Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial

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...

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

Riccobene¹,

Pushkin²,

Jandourek³

et al. 2016

“…Although CPT-F was shown to be effective against both approved indications, CAP and cSSTIs (1)(2)(3)(4)(5), precise information regarding the pharmacokinetics (PKs) of CPT in the interstitial space fluid of soft tissues is very limited to date. However, this information is considered to be highly relevant as a key input for PK/pharmacodynamic (PD) calculations and subsequently for the appropriate setting of site-specific susceptibility breakpoints.…”

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confidence: 99%

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Matzneller

Lackner

Lagler

et al. 2016

bCeftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fT MIC ) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC 0-) for free CPT in soft tissues and the AUC 0-for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fT MIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies. Ceftaroline fosamil (CPT-F; brand names, Zinforo in Europe and Teflaro in the United States) was recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of complicated skin and soft tissue infections (cSSTIs) and community-acquired pneumonia (CAP) in adults. Ceftaroline (CPT) is a cephalosporin antibiotic and acts, like all beta-lactam agents, via inhibition of peptidoglycan synthesis. In contrast to other cephalosporins, CPT is active against some resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-nonsusceptible Streptococcus pneumoniae (PNSP), and is therefore often referred to as a "fifth generation," or advanced-generation, cephalosporin. CPT-F, a water soluble N-phosphono prodrug, is converted to the active CPT in human plasma, and CPT is further converted into the inactive ring-opened metabolite CPT M-1.Although CPT-F was shown to be effective against both approved indications, CAP and cSSTIs (1-5), precise information regarding the pharmacokinetics (PKs) of CPT in the interstitial space fluid of soft tissues is very limited to date. However, this information is considered to be highly relevant as a key input for PK/pharmacodynamic (PD) cal...

“…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.…”

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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.