FENS Seminar: Hesna Yiğit, 22.2.2008, 13:40, FENS L062
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  • FENS Seminar: Hesna Yiğit, 22.2.2008, 13:40, FENS L062

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FENS Seminar
 

"Cefepime Activity against Extended-Spectrum Beta-Lactamases and studies on anti-HCV compounds"

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Hesna Yiğit

22.2.2008,  13:40, FENS L062


Cefepime Activity against Extended-Spectrum Beta-Lactamases (ESBLs).

            Extended-spectrum b-lactamase (ESBL) producing Gram-negative bacteria have developed into a therapeutic dilemma worldwide. Most ESBL producers are not resistant to cefepime (FEP); however, we lack the clinical experience to confirm this. This study examined in vitro activity of FEP as well as the clinical/bacteriological outcome of FEP treated EBSL patients.

            The organism-drug interactions were investigated by determining the in vitro activity of FEP, ceftazidime, cefotaxime, ceftriaxone, cefpodoxime, piperacillin-tazobactam, ticarcillin-clavulanic acid and ciprofloxacin against 123 clinical strains of E. coli and Klebsiella.  The isolates were representatives of the most common ESBLs worldwide such as SHV-5, SHV-2A, SHV-2, SHV-12, TEM-10, SHV-3, SHV-4, TEM-26, TEM-12, and CTX-M-10.  The data showed that 72% of the isolates had FEP MICs  £8 mg/ ml. These results show that FEP is the most active cephalosporin tested against various ESBL-producers.  Our data also suggest that FEP may be a better alternative than piperacillin-tazobactam and ticarcillin-clavulanic acid combinations which are the currently recommended drugs over FEP for treatment of ESBL producing strains of E. coli and Klebsiella. 

            In this report, we present the outcomes of 40 FEP-treated patients infected with ESBL-producing Escherichia coli or Klebsiella spp. The overall clinical outcomes of FEP-treated patients were not different (83% vs. 80% success) whether the patients were infected with a susceptible (£8 mg/mL) or a nonsusceptible strain (³8 mg/mL) to FEP. However, bacteriological outcomes showed a significant different eradication rate (83% vs. 45%, P = 0.04) with susceptible vs. nonsusceptible isolates, respectively. The 10 available patients infected with ESBL-producing Klebsiella spp. were treated with imipenem/cilastatin. Overall clinical response for these patients was 100% cure improvement, while 70% of the patient showed bacteriological eradication, 20% showed persistence, and 10% showed colonization. These results suggest that FEP can be an alternative therapy to the carbapenems for the treatment of ESBL-producing strains susceptible to FEP.

            The data was also examined for role of strain phenotype-genotype in clinical outcome.  This data suggested that if the MIC for FEP is £ 8 mg/ ml, FEP as empiric therapy would most likely result in clinical success.

Studies on anti-HCV compounds

Novel inhibitors have been identified, specifically targeting hepatitis C (HCV) proteins involved in replication.  The development of successful therapies requires an understanding of nature of resistance that develops in response to exposure to inhibitors.  Using HCV genotype 1a replicon cells, the selection and characterization of resistance to HCV target-A inhibitor, compound 1, was studied. The resistant cell line was selected in the presence of sub-optimal concentration of HCV specific compound 1. The amino acid substitutions were identified in HCV target-A, isolated form the resistant replicon cell line. When these changes were introduced to wild type replicon background, resistance to compound 1 was observed, demonstrating that these mutations were responsible for the resistant phenotype. 

To determine whether HCV replicons can be cleared by inhibitors, compound 1 was used at a high concentration to cure subgenomic 1a replicon cell line.  When wild type replicon was introduced to these cured cells, it retained its sensitivity to compound 1.  These results indicate that compound 1 is specific to HCV target-A and provide strategic guidance for the future treatment of HCV infection.