Piperacillin–Tazobactam: Antimicrobial Activity, Susceptibility, Administration and Dosage etc.

Piperacillin–tazobactam (Zosyn, Tazocin) is a beta-lactam/beta-lactamase inhibitor combination first licensed in 1993. The combination is formulated as a sodium salt in an 8:1 piperacillin–tazobactam ratio.

The Wyeth formulation has been reformulated to include ethylenediaminetetraacetic acid (EDTA) and sodium citrate, which permits simultaneous infusion with two aminoglycosides, gentamicin and amikacin, but not tobramycin (Wyeth, 2006).

Piperacillin sodium is an aminobenzyl-penicillin derivative with the chemical formula sodium 6-d( )-alpha-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino-alpha-phenylacetamido) penicillinate (see Chapter 8, Mezlocillin, Azlocillin, Apalcillin and Piperacillin). Its molecule contains a side chain with an ureido group, but because of chemical differences arising from its terminal piperazine structure, it is often not classified as an ureido-penicillin. The chemical formula is C23H26N5NaO7S and the molecular weight is 539.5; the chemical structure is shown in Figure 17.1 (Wyeth, 2006).
Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone (see Chapter 13, Tazobactam and Brobactam). Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1, 2, 3- triazol-1-ylmethyl)-4-thia- 1-azabicyclo [3.2.0] heptane-2-carboxylate-4,4-dioxide. Its chemical formula is C10H11N4NaO5S and its molecular weight is 322.3; the chemical structure of tazobactam is shown in Figure 17.1.

Figure 17.1 Chemical structure of piperacillin and tazobactam.

Piperacillin is bactericidal owing to the irreversible inhibition of penicillin-binding protein (PBP) enzymes that results in the loss of integrity of the cell wall through a complex mechanism involving autolysins that are released after binding. Although tazobactam alone lacks any intrinsic activity, its addition to piperacillin leads to increased stability of piperacillin against beta-lactamases (Perry and Markham, 1999).

Piperacillin–tazobactam has a broad spectrum of activity against the majority of Gram-positive bacteria, Gram-negative bacteria, and anaerobes. Resistant strains include methicillin-resistant Staphylococcus aureus, Enterococcus faecium, Stenotrophomonas maltophilia, and some Pseudomonas, Citrobacter, and Enterobacter species. Many clinical trials have demonstrated efficacy for the treatment of respiratory tract infections, skin and soft tissue infections, complicated intraabdominal and pelvic infection, urinary tract infections, and febrile neutropenia.

ANTIMICROBIAL ACTIVITY

In vitro activity of piperacillin–tazobactam against Gram-negative, Gram-positive, and anaerobic bacteria is summarized in Table 17.1. 

a. Routine susceptibility

Gram-positive bacteria

Piperacillin–tazobactam has excellent activity and spectrum (96–100% susceptible) against oxacillin-susceptible staphylococci, equal to or slightly greater than those of amoxicillin–clavulanate, ticarcillin– clavulanate, ceftriaxone, and ceftazidime (Baron and Jones, 1995; Marshall et al., 1995; Johnson et al., 2002).

Beta-lactamase-producing strains of S. aureus and S. epidermidis are piperacillin/tazobactam sensitive, but methicillin-resistant strains are not (Fass and Prior, 1989; Acar et al., 1993). As with amoxicillin–clavulanic acid (see Chapter 14, Amoxicillin–Clavulanic Acid (Co-Amoxiclav)), S. aureus strains which produce type C beta-lactamase are less susceptible to piperacillin–tazobactam, than type A enzyme producers. Beta-lactamase-producing Enterococcus faecalis strains are also usually susceptible, but E. faecium strains with high-level intrinsic resistance to penicillin G are resistant to this combination (Chen et al., 1993; Okhuysen et al., 1993; Jones et al., 1998).

Gram-negative anaerobic bacteria

Piperacillin–tazobactam has broad-spectrum in vitro activity against both aerobic and anaerobic Gram-negative bacteria. Surveillance studies have demonstrated that piperacillin–tazobactam susceptibility has remained stable for most species of Enterobacteriaceae and also Pseudomonas aeruginosa (Unal and Garcia-Rodriguez, 2005; Turner, 2008). Piperacillin–tazobactam is significantly less active against extendedspectrum beta-lactamase (ESBL)-producing strains of Klebsiella pneumoniae, Escherichia coli, and Proteus spp. (Jones and Pfaller, 2003). In a study of 115 ESBL-producing isolates of E. coli, VITEK-2 (bioMerieux, Marcy l’Etoile, France) activity of piperacillin/tazobactam was 97.4% compared with meropenem (100%), amikacin (100%), cefepime (94.8%), and amoxicillin–clavulanate (84.3%) (Puerto et al., 2006). The probability of attaining time above the minimum inhibitory concentration (MIC) targets of at least 70% of the dosing interval, an important pharmacodynamic indicator of clinical success, is higher with cefepime than with other antimicrobials against E. coli and K. pneumoniae strains exhibiting ESBL phenotypes. Using a stochastic model to predict timesW MIC with standard dosing regimens of piperacillin–tazobactam and cefepime, the probability of achieving target rates was greater with cefepime (Ambrose et al., 2003).

MECHANISM OF DRUG ACTION

Beta-lactam antibiotics are bactericidal as a result of the irreversible inhibition of the PBP enzymes (Samaha-Kfoury et al., 2005). Piperacillin, which is derived from ampicillin by the addition of a hydrophilic heterocyclic group to the a-amino group, has a broader spectrum of activity owing to an increased affinity for PBP-3 (Essack, 2001). Piperacillin has been demonstrated to bind selectively to PBP-3 in E. coli, which interferes with septation and hence cell division (Gin et al., 2007). Tazobactam leads to increased stability of piperacillin against beta-lactamases. Ambler classes A, C, and D beta-lactamases contain a serine residue at the active site similar to PBPs. These enzymes can hydrolyze the beta-lactam ring of some penicillin antibiotics. Tazobactam forms a stable complex with Ambler class A beta-lactamases by irreversibly binding to an acyl-enzyme formed during hydrolysis. This complex protects piperacillin from the hydrolytic activity of beta-lactamases (Yang et al., 1999; Wilke et al., 2005).

In Gram-positive bacteria, the major mechanism of resistance is the alteration of PBPs. E. faecium demonstrates intrinsic resistance to piperacillin–tazobactam due to low affinity for PBP-5 (Gin et al., 2007). Methicillin-resistant S. aureus is also intrinsically resistant because of the low affinity of PBP-2a for piperacillin (Palmer and Rybak, 1997), and mutations of PBP-2b in S. pneumoniae significantly reduces the affinity of this PBP for piperacillin (Gin et al., 2007).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Intravenous administration

Piperacillin and tazobactam are usually administered intravenously as an intermittent dose – both infused together over 5 minutes, or more commonly over 30 minutes. The usual dose is 13.5 g divided into three or four doses daily (most commonly 4.5 g 8/24 or 3.375 g 6/24). These conventional dosing regimens achieve %TW MIC of W 50% for isolates with an MIC of W 8; however, higher doses are required for isolates with an MICW8 (Kim et al., 2001; Kim et al., 2002). Maximal doses of 4.5 g 6-hourly have been used in more severe infections.

Continuous and prolonged dosing strategies

Continuous infusion has been examined in several studies including in healthy volunteers and patients with ventilator-associated pneumonia. These studies report serum levels of approximately 35 mg/l following daily continuous infusion of 12/1.5 g, whereas in the critically ill patient similar levels were observed with 8 g/1 g (Burgess and Waldrep, 2002; Buck et al., 2005; Lau et al., 2006). Piperacillin–tazobactam (128 g/l, pH 6.2) is 90% stable for up to more than 24 hours at 371C and is therefore suitable for use in portable elastomeric pumps and motor-operated syringes (Viaene et al., 2002). Recommended dosing regimens for continuous-infusion administration piperacillin–tazobactam are shown in Table 17.2.

Intraperitoneal administration

Intraperitoneal administration of piperacillin–tazobactam has been reported in a single study evaluating the pharmacokinetics of intraperitoneal (i.p.) piperacillin–tazobactam (Zaidenstein et al., 2000). Six patients with/without pseudomonas peritonitis were given an i.p. loading dose of 4 g/0.5 g piperacillin–tazobactam. Twenty-four hours after the initial dose, a maintenance dose of 0.5 g/0.0625 g piperacillin–tazobactam was administered with each dialysate exchange for a period of 1 week.

Intravitreal administration

Intravitreal piperacillin–tazobactam has been studied in an experimental rabbit model. The highest nontoxic dose to the normal retinas of adult albino rabbits is 250 mg/0.1 ml piperacillin–tazobactam (Ozkiris et al., 2004; Ozkiris et al., 2005a; Ozkiris et al., 2005b; Ozkiris et al., 2005c). It was found to be effective in P. aeruginosa and S. epidermidis rabbit models of endophthalmitis. There are two human case reports of successful treatment of P. luteola and Enterobacter endophthalmitis (Singh et al., 2007; Uy et al., 2007).

Topical administration

Topical use of piperacillin/tazobactam has been studied in the guinea pig middle ear model for the treatment of chronic suppurative otitis media where ciprofloxacin resistance is a problem (Jang et al., 2008). However, human dosing data are limited.

b. Newborn infants and children

The pharmacokinetics of piperacillin and tazobactam have been examined in 24 pediatric patients aged two months to 12 years receiving piperacillin 100 mg/kg plus tazobactam 12.5 mg/kg. Clearance is dependent on body weight but also age in children r2 years.

The maximum concentration (Cmax) for both piperacillin and tazobactam is increased relative to the maximum adult dose, but the predicted time above the minimum inhibitory concentration is slightly decreased. The dosage of piperacillin 100 mg/kg plus tazobactam 12.5 mg/kg administered every 8 hours for pediatric patients Z9 months is predicted to provide coverage 31–61% of the time for the range of MIC values of 2–16 mg/ml commonly found in intraabdominal infections in children. For pediatric patients aged two to nine months, the dose of 100/12.5 mg/kg should be reduced by a factor of 0.8 (i.e. 80/10 mg/kg), because of immature renal function. No data are available to allow additional recommendations for pediatric patients less than two months of age (Tornoe et al., 2007).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Piperacillin–tazobactam must be administered intravenously by infusion or slow bolus injection (Perry and Markham, 1999). The pharmacokinetic parameters for piperacillin/tazobactam taken from healthy volunteers are shown in Table 17.4. Consensus has not been reached as to whether piperacillin displays linear or nonlinear pharmacokinetics (Sorgel and Kinzig, 1994a; Gin et al., 2007). Tazobactam pharmacokinetics appears to be dose dependent when the drug is administered as a single agent in healthy volunteers. When administered together with piperacillin, the Cmax, area under the curve (AUC), and plasma half-life of tazobactam increase (Wise et al., 1991; Sorgel and Kinzig, 1994a; Occhipinti et al., 1997). Tazobactam half-life was prolonged when administered with high-dose piperacillin in a study assessing alternative dosing regimens, perhaps as a result of competitive inhibition of tazobactam renal elimination by piperacillin (Sorgel and Kinzig, 1994a; Occhipinti et al., 1997; Gin et al., 2007).

b. Drug distribution

Piperacillin and tazobactam are widely distributed into tissues and body fluids, with the exception of fat, owing to the hydrophilic nature of the two compounds. Piperacillin–tazobactam concentrations in fat are around 10% of plasma concentrations (Kinzig et al., 1992). Mean tissue concentrations are generally 50–100% of those in plasma. The distribution of piperacillin–tazobactam in various tissues is summarized in Table 17.5.

c. Clinically important pharmacokinetic and pharmacodynamic features

Piperacillin and tazobactam achieve peak concentrations at 1–2 hours post-infusion that reach or exceed concentrations found to be effective in vitro for most extracellular bacteria. Piperacillin–tazobactam plus gentamicin and piperacillin–tazobactam plus ciprofloxacin at physiologic concentrations are synergistic or additive at 24 hours for common bacterial isolates causing serious infections; however, piperacillin–tazobactam and gentamicin are more rapidly bactericidal (Gould and Milne, 1997; Burgess and Nathisuwan, 2002).

The T W MIC can be maximized by administration of piperacillin– tazobactam as a prolonged or continuous infusion. In a study using Monte Carlo analysis, continuous infusion doses of 8 g/1 g and 12 g/ 1.5 g over 24 hours resulted in a median level of exposure 12.62 times the MIC of P. aeruginosa [n = 496, median 4 mg/ml (range, 0.09–64)].

d. Excretion

Piperacillin is metabolized to a minor microbiologically active N-desethyl-piperacillin metabolite and to an inactive metabolite (M1) (Bryson and Brogden, 1994). Tazobactam is metabolized to a single metabolite that lacks pharmacologic and antibacterial activities. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug, with 70–80% of the administered dose excreted in the urine (Welling et al., 1983). Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile, although only piperacillin appears to be actively excreted (Sorgel and Kinzig, 1994a; Westphal et al., 1997).

e. Drug interactions

Key drug interactions for piperacillin–tazobactam are summarized in Table 17.6.

As with other penicillins, the administration of piperacillin– tazobactam may result in a false-positive reaction for glucose in the urine using a copper reduction method (CLINITESTs). It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as DIASTIXs or TES-TAPEs) are used (Wyeth, 2006).

Piperacillin–tazobactam may interfere with the Aspergillus galactomannan assay (Platelia; Bio-Rad, Marnes La Coquette, France) used to investigate invasive aspergillosis in hematology patients (Adam et al., 2004; Maertens et al., 2004; Viscoli et al., 2004; Walsh et al., 2004). In many cases the level of galactomannan exceeds the cut-off for diagnosis of invasive aspergillosis. Piperacillin–tazobactam was found to express high levels of galactomannan in vitro (Walsh et al., 2004).

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