Ticarcillin–Clavulanic Acid: Antimicrobial Activity, Susceptibility, Administration and Dosage etc.

Ticarcillin–clavulanate is an injectable antibacterial combination consisting of two agents, a beta-lactam antibiotic (ticarcillin) and a beta-lactamase inhibitor. Ticarcillin is a semisynthetic penicillin of the carboxypenicillin group. It is an alpha carboxyl 3 thienylmethyl penicillin, with the detailed formula of ticarcillin disodium being N-(2-carboxy-3,3- dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-yl)-3-thiophenemalonamic acid disodium (see Figure 16.1). Another member of this group is carbenicillin, which ticarcillin has now replaced for clinical use. These drugs fall into the group commonly referred to as the extendedspectrum penicillins (Sutherland et al., 1970). Like other penicillins, the most clinically important mechanism of resistance to ticarcillin is via the production of beta-lactamase enzymes that degrade the beta-lactam drug. Beta-lactamase inhibitors, such as clavulanic acid, can overcome this resistance mechanism in many bacteria. Clavulanic acid (or clavulanate) is a naturally occurring penicillianic acid sulfone derivative that was originally isolated from Streptomyces clavuligerus (Reading and Cole, 1977; Brown, 1986). Different beta-lactamases will differ in their degree of susceptibility to clavulanic acid. Chemically, clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate; the chemical structure is shown in Figure 16.1.

Figure 16.1 Chemical structure of ticarcillin and clavulanic acid. (a) Ticarcillin disodium. (b) Clavulanic acid. Ticarcillin and clavulanic acid have very similar pharmacokinetic properties and are therefore well suited to co-administration (Sutherland et al., 1985). Ticarcillin–clavulanate is marketed under the brand name Timentins. It can only be administered parenterally and is available in two formulations, a premixed frozen form for infusion and a powder that is reconstituted for injection. Every 3.1 g of ticarcillin–clavulanate consists of 3 g of ticarcillin and 0.1 g of clavulanic acid.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

Early reports of the clinical use of ticarcillin–clavulanate demonstrated a broad spectrum of activity against many Gram-positive, Gramnegative, and anaerobic bacteria (Rodriguez et al., 1973a; Casey and Glauser, 1983; Roselle et al., 1985). Improved activity against Pseudomonas spp. is a particular attribute of ticarcillin that distinguishes it from many other narrower-spectrum penicillins (although some Pseudomonas strains remain resistant). Table 16.1 summarizes the in vitro activity of ticarcillin–clavulanate against a variety of bacteria, although for clinical decision-making, the local susceptibility profile of bacteria should always also be considered.

Gram-positive organisms

Most Gram-positive bacteria are susceptible to ticarcillin–clavulanate, but some resistant bacteria (such as methicillin-resistant Staphylococcus aureus) are important exceptions. The beta-lactamases that may be present in methicillin-susceptible S. aureus and Enterococcus faecalis are readily inhibited by clavulanic acid, and these bacteria are therefore usually susceptible to ticarcillin–clavulanate (Barry, 1990). Importantly, penicillin and ampicillin are more effective than ticarcillin against E. faecalis and Listeria monocytogenes, and are preferred for clinical use to treat infections with these pathogens. Piperacillin–tazobactam is also usually more effective than ticarcillin– clavulanate against enterococci and may be preferable if specific treatment for this pathogen is required (Hoellman et al., 1998).

Gram-negative organisms

Ticarcillin–clavulanate has efficacy across a broad range of Gramnegative bacteria. The addition of clavulanic acid was reported to reduce the minimal inhibitory concentration (MIC) for ticarcillin by more than eight times for 92% of Enterobacteriaceae tested in large studies during the 1980s (Barry et al., 1984; Fuchs et al., 1984). In a survey of isolates in the USA between 1998 and 2001, ticarcillin– clavulanate retained activity against 74–83% of Enterobacteriaceae, 70–80% of Acinetobacter baumannii strains, and 70–80% of Pseudomonas aeruginosa strains (Karlowsky et al., 2003a; Karlowsky et al., 2003b).

It is the type of beta-lactamase and the amount present that largely determine susceptibility to ticarcillin–clavulanate for Gram-negative bacilli. Class A (e.g. TEM, SHV) and to a slightly lesser extent class D beta-lactamases are generally inhibited by clavulanate, while class B (e.g. the metallobetalactamases) and class C (e.g. Amp C) are not (Thomson et al., 1990). The class A beta-lactamases are common in Enterobacteriaceae and the addition of clavulanic acid is therefore useful for many of these commonly encountered Gram-negative organisms (Jacobs et al., 1986a; Jacobs et al., 1986b; Kempers and MacLaren, 1990).

Other bacteria

Ticarcillin–clavulanate is not clinically effective against mycobacteria, despite some species showing susceptibility in vitro (Casal et al., 1987). Case reports of apparent clinical improvement with use of ticarcillin– clavulanate for isolated strains of mycobacteria are available (Holland et al., 1994). In vitro sensitivity of Nocardia brasiliensis to ticarcillin– clavulanate has been reported (Wallace et al., 1983; Wallace et al., 1987), but clinical evidence is lacking.

Ticarcillin–clavulanate has some activity against Chlamydia trachomatis, although clinical confirmation of efficacy is limited (Bowie, 1986; Martin et al., 1986; Pastorek, 1990) and hence this drug is not recommended therapeutically for this pathogen. Similarly, rat models of Legionella pneumophila have demonstrated efficacy of ticarcillin– clavulanate, but clinical confirmation in humans is lacking and this is currently not a recommended therapeutic option (Smith et al., 1991).

b. Emerging resistance and cross-resistance

Acquired resistance to beta-lactam/beta-lactamase inhibitor combinations can occur via a variety of mechanisms. These have been described in some case series (Sanders et al., 1988a) and are discussed in a recent review (Canton et al., 2008). The bacterium may start to hyperproduce its existing beta-lactamase (via acquisition of a ‘promoter’) or it may acquire several copies of a beta-lactamase gene (e.g. via a plasmid), leading to large amounts of beta-lactamase enzyme that overwhelms the beta-lactamase inhibitor. Bacteria may acquire a new beta-lactamase enzyme from another class (one which is not inhibited by clavulanate) via a plasmid or the bacterium may be induced to produce a different chromosomally encoded betalactamase. Mutations may occur in the genes encoding existing beta-lactamases that alter their susceptibility to inhibitors or new nonbeta-lactamase-related mechanisms of resistance may be acquired by the bacterium (e.g. changes in drug target proteins, membrane permeability, drug efflux mechanisms, etc.).

Hyperproduction of beta-lactamases may be the result of multiple copies of the same beta-lactamase gene on multicopy plasmids. This has been described for TEM1 and less commonly for SHV1 and SHVESBL genes (Shannon et al., 1990; Seetulsingh et al., 1991). Similarly, the simultaneous presence of different types of beta-lactamase serves to increase the net quantity of beta-lactamase, leading to reduced susceptibility to the beta-lactamase inhibitor. The OXA-type betalactamases, for example, are weakly inhibited by clavulanate, but their presence reduces the activity of beta-lactam/beta-lactam inhibitor combination drugs against other beta-lactamases as they ‘‘occupy’’ the inhibitor.

c. In vitro synergy and antagonism

There is some in vitro evidence to suggest synergy between ticarcillin and aminoglycosides against P. aeruginosa (Comber et al., 1977; Pickering and Gearhart, 1979; White et al., 1979; White et al., 1985; Smith et al., 1989). However, the degree of synergy varies between strains and, in general, the mechanism of synergy is not understood. Checkerboard testing of 75 Gram-negative isolates showed evidence of synergy between ticarcillin and tobramycin (Marques et al., 1997; Owens et al., 1997). Notably, these in vitro observations did not appear to correlate with clinically improved outcomes when ticarcillin– clavulanate was used with or without gentamicin in 170 patients (Gilbert et al., 1998).

MECHANISM OF DRUG ACTION

Like other penicillins, the mechanism of action of ticarcillin is via inhibition of cell wall synthesis. Ticarcillin binds to penicillinbinding proteins, thus inhibiting the transpeptidation step in peptidoglycan synthesis for the cell wall. Ticarcillin–clavulanate is more effective than some other penicillins against Gram-negative bacteria owing to its superior ability to penetrate the outer cell membrane.

Clavulanic acid acts via inhibition of beta-lactamase enzymes (Bush, 1988). Beta-lactamases are enzymes produced by bacteria that degrade or modify beta-lactam drugs before they reach the penicillin-binding proteins. Clavulanic acid contains a beta-lactam ring that binds the enzyme at its active site. Initially, it acts as a competitive inhibitor, but, once bound, there is also acetylation of the enzyme and hydrolysis of the amide bond, leading to irreversible inhibition of the enzyme (Rolinson, 1991; Livermore, 1993). It acts as a suicide inhibitor. The clavulanic acid, therefore, protects the beta-lactam drug from the beta-lactamase enzyme.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Ticarcillin–clavulanate is only administered parenterally. Vials of ticarcillin–clavulanate typically contain a 30:1 ratio of the two components, with 3 g of ticarcillin and 0.1 g of clavulanic acid. Each vial is usually dissolved in 20–30 ml of sterile water, then is typically infused over a period of 20–30 minutes in 100 ml of diluent. The stability of ticarcillin– clavulanate varies with temperature, diluent, and concentration. For example, 3.1 g of ticarcillin–clavulanate in 100 ml of 0.9% NaCl is stable for 8 hours at 251C, but in 5% dextrose it is stable for 24 hours at 21– 241C and for 72 hours at 41C (Hart and Bailey, 1996). Very minimal differences in the pharmacokinetics of ticarcillin and clavulanic acid have been observed relative to the age of the recipient (Reed, 1998b). The usual dose of ticarcllin–clavulanate for adults is 3.1 g every 4–6 hours, with a maximum dose of 24 g of the ticarcillin component per day (Roselle et al., 1985).

Intraperitoneal administration of ticarcillin–clavulanate has been described, but relapses have also been reported with this mode of administration for Pseudomonas infection (Pasadakis et al., 1992). Thus, dosing via this route is not recommended.

b. Newborn infants and children

For children with a body weight of 60 kg, the recommended dose is 300/10 mg/kg/day in four divided doses. The same dose is recommended for full-term infants (Nelson et al., 1975; Nelson et al., 1978; Nelson, 1979; Jackson et al., 1986; Fricke et al., 1989; Nelson and McCracken, 1998).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

The pharmacokinetics of ticarcillin and clavulanic acid is very similar, which is why they make good companion drugs. For example, in a study performed in 12 healthy adults, six doses of 3.1 g of ticarcillin– clavulanate were given every 6 hours, and comprehensive urine and blood testing was performed to evaluate the pharmacokinetics. For ticarcillin, the steady-state half-life was 1.1 7 0.1 hours, the volume of distribution was 12.5 7 2.0 liters, and the body clearance 3.67 1.3 l/ h. For clavulanic acid, the corresponding results were a half-life of 0.9 7 0.1 hours, a volume of distribution of 18.0 7 5.0 liters, and a body clearance of 3.67 1.3 l/h (Rodriguez et al., 1973b; Reed, 1998b). Ticarcillin is 40% protein bound and clavulanic acid is 20% protein bound in the circulation (Bergan et al., 1987). The volume of distribution of ticarcillin closely resembles the volume of the extracellular fluid space, reflecting the wide distribution of this drug through body tissues (Tan and Salstrom, 1977).

b. Drug distribution

After an infusion over 30 minutes of a single dose of 50 mg/kg ticarcillin–clavulanate to an adult, the peak serum level of ticarcillin averages 324 mg/ml and clavulanic acid averages 8 mg/ml immediately after the infusion (Scully et al., 1984). At 1 and 5.5 hours after the infusion, the serum ticarcillin concentration averages 223 and 6 mg/ml, respectively, and clavulanic acid averages 4.6 and 0 mg/ml, respectively. Of note, the serum levels of clavulanate fall more rapidly than the ticarcillin levels, and so the ratio of ticarcillin to clavulanate increases over the dosing interval (Bennett et al., 1983).
c. Clinically important pharmacokinetic and pharmacodynamic features Integrated pharmacokinetic and pharmacodynamic studies have suggested that the current dosing regimens can be reliably expected to provide effective therapy for infections caused by ticarcillin– clavulanate-susceptible bacteria with MIC values of 16 mg/l or less for infections outside the central nervous system (CNS) (Reed, 1998b). Based on pharmacokinetic and pharmacodynamic studies in 12 healthy volunteers given 3.1 g of ticarcillin–clavulanate 6-hourly, Klepser et al. (1997) calculated the percentage of the dosing interval during which the serum level exceeded the MIC for four common species of bacteria. Like all penicillins, the principal determinant of efficacy of ticarcillin is the time that drug levels at the site of infection exceed the MIC for the pathogen.

d. Excretion

Ticarcillin is excreted primarily via the renal tubules, and this excretion can be inhibited by probenecid. In a 24-hour urine collection, the percentage of administered intravenous dose excreted unchanged in the urine is 79% for ticarcillin and 41% for clavulanic acid (i.e. about half of the dose of clavulanic acid is metabolized in the body prior to excretion) (Hoffken et al., 1985). The renal clearance of ticarcillin has been calculated to be approximately 112 ml/min, while that of clavulanic acid is 158 ml/min. The biliary pharmacokinetics of these drugs has been described (Brogard et al., 1989).

e. Drug interactions

Ticarcillin–clavulanate is incompatible with infusion of sodium bicarbonate and is not compatible with activated protein C (drotecogin) if co-administered via the same i.v. line using a Y junction (Mann et al., 2004). It is also incompatible with infusion of amphotericin B via a Y-site connection. Ticarcillin–clavulanate is not compatible with intravenous ciprofloxacin because of changes in the pH generated (Elmore et al., 1996).

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