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Bhalodi A.A.,Center for Anti Infective Research and Development | Crandon J.L.,Center for Anti Infective Research and Development | Biek D.,Cerexa Inc. | Nicolau D.P.,Center for Anti Infective Research and Development
Antimicrobial Agents and Chemotherapy | Year: 2012

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 μg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log10 kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log10 CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log10 kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints. Copyright © 2012, American Society for Microbiology. All Rights Reserved. Source

Riccobene T.A.,Forest Research Institute Inc. | Su S.F.,Forest Research Institute Inc. | Rank D.,Cerexa Inc.
Antimicrobial Agents and Chemotherapy | Year: 2013

This study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-β-lactam β-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days. Ceftaroline and avibactam levels in plasma and urine were measured by liquid chromatography coupled with tandem mass spectrometry. No significant differences in systemic exposure of ceftaroline or avibactam were observed when the drugs were administered alone versus concomitantly, indicating that there was no apparent pharmacokinetic interaction between ceftaroline fosamil and avibactam administered as a single dose. No appreciable accumulation of either drug occurred with multiple intravenous doses of ceftaroline fosamil/avibactam, and pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10. Infusions of ceftaroline fosamil/avibactam were well tolerated at total daily doses of up to 1,800 mg of each compound, and all adverse events (AEs) were mild to moderate in severity. Infusion-site reactions were the most common AEs reported with multiple dosing. The pharmacokinetic and safety profiles of ceftaroline fosamil/avibactam demonstrate that the 2 drugs can be administered concomitantly to provide an important broad-spectrum antimicrobial treatment option. Copyright © 2013, American Society for Microbiology. Source

Castanheira M.,JMI Laboratories | Farrell S.E.,JMI Laboratories | Krause K.M.,Cerexa Inc. | Jones R.N.,JMI Laboratories | Sader H.S.,JMI Laboratories
Antimicrobial Agents and Chemotherapy | Year: 2014

Escherichia coli (328 isolates), Klebsiella pneumoniae (296), Klebsiella oxytoca (44), and Proteus mirabilis (33) isolates collected during 2012 from the nine U.S. census regions and displaying extended-spectrum-β-lactamase (ESBL) phenotypes were evaluated for the presence of β-lactamase genes, and antimicrobial susceptibility profiles were analyzed. The highest ESBL rates were noted for K. pneumoniae (16.0%, versus 4.8 to 11.9% for the other species) and in the Mid-Atlantic and West South Central census regions. CTX-M group 1 (including CTX-M-15) was detected in 303 strains and was widespread throughout the United States but was more prevalent in the West South Central, Mid-Atlantic, and East North Central regions. KPC producers (118 strains [112 K. pneumoniae strains]) were detected in all regions and were most frequent in the Mid-Atlantic region (58 strains). Thirteen KPC producers also carried blaCTX-M. SHV genes encoding ESBL activity were detected among 176 isolates. Other β-lactamase genes observed were CTX-M group 9 (72 isolates), FOX (10), TEM ESBL (9), DHA (7), CTX-M group 2 (3), NDM-1 (2 [Colorado]), and CTX-M groups 8 and 25 (1). Additionally, 62.9% of isolates carried>2 β-lactamase genes. KPC producers were highly resistant to multiple agents, but ceftazidime-avibactam (MIC50/90, 0.5/2 μg/ml) and tigecycline (MIC50/90, 0.5/1 μg/ ml) were the most active agents tested. Overall, meropenem (MIC50,<0.06 μg/ml), ceftazidime-avibactam (MIC50, 0.12 to 0.5 μg/ml), and tigecycline (MIC50, 0.12 to 2 μg/ml) were the most active antimicrobials when tested against this collection. NDM-1 producers were resistant to all β-lactams tested. The diversity and increasing prevalence of β-lactamase-producing Enterobacteriaceae have been documented, and ceftazidime-avibactam was very active against the vast majority of β-lactamase-producing strains isolated from U.S. hospitals. Copyright © 2014, American Society for Microbiology. All Rights Reserved. Source

Ge Y.,Cerexa Inc. | Maynard D.,INC Research | Rickert D.E.,Douglas E. Rickert LLC
Antimicrobial Agents and Chemotherapy | Year: 2010

This study assessed the pharmacokinetic profiles for intramuscular and intravenous ceftaroline treatment for rats, rabbits, and monkeys. Ceftaroline, a novel cephalosporin with broad-spectrum activity against Gram-positive and Gram-negative pathogens, demonstrated favorable pharmacokinetic profiles following intramuscular administration in all 3 animal species, comparable to the levels for intravenous dosing. The areas under the plasma concentration-time curve obtained after intramuscular administration were increased in rats and similar in rabbits and monkeys, compared with the levels obtained after intravenous dosing (129%, 7.29%, and 12.7% greater in rats, rabbits, and monkeys, respectively). The data reported here support the development of an intramuscular formulation for ceftaroline. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source

Wiskirchen D.E.,Center for Anti Infective Research and Development | Crandon J.L.,Center for Anti Infective Research and Development | Furtado G.H.,Center for Anti Infective Research and Development | Williams G.,Cerexa Inc. | Nicolau D.P.,Center for Anti Infective Research and Development
Antimicrobial Agents and Chemotherapy | Year: 2011

Ceftaroline exhibits in vitro activity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producing Enterobacteriaceae when combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 against Enterobacteriaceae in a murine thigh infection model. Twelve Enterobacteriaceae isolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, fT>MIC. The change in log 10 CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a fT>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistant Enterobacteriaceae. Copyright © 2011, American Society for Microbiology. All Rights Reserved. Source

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