Beta-lactamases are responsible for the resistance of many bacteria to beta-lactam antibiotics. Many beta-lactamase inhibitors have been investigated, and the three which are most suitable for clinical use are clavulanic acid, sulbactam, and tazobactam.

Clavulanic acid is a naturally occurring beta-lactamase inhibitor which was isolated from Streptomyces clavuligerus (Reading and Cole, 1977). It contains a beta-lactam ring but, unlike the penicillins and cephalosporins, it shows only a low level of antibacterial activity. The chemical structure of clavulanic acid is shown in Figure 11.1.

Figure 11.1 Chemical structure of clavulanic acid.

ANTIMICROBIAL ACTIVITY

Clavulanic acid exhibits a weak and usually clinically insignificant antibacterial activity against most bacterial species (see Table 11.1) (Neu and Fu, 1978; Slocombe et al., 1984). By its action of inhibiting beta-lactamases, clavulanic acid in combination improves the antibacterial activity of amoxicillin and ticarcillin. 

a. Routine susceptibility

Clavulanic acid in combination with amoxicillin (amoxicillin–clavulanic acid)

Clavulanic acid neither enhances nor diminishes the activity of amoxicillin against non-beta-lactamase-producing bacteria which are normally sensitive to amoxicillin (Slocombe et al., 1984). However, unlike amoxicillin alone, co-amoxiclav readily inhibits beta-lactamaseproducing methicillin-sensitive Staphylococcus aureus and S. epidermidis strains (Bush, 1988; Goldstein and Citron, 1988), but MICs of amoxicillin in the presence of clavulanic acid for these strains are about 4-fold higher than those for enzyme-negative strains (Table 11.1) (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). Amoxicillin-resistant Gram-negative bacteria, such as Enterobacter, Providencia and Serratia spp., and Morganella morganii, which produce chromosomally mediated inducible beta-lactamases, are resistant to co-amoxiclav (Slocombe et al., 1984; Weber and Sanders, 1990; Bush et al., 1991; Kaye et al., 2004). Clavulanic acid is a weak inducer of these beta-lactamases, but this appears to have little clinical significance as co-amoxiclav has no place in the treatment of infections caused by organisms which possess these inducible enzymes (Livermore et al., 1989; Rolinson, 1989; Bush et al., 1991).

Clavulanic acid in combination with ticarcillin (ticarcillin–clavulanic acid)

Bacteria which are normally sensitive to ticarcillin are sensitive to this combination. In addition, many bacteria which are ticarcillin resistant because of beta-lactamase production are sensitive. These include betalactamase, producing strains of S. aureus, S. epidermidis, H. influenzae, Neisseria gonorrhoeae- and Moraxella catarrhalis. Most strains of Enterobacteriaceae which are ticarcillin resistant are susceptible to the combination. This embraces ticarcillin-resistant strains of E. coli, Klebsiella spp., P. mirabilis, and P. vulgaris (Arpin et al., 2005). However, in Spain only 13% of extended-spectrum beta-lactamase (ESBL)- producing stains of E. coli were susceptible to ticarcillin–clavulanic acid (Herna′ndez et al., 2005).

Ticarcillin–clavulanic acid is usually active against other Pseudomonas spp. such as P. acidovorans and B. (Pseudomonas) cepacia and also Acinetobacter spp. (Fuchs et al., 1984; Pulverer et al., 1986; Knapp et al., 1989; Murray et al., 1993). Over 90% of strains of B. (Pseudomonas) pseudomallei are susceptible to ticarcillin–clavulanic acid (Sookpranee et al., 1991). However, as with co-amoxiclav, the beta-lactamase of this organism may become insensitive to clavulanic acid during treatment in vivo. Clavulanic acid lowers the MIC of ticarcillin against Stenotrophomonas maltophilia, but for about 50% of strains the MIC is still too high to make this combination useful clinically to treat infections caused by this organism (see Table 11.1) (Khardori et al., 1990; Pankuch et al., 1994; Valdezate et al., 2001; San Gabriel et al., 2004).

b. Emerging resistance and crossresistance

The increasing frequencies of highly active ESBLs as well as other mechanisms for resistance to beta-lactams have reduced the usefulness of beta-lactam combinations with clavulanic acid. 

MECHANISM OF DRUG ACTION

Clavulanic acid is a potent inhibitor of many beta-lactamases (Reading et al., 1983). Initially it binds beta-lactamases and functions as a competitive inhibitor; this is followed by acylation of these enzymes through the beta-lactam carbonyl part of the clavulanic acid molecule. This reaction is much the same as that which occurs between a betalactamase and a labile beta-lactam antibiotic, such as penicillin G. In the latter case, the acyl enzyme undergoes rapid hydrolysis to release active enzyme, again together with penicillin degradation products. By contrast, the acyl enzyme formed by reaction with clavulanic acid is hydrolyzed only very slowly, and therefore the enzyme is transiently inhibited (Rolinson, 1984).

Chromosomally mediated beta-lactamases of K. pneumoniae, Proteus mirabilis, P. vulgaris, and B. fragilis are also readily inhibited by clavulanic acid, but chromosomally mediated beta-lactamases produced by M. morganii, P. rettgeri, S. marcescens, Enterobacter spp., and P. aeruginosa are poorly inhibited by this drug (Brown, 1981; Rolinson, 1984; Moellering, 1991; Rolinson, 1991).

MODE OF DRUG ADMINISTRATION AND DOSAGE

Clavulanic acid is available for human use only in combination with amoxicillin (co-amoxiclav; Augmentins) and ticarcillin (Timentins). For all drug administration issues related to these agents.

a. Adults

The adult dosage of 125 mg clavulanic acid three or four times daily provides adequate concentrations of the drug in the tissues to inhibit beta-lactamases (Rolinson, 1985). Note that the clavulanic acid dose is not increased in line with the amoxicillin dose in some extendedduration co-amoxiclav formulations. Therefore, simply increasing the number of tablets is not recommended since it may result in excessively high clavulanic acid doses.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

The pharmacokinetics of amoxicillin is unaffected by the simultaneous administration of clavulanic acid (Jackson et al., 1983). Serum levels attained after i.v. administration of ticarcillin are also unaffected (Bennett et al., 1983).
The bioavailability of clavulanic acid after oral administration averages some 60% of the administered dose, but this varies considerably (range 31.4–98.8%), indicating variable absorption from the gastrointestinal tract (Nilsson-Ehle et al., 1985).

b. Drug distribution

Clavulanic acid is well distributed in animals after administration of co-amoxiclav or ticarcillin–clavulanic acid. Adequate concentrations occur in peritoneal and pleural fluid, lymph, pus, and infected tissue homogenates. This is also the case for middle ear fluid (Scaglione et al., 2003) as well as in lung tissues in patients with pneumonia (Cook et al., 1994). Sometimes amoxicillin concentrations measured after co-amoxiclav were higher than those after treatment with amoxicillin alone, presumably as a result of inhibition of bacterial beta-lactamases by clavulanic acid at the site of infection (Boon et al., 1982; Woodnutt et al., 1987, Woodnutt et al., 1990).

d. Excretion

Some clavulanic acid is excreted in the urine in the active unchanged form. This occurs mainly by glomerular filtration, and tubular secretion plays only a minor, if any, role (Staniforth et al., 1983). Probenecid does not delay the excretion of clavulanic acid. The fraction of an i.v. administered dose which is excreted unchanged in urine approximates 50%. After oral administration, 18–38% of the dose is excreted unchanged in urine (Jackson et al., 1984; Jacobs et al., 1985; NilssonEhle et al., 1985). e. Drug interactions Probenecid has no effect on the serum levels of clavulanic acid, indicating that the drug is cleared by the kidney predominantly by glomerular filtration. Probenecid enhances and prolongs serum levels of amoxicillin (Staniforth et al., 1983; Jackson et al., 1984).

TOXICITY

Clavulanic acid appears to be free of serious side-effects. Adverse reactions occurring in 9700 patients participating in clinical trials with oral co-amoxiclav were: diarrhea 398 (4.1%), nausea 294 (3%), vomiting 175 (1.8%), indigestion 158 (1.6%), rash 110 (1.1%), urticaria 9, anaphylaxis 1, Candida superinfection 98 (1%), jaundice 1, and altered liver function tests 3 (Croydon, 1984). The low frequency of rashes is surprising because amoxicillin alone is associated with a higher frequency of rashes.

Gastrointestinal side-effects, such as nausea, vomiting, and diarrhea, seem to be more common with co-amoxiclav than with amoxicillin alone (Iravani and Richard, 1982; Pien, 1983; Conner, 1985). This difference is small when adults receive the usual 125-mg individual doses of clavulanic acid. When this dose is doubled to 250 mg, and combined with either the usual 0.5- or 3-g doses of amoxicillin, gastrointestinal side-effects are more frequent and severe (Crokaert et al., 1982; Lawrence and Shanson, 1985). In one study, oral administration of co-amoxiclav caused motor disturbances in the small intestine (Caron et al., 1991). The clinical significance of this is unclear.

CLINICAL USES OF THE DRUG

Clavulanic acid is not used alone, only in combination with amoxicillin or ticarcillin.

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