Single- and Multiple-Dose Study To Determine the Safety, Tolerability, and Pharmacokinetics of Ceftaroline Fosamil in Combination with Avibactam in Healthy Subjects

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...

Section: Discussionsupporting

confidence: 75%

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

“…b.i.d. was administered (12). Indeed, the mean CPT AUC 0 -24 in the rabbits was 76.2 mg · h/liter versus 65 mg · h/liter in healthy adults (12), and the mean peak plasma concentrations in the rabbits and in healthy adults were 38 mg/liter and 31 mg/liter, respectively.…”

Section: Discussionmentioning

confidence: 95%

“…was administered (12). Indeed, the mean CPT AUC 0 -24 in the rabbits was 76.2 mg · h/liter versus 65 mg · h/liter in healthy adults (12), and the mean peak plasma concentrations in the rabbits and in healthy adults were 38 mg/liter and 31 mg/liter, respectively. With this equivalent dose the plasma CPT concentration in this study exceeded the test strain MIC for Ͼ50% of the 12-h between-dose periods; this concentration provided a suitable PD parameter to obtain a bactericidal effect in vitro and in vivo (14).…”

Section: Discussionmentioning

confidence: 95%

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Ceftaroline-Fosamil Efficacy against Methicillin-Resistant Staphylococcus aureus in a Rabbit Prosthetic Joint Infection Model

Gatin

Saleh‐Mghir

Tasse

et al. 2014

c Ceftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F), demonstrates in vitro bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and is effective in rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis. However, its in vivo efficacy in a prosthetic joint infection (PJI) model is unknown. Using a MRSAinfected knee PJI model in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone and combined with rifampin (RIF) were compared. After each partial knee replacement with a silicone implant that fit into the tibial intramedullary canal was performed, 5 ؋ 10 7 MRSA CFU (MICs of 0.38, 0.006, and 1 mg/liter for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg of body weight intramuscularly [i.m.]), VAN (60 mg/kg i.m.), CPT-F plus RIF (10 mg/kg i.m.), or VAN plus RIF starting 7 days postinoculation and lasting for 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although the in vivo mean log 10 CFU/g of CPT-treated (3.0 ؎ 0.9, n ‫؍‬ 12) and VAN-treated (3.5 ؎ 1.1, n ‫؍‬ 12) crushed bones was significantly lower than those of controls (5.6 ؎ 1.1, n ‫؍‬ 14) (P < 0.001), neither treatment fully sterilized the bones (3/12 were sterile with each treatment). The mean log 10 CFU/g values for the antibiotics in combination with RIF were 1.9 ؎ 0.5 (12/14 were sterile) for CPT-F and 1.9 ؎ 0.5 (12/14 were sterile) for VAN. In this MRSA PJI model, the efficacies of CPT-F and VAN did not differ; thus, CPT appears to be a promising antimicrobial agent for the treatment of MRSA PJIs. O rthopedic joint replacement is an increasingly common surgical procedure worldwide, reflecting the aging of the population (1). While prosthetic joint infection (PJI) is uncommon, it can be a serious complication which entails major morbidity and high costs (1). Perioperative contamination is responsible for most PJIs, which are mainly caused by Staphylococcus aureus or Staphylococcus epidermidis (2). These microorganisms are often resistant to many commonly used antibiotics. At present, vancomycin (VAN) or daptomycin (DAP) combined with rifampin (RIF) is recommended as the first-line therapy of device-related osteoarticular infections due to methicillin-resistant S. aureus (MRSA) (3). However, the efficacy of VAN might not be optimal when the MIC of the responsible strain is Ͼ1 g/ml (3, 4). Strains with reduced susceptibilities to DAP were described in experimental PJI models and in patients without treatment and in those after VAN or DAP administration (4,5). Thus, alternative therapies are still needed.Ceftaroline (CPT) is a broad-spectrum cephalosporin with a high in vitro affinity for penicillin-binding protein 2a and bactericidal activity against MRSA. CPT is the active metabolite of the prodrug ceftaroline-fosamil (CPT-F). This compound was recently approved in the United States for the treatment of complicated skin...

“…There was no correlation among the fecal concentrations and a moderate increase of plasma creatinine levels. Ceftaroline and avibactam are mainly excreted through urine (20). Avibactam was also studied in combination with ceftazidime in 12 healthy volunteers (21).…”

Section: Discussionmentioning

confidence: 99%

Ecological Effect of Ceftaroline-Avibactam on the Normal Human Intestinal Microbiota

Rashid

Rosenborg

Panagiotidis

et al. 2015

Ceftaroline-avibactam is a new combination of the antibiotic ceftaroline with a novel non-␤-lactam ␤-lactamase inhibitor, avibactam. The purpose of the present study was to investigate the effect of ceftaroline-avibactam on the human intestinal microbiota. Fourteen healthy volunteers received ceftaroline-avibactam (600 mg ceftaroline fosamil and 600 mg avibactam) intravenously over 2 h every 8 h on days 1 to 6 and as a single dose on day 7. Fecal samples were collected on day ؊1 (within 24 h of the first infusion on day 1) and on days 2, 5, 7, 9, 14, and 21. Escherichia coli numbers decreased during the study and normalized on day 21. An increased number of Klebsiella bacteria appeared on day 14 and normalized on day 21. The number of other enterobacteria decreased during the study, and the number of enterococci decreased from days 2 to 7 and normalized on day 9. Candida numbers increased from days 5 to 9 and normalized after day 14. The number of lactobacilli decreased during the study and recovered on day 14. The number of bifidobacteria decreased on day 2 and normalized on day 21. The number of Bacteroides bacteria was unchanged. Clostridium difficile numbers decreased on days 7 and 9 and increased on days 14 and 21. A toxigenic C. difficile strain was detected in one volunteer on day 21 with no reported adverse events. Plasma samples were collected on days