"Cefepime Activity against Extended-Spectrum
Beta-Lactamases and studies on anti-HCV compounds"
22.2.2008, 13:40, FENS L062
Cefepime Activity against Extended-Spectrum
(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.