Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline

Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline Abstract Objectives 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. Methods 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. Results 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. Conclusions 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. Introduction Infections caused by MRSA are associated with substantial morbidity and mortality and continue to increase in incidence.1 While vancomycin remains the treatment of choice for many severe infections caused by MRSA, treatment failure and elevated MICs are leading to an increased use of alternative agents.2–6 Daptomycin and linezolid are frequently recommended and used as alternatives to vancomycin for severe MRSA infections;4 however, these antibiotics are limited by potentially inadequate concentrations at certain body sites and significant adverse reactions.4,7 Ceftaroline is a cephalosporin with potent activity against MRSA and many common Gram-negative organisms.8 Due to its activity against MRSA and favourable side effect profile, ceftaroline is sometimes used as an alternative agent for treatment of complicated infections caused by Staphylococcus aureus and other organisms that require prolonged treatment durations. Phase III trials of ceftaroline in the treatment of community-acquired pneumonia and complicated skin and skin structure infections assessed maximum treatment durations of 7 and 14 days, respectively.9–14 Data evaluating ceftaroline when used for longer durations are limited and are mostly comprised of case series.15–21 Several recent non-comparative, retrospective studies have identified a higher than anticipated risk of neutropenia in patients receiving >7 days of ceftaroline.22–25 β-Lactams are known to cause neutropenia; however, the reported incidence of >10% in these studies is concerning.26,27 Owing to lack of comparative data in these studies, it is difficult to ascertain whether ceftaroline is responsible for this unexpectedly high incidence of neutropenia or if underlying patient or clinical characteristics may be culpable. This study sought to evaluate the incidence of neutropenia in patients receiving prolonged treatment with ceftaroline compared with five other commonly used antistaphylococcal antibiotics. Patients and methods Study setting and design This retrospective cohort study included patients admitted from April 2011 to September 2017 at a six-hospital health system in the greater Portland, Oregon area. All hospitals are considered community or community teaching hospitals. Two groups were compared: the ceftaroline group and the control group, which included patients who received cefazolin, daptomycin, linezolid, nafcillin or vancomycin. Inclusion and exclusion criteria Adult patients that received inpatient treatment with ceftaroline, cefazolin, daptomycin, linezolid, nafcillin or vancomycin were screened for inclusion. We previously evaluated 77 patients who received ≥7 days of consecutive ceftaroline therapy and found that neutropenia only developed in those receiving ≥14 days.25 Based on this information, we chose to exclude those patients with inpatient courses <14 consecutive days in duration. In addition, those with active malignancy, with no baseline or no follow-up blood laboratories, or with neutropenia within 24 h of antibiotic initiation were excluded. Definitions Neutropenia was defined as an absolute neutrophil count (ANC) <1500 cells/mm3. Consecutive neutropenia was defined as neutropenia on 2 or more consecutive days. Moderate neutropenia was defined as an ANC <1000 cells/mm3. Severe neutropenia was defined as an ANC <500 cells/mm3. Charlson comorbidity index scores were calculated as previously described.28 The ANC nadir was calculated as the lowest ANC during antibiotic treatment. The primary infecting organism was the organism identified on microbiology cultures for which the antibiotic was most likely selected. Outcomes The primary outcome was the development of neutropenia during antibiotic therapy. Secondary outcomes included the development of consecutive neutropenia, moderate neutropenia, severe neutropenia and discontinuation of antibiotic due to neutropenia. Consecutive neutropenia was chosen as an outcome to identify patients that had more than a single day of transient neutropenia. In patients who met the primary outcome, the Naranjo Adverse Drug Reaction Probability Scale29 was used to assess the likelihood that the antibiotic was the cause. Statistical analysis With an estimated 18% incidence of neutropenia in the ceftaroline group,22,24,25 we calculated a control group of 460 patients was required to have 80% power to detect a difference if the incidence of neutropenia was 5% in the control group.30 Normality of data was assessed visually and by the Shapiro–Wilk test. Data were compared between the ceftaroline group and the control group using Fisher’s exact test, χ2 test, Student’s t-test and Wilcoxon rank-sum test, as appropriate. A multivariate logistic regression model was constructed to evaluate the impact of ceftaroline receipt on development of neutropenia. Covariates were included in this model if found to have a P < 0.10 on univariate analysis with P < 0.10 set for retention in the final model. Model fit was assessed by the Tukey–Pregibon link test. This same methodology was replicated for the secondary outcomes. The incidence of neutropenia between individual antibiotics was also examined using multivariate modelling as described. Finally, as we anticipated that substantial differences in clinical characteristics between antibiotic groups might exist, we performed propensity score analysis using inverse probability weights with regression adjustment. This analysis allows for covariate balance between treatment groups while simultaneously modelling the treatment outcome and preserving the whole data set.31,32 After the propensity score weighting, the balance between treatment groups was assessed by examination of raw and weighted differences and by an overidentification test. All analyses were performed in Stata version 14 (Stata-Corp, College Station, TX, USA). Results Over the study period, 219 553 courses of study antibiotics were received. However, only 753 met criteria for study inclusion with 53 patients receiving ceftaroline and 700 receiving control antibiotics (Figure 1). Substantial differences were found between the control and ceftaroline groups, including the length of stay prior to initiating the study drug, primary infecting pathogen and infectious diagnosis (Table 1). Table 1. Demographics and clinical characteristics in the control and ceftaroline groups   Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Age (years)  50.4 ± 16.8  48.9 ± 16.3  0.53  Male  427 (61.0)  30 (56.6)  0.53  Weight (kg)  83.6 ± 26.5  81.3 ± 24.6  0.53  BMI (kg/m2)  28.0 ± 8.3  26.9 ± 7.4  0.36  Race      0.92   white  587 (83.9)  44 (83.0)     Hispanic  36 (5.1)  2 (3.8)     black  35 (5.0)  3 (5.7)     Asian  14 (2.0)  1 (1.9)     other  28 (4.0)  3 (5.7)    Charlson comorbidity index score28  2 (0–3)  2 (1–4)  0.09   myocardial infarction  47 (6.7)  3 (5.7)     heart failure  95 (13.6)  9 (17.0)     peripheral vascular disease  25 (3.6)  1 (1.9)     cerebrovascular disease  36 (5.1)  1 (1.9)     dementia  17 (2.4)  2 (3.8)     chronic pulmonary disease  102 (14.6)  13 (24.5)     connective tissue disease  24 (3.4)  1 (1.9)     ulcer disease  25 (3.6)  5 (9.4)     liver disease  141 (20.1)  15 (28.3)     diabetes  206 (29.4)  21 (39.6)     hemiplegia  66 (9.4)  6 (11.3)     moderate–severe renal disease  148 (21.1)  14 (26.4)     any tumour  38 (5.4)  2 (3.8)     metastatic tumour  4 (0.6)  0 (0.0)     AIDS  10 (1.4)  0 (0.0)    Admitted to an ICU  326 (46.6)  32 (60.4)  0.052  Length of stay prior to antibiotic initiation (days)  2 (0–6)  7 (3–13)  <0.001  Consecutive days of treatment with study drug (days)  18 (15–26)  27 (18–39)  <0.001  Baseline ANC (×103 cells/mm3)  8.8 (5.8–13.5)  7.3 (5.2–11.2)  0.072  Primary infecting organism      <0.001   MSSA  247 (35.3)  1 (1.9)     MRSA  270 (38.6)  50 (94.3)     Streptococcus  21 (3.0)  0 (0.0)     Gram-negative bacillus  26 (3.7)  0 (0.0)     CoNS  27 (3.9)  0 (0.0)     empirical or culture-negative  74 (10.6)  2 (3.8)     Enterococcus species  74 (10.6)  0 (0.0)     other  8 (1.4)  0 (0.0)    Bloodstream infection  309 (44.1)  20 (37.7)  0.37  Infective endocarditis  117 (16.7)  8 (15.1)  0.76  Bone or joint infection  192 (27.4)  18 (34.0)  0.31  Skin infection  148 (21.1)  6 (11.3)  0.087  Other cardiovascular or line infection  12 (1.7)  2 (3.8)  0.29  Pneumonia  101 (14.4)  19 (35.9)  <0.001  Intra-abdominal infection  36 (5.1)  1 (1.9)  0.29  Other infections  7 (1.0)  0 (0.0)  0.47    Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Age (years)  50.4 ± 16.8  48.9 ± 16.3  0.53  Male  427 (61.0)  30 (56.6)  0.53  Weight (kg)  83.6 ± 26.5  81.3 ± 24.6  0.53  BMI (kg/m2)  28.0 ± 8.3  26.9 ± 7.4  0.36  Race      0.92   white  587 (83.9)  44 (83.0)     Hispanic  36 (5.1)  2 (3.8)     black  35 (5.0)  3 (5.7)     Asian  14 (2.0)  1 (1.9)     other  28 (4.0)  3 (5.7)    Charlson comorbidity index score28  2 (0–3)  2 (1–4)  0.09   myocardial infarction  47 (6.7)  3 (5.7)     heart failure  95 (13.6)  9 (17.0)     peripheral vascular disease  25 (3.6)  1 (1.9)     cerebrovascular disease  36 (5.1)  1 (1.9)     dementia  17 (2.4)  2 (3.8)     chronic pulmonary disease  102 (14.6)  13 (24.5)     connective tissue disease  24 (3.4)  1 (1.9)     ulcer disease  25 (3.6)  5 (9.4)     liver disease  141 (20.1)  15 (28.3)     diabetes  206 (29.4)  21 (39.6)     hemiplegia  66 (9.4)  6 (11.3)     moderate–severe renal disease  148 (21.1)  14 (26.4)     any tumour  38 (5.4)  2 (3.8)     metastatic tumour  4 (0.6)  0 (0.0)     AIDS  10 (1.4)  0 (0.0)    Admitted to an ICU  326 (46.6)  32 (60.4)  0.052  Length of stay prior to antibiotic initiation (days)  2 (0–6)  7 (3–13)  <0.001  Consecutive days of treatment with study drug (days)  18 (15–26)  27 (18–39)  <0.001  Baseline ANC (×103 cells/mm3)  8.8 (5.8–13.5)  7.3 (5.2–11.2)  0.072  Primary infecting organism      <0.001   MSSA  247 (35.3)  1 (1.9)     MRSA  270 (38.6)  50 (94.3)     Streptococcus  21 (3.0)  0 (0.0)     Gram-negative bacillus  26 (3.7)  0 (0.0)     CoNS  27 (3.9)  0 (0.0)     empirical or culture-negative  74 (10.6)  2 (3.8)     Enterococcus species  74 (10.6)  0 (0.0)     other  8 (1.4)  0 (0.0)    Bloodstream infection  309 (44.1)  20 (37.7)  0.37  Infective endocarditis  117 (16.7)  8 (15.1)  0.76  Bone or joint infection  192 (27.4)  18 (34.0)  0.31  Skin infection  148 (21.1)  6 (11.3)  0.087  Other cardiovascular or line infection  12 (1.7)  2 (3.8)  0.29  Pneumonia  101 (14.4)  19 (35.9)  <0.001  Intra-abdominal infection  36 (5.1)  1 (1.9)  0.29  Other infections  7 (1.0)  0 (0.0)  0.47  Data are presented as mean ± SD, number (%) or median (25th–75th percentile). Figure 1. View largeDownload slide Flow diagram for patients included in the study. Figure 1. View largeDownload slide Flow diagram for patients included in the study. A total of 36 (4.8%) patients met criteria for neutropenia. All patients had a Naranjo Adverse Drug Reaction Probability Scale score of 3 or 4 indicating that the drug was a possible cause of neutropenia; as all patients were experiencing an acute or chronic infectious process during the time of drug administration, an alternate explanation for neutropenia was consistently possible. Additionally, 11% (4 of 36) of the neutropenic patients had previous neutropenic episodes in the preceding months. The median time from drug initiation to neutropenia was 20 days (25th–75th percentile, 15–29 days) and was similar regardless of drug (P = 0.28). Neutropenia developed in 4.4% of those who received <21 days of therapy and in 5.3% of those who received ≥21 days (P = 0.56). In the ceftaroline group, neutropenia developed in 20.0% who received <21 days of therapy and in 15.2% of those who received ≥21 days. Interestingly, the ANC nadir of those qualifying as neutropenic appeared to be a result of lower baseline ANC in addition to the decrease in ANC during antibiotic therapy (Table 2). Upon evaluation of drug dosing and frequency, neutropenia appeared to be dose independent for all drugs. Only three of the neutropenic patients (3 of 36, 8.3%) concurrently developed thrombocytopenia (platelets <100 × 103/mm3). Seventeen of the patients with neutropenia (17 of 36, 47.2%) had only a single day of neutropenia. Of the remaining patients with consecutive neutropenia (19 of 36, 52.8%), the median duration of neutropenia was 3 days (range 2–23 days). Table 2. ANC in patients with and without neutropenia   No neutropenia (n = 717)  Neutropeniaa (n = 36)  P value  Baseline ANC (×103 cells/mm3)  8.9 (5.8–13.7)  6.4 (3.8–8.6)  <0.001  Change in ANC from baseline to nadir (×103 cells/mm3)  −3.8 (−7.7 to − 1.1)  −5.2 (−7.3 to − 3.0)  0.12  ANC nadir (×103 cells/mm3)  4.5 (3.0–6.3)  1.2 (0.9–1.4)  <0.001    No neutropenia (n = 717)  Neutropeniaa (n = 36)  P value  Baseline ANC (×103 cells/mm3)  8.9 (5.8–13.7)  6.4 (3.8–8.6)  <0.001  Change in ANC from baseline to nadir (×103 cells/mm3)  −3.8 (−7.7 to − 1.1)  −5.2 (−7.3 to − 3.0)  0.12  ANC nadir (×103 cells/mm3)  4.5 (3.0–6.3)  1.2 (0.9–1.4)  <0.001  Data are presented as median (25th–75th percentile). a Neutropenia defined as ANC <1500 cells/mm3. All outcomes occurred more frequently in the ceftaroline group (Table 3). After controlling for covariates identified in univariate analysis, receipt of ceftaroline continued to be associated with the development of neutropenia (Table 4). After controlling for these covariates, cefazolin was identified as having the lowest risk of neutropenia. Besides ceftaroline, the only other antibiotic to have a significantly greater incidence of neutropenia compared with cefazolin was nafcillin (adjusted OR 4.4, P = 0.029). Using these same predictors, but with consecutive or moderate neutropenia as the outcome variable, a similarly greater risk was identified with the receipt of ceftaroline (adjusted OR 6.8, P < 0.001 and adjusted OR 7.0, P = 0.004, respectively). As the incidence of severe neutropenia was small (n = 5), further analysis of this outcome was not conducted. Table 3. Primary and secondary outcomes in the control and ceftaroline groups   Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Neutropeniaa  27/700 (3.9)  9/53 (17.0)  <0.001   cefazolin  4/180 (2.2)       daptomycin  4/41 (9.8)       linezolid  0/28 (0.0)       nafcillin  8/103 (7.8)       vancomycin  11/348 (3.2)      Moderate neutropeniab  8/700 (1.1)  4/53 (7.6)  0.007  Consecutive neutropeniac  12/700 (1.7)  7/53 (13.2)  <0.001  Severe neutropeniad  3/700 (0.4)  2/53 (3.8)  0.042  Discontinuation due to neutropenia  4/27 (14.8)  2/9 (25.0)  –    Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Neutropeniaa  27/700 (3.9)  9/53 (17.0)  <0.001   cefazolin  4/180 (2.2)       daptomycin  4/41 (9.8)       linezolid  0/28 (0.0)       nafcillin  8/103 (7.8)       vancomycin  11/348 (3.2)      Moderate neutropeniab  8/700 (1.1)  4/53 (7.6)  0.007  Consecutive neutropeniac  12/700 (1.7)  7/53 (13.2)  <0.001  Severe neutropeniad  3/700 (0.4)  2/53 (3.8)  0.042  Discontinuation due to neutropenia  4/27 (14.8)  2/9 (25.0)  –  Data are presented as number (%). a Neutropenia defined as ANC <1500 cells/mm3. b Moderate neutropenia defined as ANC <1000 cells/mm3. c Consecutive neutropenia defined as ANC <1500 cells/mm3 for ≥2 days. d Severe neutropenia defined as ANC <500 cells/mm3. Table 4. Multivariate logistic regression model of variables associated with neutropenia   Unadjusted OR (95% CI)  P value for unadjusted OR  Adjusted OR (95% CI)  P value for adjusted OR  Age  0.96 (0.94–0.98)  <0.001  0.96 (0.94–0.98)  <0.001  Baseline ANC  0.86 (0.78–0.95)  0.004  0.88 (0.80–0.98)  0.019  Bone/joint infection  2.73 (1.39–5.37)  0.003  2.20 (1.03–4.70)  0.041  Liver disease  2.92 (1.47–5.81)  0.002  2.30 (1.09–4.86)  0.028  Ceftaroline  5.10 (2.26–11.5)  <0.001  3.97 (1.61–9.78)  0.003  Male  0.50 (0.25–0.98)  0.045  –  –  Charlson comorbidity index score28  0.82 (0.69–0.96)  0.016  –  –  Admitted to an ICU  0.41 (0.19–0.86)  0.018  –  –    Unadjusted OR (95% CI)  P value for unadjusted OR  Adjusted OR (95% CI)  P value for adjusted OR  Age  0.96 (0.94–0.98)  <0.001  0.96 (0.94–0.98)  <0.001  Baseline ANC  0.86 (0.78–0.95)  0.004  0.88 (0.80–0.98)  0.019  Bone/joint infection  2.73 (1.39–5.37)  0.003  2.20 (1.03–4.70)  0.041  Liver disease  2.92 (1.47–5.81)  0.002  2.30 (1.09–4.86)  0.028  Ceftaroline  5.10 (2.26–11.5)  <0.001  3.97 (1.61–9.78)  0.003  Male  0.50 (0.25–0.98)  0.045  –  –  Charlson comorbidity index score28  0.82 (0.69–0.96)  0.016  –  –  Admitted to an ICU  0.41 (0.19–0.86)  0.018  –  –  Propensity score weighting was conducted and covariates were well balanced between the ceftaroline and control groups. Analysis identified a higher incidence of neutropenia in those receiving ceftaroline (estimated incidence in the control and ceftaroline groups after propensity score weighting, 3.9% versus 13.1%, P = 0.049). When using consecutive or moderate neutropenia as the outcome variable, a higher incidence of neutropenia was found in those receiving ceftaroline (estimated incidence in the control and ceftaroline groups, 1.7% versus 10.7%, P = 0.037 and 1.1% versus 6.9%, P = 0.11, respectively). Discussion In patients already being treated for infection, the development of neutropenia is dangerous and may potentially lead to life-threatening complications.26 Acute neutropenia may be induced by a number of different factors including autoimmune diseases, genetic disorders, medications and even the presence of infection itself.33 Specifically, β-lactams have been associated with neutropenia. It is postulated that the mechanism of β-lactam-induced neutropenia is due to two causes: an immune-mediated process, and direct damage to the myeloid cell line.34–37 Sparse data are available evaluating the incidence of neutropenia with receipt of the antibiotics included in the control group of this study. Youngster et al.30 conducted a retrospective cohort analysis comparing the tolerability of nafcillin and cefazolin in outpatient treatment of MSSA infection. Median duration of therapy was 28 days (25th–75th percentile, 16–37 days) and 29 days (25th–75th percentile, 24–39 days) in the nafcillin and cefazolin groups, respectively. Neutropenia was identified in 8.4% and 3.3% of patients receiving nafcillin and cefazolin, which is similar to what was identified in our study (7.8% and 2.2% for nafcillin and cefazolin, respectively). Reports of neutropenia with daptomycin are virtually non-existent.38 We identified four patients who developed neutropenia while receiving daptomycin; however, none qualified as moderate neutropenia and only one had consecutive neutropenia. The significance of this finding is unknown but likely of limited value. A study from 1991 described a 12% incidence (6 of 50) of neutropenia in patients receiving vancomycin (duration of therapy ranged from 15 to 28 days) in a cardiothoracic surgical ward.39 Similarly, Pai et al.40 identified a 12% (14 of 114) incidence of neutropenia in patients receiving outpatient vancomycin for a duration of 32 ± 29 days. In contrast to these reports, we only identified neutropenia in 3.2% of patients receiving vancomycin. Although the study by Pai et al.40 included outpatients that received longer durations of vancomycin therapy, it remains unclear why this difference between studies exists. While the inhibitory effect of linezolid on platelets has been known for some time,41 case reports associating linezolid use to neutropenia are few42,43 with several reports suggesting no such association.44,45 No patients in our study were found to have neutropenia while receiving treatment with linezolid. Several reports have previously associated prolonged ceftaroline treatment with the development of neutropenia. Zasowski et al.46 reported a 1.4% incidence of neutropenia in 211 patients receiving ceftaroline for a minimum of 72 h with a median treatment duration of 11 days (25th–75th percentile, 5–15 days). It is interesting to note that the three patients who developed neutropenia did so on days 13, 15 and 20.46 Dellabella et al.23 found a 4% incidence of neutropenia when evaluating 74 patients with a median duration of ceftaroline therapy of 7 days (25th–75th percentile 4–14 days). Duration was not reported with respect to neutropenia but development of any identified adverse effects (neutropenia, other haematological toxicities and rash) was associated with a longer median treatment duration (17 versus 6.5 days, P = 0.002).23 Subsequent case series were published with the express intent of examining incidence of neutropenia in patients treated with ≥7 days of ceftaroline therapy. LaVie et al.24 identified an 18% incidence of neutropenia in 39 patients receiving ceftaroline therapy for ≥7 days with a median duration of therapy of 27 days (range 9–125 days). Of the seven patients who developed neutropenia, four developed severe neutropenia. Patients who developed neutropenia were more likely to be female (P = 0.030) and were found to have a lower BMI (P = 0.24).24 Furtek et al.22 described a 10% incidence of neutropenia when evaluating 67 patients receiving ≥7 days of ceftaroline therapy. Five of the seven neutropenic patients developed severe neutropenia; two patients received 3 days of granulocyte colony stimulating factor to aid neutrophil recovery. Median duration of ceftaroline therapy was associated with development of neutropenia (15 versus 26 days, P = 0.048). When stratified by duration, the authors found a 14% incidence of neutropenia in patients receiving ≥14 days and a 21% incidence in those whose therapy extended >21 days.22 Consistent with the results of these previous studies, our study identified a higher than anticipated incidence of neutropenia in patients receiving ceftaroline. We failed to identify gender or BMI as significant predictors of neutropenia in the ceftaroline or control groups in multivariate analysis. Contrary to these previous studies, only two patients who received ceftaroline developed severe neutropenia. The reason for this difference is not known but may be due to chance or a difference in clinical characteristics such as baseline ANC. In contrast to Furtek et al.,22 we did not identify a greater risk of neutropenia in those receiving greater durations of treatment. This was true for the ceftaroline and control groups. To our knowledge, this is the first study of neutropenia associated with ceftaroline to include a control group and attempt to control for confounding factors. We found that ceftaroline continued to be associated with a greater incidence of neutropenia after multivariate logistic regression and propensity score weighting. Several covariates were found to be associated with neutropenia including the presence of bone and joint infections. The reason for this association remains unclear. Rifampicin is commonly used concurrently with other antibiotic therapy in bone and joint infections and has been previously associated with the development of neutropenia;47,48 however, only five of the patients with neutropenia were concurrently receiving rifampicin. Removal of the bone and joint infection covariate from the multivariate models failed to alter the statistical significance of other associations and did not substantially alter the estimated ORs. A substantial number of patients experienced transient neutropenia that occurred on just 1 day during antibiotic therapy (17 of 36, 47.2%) with subsequent resolution. Further study is needed; however, patients with transient neutropenia may be experiencing a normal infectious or other process that is unrelated to drug-induced neutropenia. Because of this possibility, we chose to evaluate consecutive neutropenia as a separate outcome. Analysis of this more stringent definition failed to alter the finding that ceftaroline was associated with neutropenia. Of peculiar interest is the low rate of antibiotic discontinuation identified in those with neutropenia (Table 3). After reviewing clinician notes, we identified two possible causes: (i) some clinicians failed to acknowledge neutropenia in the patient record, whether deliberately or not, and (ii) some clinicians identified the antibiotic to be the most likely cause of neutropenia but chose to continue therapy as the risk of switching therapy was deemed riskier than the neutropenia. Many of these patients were treatment experienced with previous antibiotic courses and many were considered to be on last line (or next to last line) therapy; this may have influenced clinicians to continue therapy despite neutropenia. Several substantial limitations are present in this study. First, as ceftaroline was used almost exclusively as salvage therapy in patients who failed previous therapies, substantial differences existed between treatment groups. We attempted to control for these differences; however, hidden selection bias may have persisted and influenced the results. Second, we included a control group of patients who received various antibiotics for similar indications. Comparison with additional antibiotics, including other β-lactams in addition to cefazolin and nafcillin, may have identified further results. The comparative antibiotics included in this study were chosen as they are most commonly used for treatment of staphylococcal infections and we felt this would limit heterogeneity. Third, we chose to exclude patients with durations <14 days. While it may have been ideal to include all patients and stratify based on duration of therapy, we chose to exclude patients receiving shorter durations for several reasons: (i) some clinical trial evidence does exist for patients receiving 7–14 days of ceftaroline therapy; (ii) patients receiving ≥14 days of therapy were more likely to be on a stable, definitive antibiotic regimen for a documented infection, which allowed for comparison with the control group by infecting pathogen and infectious diagnosis; and (iii) the outcomes of patients receiving ≥14 days of therapy were less likely to be influenced by previous antibiotic therapies that were received. Finally, while our six-hospital system does include a burn unit, level 1 trauma centre and oncology services, our results may not extrapolate to other health systems as our system is primarily community-based and does not include several at risk populations. The results of this study suggest that ceftaroline therapy of ≥14 days is associated with a greater incidence of neutropenia as compared with other antibiotics that are often used for treatment of staphylococcal infections. The efficacy and safety of ceftaroline for prolonged durations is unknown as data are limited.18,19,21,49,50 Large prospective studies are needed to assess the efficacy of ceftaroline for prolonged durations as well as to assess safety. Despite this lack of data, we believe that ceftaroline will continue to be used for prolonged durations. We suggest that clinicians routinely monitor ANC and take appropriate action if neutropenia develops. Acknowledgements We would like to thank the pharmacy department for their support of this research. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Boucher HW, Corey GR. Epidemiology of methicillin-resistant Staphylococcus aureus. Clin Infect Dis  2008; 46 Suppl 5: S344– 9. Google Scholar CrossRef Search ADS PubMed  2 Howden BP, Davies JK, Johnson PD et al.   Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev  2010; 23: 99– 139. Google Scholar CrossRef Search ADS PubMed  3 Kelley PG, Gao W, Ward PB et al.   Daptomycin non-susceptibility in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA): implications for therapy after vancomycin treatment failure. J Antimicrob Chemother  2011; 66: 1057– 60. Google Scholar CrossRef Search ADS PubMed  4 Liu C, Bayer A, Cosgrove SE et al.   Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis  2011; 52: e18– 55. 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J Antimicrob Chemother  2012; 67: 1267– 70. Google Scholar CrossRef Search ADS PubMed  20 Lin JC, Aung G, Thomas A et al.   The use of ceftaroline fosamil in methicillin-resistant Staphylococcus aureus endocarditis and deep-seated MRSA infections: a retrospective case series of 10 patients. J Infect Chemother  2013; 19: 42– 9. Google Scholar CrossRef Search ADS PubMed  21 Lalikian K, Parsiani R, Won R et al.   Ceftaroline for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus: a case series. J Chemother  2017; doi:10.1080/1120009X.2017.1351729. 22 Furtek KJ, Kubiak DW, Barra M et al.   High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother  2016; 71: 2010– 3. Google Scholar CrossRef Search ADS PubMed  23 Dellabella A, Roshdy D, Martin KE. High incidence of adverse effects with extended use of ceftaroline. Ann Pharmacother  2016; 50: 1068– 9. Google Scholar CrossRef Search ADS PubMed  24 LaVie KW, Anderson SW, O'Neal HRJr et al.   Neutropenia associated with long-term ceftaroline use. Antimicrob Agents Chemother  2015; 60: 264– 9. Google Scholar CrossRef Search ADS PubMed  25 Saedi-Kwon H, Schwartz J, Turner RB. Incidence of neutropenia with long-term ceftaroline therapy. In: Abstracts of the Fifty-First Midyear Clinical Meeting, American Society of Health-System Pharmacists, Las Vegas, NV, USA, 2016. Abstract 5a-190. American Society of Hospital-Pharmacists, Bethsada, MD, USA. 26 Fausel CA. Neutropenia and agranulocytosis. In: Tisdale JE, Miller DA. Drug-Induced Diseases Prevention, Detection, and Management , 2nd edn. Bethesda, MD: American Society of Health Systems Pharmacists, 2010; 962– 71. 27 Wright AJ. The penicillins. Mayo Clin Proc  1999; 74: 290– 307. 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Google Scholar CrossRef Search ADS PubMed  46 Zasowski EJ, Trinh TD, Claeys KC et al.   Multicenter observational study of ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother  2017; 61: 1– 9. 47 Mattson K. Side effects of rifampicin. A clinical study. Scand J Respir Dis Suppl  1973; 82: 1– 52. Google Scholar PubMed  48 Jenkins PF, Williams TD, Campbell IA. Neutropenia with each standard antituberculosis drug in the same patient. Br Med J  1980; 280: 1069– 70. Google Scholar CrossRef Search ADS PubMed  49 Fabre V, Ferrada M, Buckel WR et al.   Ceftaroline in combination with trimethoprim-sulfamethoxazole for salvage therapy of methicillin-resistant Staphylococcus aureus bacteremia and endocarditis. Open Forum Infect Dis  2014; 1: ofu046. Google Scholar PubMed  50 Casapao AM, Davis SL, Barr VO et al.   Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy. Antimicrob Agents Chemother  2014; 58: 2541– 6. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline

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Abstract

Abstract Objectives 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. Methods 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. Results 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. Conclusions 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. Introduction Infections caused by MRSA are associated with substantial morbidity and mortality and continue to increase in incidence.1 While vancomycin remains the treatment of choice for many severe infections caused by MRSA, treatment failure and elevated MICs are leading to an increased use of alternative agents.2–6 Daptomycin and linezolid are frequently recommended and used as alternatives to vancomycin for severe MRSA infections;4 however, these antibiotics are limited by potentially inadequate concentrations at certain body sites and significant adverse reactions.4,7 Ceftaroline is a cephalosporin with potent activity against MRSA and many common Gram-negative organisms.8 Due to its activity against MRSA and favourable side effect profile, ceftaroline is sometimes used as an alternative agent for treatment of complicated infections caused by Staphylococcus aureus and other organisms that require prolonged treatment durations. Phase III trials of ceftaroline in the treatment of community-acquired pneumonia and complicated skin and skin structure infections assessed maximum treatment durations of 7 and 14 days, respectively.9–14 Data evaluating ceftaroline when used for longer durations are limited and are mostly comprised of case series.15–21 Several recent non-comparative, retrospective studies have identified a higher than anticipated risk of neutropenia in patients receiving >7 days of ceftaroline.22–25 β-Lactams are known to cause neutropenia; however, the reported incidence of >10% in these studies is concerning.26,27 Owing to lack of comparative data in these studies, it is difficult to ascertain whether ceftaroline is responsible for this unexpectedly high incidence of neutropenia or if underlying patient or clinical characteristics may be culpable. This study sought to evaluate the incidence of neutropenia in patients receiving prolonged treatment with ceftaroline compared with five other commonly used antistaphylococcal antibiotics. Patients and methods Study setting and design This retrospective cohort study included patients admitted from April 2011 to September 2017 at a six-hospital health system in the greater Portland, Oregon area. All hospitals are considered community or community teaching hospitals. Two groups were compared: the ceftaroline group and the control group, which included patients who received cefazolin, daptomycin, linezolid, nafcillin or vancomycin. Inclusion and exclusion criteria Adult patients that received inpatient treatment with ceftaroline, cefazolin, daptomycin, linezolid, nafcillin or vancomycin were screened for inclusion. We previously evaluated 77 patients who received ≥7 days of consecutive ceftaroline therapy and found that neutropenia only developed in those receiving ≥14 days.25 Based on this information, we chose to exclude those patients with inpatient courses <14 consecutive days in duration. In addition, those with active malignancy, with no baseline or no follow-up blood laboratories, or with neutropenia within 24 h of antibiotic initiation were excluded. Definitions Neutropenia was defined as an absolute neutrophil count (ANC) <1500 cells/mm3. Consecutive neutropenia was defined as neutropenia on 2 or more consecutive days. Moderate neutropenia was defined as an ANC <1000 cells/mm3. Severe neutropenia was defined as an ANC <500 cells/mm3. Charlson comorbidity index scores were calculated as previously described.28 The ANC nadir was calculated as the lowest ANC during antibiotic treatment. The primary infecting organism was the organism identified on microbiology cultures for which the antibiotic was most likely selected. Outcomes The primary outcome was the development of neutropenia during antibiotic therapy. Secondary outcomes included the development of consecutive neutropenia, moderate neutropenia, severe neutropenia and discontinuation of antibiotic due to neutropenia. Consecutive neutropenia was chosen as an outcome to identify patients that had more than a single day of transient neutropenia. In patients who met the primary outcome, the Naranjo Adverse Drug Reaction Probability Scale29 was used to assess the likelihood that the antibiotic was the cause. Statistical analysis With an estimated 18% incidence of neutropenia in the ceftaroline group,22,24,25 we calculated a control group of 460 patients was required to have 80% power to detect a difference if the incidence of neutropenia was 5% in the control group.30 Normality of data was assessed visually and by the Shapiro–Wilk test. Data were compared between the ceftaroline group and the control group using Fisher’s exact test, χ2 test, Student’s t-test and Wilcoxon rank-sum test, as appropriate. A multivariate logistic regression model was constructed to evaluate the impact of ceftaroline receipt on development of neutropenia. Covariates were included in this model if found to have a P < 0.10 on univariate analysis with P < 0.10 set for retention in the final model. Model fit was assessed by the Tukey–Pregibon link test. This same methodology was replicated for the secondary outcomes. The incidence of neutropenia between individual antibiotics was also examined using multivariate modelling as described. Finally, as we anticipated that substantial differences in clinical characteristics between antibiotic groups might exist, we performed propensity score analysis using inverse probability weights with regression adjustment. This analysis allows for covariate balance between treatment groups while simultaneously modelling the treatment outcome and preserving the whole data set.31,32 After the propensity score weighting, the balance between treatment groups was assessed by examination of raw and weighted differences and by an overidentification test. All analyses were performed in Stata version 14 (Stata-Corp, College Station, TX, USA). Results Over the study period, 219 553 courses of study antibiotics were received. However, only 753 met criteria for study inclusion with 53 patients receiving ceftaroline and 700 receiving control antibiotics (Figure 1). Substantial differences were found between the control and ceftaroline groups, including the length of stay prior to initiating the study drug, primary infecting pathogen and infectious diagnosis (Table 1). Table 1. Demographics and clinical characteristics in the control and ceftaroline groups   Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Age (years)  50.4 ± 16.8  48.9 ± 16.3  0.53  Male  427 (61.0)  30 (56.6)  0.53  Weight (kg)  83.6 ± 26.5  81.3 ± 24.6  0.53  BMI (kg/m2)  28.0 ± 8.3  26.9 ± 7.4  0.36  Race      0.92   white  587 (83.9)  44 (83.0)     Hispanic  36 (5.1)  2 (3.8)     black  35 (5.0)  3 (5.7)     Asian  14 (2.0)  1 (1.9)     other  28 (4.0)  3 (5.7)    Charlson comorbidity index score28  2 (0–3)  2 (1–4)  0.09   myocardial infarction  47 (6.7)  3 (5.7)     heart failure  95 (13.6)  9 (17.0)     peripheral vascular disease  25 (3.6)  1 (1.9)     cerebrovascular disease  36 (5.1)  1 (1.9)     dementia  17 (2.4)  2 (3.8)     chronic pulmonary disease  102 (14.6)  13 (24.5)     connective tissue disease  24 (3.4)  1 (1.9)     ulcer disease  25 (3.6)  5 (9.4)     liver disease  141 (20.1)  15 (28.3)     diabetes  206 (29.4)  21 (39.6)     hemiplegia  66 (9.4)  6 (11.3)     moderate–severe renal disease  148 (21.1)  14 (26.4)     any tumour  38 (5.4)  2 (3.8)     metastatic tumour  4 (0.6)  0 (0.0)     AIDS  10 (1.4)  0 (0.0)    Admitted to an ICU  326 (46.6)  32 (60.4)  0.052  Length of stay prior to antibiotic initiation (days)  2 (0–6)  7 (3–13)  <0.001  Consecutive days of treatment with study drug (days)  18 (15–26)  27 (18–39)  <0.001  Baseline ANC (×103 cells/mm3)  8.8 (5.8–13.5)  7.3 (5.2–11.2)  0.072  Primary infecting organism      <0.001   MSSA  247 (35.3)  1 (1.9)     MRSA  270 (38.6)  50 (94.3)     Streptococcus  21 (3.0)  0 (0.0)     Gram-negative bacillus  26 (3.7)  0 (0.0)     CoNS  27 (3.9)  0 (0.0)     empirical or culture-negative  74 (10.6)  2 (3.8)     Enterococcus species  74 (10.6)  0 (0.0)     other  8 (1.4)  0 (0.0)    Bloodstream infection  309 (44.1)  20 (37.7)  0.37  Infective endocarditis  117 (16.7)  8 (15.1)  0.76  Bone or joint infection  192 (27.4)  18 (34.0)  0.31  Skin infection  148 (21.1)  6 (11.3)  0.087  Other cardiovascular or line infection  12 (1.7)  2 (3.8)  0.29  Pneumonia  101 (14.4)  19 (35.9)  <0.001  Intra-abdominal infection  36 (5.1)  1 (1.9)  0.29  Other infections  7 (1.0)  0 (0.0)  0.47    Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Age (years)  50.4 ± 16.8  48.9 ± 16.3  0.53  Male  427 (61.0)  30 (56.6)  0.53  Weight (kg)  83.6 ± 26.5  81.3 ± 24.6  0.53  BMI (kg/m2)  28.0 ± 8.3  26.9 ± 7.4  0.36  Race      0.92   white  587 (83.9)  44 (83.0)     Hispanic  36 (5.1)  2 (3.8)     black  35 (5.0)  3 (5.7)     Asian  14 (2.0)  1 (1.9)     other  28 (4.0)  3 (5.7)    Charlson comorbidity index score28  2 (0–3)  2 (1–4)  0.09   myocardial infarction  47 (6.7)  3 (5.7)     heart failure  95 (13.6)  9 (17.0)     peripheral vascular disease  25 (3.6)  1 (1.9)     cerebrovascular disease  36 (5.1)  1 (1.9)     dementia  17 (2.4)  2 (3.8)     chronic pulmonary disease  102 (14.6)  13 (24.5)     connective tissue disease  24 (3.4)  1 (1.9)     ulcer disease  25 (3.6)  5 (9.4)     liver disease  141 (20.1)  15 (28.3)     diabetes  206 (29.4)  21 (39.6)     hemiplegia  66 (9.4)  6 (11.3)     moderate–severe renal disease  148 (21.1)  14 (26.4)     any tumour  38 (5.4)  2 (3.8)     metastatic tumour  4 (0.6)  0 (0.0)     AIDS  10 (1.4)  0 (0.0)    Admitted to an ICU  326 (46.6)  32 (60.4)  0.052  Length of stay prior to antibiotic initiation (days)  2 (0–6)  7 (3–13)  <0.001  Consecutive days of treatment with study drug (days)  18 (15–26)  27 (18–39)  <0.001  Baseline ANC (×103 cells/mm3)  8.8 (5.8–13.5)  7.3 (5.2–11.2)  0.072  Primary infecting organism      <0.001   MSSA  247 (35.3)  1 (1.9)     MRSA  270 (38.6)  50 (94.3)     Streptococcus  21 (3.0)  0 (0.0)     Gram-negative bacillus  26 (3.7)  0 (0.0)     CoNS  27 (3.9)  0 (0.0)     empirical or culture-negative  74 (10.6)  2 (3.8)     Enterococcus species  74 (10.6)  0 (0.0)     other  8 (1.4)  0 (0.0)    Bloodstream infection  309 (44.1)  20 (37.7)  0.37  Infective endocarditis  117 (16.7)  8 (15.1)  0.76  Bone or joint infection  192 (27.4)  18 (34.0)  0.31  Skin infection  148 (21.1)  6 (11.3)  0.087  Other cardiovascular or line infection  12 (1.7)  2 (3.8)  0.29  Pneumonia  101 (14.4)  19 (35.9)  <0.001  Intra-abdominal infection  36 (5.1)  1 (1.9)  0.29  Other infections  7 (1.0)  0 (0.0)  0.47  Data are presented as mean ± SD, number (%) or median (25th–75th percentile). Figure 1. View largeDownload slide Flow diagram for patients included in the study. Figure 1. View largeDownload slide Flow diagram for patients included in the study. A total of 36 (4.8%) patients met criteria for neutropenia. All patients had a Naranjo Adverse Drug Reaction Probability Scale score of 3 or 4 indicating that the drug was a possible cause of neutropenia; as all patients were experiencing an acute or chronic infectious process during the time of drug administration, an alternate explanation for neutropenia was consistently possible. Additionally, 11% (4 of 36) of the neutropenic patients had previous neutropenic episodes in the preceding months. The median time from drug initiation to neutropenia was 20 days (25th–75th percentile, 15–29 days) and was similar regardless of drug (P = 0.28). Neutropenia developed in 4.4% of those who received <21 days of therapy and in 5.3% of those who received ≥21 days (P = 0.56). In the ceftaroline group, neutropenia developed in 20.0% who received <21 days of therapy and in 15.2% of those who received ≥21 days. Interestingly, the ANC nadir of those qualifying as neutropenic appeared to be a result of lower baseline ANC in addition to the decrease in ANC during antibiotic therapy (Table 2). Upon evaluation of drug dosing and frequency, neutropenia appeared to be dose independent for all drugs. Only three of the neutropenic patients (3 of 36, 8.3%) concurrently developed thrombocytopenia (platelets <100 × 103/mm3). Seventeen of the patients with neutropenia (17 of 36, 47.2%) had only a single day of neutropenia. Of the remaining patients with consecutive neutropenia (19 of 36, 52.8%), the median duration of neutropenia was 3 days (range 2–23 days). Table 2. ANC in patients with and without neutropenia   No neutropenia (n = 717)  Neutropeniaa (n = 36)  P value  Baseline ANC (×103 cells/mm3)  8.9 (5.8–13.7)  6.4 (3.8–8.6)  <0.001  Change in ANC from baseline to nadir (×103 cells/mm3)  −3.8 (−7.7 to − 1.1)  −5.2 (−7.3 to − 3.0)  0.12  ANC nadir (×103 cells/mm3)  4.5 (3.0–6.3)  1.2 (0.9–1.4)  <0.001    No neutropenia (n = 717)  Neutropeniaa (n = 36)  P value  Baseline ANC (×103 cells/mm3)  8.9 (5.8–13.7)  6.4 (3.8–8.6)  <0.001  Change in ANC from baseline to nadir (×103 cells/mm3)  −3.8 (−7.7 to − 1.1)  −5.2 (−7.3 to − 3.0)  0.12  ANC nadir (×103 cells/mm3)  4.5 (3.0–6.3)  1.2 (0.9–1.4)  <0.001  Data are presented as median (25th–75th percentile). a Neutropenia defined as ANC <1500 cells/mm3. All outcomes occurred more frequently in the ceftaroline group (Table 3). After controlling for covariates identified in univariate analysis, receipt of ceftaroline continued to be associated with the development of neutropenia (Table 4). After controlling for these covariates, cefazolin was identified as having the lowest risk of neutropenia. Besides ceftaroline, the only other antibiotic to have a significantly greater incidence of neutropenia compared with cefazolin was nafcillin (adjusted OR 4.4, P = 0.029). Using these same predictors, but with consecutive or moderate neutropenia as the outcome variable, a similarly greater risk was identified with the receipt of ceftaroline (adjusted OR 6.8, P < 0.001 and adjusted OR 7.0, P = 0.004, respectively). As the incidence of severe neutropenia was small (n = 5), further analysis of this outcome was not conducted. Table 3. Primary and secondary outcomes in the control and ceftaroline groups   Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Neutropeniaa  27/700 (3.9)  9/53 (17.0)  <0.001   cefazolin  4/180 (2.2)       daptomycin  4/41 (9.8)       linezolid  0/28 (0.0)       nafcillin  8/103 (7.8)       vancomycin  11/348 (3.2)      Moderate neutropeniab  8/700 (1.1)  4/53 (7.6)  0.007  Consecutive neutropeniac  12/700 (1.7)  7/53 (13.2)  <0.001  Severe neutropeniad  3/700 (0.4)  2/53 (3.8)  0.042  Discontinuation due to neutropenia  4/27 (14.8)  2/9 (25.0)  –    Control antibiotics (n = 700)  Ceftaroline (n = 53)  P value  Neutropeniaa  27/700 (3.9)  9/53 (17.0)  <0.001   cefazolin  4/180 (2.2)       daptomycin  4/41 (9.8)       linezolid  0/28 (0.0)       nafcillin  8/103 (7.8)       vancomycin  11/348 (3.2)      Moderate neutropeniab  8/700 (1.1)  4/53 (7.6)  0.007  Consecutive neutropeniac  12/700 (1.7)  7/53 (13.2)  <0.001  Severe neutropeniad  3/700 (0.4)  2/53 (3.8)  0.042  Discontinuation due to neutropenia  4/27 (14.8)  2/9 (25.0)  –  Data are presented as number (%). a Neutropenia defined as ANC <1500 cells/mm3. b Moderate neutropenia defined as ANC <1000 cells/mm3. c Consecutive neutropenia defined as ANC <1500 cells/mm3 for ≥2 days. d Severe neutropenia defined as ANC <500 cells/mm3. Table 4. Multivariate logistic regression model of variables associated with neutropenia   Unadjusted OR (95% CI)  P value for unadjusted OR  Adjusted OR (95% CI)  P value for adjusted OR  Age  0.96 (0.94–0.98)  <0.001  0.96 (0.94–0.98)  <0.001  Baseline ANC  0.86 (0.78–0.95)  0.004  0.88 (0.80–0.98)  0.019  Bone/joint infection  2.73 (1.39–5.37)  0.003  2.20 (1.03–4.70)  0.041  Liver disease  2.92 (1.47–5.81)  0.002  2.30 (1.09–4.86)  0.028  Ceftaroline  5.10 (2.26–11.5)  <0.001  3.97 (1.61–9.78)  0.003  Male  0.50 (0.25–0.98)  0.045  –  –  Charlson comorbidity index score28  0.82 (0.69–0.96)  0.016  –  –  Admitted to an ICU  0.41 (0.19–0.86)  0.018  –  –    Unadjusted OR (95% CI)  P value for unadjusted OR  Adjusted OR (95% CI)  P value for adjusted OR  Age  0.96 (0.94–0.98)  <0.001  0.96 (0.94–0.98)  <0.001  Baseline ANC  0.86 (0.78–0.95)  0.004  0.88 (0.80–0.98)  0.019  Bone/joint infection  2.73 (1.39–5.37)  0.003  2.20 (1.03–4.70)  0.041  Liver disease  2.92 (1.47–5.81)  0.002  2.30 (1.09–4.86)  0.028  Ceftaroline  5.10 (2.26–11.5)  <0.001  3.97 (1.61–9.78)  0.003  Male  0.50 (0.25–0.98)  0.045  –  –  Charlson comorbidity index score28  0.82 (0.69–0.96)  0.016  –  –  Admitted to an ICU  0.41 (0.19–0.86)  0.018  –  –  Propensity score weighting was conducted and covariates were well balanced between the ceftaroline and control groups. Analysis identified a higher incidence of neutropenia in those receiving ceftaroline (estimated incidence in the control and ceftaroline groups after propensity score weighting, 3.9% versus 13.1%, P = 0.049). When using consecutive or moderate neutropenia as the outcome variable, a higher incidence of neutropenia was found in those receiving ceftaroline (estimated incidence in the control and ceftaroline groups, 1.7% versus 10.7%, P = 0.037 and 1.1% versus 6.9%, P = 0.11, respectively). Discussion In patients already being treated for infection, the development of neutropenia is dangerous and may potentially lead to life-threatening complications.26 Acute neutropenia may be induced by a number of different factors including autoimmune diseases, genetic disorders, medications and even the presence of infection itself.33 Specifically, β-lactams have been associated with neutropenia. It is postulated that the mechanism of β-lactam-induced neutropenia is due to two causes: an immune-mediated process, and direct damage to the myeloid cell line.34–37 Sparse data are available evaluating the incidence of neutropenia with receipt of the antibiotics included in the control group of this study. Youngster et al.30 conducted a retrospective cohort analysis comparing the tolerability of nafcillin and cefazolin in outpatient treatment of MSSA infection. Median duration of therapy was 28 days (25th–75th percentile, 16–37 days) and 29 days (25th–75th percentile, 24–39 days) in the nafcillin and cefazolin groups, respectively. Neutropenia was identified in 8.4% and 3.3% of patients receiving nafcillin and cefazolin, which is similar to what was identified in our study (7.8% and 2.2% for nafcillin and cefazolin, respectively). Reports of neutropenia with daptomycin are virtually non-existent.38 We identified four patients who developed neutropenia while receiving daptomycin; however, none qualified as moderate neutropenia and only one had consecutive neutropenia. The significance of this finding is unknown but likely of limited value. A study from 1991 described a 12% incidence (6 of 50) of neutropenia in patients receiving vancomycin (duration of therapy ranged from 15 to 28 days) in a cardiothoracic surgical ward.39 Similarly, Pai et al.40 identified a 12% (14 of 114) incidence of neutropenia in patients receiving outpatient vancomycin for a duration of 32 ± 29 days. In contrast to these reports, we only identified neutropenia in 3.2% of patients receiving vancomycin. Although the study by Pai et al.40 included outpatients that received longer durations of vancomycin therapy, it remains unclear why this difference between studies exists. While the inhibitory effect of linezolid on platelets has been known for some time,41 case reports associating linezolid use to neutropenia are few42,43 with several reports suggesting no such association.44,45 No patients in our study were found to have neutropenia while receiving treatment with linezolid. Several reports have previously associated prolonged ceftaroline treatment with the development of neutropenia. Zasowski et al.46 reported a 1.4% incidence of neutropenia in 211 patients receiving ceftaroline for a minimum of 72 h with a median treatment duration of 11 days (25th–75th percentile, 5–15 days). It is interesting to note that the three patients who developed neutropenia did so on days 13, 15 and 20.46 Dellabella et al.23 found a 4% incidence of neutropenia when evaluating 74 patients with a median duration of ceftaroline therapy of 7 days (25th–75th percentile 4–14 days). Duration was not reported with respect to neutropenia but development of any identified adverse effects (neutropenia, other haematological toxicities and rash) was associated with a longer median treatment duration (17 versus 6.5 days, P = 0.002).23 Subsequent case series were published with the express intent of examining incidence of neutropenia in patients treated with ≥7 days of ceftaroline therapy. LaVie et al.24 identified an 18% incidence of neutropenia in 39 patients receiving ceftaroline therapy for ≥7 days with a median duration of therapy of 27 days (range 9–125 days). Of the seven patients who developed neutropenia, four developed severe neutropenia. Patients who developed neutropenia were more likely to be female (P = 0.030) and were found to have a lower BMI (P = 0.24).24 Furtek et al.22 described a 10% incidence of neutropenia when evaluating 67 patients receiving ≥7 days of ceftaroline therapy. Five of the seven neutropenic patients developed severe neutropenia; two patients received 3 days of granulocyte colony stimulating factor to aid neutrophil recovery. Median duration of ceftaroline therapy was associated with development of neutropenia (15 versus 26 days, P = 0.048). When stratified by duration, the authors found a 14% incidence of neutropenia in patients receiving ≥14 days and a 21% incidence in those whose therapy extended >21 days.22 Consistent with the results of these previous studies, our study identified a higher than anticipated incidence of neutropenia in patients receiving ceftaroline. We failed to identify gender or BMI as significant predictors of neutropenia in the ceftaroline or control groups in multivariate analysis. Contrary to these previous studies, only two patients who received ceftaroline developed severe neutropenia. The reason for this difference is not known but may be due to chance or a difference in clinical characteristics such as baseline ANC. In contrast to Furtek et al.,22 we did not identify a greater risk of neutropenia in those receiving greater durations of treatment. This was true for the ceftaroline and control groups. To our knowledge, this is the first study of neutropenia associated with ceftaroline to include a control group and attempt to control for confounding factors. We found that ceftaroline continued to be associated with a greater incidence of neutropenia after multivariate logistic regression and propensity score weighting. Several covariates were found to be associated with neutropenia including the presence of bone and joint infections. The reason for this association remains unclear. Rifampicin is commonly used concurrently with other antibiotic therapy in bone and joint infections and has been previously associated with the development of neutropenia;47,48 however, only five of the patients with neutropenia were concurrently receiving rifampicin. Removal of the bone and joint infection covariate from the multivariate models failed to alter the statistical significance of other associations and did not substantially alter the estimated ORs. A substantial number of patients experienced transient neutropenia that occurred on just 1 day during antibiotic therapy (17 of 36, 47.2%) with subsequent resolution. Further study is needed; however, patients with transient neutropenia may be experiencing a normal infectious or other process that is unrelated to drug-induced neutropenia. Because of this possibility, we chose to evaluate consecutive neutropenia as a separate outcome. Analysis of this more stringent definition failed to alter the finding that ceftaroline was associated with neutropenia. Of peculiar interest is the low rate of antibiotic discontinuation identified in those with neutropenia (Table 3). After reviewing clinician notes, we identified two possible causes: (i) some clinicians failed to acknowledge neutropenia in the patient record, whether deliberately or not, and (ii) some clinicians identified the antibiotic to be the most likely cause of neutropenia but chose to continue therapy as the risk of switching therapy was deemed riskier than the neutropenia. Many of these patients were treatment experienced with previous antibiotic courses and many were considered to be on last line (or next to last line) therapy; this may have influenced clinicians to continue therapy despite neutropenia. Several substantial limitations are present in this study. First, as ceftaroline was used almost exclusively as salvage therapy in patients who failed previous therapies, substantial differences existed between treatment groups. We attempted to control for these differences; however, hidden selection bias may have persisted and influenced the results. Second, we included a control group of patients who received various antibiotics for similar indications. Comparison with additional antibiotics, including other β-lactams in addition to cefazolin and nafcillin, may have identified further results. The comparative antibiotics included in this study were chosen as they are most commonly used for treatment of staphylococcal infections and we felt this would limit heterogeneity. Third, we chose to exclude patients with durations <14 days. While it may have been ideal to include all patients and stratify based on duration of therapy, we chose to exclude patients receiving shorter durations for several reasons: (i) some clinical trial evidence does exist for patients receiving 7–14 days of ceftaroline therapy; (ii) patients receiving ≥14 days of therapy were more likely to be on a stable, definitive antibiotic regimen for a documented infection, which allowed for comparison with the control group by infecting pathogen and infectious diagnosis; and (iii) the outcomes of patients receiving ≥14 days of therapy were less likely to be influenced by previous antibiotic therapies that were received. Finally, while our six-hospital system does include a burn unit, level 1 trauma centre and oncology services, our results may not extrapolate to other health systems as our system is primarily community-based and does not include several at risk populations. The results of this study suggest that ceftaroline therapy of ≥14 days is associated with a greater incidence of neutropenia as compared with other antibiotics that are often used for treatment of staphylococcal infections. The efficacy and safety of ceftaroline for prolonged durations is unknown as data are limited.18,19,21,49,50 Large prospective studies are needed to assess the efficacy of ceftaroline for prolonged durations as well as to assess safety. Despite this lack of data, we believe that ceftaroline will continue to be used for prolonged durations. We suggest that clinicians routinely monitor ANC and take appropriate action if neutropenia develops. Acknowledgements We would like to thank the pharmacy department for their support of this research. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Boucher HW, Corey GR. Epidemiology of methicillin-resistant Staphylococcus aureus. 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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

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