ppi-0903 and Renal-Insufficiency

Ceftaroline fosamil is a parenteral cephalosporin indicated for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Ceftaroline, the active component of ceftaroline fosamil, exhibits broad-spectrum bactericidal activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common gram-negative pathogens. The objective of the studies presented herein was to establish the pharmacokinetic profile of ceftaroline in healthy subjects and special populations of interest, such as elderly subjects, subjects with renal impairment, or subjects with end-stage renal disease on intermittent hemodialysis. The mean half-life of ceftaroline in healthy subjects was approximately 2.6 hours, and urinary excretion was the primary route of elimination. Ceftaroline Cmax and AUC values increased in proportion to dose increases within the range of 50-1000 mg, demonstrating an approximately linear pharmacokinetic profile following intravenous infusion. The pharmacokinetic parameters of ceftaroline were modestly altered in elderly subjects compared with younger adults, which was attributed to decreased renal function in elderly subjects. Ceftaroline pharmacokinetic parameters varied with different degrees of renal impairment, resulting in recommended dosage adjustments for patients with moderate to severe impairment. Ceftaroline fosamil was generally well tolerated regardless of age or severity of renal impairment.

Topics: Adolescent; Adult; Aged; Aging; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Half-Life; Humans; Infusions, Intravenous; Kidney; Kidney Failure, Chronic; Male; Prodrugs; Renal Dialysis; Renal Elimination; Renal Insufficiency; Severity of Illness Index; Young Adult

Ceftaroline could be suitable to treat early-onset ventilator-associated pneumonia (VAP) because of its antibacterial spectrum. However, augmented renal clearance (ARC) is frequent in ICU patients and may affect ceftaroline pharmacokinetics and efficacy. The objective of the study was to explore the impact of ARC on ceftaroline pharmacokinetics and evaluate whether the currently recommended dosing regimen (600 mg every 12 h) is appropriate to treat VAP in ICU patients.. A population pharmacokinetic model was developed using pharmacokinetic data from 18 patients with measured creatinine clearance (CLCR) ranging between 83 and 309 mL/min. Monte Carlo simulations were conducted to determine the PTA and the cumulative fraction of response (CFR) against Streptococcus pneumoniae and MRSA for five dosing regimens. Study registered at ClinicalTrials.gov (NCT03025841).. Ceftaroline clearance increased non-linearly with CLCR, with lower concentrations and lower probability of reaching pharmacokinetic/pharmacodynamic targets when CLCR increases. For the currently recommended dosing regimen, the probability of having unbound ceftaroline concentrations above the MIC over the entire dose range is greater than 90% for MICs below 0.125 mg/L. Considering the distribution of MICs, this regimen would not be effective against MRSA infections (CFR between 21% and 67% depending on CLCR), but would be effective against S. pneumoniae infections (CFR >86%).. The recommended dosing regimen of ceftaroline seems sufficient for covering S. pneumoniae in ICU patients with ARC, but not for MRSA. Among the dosing regimens tested it appears that a constant infusion (50 mg/h) after a loading dose of 600 mg could be more appropriate for MRSA infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Critical Care; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Monte Carlo Method; Pneumonia; Renal Insufficiency; Streptococcus pneumoniae

Topics: Adolescent; Adult; Age Factors; Anti-Bacterial Agents; Area Under Curve; Ceftaroline; Cephalosporins; Child; Child, Preschool; Computer Simulation; Female; Humans; Infant; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Models, Biological; Renal Insufficiency

Ceftaroline fosamil is a fifth-generation cephalosporin approved as a treatment for adults and children with community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. However, its pharmacokinetics have not been fully evaluated in children with renal impairment. This study aimed to propose proper ceftaroline dosages optimized for the renally impaired pediatric population using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of ceftaroline was established and verified to simulate its disposition in the healthy population and renally impaired adults and to predict the exposure in renally impaired pediatric patients. Consistency was confirmed between simulated and observed data after intravenous administration of various ceftaroline regimens; fold errors were within the 2-fold error range. Among 6-year-old children, healthy subjects had 1.5-fold, 2-fold, and 2.6-fold lower areas under the plasma concentration-time curve (AUCs) than the moderate, severe, and end-stage renally impaired patient groups, respectively; among 1-year-old children, healthy subjects had 1.5-fold, 2.1-fold, and 2.5-fold lower AUCs than the respective renally impaired patient groups; among 1-month-old children, healthy subjects had 1.5-fold, 1.8-fold, and 2.2-fold lower AUCs than the respective renally impaired patient groups. The proposed dosage should be adjusted to 8, 6, and 5 mg/kg every 8 hours for patients aged ≥2 years to <18 years (≤33 kg) with moderate, severe, and end-stage renal impairment, respectively; 5, 4, and 3 mg/kg every 8 hours for patients aged 2 months to <2 years with moderate, severe, and end-stage renal impairment, respectively; 4, 3.5, and 2.5 mg/kg every 8 hours for patients 0 to <2 months of age with moderate, severe, and end-stage renal impairment, respectively. Furthermore, pharmacodynamic investigations demonstrated that adequate antimicrobial effects were attained at the proposed doses in 3 age groups. Hence, our PBPK model can be an effective tool to support ceftaroline dosage proposals for renally impaired pediatric patients.

Topics: Adolescent; Anti-Bacterial Agents; Area Under Curve; Ceftaroline; Cephalosporins; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Glomerular Filtration Barrier; Half-Life; Humans; Male; Metabolic Clearance Rate; Microbial Sensitivity Tests; Patient Acuity; Renal Insufficiency

Encephalopathy complicates beta-lactam therapy, particularly with impaired renal function, though no studies have reported ceftaroline-associated encephalopathy. Among 28 patients with estimated glomerular filtration rates <30 mL/min who received ≥5 days of ceftaroline, 3 developed encephalopathy. Ceftaroline, when dosed supra-therapeutically for serious infections, may be a cause of antibiotic-associated encephalopathy.

Topics: Anti-Bacterial Agents; Brain Diseases; Ceftaroline; Cephalosporins; Humans; Renal Insufficiency

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter retrospective study, conducted in the USA, describing the contemporary use of ceftaroline fosamil. Ceftaroline is primarily excreted by the kidneys and the dose should be reduced in patients with moderate to severe renal insufficiency. This article describes the clinical effectiveness of ceftaroline fosamil in the treatment of acute bacterial skin and skin structure infection (ABSSSI) or community-acquired bacterial pneumonia (CABP) patients with renal insufficiency. There were 985 ABSSSI patients and 344 CABP patients, of which 22 and 31%, respectively, had renal insufficiency. Ceftaroline fosamil was mostly administered to patients as second-line therapy. Overall clinical success was 78-91% among ABSSSI or CABP patients with renal insufficiency and, overall, >50% of patients were discharged to home. Ceftaroline fosamil is an effective treatment option for ABSSSI or CABP patients with renal insufficiency.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Humans; Male; Middle Aged; Pneumonia; Renal Insufficiency; Retrospective Studies; Skin Diseases, Bacterial; Young Adult