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Evaluation of ceftaroline activity versus ceftriaxone against clinical isolates of Streptococcus pneumoniae with various susceptibilities to cephalosporins in an in vitro pharmacokinetic/pharmacodynamic model.

ABSTRACT: Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fC(max)] is 15.2 ?g/ml, and half-life [T(1/2)] is 2.5 h) versus ceftriaxone at 1 g q24h (fC(max) = 23 ?g/ml, T(1/2) = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 10(7) CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ? 3 log(10) CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ? 0.008, 0.25, 0.25, and 0.5 ?g/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 ?g/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, -5.49 log(10) CFU/ml) and was significantly (P ? 0.012) better than ceftriaxone (72 to 96 h, -2.03 log(10) CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [-5.91 log(10) CFU/ml, P ? 0.002], SP 90 [-5.26 log(10) CFU/ml, P ? 0.008], and SP1466 [-5.14 log(10) CFU/ml, P ? 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.

SUBMITTER: Steed ME

PROVIDER: S-EPMC3346590 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Evaluation of ceftaroline activity versus ceftriaxone against clinical isolates of Streptococcus pneumoniae with various susceptibilities to cephalosporins in an in vitro pharmacokinetic/pharmacodynamic model.

Steed Molly E ME Vidaillac Céline C Winterfield Patricia P Biek Donald D Rybak Michael J MJ

Antimicrobial agents and chemotherapy 20120221 5

Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fC(max)] is 15.2 μg/ml, and half-life [T(1/2)] is 2.5 h) versus ceftriaxone at 1 g q24h (fC(max) = 2 ...[more]

PMID: 22354289

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Project description:To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.

Project description:The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse.We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively.The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4?mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug.Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.

Dataset Information

Evaluation of ceftaroline activity versus ceftriaxone against clinical isolates of Streptococcus pneumoniae with various susceptibilities to cephalosporins in an in vitro pharmacokinetic/pharmacodynamic model.

Publications

Evaluation of ceftaroline activity versus ceftriaxone against clinical isolates of Streptococcus pneumoniae with various susceptibilities to cephalosporins in an in vitro pharmacokinetic/pharmacodynamic model.

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