Comparison of Neutropenia Associated with Ceftaroline or Ceftriaxone in Patients Receiving at Least 7 Days of Therapy for Severe Infections

Abstract

STUDY OBJECTIVE Ceftarolinefosamil is a cephalosporin with broad clinical utility; however, limited data suggest that prolonged ceftaroline exposure may be associated with neutropenia. The objective was to determine drug and patient factors associated with neutropenia in patients receiving ceftaroline or ceftriaxone for deep-seated infections. DESIGN Retrospective, ratio-matched cohort study. SETTING Four acute-care hospitals within an urban health care system. PATIENTS A total of 176 hospitalized adults who received definitive ceftaroline (44 patients) or ceftriaxone (132 patients) therapy for at least 7 days between January 2013 and April 2017 for any of the following indications: bone and joint infections (BJI), infective endocarditis (IE), or bloodstream infections (BSI). MEASUREMENTS AND MAIN RESULTS The primary outcome was development of neutropenia while receiving cephalosporin therapy, defined as an absolute neutrophil count (ANC) <1500 cells/mm 3 . Neutropenia severity and patient characteristics were described and compared between the ceftaroline and ceftriaxone groups. The median (interquartile range [IQR]) antibiotic prescription duration was 41 (29-44) days for the ceftaroline group and 40 (28-44) days for the ceftriaxone group (p=0.9). Cephalosporin indications were 112 (64%) BJI, 27 (15%) BSI, 16 (9%) IE, and 21 (12%) multiple infections; ceftaroline was more commonly used in BJI (p=0.03), and ceftriaxone was more commonly used in IE (p=0.01). Neutropenia developed in 16 (9%) patients: 8 (18%) in the ceftaroline group and 8 (6%) in the ceftriaxone group (p=0.03). Median (IQR) onset to neutropenia was 22 (15-28) days, and median (IQR) change in ANC was 2.86 (1.50-4.08) cells/mm 3 ; most cases of neutropenia were mild (12 patients [75%]). The median (IQR) time to mild or moderate-severe neutropenia was not significantly different (p=0.68): 22 (14-28) and 22 (21-36) days, respectively. Treatment was discontinued in 4 (25%) patients due to neutropenia. Ceftaroline use was independently associated with neutropenia (adjusted odds ratio 3.2, 95% confidence interval 1.2-10.5) after adjusting for lower body mass index strata (18.5-25 kg/m 2 ).

A Review of β-Lactam–Associated Neutropenia and Implications for Cross-reactivity

“…9,55,58-62 The reported incidence of ceftaroline-induced neutropenia following 1 to 2 weeks of therapy varies from 7% to 18% and increases to 21% with 3 weeks of therapy. 9,55,58,60,62 In 1 large cohort study evaluating characteristics of drug-induced neutropenia following 2 weeks of therapy, the incidence of neutropenia with ceftaroline was found to be 17%, compared with only 2% for cefazolin. The study, which included ceftaroline, cefazolin, and nafcillin, did not find any evidence of a dose-dependent effect on the development of neutropenia.…”

“…9 The most common dosing strategy utilized in reported cases of ceftaroline-induced neutropenia was 600 mg every 12 hours, followed by the off-label dose of 600 mg every 8 hours. 55,58-62…”

“…The incidence of ceftriaxone-induced neutropenia in 1 retrospective cohort study was 6%, with durations of therapy equaling or exceeding 7 days. 55 A recent literature summary of ceftriaxone-induced neutropenia demonstrated a mean time to neutropenia of 23 days, a mean time to recovery of 6.5 days, and a mean ANC nadir of 0.1 × 10 3 / µL. 8 The vast majority of cases of ceftriaxone-induced neutropenia have reported a daily dose of 2 g. 3,8,55 Regarding cefepime, 1 study identified a 62% incidence (8/13) of cefepime-induced neutropenia, with extended courses using a dose of 2 g every 12 hours, with an average neutropenia onset of 25 days.…”

“…57 Ceftaroline, despite having arguably less clinical experience relative to other agents in this review, has amassed a considerable amount of attention for its propensity to cause neutropenia with extended courses of therapy. 9,55,[58][59][60][61][62] The reported incidence of ceftaroline-induced neutropenia following 1 to 2 weeks of therapy varies from 7% to 18% and increases to 21% with 3 weeks of therapy. 9,55,58,60,62 In 1 large cohort study evaluating characteristics of druginduced neutropenia following 2 weeks of therapy, the incidence of neutropenia with ceftaroline was found to be 17%, compared with only 2% for cefazolin.…”

“…9 The most common dosing strategy utilized in reported cases of ceftaroline-induced neutropenia was 600 mg every 12 hours, followed by the off-label dose of 600 mg every 8 hours. 55,[58][59][60][61][62] Reports of neutropenia are sparse with the carbapenems, a subclass of the penems class of β-lactams, possibly owing to their reserved indication for use, lack of prolonged use, and/or low immunogenicity. 6,[63][64][65] A pooled safety analysis of 3470 patients treated with imipenem-cilastatin in clinical trials demonstrated a 0.9% incidence of neutropenia, which dropped to 0.3% when limited to cases that were probably or definitely drug induced.…”