probenecid 1000mg single oral dose

87/88 (99%)

28/29 (97%)

59/59 (100%)

57/58 (98%)

19/20 (95%)

38/38 (100%)

144/161 (89%)

5/8 (62%)

139/153 (91%)

dose (e) AMX/CA 3000/250mg + probenecid 1000mg single oral dose

Munday et al. (1985) Osato et al.

PPNG

6 hours apart

(1985) De Silva et al. (1984)

Cure rate in assessable patients

Treatment

5 or 2 anogenital 5 or 2 PPNG genital 5 genital

Abbreviations: tid

121/121 (100%) 92/92 (100%)

= 3 times daily; 1M = intramuscularly; PPNG = penicillinase-producing N.

numbers of patients (Cho et al. 1983; Takase et al. 1982). Obwegeser et al. (1989) more recently reported the results of treatment of 100 unselected consecutive patients with salpingitis using amoxicillin/clavulanic acid 1000/200mg 6-hourly for 3 days parenterally followed by 1000/250mg 8-hourly for a further 6 days orally. At the end of therapy

73/73 (100%)

21/21 (100%)

gonorrhoeae.

95 were clinically cured, 3 markedly improved, and 2 failed. After 2 weeks' follow-up 71/79 assessable patients were cured while 3 had a relapse or infection. Other recent studies in patients with pelvic inflammatory disease have indicated that addition of doxycycline to amoxicillin/clavulanic acid improved efficacy by extending the antibacterial ac-

Drugs 39 (2) 1990

290

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

Patient type (study design)

Amoxicillin (AMX)

Lomefloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Minocycline: A review of its antibacterial and pharmacokinetic properties and therapeutic use.

Tobramycin: a review of its antibacterial and pharmacokinetic properties and therapeutic use.

Teicoplanin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential.

Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia.

Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer.

Isradipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease.

Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis.

mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer.

Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections.

Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.

Halofantrine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic potential.

Celiprolol. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease.

Lansoprazole. A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic efficacy in acid-related disorders.

Amiodarone. An overview of its pharmacological properties, and review of its therapeutic use in cardiac arrhythmias.

Posaconazole: An Update of Its Clinical Use.

Ketotifen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders.

Diltiazem. A reappraisal of its pharmacological properties and therapeutic use.

Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection.

Olsalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in inflammatory bowel disease.

Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.

Paroxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness.

Cilazapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cardiovascular disease.