ppi-0903 and Neutropenia

Ceftaroline is a broad-spectrum, methicillin-resistant Staphylococcus aureus (MRSA)-active β-lactam approved for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired pneumonia. Because of its favorable spectrum and pharmacokinetics, ceftaroline is frequently utilized for infections such as osteomyelitis and endocarditis. Ceftaroline has been associated with neutropenia, but evaluation of other adverse events remains limited.. To describe the rates and types of ceftaroline-associated adverse events and determine if patients' baseline allergies affect the rates of an adverse event.. A single-center, retrospective, observational analysis was conducted of all patients who received ceftaroline between November 4, 2011, and March 28, 2017, at the VA Saint Louis Health Care System. The Naranjo algorithm was utilized as a standardized method to evaluate likelihood that the adverse events were caused by ceftaroline therapy. Ceftaroline dose, duration, indication, and baseline allergy information were collected for all patients.. There were 75 patients who received 78 courses of ceftaroline identified for inclusion. The most common indications were osteomyelitis (51.3%) and ABSSSI (16.7%). Overall, 13/75 (17.3%) patients developed an adverse event, and 10/75 (13.3%) required discontinuation of ceftaroline. Rash was the most common adverse reaction and occurred in 7/75 (9.3%) patients, followed by neutropenia in 3/75 (4.0%) patients. There were no differences in baseline allergy characteristics between patients who experienced an adverse reaction to ceftaroline and those who did not.. When compared with clinical trials, ceftaroline use appears to be associated with an increased rate of overall adverse events, which is driven by cutaneous reactions.

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Exanthema; Female; Humans; Hypersensitivity; Incidence; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Neutropenia; Staphylococcal Infections

Ceftaroline is often used in durations greater than that studied in clinical trials. Several retrospective, non-comparative studies have suggested a higher than anticipated incidence of neutropenia in patients receiving prolonged treatment with ceftaroline. We sought to determine if ceftaroline was associated with neutropenia by comparing the incidence with ceftaroline treatment with treatment with several comparative antibiotics.. Patients receiving 14 or more consecutive days of treatment with ceftaroline were compared with patients receiving cefazolin, daptomycin, linezolid, nafcillin or vancomycin (control group). The primary outcome was the development of neutropenia. Multivariate logistic regression and propensity score weighting using inverse probability weights with regression adjustment were used to control for confounding variables.. A total of 753 patients were included (53 that received ceftaroline and 700 that received a comparative antibiotic). Ceftaroline was associated with a greater incidence of neutropenia as compared with the control group (17.0% versus 3.9%, P < 0.001). Several covariates were also associated with neutropenia and included younger age, lower baseline absolute neutrophil count, liver disease and bone and joint infections. After controlling for these confounders, receipt of ceftaroline continued to be associated with the development of neutropenia (adjusted OR 3.97, P = 0.003). Analysis after propensity score weighting confirmed this finding.. The results of this study suggest that prolonged treatment with ceftaroline is associated with a greater incidence of neutropenia as compared with other antibiotics that are often used for treatment of staphylococcal infections. Careful monitoring of absolute neutrophil count is recommended in patients receiving >14 days of ceftaroline.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefazolin; Ceftaroline; Cephalosporins; Daptomycin; Female; Humans; Incidence; Leukocyte Count; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Neutropenia; Retrospective Studies; Staphylococcal Infections; Vancomycin

Ceftaroline is a fifth-generation cephalosporin with potent antimicrobial activity against Gram-positive and Gram-negative pathogens. Neutropenia is a rare serious adverse event for the class of cephalosporins; however, we observed several cases of severe neutropenia in our outpatient infectious disease practice believed to be associated with ceftaroline use. The aim of this study was to determine the incidence of neutropenia among patients receiving ceftaroline therapy for more than 7 days. We conducted a retrospective cohort analysis of patients admitted to an 800-bed regional medical center between June 2012 and December 2014 who received ceftaroline for more than 7 days to assess the incidence of developing clinically significant neutropenia. Demographic and patient care data points as well as underlying admitting and chronic diagnoses were retrospectively collected from the medical record. Clinically significant neutropenia was defined as an absolute neutrophil count (ANC) less than 1,500 cells/mm(3). Analysis was performed to determine the incidence, severity, and outcome of neutropenia following ceftaroline administration. A total of 39 patients were included in the cohort. The median duration of therapy was 27 days. Seven patients (18%) developed neutropenia while on ceftaroline therapy. Four (10%) of the neutropenic patients had an ANC of <500 cells/mm(3). The median first neutropenic day was day 17, with the median ANC nadir of 432 cells/mm(3) on day 24. We determined that extended ceftaroline infusion is associated with the development of neutropenia. We recommend obtaining a complete blood count (CBC) with differential at the onset of therapy and weekly thereafter. Should the ANC fall below 2,500 cells/mm(3), then twice-weekly CBCs should be monitored for the duration of ceftaroline therapy, and therapy should be discontinued if the ANC falls to 1,500 cells/mm(3) or less.

Topics: Adult; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Leukocyte Count; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Neutropenia; Neutrophils; Retrospective Studies; Staphylococcal Infections; Time Factors

We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline.. We retrospectively identified adult patients who received ceftaroline for ≥7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia.. The overall rate of incident neutropenia was 10%-14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22-44; range 13-68) in patients who developed neutropenia and 15 days (IQR 9-29; range 7-64) in patients without neutropenia] was associated with incident neutropenia (P = 0.048). The median total number of ceftaroline doses received [63 (IQR 44-126; range 36-198) by neutropenic patients and 32 (IQR 22-63; range 14-180) by non-neutropenic patients] was also associated with incident neutropenia (P = 0.023).. The overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use.

Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Boston; Ceftaroline; Cephalosporins; Female; Humans; Incidence; Male; Middle Aged; Neutropenia; Retrospective Studies; Risk Factors; Young Adult

In light of the in vivo/in vitro discordance among beta-lactams against Gram-negative pathogens, we compared the in vivo pharmacodynamics of humanized ceftaroline against 9 Staphylococcus aureus strains (MICs of 0.13 to 1 mg/liter) from published in vitro studies using standard and high inocula in the murine thigh infection model. Consistent with the in vitro findings, mean reductions of ≥1 log10 CFU were observed for ceftaroline against all strains using both standard and high inocula. These results suggest in vivo/in vitro concordance with no observed inoculum effect.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Female; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Penicillin-Binding Proteins; Staphylococcal Infections; Staphylococcus aureus

A case of profound neutropenia and agranulocytosis associated with the off-label use of ceftaroline is reported.. A 67-year-old Caucasian man arrived at the emergency room with right shoulder pain and weakness that radiated to his right chest, back, and right arm. A review of symptoms was notable for two days of burning with urination associated with decreased urinary output and decreased appetite. Multiple tests revealed the presence of methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis, which was treated with an off-label dosage of ceftaroline (600 mg intravenously every eight hours). At the start of ceftaroline therapy, the patient's baseline absolute neutrophil count (ANC) was 6640 cells/μL and decreased to 816 cells/μL by day 19, eventually falling to 0 cells/μL on day 21 of therapy. Ceftaroline was then discontinued due to the suspicion that the neutropenia was secondary to maturation arrest of the bone marrow. The patient was switched to i.v. daptomycin to finish a six-week course of antibiotics. Interventional radiology placed a drain in the patient's right shoulder during the hospital stay, with symptom improvement. His white blood cell count continued to increase after ceftaroline discontinuation, reaching 6.5×10(3) cells/μL with a differential of 56.6% segmented neutrophils and 28.4% lymphocytes after nine days off of ceftaroline.. A 67-year-old man developed profound neutropenia and agranulocytosis after three weeks of high-dose ceftaroline therapy for the treatment of MRSA septic arthritis. His neutropenia resolved after ceftaroline discontinuation and treatment with an alternative antibiotic.

Topics: Aged; Agranulocytosis; Anti-Bacterial Agents; Arthritis, Infectious; Ceftaroline; Cephalosporins; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Neutropenia; Off-Label Use

The US Food and Drug Administration approved ceftaroline in 2010 for the treatment of community-acquired pneumonia and skin and soft-tissue infections. The most common adverse reactions are diarrhoea, nausea and rash. To present the first case of neutropenia directly related to ceftaroline.. A 90-year-old female was given ceftaroline for treatment of a pneumonia complicated by methicillin-resistant Staphylococcus aureus bacteraemia and possible vertebral osteomyelitis. After 25 days of ceftaroline, she developed neutropenia. Ceftaroline was discontinued and her white blood cell count returned to normal within one week.. Although neutropenia is a potential cephalosporin class effect, we present the first case of neutropenia directly related to ceftaroline. Agranulocytosis and neutropenia are rare, yet potentially life-threatening adverse effects of cephalosporins. Healthcare providers should be aware of the potential for ceftaroline to cause neutropenia, particularly in patients treated for greater than two weeks.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Neutropenia; Pneumonia, Bacterial

Ceftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, including Enterobacteriaceae, and Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinical Enterobacteriaceae in both neutropenic and immunocompetent mouse thigh infection models. Thirty-five Enterobacteriaceae isolates with ceftaroline MICs ranging from 0.25 to 32 μg/ml were selected for the neutropenic model, and five Escherichia coli isolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log(10) CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with a MIC of ≤ 1 μg/ml. Similar efficacy was seen in the immunocompetent model against isolates with a MIC of ≤ 2 μg/ml, and enhanced efficacy was observed against the isolate with a MIC of 4 μg/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy against Enterobacteriaceae with MICs of ≤ 1 μg/ml and enhanced efficacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Drug Administration Schedule; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Female; Humans; Immunocompetence; Injections, Intravenous; Klebsiella; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Phenotype; Thigh

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 μg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log(10) kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log(10) CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log(10) kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Dose-Response Relationship, Drug; Female; Humans; Immunocompromised Host; Lung; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia; Pneumonia, Staphylococcal; Protein Binding