Extended for serious infections. The use of piperacillin-tazobactam

Extended spectrum ?-lactamases (ESBLs) are increasing causes of resistance in Enterobacteriaceae infections, led to a growing utilization of broad-spectrum antibiotics, mostpredominantly the carbapenem agents. The effective carbapenem-sparing alternatives for themanagement of these infections have reviewed for active empirical therapy and choices of definitive treatment. We performed a literature search of clinical studies published in Englishfrom January 2000 to October 2017 using the PubMed database with the search terms “extended spectrum beta lactamase(s)” AND “treatment” and “ESBLs” AND “treatment”.

Recent studies demonstrated a correlation between the minimum inhibitory concentrations(MICs) of causative organisms and the clinical outcomes, and pharmacokinetic/pharmacodynamic modelling indicated the importance of the MICs inachieving therapeutic targets. Based on the available data, carbapenems are considered thedrugs of choice for serious infections. The use of piperacillin-tazobactam and cefepime in thetreatment of ESBL-producing Enterobacteriaceae is not widely recommended, especially inpatients with critical conditions and empirical therapy strategy. The use of carbapenems maybe reserved for patients with severe infections or critical illness caused by ESBL-producing bacteria. De-escalation therapy should always be performed if feasible, alternative therapeuticapproaches may be considered based on the susceptibility test results and clinical settings. Keywords: Extended-spectrum beta-lactamases; Carbapenem; Enterobacteriaceae; Beta-lactam/beta-lactamase inhibitor; MIC; Cefepime; Outcomes   1. Introduction An increasing resistance to beta-lactams in the Enterobacteriaceae is one of the top globalthreats in the antibiotic resistance crisis 1-3. Organisms belonging to the Enterobacteriaceaefamily are common Gram-negative pathogens that cause urinary tract infections (UTIs), community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), bloodstream infections (BSIs), and intra-abdominal infections (IAIs) 4.

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The prevalence of extended-spectrum beta-lactamase (ESBL) is higher in the Enterobacteriaceae isolates fromAsia, Latin America, and the Middle East 5, reaching 60% in Klebsiella pneumoniae isolates from Argentina and 48% in Escherichia coli isolates from Mexico 6, 7. In the recentreport from Latin America as a part of the Tigecycline Evaluation and Surveillance Trial(TEST) global surveillance study, 36.3% (1465/4032) of K. pneumoniae isolates, 16.

4%(67/409) of K. oxytoca isolates, and 25.4% (1246/4912) of E. coli isolates were ESBLproducers 8. The report from the Study for Monitoring Antimicrobial Resistance Trends(SMART) showed the incidence of ESBL-producers among UTI-associated E.

coli, K.pneumoniae, and Proteus mirabilis to be 43%, 54%, and 4%, respectively, and amongIAI-associated isolates, to be 49%, 56%, and 12%, respectively 9.The production of beta-lactamase is the most common mechanism that leads to resistance tobeta-lactam antibiotics among Enterobacteriaceae. ESBLs are capable of hydrolysing mostpenicillins, extended-spectrum cephalosporins, and aztreonam, but their activity is suppressedin the presence of a beta-lactamase inhibitor 1, 3. ESBL-producing organisms are oftenlinked to treatment failure with cephalosporins (such as cefotaxime or ceftazidime) and haveserious consequences for infection control 3, 10.Community- and hospital-acquired infections due to ESBL-producing Enterobacteriaceae are prevalent worldwide. Serious infections with ESBL-producing isolates are associated with78 high rates of mortality, making early detection and adequate medical management essential to79 ensure optimal patient outcomes 2, 11-14. Many controversies have centred on the80 recommendations for the testing and reporting of antibiotic susceptibility of potential81 ESBL-producing Enterobacteriaceae 14.

The current version of the Clinical Laboratory82 Standards Institute (CLSI) susceptibility guidelines, which was published in 2010, no longer83 advocates for phenotypic testing of ESBL production 15. Recent studies demonstrated a84 correlation between minimum inhibitory concentration (MIC) and clinical outcome, along85 with pharmacokinetic/pharmacodynamic (PK/PD) modelling, demonstrated the importance of86 the MIC to achieve therapeutic targets, the CLSI has assigned lower susceptibility breakpoints87 for aztreonam and most cephalosporins 15. The revised guidelines recommend the lower88 MIC breakpoints to direct antibiotic selection with recommended the dosage 15.8990 Carbapenems are widely regarded as the antibiotics of choice for the treatment of91 ESBL-producing Enterobacteriaceae infections, even though the in vitro antibacterial activity92 of other beta-lactams has been demonstrated 3, 10-13, 16, 17. However, indiscriminate93 carbapenem use is not without consequence and has contributed to the emergence of94 carbapenem-resistant Enterobacteriaceae (CRE) 18. However, the use of non-carbapenem95 beta-lactams for the treatment of ESBL-producing Enterobacteriaceae infections has yielded96 conflicting results 18 ,19, and certain infections and patient characteristics may support the97 use of non-carbapenem beta-lactams 10-12, 18, 20, 21.

9899 Here, we review the microbiology and epidemiology of ESBLs, recent changes in CLSI100 susceptibility guidelines for ESBLs, and the clinical and PK/PD data supporting the101 relationship between in vitro susceptibility and clinical outcome 11, 15,and discuss available6102 data on the use of cephamycins, cefepime, piperacillin-tazobactam, and new103 beta-lactambeta-lactamase inhibitors (BLBLIs, such as ceftolozane-tazobactam and104 ceftazidime-avibactam) for the treatment of ESBL infections. In addition, clinical105 considerations for antimicrobial selection for the treatment of infections caused by106 ESBL-producing Enterobacteriaceae from various sources are discussed.1071087109 2. Literature review110 Data for this review were identified by searching Medline and the references from relevant111 articles; many articles were also identified by searching the extensive files of the authors.

Search schemes included “extended spectrum beta lactamase(s)” AND “treatment” and “ESBLs” AND “treatment”. To assess the potential differences in the efficacy among drugs, we only included studies that had specific outcome details for ESBL-producing Enterobacteriaceae infections and that reported an outcome(s) in association with an116 antimicrobial agent to which the organism was susceptible in vitro. Only papers in the English117 language were reviewed.1181198120 3. Current controversy for the treatment of infections due to ESBL-producing121 Enterobacteriaceae122 Many controversies have centred on the recommendations for the testing and reporting of123 antibiotic susceptibility of potential ESBL-producing organisms 11. The recent version of124 the CLSI susceptibility guidelines published in 2010 no longer advocates for phenotypic125 testing of ESBL-producing Enterobacteriaceae and recommends the lower MIC breakpoints126 to direct antibiotic selection 15.

ESBLs may be present even when the organisms were127 shown to be susceptible to cefotaxime or ceftazidime 22-25. The implication of these studies128 that a disconnect exists between in vitro and in vivo studies among ESBL-producing isolates129 quickly became an established paradigm 11.130131 3.1.

Clinical impact of inoculum effect and minimum inhibitory concentrations (MICs) of132 antibiotics133 The activity of beta-lactams against ESBL-producing Enterobacteriaceae can be improved if134 they are combined with a beta-lactamase inhibitor (BLI); whether the adequacy of such an135 improvement to render the organism clinically susceptible depends on the beta-lactam, the136 BLI, and the particular ESBL variants 26. Of note, several less common varieties of ESBLs137 are “inhibitor-resistant”, i.e., the addition of a BLI does not enhance the activity of a138 beta-lactam to an appreciable extent 27. Hydrol


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