Extended performed if feasible, alternative therapeutic approaches may be

Extended spectrum ?-lactamases (ESBLs) are increasing causes of resistance in Enterobacteriaceae infections, led to a growing utilization of broad-spectrum antibiotics, most
predominantly the carbapenem agents. The effective carbapenem-sparing alternatives for the
management of these infections have reviewed for active empirical therapy and choices of definitive treatment. We performed a literature search of clinical studies published in English
from 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 in
achieving therapeutic targets. Based on the available data, carbapenems are considered the
drugs of choice for serious infections. The use of piperacillin-tazobactam and cefepime in the
treatment of ESBL-producing Enterobacteriaceae is not widely recommended, especially in
patients with critical conditions and empirical therapy strategy. The use of carbapenems may
be reserved for patients with severe infections or critical illness caused by ESBL-producing bacteria. De-escalation therapy should always be performed if feasible, alternative therapeutic
approaches 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 global
threats in the antibiotic resistance crisis 1-3. Organisms belonging to the Enterobacteriaceae
family 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. The prevalence of extended-spectrum beta-lactamase (ESBL) is higher in the Enterobacteriaceae isolates from
Asia, 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 recent
report 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 ESBL
producers 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 among
IAI-associated isolates, to be 49%, 56%, and 12%, respectively 9.
The production of beta-lactamase is the most common mechanism that leads to resistance to
beta-lactam antibiotics among Enterobacteriaceae. ESBLs are capable of hydrolysing most
penicillins, extended-spectrum cephalosporins, and aztreonam, but their activity is suppressed
in the presence of a beta-lactamase inhibitor 1, 3. ESBL-producing organisms are often
linked to treatment failure with cephalosporins (such as cefotaxime or ceftazidime) and have
serious 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 with
78 high rates of mortality, making early detection and adequate medical management essential to
79 ensure optimal patient outcomes 2, 11-14. Many controversies have centred on the
80 recommendations for the testing and reporting of antibiotic susceptibility of potential
81 ESBL-producing Enterobacteriaceae 14. The current version of the Clinical Laboratory
82 Standards Institute (CLSI) susceptibility guidelines, which was published in 2010, no longer
83 advocates for phenotypic testing of ESBL production 15. Recent studies demonstrated a
84 correlation between minimum inhibitory concentration (MIC) and clinical outcome, along
85 with pharmacokinetic/pharmacodynamic (PK/PD) modelling, demonstrated the importance of
86 the MIC to achieve therapeutic targets, the CLSI has assigned lower susceptibility breakpoints
87 for aztreonam and most cephalosporins 15. The revised guidelines recommend the lower
88 MIC breakpoints to direct antibiotic selection with recommended the dosage 15.
90 Carbapenems are widely regarded as the antibiotics of choice for the treatment of
91 ESBL-producing Enterobacteriaceae infections, even though the in vitro antibacterial activity
92 of other beta-lactams has been demonstrated 3, 10-13, 16, 17. However, indiscriminate
93 carbapenem use is not without consequence and has contributed to the emergence of
94 carbapenem-resistant Enterobacteriaceae (CRE) 18. However, the use of non-carbapenem
95 beta-lactams for the treatment of ESBL-producing Enterobacteriaceae infections has yielded
96 conflicting results 18 ,19, and certain infections and patient characteristics may support the
97 use of non-carbapenem beta-lactams 10-12, 18, 20, 21.
99 Here, we review the microbiology and epidemiology of ESBLs, recent changes in CLSI
100 susceptibility guidelines for ESBLs, and the clinical and PK/PD data supporting the
101 relationship between in vitro susceptibility and clinical outcome 11, 15,and discuss available6
102 data on the use of cephamycins, cefepime, piperacillin-tazobactam, and new
103 beta-lactambeta-lactamase inhibitors (BLBLIs, such as ceftolozane-tazobactam and
104 ceftazidime-avibactam) for the treatment of ESBL infections. In addition, clinical
105 considerations for antimicrobial selection for the treatment of infections caused by
106 ESBL-producing Enterobacteriaceae from various sources are discussed.
109 2. Literature review
110 Data for this review were identified by searching Medline and the references from relevant
111 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 an
116 antimicrobial agent to which the organism was susceptible in vitro. Only papers in the English
117 language were reviewed.
120 3. Current controversy for the treatment of infections due to ESBL-producing
121 Enterobacteriaceae
122 Many controversies have centred on the recommendations for the testing and reporting of
123 antibiotic susceptibility of potential ESBL-producing organisms 11. The recent version of
124 the CLSI susceptibility guidelines published in 2010 no longer advocates for phenotypic
125 testing of ESBL-producing Enterobacteriaceae and recommends the lower MIC breakpoints
126 to direct antibiotic selection 15. ESBLs may be present even when the organisms were
127 shown to be susceptible to cefotaxime or ceftazidime 22-25. The implication of these studies
128 that a disconnect exists between in vitro and in vivo studies among ESBL-producing isolates
129 quickly became an established paradigm 11.
131 3.1. Clinical impact of inoculum effect and minimum inhibitory concentrations (MICs) of
132 antibiotics
133 The activity of beta-lactams against ESBL-producing Enterobacteriaceae can be improved if
134 they are combined with a beta-lactamase inhibitor (BLI); whether the adequacy of such an
135 improvement to render the organism clinically susceptible depends on the beta-lactam, the
136 BLI, and the particular ESBL variants 26. Of note, several less common varieties of ESBLs
137 are “inhibitor-resistant”, i.e., the addition of a BLI does not enhance the activity of a
138 beta-lactam to an appreciable extent 27. Hydrol