Daptomycin-associated myopathy is a known adverse effect, so creatine phosphokinase (CPK) monitoring is advised. Statin coadministration with daptomycin was found to increase risk of myopathy and rhabdomyolysis. During coadministration, we recommend enhanced CPK monitoring and consideration of withholding statins.
Keywords: daptomycin, myopathy, rhabdomyolysis, statin, drug-drug interaction
Abstract
Background
Daptomycin-associated myopathy has been identified in 2%–14% of patients, and rhabdomyolysis is a known adverse effect. Although risk factors for daptomycin-associated myopathy are poorly defined, creatine phosphokinase (CPK) monitoring and temporary discontinuation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or “statins,” has been recommended.
Methods
We conducted a single-center, retrospective, matched case-control risk factor analysis in adult and pediatric patients from 2004 to 2015. Patients in whom myopathy (defined as CPK values above the upper limit of normal) developed during daptomycin treatment were matched 1:1 to no-myopathy controls with at least the same duration of therapy. Risk factors independently associated with myopathy were determined using multivariable conditional logistic regression. Secondary analysis was performed in patients with rhabdomyolysis, defined as CPK values ≥10 times the upper limit of normal.
Results
Of 3042 patients reviewed, 128 (4.2%) were identified as having daptomycin-associated myopathy, 25 (0.8%) of whom had rhabdomyolysis; 121 (95%) of the 128 were adults, and the mean duration of therapy before CPK elevation was 16.7 days (range, 1–58 days). In multivariate analysis, deep abscess treatment (odds ratio, 2.80; P = .03), antihistamine coadministration (3.50; P = .03), and statin coadministration (2.60; P = .03) were independent risk factors for myopathy. Obesity (odds ratio, 3.28; P = .03) and statin coadministration (4.67; P = .03) were found to be independent risk factors for rhabdomyolysis, and older age was associated with reduced risk (0.97; P = .05).
Conclusions
Statin coadministration with daptomycin was independently associated with myopathy and rhabdomyolysis. This is the first study to provide strong evidence supporting this association. During coadministration, we recommend twice-weekly CPK monitoring and consideration of withholding statins.
Daptomycin is a lipopeptide antibiotic with bactericidal activity against gram-positive organisms [1]. It was approved by the US Food and Drug Administration for complicated skin and soft-tissue infections in 2003 and for Staphylococcus aureus bacteremia and right-sided endocarditis in 2005 [2, 3]. Daptomycin has become a much-needed therapeutic option for infections caused by methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus [4, 5].
Initial phase I studies revealed that daptomycin caused significant muscle toxicity when administered twice daily, which led to discontinuation of clinical investigation in 1991 [6]. However, a study in dogs in 1999 showed once-daily daptomycin dosing minimized muscle injury compared with thrice-daily dosing [7]. This led to reinvestigation of daptomycin’s clinical utility and ultimate Food and Drug Administration approval. Studies have shown that daptomycin-associated myopathy occurs in 2%–14% of patients [2, 3, 8–16] and is frequently seen in obese patients [13, 17]. In addition, rhabdomyolysis has been reported in as many as 5% of patients receiving daptomycin [18–20]. Thus, weekly monitoring of creatine phosphokinase (CPK) values is recommended to identify the development of muscle toxic effects [21].
Similarly, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or “statins,” have also been shown to induce myopathy in 5%–10% of patients. Risk factors for statin-associated myopathy include coadministration of agents with the same metabolic pathway [22, 23]. Statins are metabolized primarily by cytochrome P450 enzymes in the liver; there is no evidence of daptomycin metabolism by cytochrome P450s or hepatic metabolism [24, 25]. The manufacturer of daptomycin recommends considering temporarily suspending statins during daptomycin treatment to avoid a potential drug-drug interaction, despite limited supporting data. Clinical practice guidelines for MRSA treatment do not recommend such withholding [26]. Multiple studies have reported no increased risk of myopathy or rhabdomyolysis during statin coadministration with daptomycin [11–13, 15, 16, 27–29]; however, many of these studies were not designed to assess the risk of myopathy, and very few patients with elevated CPK values were identified.
To better assess clinical risk factors associated with the development of daptomycin-associated myopathy and to specifically investigate whether statin coadministration is a risk factor for myopathy, we performed a retrospective, matched case-control study among patients treated with daptomycin.
METHODS
Study Design
A single-center, retrospective, matched case-control risk factor analysis was performed in adult and pediatric patients at an academic medical center in Nashville, Tennessee. Cohort identification and review was performed using the Synthetic Derivative, a deidentified database of clinical and demographic data, which included 1964140 unique individual electronic medical records (EMRs) at the time of the study [30]. Patient records were evaluated from 2004 to 2015.
Identification of Case Patients and Controls
A total of 3042 records with the term “daptomycin” in clinical notes (history and physical examinations, progress notes, consultation notes, medication lists, problem lists, discharge summaries, clinical communications, or medication administration records) were identified as those with potential daptomycin exposure. From these records, potential myopathy cases were identified based on keywords, International Classification of Diseases, Ninth Revision codes, and CPK values (Supplemental Material). Potential controls were identified as those records lacking any evidence of myopathy. Records identified as those of potential case patients or controls were then further reviewed manually. Inclusion criteria for both case patients and controls were evidence of ≥3 days of daptomycin, documentation of a normal baseline CPK value, ≥1 follow-up CPK measurement during therapy, no surgical interventions within 7 days after daptomycin initiation, and no alternate causes of CPK elevation explicitly documented in the record. Institution guidelines recommended weekly CPK monitoring during therapy.
Patients who met all inclusion criteria and had CPK values elevated to >200 U/L (>1 times the upper limit of normal [ULN]) during daptomycin treatment were included as myopathy case patients. The subset of patients with CPK elevations >2000 U/L (≥10 times the ULN), consistent with World Health Organization grade IV toxicity, were further defined as rhabdomyolysis case patients. Owing to incomplete documentation, the presence or absence of symptoms could not be collected reliably in this retrospective study, so myopathy and rhabdomyolysis definitions are based on biochemical criteria. Each myopathy case patient was matched 1:1 with a no-myopathy control who received at least the duration of therapy but was otherwise selected at random from potential controls. All controls maintained normal CPK values, and clinical notes contained no evidence of myopathy symptoms during therapy. Rhabdomyolysis case patients were matched 1:4 with controls, using the same strategy.
Data Collection
Manual record review was performed for all case patients and controls included in this study. Patient demographics, comorbid conditions, concomitant medications, laboratory data, and clinical data were extracted. Creatinine clearance (CrCl) was calculated based on both actual body weight (ABW) and ideal body weight (IBW), using the Cockcroft-Gault equation ([(140 − age) × weight]/[72 × SCr]) × 0.85 (if female; SCr: serum creatinine). Daptomycin dosing for each individual was calculated as milligrams per kilogram per dose, based on ABW, per institution guidelines (guidelines also recommend renal dosing for CrCl <30 mL/min, weekly CPK monitoring, and antimicrobial stewardship approval). Patients who received more frequent dosing than the recommended 24- or 48-hour intervals, for CrCl ≥30 or <30 mL/min, respectively, were considered to be overdosed [21]. This was done for both IBW and ABW to assess the potential risk of dosing based on ABW in obese patients. The package insert recommends calculating CrCl using ABW [21]. All patient information was extracted into a Research Electronic Data Capture (REDCap) database generated for the purpose of this study [31].
Statistical Analysis
All analyses were performed using Stata software (version 14.1; StataCorp). Two analyses were performed, one comparing patients with myopathy (defined as elevated CPK) with the 1:1-matched controls, and another comparing those with rhabdomyolysis with the 1:4 matched controls. Odds ratios and statistical significance of multiple risk factors were estimated using conditional logistic regression and McNemar tests for matched pairs and groups. Univariate analyses were performed, and risk factors with a P value <.10 were considered significant and were included in the multivariate analysis models. In multivariate analyses, differences were considered significant at P ≤ .05. P values were not corrected for multiple comparisons.
RESULTS
EMR data from 1964140 individuals in the Synthetic Derivative database were initially screened for potential daptomycin exposure, which identified 3042 (0.2%) records that mentioned daptomycin. Further screening to detect potential cases of daptomycin-associated myopathy identified 1294 potential case patients, each of which was manually reviewed for study inclusion; 1166 failed to meet inclusion criteria (mostly owing to incomplete available data).
In all, 128 (4.2%) of the original 3042 patients with daptomycin mentioned in the record were ultimately identified as having daptomycin-associated myopathy (Figure 1), including 69 (2.3%) with World Health Organization grade II toxicity with CPK values ≥2.5 times the ULN and 25 (0.8%) with evidence of rhabdomyolysis. Cases in children were rare; 121 (95%) of myopathy and 23 (92%) of rhabdomyolysis cases occurred in adults. Although the study period included individuals from 2004–2015, daptomycin use increased over time; thus, the majority of myopathy and rhabdomyolysis cases (93 [73%] and 19 [76%], respectively) occurred between 2010 and 2015.
Figure 1.
Study flowchart.
Bacteremia (108 cases; 42.2%) and osteomyelitis (104 cases; 40.6%) represented the majority of infections being treated in this study. “Vancomycin allergy/intolerance” was the most common indication for daptomycin use in this study (136 patients; 53%), whereas “directed therapy for resistant gram-positive infections” was noted in only 62 patients (24%).
The mean duration of therapy was 25 (range, 3–176) days for patients with myopathy and 13 (1–24) days for those with rhabdomyolysis. The mean duration of therapy before CPK elevation was 16.7 (range, 1–58) days in patients with myopathy without rhabdomyolysis and 11.2 (1–24) days in those with rhabdomyolysis (P = .02; data not shown). In all, 60 (46.9%) patients with CPK elevation discontinued daptomycin treatment owing to toxicity.
Patient demographics and comorbid conditions are shown in Table 1. Univariate analysis revealed body mass index (BMI) >30 kg/m2 (P = .03) as a risk factor for myopathy, whereas older age (P = .04), cirrhosis (P = .05), alcohol abuse (P = .04), cancer (P = .09), and dialysis (P = .06) were protective. Analysis of rhabdomyolysis case patients compared with controls identified female sex (P = .09) and BMI >30 kg/m2 (P = .01) as risk factors, and older age was again associated with reduced risk (P = .08).
Table 1.
Univariate Analysis of Demographic Characteristics and Comorbid Conditions in Patients With Myopathy or Rhabdomyolysis During Daptomycin Therapy Compared With Controls
| Characteristic or Condition | Myopathy | Rhabdomyolysis | ||||||
|---|---|---|---|---|---|---|---|---|
| Patients, No. (%)a | OR | P Value | Patients, No. (%)a | OR | P Value | |||
| Controls (n = 128) |
Case Patients (n = 128) |
Controls (n = 100) |
Case Patients (n = 25) |
|||||
| Demographics | ||||||||
| Age, y, mean (SD) | 53.2 (18.2) | 48.2 (17.1) | 0.99 | .04b | 52.3 (18.9) | 45.6 (14.9) | 0.98 | .08b |
| Female sex | 50 (39) | 57 (45) | 1.30 | .35 | 37 (37) | 14 (56) | 2.20 | .09b |
| White race | 106 (83) | 98 (77) | 0.97 | .82 | 81 (81) | 18 (72) | 0.95 | .84 |
| BMI >30 kg/m2 | 45 (35) | 61 (48) | 1.84 | .03b | 37 (37) | 17 (68) | 4.16 | .01b |
| Comorbid conditions | ||||||||
| CHF | 13 (10) | 17 (13) | 1.36 | .44 | 8 (8) | 2 (8) | 1.00 | >.99 |
| Cirrhosis | 8 (6) | 1 (1) | 0.13 | .05b | 7 (7) | 0 (0) | … | .17 |
| CKD | 21 (16) | 22 (17) | 1.06 | .87 | 18 (18) | 8 (32) | 2.13 | .13 |
| Dialysis | 17 (13) | 8 (6) | 0.40 | .06b | 16 (16) | 5 (20) | 1.29 | .64 |
| COPD | 11 (9) | 14 (11) | 1.33 | .51 | 7 (7) | 3 (12) | 1.77 | .42 |
| DM | 38 (30) | 44 (34) | 1.26 | .41 | 27 (27) | 11 (44) | 2.04 | .11 |
| HIV infection | 3 (2) | 1 (1) | 0.33 | .34 | 1 (1) | 0 (0) | 0.00 | >.99 |
| Cancer | 33 (26) | 22 (17) | 0.58 | .09b | 27 (27) | 3 (12) | 0.37 | .13 |
| BMT | 9 (7.0) | 11 (9) | 1.22 | .66 | 9 (9) | 2 (8) | 2.00 | .57 |
| Thyroid disease | 14 (11) | 14 (11) | 1.00 | >.99 | 11 (11) | 5 (20) | 1.97 | .25 |
| Paraplegia | 4 (3) | 8 (6) | 2.00 | .60 | 2 (2) | 0 (0) | … | .48 |
| Tobacco use | 33 (6) | 25 (20) | 0.67 | .21 | 23 (23) | 2 (8) | 0.30 | .12 |
| Alcohol abuse | 11 (9) | 3 (2) | 0.20 | .04b | 7 (7) | 0 (0) | … | >.99 |
Abbreviations: BMI, body mass index; BMT, bone marrow transplant; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; HIV, human immunodeficiency virus; OR, odds ratio; SD, standard deviation.
aData represent No. (%) of patients unless otherwise specified.
bSignificant at P < .10.
Univariate analysis of clinical characteristics was performed (Table 2). Daptomycin dosing did not differ between groups (6.3 and 6.1 mg/kg per dose in myopathy case patients and controls, respectively; P = .32). Myopathy case patients were more likely to have been treated for osteomyelitis (P = .02) or deep abscess (P = .02), and less likely to have infections with methicillin-resistant Staphylococcus epidermidis (P = .08) or treatment for blood stream infections (P = .06). In the rhabdomyolysis subgroup, daptomycin dosing amounts again did not differ between case patients and controls, but the former were less likely to have had daily dosing. Rhabdomyolysis case patients were more likely to have been treated with an overdose (by frequency) of daptomycin, as defined by their IBW (P = .05) but not by their ABW (P = .15). Rhabdomyolysis case patients were more likely to have been treated for deep abscess (P = .01), peritonitis (P = .09), or MRSA infection (P = .10). Case patients also had lower CrCl, calculated based on IBW (P = .08).
Table 2.
Univariate Analysis of Clinical Characteristics in Patients With Myopathy or Rhabdomyolysis During Daptomycin Therapy Compared With Controls
| Characteristic | Myopathy | Rhabdomyolysis | ||||||
|---|---|---|---|---|---|---|---|---|
| Patients, No. (%)a | OR | P Value | Patients, No (%)a | OR | P Value | |||
| Controls (n = 128) |
Case Patients (n = 128) |
Controls (n = 100) |
Case Patients (n = 25) |
|||||
| Infection | ||||||||
| BSI | 60 (47) | 44 (34) | 0.63 | .06b | 48 (48) | 8 (32) | 0.53 | .16 |
| Osteomyelitis | 43 (34) | 61 (48) | 1.95 | .02b | 30 (30) | 7 (28) | 0.91 | .85 |
| SSTI | 15 (12) | 18 (14) | 1.23 | .58 | 14 (14) | 4 (16) | 1.33 | .80 |
| Deep abscessc | 11 (9) | 24 (19) | 2.63 | .02b | 9 (9) | 8 (32) | 4.40 | .01b |
| Endovascular | 10 (8) | 6 (5) | 0.56 | .29 | 5 (5) | 0 (0) | … | >.99 |
| UTI or pyelonephritis | 6 (2) | 6 (2) | 1.00 | >.99 | 4 (4) | 1 (4) | 1.00 | >.99 |
| PJI | 7 (6) | 8 (6) | 1.14 | .80 | 5 (5) | 2 (8) | 1.60 | .57 |
| Septic arthritis | 3 (2) | 7 (6) | 3.00 | .18 | 2 (2) | 1 (4) | 2.00 | .57 |
| Pneumonia | 2 (2) | 3 (2) | 1.50 | .66 | 1 (1) | 1 (4) | 4.00 | .33 |
| Peritonitis | 1 (1) | 2 (2) | 2.00 | .57 | 1 (1) | 2 (8) | 8.00 | .09b |
| Other | 4 (3) | 4 (3) | 1.00 | >.99 | 3 (3) | 1 (4) | 1.16 | .80 |
| Pathogen | ||||||||
| MRSA | 31 (24) | 41 (32) | 1.44 | .18 | 20 (20) | 9 (36) | 2.33 | .10b |
| MSSA | 7 (6) | 7 (6) | 1.00 | >.99 | 6 (6) | 1 (4) | 0.67 | .71 |
| MRSE | 9 (7) | 3 (2) | 0.25 | .08b | 8 (8) | 0 (0) | … | >.99 |
| VRE | 23 (18) | 20 (16) | 0.85 | .62 | 19 (19) | 5 (20) | 1.07 | .91 |
| VSE | 1 (1) | 4 (3) | 4.00 | .23 | 0 (0) | 1 (4) | 0.03 | >.99 |
| Streptococcus species | 2 (2) | 0 (0) | … | >.99 | 1 (1) | 0 (0) | … | >.99 |
| Polymicrobial | 25 (20) | 20 (16) | 0.78 | .44 | 20 (20) | 3 (12) | 0.56 | .37 |
| Other | 1 (1) | 2 (2) | 2.00 | .57 | 1 (1) | 0 (0) | … | >.99 |
| No culture | 29 (23) | 31 (24) | 1.10 | .76 | 25 (25) | 6 (24) | 0.94 | .91 |
| Patient laboratory values, mean (SD) | ||||||||
| CrCl, mL/min | ||||||||
| ABW | 83.1 (49.5) | 78.0 (62.8) | 1.00 | .42 | 81.5 (50.7) | 60.9 (51.4) | 0.99 | .12 |
| IBW | 75.4 (42.1) | 69.9 (50.7) | 1.00 | .45 | 73.7 (41.9) | 54.3 (40.4) | 0.99 | .08b |
| Calcium, mg/dL | 8.7 (0.8) | 8.5 (0.7) | 0.83 | .25 | 8.6 (0.8) | 8.6 (0.8) | 0.87 | .63 |
| Albumin, g/dL | 3.2 (0.7) | 3.1 (0.6) | 0.82 | .40 | 3.1 (0.7) | 2.9 (0.6) | 0.61 | .23 |
| Protein, g/dL | 6.5 (1.0) | 6.6 (1.0) | 1.05 | .78 | 6.4 (1.1) | 6.2 (1.0) | 0.87 | .59 |
| Daptomycin dose | ||||||||
| Mean (SD), mg/kgd | 6.1 (1.3 | 6.3 (1.3 | 1.10 | .32 | 6.1 (1.3 | 6.3 (1.3 | 1.12 | .52 |
| At 24-h intervals | 97 (76) | 101 (80) | 0.96 | .89 | 73 (73) | 13 (52) | 0.42 | .05b |
| At 48-h intervals | 31 (24) | 25 (20) | 0.75 | .36 | 27 (27) | 10 (40) | 1.75 | .22 |
| Overdose (ABW)e | 3 (2) | 5 (4) | 1.67 | .48 | 2 (2) | 2 (8) | 6.00 | .15 |
| Overdose (IBW)f | 6 (5) | 8 (6) | 1.40 | .57 | 4 (4) | 4 (16) | 4.70 | .05b |
Abbreviations: ABW, actual body weight; BSI, blood stream infection; CrCl, creatinine clearance; IBW, ideal body weight; MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; MSSA, methicillin-sensitive S. aureus; OR, odds ratio; PJI, prosthetic joint infection; SD, standard deviation; SSTI, skin and soft-tissue infection; UTI, urinary tract infection; VRE, vancomycin-resistant Enterococcus; VSE, vancomycin-sensitive Enterococcus.
aData represent No. (%) of patients unless otherwise specified.
bSignificant at P < .10.
cExcludes superficial soft-tissue abscess and includes paravertebral, intra-abdominal, deep tissue abscess.
dBased on ABW.
ePatients with overdose, based on frequency of dosing, according to CrCl calculated using ABW.
fPatients with overdose, based on frequency of dosing, according to CrCl calculated using IBW.
Of the 256 case patients and controls, 55 (21.5%) were taking statins before the start of daptomycin therapy. Statins were discontinued with the start of daptomycin in only 9 (16%) of the 55. In univariate analysis, daptomycin coadministration with statins was associated with the development of both myopathy (P < .01) and rhabdomyolysis (P = .02) (Table 3). Daptomycin coadministration with antihistamines was associated with development of myopathy (P < .01) but not rhabdomyolysis (P = .42). Daptomycin coadministration with fibrates was associated with development of rhabdomyolysis (P = .09) but not myopathy (P = 1.0) (Table 3).
Table 3.
Univariate Analysis of Concomitant Medications Prescribed in Patients With Myopathy or Rhabdomyolysis During Daptomycin Therapy Compared With Controls
| Medication | Myopathy | Rhabdomyolysis | ||||||
|---|---|---|---|---|---|---|---|---|
| Patients, No. (%) | OR | P Value | Patients, No. (%) | OR | P Value | |||
| Controls (n = 128) |
Case Patients (n = 128) |
Controls (n = 100) |
Case Patients (n = 25) |
|||||
| Statin | 14 (11) | 32 (25) | 3.00 | <.01a | 12 (12) | 8 (32) | 4.30 | .02a |
| SSRI | 32 (25) | 30 (23) | 0.92 | .77 | 21 (21) | 4 (16) | 0.70 | .56 |
| β-Blocker | 48 (38) | 46 (36) | 0.94 | .80 | 33 (33) | 9 (36) | 1.15 | .77 |
| Antihistamine | 5 (4) | 19 (15) | 3.80 | <.01a | 4 (4) | 2 (8) | 2.00 | .42 |
| Antipsychotics | 15 (12) | 17 (13) | 1.15 | .71 | 13 (13) | 4 (16) | 1.25 | .71 |
| Fibrate | 4 (3) | 4 (3) | 1.00 | >,99 | 1 (1) | 2 (8) | 8.00 | .09a |
| Colchicine | 1 (1) | 2 (2) | 2.00 | .57 | 1 (1) | 0 (0) | … | >,99 |
| Steroids | 21 (16) | 17 (13) | 0.75 | .45 | 19 (19) | 8 (32) | 1.88 | .18 |
| Amiodarone | 10 (8) | 6 (5) | 0.56 | .29 | 8 (8) | 1 (4) | 0.48 | .50 |
| Cyclosporine | 3 (2) | 4 (3) | 1.50 | .66 | 3 (3) | 1 (4) | 1.33 | .80 |
Abbreviations: OR, odds ratio; SSRI, selective serotonin reuptake inhibitor.
aSignificant at P < .10.
Factors significantly associated with myopathy in the univariate analyses were included in a multivariate model (Table 4). Other potential risk factors, such as chronic kidney disease and diabetes, were not included in the multivariate analysis, although, given the trend toward association in univariate analysis, clinical significance is possible. In this multivariate analysis, treatment for deep abscess infections (P = .03), antihistamine coadministration (P = .03), and statin coadministration (P = .03) were found to be independent risk factors for myopathy. In the rhabdomyolysis subgroup, the multivariable model included age, BMI >30 kg/m2, and statin coadministration. BMI >30 kg/m2 and statin coadministration were independently associated with increased risk of daptomycin-associated rhabdomyolysis, whereas older age was protective (P = .03, P = .03, and P = .05 respectively).
Table 4.
Multivariate Comparison of Risk Factors in Patients With Myopathy or Rhabdomyolysis During Daptomycin Therapy Compared With Controls
| Risk Factor | Myopathy | Rhabdomyolysis | ||
|---|---|---|---|---|
| OR | P Value | OR | P Value | |
| Age | 0.99 | .16 | 0.97 | .05a |
| BMI >30 kg/m2 | 1.48 | .25 | 3.28 | .03a |
| Cirrhosis | 0.16 | .10 | … | … |
| Dialysis | 0.39 | .14 | … | … |
| Cancer | 0.55 | .16 | … | … |
| Bacteremia | 1.28 | .53 | … | … |
| Osteomyelitis | 1.74 | .11 | … | … |
| Deep abscess | 2.80 | .03a | … | … |
| Antihistamine coadministration | 3.50 | .03a | … | … |
| Statin coadministration | 2.60 | .03a | 4.67 | .03a |
Abbreviations: BMI, body mass index; OR, odds ratio.
aSignificant at P ≤ .05.
In multivariate analysis, statin coadministration was associated with the development of both daptomycin-associated myopathy and rhabdomyolysis. Five statin drugs were coadministered with daptomycin, including simvastatin (n = 23), atorvastatin (n = 10), pravastatin (n = 5), rosuvastatin (n = 4), and lovastatin (n = 4). When administered with daptomycin, all statins were associated with higher rates of myopathy than in patients not receiving statins; however, pravastatin was associated with the greatest risk of rhabdomyolysis (P = .03; odds ratio, 12.0; data not shown). One of these 5 patients had a history of simvastatin and atorvastatin intolerance.
DISCUSSION
During daptomycin treatment, development of myopathy is unpredictable, and specific risk factors associated with toxicity are not well defined. We performed a case-control risk factor analysis of daptomycin-associated myopathy and rhabdomyolysis. To our knowledge, this is the first study designed specifically to evaluate patients with known toxicity for this purpose. Many retrospective studies have described the incidence of daptomycin-associated myopathy. Owing to a limited number of cases in these studies, it has been difficult to adequately assess various risks of toxicity [13–15, 18, 20, 32–34]. It has been postulated that statin coadministration with daptomycin could increase risk of myopathy; however, no studies have proved this association.
Using our institution’s deidentified EMR, the Synthetic Derivative database [30], nearly 2 million patient records were evaluated for possible daptomycin administration and toxicity. This unique database allowed us to identify all potential cases of daptomycin-associated myopathy at this institution since introduction of daptomycin in 2004. In this study, 3042 individuals with potential daptomycin exposure were identified, based on having the term “daptomycin” in clinical notes. Based on further review, 128 cases of daptomycin-associated myopathy were identified, 25 (20%) of which were cases of rhabdomyolysis, providing minimum incidence rates of 4.2% and 0.8%, respectively. The true incidences of daptomycin-associated myopathy and rhabdomyolysis may be higher than these estimates, because daptomycin exposure was confirmed for all of the case patients and matched controls but not for all 3042 potentially exposed individuals. In addition, failure to document CPK values in the EMR may lead to incomplete ascertainment of all cases. Consequently, the true incidence of daptomycin-associated toxicity is probably higher. To our knowledge, this cohort of 128 case patients with daptomycin-associated myopathy is the largest to date in the literature.
The risk of toxicity was evaluated in patients prescribed daptomycin coadministered with medications previously reported to cause myopathy. We found that statin coadministration with daptomycin is a significant risk factor for the development of both myopathy and rhabdomyolysis. This association persisted in multivariate models of both groups. Ours is the first report showing a definitive increased risk of toxicity in patients on daptomycin and statins simultaneously.
Bland et al [28] reviewed statin coadministration with daptomycin and found that CPK values became elevated in 5 (10.2%) of 49 patients, compared with 9 (5.3%) of 171 patients receiving daptomycin alone, but they were unable to show statistical significance (P = .33). Other studies have evaluated the risk of myopathy in patients taking daptomycin coadministered with statins and have either shown no increased risk [29] or have shown a trend toward increased risk of toxicity [11–13, 15, 16, 27]; however, a true association has not yet been reported. One study, in fact, reported that concomitant statin and daptomycin administration is safe; however, the study cohort included only 10 patients receiving daptomycin with an elevated CPK levels, and only 3 of these were simultaneously taking a statin [12]. In comparison, our study evaluated 128 patients who with an elevated CPK value during daptomycin treatment, 32 of whom were receiving concomitant statin therapy.
The manufacturer recommends that while on daptomycin, “consideration should be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors” [21]. Despite this suggestion, we found that only 16% of patients taking a statin at daptomycin initiation had their statin withheld. The data presented in this study support the manufacturer’s recommendation to consider withholding statins during daptomycin treatment. However, individual patient risk must be carefully considered, possibly in collaboration with the patient’s cardiologist, because benefits of statin therapy are well documented. For patients with severe coronary artery disease or when continuation of statins outweigh potential risk of myopathy, more frequent CPK monitoring should be performed as the manufacturer suggests, perhaps twice weekly [21].
Antihistamine-induced rhabdomyolysis has been reported in cases of overdose, [35] though this is not a common adverse effect when taken as recommended. In our study, there was an increased risk of myopathy, but not rhabdomyolysis, in patients prescribed both daptomycin and antihistamines. Given infrequent antihistamine use in this group, further studies are needed to better evaluate this potential association.
Interestingly, CPK elevation occurred more rapidly in the subset of patients who went on to have rhabdomyolysis than with patients who had myopathy with a peak CPK <10 times the ULN. Daptomycin dosing was not associated with increased risk of muscle toxicity in this cohort. Recent studies have shown that higher daptomycin dosing is more efficacious for severe infection without increasing risk for muscle toxicity [20, 36–38]. Owing to the time period of our study (2004–2015), most patients received lower-dose daptomycin (6.3 and 6.1 mg/kg in case patients and controls, respectively) rather than the recently recommended higher dosing regimens.
Older patients were less likely to have myopathy in the univariate analysis, although this association was not statistically significant in the multivariate analysis. In the rhabdomyolysis subgroup, older age was protective in both analyses. The average age of patients with rhabdomyolysis was 7 years younger than that in controls. The reason for this association is uncertain. Younger patients are probably more active, whereas elderly patients likely have less muscle mass, which perhaps could lead to a decreased risk of muscle toxicity. Studies of statin drugs have identified older age and decreased muscle mass as risk factors for myopathy, contrary to our findings in patients with daptomycin-associated toxicity [23].
Daptomycin-associated myopathy has previously been reported in obese patients [13, 18, 39, 40]. Bookstaver and colleagues [13] found that 13.7% of patients with a BMI >30 kg/m2 treated with daptomycin experienced an elevated CPK >500 U/L, though nonobese patients were not included as a comparator. Our study noted that obesity (BMI >30 kg/m2) is a significant risk factor for daptomycin-associated rhabdomyolysis. Daptomycin dosing is typically calculated using ABW, per the package insert, which recommends no dosage adjustment for obese patients. Institution guidelines in place during this study recommended dosing based on ABW. A prior study performed by Ng et al [41] revealed no significant change in therapeutic clinical outcomes in patients treated with daptomycin with dosage based on IBW versus ABW. Given these prior findings, along with our findings of increased toxicity in obese patients, perhaps daptomycin dosing in obese patients should be calculated using IBW rather than ABW. Further studies are needed to assess drug efficacy and clinical outcomes of patients treated with daptomycin dosed according to IBW rather than ABW.
This study has some limitations. First, its retrospective nature probably resulted in incomplete ascertainment of all daptomycin exposures during the study period. In addition, given that the definition of myopathy and rhabdomyolysis relied on laboratory data, dependence on providers to have monitored CPK values limited potential identification of additional cases. CPK values fluctuate and can be elevated for a number of reasons. Thus, causation is difficult to prove in this risk factor analysis, although careful record review was performed to rule out potential secondary causes of CPK elevation. The presence or absence of musculoskeletal symptoms could not reliably be collected in this retrospective study, thus myopathy and rhabdomyolysis definitions were based on biochemical criteria, as in other studies [11, 15, 16, 28]. Finally, risk factor analysis might be limited by the sample size of identified cases; however, this is the largest collection of daptomycin-associated myopathy cases reported in the literature. Consequently, further studies to ascertain the impact of the identified risk factors may provide more conclusive data to guide appropriate clinical use of daptomycin.
The current study evaluated the largest-to-date cohort of patients who experienced myopathy, defined as an elevated CPK value, while taking daptomycin. Based on these findings, we recommend twice-weekly CPK monitoring during daptomycin therapy in patients with concomitant statin therapy and in obese patients. Our data support the manufacturer’s recommendation to consider withholding statins during on daptomycin therapy in select patients.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments. Special thanks to Matthew Greene, MD and Whitney Nesbitt, PharmD for support during this study.
Financial support. This work was supported by the National Center for Advancing Translational Sciences at the National Institutes of Health (grant UL1 TR000445).
Potential conflicts of interest. P. W. W. serves as a paid consultant on the Cumberland Pharmaceuticals Medical Advisory Committee. S. L. V. D. is supported by a Burroughs Wellcome Foundation Innovation in Regulatory Science Award and has received an honorarium as an invited speaker for Merck. All other authors report no potential conflicts of Interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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