This cohort study demonstrated that salvage therapy using daptomycin at high doses (> 6 mg/kg to 12 mg/kg) for prior antibiotic treatment failure and intolerance was generally effective and well-tolerated in Taiwanese patients. For use of high-dose daptomycin, only two prospective clinical studies had been published to date
[11, 15], and all studies were done in western countries (Italy and the United States). To our knowledge, this is the first clinical data describing the use of daptomycin at more than 6 mg/kg in Asian populations. Nearly 90% of our patients received daptomycin following vancomycin or teicoplanin failure, probably owing to the requirement of prospective audit in NTUH. Pre-exposure of glycopeptide might result in elevated MIC of both vancomycin and daptomycin simultaneously
[5, 24, 28–30]. Our results support using higher dose of daptomycin for difficult-to-treat infections caused by resistant pathogens, compatible with other reports
The clinical success rates of treatment with high dose daptomycin were 75-94% in the literature
[13, 15–17]. Bassetti et al. compared patients receiving daptomycin at doses > 6 mg/kg/day and those receiving ≤ 6 mg/kg/day (standard doses) in documented S. aureus infections
. Both microbiological success (93% versus 68%, p < 0.05) and clinical success (94% versus 73%, P = 0.05) were significantly superior in the high dose group than the standard dose group. However, the duration of therapy was also significantly longer in the high dose group, which may be a potential limitation. In our cohort, the clinical success rate was 77.6% overall, 80.5% in ICU patients, 79.6% in patients with bacteremia, or 79.2% in patients with MRSA isolates with vancomycin MIC ≥ 2 μg/mL. Compared to patients receiving ≤ 8 mg/kg of daptomycin, those treated with daptomycin > 8 mg/kg did not have better clinical outcomes but had higher rates of CPK level elevations.
The optimal dose of daptomycin is still unknown. In this study, we failed to demonstrate better survival rate, clinical success or microbiological success in patients with daptomycin > 8 mg/kg, compared with those with ≤ 8 mg/kg. It is possible that the physicians in charge tended to prescribe higher doses for sicker patients with more severe infections. However, the baseline characteristics (including Charlson index, Pitt score, ICU stay, and SOFA score) were similar between these two dosing groups, except that more patients with endocarditis were treated with doses > 8 mg/kg. In addition, our small sample size may lack sufficient power to detect small differences between treatment groups. To determine the efficacy of treatment with daptomycin > 8 mg/kg, further investigations in larger cohorts with randomization are warranted.
Approximately 60% of our patients received high-dose daptomycin during ICU admission. This proportion of ICU stay (61.2%) in our cohort is higher than prior reports (25-36%)
[17, 31]. These ICU patients did not have worse clinical responses or microbiologic outcome despite of higher mortality rate. The efficacy of high-dose daptomycin might be similar in critically-ill patients, and further investigations are needed to confirm our finding.
Overall, defined CPK level elevations occurred in 6.6% of patients in this study. This incidence was similar to the findings from previous studies of high dose daptomycin therapy (3.2-8.3%)
[2, 13–15, 17]. In our study, the incidence of defined CPK level elevations was significantly higher in patients treated with daptomycin > 8 mg/kg (16.7% versus 0%, p = 0.02). This finding is not unexpected, since Bhavnani et al. demonstrated that both AUC and minimum serum concentration (Cmin) of daptomycin were significantly associated with CPK elevations. A Cmin ≥ 24.3 mg/L could lead to a > 30-fold higher risk of CPK elevations. By using Monte Carlo simulations, they also established probabilities of elevated CPK levels stratified by dose
. Among our patients with daptomycin > 8 mg/kg, the rate of elevated CPK levels (16.7%) was slightly higher than their prediction (10.7-15.3%). These findings indicate the association of musculoskeletal toxicity with higher doses of daptomycin. Our results also confirmed that CPK level elevations became apparent about 2-week use of daptomycin
. Potential adverse events of musculoskeletal toxicity should be alerted if prolonged use of high dose daptomycin, especially after 2 weeks of daptomycin therapy.
Figueroa et al. reported 61 patients treated with a mean dose of 8 mg/kg of daptomycin for a median of 25 days, and 3 patients had musculoskeletal symptoms with grade 3 CPK level elevations (>1000 U/L). All three patients received 8 mg/kg of daptomycin and two of them had body mass index (BMI) class III obesity
. In the study from Bhavnani et al., 4 of 6 patients with elevated CPK levels were obese
. According to the daptomycin package insert, total body weight (TBW) is the appropriate dosing weight. But dosing daptomycin based on TBW can result in significantly higher maximum serum concentration and AUC in morbidly obese subjects
. This could explain why obesity was a risk factor for CPK elevation
. However, among our 4 patients with elevations of CPK level, none were obese (BMI range, 17.9-28.7 kg/m2; median, 23.4 kg/m2). Clinicians should be aware of musculoskeletal toxicity of high-dose daptomycin, even in non-obese patients.
As an observational, uncontrolled, nonrandomized study with a small sample size, there are limitations in our study. First, our study was based on clinical observation, therefore routine follow-up of cultures and CPK levels at regular intervals were not mandatory. Second, we did not check MIC of daptomycin, and only 77.4% of MRSA isolates were checked for MIC of vancomycin. Third, we did not perform pharmacokinetic analyses.