Abstract
Objectives
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.
Methods
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.
Results
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).
Conclusions
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.
Introduction
Ceftaroline is FDA approved for treatment of acute bacterial skin and soft-tissue infections (SSTIs) and community-acquired pneumonia (CAP).1 However, clinicians have treated bacteraemia, endocarditis and osteomyelitis with higher doses and longer durations.2–4 Safety data for off-label indications are sparse and include two case reports and a small case series. Rimawi et al.5 reported severe neutropenia, with an absolute neutrophil count (ANC) of 0 cells/mm3, occurring ∼25 days into ceftaroline therapy with resolution 1 week after discontinuation in a 90-year-old female. Similarly, Yam and Kwan6 reported severe neutropenia (ANC = 32 cells/mm3) with peripheral eosinophilia in a 67-year-old male treated with ∼3 weeks of ceftaroline for MRSA septic arthritis. Resolution of neutropenia occurred 9 days after discontinuation. Further, Jain et al.7 described ceftaroline discontinuation among 4 of 12 patients receiving a median of 12 days of ceftaroline due to haematological toxicity: 2 patients developed isolated neutropenia and 2 neutropenia with either thrombocytopenia or anaemia. Resolution occurred a median of 7 days after discontinuation. Finally, Varada et al.8 found incident agranulocytosis among 4/29 (13.8%) patients receiving ceftaroline therapy: 2/18 (11%) receiving >2 weeks of ceftaroline monotherapy and 2/11 (18%) patients treated with ceftaroline plus clindamycin. We sought to assess the incidence of and risk factors for neutropenia in a cohort of patients receiving ceftaroline at two large academic medical centres.
Patients and methods
We performed a retrospective evaluation of long-term ceftaroline use at Brigham and Women's Hospital and Massachusetts General Hospital in Boston, MA, USA. Patients ≥18 years of age receiving ceftaroline for ≥7 days consecutively between November 2010 and March 2015 were included. Patients with baseline neutropenia, defined as an ANC of ≤1800 cells/mm3 at the start of ceftaroline therapy, active receipt of chemotherapy or radiation or missing laboratory data in the electronic medical record were excluded.
Neutropenia was defined as an ANC of ≤1800 cells/mm3 and further classified as mild (1000–1800 cells/mm3), moderate (500–1000 cells/mm3) or severe (<500 cells/mm3). To assess the likelihood of ceftaroline as the cause of neutropenia, we used the Naranjo adverse drug reaction probability scale.9 Clinical characteristics, including age, gender, medication allergies, baseline creatinine clearance using the Cockcroft–Gault equation, renal dysfunction (estimated glomerular filtration rate <50 mL/min per unit of body surface area), duration of ceftaroline exposure, total daily ceftaroline dose, ceftaroline dose per kilogram of body mass and the development of incident rash, fever, anaemia or thrombocytopenia during ceftaroline therapy, were recorded. All patients had orders for complete blood count (CBC) monitoring at least weekly over their ceftaroline course. We assessed whether clinical factors were associated with incident neutropenia using Fisher's exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. The rate of incident neutropenia was calculated in the cohort by duration of ceftaroline exposure.
Results
Sixty-seven patients received ceftaroline for ≥7 days; 28 (42%) were male and the median age was 50 years (IQR 38–67; range 24–93). Ceftaroline was prescribed for bloodstream infections or infective endocarditis in 32 (48%), bone and joint infections in 22 (33%), pneumonia in 11 (16%) and meningitis in 2 (3%) patients. The microbiological aetiology included MRSA in 43 (64%), MSSA in 3 (4%), coagulase-negative Staphylococcus in 3 (4%), Streptococcus sanguinis in 1 (1%), polymicrobial in 12 (18%) and unspecified, with empirical treatment, in 5 (7%) patients.
Patients had documented CBC values at least weekly over their ceftaroline course, with some missing CBC values in 2 of 67 patients (3%). Seven of 67 patients (10%) developed incident neutropenia a median of 29 days (range 13–64) after starting ceftaroline. Among neutropenic patients, five (71%) cases were severe and two (29%) mild. Two patients with severe neutropenia received 3 days of filgrastim to aid neutrophil recovery. Febrile neutropenia occurred in two patients with severe neutropenia, one of whom developed Enterobacter cloacae bacteraemia. One patient with severe neutropenia also had concurrent eosinophilia and rash. Ceftaroline was discontinued in six of seven neutropenic patients. Five of seven (71%) neutropenic patients were followed to resolution of neutropenia, which occurred a median of 7 (range 3–11) days after ceftaroline discontinuation. In all seven cases of incident neutropenia, the Naranjo score indicated a probable association with ceftaroline exposure (range 6–7).9
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], including doses received after the onset of incident neutropenia, was also associated with the development of neutropenia (P = 0.023). The overall rate of incident neutropenia was 10%–14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. We found no association between age, gender, prior antibiotic allergies, renal dysfunction or body mass-adjusted ceftaroline dose and incident neutropenia. Only one of the seven patients who developed ceftaroline-associated neutropenia (Case 4 below) received concomitant antimicrobial therapy, as outlined in more detail below.
White blood cell (WBC) count and ANC trends of each patient with ceftaroline-associated neutropenia are illustrated in Figure 1.
Figure 1.
WBC count (×103/mm3) and ANC (cells/mm3) trends of each patient with ceftaroline-associated neutropenia. GCSF, granulocyte colony-stimulating factor.
Case 1
A 40-year-old female was treated for MRSA prosthetic knee infection with 400 mg of ceftaroline every 8 h for 13 days. Her baseline creatinine clearance was 41 mL/min. The patient became neutropenic on day 12, with a nadir ANC of 16 cells/mm3 on day 14, without clinical complications. Ceftaroline was discontinued on day 13.
Case 2
Ceftaroline at 600 mg every 12 h was administered to a 47-year-old male with MRSA intrathecal pump-associated infection for 32 days. His baseline creatinine clearance was 87 mL/min. Nadir ANC was 1605 cells/mm3 at day 30. Ceftaroline was discontinued on day 32 with count recovery 8 days later.
Case 3
A 79-year-old female received 600 mg of ceftaroline every 8 h for 30 days for MRSA lumbar osteomyelitis with hardware involvement. Her baseline creatinine clearance was 68 mL/min. Nadir ANC was 1591 cells/mm3 on day 29. Owing to neutropenia and decreased renal function, ceftaroline was decreased to 400 mg every 8 h on day 30. Count recovery occurred by day 39 and treatment was completed on day 42 without complication. There was further count recovery to an ANC of 2782 cells/mm3 14 days after ceftaroline discontinuation.
Case 4
A 36-year-old male with MRSA endocarditis and multiple brain infarcts and abscesses received 600 mg of ceftaroline every 8 h. His baseline creatinine clearance was 110 mL/min. This patient received several concomitant antimicrobials over his ceftaroline course, including doxycycline from days 2 to 30, intravenous gentamicin from days 7 to 9, ciprofloxacin from days 22 to 24, daptomycin on days 23 and 24, linezolid from days 25 to 37 and rifampicin from days 28 to 39. Neutropenia developed on day 67, with an ANC of 1080 cells/mm3. The ceftaroline course was stopped on day 71 and the nadir ANC was 0 cells/mm3 4 days after discontinuation. Clinical complications of neutropenia included E. cloacae bacteraemia treated first with ceftazidime and then with meropenem. The patient received filgrastim to aid count recovery, with resolution of neutropenia 9 days after discontinuing ceftaroline.
Case 5
A 33-year-old female with MRSA endocarditis, multiple infarcts and lumbar abscess received 600 mg of ceftaroline every 8 h. Her baseline creatinine clearance was 85 mL/min. Neutropenia developed on day 20 with an ANC of 1449 cells/mm3 and a nadir ANC of 8 cells/mm3 on day 22. Ceftaroline was discontinued on day 25 and the patient received filgrastim with count recovery 3 days later.
Case 6
A 74-year-old female with MSSA mycotic aneurysm received 600 mg of ceftaroline every 12 h. Her baseline creatinine clearance was 50 mL/min. She was readmitted on day 25 with febrile neutropenia, desquamating rash and eosinophilia and ceftaroline was discontinued. She had severe neutropenia, with an ANC of 0 cells/mm3 on day 26. Count recovery occurred without intervention 7 days after ceftaroline discontinuation.
Case 7
A 70-year-old male with recurrent infected aortobifemoral bypass graft infection was empirically treated with vancomycin and ceftriaxone. The patient had replacement of his bypass graft, with the development of post-operative oliguric renal failure requiring 5 days of haemodialysis. He started 400 mg of ceftaroline every 12 h 8 days after he no longer required haemodialysis; his baseline creatinine clearance at the start of his ceftaroline course was 20 mL/min. He developed severe neutropenia, with an ANC of 209 cells/mm3 on day 21, at which time ceftaroline was discontinued. Eight days later, the ANC rose to 650 cells/mm3.
Discussion
Ceftaroline was well tolerated in clinical trials leading to FDA approval for SSTIs and CAP. While longer courses are often used to treat challenging cases of bacteraemia, endocarditis and osteomyelitis,2–4 safety data in this context are limited. Here, we report an unexpectedly high rate of incident neutropenia, often severe, in a cohort receiving ceftaroline at two large academic medical centres, with an association between longer duration of exposure and incident neutropenia.
While prior reports described neutropenia in patients receiving ceftaroline,5–7 this is the first study systemically assessing the incidence and association of clinical factors with ceftaroline-associated neutropenia. As in prior reports,5–7 neutropenia resolved after ceftaroline discontinuation. Limitations of this study include its retrospective nature and missing haematological parameters on some patients following hospital discharge.
These data support an association between cumulative ceftaroline exposure and incident neutropenia, which developed in 14% and 21% of patients exposed for ≥2 and ≥3 weeks, respectively. These rates were similar to those observed by Jain et al.7 (33%) and Varada et al.8 (5%–18%). Historically, 5%–34% of patients receiving other β-lactam agents (including piperacillin/tazobactam and penicillin) for prolonged durations developed incident neutropenia.10–12 However, the rate and severity of neutropenia complicating ceftaroline treatment was unexpectedly high in our cohort, with two patients developing febrile neutropenia, one of whom developed E. cloacae bacteraemia. The exact mechanism by which β-lactams cause myelosuppression is unknown, whether immune-mediated destruction of neutrophils or inhibition of granulopoiesis. Only one patient in our cohort had concurrent eosinophilia and rash with neutropenia and we found no association between prior antibiotic allergies, renal dysfunction or total daily dose of ceftaroline normalized to body mass and incident neutropenia. In all cases, neutropenia resolved with ceftaroline discontinuation.
Ceftaroline is an attractive option for management of infections requiring prolonged treatment, such as bacteraemia, endocarditis and osteomyelitis, particularly for infections caused by MRSA or vancomycin-intermediate Staphylococcus aureus strains. Given the risk of neutropenia with prolonged courses, close monitoring of haematological parameters is warranted in patients receiving ≥2 weeks of ceftaroline and discontinuation of ceftaroline is likely to resolve cases of incident neutropenia.
Funding
This project was funded, in part, by a grant from the Brigham and Women's Physicians Organization. S. K. is supported by a grant from the National Institutes of Health (K23 AI097225).
Transparency declarations
None to declare.
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