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Prolonged Infusion Piperacillin-Tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients

Results of a Systematic Review and Meta-Analysis*

Rhodes, Nathaniel J., PharmD, MSc, BCPS1,2; Liu, Jiajun, PharmD3; O’Donnell, J. Nicholas, PharmD, MSc, BCPS4; Dulhunty, Joel M., PhD5,6,7; Abdul-Aziz, Mohd H., BPharm (Hons), MClinPharm, PhD8; Berko, Patsy Y., BA1; Nadler, Barbara, MS9; Lipman, Jeffery, MBBCh, DA, FFA, FFA (Crit Care), FCICM, MD5,6; Roberts, Jason A., BPharm (Hons), PhD, BAppSc, FSHP5,6,10,11

doi: 10.1097/CCM.0000000000002836
Clinical Investigations

Objective: Piperacillin-tazobactam is a commonly used antibiotic in critically ill patients; however, controversy exists as to whether mortality in serious infections can be decreased through administration by prolonged infusion compared with intermittent infusion. The purpose of this systematic review and meta-analysis was to describe the impact of prolonged infusion piperacillin-tazobactam schemes on clinical endpoints in severely ill patients.

Design: We conducted a systematic literature review and meta-analysis searching MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to April 1, 2017, for studies.

Interventions: Mortality rates were compared between severely ill patients receiving piperacillin-tazobactam via prolonged infusion or intermittent infusion. Included studies must have reported severity of illness scores, which were transformed into average study-level mortality probabilities.

Measurements and Main Results: Two investigators independently screened titles, abstracts, and full texts of studies meeting inclusion criteria for this systematic review and meta-analysis. Variables included author name, publication year, study design, demographics, total daily dose(s), average estimated creatinine clearance, type of prolonged infusion, prevalence of combination therapy, severity of illness scores, infectious sources, all-cause mortality, clinical cure, microbiological cure, and hospital and ICU length of stay. The review identified 18 studies including 3,401 patients who received piperacillin-tazobactam, 56.7% via prolonged infusion. Across all studies, the majority of patients had an identified primary infectious source. Receipt of prolonged infusion was associated with a 1.46-fold lower odds of mortality (95% CI, 1.20–1.77) in the pooled analysis. Patients receiving prolonged infusion had a 1.77-fold higher odds of clinical cure (95% CI, 1.24–2.54) and a 1.22-fold higher odds of microbiological cure (95% CI, 0.84–1.77). Subanalyses were conducted according to high (≥ 20%) and low (< 20%) average study-level mortality probabilities. In studies reporting higher mortality probabilities, effect sizes were variable but similar to the pooled results.

Conclusions: Receipt of prolonged infusion of piperacillin-tazobactam was associated with reduced mortality and improved clinical cure rates across diverse cohorts of severely ill patients.

1Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, IL.

2Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL.

3Edward Hines Jr. Veterans Administration Hospital, Chicago, IL.

4Albany College of Pharmacy and Health Sciences, Albany, NY.

5Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia.

6University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

7Redcliffe Hospital, Brisbane, QLD, Australia.

8School of Pharmacy, International Islamic University Malaysia, Kuantan, Malaysia.

9Midwestern University, Library Sciences, Glendale, AZ.

10Department of Pharmacy, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia.

11Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.

*See also p. 333.

New affiliations for Dr. Liu: Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, IL; and Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Dr. Roberts’ institution received funding from Bayer, Achaogen, The Medicines Company, MSD, bioMerieux, Astellas, and Infectopharm. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Nathaniel J. Rhodes, PharmD, MSc, Assistant Professor of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, 555 31st St., Downers Grove, IL 60515. E-mail:

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