Pilmis et al. Ann. Intensive Care (2017) 7:113 DOI 10.1186/s13613-017-0334-x REVIEW Open Access Piperacillin–tazobactam as alternative to carbapenems for ICU patients Benoit Pilmis1,2, Vincent Jullien3,4, Alexis Tabah5,6, Jean‑Ralph Zahar7,8* and Christian Brun‑Buisson9 Abstract Several studies suggest that alternatives to carbapenems, and particulary beta-lactam/beta-lactamase inhibitor combinations, can be used for therapy of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL- PE)-related infections in non-ICU patients. Little is known concerning ICU patients in whom achieving the desired plasmatic pharmacokinetic/pharmacodynamic (PK/PD) target may be difcult. Also, in vitro susceptibility to beta- lactamase inhibitors might not translate into clinical efcacy. We reviewed the recent clinical studies examining the use of BL/BLI as alternatives to carbapenems for therapy of bloodstream infection, PK/PD data and discuss potential ecological beneft from avoiding the use of carbapenems. With the lack of prospective randomized studies, treating ICU patients with ESBL-PE-related infections using piperacillin–tazobactam should be done with caution. Current data suggest that BL/BLI empirical use should be avoided for therapy of ESBL-PE-related infection. Also, defnitive therapy should be reserved to patients in clinical stable condition, after microbial documentation and results of susceptibility tests. Optimization of administration and higher dosage should be used in order to reach pharmacological targets. Keywords: Carbapenems, ESBL, Alternatives, Ecological consequences, Outcome Introduction of alternatives to carbapenems such as cephamycins, Since the 1980s, extended-spectrum beta-lactamase piperacillin–tazobactam and others for the treatment of (ESBL)-producing Enterobacteriaceae (ESBL-PE) have ESBL-PE infections should be investigated. A recent sys- been spreading worldwide [1, 2]. Several reports under- tematic review, including two randomized controlled tri- line the concomitant increasing use of carbapenems als and 12 cohort studies, highlighted that the efects of [3, 4]. Indeed, the recently published 2015 ESAC report ADE on antimicrobial resistance have not been properly noted a threefold increased use of carbapenems between studied [7]. However, this strategy is largely promoted by 2010 and 2014 [5]. Tis induces a selective pressure for several scientifc societies and specifcally in critically ill carbapenem-resistant isolates, and recent data suggest patients [8, 9]. Indeed, for severely ill patients, interna- that even a brief exposure to carbapenems increases the tional guidelines recommend the use of broad-spectrum risk of colonization with carbapenem-resistant bacteria antibiotics as frst-line therapy to minimize the risk of (CRB) in intensive care unit patients [6]. inadequate initial antimicrobial treatment, and suggest To reduce the ecological risk associated with the streamlining initial antibiotic therapy and narrowing the increased consumption of last-line antibiotics, two spectrum whenever possible once the pathogen(s) are main strategies are available: (1) searching for alterna- identifed [10]. tive treatments for ESBL-PE-related infections and (2) Until recently, the common rule is to treat infections antimicrobial de-escalation (ADE). Terefore, the use caused by ESBL-producing organism with carbapenems. However, ESBLs are inhibited in vitro by beta-lactamase inhibitors and several studies have suggested the use *Correspondence: [email protected] 7 Département de Microbiologie Clinique, Unité de Contrôle et of β-lactam/β-lactamase inhibitor combinations (BL/ de Prévention du risque Infectieux, Groupe Hospitalier Paris Seine BLIs) such as piperacillin–tazobactam as a carbapenem- Saint‑Denis, AP-HP, CHU Avicenne, 125 rue de Stalingrad, 9300 Bobigny, sparing strategy for the treatment of ESBL-PE-related France Full list of author information is available at the end of the article infections [11–13]. Te recent EUCAST and CLSI [14, © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Pilmis et al. Ann. Intensive Care (2017) 7:113 Page 2 of 17 15] guidelines include BL/BLIs and other beta-lactams restricted inclusion to studies published in the English, (cefepime, third generation cephalosporins, temocillin, Spanish and French languages. cefoxitin) as treatment options for infections caused by ESBL-producing organisms. For a long time, AST catego- Selection criteria rization was based not only on MIC and zone diameter We screened and included studies in three categories measurements but also on the detection of individual according to the following criteria: (1) pharmacokinet- resistance mechanisms, i.e., interpretative reading. Even ics and pharmacodynamics studies, where all studies if in vitro results indicated susceptibility to a drug, the investigating the PK/PD of the potential alternatives to reported category was edited to “resistant” if the pres- carbapenems in ICU patients were included. (2) For clini- ence of a resistance mechanism was confrmed, e.g., in cal studies, we restricted inclusion to studies reporting the case of extended-spectrum beta-lactamases (ESBLs). mortality of patients receiving empirical or defnitive To limit the consumption of carbapenems, CLSI and treatment with a non-carbapenem therapy for an ESBL EUCAST recently abandoned editing of AST reports bacteremia in adult patients. Patients with community-, based on the detection of ESBLs. hospital- and healthcare-associated bacteremia were While several studies are conducted in ICU, data eligible for inclusion. (3) Finally, considering ecological remain scarce concerning other beta-lactams in non- studies, we included any published article reporting car- ICU- [16, 17] and ICU-infected [18–21] patients. Tere- bapenem-resistant Enterobacteriaceae (CRE). Among the fore, only BL/BLIs such as piperacillin–tazobactam eligible articles, studies were included if they reported on (Pip–Taz) could be used in ICU patients, but there are exposure to any previous antibiotic class as a risk factor concerns that: (1) no randomized controlled trials com- associated with CRE acquisition. pared specifcally carbapenems to Pip–Taz for the treat- ment of ESBL-PE-related infections [22]; (2) in vitro Results susceptibility to β-lactamase inhibitors might not predict Microbiological susceptibility clinical efcacy; and (3) the success of BL/BLIs depends Several studies suggested that ESBL-PE were susceptible on pharmacokinetic–pharmacodynamic target attain- to non-carbapenem beta-lactams. However, the preva- ment, which current dosing recommendations may not lence of susceptibility depends on the species concerned, guarantee. Terefore, alternatives are seldom used in the antibiotic class and local epidemiology. ESBL-pro- clinical practice for treating serious infections caused by ducing E. coli is usually regarded as more susceptible ESBL-PE. to all beta-lactams than ESBL-producing K. pneumo- In critically ill patients, pharmacokinetics of beta-lac- niae, piperacillin–tazobactam (Pip–Taz) being the most tam antibiotics difers from healthy volunteers. Lower efective antibiotic [28]. North American data from the than expected concentrations have been reported for 2010–2014 SMART programs fnd that 4, 10 and 46% meropenem, piperacillin, amoxicillin, as well as for ceph- of ESBL-producing E. coli were susceptible to ceftriax- alosporins [23–26]. Besides, the risk of treatment failure one, cefepime and ceftazidime, respectively [28], whereas may be exacerbated when using antibiotics exposed to 96–98 and 69% of ESBL-producing E. coli isolates from the inoculum efect [27], as are most beta-lactams. urinary tract [29] and from patients with pneumonia [30] Tis narrative review, based on microbiological, phar- were found susceptible in vitro to Pip–Taz, respectively. macodynamics, clinical and ecological data, describes the Conversely, only 26.9% of ESBL-producing Klebsiella available evidence for the use of Pip–Taz as an alternative spp. isolates from patients with pneumonia were suscep- to carbapenems in critically ill patients and to provide tible to Pip–Taz [30]. Asian data on ESBL-producing E. some guidance to prescribers for using these drugs when coli fnd similar susceptibilities, with 1.6, 9.5, 33.4 and treating infections caused by ESBL-PE. 84.5% isolates susceptible to cefotaxime, cefepime, cef- tazidime and Pip–Taz, respectively [29]. It is noteworthy Methods that in silico PK/PD studies aiming to evaluate the use of Literature search alternatives to carbapenems for treatment of ESBL-PE A literature search was performed via PubMed, including infections suggest that ESBL-Kp susceptibility is over- all records from 1990 through April 2016. Te following estimated by conventional methods in comparison with search pattern was applied: (ESBL OR extended-spec- E-test susceptibility testing. trum β-lactamases) AND (infection) AND (cefepime OR cefoxitine OR cephamycins OR fomoxef OR BL/BLI OR Pharmacokinetics and pharmacodynamics studies Piperacillin–tazobactam OR Carbapenems OR temocil- According to epidemiological data, two main antibiotics lin OR alternatives). Reference lists were