FormalPara Key Summary Points

Daptomycin doses 8–12 mg/kg are recommended by the Clinical and Laboratory Standards Institute for susceptible dose-dependent (SDD) Enterococcus species.

However, data remain limited regarding safety outcomes of SDD dosing, compared to the standard 4–6 mg/kg dosing approved by the US Food and Drug Administration.

This retrospective cohort study compared safety outcomes of high-dose versus standard-dose daptomycin for enterococcal infections.

High-dose daptomycin was not associated with increased laboratory abnormalities or adverse drug reactions compared to standard-dose daptomycin.

Coupled with previous literature demonstrating daptomycin’s dose-dependent efficacy, these findings support the use of SDD daptomycin dosing.

Introduction

Since January 2019, the Clinical and Laboratory Standards Institute has issued multiple revisions to daptomycin breakpoints in Enterococcus spp., specifically creating a susceptible dose-dependent (SDD) category (Supplemental Table 1). Under this guidance, SDD Enterococcus isolates should be treated with daptomycin 8–12 mg/kg, compared to the standard dosage of 4–6 mg/kg used for fully susceptible isolates [1, 2]. This change was in response to literature demonstrating superior efficacy outcomes with higher doses of daptomycin [3,4,5,6]. However, data remains limited regarding the safety outcomes of daptomycin doses ≥ 8 mg/kg compared to 4–6 mg/kg in enterococcal infections. Existing literature is inconsistent, with several studies detecting dose-dependent toxicity, several detecting no difference, and many failing to assess this endpoint [6,7,8,9].

We performed a 2-year retrospective cohort study to compare the clinical outcomes of daptomycin ≥ 7.5 mg/kg (high dose) versus ≤ 6.5 mg/kg (standard dose) for enterococcal infections. The primary outcome was patient safety based on a composite endpoint of elevated creatine kinase (CK), daptomycin-related peripheral blood eosinophilia, eosinophilic pneumonitis, elevated alanine aminotransferase (ALT), and elevated alkaline phosphatase (ALP). A secondary aim was to identify risk factors for daptomycin adverse effects. We hypothesized there would be no difference in adverse drug reaction (ADR) rates between standard- and high-dose daptomycin.

Methods

Ethics

This study was deemed to be exempt by the Mayo Clinic Institutional Review Board (approval number Mod20-011769-02) and was conducted in accordance with the Declaration of Helsinki and national and institutional standards. Informed consent was waived because of the retrospective nature of the study. The analysis used anonymized clinical data.

Study Setting, Design, and Population

This was a retrospective cohort study conducted at the Mayo Clinic Hospital in Rochester, MN. Data were collected from the electronic health record across two 1-year periods (May 1, 2017 to May  1, 2018 and September 1, 2019 to September 1, 2020). These time periods correlated with an implementation of SDD reporting that resulted in median daptomycin doses increasing from 6.4 to 8.5 mg/kg, with a washout period in between. To allow for adjustments in dose rounding, patients in the standard-dose group were defined as those who received an average daptomycin dose of ≤ 6.5 mg/kg based on adjusted body weight (AdjBW), as per our usual institutional practice. Patients in the high-dose group were defined as those who received an average daptomycin dose of ≥ 7.5 mg/kg based on AdjBW.

Patients who met the following criteria were included: age ≥ 18 years, Minnesota research authorization, Enterococcus cultured from sterile sources or vancomycin-resistant Enterococcus (VRE) from urine with a daptomycin MIC of 2 or 4 mg/L, and inpatient or outpatient treatment with daptomycin for ≥ 48 h. For patients with multiple eligible encounters for the same infection, only the first encounter was included. Patients were excluded if they had an enterococcal pulmonary infection or were pregnant or incarcerated.

Microbiologic Methods and Data Collection

A microbiology report identifying patients with an Enterococcus spp. isolate with daptomycin susceptibilities within the study time frame was reviewed for inclusion and exclusion criteria. Organisms were identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI–TOF MS) using the Bruker MALDI–TOF MS system (Bruker Daltonics, Inc., Billerica, MA, USA). Daptomycin testing was performed using gradient diffusion testing (Etest, bioMérieux, Marcy l’Etoile, France).

Data were manually collected via chart review on patients who met study criteria. Potential cases of liver injury were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) and Roussel Uclaf Causality Assessment Method (RUCAM) causality scoring. Data were stored in a Research Electronic Data Capture (REDCap) database.

Outcomes and Clinical Definitions

The primary outcome was a composite safety endpoint of the occurrence of specific ADRs or laboratory abnormalities that might be daptomycin-mediated: CK elevation, peripheral blood eosinophilia, acute eosinophilic pneumonitis, ALT elevation, and/or ALP elevation. All values were assessed from the time of daptomycin initiation to 3 days after daptomycin discontinuation. Patients were considered not to have met the composite endpoint if they had documented measurement of at least one ADR parameter and did not have an ADR based on the following definitions. Creatinine kinase, ALT, and ALP elevations were defined as values at least three times the upper limit of normal, based on our institution’s reference values (CK: 39–308 units/liter [U/L] for men, 26–192 U/L for women; ALT: 7–55 U/L for men, 7–45 U/L for women; ALP: 40–129 U/L for men, 35–104 U/L for women). Peripheral blood eosinophilia was defined as an eosinophil count > 1% of the total white blood cell count. Daptomycin-related peripheral blood eosinophilia was defined as an eosinophil count ≥ 5% of the total white blood cell count on two consecutive blood draws [10]. Daptomycin-induced eosinophilic pneumonitis was categorized as definite, probable, or unlikely, using criteria previously defined in the literature. Definite cases were those that met all the following criteria: concurrent exposure to daptomycin, fever, dyspnea with increased oxygen requirement or requiring mechanical ventilation, new infiltrates on chest radiograph X-ray or computed tomography (CT) scan, bronchoalveolar lavage (BAL) with > 25% eosinophils, and clinical improvement following daptomycin withdrawal. Probable cases were those that met all the following criteria: concurrent exposure to daptomycin, dyspnea with increased oxygen requirement or requiring mechanical ventilation, new infiltrates on chest X-ray or CT scan, BAL with > 25% eosinophils OR peripheral eosinophilia, and clinical improvement following daptomycin withdrawal. Unlikely cases were all other cases that did not meet the criteria for other categories [11].

Statistical Analysis

Data were summarized using means and standard deviations or medians and interquartile ranges for continuous data, and frequencies and percentages for categorical data. Baseline characteristics were compared between dosing groups using either t tests or Wilcoxon rank sum tests for continuous data and chi-square or Fisher’s exact tests for categorical data. Logistic regression was used to assess the association between dosing group and having any safety-related outcome both univariately and after adjusting for other factors in a multivariable model. The variables in the multivariable model were selected using stepwise selection, forcing dosing group in the model. p values ≤ 0.05 were considered statistically significant. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC, USA).

Results

A total of 119 patients had enterococcal isolates that met inclusion criteria; 75.6% (90/119) were identified as Enterococcus faecium, 20.2% (24/119) were identified as non-faecium species (18/119 Enterococcus faecalis, 5/119 Enterococcus gallinarum, 1/119 Enterococcus hirae), and 4.2% (5/119) were only identified to the genus level (Fig. 1). There were 76 (64%) patients included in the standard-dose group and 43 (36%) patients in the high-dose group. Baseline characteristics are summarized in Table 1. The mean patient age was 60.7 years, and the median weight was 76.1 kg. There were no significant between-group differences in baseline serum creatine (SCr), CK, or liver function tests (LFTs). Median daptomycin doses, based on AdjBW, were 6.0 mg/kg (IQR 5.4, 6.1; median dose 410 mg) in the standard-dose cohort, compared to 8.1 mg/kg (IQR 7.9, 9.6; median dose 580 mg) in the high-dose cohort. Median durations were 13.5 days (IQR 7, 23) in the standard-dose cohort and 16 days (IQR 10, 44) in the high-dose cohort (p = 0.02). There were statistically significant differences in daptomycin dosing frequency between the standard- and high-dose cohorts.

Fig. 1
figure 1

Application of inclusion and exclusion criteria. VRE vancomycin-resistant Enterococcus, MIC minimal inhibitory concentration

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Table 1 Baseline characteristics of patients included in safety analysis
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The composite endpoint occurred in 37 patients (32.2%), including 24/76 (32.0%) of the standard-dose group and 13/43 (32.5%) of the high-dose group (p = 0.96) (Table 2). There were no significant between-group differences in the incidence of any individual ADR, though there was a significant difference in time to onset of ALT elevation, occurring at a median of 1 day in the standard-dose cohort versus 31 days in the high-dose cohort (p = 0.004) (time to event curves, Supplementary Fig. 1). Within the total population, the most common event was liver function test (LFT) elevation (ALP elevation 21/84 [25.0%], ALT elevation 14/94 [14.9%]). On the basis of the NCI CTCAE Version 5.0, there were no between-group differences in the severity of hepatotoxicity [12]. RUCAM causality scoring revealed that of the 25 patients who experienced LFT elevations, daptomycin was considered to be unrelated in 19 cases (did not qualify for scoring per RUCAM criteria), excluded as a cause in 2 cases (RUCAM score ≤ 0), and an unlikely cause in 4 cases (RUCAM score 1–2) [13]. The second most common event was daptomycin-related peripheral eosinophilia, occurring in 16.5% (15/91) of the total population; however, there were no incidents of eosinophilic pneumonitis. The incidence of CK elevation was rare, at only 2.9% (3/104) of the total cohort. Of the three cases of CK elevation, two were asymptomatic and one was associated with upper extremity pain.

Table 2 Safety outcomes of patients treated with standard- versus high-dose daptomycin
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Despite a relatively high rate of laboratory abnormalities, there were only three cases (8.1% of patients experiencing the composite endpoint) in which daptomycin was dose-reduced or temporarily held: two cases with asymptomatic CK elevations and one case with symptomatic CK elevation (upper extremity pain), ALT elevation, and ALP elevation. There were no cases in which daptomycin was permanently discontinued as a result of an ADR.

Daptomycin dose was not associated with an increased risk of the composite outcome on multivariable analysis (p = 0.81), nor was concurrent statin administration on univariate analysis (p = 0.45). On multivariable analysis, factors associated with ADR occurrence included concurrent usage of an antihistamine (OR 3.24, 95% CI 1.16–9.02, p = 0.025) or piperacillin–tazobactam (OR 2.37, 95% CI 1.02–5.53, p = 0.045), (Table 3, Supplemental Table 2). The most frequent ADR in patients with concomitant antihistamine usage was daptomycin-related peripheral eosinophilia (N = 7), followed by ALT elevation (N = 4) and ALP elevation (N = 4). The most frequent ADR in patients with concomitant piperacillin–tazobactam was ALP elevation (N = 15), followed by ALT elevation (N = 11), daptomycin-related peripheral eosinophilia (N = 7), and CK elevation (N = 3).

Table 3 Univariate and multivariable logistic regression assessing associations with the composite outcome
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Discussion

In this retrospective cohort study, high-dose daptomycin was not associated with an increased rate of ADRs or laboratory abnormalities compared to standard-dose daptomycin. Our results correlate with previous studies that found no difference in the rates of CK elevation between higher versus lower doses of daptomycin, in which median doses ranged from 6.02 to 10.2 mg/kg [6, 9].

Despite a relatively high rate of ADRs or laboratory abnormalities, daptomycin dose decreases were rare, and there were no permanent cessations. Further, RUCAM causality scoring suggested hepatic dysfunction was not clearly attributable to daptomycin. This suggests daptomycin may be associated with a high rate of laboratory abnormalities that are generally subclinical and/or might be attributed to other causes.

Additionally, we found concomitant usage of antihistamines, but not statins, was associated with the composite safety outcome, primarily driven by daptomycin-related peripheral eosinophilia; other studies have reported concomitant statin and antihistamine use as risk factors for CK elevation, myopathy, and rhabdomyolysis [9, 14, 15]. We also found that concomitant piperacillin–tazobactam was associated with the composite outcome, primarily driven by LFT elevation. Further research is needed to better elucidate the effects of antihistamines, statins, and piperacillin–tazobactam used concomitantly with daptomycin.

This study is not without limitations. As a retrospective observational study, our findings were subject to confounding factors, including baseline differences in comorbidities, severity of illness, and concomitant medications, as well as the logistical limitations of chart review. Only a relatively small sample size met inclusion criteria, which may have impacted our ability to detect statistically meaningful differences; however, a 0.5% absolute difference in composite outcome occurrence is likely not clinically meaningful. Additionally, it is possible that the definitions used for the composite endpoint could have led to attribution of daptomycin-mediated ADR when elevated laboratory values may have reflected baseline abnormalities or derangements from other causes. Our use of RUCAM scoring aimed to mitigate this. Finally, given a median dose of 8.1 mg/kg (IQR 7.9, 9.6) in our high-dose cohort, we cannot draw strong conclusions regarding doses in the 10–12 mg/kg range recommended for SDD isolates. Of note, one prior study reported a 3.9% rate of highly elevated CK (> 2000 U/L) with daptomycin doses ≥ 11 mg/kg compared to a 1.1% rate with doses 8 to < 11 mg/kg [8].

Conclusion

These limited data suggest that the occurrence of ADRs or laboratory abnormalities with daptomycin did not appear dose-related and rarely resulted in therapy modification. Coupled with previous literature demonstrating daptomycin’s dose-dependent efficacy, our safety findings support the use of 8–10 mg/kg of daptomycin for SDD enterococcal infections.