Meropenem o piperacillina / tazobactam ? Lo studio MERINO e dintorni Roma, 11 aprile 2019

1. Meropenem o piperacillina/tazobactam? Lo studio MERINO e dintorniRoma, 11 aprile 2019 Claudio M. Mastroianni Dipartimento Sanità Pubblica e Malattie Infettive

2. Extended-spectrum β-lactamase (ESBL)–producing organisms ESBL • Since 1980: have been recognized as a global threat • ESBLs are most prevalent among Escherichia coli and Klebsiella species

3. Proportion of ESBL-producing Klebsiella pneumoniaeEDCD 2000 2017

5. Mortality according to riskscore <11:5-6% >11: 35-46% (NPP:94%) JAC 2017; 72: 906-913

6. Fecal Colonization With Extended-spectrum Betalactamase–Producing Enterobacteriaceae and Risk Factors Among Healthy Individuals: A Systematic Review and Metanalysis Kranika S et al. ClinInfectDis 2016;63:310 • Pooledprevalence of ESBL colonizationamonhealthyindividuals 14%, increasing trend of 5.4% annually

7. Colonization and infection with extended spectrum beta-lactamase producing Enterobacteriaceae in high-risk patients – Review of the literature from a clinicalperspective Biehl LM et al. CritRevMicrobiol, 2016

8. A simple scoring algorithm predicting extended-spectrum beta-lactamase producers in adults with community-onset monomicrobial Enterobacteriaceae bacteremia Lee C-H et al. Medicine (2017)

9. Treatment strategies • Over time, carbapenems (CPB) have become the first-line treatment option for infections due to ESBL-GNR, even when in vitro activity to other β-lactams is demonstrated • CBP use correlated to increased incidence of carbapenem resistant Enterobacteriaceae (CRE) • Impact of non-carbapenem beta-lactams options

10. Third-generation cephalosporins, particularly ceftriaxone and cefotaxime are associated with poor outcomes and not considered for the treatment of ESBL-associated infections • The increased hydrolytic activity of ESBLs against these drugs

11. β-Lactam/β-lactam inhibitors (BL/BLIs) • Reassessing the possibility of treatment of ESBLs with piperacillin-tazobactam (PTZ) • Impact of newer BL/BLs

13. Venditti M, Readfiles, 2018

17. CONCLUSIONS CBPs should be used as preferred therapy for patients suspected to have ESBL bacteremia For patients at high risk of invasive ESBL infections, early carbapenem therapy should be considered.

19. CONCLUSIONS BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems

23. BL-BLIs Carbapenems • Low to moderate-severityinfections • Urinary or biliarysources • Piperacillin/tazobactam MIC < 4 µg/ml • Criticallyillpatients • High inoculuminfections • ElevatedPiperacillin/tazobactamMICs PTZ: 4.5 g every 6 hours or 4.5 g every 8 hours asextendedinfusion Tamma P and Rodriguez-Bano J Clin Infect Dis 2017; 64(7): 972–980

25. Points of agreement • The decision to use PTZ to treat an infection with an ESBL-GNR is complex and requires consideration of the source of the infection, the severity of the infection, the identity of the organism, the MIC of the organism, and the dosage of antibiotic used. • PTZ may be effective for treating invasive ESBL-GNR infections in patients who are not critically ill and who have a lower inoculum of infection and a lower MIC (2 g/ml). • The strongest data supporting the use of a BLBLI for treating infections caused by ESBL-GNR are those from urinary tract infections and possibly biliary tract infections. • Therapy using BLBLIs appears to be less effective than carbapenem therapy for bloodstream infections due to ESBL-GNR. • If PTZ is used for these infections, the laboratory should report MIC data and perform ESBL confirmatory testing to provide clinicians with optimal information for clinical decisions. • Laboratories that perform ESBL confirmatory testing should consider inclusion of a comment indicating that PTZ therapy may be inadequate for treating bloodstream infections or other serious infections.

26. The hope • «Perhaps the discrepancies between these studies will be resolved with the MERINO trial” • «Hopefully, lingering questions will be answered by the MERINO study, the first randomized controlled trial to address the issue of the use of meropenem versus PTZ for ESBL bloodstream infections» • PD Tamma, J Rodriguez-Baňo 2018

28. Objectives and study population • To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. • Patients were screened for enrollment in 26 hospitals in 9 countries (Australia, New Zealand, Singapore, Italy, Turkey, Lebanon, South Africa, Saudi Arabia, and Canada) from February 2014 to July 2017. • Adult patients were eligible if they had at least 1 positive blood culture with E. coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin tazobactam.

29. Randomization and stratification • 1646 ptsscreened: • 391 (23.8%) randomized, 379 included (191 MER, 188 PTZ) • Ptswererandomizedwithin 72 h of index bloodcultures • Patients were stratified according to infecting species (E coli or Klebsiella spp; groups E or K), presumed source of infection (urinary tract or elsewhere), and severity of disease (Pitt bacteremia score ≤4 or >4). • A high-risk stratum (E2 or K2) was defined by nonurinary source for BSI and Pitt score greater than 4

30. Randomization scheme

31. Intervention and primary outcome • Meropenem, 1 g, was administered every 8 hours intravenously • Piperacillin-tazobactam, 4.5 g,was administered every 6 hours intravenously. • Each dose of study drug was infused over 30 minutes. • Study drug was administered for a minimum of 4 calendar days after randomization and up to 14 days, with the total duration of therapy determined by the treating clinician. • The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5%was used.

32. Interim analysisEarly stop • Following the DSMB review at 340 patients enrolled, a difference in the primary outcome was observed, at a significance level approximating the prespecified stopping rule (P = .004). • This analysis showed that completing full enrollment was highly unlikely to demonstrate noninferiority of piperacillin tazobactam. • To demonstrate superiority of meropen: need for higher number of patients

33. In the pip-tazo group 23 of 187 patients (12.3%) died within 30 days, compared to 7 of 191 (3.7%) in the meropenem group (risk difference, 8.6% [1-sided 97.5% confidence interval (CI), −∞ to 14.5%]). P = .90 for noninferiority • «Among patients with E. coli or K. pneumoniaebloodstream infection (BSI) and ceftriaxone resistance, definitive treatment with piperacillin-tazobactamcompared with meropenemdidnot result in a non-inferior 30-day mortality.”

34. Findings • With a pre-defined non-inferiority margin of 5%, the authors correctly concluded that these data do not support that pip-tazo is non-inferior to meropenem. • Unexpected results of their study may instead have the opposite effect • The study did not demonstrate also the superiority of meropenem.

35. The MERINO trial has important implications for clinicians, clinical microbiologists, and antibiotic stewardship • The results of the MERINO trial make clear that piperacillin-tazobactam should no longer be considered an alternative to meropenem for definitive treatment of bloodstream infection due to ceftriaxone-resistant E. coli or K. pneumoniae.

36. Advantages • Addresses a pertinent clinical question • Pragmatic design of this trial is generalizability to a broad spectrum of acute care settings • Addresses the relevant clinical outcome • Transparent reporting

37. QUESTIONS ????

38. Unbalanced variables in the treatment groups More patients in the PTZ treatment group had nonurinary sources of bacteremia, which was shown in 2 previous studies to lead to worse outcomes for PTZ-based regimens. Although Pitt bacteremia scores were similar between the 2 groups, there were more immunocompromised and neutropenic patients in the PTZ group than the meropenem group.

39. All-cause mortality • All deaths were unrelated to the infection and instead resulted from the underlying diseases (metastatic cancer or end-stage liver disease), and half occurred after 15 days • The lack of infectious mortality could explain the lack of association between PIP/TAZ MICs and mortality. • Secondary outcomes more directly related to infection showed no significantdifferences.

40. ... Nonostante il trend favorisse meropenem non c’era differenza statisticamente significativa in termini di successo microbiologico al giorno 4 e recidiva nei primi 30 giorni.

41. The 30-day mortality of 3.7% in the meropenem group and 12.3% mortality with pip-tazo. • How didmeropenempreventmortality • How didpip-tazokill patients? • The authorsprovide short narratives of allfatalseriousadverse events, and death following treatment failure of the infection for whichpip-tazowasprescribedwas not observed.  • Most patients died from malignancies or yeast infections, for whichbothantibiotics are consideredineffective. BLOG https://reflectionsipc.com/2018/09/21/an-endless-one-sided-confidence-in-pip-tazo/

42. Source control not reported • Patients in the piperacillin-tazobactam group had more infections that often require surgical care to control the source of infection than in the meropenem group (intra-abdominal, surgical site, and skin and soft tissue infections: 24.5% vs 17.3%, respectively) • Adequate source control was not described, although it can affect mortality

43. Geographical distribution • Mortality in the piperacillin-tazobactam group was much higher in the 3 sites from Turkey and South Africa. • Excluding these sites would reduce the mortality in the piperacillin-tazobactam group from 12.3% to 9.4%. Comments of Rodriguez-Bano, JAMA

44. Potenza dello studio • Lo studio è stato calibrato per avere una potenza sufficiente per stabilire la non-inferiorità in termini di all-cause mortality a 30 giorni. • La risposta clinica e microbiologica a 4 giorni e l’eventuale sviluppo di recidive sono parametri più direttamente correlabili all’effetto diretto della terapia antibiotica rispetto alla all-cause mortality a 30 giorni!

45. Microbiological limitations • Local and central antibiotic susceptibility testing using gradient tests may underestimatepiperacillin-tazobactam resistance • Central testing MIC>8 mg/L in 6/132 isolates tested

46. Microbiological limitations • Il 10% degliisolatiavevageni di resistenzalegati ad ampCchenotoriamente non è inibitaefficientemente da tazobactam • Nel 67% deiceppi era inoltreriscontrata la presenza di genibla OXA-1, cosachepuòrendersiresponsabile di scarsaefficacia del tazoctam • La MIC di piperacillina/tazobactam non era correlataagli outcome clinici.

49. Contamination between groups 26/188 empirical therapy with MER 38/188 step down therapy (on day 5 after randomization) with MER = 64/188 (34%) received MER

50. Il protocollo dello studio prevedeva non solo la possibilità di aver ricevuto in empirico l’uno o l’altro farmaco... ma anche la possibilità di step-down therapy. La durata media di utilizzo del farmaco dello studio è stata di soli 6 giorni!!