In this article the literature comparing piperacillin-tazobactam versus carbapenems for ESBL infections is provided in table format. Consideration for the strengths and limitations of existing data are discussed.
Authored By: Melissa Santibañez, Pharm.D., BCCCP;1 Andrea Duque, Pharm.D.;2 Taylor Harris, Pharm.D.3
1Assistant Professor, Nova Southeastern University College of Pharmacy, Fort Lauderdale FL
2Larkin University College of Pharmacy, Miami FL
3PGY1 Community-Based Pharmacy Resident, Nova Southeastern University College of Pharmacy, Fort Lauderdale FL
Article Posted: 27 June 2021
Question: Can piperacillin/tazobactam be used as a carbapenem-sparing strategy for extended-spectrum beta-lactamase (ESBL) infections?
Multi-drug resistant organisms (MDROs) have become increasingly common when treating infectious processes and are generally defined in Gram negative bacteria by the presence of resistance to >1 antibiotic in >3 antimicrobial drug classes.1 The central goal of antimicrobial stewardship in an atmosphere of MDROs includes limiting unnecessary exposure to broad-spectrum agents. In doing this, we are attempting to preserve agents used for MDROs until such time that we must use them. This plus good infection control is essential toward combating MDROs.2 The desire to save last-line agents encourages clinicians to explore the use of alternative yet effective treatments for MDROs.
Extended-spectrum beta-lactamase (ESBL) production is a subtype of enzymatic deactivation that confers resistance to many penicillins, cephalosporins (except the cephamycins), and the monobactams. ESBL-producing Enterobacteriaceae (e.g., Proteus species, Escherichia coli, and Klebsiella spp (AKA, the “PEcK” organisms) are encountered all too commonly in clinical practice today. Carbapenems (e.g., meropenem) are generally considered the drugs of choice for carbapenem-susceptible ESBL-producing isolates.3 However, it is possible for an ESBL producer to have other resistance mechanisms conferring simultaneous carbapenem resistance.
Piperacillin is a ureidopenicillin that is susceptible to hydrolytic cleavage and inactivation by bacterial penicillinases and ESBLs. The addition of the beta-lactamase inhibitor tazobactam expands the activity of piperacillin alone, allowing it to overcome enzymatic cleavage by some beta-lactamases. Tazobactam inhibits ESBL enzymes, and ESBL-producing bacteria are frequently susceptible to beta-lactam/beta-lactamase inhibitors in vitro. Given its ability to retain activity when many other drugs do not, piperacillin/tazobactam (PZT, Zosyn) may provide a carbapenem-sparing treatment for ESBLs.
There are limited head-to-head studies between PZT and carbapenems for ESBL infections, and the available literature has not universally found statistically significant differences across all clinical outcomes. The table below highlights 14 select studies comparing outcomes in PZT versus carbapenems for ESBL infections (in reverse chronological order). Please note that this is not an exhaustive list of all published literature, but does provide a glimpse at some of the existing data.
Summary of studies comparing outcomes of piperacillin-tazobactam versus carbapenems for ESBL infections
Click here or below to view the full Table 1 PDF.
Data Summary & Considerations
The data seems to support that PZT may be most useful (or at least non-inferior to carbapenems) for ESBL E. coli infections. However, robust clinical studies assessing this are lacking in the literature. Despite non-inferiority of PZT compared to carbapenem therapy as described in multiple prospective and retrospective studies (until MERINO was published), a global difference in efficacy favoring PZT in all ESBL infection types remains to be fully elucidated.
Moreover, while mortality is a significant outcome, it may not represent the most appropriate clinical endpoint to assess infection resolution. Mortality itself has typically been defined as a 30-day all-cause mortality or in-hospital mortality, as opposed to an infection-related mortality. A recent systematic review/meta-analysis of 21 studies (encompassing 1584 patients) determined no significant effect on all-cause mortality from either carbapenem or non-carbapenem use for either empiric or definitive therapy.18 However, most non-carbapenem regimens were cephalosporins or fluoroquinolones, combination regimens were included, and both retrospective and prospective trials were included in the analysis.18 Upon conducting a subgroup analysis of the 13 studies examining carbapenems and BLBLI regimens, there remained no significant effect on all-cause mortality from either carbapenem or BLBLI use for either empiric or definitive therapy.18 The available literature has almost universally lacked an assessment of other infection-related clinical outcomes as primary study outcomes, such as microbiological cure, clinical cure, infection-related length of stay, infection-related costs, and rate of repeat infections. Additionally, most studies have typically examined PZT for empiric use only, and the full effect of PZT as definitive therapy in these patients remains unclear.
Finding the ideal patient to receive PZT for infections caused by ESBL-producing organisms remains a challenge. PZT may be an effective alternative to carbapenems for ESBL-associated infections under the right circumstances (e.g., monomicrobial E. coli urinary tract infections), however identifying such patients may be a challenge in clinical practice due to the myriad of factors that must be considered for a given case. Until such work is completed, clinicians should consider PZT as a possible alternative to carbapenems for ESBLs but should also take note of the limitations discussed above.
REFERENCES & READINGS
1. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert propnosal for interim standard definitions for acquired resistance. Clin Microbial Infect. 2012;18(3):268-81.
2. Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:159-77.
3. Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med. 2010;362:1804-13.
4. Sharara SL, Amoah J, Pana ZD, Simner PJ, Cosgrove SE, Tamma PD. Is piperacillin-tazobactam effective for the treatment of pyelonephritis caused by ESBL-producing organisms? Clin Infect Dis. 2019. [ePub ahead of print.] doi:10.1093/cid/ciz1205.
5. Nasir N, Ahmed S, Razi S, Awan S, Mahmood SF. Risk factors for mortality of patients with ceftriaxone resistant E. coli bacteremia receiving carbapenem versus beta lactam/beta lactamase inhibitor therapy. BMC Res Notes. 2019;12(1):611.
6. Benanti GE, Brown ART, Shigle TL, et al. Carbapenem versus cefepime or piperacillin-tazobactam for empiric treatment of bacteremia due to extended-spectrum-β-lactamase-producing Escherichia coli in patients with hematologic malignancy. Antimicrob Agents Chemother. 2019;63(2):e01813-8.
7. John R, Colley P, Nguyen HL, Berhe M. Outcomes analysis in patients with extended-spectrum beta-lactamase bacteremia empirically treated with piperacillin/tazobactam versus carbapenems. Proc (Bayl Univ Med Cent). 2019;32(2):187‐91.
8. Harris PNA, Tambyah PA, Lye DC, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E. coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. J Am Med Assoc. 2018;320:984-94.
9. Tullos JB, Stoudenmire LL, Pouliot JD. Piperacillin-tazobactam versus carbapenems for the treatment of nonbacteremic urinary tract infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae. Hosp Pharm. 2018;xx:1-6. doi: 10.1177/0018578718817933.
10. Yoon YK, Kim JH, Sohn JW, Yang KS, Kim MJ. Role of piperacillin/tazobactam as a carbapenem-sparing antibiotic for treatment of acute pyelonephritis due to extended-spectrum β-lactamase-producing Escherichia coli. Int J Antimicrob Agents. 2017. doi: 10.1016/j.ijantimicag.2016.12.017.
11. Ko JH, Lee NR, Joo EJ, et al. Appropriate non-carbapenems are not inferior to carbapenems as initial empirical therapy for bacteremia caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: a propensity score weighted multicenter cohort study. Eur J Clin Microbiol Infect Dis. 2018;37:305-11.
12. Seo YB, Lee J, Kim YK, et al. Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli. BMC Infect Dis. 2017;17:404.
13. Ng TM, Khong WX, Harris PNA, et al. Empiric piperacillin-tazobactam versus carbapenems in the treatment of bacteraemia due to extended-spectrum βlactamase-producing Enterobacteriaceae. PLoS One. 2016;11:e0153696.
14. Tamma PD, Han JH, Rock C, et al. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. Clin Infect Dis. 2015;60:1319-25.
15. Tsai H, Chen Y, Tang H, et al. Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis. Diag Microbiol Infect Dis. 2014;80:222-6.
16. Retamar P, Lopez-Cerero L, Muniain MA, et al. Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-β-lactamase-producing Escherichia coli. Antimicrob Agents Chemother. 2013;57:3402-4.
17. Rodriguez-Baño J, Navarro MD, Retamar P, et al. β-lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum βlactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012;54:167-74.
18. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis. J Antimicrob Chemother. 2012;67(12):2793-803.
ABOUT THE AUTHORS
Melissa Santibañez, Pharm.D., BCCCP, is a South Florida native who received a bachelors of science degree from the University of Miami (Coral Gables, FL) in 2008 followed by a doctor of pharmacy degree from Nova Southeastern University (Fort Lauderdale, FL) in 2015. During and prior to her time in pharmacy school she gained vast experience in the hospital pharmacy setting, including serving as a pharmacy buyer. As a fourth-year pharmacy student she completed the 6-month Advanced Clinical Experience Program hosted by Jackson Memorial Hospital (Miami, FL), an intensive program intended to strengthen clinical skills and prepare students for post-graduate residency training.
Dr. Santibañez completed a PGY1 Pharmacy Practice Residency at the University of Illinois at Chicago (Chicago, IL) in June 2016, followed by a PGY2 Critical Care Pharmacy Residency at NewYork-Presbyterian Hospital (New York City, NY) in June 2017. She was an Assistant Professor within the Department of Clinical and Administrative Sciences at Larkin University College of Pharmacy (Miami, FL) for 3.5 years. Currently, she is an Assistant Professor of Critical Care within the Department of Pharmacy Practice at Nova Southeastern University College of Pharmacy (Fort Lauderdale, FL) with a clinical practice site at Memorial Regional Hospital (Hollywood, FL).
She continues to be active in scholarly activity and her current practice areas of interest include antimicrobial stewardship in the intensive care unit, hemostasis and reversal of anticoagulation, heart failure, and pharmacist burnout.
In her spare time, Melissa is a practicing martial artist, having trained in seminars under the grandmasters in Muay Thai kickboxing, Filipino Kali and Eskrima, and Wing Chun Gung Fu. She also occasionally goes mountain biking and competes in obstacle course races, most notably the Ragnar Relay race from Miami to Key West in 2014.
Andrea Duque, Pharm.D. received her Doctorate of Pharmacy degree from Larkin University College of Pharmacy (LUCOP). She was born and raised in Miami, Florida, earned her Associate’s in Arts Degree from Miami-Dade College, and completed her pharmacy prerequisites at Florida International University. She chartered and served as the Director of Finance for the LUCOP Industry Pharmacists Organization (IPhO) student chapter. She also chartered and served as the Student Liaison for the LUCOP Student College of Clinical Pharmacy (SCCP) student chapter.
Dr. Duque previously completed research involving pharmacotherapeutic management of patients with heart failure with a recovered ejection fraction and won LUCOP’s local competition for the ASHP Clinical Skills Competition. Her passion for improving patient outcomes through antimicrobial stewardship was ignited by her infectious diseases professor. As a student and new practitioner, she recognized the obligation to seek out as much knowledge as she can to fight these resistant organisms and maximize wins for her patients. As the current COVID-19 pandemic puts a halt on her favorite hobby of traveling, she finds comfort in watching Netflix and enjoys work out videos she knows she will never actually complete.
Taylor Harris, Pharm.D. was born and raised in South Florida and obtained her Pharm.D. from Larkin University College of Pharmacy (Miami, FL) in May 2021. Dr. Harris graduated from Nova Southeastern University (Ft. Lauderdale, FL) in 2018 with a Bachelors of Science in Biology and a minor in Entrepreneurship. Throughout her undergraduate and graduate studies, she worked as a pharmacy technician at CVS pharmacy and then at Publix Pharmacy, ultimately as a pharmacist intern. Dr. Harris will be completing a PGY1 community-based pharmacy residency program at Nova Southeastern University College of Pharmacy.
While at Nova Southeastern University, Dr. Harris fell in love with the microbiology courses she took. It was then that she began eagerly anticipating the infectious diseases courses offered in pharmacy school. During IPPEs, she was exposed to the possibility of being an infectious diseases pharmacist, and she then proceeded to seek out an APPE in infectious diseases. Experiencing the world of infectious diseases within her didactic pharmacy coursework solidified her interest in pursuing an infectious diseases-related career path, potentially in academia. Her current infectious diseases interests include antimicrobial stewardship, bacterial infections, HIV/AIDS, and sepsis.
Dr. Harris has demonstrated strong pharmacy advocacy efforts, educating both pharmacists and other students to advocate for the profession. She has worked closely with Dade County Pharmacy Association (DCPA) and the Florida Pharmacy Association (FPA) to implement potential resolutions to help ease the stress and unsafe working environments under which retail pharmacists currently work. She has also worked closely with state legislators to help raise awareness for pharmacy-related issues such as working environments, collaborative practice, and pharmacy benefit manager transparency. Dr. Harris coordinated an educational event at Larkin University in 2019 with Florida House Representative Shevrin Jones, during which students and faculty were educated on grassroots advocacy efforts and how to utilize their voices to facilitate change. She also planned Larkin University’s trip to Tallahassee for Florida Legislative Days 2020. She encouraged a large group of LUCOP students to attend, trained them, and set up meetings between students and legislators during the two-day event.
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