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1.  Efficacy of Human-Simulated Exposures of Tomopenem (Formerly CS-023) in a Murine Model of Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus Infection▿ 
Antimicrobial Agents and Chemotherapy  2011;55(11):5004-5009.
Tomopenem (formerly CS-023) is a novel carbapenem with improved activity against diverse hospital pathogens, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), and has a half-life about twice longer than the half-lives of other carbapenems such as imipenem and meropenem. Our objective in this study was to estimate the efficacy of tomopenem in humans by human-simulated exposures in a neutropenic murine thigh infection model against 9 clinical isolates of P. aeruginosa with MICs of 4 to 32 μg/ml and 9 clinical isolates of MRSA with MICs of 4 to 16 μg/ml. Human-simulated dosing regimens in neutropenic mice were designed to approximate the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f%TMIC) observed with tomopenem at 750 and 1,500 mg given as a 0.5-h infusion three times a day (TID) in humans. As reported previously, there was no difference between the target values of P. aeruginosa and MRSA required for efficacy (K. Sugihara et al., Antimicrob. Agents Chemother. 54:5298-5302, 2010). Tomopenem at 750 mg showed bactericidal or bacteriostatic effects against 10 of 11 strains of P. aeruginosa and MRSA with MICs of ≤8 μg/ml (f%TMIC ≥ 41), and tomopenem at 1,500 mg showed bactericidal effects against 16 of 17 strains of P. aeruginosa and MRSA with MICs of ≤16 μg/ml (f%TMIC ≥ 43). Meropenem at 1,000 mg TID was tested for comparison purposes and showed bactericidal or bacteriostatic effects against 3 of 4 strains of P. aeruginosa with MICs of ≤4 μg/ml (f%TMIC ≥ 33). From these results, tomopenem is expected to be effective with an f%TMIC of over 40 against P. aeruginosa and MRSA strains with MICs of ≤8 μg/ml at doses of 750 mg TID and strains with MICs of ≤16 μg/ml at doses of 1,500 mg TID.
doi:10.1128/AAC.00068-11
PMCID: PMC3195026  PMID: 21844314
2.  Impact of Granulocytes on the Antimicrobial Effect of Tedizolid in a Mouse Thigh Infection Model▿ 
Antimicrobial Agents and Chemotherapy  2011;55(11):5300-5305.
Tedizolid (TR-700, formerly torezolid) is the active component of the new oxazolidinone prodrug tedizolid phosphate (TR-701). We had previously demonstrated that tedizolid possessed potent antistaphylococcal activity superior to that of linezolid in a neutropenic mouse thigh infection model (A. Louie, W. Liu, R. Kulawy, and G. L. Drusano, Antimicrob. Agents Chemother. 55:3453-3460, 2011). In the current investigation, we used a mouse thigh infection model to delineate the effect of an interaction of TR-700 and granulocytes on staphylococcal cell killing. We compared the antistaphylococcal killing effect of doses of TR-701 equivalent to human exposures ranging from 200 to 3,200 mg/day in both granulocytopenic and normal mice. The mice were evaluated at 24, 48, and 72 h after therapy initiation. In granulocytopenic mice, a clear exposure response in which, depending on the time point of evaluation, stasis was achieved at “human-equivalent” doses of slightly below 2,300 mg/day (at 24 h) to slightly below 2,000 mg/day (at 72 h) was observed. In immune-normal animals, stasis was achieved at human-equivalent doses of slightly greater than 100 mg/day or less. The variance in bacterial cell killing results was attributable to the presence of granulocytes (without drug), the direct effect of TR-700 on Staphylococcus aureus, and the effect of the drug on Staphylococcus aureus mediated through granulocytes. The majority of the bacterial cell killing in normal animals was attributable to the effect of TR-700 mediated through granulocytes. Additional studies need to be undertaken to elucidate the mechanism underlying this observation.
doi:10.1128/AAC.00502-11
PMCID: PMC3195040  PMID: 21911576
3.  Mutation in the sdeS Gene Promotes Expression of the sdeAB Efflux Pump Genes and Multidrug Resistance in Serratia marcescens▿ 
Serratia marcescens gained resistance to both biocides and antibiotics on expressing the SdeAB efflux pump, following exposure to increasingly higher concentrations of a biocide (H. Maseda et al., Antimicrob. Agents Chemother. 53:5230–5235, 2009). To reveal the regulatory mechanism of sdeAB expression, wild-type cells were subjected to transposon-mediated random mutagenesis, and a mutant with antibiotic resistance, which mimicked the phenotype of the previous biocide-resistant cells, was obtained. The transposon element was found in the chromosomal DNA downstream of the sdeAB operon. Sequencing revealed the presence of an open reading frame (ORF) encoding a protein with 159 amino acid residues that is highly similar to the BadM-type transcriptional repressor, designated sdeS. The level of sdeB::xylE reporter gene expression, undetectable in the wild-type cells, appeared to be fully comparable to that in the biocide-resistant cells. Nucleotide sequencing of the mutant revealed sdeS to have a single G-to-A base substitution at position 269 that converted Trp90 to a stop codon. Introduction of a plasmid-borne intact sdeS into the mutant cells and the biocide-resistant cells resulted in a reduction in sdeB::xylE reporter activity to an undetectable level. These results suggested that SdeS functions as a repressor of the sdeAB operon. It was concluded that the original biocide-resistant cells had an impaired sdeS and, therefore, a derepressed level of the SdeAB efflux pump.
doi:10.1128/AAC.01755-10
PMCID: PMC3101466  PMID: 21422216
11.  Dose Adjustment of Polymyxins for Renal Insufficiency 
doi:10.1128/AAC.05080-11
PMCID: PMC3186980  PMID: 21921118
14.  Determination of Meropenem Penetration into the Lung from Sparse Data 
Antimicrobial Agents and Chemotherapy  2011;55(12):5959-5961.
doi:10.1128/AAC.05066-11
PMCID: PMC3232754  PMID: 22081725
17.  In Vitro Potency of Various Polymyxin B Components▿ 
doi:10.1128/AAC.00119-11
PMCID: PMC3165278  PMID: 21709096
19.  Rates of Treatment Discontinuation Due to Adverse Events for Echinocandins 
doi:10.1128/AAC.00055-11
PMCID: PMC3122447  PMID: 21680793
23.  Joint population pharmacokinetic analysis of zidovudine, lamivudine, and their active intracellular metabolites in HIV patients 
The population pharmacokinetic parameters of AZT and 3TC and their active intracellular metabolites were described from 75 naïve HIV infected patients receiving oral combination of AZT and 3TC twice daily, as part of their multitherapy treatment in the COPHAR2 – ANRS 111 trial. Four blood samples per patient were taken after two weeks of treatment to measure the concentration at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients among those 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between mean plasma and intracellular concentrations of each drugs. A one compartment model with first order absorption and elimination best described plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. AZT and 3TC half-lives were 0.81 h (94.8%) and 2.97 h (39.2%), respectively whereas intracellular half-lives for AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent clearance of AZT as well as on mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma and intracellular concentration were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once versus twice daily regimens suggested that daily dosing regimen with double doses could be appropriate.
doi:10.1128/AAC.01487-10
PMCID: PMC3122424  PMID: 21576446
Adult; Anti-HIV Agents; pharmacokinetics; Chromatography, Liquid; Cytidine Triphosphate; analogs & derivatives; pharmacokinetics; Dideoxynucleotides; pharmacokinetics; Female; Humans; Lamivudine; analogs & derivatives; pharmacokinetics; Male; Middle Aged; Models, Theoretical; Sex Factors; Tandem Mass Spectrometry; Young Adult; Zidovudine; pharmacokinetics
25.  Helicobacter pylori Resistance to Rifabutin in the Last 7 Years ▿ 
Antimicrobial Agents and Chemotherapy  2011;55(11):5374-5375.
A low rate of resistance (0.24%) to rifabutin was noted in Helicobacter pylori strains isolated from 414 Japanese patients. The only rifabutin-resistant strain detected showed a point mutation in the rpoB gene and was isolated from a patient with a history of rifampin treatment for pulmonary tuberculosis.
doi:10.1128/AAC.05437-11
PMCID: PMC3195021  PMID: 21896915

Results 1-25 (740)