Amoxicillin–clavulanic acid: Antimicrobial Activity, Susceptibility, Administration and Dosage etc.

Amoxicillin–clavulanic acid (co-amoxiclav) is a combination product consisting of the semisynthetic antibiotic amoxicillin with the beta-lactamase inhibitor clavulanic acid as a potassium salt. It contains a beta-lactam ring and the sulfur of the penicillin thiazolidine ring is replaced with oxygen to form an oxazolidine ring (see Figure 14.1). Clavulanic acid has weak intrinsic beta-lactam activity, but its clinical utility relates to its potent inhibition of many beta-lactamases (Reading et al., 1983) and its ability to protect substrate drugs from hydrolysis (Bush, 1988). The molecular formula of clavulanic acid is C8H8KNO5. Chemically, clavulanate potassium is potassium -(2R,5R)- 3-(2-hydroxyethylidine)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2- carboxylate and has a molecular weight of 237.25.

Figure 14.1 Chemical structure of clavulanic acid.

A large number of different formulations containing variable ratios of amoxicillin–clavulanic acid in powder for syrup, chewable tablets, tablets and pharmacokinetically enhanced formulations have been marketed, predominantly as Augmentins. An intravenous formulation is also available in some countries. Co-amoxiclav retains the antimicrobial activity of amoxicillin, and in addition has activity against amoxicillin-resistant strains when the mechanism of resistance is due to production of beta-lactamases susceptible to inhibition by clavulanic acid. This includes plasmid-encoded betalactamases produced by Staphylococcus aureus, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, Escherichia coli, other Enterobacteriaceae, and Bacteroides fragilis (Wright, 1999). Clavulanic acid inhibits most extended-spectrum beta-lactamase (ESBLs) in vitro, but in vivo its activity is limited (Gupta, 2007). Chromosomally encoded beta-lactamases produced by Enterobacter spp., Citrobacter spp., Serratia spp., and Pseudomonas spp., are not inhibited by clavulanic acid (Wright, 1999).

ANTIMICROBIAL ACTIVITY

Clavulanic acid has no effect on the activity of amoxicillin against non-beta-lactamase-producing bacteria, which are normally sensitive to amoxicillin (Slocombe et al., 1984). Similarly, ampicillin-susceptible strains would, with rare exceptions, also be susceptible to coamoxiclav. Brumfitt et al. (1983) reported a phenomenon of in vitro ampicillin-susceptible, co-amoxiclav-resistant strains of E. cloacae, C. freundii, and S. marcescens, which was attributed to a greater activity of ampicillin than amoxicillin against these isolates. This is unlikely to be clinically significant as ampicillin would not generally be considered to have activity against these bacteria. Where an organism is susceptible to amoxicillin, this agent should be used in preference to co-amoxiclav, unless activity against other pathogens in a polymicrobial infection is desired. The activity of co-amoxiclav against selected Gram-positive, Gram-negative, anaerobic bacteria and common respiratory pathogens is summarized in Table 14.1.

a. Routine susceptibility

Gram-positive bacteria

In contrast to amoxicillin alone, strains of beta-lactamase-producing methicillin-sensitive S. aureus and coagulase-negative staphylococci are readily inhibited by co-amoxiclav (Bush, 1988; Goldstein and Citron, 1988). Minimum inhibitory concentrations (MICs) are slightly higher than for penicillin-sensitive S. aureus (Fuchs et al., 1983; Slocombe et al., 1984). Co-amoxiclav shows greater in vitro activity than flucloxacillin against many beta-lactamase-producing strains; this in vitro advantage does not occur with S. aureus strains which produce large amounts of beta-lactamase (Thomas et al., 1985). Staphylococcal beta-lactamases are molecular class A (Bush group 2a) and are further subdivided, initially serologically, into subtypes A to D (Richmond, 1965; Livermore, 1995). The epidemiologic distribution of these varies: types A and C are most common and type D is rare (Livermore, 1995). Organisms with type C beta-lactamases are less susceptible to co-amoxiclav and to other beta-lactamase inhibitors such as piperacillin–tazobactam (Bonfiglio and Livermore, 1994; see Chapter 17, Piperacillin–Tazobactam). Methicillin-resistant S. aureus and coagulase-negative staphylococci are resistant to co-amoxiclav (Graninger et al., 1989).

Gram-negative aerobic bacteria

Beta-lactamase-producing strains of Neisseria gonorrhoeae, H. influenzae, H. ducreyi, and M. catarrhalis are susceptible to co-amoxiclav (Girouard et al., 1981; Farmer and Reading, 1982; Alvarez et al., 1985; Dangor et al., 1988; Cooper et al., 1990). Strains of N. gonorrhoeae, and H. influenzae that are intrinsically resistant to penicillin G and amoxicillin are co-amoxiclav resistant (Powell et al., 1991). Beta-lactamase-producing gonococcal strains that possess a 3.2-megadalton beta-lactamase plasmid are more sensitive to co-amoxiclav than strains possessing a 2.9-, 3.05-, or 4.4-megadalton plasmid (Rice and Knapp, 1994). Neisseria meningitidis remains highly susceptible to amoxicillin. Anta et al. (2002) observed that clavulanic acid at subinhibitory concentrations enhanced the in vitro bactericidal activity of amoxicillin against N. meningitidis and suggested that co-amoxiclav could have a potential role in nasopharyngeal eradication of the organism.

Co-amoxiclav inhibits many Enterobacteriacae which produce betalactamases associated with amoxicillin resistance. Thus, amoxicillinresistant E. coli, Klebsiella pneumoniae, Proteus mirabilis, some Citrobacter spp., and, to a lesser extent, Yersinia enterocolitica are often co-amoxiclav sensitive (Gaspar and Soriano, 1981; Fuchs et al., 1983; Slocombe et al., 1984; Bush, 1988; Roy et al., 1989; Kahlmeter, 2003).

Other bacteria

Co-amoxiclav partially inhibits Chlamydia trachomatis in vitro and also in experimental animal infections (Bowie, 1986; Beale et al., 1991), but there is no evidence of clinical efficacy in humans. Beta-lactam resistance in Mycobacterium spp. has been attributed to beta-lactamase production, poor cell wall permeability and the mycobacterial peptidoglycan (Hugonnet and Blanchard, 2007). However, beta-lactam permeability appears to be acceptable (Chambers, 1995) and resistance is primarily due to production of a class A beta-lactamase encoded by blaC (Flores et al., 2005).

b. Emerging resistance and cross-resistance

The emergence of E. coli strains resistant to co-amoxiclav occurred in Europe in the 1990s and the prevalence was found to be around 5% in an epidemiologic survey by Leflon-Guibout et al. (2000). Initially, resistance was predominantly associated with hyperproduction of TEM-type beta-lactamases, but other mechanisms, including plasmidencoded or hyperproduction of class C beta-lactamases and OXA class D beta-lactamases, has occurred (Kaye et al., 2004). A number of class A TEM and SHV enzymes resistant to inhibitors (class 2br) have now been reported in Europe (Bonomo and Rice, 1999) and the USA (Kaye et al., 2004). The inhibitor-resistant TEM (IRT) enzymes occur in E. coli, Klebsiella spp., and P. mirabilis and are associated with mutations at a number of sites including Met69, Arg 244, and Asn 276 (Bonomo and Rice, 1999).

MECHANISM OF DRUG ACTION

Clavulanic acid is a beta-lactam compound and has weak intrinsic antibacterial activity resulting from a mode of action similar to that of penicillin G (see Chapter 1, Benzylpenicillin (Penicillin G)). The mechanism of inhibition of the serine beta-lactamases (predominantly class A enzymes) is complex and eventually results in irreversible acylation of the beta-lactamase (Figure 14.2); thus clavulanic acid acts as a ‘‘suicide inhibitor’’ (Knowles, 1985). Clavulanic acid is first recognized by the beta-lactamase, leading to the formation of the Michaelis–Menten complex (Bonomo and Rice, 1999). Nucleophilic attack by the active catalytic serine site of beta-lactamase on the carbonyl carbon results in a covalent acyl intermediate and opening of the beta-lactam ring.

Figure 14.2 Mechanism of action of clavulanic acid. Reproduced with permission from Wright, 1999.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Co-amoxiclav is available in a variety of different marketed strengths and formulations in different countries (see Table 14.2). For oral administration, 375-mg (250 mg amoxicillin/125 mg clavulanic acid) and 625-mg (500/125 mg) tablets are generally available. An 875/ 125 mg combination is available in some countries, including the USA and Australia. An extended-release ‘‘pharmacokinetically enhanced’’ formulation marketed in the USA contains 1000 mg amoxicillin and 62.5 mg clavulanic acid.

b. Newborn infants and children

There are insufficient data to determine optimal oral dosing regimens in newborns and infants less than two to three months of age. Children W40 kg in weight can generally be administered adult recommended doses. The 250/125 mg chewable tablet and the extended-release 1000/62.5 mg formulation are not recommended in children less than 12 and 16 years of age, respectively. Dosing recommendations vary somewhat with the different pediatric formulations. With the early amoxicillin–clavulanic acid suspensions in a 4:1 ratio, daily doses of co-amoxiclav of 25–50 mg/kg/day administered in three divided doses were recommended (Dambro et al., 1984; Gooch et al., 1984) increasing to 50–75 mg/kg/day co-amoxiclav (40–60 mg amoxicillin plus 10–15 mg clavulanic acid) for more serious infections (Nelson et al., 1982; Schaad et al., 1986). Some authors have used higher doses for serious infections (120/30 mg/kg/day) in three divided doses (Dagan and Bar-David, 1989). Twice-daily co-amoxiclav 50/12.5 mg/ kg was satisfactory for the treatment of children with acute otitis media (Jacobsson et al., 1993).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

The oral bioavailability of clavulanic acid (125 mg) is slightly better in the presence of amoxicillin (Adam et al., 1982) and when co-administered with amoxicillin is approximately 60 7 23% – however, this varies considerably (range, 31–99%), indicating very variable absorption from the gastrointestinal tract (Nilsson-Ehle et al., 1985). Vree et al. (2003) examined the absorption of varying doses of amoxicillin (250–875 mg) with 125 mg clavulanic acid. With the highest dose of amoxicillin, broadening of the tmax was attributed to a rate-limiting step in absorption. For the AUCamox/AUCclav regression curve for 875 mg amoxicillin a negative slope was observed, suggesting that the saturable absorption for amoxicillin is influenced by clavulanic acid (Vree et al., 2003). The regression lines for 250/125 mg and 500/ 125 mg were positive, suggesting no effect of clavulanic acid on absorption of these doses of amoxicillin; this is in agreement with earlier studies which concluded that the pharmacokinetics of amoxicillin is unaffected by simultaneous administration of clavulanic acid (Jackson et al., 1983).

b. Drug distribution

After an oral dose of 625 mg co-amoxiclav (125 mg clavulanic acid) a mean peak serum clavulanic acid level of 3.49 mg/ml is attained with a tmax of 45–75 min. Doubling the dose of clavulanic acid to 250 mg increases, but does not double, serum levels (Adam et al., 1982; Jackson et al., 1983). Amoxicillin serum concentrations achieved when administered as co-amoxiclav are similar to equivalent doses of amoxicillin alone. In children given co-amoxiclav 20/5 mg/ kg when fasted, mean plasma concentrations at 40–90 minutes were 7.2 mg/ml for amoxicillin and 2.0 mg/ml for clavulanic acid (Schaad et al., 1986). With a suspension formulation with a 7:1 ratio of amoxicillin–clavulanic acid administered to children at 22.5/3.2 mg/kg twice daily, steady-state Cmax was 12.0/5.5 mg/ml, and tmax was 1.3 hours for both components (Reed, 1996).

c. Clinically important pharmacokinetic and pharmacodynamic features

As for other beta-lactam drugs, the bacteriologic efficacy of coamoxiclav is dependent on the time that serum levels exceed the MIC of the pathogen being treated (Craig, 1998). Therapeutic efficacy for amoxicillin against S. pneumoniae and H. influenzae requires a time above MIC (TWMIC) for 40–50% of the dosing interval (MacGowan et al., 2004). The TWMIC for the amoxicillin component (for various MICs) achieved with the different co-amoxiclav formulations and doses is shown in Table 14.4 and demonstrates that the higher dosing regimens can achieve theoretically effective pharmacodynamic parameters against organisms with higher amoxicillin MICs. 

d. Excretion

Clavulanic acid is excreted in the urine in the active, unchanged form, but to a lesser extent than amoxicillin. Excretion occurs mainly by glomerular filtration, and tubular secretion pays only a minor, if any, role (Staniforth et al., 1983). Thus, probenecid has no effect on renal excretion of clavulanic acid. After administration of 125 mg clavulanic acid with amoxicillin 500 mg, cumulative excretion of clavulanic acid (as a percentage of the dose administered) at 2, 4, and 6 hours was approximately 14%, 26%, and 28%, respectively (Ferslew et al., 1984).

e. Drug interactions

Minimal drug interactions occur with co-amoxiclav. Probenecid decreases renal tubular secretion of amoxicillin, but does not affect the clavulanic acid component (Staniforth et al., 1983); the combination should be avoided. Co-amoxiclav has been reported to interact with warfarin (increasing the international normalized ratio, INR); this has been attributed to effects on vitamin K-producing gut flora (Davydov et al., 2003), and was considered a ‘‘probable’’ interaction by Holbrook et al. (2005). Similar effects to ampicillin on oral contraceptive absorption, reduced urinary estriol excretion, and increased incidence of rash when co-administered with allopurinol could be associated with the amoxicillin component.

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