Journal name: Infection and Drug Resistance Article Designation: Original Research Year: 2018 Volume: 11 Infection and Drug Resistance Dovepress Running head verso: Lee et al Running head recto: Therapy of cefotaxime-resistant Enterobacteriaceae BSI open access to scientific and medical research DOI: http://dx.doi.org/10.2147/IDR.S146923 Open Access Full Text Article ORIGINAL RESEARCH Clinical benefit of ertapenem compared to flomoxef for the treatment of cefotaxime- resistant Enterobacteriaceae bacteremia Chen-Hsiang Lee1,2 Objectives: Cefotaxime-resistant Enterobacteriaceae (CE) infections are intractable, with I-Ling Chen3 limited treatment options. Though carbapenems are frequently prescribed for CE infections, Chia-Chin Li4 the emergence of carbapenem-resistant Enterobacteriaceae is of huge concern. Flomoxef is Chun-Chih Chien4 effective against CE in vitro, and some clinical data on its demonstrated effectiveness against CE bloodstream infections (BSIs) exists. 1Department of Internal Medicine, Division of Infectious Diseases, Patients and methods: We conducted a retrospective study on adults with BSI caused by Kaohsiung Chang Gung Memorial, flomoxef-susceptible CE to investigate the efficacy of flomoxef compared with that of ertape- 2 Hospital, Chang Gung University, nem. The outcome was evaluated with propensity score-based matching and logistic regression College of Medicine, 3Department of Pharmacy, 4Department of Laboratory analysis. For personal use only. Medicine, Kaohsiung Chang Gung Results: Demographic and clinical characteristics of patients treated with flomoxef (n = 58) or Memorial Hospital, Kaohsiung, Taiwan ertapenem (n = 188) were compared. In the multivariate analysis, severe sepsis (adjusted odds ratio [AOR] = 3.84; 95% confidence interval [CI], 1.16–12.78; p = 0.03), high BSI mortality score (AOR = 5.59; 95% CI, 2.37–13.21; p < 0.01), ultimately or rapidly fatal comorbidity (AOR = 10.60; 95% CI, 3.43–32.75; p < 0.01), and pneumonia (AOR = 10.11; 95% CI, 3.43–29.81; p < 0.01) were independently associated with 28-day mortality. Using propensity scores, 58 flomoxef-treated patients were matched to 116 ertapenem-treated patients. There were no intergroup differences in BSI severity, comorbidity, or BSI sources. The 28-day mortality rates (20.7% vs 13.8%, p = 0.28) did not differ significantly. However, hospitalization length was shorter in the ertapenem group (10.2 ± 8.5 vs. 14.6 ± 9.4 days, p < 0.01). Conclusion: Although similar outcomes were observed between the groups, ertapenem therapy Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 07-Dec-2018 was associated with a shorter hospitalization time in adults after CE BSI. Keywords: bacteremia, cephamycin, ESBL, flomoxef, outcomes, MIC Introduction In 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered the minimum inhibitory concentration (MIC) breakpoints for many β-lactam antibiotics, including extended-spectrum cephalosporins, to enhance the detection of known resistance among Enterobacteriaceae. The CLSI Antibiotic Subcommittee asserted that routine extended-spectrum -lactamase (ESBL) testing was no longer necessary and that treat- Correspondence: Chen-Hsiang Lee β Department of Internal Medicine, ment decisions can be solely based on MICs.1 Escherichia coli (E. coli), Klebsiella Kaohsiung Chang Gung Memorial species, and Proteus mirabilis (P. mirabilis) have not, since, been routinely evaluated Hospital, 123 Ta-Pei Road, Niao Sung District, Kaohsiung 833, Taiwan for ESBL production. Of note, the new breakpoint MIC defining ceftriaxone or cefo- Tel +886 7 731 7123 ext 8304 taxime susceptibility (1 mg/L) is lower than the corresponding new breakpoint for Fax +886 7 732 2402 1 Email [email protected] ceftazidime (4 mg/L). High rates of susceptibility to ceftazidime have been found submit your manuscript | www.dovepress.com Infection and Drug Resistance 2018:11 257–266 257 Dovepress © 2018 Lee et al. This work is published and licensed by Dove Medical Press Limited. 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Powered by TCPDF (www.tcpdf.org) 1 / 1 Lee et al Dovepress among prevalent CTX-M-producing E. coli, Klebsiella spe- 1) mono-microbial bacteremia confirmed by the isolation cies, and P. ­mirabilis.2,3 This suggests that the CLSI ceftazi- of cefotaxime-resistant Enterobacteriaceae from blood cul- dime breakpoint might be too high to be a reliable ESBL tures of patients showing sepsis syndrome and 2) definitive marker. Cefotaxime non-susceptibility afforded the detection parenteral therapy with flomoxef or ertapenem for more of >95% of ESBL true-positive isolates.3 Thus, evaluating than 48 h until termination of the antimicrobial therapy or cefotaxime susceptibility may be the optimal strategy to death. Definitive therapy was defined as the circumstance predict ESBL presence in Enterobacteriaceae. where ertapenem or flomoxef monotherapy was used to Carbapenems remain the mainstay for treatment of treat a cefotaxime-resistant Enterobacteriaceae bloodstream infections with high-inoculum ESBL-producers.4,5 However, infection (BSI), and the strain showed in vitro susceptibility their use should be restricted, considering the emergence of to the prescribed drug.1 Antimicrobial susceptibility was carbapenem-resistant organisms.6 Alternative treatments determined using a standard broth micro-dilution method, are urgently needed to relieve the selective pressure for and interpreted according to the breakpoints suggested by the carbapenem.7 Thus, over the past decades, numerous stud- CLSI.1 The MICs of cefotaxime and flomoxef were≤ 1 and ≤8 ies have been conducted to determine possible alternatives. mg/L, respectively.1,11 Selection of the appropriate antimicro- Flomoxef – classified as a 1-oxacephem cephamycin – was bial regimen was at the discretion of the attending physician. found to be stable in the presence of β-lactamase and active The following intravenous doses or adjusted equivalents for against cephalosporin-resistant strains.8 While flomoxef has renal insufficiency were prescribed: ertapenem (1 g/24 h) or the potential to be effective against β-lactamase–producing flomoxef (1 g/8 h). Through the antimicrobial stewardship strains, clinical data with regard to its potential value for the system in the hospital,12 all ertapenem and flomoxef prescrip- treatment of ESBL-associated infections are currently lim- tions had been approved by infectious disease specialists for ited.9 Some researchers are reluctant to use cephamycins as their indications and dosages. first-line therapy for infections with ESBL-producing organ- isms.10 Furthermore, the updated CLSI breakpoints obviate For personal use only. Definitions ESBL screening, suggesting that the new CLSI breakpoint Medical records of flomoxef (Shionogi, Osaka, Japan) - or for cefotaxime susceptibility could be safely used to predict ertapenem (MSD, Kenilworth, NJ, USA) -treated patients were ESBL presence in Enterobacteriaceae. However, no clini- reviewed and compared. Blood samples for the first positive cal studies have verified flomoxef’s efficacy through using cultures collected within 48 h of admission were defined as ertapenem as the comparator in patients with bacteremia community-onset infections, whereas those obtained after caused by cefotaxime-resistant Enterobacteriaceae. There- 48 h were categorized as hospital-onset infections. The fore, we aimed to compare therapeutic efficacies of flomoxef severity of underlying medical conditions was classified as and ertapenem therapy in the management of bacteremia nonfatal, fatal, and ultimately fatal.13 Pitt bacteremia scores caused by cefotaxime-resistant Enterobacteriaceae. were used to evaluate the severity of bacteremia on the day of onset.14 Furthermore, enrolled patients were stratified by Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 07-Dec-2018 Patients and methods BSI mortality risk score; patients with guarded prognoses had Setting scores ≥5, and those with good prognoses had scores <5.15 This study was conducted at Kaohsiung Chang Gung Memo- Inappropriate empirical antibiotic therapy was defined as rial Hospital, a tertiary-care medical center in southern the first dose of appropriate antimicrobial agent that was not Taiwan. The Institutional Review Board of the Chang Gung administered within the first 24 h after blood samples were Memorial Hospital approved the study (No. 201601503B0) drawn.16 Antibiotic therapy was considered appropriate if the and waived the need for patient consent due to the retrospec- route and dosage of the antimicrobial agent was administered tive nature of the study. The patient data was anonymized to as recommended by the Sanford Guide,17 and isolated patho- maintain confidentiality. gens were susceptible in vitro to the prescribed agent with During 2011–2015, blood culture records from adult reference to contemporary CLSI breakpoints.1 BSI sources patients