Piperacillin–Tazobactam: Clinical Uses and Toxicity

Piperacillin–tazobactam is used for a wide variety of clinical indications. Table 17.7 summarizes the randomized clinical trials that have assessed the clinical efficacy of this drug.

Clinical Uses

a. Intra-abdominal and pelvic infection

Piperacillin–tazobactam is an effective antimicrobial for the treatment of complicated intra-abdominal infections (IAIs) with clinical and microbiologic response rates similar to those of imipenem, ertapenem, and moxifloxacin. A meta-analysis of 40 clinical trials in 5094 patients with secondary peritonitis demonstrated equivalence among various agents for efficacy and toxicity (Wong et al., 2005). No specific recommendations can be made for the use of antibiotics as first-line treatment of secondary peritonitis in adults as all regimens showed equivocal efficacy. Other factors such as local guidelines and preferences, ease of administration, costs, and availability must therefore be taken into consideration in deciding the antibiotic regimen of choice.

Pharmacodynamic profiling using Monte Carlo simulation for secondary peritonitis found that the cumulative fraction of response (CFR) was Z90% for piperacillin–tazobactam 3.375 g 6-hourly, cefepime 1 g 12-hourly, and ceftazidime 2 g 8-hourly both with metronidazole, and imipenem–cilastatin 500 mg 6-hourly (Eagye et al., 2007a).

Since 2000, several randomized clinical trials (RCTs) have compared piperacillin–tazobactam with various comparators for the treatment of complicated IAI and pelvic infection. These are summarized in Table 17.7. Overall, the clinical response rates and microbiologic cure rates for piperacillin–tazobactam are similar to those for moxifloxacin, once-daily ertapenem, imipenem, and ciprofloxacin plus metronidazole. Pooled data from clinical trials have been used to compare piperacillin– tazobactam and imipenem–cilastatin based on clinical outcomes of studies with different lengths of follow-up (between 2 and 6 weeks) (Dietrich et al., 2001). 

b. Lower respiratory tract infections

The spectrum of activity of piperacillin–tazobactam extends to most pathogens encountered in severe bacterial pneumonia. The majority of nosocomial pneumonia clinical trials have used a combination of piperacillin–tazobactam and an aminoglycoside. In general, the clinical efficacy of the piperacillin–tazobactam arm was similar to imipenem, ceftazidime, and aztreonam for nosocomial pneumonia including patients in ICUs and those who were mechanically ventilated. The clinical and microbiologic cure rates have favored the piperacillin–tazobactam (plus aminoglycoside) arm in several studies (Brun-Buisson et al., 1998; Jaccard et al., 1998; Joshi et al., 1999). Two double-blind RCTs have compared piperacillin–tazobactam and imipenem (Joshi et al., 2006; Schmitt et al., 2006). In the study by Joshi et al. (2006), microbiologic cure rates were higher for Grampositive infections (83% for piperacillin–tazobactam vs 75% for imipenem) than for Gram-negative infections (72% for piperacillin– tazobactam vs 77% for imipenem). Superinfection rates were also lower in the piperacillin–tazobactam arm (Joshi et al., 2006). A single study has demonstrated efficacy of piperacillin–tazobactam as a single agent compared with amoxicillin–clavulanate with a single dose of aminoglycoside (Speich et al., 1998).

c. Bacteremia

Empiric antibiotic therapy for severe sepsis should be selected according to the bacterial epidemiology within each unit or hospital and the aim should be to optimize outcome while attempting to reduce the potential for resistance development. The broad spectrum of piperacillin–tazobactam activity and dosing that achieves or exceeds concentrations found to be effective in vitro for the most common Gram-negative pathogens causing sepsis makes it an excellent option as an empiric first-line agent for sepsis (see earlier under 2a. Routine susceptibility). However, outcomes of infections in relation to the MIC of the infecting pathogen have shown decreasing clinical efficacy with increased MICs, highlighting the importance of pharmacodynamics and pharmacokinetics in the management of infection (see earlier under 5. Pharmacokinetics and pharmacodynamics).

d. Skin and soft tissue infections

The efficacy of piperacillin–tazobactam has been well demonstrated in the treatment of 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. Six double-blind RCTs have demonstrated equivalence of piperacillin–tazobactam with moxifloxacin (Giordano et al., 2005; Lipsky et al., 2007), ertapenem (Graham et al., 2002; Gesser et al., 2004a; Gesser et al., 2004b; Lipsky et al., 2005), and clina- floxacin (Siami et al., 2001). In particular, oral switch to amoxicillin– clavulanate from i.v. piperacillin–tazobactam was as efficacious as i.v. to oral moxifloxacin (Giordano et al., 2005; Lipsky et al., 2007).

e. Empiric treatment of fever in neutropenic patients

Piperacillin–tazobactam has been studied as both part of a dualtherapy regimen and as a single agent for the treatment of fever and neutropenia since 1998. Dual-therapy regimens usually included an aminoglycoside. A meta-analysis of beta-lactam monotherapy versus beta-lactam plus aminoglycoside included 47 trials in 4707 patients, the majority with hematologic malignancies (Paul et al., 2006). Only nine trials included the same beta-lactam in each arm. Although there was significant heterogeneity, there was no difference in all-cause fatality between the two arms, and no difference in clinical failure. There was significantly increased toxicity in the aminoglycoside arm. Piperacillin–tazobactam has been included in seven trials as monotherapy. The comparator agent was cefepime in four trials (Bohme et al., 1998; Hess et al., 1998; Corapcioglu et al., 2006; Harter et al., 2006) and carbapenem in two trials (Reich et al., 2005). The subgroup analysis, when comparing piperacillin–tazobactam and comparators, demonstrated an all-cause mortality of 0.62 (95% CI 0.34–1.13).

Piperacillin/tazobactam appeared to have an advantage over cefepime but not carbapenems for treatment failure, however, the sample size was small.

f. Bacterial meningitis

Kern et al. (1990) evaluated the therapeutic efficacy of piperacillin– tazobactam in animal experimental meningitis due to a beta-lactamaseproducing strain of E. coli. Only at the relatively high doses of 160/20 and 200/25 mg/kg/h piperacillin–tazobactam was the bactericidal activity of the combination similar to that of 10 and 25 mg/kg/h ceftriaxone, respectively. In another experimental model, increased dosing of tazobactam (80:25 mg/kg/h) was effective in reducing hydrolysis of piperacillin by TEM-3 extended-spectrum beta-lactamase-producing K. pneumoniae (Leleu et al., 1994). 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.

g. Surgical prophylaxis

Piperacillin–tazobactam surgical prophylaxis has been studied in a placebo-controlled RCT involving 501 patients undergoing hernia repair and breast surgery (Cormio et al., 2002). The use of placebo, prolonged surgery ofW45 minutes, and diabetes were independently associated with increased risk of infection. Another placebo-controlled study comparing piperacillin–tazobactam and cefuroxime significantly reduced periostomal wound infection in patients undergoing percutaneous endoscopic gastroscopy insertion (Gossner et al., 1999). Other RCTs have compared piperacillin–tazobactam with ciprofloxacin (Cormio et al., 2002) and cefuroxime (Brewster et al., 1995) for prostatic surgery with similar efficacy. A 3-day course of piperacillin–tazobactam compared with a single dose for minimum incision endoscopic surgery for radical prostatectomy showed a reduced infection rate (3.8% vs 6.1%) that was not statistically significant (Sakura et al., 2008).

Piperacillin–tazobactam has also been used as antibiotic prophylaxis for various procedures involving the liver and biliary tract with reported success (Geschwind et al., 2002; Berger et al., 2006; Elias et al., 2006).

TOXICITY

In general, piperacillin–tazobactam is a combination with low toxicity. All reported side-effects are those which could occur with piperacillin alone. The most common adverse affects reported are diarrhea and dermatologic reactions. In the phase I and II studies, 4.6% of 944 treated patients developed a gastrointestinal disturbance, usually diarrhea (3.8%). 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, SGOT, SGPT, and total bilirubin. This resolved either during treatment or after the cessation of the drug.

a. Clostridium difficile infection

Antimicrobial agents such as the third-generation cephalosporins, lincosamides, and aminopenicillins are well known for their propensity to induce Clostridium difficile infection (CDI), but the definitive reasons why remain to be elucidated. Despite their broad spectrum of activity against both aerobic and anaerobic bacteria, the ureidopenicillins remain a class of antimicrobials infrequently associated with the development of CDI (Baines et al., 2005). In fact, the use of piperacillin–tazobactam has been temporally associated with reduced rates of C. difficile diarrhea; however, the reason for this is unclear (Settle et al., 1998; Alston and Ahern, 2004; Wilcox et al., 2004). 

b. Hematologic effects

Piperacillin-induced neutropenia is rare and usually reversible. The etiology is thought to be proliferation arrest of myeloid cells; however, IgG antibodies against penicillins have also been found. A systematic review of neutropenia associated with the use of piperacillin with and without tazobactam was reported by Scheetz et al. (2007).

c. Hypersensitivity

Piperacillin may provoke any of the reactions which occur with penicillin G; thus piperacillin is contraindicated in patients with a history of penicillin hypersensitivity. In a survey of 485 hospitalized patients treated by piperacillin, the frequency of hypersensitivity reactions, such as drug fever, rashes, pruritus, and eosinophilia, was approximately 4% (Gooding et al., 1982). Among 63 patients whose chronic Pseudomonas osteomyelitis was treated with high doses of extended-spectrum penicillins for prolonged periods, side-effects such as rash, drug fever, and eosinophilia were more common in patients treated with ureidopenicillins than in those treated with carbenicillin (Lang et al., 1991; Fahim et al., 2006).

d. Neurotoxicity

High doses of piperacillin–tazobactam given intravenously, similar to ‘‘massive’’ doses of penicillin G, may have the propensity to cause neurotoxicity. Hemodialysis has been shown to rapidly terminate the piperacillin-induced encephalopathy (Lin et al., 2007).

Paresthesia has been associated in a single case report of a 27-year old man with delayed-type hypersensitivity syndrome due to piperacillin–tazobactam (Lambourne et al., 2006).

e. Electrolyte and acid-base disturbance

Piperacillin and tazobactam are both monosodium salts, and the combination product contains a total of 2.79 mEq (64 mg) of sodium per gram of piperacillin. Fluid overload and hypokalemia should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

f. Fetal toxicity

Teratology studies were performed in mice and rats given a piperacillin and tazobactam combination at doses one or two times, respectively, the human dose based on body surface area (mg/m2 ) revealed no evidence of harm to the fetus. In addition, no evidence of harm to the fetus was found when tazobactam was administered to mice and rats at doses of up to 6 and 14 times the human dose, respectively, based on body surface area (mg/m2). Tazobactam crosses the placenta in mice; concentrations in the fetus are 10% or less of those found in maternal plasma.

References

Esposito S, Leone S, Noviello S et al. (2006). Antibiotic prophylaxis in hernia repair and breast surgery: a prospective randomized study comparing piperacillin/tazobactam versus placebo. J Chemother 18: 278.
Essack SY (2001). The development of beta-lactam antibiotics in response to the evolution of beta-lactamases. Pharm Res 18: 1391.
Eucast. EUCAST clinical MIC breakpoints. www.srga.org/eucastwt/MICTAB/ MICpenicillins.html, 2008.
Fahim S, Jain V, Victor G, Pierscianowski T (2006). Piperacillin-tazobactaminduced drug hypersensitivity syndrome. Cutis 77: 353.
Fass RJ, Prior RB (1989). Comparative in vitro activities of piperacillintazobactam and ticarcillin-clavulanate. Antimicrob Agents Chemother 33: 1268.
Gorschluter M, Hahn C, Fixson A et al. (2003). Piperacillin-tazobactam is more effective than ceftriaxone plus gentamicin in febrile neutropenic patients with hematological malignancies: a randomized comparison. Support Care Cancer 11: 362.
Gossner L, Keymling J, Hahn EG, Ell C (1999). Antibiotic prophylaxis in percutaneous endoscopic gastrostomy (PEG): a prospective randomized clinical trial. Endoscopy 31: 119.
Gould IM, Milne K (1997). In-vitro pharmacodynamic studies of piperacillin/ tazobactam with gentamicin and ciprofloxacin. J Antimicrob Chemother 39: 53.
Graham DR, Lucasti C, Malafaia O et al. (2002). Ertapenem once daily versus piperacillin-tazobactam 4 times per day for treatment of complicated skin and skin-structure infections in adults: results of a prospective, randomized, double-blind multicenter study. Clin Infect Dis 34: 1460.
Harter C, Schulze B, Goldschmidt H et al. (2006). Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial. Bone Marrow Transplant 37: 373.
Hess U, Bohme C, Rey K, Senn HJ (1998). Monotherapy with piperacillin/ tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients. Support Care Cancer 6: 402.
Joshi M, Bernstein J, Solomkin J et al. (1999). Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin for the treatment of patients with nosocomial lower respiratory tract infection. Piperacillin/tazobactam Nosocomial Pneumonia Study Group. J Antimicrob Chemother 43: 389.
Joshi M, Metzler M, McCarthy M et al. (2006). Comparison of piperacillin/ tazobactam and imipenem/cilastatin, both in combination with tobramycin, administered every 6 h for treatment of nosocomial pneumonia. Respir Med 100: 1554.
Kadima TA, Weiner JH (1997). Mechanism of suppression of piperacillin resistance in enterobacteria by tazobactam. Antimicrob Agents Chemother 41: 2177.
Kern W, Kennedy SL, Sachdeva M et al. (1990). Evaluation of piperacillintazobactam in experimental meningitis caused by a beta-lactamaseproducing strain of K1-positive Escherichia coli. Antimicrob Agents Chemother 34: 697.
Kim A, Sutherland CA, Kuti JL, Nicolau DP (2007). Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion? Pharmacotherapy 27: 1490.
Kim MK, Xuan D, Quintiliani R et al. (2001). Pharmacokinetic and pharmacodynamic profile of high dose extended interval piperacillintazobactam. J Antimicrob Chemother 48: 259.