Tazobactam: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Tazobactam (YTR 830) is a penicillinate sulfone, structurally related to sulbactam; the chemical structure is shown in Figure 13.1. Being a beta-lactamase inhibitor, it is synergistic with many beta-lactamaselabile drugs, such as penicillin G, ampicillin, or piperacillin against many bacterial species which produce beta-lactamases (Aronoff et al., 1984; Akova et al., 1990).

For clinical use only, tazobactam combined with piperacillin has been made available. Each adult dose contains 4 g piperacillin and 0.5 g tazobactam. The combination of piperacillin/tazobactam may have some advantages over other beta-lactam/beta-lactamase inhibitor combinations such as co-amoxiclav, ticarcillin–clavulanate and ampicillin–sulbactam. First, piperacillin is easier to protect against TEM beta-lactamases. This is probably because of the lower affinity of piperacillin for these enzymes (Livermore, 1993).

Tazobactam inhibits all beta-lactamases inhibited by clavulanic acid, but in addition it also has some activity against chromosomally-mediated induced (or derepressed) enzymes of Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and sometimes Pseudomonas aeruginosa.

Figure 13.1 Chemical structure of various beta-lactamase inhibitors, including tazobactam and brobactam. From: Mascaretti et al. (1995).

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility Gram-positive bacteria

Beta-lactamase-producing strains of Staphylococcus aureus and S. epidermidis are piperacillin–tazobactam sensitive, but methicillinresistant strains are not (Fass and Prior, 1989; Acar et al., 1993). As with amoxicillin–clavulanic acid, S. aureus strains which produce type C beta-lactamase are less susceptible to piperacillin–tazobactam than type A enzyme producers. Beta-lactamase-producing E. faecalis strains are also usually susceptible, but E. faecium strains with high-level intrinsic resistance to penicillin G are also resistant to this combination (Jones et al., 1989; Chen et al., 1993; Okhuysen et al., 1993).

The addition of tazobactam does not affect the activity of piperacillin against sensitive strains of streptococci, enterococci, and Listeria monocytogenes. Tazobactam does not improve the action of piperacillin against penicillin G-resistant pneumococci or against resistant strains of Corynebacterium jeikeium (Jones and Barry, 1989). Only very few strains of Gram-positive anaerobes such as Clostridium spp. produce betalactamase and these are sensitive to piperacillin/tazobactam. All others are sensitive to piperacillin alone (Appelbaum et al., 1993).

Gram-negative aerobic bacteria Beta-lactamase-producing strains of Neisseria gonorrhoeae, N. meningitidis, Haemophilus influenzae, and Moraxella catarrhalis are piperacillin– tazobactam sensitive. Tazobactam also enhances the activity of piperacillin against most strains of Escherichia coli, Klebsiella, Proteus, and Providencia spp., Citrobacter diversus, and M. morganii. It only occasionally enhances the activity of piperacillin against Enterobacter spp., C. freundii, and S. marcescens. Tazobactam usually does not enhance the activity of piperacillin against Aeromonas hydrophila, P. aeruginosa, Burkholderia (Pseudomonas) cepacia, S. maltophilia, and Acinetobacter spp. (Fass and Prior, 1989; Jones and Barry, 1989; Kuck et al., 1989; Acar et al., 1993; Chen et al., 1993; Stobberingh et al., 1994).

Gram-negative anaerobic bacteria

Bacteroides fragilis and other anaerobes of the B. fragilis group, such as B. vulgatus, B. distasonis, and indole-positive B. thetaiotaomicron and B. ovatus, are nearly always piperacillin–tazobactam susceptible (Bourgault et al., 1992; Namavar et al., 1994; Betriu et al., 2008). This also applies to cefoxitin-resistant strains (Aldridge, 1993). The Prevotella spp., such as P. bivia, P. disiens, and P. melaninogenica, and bacteria of the Porphyromonas and Fusobacterium spp. are also nearly always susceptible to piperacillin–tazobactam (Appelbaum et al., 1986; Eliopoulos et al., 1989; Appelbaum, 1993; Appelbaum et al., 1993).

b. Emerging resistance and cross-resistance

Extended-spectrum beta-lactamases (ESBLs) are mainly found in Enterobacteriaceae, in particular in Klebsiella spp. and E. coli. A piperacillin–tazobactam combination is effective against a higher proportion of E. coli and Klebsiella spp. strains (which produce these enzymes) than ticarcillin–clavulanic acid. However, some 18% of E. coli and Klebsiella spp. strains are not inhibited by piperacillin/ tazobactam (Kempers and MacLaren, 1990; Thomson et al., 1990). The efficacy of tazobactam in combination with piperacillin was studied in vitro and in rabbit experimental endocarditis due to a K. pneumoniae strain producing an ESBL, TEM 3. This strain was resistant to piperacillin.

Clinically, emergence of resistance to piperacillin–tazobactam during treatment with that antibiotic has been demonstrated in a case of endocarditis caused by an ESBL-producing strain of K. pneumoniae (Zimhony et al., 2006).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Tazobactam has been administered as piperacillin–tazobactam in a dose of 4.5 g (4 g piperacillin plus 0.5 g tazobactam), infused together i.v. over 5 minutes or, more commonly, over 30 minutes, similar to penicillin G, given 8-hourly (Brismar et al., 1992; Eklund et al., 1993; Strayer et al., 1994). Some clinical investigators have used lower dosages for less severe infections (e.g. 2 g piperacillin plus 0.5 g tazobactam 8-hourly) or a higher doses (e.g. 4 g piperacillin plus 0.5 g tazobactam 6-hourly) for more severe infections (Wise, 1993).

c. Altered dosages Impaired renal function

The pharmacokinetics of piperacillin and tazobactam differs slightly, but this difference is not so great as to warrant independent dosage adjustment of both agents in patients with renal failure. In anuric patients treated with continuous veno-venous hemodialysis, the half-life of piperacillin was 5.6 hours and of tazobactam 5.6 hours with a considerable interpatient variability (Mueller et al., 2002). Hence, monitoring of piperacillin concentrations was recommended in such patients. Peritoneal dialysis removes very little piperacillin and tazobactam, so extra dosing is not required after such dialysis (So¨rgel and Kinzig, 1993).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

The serum levels of piperacillin administered as a single drug are the same as when the drug is given together with tazobactam (So¨rgel and Kinzig, 1993). By contrast, piperacillin inhibits renal clearance of tazobactam, leading to higher tazobactam serum levels and a prolongation of its elimination half-life. Piperacillin probably inhibits tubular secretion of tazobactam.

b. Drug distribution

The distribution of piperacillin in the body is described in Chapter 17, Piperacillin–Tazobactam. After a single i.v. dose of 4 g piperacillin and 0.5 g tazobactam, the latter is well distributed in many body fluids and tissues. The concentrations in fatty tissue and muscle have been estimated to be 10–13% and 18–30% of the levels in plasma, respectively. Adequate tazobactam concentrations are also reached in normal human bone tissue (Incavo et al., 1994). High concentrations of tazobactam are reached in skin and gastrointestinal mucosa, where concentration of the drug exceeds the levels in plasma after 1 hour (Kinzig et al., 1992). High tazobactam concentrations are also attained in lung tissue and bronchial secretions, but its concentration is lower in the gallbladder wall.

c. Clinically important pharmacokinetic and pharmacodynamic features

Similar to other beta-lactam antibiotics, the factor which decides the pharmacodynamic activity of both piperacillin and tazobactam is the time above the minimal inhibitory concentration (MIC). Lodise et al. (2004) showed that for piperacillin–tazobactam at a dose of 3.375 g piperacillin every 6 hours, a concentration exceeding an MIC of r8 mg/l was achieved in 5% of patients using a Monte Carlo simulation model. With administration every 4 hours, the concentrations exceeded an MIC of r16 mg/l. Similar results were reported by Ambrose et al. (2003), who used a stochastic model.

d. Excretion

Both piperacillin and tazobactam are mainly eliminated via the kidneys by both tubular secretion and glomerular filtration. Probenecid reduces the renal elimination of both drugs (So¨rgel and Kinzig, 1993).

Piperacillin’s excretion is unaffected by tazobactam, but piperacillin slows the renal excretion of tazobactam. Overall, 50–60% of the administered dose of both drugs is excreted via the kidneys. Biliary excretion of both drugs is probably low (o5%) (So¨rgel and Kinzig, 1993), although some authors have reported high levels of piperacillin in the biliary tract in patients with no bile duct obstruction. The remainder of both drugs is inactivated, probably chiefly in the liver.

TOXICITY

All reported side-effects are those which may occur with piperacillin alone. Some 4.6% of 944 treated patients developed a gastrointestinal disturbance, usually diarrhea. Diarrhea was the only event reported more often after treatment with piperacillin–tazobactam than with piperacillin alone. Twenty-one patients (2.2%) had drug-related skin rash, erythema, or pruritus. Some patients developed abnormal liver function tests with elevated alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and total bilirubin. This resolved either during treatment or after the cessation of the drug. These adverse reactions were usually not severe, and in most patients therapy could be continued (Kuye et al., 1993).

During piperacillin–tazobactam administration, changes in intestinal microflora can be expected with a slight decrease in the number of enterobacteria and enterococci, as well as some anaerobic bacteria, such as Eubacteria, Lactobacilli, and Clostridium spp. (Nord et al., 1992).

CLINICAL USES OF THE DRUG

a. Intra-abdominal and pelvic infections

Piperacillin/tazobactam in a dosage of 4 g piperacillin plus 0.5 g tazobactam i.v. 8-hourly appears to be effective and safe in the treatment of peritonitis, usually due to a perforated viscus. Slightly superior results have been obtained with piperacillin–tazobactam compared with imipenem–cilastatin in the treatment of some of these infections (Brismar et al., 1992; Eklund et al., 1993).

b. Lower respiratory tract infections

In an open noncomparative study, the majority of patients with pneumonia responded well to piperacillin 4 g plus tazobactam 0.5 g i.v. 8-hourly (Mouton et al., 1993). The main causative organisms were Streptococcus pneumoniae, K. pneumoniae, and H. influenzae. In one comparative trial, piperacillin–tazobactam appeared superior to ticarcillin–clavulanic acid for the treatment of community-acquired bacterial lower respiratory tract infections (Shlaes et al., 1994).

c. Bacteremia

Wise (1993) reported his experience with piperacillin–tazobactam in various types of bacteremia. Most of the patients had a bacteremia in which the focus of infection was the urinary tract and the causative organisms was one of the Enterobacteriaceae such as E. coli, Klebsiella spp., and P. mirabilis. The results of treatment were good in this group, although a small number of these patients did not respond to piperacillin–tazobactam therapy.

d. Skin and soft tissue infections

The results of piperacillin/tazobactam treatment have been good and comparable with those obtained with ticarcillin–clavulanic acid (see Chapter 16, Ticarcillin–Clavulanic Acid) in chronic and complicated skin and soft tissue infections, such as cellulitis with drainage, cutaneous abscesses, diabetic or ischemic foot infections, and infected wounds and ulcers with drainage (Tan et al., 1993; Tassler et al., 1993).

e. Empiric treatment of fever in neutropenic patients

In one prospective randomized trial, piperacillin–amikacin plus teicoplanin was compared with piperacillin–tazobactam plus amikacin. If there was persistence of fever, patients in the latter group also received teicoplanin on day 4, and this was necessary in a large proportion of the second group. It was concluded that piperacillin– tazobactam plus amikacin may be a reasonable combination to use in these patients, provided that either vancomycin or teicoplanin is added in unresponsive cases (Micozzi et al., 1993).

f. Bacterial meningitis

Kern et al. (1990) evaluated the therapeutic efficacy of piperacillin– tazobactam in animal experimental meningitis due to a beta-lactamase-producing strain of E. coli. Only at the relatively high doses of 160/20 and 200/25 mg of piperacillin–tazobactam per kg per hour was the bactericidal activity of this combination similar to that of 10 and 25 mg of ceftriaxone per kg per hour, respectively. As several of the third-generation cephalosporins are very effective for the treatment of bacterial meningitis caused by Gram-negative bacilli, it is unlikely that piperacillin–tazobactam will gain a place in the treatment of this disease.

References

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