Methicillin-resistant<i>Staphylococcus aureus</i>nosocomial pneumonia patients treated with ceftaroline: retrospective case series of 10 patients

bStaphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ϳ10 6 CFU/ml. Time-kill curves were constructed, and microbiological response (change in log 10 CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log 10 CFU/ml was largest for ceftaroline q8h (reductions of >3 log 10 CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log 10 CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log 10 CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log 10 CFU/ml increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia.

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

In Vitro Activity of Human-Simulated Epithelial Lining Fluid Exposures of Ceftaroline, Ceftriaxone, and Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus

MacVane

Nicolau

et al. 2014

“…An analysis of more recent data from CAPTURE reported a clinical success rate of 62% (13/21) for patients with MRSA HAP or VAP (37). Most patients in this study (93%) received ceftaroline fosamil every 12 h. In addition, in a case series, ceftaroline fosamil at 600 mg q12h showed efficacy in patients with nosocomial pneumonia due to MRSA, with clinical success achieved in 6/10 patients (38). Three patients expired due to noninfectious causes, and one patient relapsed.…”

Section: Discussionmentioning

confidence: 87%

Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects

Riccobene¹,

Pushkin²,

Jandourek³

et al. 2016

c Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with bactericidal activity against Grampositive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to (i) evaluate ceftaroline concentrations in human plasma and epithelial lining fluid (ELF) and (ii) develop a population pharmacokinetic (PK) model for plasma and ELF to be used in PK/pharmacodynamic (PD) target attainment simulations. Ceftaroline concentrations in ELF and plasma at steady state (day 4) were measured in healthy adult subjects for two dosages: 600 mg every 12 h (q12h) and 600 mg every 8 h (q8h). Both were well tolerated with no serious adverse events. The penetration of free ceftaroline into ELF, assuming 20% protein binding in plasma and no protein binding in ELF, was Ϸ23%. The population PK model utilized a two-compartment model for both ceftaroline fosamil and ceftaroline. Goodness-of-fit criteria revealed the model was consistent with observed data and no systematic bias remained. At 600 mg q12h and a MIC of 1 mg/liter, 98.1% of simulated patients would be expected to achieve a target free drug concentration above the MIC (fT>MIC) in plasma of 42%, and in ELF 81.7% would be expected to achieve a target fT>MIC of 17%; at 600 mg q8h, 100% were predicted to achieve an fT>MIC in plasma of 42% and 94.7% to achieve an fT>MIC of 17% in ELF. The literature and data suggest the 600 mg q12h dose is adequate for MICs of <1 mg/liter. There is a need for clinical data in patients with MRSA pneumonia and data to correlate PK/PD relationships in ELF with clinical outcomes. C eftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin antibiotic with bactericidal activity against Gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) (1, 2). Ceftaroline is also active in vitro against Gram-negative organisms such as Haemophilus influenzae and Moraxella catarrhalis and non-extended-spectrum ␤-lactamaseproducing Enterobacteriaceae (1, 2). Ceftaroline fosamil is approved in the United States for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), with approval in Europe for similar indications. At a dosage of 600 mg every 12 h (q12h), ceftaroline fosamil demonstrated noninferiority to ceftriaxone given at 1 g q24h in the treatment of patients with moderate to severe CABP in two phase 3 clinical studies (ClinicalTrials registration no. NCT00621504 and NCT00509106) (3-5). Ceftaroline fosamil (600 mg q12h) has also been demonstrated to be superior to ceftriaxone (2 g q24h) in the treatment of Asian patients with community-acquired pneumonia (ClinicalTrials registration no. NCT01371838) (6), and in a recent meta-analysis ceftaroline fosamil was shown to be superior to ceftriaxone as an empirical treatment for adult patients hospitalized with PORT risk class 3 to 4 community-acquired pneumonia (7). Ceftaro...

“…Ceftaroline has in vitro bactericidal activity against MDR-MRSA, has a good safety profile, and has been approved by the Food and Drug Administration for treating adults with ABSSSI and CABP (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). This report from Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) summarizes the in vitro activity of ceftaroline against S. aureus isolates collected in Latin America during 2012, including molecular characterization of isolates with reduced susceptibility to ceftaroline.…”

mentioning

confidence: 99%

In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolates Collected in 2012 from Latin American Countries as Part of the AWARE Surveillance Program

Biedenbach¹,

Hoban²,

Reiszner

et al. 2015

The in vitro activities of ceftaroline and comparators, using broth microdilution, were determined against 1,066 Staphylococcus aureus isolates from hospitalized patients. Seventeen medical centers from Latin American countries contributed isolates. Methicillin-resistant S. aureus (MRSA) percentages ranged from 46% (Brazil) to 62% (Argentina). All methicillin-susceptible S. aureus (MSSA) isolates were susceptible to ceftaroline. Ceftaroline activity against MRSA varied with MIC 90 s of 0.5 (Venezuela) to 2 (Brazil, Chile, and Colombia) g/ml, which was the highest MIC value. ST-5 was the most common sequence type.