Is piperacillin-tazobactam still a valid option for treating infections by ESBL-producing bacteria?

When isolates are susceptible

Is piperacillin-tazobactam still a valid option for treating infections by ESBL-producing bacteria?

Following the MERINO study (1), the consensus of the scientific community (2) is NO. Despite in vitro susceptibility, piperacillin-tazobactam (PTZ) should not be used for extended-spectrum beta-lactamases (ESBL) bacteremia. This landmark randomized controlled trial compared PTZ to meropenem (MER) for treatment of ceftriaxone-resistant E. coli and K. pneumoniae (both PTZ- and MER-susceptible) and found a significant 30-day mortality benefit favoring MER (1). In an era of rising gram-negative resistance (3), the trial’s impact was profound - yet its conclusions challenge core principles of antibiotic stewardship, such as de-escalation (4). This blog post explores the MERINO study in greater detail, according to the following questions:

1. What was the impact of the MERINO study on treatment approaches of ESBL-producing infections?

2. Why MERINO study’s intrinsic flaws may invalidate its conclusions?

3. How to deal with the results from the MERINO study?

1. What was the impact of the MERINO-trial on treatment approaches of ESBL-producing infections?

Before MERINO, the evidence about the equality of PTZ and MER for treatment of ESBL-producing bacteremia was mixed. For instance, the INCREMENT trial, the largest observational trial with nearly 1000 patients, observed similar outcomes between PTZ and MER for ESBL-producing Enterobacteriaceae bloodstream infections, provided in vitro PTZ susceptibility (5). Moreover, two meta-analyses published the same year as MERINO, reported no statistical difference between MER and PTZ, either as empirical or as definitive therapy, although heterogeneity among included studies was high (3).

MERINO was the first, randomized controlled trial to compare PTZ and MER for treatment of third-generation cephalosporin -esistant E. coli and K. pneumoniae. Designed as a non-inferiority trial, it was halted early due to a striking difference in 30-day mortality: 12.3% in the PTZ arm versus 3.7% in the MER arm (1). This finding had a profound impact on clinical practice. Both IDSA and ESCMID updated their guidelines, recommending almost exclusively carbapenems as treatment of choice for bloodstream and severe infections caused by third-generation cephalosporins-resistant Enterobacteriaceae, even when isolates remain susceptible to PTZ (6,7).

A few years after MERINO, the journal JAC-Antimicrobial Resistance published a PRO/CON debate on carbapenems exclusivity for ceftriaxone-resistant Enterobacteriaceae (8). Notably, even the CON-argumentation conceded that alternatives to carbapenems might only be appropriate for mild urinary or biliary tract infections (9).

2. Why MERINO study’s intrinsic flaws may invalidate its conclusions?

The MERINO study is undeniable a landmark trial, addressing a critical clinical question with a pragmatic design. However, its conclusions have been challenged for several reasons:

I) The MERINO study was an undersized trial, which was prematurely terminated.

When the third interim analysis indicated PTZ was unlikely to meet non-inferiority criteria compared to MER, the MERINO study was stopped (1). While ethically justified, this decision was influenced by an assumption in the sample size calculation: PTZ mortality was assumed to be 10%, compared to 14% for MER, reducing the required sample size to 454 patients - far fewer than the 1683 needed if both mortalities were assumed equal (10, 11). As a result, the trial was stopped after recruiting only 22.5% of a more appropriate sample size, increasing vulnerability to random events (11). As most death in the PTZ arm were due to advanced cancer or end-stage liver disease (12), random events likely contributed to the observed 30-day mortality difference.

2) The dosing of PTZ in the MERINO study was suboptimal.

PTZ was administered as 4 grams every 6 hours in a 30-minute infusion. However, a recent meta-analysis demonstrated the superiority of prolonged beta-lactam infusions in sepsis and septic shock (13). Additionally, some pharmacokinetics/pharmacodynamics (PK/PD) studies show that achieving 100% > T_4xMIC is independently associated with microbiological success (14). Especially in ESBL producers with minimum inhibitory concentration (MIC) > 8 mg/L, the likelihood of reaching this target was only 57% in one study when PTZ was given similarly as in MERINO (15). Excluding all MERINO participants with isolates that had a MIC > 8 mg/L by broth microdilution, would have reduced the mortality in the PTZ arm to 4%, resulting in a negative study (9).

3) Non-inferiority was favored by several other factors.

• The mean duration of antibiotic therapy in MERINO was 13.2 days in the PTZ arm and 13.7 days in the MER (1). However, the recent BALANCE trial demonstrated that 7 days of antimicrobial treatment for bloodstream infections is adequate (16).

• Of the total antimicrobial duration, for about half the time participants did not receive the intervention drug, both during empirical and step-down therapy (1).

• Important crossover occurred during the total treatment between PTZ and MER: 26.2% of participants in the MER arm received empirical beta-lactam/beta-lactam inhibitor therapy, while respectively 13.8 and 20.2% of those in the PTZ arm received a carbapenem during empirical or step-down therapy (1).

• At randomization, 40.7% of participants had resolved signs of infection, defined as clinical and microbiological resolution (1).

• Disease severity was low, with only 1.6% of participants having severe infections caused by E. coli or K. pneumoniae (1).

In conclusion: Considering all these facts, it seems much more unlikely that the observed 3-fold increase in all-cause mortality was due to a true difference in efficacy between PTZ and MER (3, 9, 11).

4) Inaccuracies in PTZ susceptibility were the primary reason for the significant mortality difference.

A post-hoc analysis reassessed the PTZ susceptibility by broth microdilution (instead of routinely used methods during the MERINO study, such as Vitek 2, disc diffusion, or E-test) (17). Of all isolates re-tested, 6% were found to be no longer susceptible to PTZ. This change in susceptibility was likely due to the presence of OXA-1, a narrow-spectrum beta-lactamase, known to increase PTZ MICs to 8 to 16 mg/L. Re-analysis of the original trial, excluding patients with PTZ resistant strains, yielded no significant difference (17). However, repeat testing is difficult to interpret due to methodological differences (e.g. different inoculum used) (18). Moreover, inaccuracies in PTZ susceptibility testing remain an issue in current practice (8,18).

3. How to deal with the results from the MERINO study?

 

In the face of rising carbapenem resistance, minimizing unnecessary use of these antibiotics is crucial (9). While awaiting the results of PeterPen - an ongoing randomized trial designed to reassess MERINO’s conclusions (11), several evidence-based actions can be taken:

I. Not every infection caused by ESBL-producing Enterobacteriaceae requires carbapenem therapy. Both IDSA and ESCMID recommend carbapenem-sparing alternatives for non-severe infections, particularly those originating from the urinary tract (6,7).

II. Optimize the PTZ-dosing by using prolonged or continuous infusions (13). As previously mentioned, adequate dosing significantly improves PK/PD target attainment in less susceptible strains (14).

III. Apply a conservative MIC susceptibility breakpoint of ≤ 8 mg/L for PTZ. This threshold is now supported by EUCAST and revised CLSI guidance (11,18). While the CLSI update still considers a MIC of 16 mg/L as susceptible when PTZ is administered by extended infusion (18), both a post-hoc analysis of MERINO and observational studies suggest that a breakpoint of ≤ 8 mg/L is more appropriate (9,11,15,17).

IV. Check for indirect signs of OXA-1 presence. Although no direct molecular test for OXA-1 is currently available (18), indirect clues can help identify its presence. First of all, OXA-1 can be excluded if the isolate is susceptible to both PTZ and amoxicillin-clavulanate (9). Additionally, true PTZ susceptibility can be confirmed using a reformulated E-test (18).

References:

 1. 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. JAMA. 2018 Sep 11;320(10):984-994.

 2. Walker MK, Diao G, Warner S, et al. Carbapenem use in extended-spectrum cephalosporin-resistant Enterobacterales infections in US hospitals and influence of IDSA guidance: a retrospective cohort study. Lancet Infect Dis. 2024 Aug;24(8):856-867.

3. Karaiskos I, Giamarellou H. Carbapenem-Sparing Strategies for ESBL Producers: When and How. Antibiotics (Basel). 2020 Feb 5;9(2):61. doi: 10.3390/antibiotics9020061.

 4. Shrestha J, Zahra F, Cannady, Jr P. Antimicrobial Stewardship. [Updated 2023 Jun 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

5. Gutiérrez-Gutiérrez B, Pérez-Galera S, Salamanca E, et al. A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016 Jun 20;60(7):4159-69.

 6. Paul M, Carrara E, Retamar P, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect. 2022 Apr;28(4):521-547.

7. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clin Infect Dis. 2023 Jul 18:ciad428.

8. Tamma PD, Mathers AJ. Navigating treatment approaches for presumed ESBL-producing infections. JAC Antimicrob Resist. 2021 Feb 24;3(1):dlaa111.

9. Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Pascual A. CON: Carbapenems are NOT necessary for all infections caused by ceftriaxone-resistant Enterobacterales. JAC Antimicrob Resist. 2021 Feb 24;3(1):dlaa112.

10. Missing Information on Sample Size. JAMA. 2019 Jun 18;321(23):2370. doi: 10.1001/jama.2019.6706. Erratum for: JAMA. 2018 Sep 11;320(10):984-994.

11. Bitterman R, Koppel F, Mussini C, et al. Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen). BMJ Open. 2021 Feb 8;11(2):e040210.

12. Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Kahlmeter G. Antibiotics for Ceftriaxone-Resistant Gram-Negative Bacterial Bloodstream Infections. JAMA. 2019 Feb 12;321(6):612-613.

13. Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA. 2024 Aug 27;332(8):638-648.

14. Gatti M, Rinaldi M, Tonetti T, et al. Comparative Impact of an Optimized PK/PD Target Attainment of Piperacillin-Tazobactam vs. Meropenem on the Trend over Time of SOFA Score and Inflammatory Biomarkers in Critically Ill Patients Receiving Continuous Infusion Monotherapy for Treating Documented Gram-Negative BSIs and/or VAP. Antibiotics (Basel). 2024 Mar 25;13(4):296.

15. Zha L, Li X, Ren Z, et al. Pragmatic Comparison of Piperacillin/Tazobactam versus Carbapenems in Treating Patients with Nosocomial Pneumonia Caused by Extended-Spectrum β-Lactamase-Producing Klebsiella pneumoniae. Antibiotics (Basel). 2022 Oct 10;11(10):1384.

16. Daneman N, Rishu A, Pinto R, et al. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. N Engl J Med. 2025 Mar 13;392(11):1065-1078.

17. Henderson A, Paterson DL, Chatfield MD, et al. Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study. Clin Infect Dis. 2021 Dec 6;73(11):e3842-e3850.

 18. Manuel C, Maynard R, Humphries RM. Evaluation of Piperacillin-Tazobactam ETEST for the Detection of OXA-1 Resistance Mechanism among Escherichia coli and Klebsiella pneumoniae. J Clin Microbiol. 2022 Dec 21;60(12):e0143022.