Patterns of Care and Treatment Outcomes for Outpatient Daptomycin-Containing Regimens in Osteomyelitis



 

Thomas Delate, PhDMS1,2; Julia K Nguyen, PharmD3; Jonathan T Truong, MD4; Fang Niu, MS5; Arman Haghighatgoo, PharmD3

Perm J 2021;25:20.297

https://doi.org/10.7812/TPP/20.297
E-pub: 05/26/2021

ABSTRACT

Background: Use of daptomycin at doses ≥ 6 mg/kg for treatment of osteomyelitis is increasing in clinical practice; unfortunately, limited data are available to guide optimal dosing and duration. The objective of this study was to assess daptomycin dosing and duration regimens for osteomyelitis treatment.

Methods: This was a retrospective, multi-site, cohort study conducted in an integrated healthcare delivery system. Nonpregnant patients ≥ 18 years of age with osteomyelitis diagnosed between November 1, 2003 and June 30, 2011, ≥ 2 weeks outpatient daptomycin therapy, and ≥ 1 month of follow-up were included. Daptomycin doses < 6 mg/kg and ≥ 6 mg/kg at durations of < 6 weeks and ≥ 6 weeks were examined with univariate and multivariate analyses to assess treatment success and all-cause mortality.

Results: A total of 247 patients were included, with 39 (15.8%), 37 (15.0%), 107 (43.3%), and 64 (25.9%) receiving < 6 mg/kg and ≥ 6 weeks, < 6 mg/kg and < 6 weeks, ≥ 6 mg/kg and ≥ 6 weeks, and ≥ 6 mg/kg and < 6 weeks of daptomycin therapy, respectively. Patients had a mean age of 58 years and had received prior vancomycin therapy (65.6%). Patients receiving < 6 weeks of therapy were less likely to experience treatment success compared with ≥ 6 weeks (41.5% vs 25.3%, adjusted odds ratio = 0.55; 95% confidence interval = 0.31-0.98) independent of duration. There were no differences across groups in mortality after adjustment.

Conclusion: In a diverse clinical population, daptomycin for treatment of osteomyelitis of 6 weeks or longer duration was associated with success independent of dose. This finding supports longer treatment with daptomycin as a first-line agent in antimicrobial stewardship initiatives.

Key Points

This retrospective cohort study evaluated 247 patients who were treated outpatient with daptomycin for osteomyelitis. After multivariable adjustment, including MRSA and risk scores, ≥ 6 weeks daptomycin treatment duration was associated with clinical success independent of daptomycin dose.

INTRODUCTION

Osteomyelitis, an inflammation of bone tissue commonly caused by Staphylococcus aureus, requires adequate antimicrobial therapy often in combination with extensive surgical debridement.1 In vertebral osteomyelitis treatment guidelines, the Infectious Diseases Society of America (IDSA) strongly recommends vancomycin as first therapy choice for a duration of 6 weeks or alternative parenteral/highly bioavailable oral antimicrobial therapy despite the low quality of supporting evidence.2

Despite its historic low acquisition cost, concerns may limit vancomycin use as monotherapy in methicillin-resistant S. aureus (MRSA) osteomyelitis due to its treatment failure rates as high as 46% and emergence of vancomycin-intermediate S. aureus.3-5 In addition, costly routine monitoring and pharmacokinetic dose adjustments to prevent vancomycin-associated nephrotoxicity and renal failure support consideration of other empiric anti-MRSA agents.6

Daptomycin is a rapid, concentration-dependent bactericidal agent that, unlike vancomycin, is able to kill high inocula of both susceptible and resistant (vancomycin mic >1.5 µg/mL) staphylococci in 24 hours.7 It is administered via once daily 2- or 30-minute infusion, has a modest side effect profile, and penetrates bone.8 Available as a generic since 2016, its acquisition cost no longer remains high as the first cyclic lipopeptide of its class. Unfortunately, there are few studies of daptomycin use in patients with osteomyelitis.

One observational study noted clinical success rates of 81%-83% with first-line daptomycin dosing between 6 and 10 mg/kg/d for treatment of staphylococcal osteomyelitis.9 A retrospective study of device-associated osteomyelitis stratified by daily daptomycin dose of < 6 mg/kg, 6-< 8 mg/kg, and ≥ 8 mg/kg reported that the longest time to treatment failure was observed in the 6 to < 8 mg/kg group.10 Although available data continue to drive higher daptomycin dosing (ie, ≥ 6 mg/kg/d) for indications such as endocarditis and bacteremia, extrapolation may not be apparently applicable to Staphylococcus predominant osteomyelitis.11 Prudent dosing strategies for dose optimization are warranted for antimicrobial stewardship, conservation of healthcare resources, and patient safety. Thus, the aim of this study was to describe the patterns of care and treatment outcomes for daptomycin-containing dosing regimens for osteomyelitis in the outpatient parenteral setting.

MATERIALS AND METHODS

Study Design and Setting

This was a retrospective, cohort study of outpatient daptomycin use in patients with osteomyelitis conducted in the Kaiser Permanente Northern and Southern California (KPCA) regions. The KPCA regions are integrated healthcare delivery systems and serve approximately 8 million members. Patients diagnosed with acute osteomyelitis (ie, not recurrent defined as diagnosis within 2 weeks of onset of symptoms) between November 1, 2003 and June 30, 2011 were identified. Electronic chart reviews were conducted by multiple unblinded reviewers under the supervision of site investigators. Patients were followed from date of daptomycin initiation until February 14, 2014; disenrollment from KPCA; or death.

The KPCA outpatient parenteral antimicrobial therapy (OPAT) program receives referrals from hospital, infusion center, medical clinic, and skilled nursing facility settings for treatment of long-term parenteral antimicrobials. The OPAT offers significant benefits through shorter or avoided hospital stays, prevention of hospital-associated conditions, and improved patient quality of life.12 Antimicrobial stewardship oversight is provided by prescriber consultation with the OPAT interdisciplinary team, which includes an infectious diseases physician, a specialist pharmacist, and a home health nurse coordinator at initiation of care and during follow-up. Coded and free-text medical, laboratory, emergency department, hospitalization, and membership information from within the delivery system, as well as from contracted and affiliated facilities, are captured in KPCA’s administrative and claims databases. The Kaiser Permanente Southern California Institutional Review Board reviewed and approved all study activities. Because this was a retrospective evaluation, informed consent was not required.

Patient Population

Patients aged ≥ 18 years with a diagnosis of acute osteomyelitis, defined as an International Classification of Diseases Ninth Edition 730.xx related code, between November 1, 2003 and June 30, 2011 who were enrolled in the OPAT for at least 2 weeks with a daptomycin prescription after diagnosis were eligible for inclusion. Confirmation of diagnosis was made with relevant positive bacterial culture from blood or overlying ulcers, wounds, fistulas, etc. for susceptible Staphylococcus, Streptococcus, and Enterococcus within 6 weeks before and up to 2 days after initiation of parenteral antibiotic or via biopsy or radiography (e.g., magnetic resonance imaging, x-ray, bone scan). In addition, patients had to have received at least 2 weeks of parenteral antimicrobial therapy in the outpatient setting (defined as infusion center, skilled nursing facility, or home), > 1 month of follow-up from conclusion of therapy, and crossover exposure to daptomycin in the setting of vancomycin allergy, vancomycin-resistant Enterococcus, elevation in serum creatinine > 0.5 mg/dL while on vancomycin, and vancomycin minimum inhibitory concentration (MIC) > 1 µg/mL. All diagnoses were verified via manual chart review. The study index date was the date of OPAT enrollment. Continuous enrollment in KPCA during the 6 months prior to index date was required to collect baseline characteristics reliably.

Data Collection

Information on osteomyelitis diagnoses and patient characteristics was obtained from queries of the KPCA electronic, administrative databases. Patient characteristics included age, sex, weight, and comorbidities. Information on daptomycin dose and duration of use were obtained from the OPAT administration database. Information on clinical outcomes, prior vancomycin use, MRSA infection status, adverse events, and mortality were obtained from electronic chart reviews.

Clinical Outcomes

The primary outcome was clinical success. This was defined as a composite of infection resolution and improvement. Resolution was defined as a subsiding of the pathologic state based on clinical signs and symptoms of normal baseline surrogate biomarkers: C-reactive protein and erythrocyte sedimentation rates, confirmatory imaging, or negative bacterial culture. Improvement was defined as partial resolution of clinical signs and symptoms. Failure was defined as clinical failure, microbiologic failure, death, or premature discontinuation within 12 weeks of treatment initiation. Clinical failure was defined as having no response on the basis of ongoing signs and symptoms of infection and the presence of persistent abnormal biomarkers or documented surgical intervention. Microbiologic failure was defined as persistent or relapsing S. aureus infection demonstrated by either ongoing positive cultures leading to discontinuation of treatment or subsequent isolation of S. aureus of the same strain type after apparent clinical improvement. Secondary outcomes included all-cause mortality and daptomycin-related adverse events. Elevated serum creatinine was defined as > 0.5 mg/dL above the recorded value at time of initiation of therapy. Elevated creatinine phosphokinase (CPK) was defined as > 170 (U/L) with or without acute renal failure. Leukopenia was defined as an absolute white blood cell count of less than 4000/µL requiring change in therapy. An adjudication panel comprised of study investigators representing infectious diseases medical specialty and outpatient parenteral antimicrobial pharmacy blinded to treatment reached consensus to determine final diagnosis and outcome(s) for questionable cases.

Data Analysis

No a priori power analysis was performed because this study was primarily descriptive in nature and all patients meeting eligibility criteria during the study period were included. Patients were categorized based on initial daily daptomycin dose and continuous duration of therapy: ≥ 6 mg/kg and ≥ 6 weeks, ≥ 6 mg/kg and < 6 weeks, < 6 mg/kg and ≥ 6 weeks, and < 6 mg/kg and < 6 weeks. Categorization of doses at < 6 mg/kg vs ≥ 6 mg/kg was performed to assess the lowest effective dose based on the FDA-approved 6 mg/kg dosing for S. aureus. Age was determined as of the index date. The presence of specific comorbidities was determined using the Quan adaptation of the Charlson comorbidity index (CCI).13 The algorithm was applied to diagnoses collected during the 6 months prior to the index date to provide a 30-point comorbidity score for each patient. Comorbidities reported include chronic kidney disease stage 3-5, diabetes, and hypertension.

Patient characteristics are reported as means and standard deviations or medians and interquartile ranges for interval- and ratio-level variables (eg, age) and percentages for nominal- and ordinal-level variables (eg, sex, comorbidity history). The Shapiro-Wilk test was used to assess normality for interval- and ratio-level variables. Differences across/between patient groups were tested using ANOVA/t-tests or nonparametric equivalent tests for interval- and ratio-level variables and the χ2 tests of association or Fischer’s exact test for nominal- and ordinal-level variables. A multivariate logistic regression model was constructed to identify factors associated with clinical success including independent dose (< 6 mg/kg vs ≥ 6 mg/kg) and duration (< 6 weeks vs ≥ 6 weeks) variables to increase power to detect differences with these factors. A Cox proportional hazard model was constructed to identify factors associated with time to all-cause mortality. All models were adjusted, based on clinical judgement (eg, variable indicates a risk of more serious infection) and statistical analysis (ie, variable with p value < 0.2 in the across groups univariate analysis), for age, sex, diabetes comorbidity, presence of orthopedic hardware, surgical debridement, inpatient length of stay, MRSA status, prior vancomycin use, and CCI. A Nelson–Aalen cumulative hazard curve was constructed with the dose/duration groups to describe time to all-cause mortality. Safety of daptomycin use was described by frequency of reported adverse events and elevated creatinine phosphokinase. All data were analyzed using SAS version 9.4 (SAS Institute, Cary, NC). The alpha was set at 0.05.

RESULTS

During the 8-year study period, 2464 patients were identified as having a diagnosis of osteomyelitis and had received ≥ 2 weeks of OPAT. Of these, 1580 patients were initiated initially on vancomycin, and 247 patients met all eligibility requirements (Figure 1). There were 39 (15.8%), 37 (15.0%), 107 (43.3%), and 64 (25.9%) patients who received < 6 mg/kg and ≥ 6 weeks, < 6 mg/kg and < 6 weeks, ≥ 6 mg/kg and ≥ 6 weeks, and ≥ 6 mg/kg and < 6 weeks of daptomycin therapy, respectively (Table 1). There were 65 (26.3%), 11 (4.5%), 137 (55.5%), 13 (5.3%), 15 (6.1%), 3 (1.2%), and 3 (1.2%) patients who received 4, 5, 6, 7, 8, 9, and 10 mg/kg, respectively.

tpj20297f1

Figure 1. Patient disposition.

Table 1. Patient characteristics by daptomycin dose and duration (N = 247)

Characteristic < 6 mg/kg and ≥ 6 wk (n = 39) < 6 mg/kg and < 6 wk (n = 37) ≥ 6 mg/kg and ≥ 6 wk (n = 107) ≥ 6 mg/kg and < 6 wk (n = 64) p valuea
Age ≥ 65 years (n, %) 14, 35.9% 21, 56.8% 39, 36.4% 20, 31.3% 0.074
Female (n, %) 22, 56.4% 14, 37.8% 31, 29.0% 26, 40.6% 0.023
Infection site (n, %)
 Head 2, 5.1% 0, 0.0% 3, 2.8% 1, 1.6% 0.151
 Lower extremity 25, 64.1% 28, 75.7% 57, 53.3% 39, 60.9%
 Pelvis 4, 10.3% 0, 0.0% 7, 6.5% 3, 4.7%
Spine 3, 7.7% 3, 8.1% 28, 26.2% 12, 18.8%
 Thorax 0, 0.0% 2, 5.4% 1, 0.9% 2, 3.1%
 Upper extremity 5, 12.8% 4, 10.8% 11, 10.3% 7, 10.9%
Mean body mass index (kg, SD) 30.3 (6.1) 33.2 (12.2) 30.3 (7.4) 30.3 (9.2) 0.674
Diabetes comorbidity (n, %) 18, 46.2% 21, 56.8% 49, 45.8% 30, 46.9% 0.699
Kidney disease stage 3-5 (n, %) 10, 25.6% 13, 35.1% 20, 18.7% 18, 28.1% 0.198
Surgical debridement (n, %) 31, 79.5% 28, 75.7% 78, 72.9% 45, 70.3% 0.762
Presence of orthopedic hardware (n, %) 11, 28.2% 4, 10.8% 31, 29.0% 18, 28.1% 0.157
Mean inpatient length of stay (days, SD) 3.9 (4.4) 7.7 (11.3) 6.7 (10.2) 8.3 (11.1) 0.058
Mean Charlson comorbidity index (SD) 4.3 (2.99) 5.2 (3.27) 3.4 (2.51) 4.3 (3.14) 0.022
MRSA infection (n, %) 20, 51.3% 14, 37.8% 47, 43.9% 24, 38.1% 0.543
Other infectious agents (n, %)
 Coagulase negative Staphylococcus 3, 7.7% 4, 10.8% 20, 18.7% 11, 17.2% 0.331
 Diptheroids 0, 0.0% 0, 0.0% 1, 0.9% 0, 0.0% 0.726
 Enterobactericiae (Proteus, Morganella, Providencia, Klebsiella) 3, 7.7% 3, 8.1% 7, 6.5% 4, 6.3% 0.980
 Enterococcus 5, 12.8% 5, 13.5% 6, 5.6% 5, 7.8% 0.345
 Pseudomonas 2, 5.1% 1, 2.7% 2, 1.9% 4, 6.3% 0.770
 Methicillin-sensitive Staphylococcus aureus 4, 10.3% 4, 10.8% 13, 12.1% 7, 10.9% 0.987
 Stenotrophomonas 1, 2.6% 0, 0.0% 1, 0.9% 0, 0.0% 0.510
 Streptococcus 2, 5.1% 0, 0.0% 1, 0.9% 4, 6.3% 0.115
Administered anti-infectives (n, %)
 Cephalosporin, Carbapenem, or Β-lactam 4, 10.3% 9, 24.3% 11, 10.3% 8, 12.5% 0.159
 Combination of agents 4, 10.3% 1, 2.7% 6, 5.6% 3, 4.7% 0.520
 Other single agent 1, 2.6% 7, 18.9% 5, 4.7% 3, 4.7% 0.010
 Vancomycin only 28, 71.9% 18, 48.6% 82, 76.6% 44, 68.8% 0.016
 None 2, 5.1% 1, 2.7% 3, 2.8% 6, 9.4% 0.243

a. Across groups comparison.

MRSA = methicillin-resistant S. aureus.

Patients primarily were male, were < 65 years of age, had a body mass index > 30, and had prior vancomycin exposure. The majority of osteomyelitis sites were lower extremity infections (60.3%). The mean daptomycin dose was 5.7 mg/kg (±1.3), and median duration of treatment was 36 days (interquartile range [IR] = 16-54 days). The median durations of prior antibiotic treatment and all combined antibiotic treatments were 10 (IR = 1-28) and 49 (IR = 30-79) days, respectively. Patients in the < 6 mg/kg and < 6 weeks group had the highest mean CCI (p = 0.022). Patients in the ≥ 6 mg/kg and ≥ 6 weeks group had the highest percentage of vancomycin use (p = 0.016).

Comparing patients who received < 6 mg/kg with ≥ 6 mg/kg of daptomycin, patients who received < 6 mg/kg were more likely to be female and had a higher mean CCI but were less likely to have had vancomycin use (all p < 0.05) (Table 2). Comparing patients who had < 6 weeks to ≥ 6 weeks duration of daptomycin therapy, patients who had < 6 weeks of therapy had a higher mean CCI and were less likely to have had vancomycin use (both p < 0.05).

Table 2. Select patient characteristics by < 6 vs ≥ 6 mg/kg daptomycin dose and < 6 vs ≥ 6 wk duration (N = 247)

Characteristic < 6 mg/kg (n = 76) ≥ 6 mg/kg (n = 171) p-value1 6 wk (n = 101) ≥ 6 wk (n = 146) p valuea
Age ≥ 65 years (n, %) 35, 46.1% 59, 34.5% 0.084 41, 40.6% 53, 36.3% 0.495
Female (n, %) 36, 47.4% 57, 33.3% 0.036 40, 39.6% 53, 36.3% 0.598
Mean body mass index (kg, SD) 31.8 (9.7) 30.3 (8.1) 0.279 31.4 (10.5) 30.3 (7.1) 0.859
Diabetes comorbidity (n, %) 39, 51.3% 79, 46.2% 0.457 51, 50.5% 67, 45.9% 0.476
Kidney disease stage 3-5 (n, %) 23, 30.3% 38, 22.2% 0.176 31, 30.7% 30, 20.5% 0.069
Surgical debridement (n, %) 58, 77.3% 121, 72.0% 0.385 71, 71.7% 108, 75.0% 0.568
Presence of orthopedic hardware (n, %) 15, 19.7% 46, 26.9% 0.228 21, 20.8% 40, 27.4% 0.237
Mean inpatient length of stay (days, SD) 5.4 (8.2) 7.3 (10.6) 0.098 7.9 (11.0) 5.9 (9.1) 0.086
Mean Charlson comorbidity index (SD) 4.8 (3.1) 3.8 (2.8) 0.018 4.6 (3.2) 3.7 (2.7) 0.025
MRSA infection (n, %) 34, 44.7% 71, 41.5% 0.637 38, 37.6% 67, 45.9% 0.196
Administered anti-infectives (n, %)
Cephalosporin, carbapenem, or β-lactam 13, 17.1% 19, 11.1% 0.195 17, 16.8% 15, 10.3% 0.131
Combination of agents 5, 6.6% 9, 5.3% 0.680 4, 4.0% 10, 6.8% 0.334
Other single agent 8, 10.5% 8, 4.7% 0.085 10, 9.9% 6, 4.1% 0.069
Vancomycin only 46, 60.5% 126, 73.7% 0.038 62, 61.4% 110, 75.3% 0.019
None 3, 3.9% 9, 5.3% 0.657 7, 6.9% 5, 3.4% 0.208

a. Between groups.

MRSA = methicillin-resistant S. aureus.

In univariate analyses, daptomycin duration < 6 weeks was associated with clinical failure (p = 0.007) (Table 3). In multivariate analysis of clinical success, daptomycin duration < 6 weeks was associated independently with being less likely to achieve clinical success (adjusted odds ratio = 0.56; 95% confidence interval [CI] = 0.31-0.97; p = 0.046) (Table 4). Patients in the ≥ 6 mg/kg and ≥ 6 weeks group had the lowest mortality (12, 11.2%) compared with the < 6 mg/kg and ≥ 6 weeks (12, 30.8%), < 6 mg/kg and < 6 weeks (11, 29.7%), and ≥ 6 mg/kg and < 6 weeks (15, 23.4%) groups (p = 0.015). After adjustment, there were no differences in time-to-death across the groups (Figure 2).

Table 3. Select patient characteristics by clinical outcome status

Characteristic Clinical success (n = 168) Clinical failure (n = 79) p value
Daptomycin dose < 6 mg/kg (n, %) 54, 32.1% 22, 27.9% 0.495
Daptomycin duration < 6 wk (n, %) 59, 35.1% 42, 53.2% 0.007
Age ≥ 65 years (n, %) 64, 38.1% 30, 38.0% 0.986
Female (n, %) 63, 37.5% 30, 38.0% 0.943
Mean weight (kg, SD) 91.3 (27.4) 92.7 (28.7) 0.719
Diabetes comorbidity (n, %) 75, 44.6% 43, 54.4% 0.151
Surgical debridement (n, %) 125, 74.4% 57, 72.2% 0.708
Presence of orthopedic hardware (n, %) 50, 30.5% 14, 17.7% 0.044
Mean inpatient length of stay (days, SD) 6.1 (8.3) 8.3 (12.9) 0.281
Mean Charlson comorbidity index (SD) 3.9 (2.9) 4.3 (3.0) 0.310
MRSA infection (n, %) 70, 41.7% 35, 44.9% 0.636
Vancomycin use (n, %) 115, 68.5% 47, 59.5% 0.167
Kidney disease stage 3-5 (n, %) 37, 22.0% 24, 30.4% 0.156

MRSA = methicillin-resistant S. aureus.

Table 4. Patient characteristics tested for association with clinical success

Factor Odds ratio 95% confidence interval p value
Lower Upper
Daptomycin dose < 6 mg/kg 1.45 0.76 2.78 0.257
Daptomycin duration < 6 wk 0.56 0.31 0.97 0.046
Female 0.84 0.45 1.57 0.588
Age ≥ 65 years 1.03 0.50 2.10 0.945
Diabetes comorbidity 0.75 0.39 1.4 0.370
Presence of orthopedic hardware 1.98 0.94 4.17 0.071
Inpatient length of stay 0.98 0.96 1.01 0.181
MRSA infection 0.90 0.50 1.63 0.731
Vancomycin use 1.56 0.84 2.90 0.158
Kidney disease stage 3-5 0.74 0.36 1.42 0.404
Charlson comorbidity index 1.02 0.90 1.15 0.790

c-statistic = 0.666; 95% confidence interval 0.594-0.737.

MRSA = methicillin-resistant S. aureus.

tpj20297f2

Figure 2. Nelson–Aalen cumulative hazard of mortality curve.

Within the survival analysis, age ≥ 65 years (adjusted hazard ratio = 2.93; 95% CI = 1.38-6.24; p = 0.005) and increased Charlson Comorbidity Index (adjusted hazard ratio = 1.22; 95% CI = 1.08-1.37; p = 0.001) were associated with a higher likelihood of all-cause mortality (Table 5).

Table 5. Cox proportional hazards modeling of all-cause mortality

Factors Hazard ratio 95% confidence interval p value
Lower Upper
< 6 mg/kg daptomycin dose and ≥ 6 wk duration 1.96 0.78 4.91 0.151
≥ 6 mg/kg daptomycin dose and < 6 wk duration 1.45 0.61 3.47 0.406
≥ 6 mg/kg daptomycin dose and ≥ 6 wk duration 0.66 0.26 1.69 0.391
< 6 mg/kg daptomycin dose and < 6 wk duration --- ---- ---- ----
Female 0.60 0.29 1.23 0.162
Age ≥ 65 years 2.93 1.38 6.24 0.005
Diabetes comorbidity 0.92 0.48 1.79 0.813
Presence of orthopedic hardware 0.33 0.12 0.94 0.039
Inpatient length of stay 1.02 1.01 1.04 0.025
MRSA infection 1.52 0.80 2.91 0.205
Vancomycin use 1.08 0.55 2.11 0.829
Kidney disease stage 3-5 1.45 0.73 2.90 0.294
Charlson Comorbidity Index 1.22 1.08 1.37 0.001

MRSA = methicillin-resistant S. aureus.

In across-groups (≥ 6 mg/kg and ≥ 6 weeks, ≥ 6 mg/kg and < 6 weeks, < 6 mg/kg and ≥ 6 weeks, and < 6 mg/kg and < 6 weeks) analyses, the frequencies of adverse effects were equivalent for overall adverse effects (n = 66; 26.7%; p = 0.189), elevated CPK that resulted in discontinuation of daptomycin (n = 47; 19%; p = 0.417), muscle cramps (n = 9; 3.6%; p = 0.605), elevated serum creatinine (n = 12; 4.9%; p = 0.673, and paresthesia (n = 1; 0.4%; p = 0.148). There were no differences in daptomycin discontinuation across the groups (p = 0.165). In between-groups (< 6 mg/kg vs ≥ 6 mg/kg and < 6 weeks vs ≥ 6 weeks) analyses, only the frequency of overall adverse effects was higher in the > 6 mg/kg group (30.4% vs 18.4%; p = 0.049) independent of duration. Severe side effects, such as eosinophilic pneumonia and Clostridium difficile-associated diarrhea, were not observed.

DISCUSSION

This retrospective cohort study of 247 patients with osteomyelitis from 2 integrated healthcare delivery systems who were treated with outpatient daptomycin identified that a dosing duration ≥ 6 weeks was associated independently with clinical success (a composite of infection resolution and improvement). Additionally, we identified that dose was not independently associated with clinical success. Although we observed that patients in the ≥ 6 mg/kg dosing and ≥ 6 weeks duration group had the numerically highest survivorship, our study was likely underpowered to identify a statistically significant value. To our knowledge, this is the first study to identify that standard daptomycin dosing of ≥ 6 mg/kg for ≥ 6 weeks appears to be a reasonable treatment option for S. aureus osteomyelitis. This finding is aligned with the IDSA’s recommendations, based on expert opinion, for high-dose daptomycin (8-10 mg/kg) in select populations (eg, persistent MRSA bacteremia and vancomycin treatment failures, native valve endocarditis caused by Staphylococci) even though IDSA does not explicitly recommend high-dose daptomycin for osteomyelitis.14

Although suboptimal dosing of daptomycin has been attributed to the development of resistance during therapy and treatment failure, a more complex picture unfolds for different types of bacteria and infections. High-dose daptomycin 10 mg/kg was associated with lower 30-day mortality for the treatment of vancomycin-resistant Enterococcus bacteremia compared with lower daily doses.15 Limited information exists examining daptomycin use in patients with osteomyelitis. In a small retrospective study, Moenstar et al16 matched 17 daptomycin-receiving patients to 34 vancomycin-receiving patients. They reported daptomycin dosing ranging from 3.7 to 7.2 mg/kg, and significantly fewer patients treated with daptomycin had a recurrence. Malizos et al’s9 retrospective study of device-associated osteomyelitis reported that the longest time to treatment failure was observed in a ≥ 6 to < 8 mg/kg treatment group, although the clinical significance of this finding was limited due to small sample sizes for < 6 mg/kg (n = 10) and ≥ 8 mg/kg (n = 6). Our findings support this evidence and provide additional information on the patient characteristics associated with daptomycin clinical failure.

The strengths of our study include broad sampling to reduce practice bias, nonmanufacturer sponsorship minimizing conflict of interest, high cohesion of OPAT antimicrobial stewardship initiatives in an integrated healthcare delivery system, and validation of diagnoses with imaging and cultures. We did identify modest rates of adverse effects. Over 20% of patients experienced elevated CPK. Clinical trial data identified 5.6% of patients experienced a CPK at 6 mg/kg dosing.17 The authors extrapolated to higher doses and hypothesized that up to 15.3% of patients would experience a CPK elevation at 10 mg/kg.17 The upper dose limit in our patients was 10 mg/kg; nevertheless, we had a numerically higher rate of elevated CPK. Our higher rate may be related to concomitant statin (owing to substantial diabetes comorbidity in our sample) and daptomycin therapy dosing based on actual body weight in the earlier years of our study.

Our study did have limitations. Prior antibiotic exposure without a washout-window limits the extrapolation of daptomycin’s effect in an antibiotic-naive population. Assessment for reduced daptomycin susceptibility or poor clinical response through repeat cultures was not performed. Additionally, although the poor outcomes seen among patients with < 6 weeks of treatment, dosing < 6 mg/kg, and body mass index > 30 could be attributed to inadequate dosing, the manufacturer FDA-approved dosing remains based on actual body weight up to a maximum of 6 mg/kg. This likely represented real-time dosing and was sufficient. Although overall rates of daptomycin resistance in S. aureus remain rare, daptomycin susceptibility and MIC were not performed during the study period. Furthermore, combined antibiotic regimens with vascular reconstruction and surgical debridement were not evaluated. We adjusted for potential confounders; however, other (eg, socioeconomic factors) and unknown confounding may have been present. Patients who failed therapy may have been less likely to remain on or to tolerate therapy for 6 weeks, thus leading to fewer patients who experienced clinical success.

Future research to assess initiation of standard dose daptomycin for first-line treatment of MRSA osteomyelitis and its effect on vancomycin-selective pressure may offer a global antimicrobial stewardship strategy. This would enhance current literature on dose-optimization dosing protocols and the role of oral antibiotic therapy.18-20 Exploration of vehicles such as acrylic microparticles to improve daptomycin activity/delivery can be affected by biofilm maturity and bacterial strain could facilitate drug enhancement.21 Evaluation of selective combination therapy such as rifampicin to overcome resistance where higher daptomycin dosing is unlikely to achieve therapeutic area under curve/MIC ratios would be informative.

CONCLUSIONS

Osteomyelitis is a costly infection that can lead to multiple complications and can become poorly responsive to antibiotic treatment alone. This study identified that daptomycin dosing at a prolonged duration of ≥ 6 weeks was associated independently with clinical success after adjustment for daptomycin dose and other potential confounders. Future prospective research is needed to identify the most appropriate daptomycin dosing and duration for osteomyelitis.

Disclosure Statement

The author(s) have no conflicts of interest to disclose. No information in this manuscript has been presented or published elsewhere. All information pertaining to the role of the sponsor is disclosed on the title page.

Data Sharing Statement

The data used for this study contain protected health information; thus, individual level data may not be made publicly available due to the Institutional Review Board, business, and privacy concerns. Data are available for researchers who meet the criteria for access to confidential data. Please contact the KPSC Institutional Review Board (kpsc.irb@kp.org) for more information.

Author Affiliations

1Pharmacy Outcomes Research Group, Kaiser Permanente National Pharmacy, Aurora, CO

2Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO

3Kaiser Permanente Southern California Outpatient Infusion Pharmacy, Panorama City Medical Center, Panorama City, CA

4Kaiser Permanente Southern California Infectious Diseases Clinic, Lancaster, CA

5Pharmacy Outcomes Research Group, Kaiser Permanente National Pharmacy, Downey, CA

Corresponding Author

Julia K Nguyen, PharmD (Julia.K.Nguyen@kp.org); Thomas Delate, PhD, MS (Tom.Delate@kp.org)

Author Contributions

Thomas Delate, PhD, designed the research, interpreted the analysis, revised the manuscript, and approved the version of the manuscript for submission. Julia K Nguyen, PharmD, designed the research, interpreted the analysis, revised the manuscript, extracted information from data sources, drafted the initial version of the manuscript, and approved the version of the manuscript for submission. Jonathan T Truong, MD, designed the research, interpreted the analysis, revised the manuscript, drafted the initial version of the manuscript, approved the version of the manuscript for submission. Fang Niu, MS, designed the research, interpreted the analysis, revised the manuscript, performed the statistical analysis, and approved the version of the manuscript for submission. Arman Haghigatgoo, PharmD, designed the research, interpreted the analysis, revised the manuscript, and approved the version of the manuscript for submission. All authors have made substantial contributions to all the following: 1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, 2) drafting the article or revising it critically for important intellectual content, and 3) final approval of the version to be submitted.

Funding

This work was supported by a Kaiser Permanente Southern California Regional Research Committee grant from the Southern California Permanente Medical Group Research and Evaluation Department and Direct Community Benefit Investment funds. Additional funding and support were provided by the Pharmacy Outcomes Research Group, Kaiser Permanente National Pharmacy. Financial support for the conduct of the research and preparation of the article was provided by Kaiser Permanente.

Abbreviations

AHR, adjusted hazard ratio; ANOVA, analysis of variance; CCI, Charlson comorbidity index; ClCr, Creatinine Clearance; CPK, creatinine phosphokinase; FDA, Food & Drug Agency; IDSA, Infectious Diseases Society of America; KPCA, Kaiser Permanente Northern and Southern California; Mg/kg, milligram per kilogram; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; OPAT, outpatient parenteral antimicrobial therapy

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Keywords: antimicrobial stewardship, bone diseases, daptomycin, home infusion therapy, infectious, vancomycin

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