3 research outputs found
A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilatorassociated pneumonia
INTRODUCTION: The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria. METHODS: This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011). RESULTS: The study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0). CONCLUSIONS: Among patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0058969
Epidemiological cut-offs for Sensititre susceptibility testing of Mycobacterium tuberculosis : interpretive criteria cross validated with whole genome sequencing
Universal drug susceptibility testing (DST) is an important requirement of the End TB Strategy. The
Sensititre broth micro-dilution assay (BMD) tests multiple drugs quantitatively. We defined interpretive
criteria for this assay and analysed genotypic-phenotypic relationships. 385 Mycobacterium tuberculosis
clinical isolates were processed for BMD and whole genome sequencing. The epidemiological cut-off
value 99% (ECV99) amongst genotypically wild type (gWT) strains defined susceptibility. Minimum
inhibitory concentration distributions of the resistance-associated variants (RAVs) for each drug
were analysed. Susceptibility (μg/mL) criteria were determined as follows: rifampicin (≤0.125),
isoniazid (≤0.25), ethambutol (≤2.0), moxifloxacin (≤0.5), levofloxacin (≤1.0), amikacin (≤2.0),
kanamycin (≤8.0), capreomycin (≤4.0), clofazimine (≤0.25) and linezolid (≤2.0). Most drugs showed
clear separation between gWT and RAV. Isoniazid showed a tri-modal pattern with 14/17 strains at
ECV99 harbouring a fabG1 c. -15C > T RAV. Ethambutol RAVs at embB codons 306, 405 and 497 were
responsible for resistance and showed differential distributions. Moxifloxacin RAVs (gyrA codon 90)
were a dilution or two higher than the ECV99 while gyrB RAVs were uncommon and showed drug
specific resistance propensity. Interpretive criteria established were robust facilitating progress towards
universal DST and individualised precision medicine. This study demonstrates the value of quantitative
DST to accurately interpret mutation data.Janssen Pharmaceuticalshttp://www.nature.com/srepam2021Medical Microbiolog