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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.


Lucasti C.,South Jersey Infectious Diseases | Popescu I.,Fundeni Clinical Institute | Ramesh M.K.,Victoria Hospital | Lipka J.,Astrazeneca | And 3 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2013

Objectives: Avibactam, a novel non-β-lactam β-lactamase inhibitor, restores the in vitro activity of ceftazidime against class A, C and some class D β-lactamase-producing pathogens, including those commonly associated with complicated intra-abdominal infections (cIAIs). This randomized, active-controlled, double-blind, Phase II trial (NCT00752219) aimed to evaluate the safety and efficacy of ceftazidime/avibactam plus metronidazole compared with meropenem in hospitalized patients with cIAI. Methods: Adults with confirmed cIAI requiring surgical intervention and antibiotics were randomized 1: 1 to receive intravenously either (i) 2000 mg of ceftazidime plus 500 mg of avibactam plus a separate infusion of 500 mg of metronidazole or (ii) 1000 mg of meropenem plus placebo every 8 h for a minimum of 5 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 2 weeks after the last dose of study therapy. Results: Overall, 101 patients received ceftazidime/avibactam plus metronidazole; 102 received meropenem. The median duration of treatment was 6.0 and 6.5 days, respectively. Favourable clinical response at the TOC visit in the ME population was observed in 91.2% (62/68) and 93.4% (71/76) of patients in the ceftazidime/avibactam plus metronidazole and meropenem groups, respectively (observed difference: -2.2%; 95% CI: -20.4%, 12.2%). The incidence of treatment-emergent adverse events was similar for ceftazidime/avibactam plus metronidazole (64.4%) and meropenem (57.8%). Conclusions: Ceftazidime/avibactam plus metronidazole was effective and generally well tolerated in patients with cIAI, with a favourable clinical response rate in the ME population of >90%, similar to that of meropenem. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Biek D.,Cerexa Inc. | Critchley I.A.,Cerexa Inc. | Riccobene T.A.,Forest Research Institute Inc. | Thye D.A.,Cerexa Inc.
Journal of Antimicrobial Chemotherapy | Year: 2010

Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available β-lactams. The activity of ceftaroline against MRSA and the β-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T>MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T>MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T>MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤2mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


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.


Bhalodi A.A.,Hartford Hospital | Crandon J.L.,Hartford Hospital | Biek D.,Cerexa Inc. | Nicolau D.P.,Hartford Hospital
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.


Wiskirchen D.E.,Hartford Hospital | Crandon J.L.,Hartford Hospital | Furtado G.H.,Hartford Hospital | Williams G.,Cerexa Inc. | Nicolau D.P.,Hartford Hospital
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.


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.


Keepers T.R.,Cerexa Inc. | Gomez M.,Cerexa Inc. | Celeri C.,Cerexa Inc. | Nichols W.W.,Astrazeneca | Krause K.M.,Cerexa Inc.
Antimicrobial Agents and Chemotherapy | Year: 2014

Avibactam, a non-β-lactam β-lactamase inhibitor with activity against extended-spectrum β-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of ceftazidime against most ceftazidime-resistant organisms producing these enzymes. In this study, the bactericidal activity of ceftazidime-avibactam against 18 Pseudomonas aeruginosa isolates and 15 Enterobacteriaceae isolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidime-avibactam MICs (0.016 to 32 μg/ml) were lower than those for ceftazidime alone (0.06 to ≥256 μg/ml) against all isolates except for 2 P. aeruginosa isolates (1 blaVIM-positive isolate and 1 blaOXA-23-positive isolate). The minimum bactericidal concentration/MIC ratios of ceftazidime-avibactam were ≤4 for all isolates, indicating bactericidal activity. Human serum and human serum albumin had a minimal effect on ceftazidime-avibactam MICs. Ceftazidime-avibactam time-kill kinetics were evaluated at low MIC multiples and showed time-dependent reductions in the number of CFU/ml from 0 to 6 h for all strains tested. A ≥3-log10 decrease in the number of CFU/ml was observed at 6 h for all Enterobacteriaceae, and a 2-log10 reduction in the number of CFU/ml was observed at 6 h for 3 of the 6 P. aeruginosa isolates. Regrowth was noted at 24 h for some of the isolates tested in time-kill assays. These data demonstrate the potent bactericidal activity of ceftazidime-avibactam and support the continued clinical development of ceftazidime-avibactam as a new treatment option for infections caused by Enterobacteriaceae and P. aeruginosa, including isolates resistant to ceftazidime by mechanisms dependent on avibactam-sensitive β-lactamases. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Riccobene T.A.,Forest Research Institute Inc. | Rekeda L.,Cerexa Inc. | Rank D.,Cerexa Inc. | Llorens L.,Cerexa Inc.
Antimicrobial Agents and Chemotherapy | Year: 2013

A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Rank D.R.,Cerexa Inc. | Friedland H.D.,Cerexa Inc. | Laudano J.B.,Forest Research Institute
Journal of Antimicrobial Chemotherapy | Year: 2011

Objectives: Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is a broad-spectrum, parenteral cephalosporin approved for treatment of moderate to severe bacterial infections, including community-acquired pneumonia (CAP). This report provides an integrated safety summary of the ceFtarOline Community-acquired pneUmonia trial versuS ceftriaxone (FOCUS) 1 and 2 trials (registration numbers: NCT00621504 and NCT00509106). Methods: Patients hospitalized with CAP requiring intravenous therapy and having Pneumonia Outcomes Research Team (PORT) risk class scores of III or IV were randomized (1:1) to receive 600 mg of ceftaroline fosamil administered intravenously every 12 h or 1 g of ceftriaxone administered intravenously every 24 h for 5-7 days. All patients were followed for treatment-emergent adverse events (TEAEs) occurring from the start of the initial study drug infusion up to the test-of-cure visit; serious adverse events (SAEs) including deaths occurring up to the late follow-up visit or within 30 days after the last dose were additionally recorded. Scheduled laboratory testing was conducted up to the test-of-cure visit; unscheduled testing continued up to the late follow-up visit. Results: A total of 1228 patients (613 in the ceftaroline fosamil group and 615 in the ceftriaxone group) received any amount of drug and were included in the safety analysis. The incidences of TEAEs (47.0% versus 45.7%), SAEs (11.3% versus 11.7%), discontinuations (4.4% versus 4.1%) and deaths (2.4% versus 2.0%) were similar between the ceftaroline fosamil and the ceftriaxone groups, respectively. Diarrhoea (4.2%), headache (3.4%) and insomnia (3.1%) were the most commonly reported TEAEs in patients treated with ceftaroline fosamil. The distribution of TEAEs based on severity was also similar between groups, and the majority of patients in both treatment groups (~75%) had either no TEAEs or only mild TEAEs. Conclusions: The data from the FOCUS 1 and FOCUS 2 trials presented in this integrated safety summary demonstrate that ceftaroline fosamil is well tolerated, with a tolerability profile similar to ceftriaxone and the cephalosporin class overall, with no unexpected safety concerns being identified. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

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