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    Antimicrobial susceptibility profile of ceftolozane/tazobactam, ceftazidime/avibactam and cefiderocol against carbapenem-resistant Pseudomonas aeruginosa clinical isolates from Türkiye
    (Springer, 2024) Buyukyanbolu, Ecem; Genc, Leyla; Cyr, Elizabeth A.; Karakus, Mehmet; Comert, Fusun; Otlu, Baris; Aktas, Elif
    Purpose Carbapenem resistant Pseudomonas aeruginosa (CR-PA) is escalating worldwide and leaves clinicians few therapeutic options in recent years, beta-lactam/beta-lactamase inhibitor combinations (ceftolozane-tazobactam, ceftazidime-avibactam) and a new siderophore cephalosporin (cefiderocol) have been approved for the treatment of P. aeruginosa infection and have shown potent activity against isolates defined as carbapenem resistant. The aim of this study was to determine the phenotypic profile of these agents against CR-PA in the emerging setting of carbapenemases. Methods CR-PA clinical isolates were collected from three teaching hospitals in different geographical regions between January 2017-December 2021. All isolates were subjected to phenotypic carbapenemase testing using modified carbapenem inactivation method. MICs were determined by reference broth microdilution and evaluated according to EUCAST standards, while genotypic profiling was determined using PCR methods. Results 244 CR-PA sourced most frequently from the respiratory tract (32.2%), blood (20.4%) and urine (17.5%) were evaluated. Of all isolates, 32 (13.1%) were phenotypically and 38 (15.6%) were genotypically defined as carbapenemase-positive. The most common carbapenemase was GES (63.1%), followed by VIM (15.8%). The MIC50/90(S%) of ceftazidime/avibactam, ceftolozane/tazobactam and cefiderocol in all CR-PA isolates were 4 and 32 (80%), 1 and > 64 (69%) and 0.25 and 1 mg/L (96%), respectively. Cefiderocol was also the most active agent in carbapenemase-positive isolates (90%). Conslusion While ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against CR-PA devoid of carbapenemases, cefiderocol provided potent in vitro activity irrespective of carbapenemase production. When considering the potential clinical utility of newer agents against CR-PA, regional variations in carbapenemase prevalence must be considered.
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    Determination of the presence of carbapenemase enzymes in carbapenem-resistant Pseudomonas aeruginosa isolates by susceptibility test based algorithm
    (Elsevier Science Inc, 2024) Ocal, Murat; Buyukyanbolu, Ecem; Karakus, Mehmet; Koca, Oznur; Tanriverdi, Seren; Erdogan, Fatma; Comert, Fusun
    Purpose: Phenotypic methods have been proposed for the detection of carbapenemase production. These tests can have slower turnaround times. With the sensitivity-based algorithm described by Gill et al. will be possible to detect the carbapenemase. Methods: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) isolates from three hospitals between January 2017 and December 2021 were included. The modified carbapenemase-inactivation-method(mCIM) and two algorithms were used, defined as primary algorithm, i.e. ceftazidime and cefepime non-susceptible in addition to imipenem or meropenem resistance and secondary algorithm, i.e. ceftolozane/tazobactam non-susceptible in addition to imipenem or meropenem resistance. PCR testing was performed on all isolates. Results: 256 CRPA isolates were included in the study. When the primary or secondary algorithm criteria were applied, there were 173 isolates that met one or both of them. Of these, 29 were CIM-positive isolates. Conclusion: In our study, the use of the algorithm reduced the need for CIM testing by 32 %.
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    Dose optimization of piperacillin/tazobactam, cefepime, and ceftazidime for carbapenem-resistant Pseudomonas aeruginosa isolates in Turkiye
    (Springer, 2025) Buyukyanbolu, Ecem; Gill, Christian M.; Genc, Leyla; Karakus, Mehmet; Comert, Fusun; Otlu, Baris; Aktas, Elif
    Introduction Although CRPA may test susceptible to other beta-lactams such as ceftazidime (CAZ), cefepime (FEP), and piperacillin/tazobactam (TZP), reduced potency has been observed. We assessed the adequacy of EUCAST Susceptible (S) or Susceptible Increased Exposure (SIE)/(I) doses for CAZ, FEP, and TZP against CRPA clinical isolates. Methods CRPA isolates were collected from patients at three Turkish hospitals. CAZ, FEP, and TZP MICs were determined using broth microdilution. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for a free time above the MIC (fT > MIC) targets for various doses of each agent against isolates defined as susceptible. fT > MIC targets were 70% for CAZ or FEP and 50% for TZP. Cumulative fraction of response (CFR) was calculated. Optimal PTA and CFR was 90% target achievement. Results The percentages of isolates SIE/I to CAZ, FEP, and TZP were 49,8%, 47%, and 31,8% respectively. Reduced potency was noted with 54,1% of CAZ-S isolates having MICs of 4 or 8 mg/L. Of the FEP and TZP-S isolates, MICs at the breakpoint (8 and 16 mg/L, respectively) were the mode with 45,2 and 53,9% of isolates for each, respectively. At an MIC of 8 mg/L for CAZ, the EUCAST standard dose was insufficient (CFR of 85%). 3 h infusions of EUCAST SIE doses were required for 90% PTA at MIC of 8 mg/L and an optimized CFR of 100%. For FEP, the SIE dose of 2 g q8h 0.5 h infusion of was effective (CFR 96%), utilization of an extended 3 h infusion further optimized the PTA at 8 mg/L (CFR 99%). For TZP, the standard dose of 4.5 q6h administered as a 0.5 h infusion was inadequate (CFR 86%). A standard TZP dose with an extended infusion (4.5 g q8h over 4 h) and the SIE dose 4.5 g q6h 3 h infusion resulted in CFRs > 95%. Conclusion These data support the EUCAST SIE breakpoints for FEP and TZP. To optimize PTA at the SIE breakpoint for CAZ, prolonged infusion is required.