Update: Does extended infusion piperacillin-tazobactam (Zosyn) improve clinical outcomes?

Introduction

In 2012, the Drug Information Group reviewed the literature related to extended infusions of piperacillin-tazobactam, which can be accessed here.¹ Additional literature has been published since the last review, and the purpose of this article is to describe the updated literature on the use of extended or continuous piperacillin-tazobactam infusions. This FAQ will focus on the specific areas of clinical efficacy, safety, and pediatrics where literature was lacking at the time of last review.

Clinical efficacy

In the 2012 FAQ all included clinical evidence was based on retrospective data with 4 hour infusions of piperacillin-tazobactam. Additional literature including prospective, randomized studies; studies with alternative infusion lengths including continuous infusion; and systematic reviews/meta-analyses were reviewed to provide a more comprehensive picture.

Efficacy of prolonged infusions

Several systematic reviews/meta-analyses comparing prolonged infusions of beta-lactams (including piperacillin-tazobactam) with traditional, short-term intermittent infusions have been conducted.^2-10 Although there are differences in methodologies, patient populations, and antibiotic dosing/administration strategies, the overall evidence supports equal or superior efficacy of prolonged piperacillin-tazobactam infusions compared with intermittent infusions for most patients. It appears that patients who are at risk of infection with a drug-resistant pathogen and those who are severely ill are most likely to benefit from prolonged infusion.

A more detailed look at the most recent meta-analysis specific to piperacillin-tazobactam by Rhodes and colleagues provides an up-to-date summary of the current literature.² The meta-analysis included 18 studies comparing prolonged infusion (including extended infusion and continuous infusion) of piperacillin-tazobactam with standard intermittent infusion in severely ill patients. The authors chose all-cause mortality at first follow-up as their primary endpoint. A total of 3401 patients were included  with 56.7% of those receiving prolonged infusion. The overall mortality rate was 13.5% in the prolonged infusion group compared with 19.5% in the intermittent infusion group. The odds ratio (OR) for death in the fixed-effects model was significantly lower with prolonged infusion (OR 0.69; 95% confidence interval [CI], 0.56 to 0.84). Other endpoints are summarized in Table 1. Heterogeneity was deemed low or moderate for most outcomes with the exception of intensive care unit length of stay. This meta-analysis supports the use of prolonged infusion dosing strategies for piperacillin-tazobactam similar to previously conducted meta-analyses.

One noteworthy clinical trial has been published since the 2018 meta-analysis. Ram and colleagues conducted a single-center, open-label, randomized trial in 105 patients with febrile neutropenia.¹¹ Patients were treated with either piperacillin-tazobactam (4.5 g every 8 hours) or ceftazidime (2 g every 8 hours) and randomized to either a 30-minute infusion or a 4-hour extended infusion. Patients in the extended infusion group received an initial loading dose over 30 minutes with the first extended infusion administered 6 hours later. The primary endpoint was overall response (resolution of fever and other signs and symptoms plus sterile blood culture) on day 4 after symptom onset. The majority of patients (91.4%) were initially treated with piperacillin-tazobactam. In the intention to treat population, 32 patients (55.1%) in the 30-minute infusion arm responded compared with 35 patients (74.4%) who received the extended infusion (absolute difference, 19.3%; 95% CI, 1.4% to 37.1%). The number needed to treat was 5 patients for each response. The authors concluded that extended infusion of beta-lactams improves outcomes in patients with febrile neutropenia compared to short infusion durations.

Continuous versus extended infusion

Although the above meta-analysis did not attempt to differentiate outcomes with piperacillin-tazobactam given as an extended infusion (infused over 3 or 4 hours) or as a continuous infusion (infused over 24 hours), an editorial accompanying this article performed further analysis.¹² The authors found no significant difference in mortality between these 2 methods using meta-regression (absolute difference in mortality 1.8%; 95% CI -3.8% to 7.4%). With no differences found in mortality, the authors concluded that extended infusion regimens are preferred to continuous infusion regimens based on the lack of information supporting long-term stability of piperacillin-tazobactam. However, the authors of the original meta-analysis argued that differences in study design and patient populations prohibit comparison between extended infusion and continuous infusion studies. No study directly comparing these methods was identified.

Pediatrics

The clinical efficacy of extended-infusion piperacillin-tazobactam was described in a retrospective case series of 50 children.¹³ Piperacillin-tazobactam was administered over 4 hours at a median dose of 111.4 mg/kg every 8 hours. The median age was 5 years. All patients achieved microbiologic cure and 74% were clinically cured. The authors concluded that piperacillin-tazobactam given by extended infusion is effective in pediatric patients, but additional study is necessary.

Safety

The majority of literature on the safety of prolonged infusions focuses on the risk of nephrotoxicity.^14-17  A large, retrospective, matched cohort study identified 2390 adult patients who had received piperacillin, cefepime, or meropenem for at least 48 hours.¹⁵ A total of 1700 patients received standard intermittent infusions while 690 received prolonged infusion. The incidence of acute kidney injury was similar between groups (21.6% with prolonged infusion compared with 18.6% with intermittent infusion). Nephrotoxicity is a concern with concomitant vancomycin and piperacillin-tazobactam. A couple of studies have evaluated whether extended infusions of piperacillin-tazobactam increase this risk compared with standard infusion length; however, both studies found similar rates of nephrotoxicity in patients who received either extended or standard infusions of piperacillin-tazobactam.^16,17

Ongoing Studies

A phase 3 study known as the Beta-Lactam Infusion Group (BLING) III trial comparing intermittent beta-lactams with continuous infusion beta-lactams is ongoing.¹⁸ Patients in this study receive either continuous or intermittent infusion of a beta-lactam (either piperacillin-tazobactam or meropenem). It is expected to enroll 7000 critically ill patients with sepsis by 2021. A study designed to evaluate whether therapeutic drug monitoring with prolonged piperacillin-tazobactam infusions is beneficial is also underway.¹⁹

Conclusion

The efficacy of piperacillin-tazobactam as a prolonged infusion is now well documented in the literature. Although there are few prospective trials, multiple meta-analyses/systematic reviews have found benefit, including improved mortality, with prolonged infusions compared to standard intermittent infusions. Retrospective studies on the safety of prolonged infusions have focused on nephrotoxicity. Although the data are limited, there does not appear to be increased nephrotoxicity with prolonged infusion of piperacillin-tazobactam. At this time, it remains unclear whether extended infusion (generally over 4 hours) or continuous infusion is preferred. A large, prospective trial known as BLING III may offer additional insight into the safety and efficacy of continuous infusion beta-lactam antibiotics.

References

1. Does extended infusion piperacillin-tazobactam (Zosyn) improve clinical outcomes? UIC Drug Information Group website. https://pharmacy.uic.edu/departments/pharmacy-practice//centers-and-sections/drug-information-group/2014/2012/november-2012-faqs. Published November 2012. Accessed June 24, 2019.
2. Rhodes NJ, Liu J, O'Donnell JN, et al. Prolonged infusion piperacillin-tazobactam decreases mortality and improves outcomes in severely ill patients: results of a systematic review and meta-analysis. Crit Care Med. 2018;46(2):236-243.
3. Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2018;18(1):108-120.
4. Yang H, Cui X, Ma Z, Liu L. Evaluation outcomes associated with alternative dosing strategies for piperacillin/tazobactam: a systematic review and meta-analysis. J Pharm Pharm Sci. 2016;19(2):274-289.
5. Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous versus intermittent β-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681-91.
6. Yang H, Zhang C, Zhou Q, Wang Y, Chen L. Clinical outcomes with alternative dosing strategies for piperacillin/tazobactam: a systematic review and meta-analysis. PLoS One. 2015;10(1):e0116769.
7. Yusuf E, Spapen H, Piérard D. Prolonged vs intermittent infusion of piperacillin/tazobactam in critically ill patients: a narrative and systematic review. J Crit Care. 2014;29(6):1089-1095.
8. Teo J, Liew Y, Lee W, Kwa AL. Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: a meta-analysis. Int J Antimicrob Agents. 2014;43(5):403-411.
9. Shiu J, Wang E, Tejani AM, Wasdell M. Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database Syst Rev. 2013 Mar 28;(3):CD008481.
10. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56(2):272-282.
11. Ram R, Halavy Y, Amit O, et al. Extended vs bolus infusion of broad-spectrum β-lactams for febrile neutropenia: an unblinded, randomized trial. Clin Infect Dis. 2018;67(8):1153-1160.
12. Messori A, Tulli G, Caccese E, Trippoli S, Marinai C. Piperacillin-tazobactam: extended infusion versus continuous infusion. Crit Care Med. 2018;46(7):e725.
13. Knoderer CA, Karmire LC, Andricopulos KL, Nichols KR. Extended infusion of piperacillin/tazobactam in children. J Pediatr Pharmacol Ther. 2017;22(3):212-217.
14. McCormick H, Tomaka N, Baggett S, et al. Comparison of acute renal injury associated with intermittent and extended infusion piperacillin/tazobactam. Am J Health Syst Pharm. 2015;72(11 Suppl 1):S25-S30.
15. Cotner SE, Rutter WC, Burgess DR, Wallace KL, Martin CA, Burgess DS. Influence of β-lactam infusion strategy on acute kidney injury. Antimicrob Agents Chemother. 2017;61(10):e00871-17.
16. Mousavi M, Zapolskaya T, Scipione MR, Louie E, Papadopoulos J, Dubrovskaya Y. Comparison of rates of nephrotoxicity associated with vancomycin in combination with piperacillin-tazobactam administered as an extended versus standard infusion. Pharmacotherapy. 2017;37(3):379-385.
17. Karino S, Kaye KS, Navalkele B, et al. Epidemiology of acute kidney injury among patients receiving concomitant vancomycin and piperacillin-tazobactam: opportunities for antimicrobial stewardship. Antimicrob Agents Chemother. 2016;60(6):3743-3750.
18. Lipman J, Brett SJ, De Waele JJ, et al. A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis: BLING III. Crit Care Resusc. 2019;21(1):63-68.
19. Hagel S, Fiedler S, Hohn A, et al; TARGET Study Group. Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam to improve outcome in patients with sepsis (TARGET): a prospective, multi-centre, randomised controlled trial. Trials. 2019;20(1):330.

Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
August 2019

The information presented is current as of July 11, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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