title: Piperacillin/tazobactam as an alternative antibiotic therapy to carbapenems in the treatment of urinary tract infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae: an in silico pharmacokinetic study.
abstract: Piperacillin/tazobactam (TZP) as an alternative treatment to carbapenems for infections involving extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE) remains debated. In this study, the probabilities of pharmacodynamic (PD) target attainment with different TZP regimens in ESBL-producing Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp) were evaluated in the context of pyelonephritis. Minimum inhibitory concentrations (MICs) of 144 ESBL-Ec and 111 ESBL-Kp from pyelonephritis were measured, and two previously published population pharmacokinetic models were used to determine by Monte Carlo simulation the probabilities of reaching two PD targets (50%fT>MICand 100%fT>MIC) with TZP doses of 4 g three times daily and 4.5 g four times daily given as short (1 h) or prolonged (4 h) infusions or as 12-18 g/day continuous infusions. Only MICs of the 133 ESBL-Ec and 74 ESBL-Kp strains susceptible to TZP according to inhibition zone diameter were considered for the simulations. Results were similar with the two models, and only prolonged and continuous infusions allowed to reach 50%fT>MICwith a probability of >90% irrespective of bacterial species. Continuous infusion and prolonged infusion combined with the maximum dosage were the only condition allowing to achieve 100%fT>MICwith a probability of >70% with this population of ESBL-Ec. A probability of >90% to reach 100%fT>MICwith ESBL-Kp could be obtained only with the 18 g/day continuous-infusion regimen. TZP may be used for treatment for mild pyelonephritis involving susceptible ESBL-Ec provided that administration modalities are optimised. Conversely, for ESBL-Kp the risk of treatment failure may be higher, supporting the use of continuous infusion.
authors.affiliation: Université Paris Descartes, Paris, France; Service de microbiologie-hygiène hospitalière, Hôpital Necker-Enfants malades, AP-HP, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Guet-Revillet
authors.affiliation: Service de microbiologie-hygiène hospitalière, Hôpital Necker-Enfants malades, AP-HP, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Tomini
authors.affiliation: Service de bactériologie-virologie-hygiène, Hôpital Henri-Mondor, AP-HP, Créteil, France; Université Paris-Est, Créteil, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Emirian
authors.affiliation: Université Paris Descartes, Paris, France; Service de microbiologie-hygiène hospitalière, Hôpital Necker-Enfants malades, AP-HP, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Join-Lambert
authors.affiliation: Université Paris Descartes, Paris, France; Service de microbiologie-hygiène hospitalière, Hôpital Necker-Enfants malades, AP-HP, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Lécuyer
authors.affiliation: Université Paris-XIII, Bobigny, France; Unité clinique de prévention des infections, Hôpitaux universitaires Paris Seine-Saint-Denis, France. Electronic address: jrzahar@gmail.com.
authors.forename: Jean-Ralph
authors.initials: JR
authors.lastname: Zahar
authors.affiliation: Service de pharmacologie, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France; UMR 1129, Paris Descartes, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001426:Bacterial Proteins / Q000378:metabolism*; D003198:Computer Simulation; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077725:Piperacillin, Tazobactam Drug Combination; D011704:Pyelonephritis / Q000188:drug therapy*; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D065093:beta-Lactamase Inhibitors; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D001618:beta-Lactamases; C063912:carbapenemase; D010878:Piperacillin
keywords: ESBL; Piperacillin; Pyelonephritis; Tazobactam; UTI