Daptomycin in combination with rosuvastatin induced blood creatine phosphokinase elevation

Abstract

We present the case of a 73-year-old male patient who was hospitalised with infective endocarditis, and report an elevation in his blood creatine phosphokinase (CPK) after receiving daptomycin and rosuvastatin therapy concomitantly. His previous home-scheduled medications included apixaban, ivabradine, metformin, rosuvastatin 20 mg, ginkgo biloba and trimetazidine, and he continued to receive these medications at the hospital. After three sets of blood cultures were taken, empirical treatment was started with vancomycin and gentamicin. On the eighth day of treatment, daptomycin and ampicillin-sulbactam were initiated due to ampicillin-resistant Enterococcus faecalis growth in the patient’s blood culture. Daptomycin and rosuvastatin were discontinued on the 23rd day of treatment because of blood CPK elevation (2416 U/L) and linezolid was started instead of daptomycin. Six days after discontinuation of daptomycin and rosuvastatin, the CPK concentrations returned to normal range.

Background

Daptomycin prescribing information recommends that statins should be discontinued temporarily while receiving daptomycin.¹ Studies designed to evaluate the risk of musculoskeletal toxicity that arises from concomitant use of daptomycin and statins have different results. Some studies concluded that the risk of myopathy does not increase in patients who received statin concurrently with daptomycin. However, other studies concluded the exact opposite.^2–5

We present this case in order to draw attention to possible musculoskeletal toxicity due to concomitant daptomycin and rosuvastatin therapy.

Case presentation

A 73-year-old male patient with a history of coronary artery disease, hyperthyroidism and benign prostatic hyperplasia was hospitalised with fever (39.9°C), shivering and lack of appetite, with a serum creatinine concentration of 1.33 mg/dL. His weight was 78 kg and body mass index was 26 kg/m². His previous home-scheduled medications included apixaban, ivabradine, metformin, rosuvastatin 20 mg, ginkgo biloba and trimetazidine, and he continued to receive these medications at the hospital. A transoesophageal echocardiogram showed vegetation and the patient was diagnosed with infective endocarditis. An infectious diseases service consultation was requested. Three sets of blood cultures were taken and empirical treatment was started. On the eighth day of treatment, daptomycin was initiated. On the 23rd day, the patient’s blood creatine phosphokinase (CPK) concentration was 2416 U/L. He was suffering from moderate muscle pain and felt very tired. There was no significant change in creatinine (1.60 mg/dL). There was no other reason for CPK elevation during this time period, such as surgery, minor procedure, trauma, electrolyte disturbances, crush injuries or falls. We considered the patient had myositis due to concomitant rosuvastatin and daptomycin therapy. As a result of the recommendation of clinical pharmacists, daptomycin and rosuvastatin treatments were discontinued and linezolid was started instead of daptomycin. The patient’s symptoms improved 3 days after both daptomycin and rosuvastatin were discontinued.

Investigations

We closely monitored the serum CPK and creatinine of the patient receiving daptomycin and rosuvastatin. Baseline (day 8) serum CPK and creatinine were 22 U/L and 1.50 mg/dL, respectively. The patient’s blood CPK and creatinine values during treatment are shown in table 1. On the 23rd day of treatment, the patient's blood CPK was 2416 U/L (normal range 30–200 U/L). Therefore, we discontinued daptomycin and rosuvastatin, and we continued to monitor serum CPK and creatinine levels. His CPK value was within the normal range 6 days after both medications were discontinued.

Table 1.

Laboratory investigations

Day	Creatinine (mg\dL)	CPK (U\L)
Day 1	1.33
Day 2	1.44	21
Day 6	1.75	22
Day 8	1.5	22
Day 13	1.4	29
Day 19	1.59	481
Day 23	1.6	2416
Day 24	1.6	2660
Day 25	1.53	2504
Day 27	1.46	713
Day 28	1.59	366
Day 29	1.48	161
Day 31	1.43	48

CPK, creatine phosphokinase.

Treatment

Empirical treatment was started with vancomycin 15 mg/kg three times daily and gentamicin 1 mg/kg three times daily. Because of Enterococcus faecalis growth in the blood culture of the patient, an infectious diseases consultation was requested again. On the fourth day, the previous antibiotics were stopped, and linezolid 600 mg twice daily and ceftriaxone 2 g twice daily were initiated. On the eighth day, linezolid and ceftriaxone were stopped, and ampicillin-sulbactam 3 g four times daily and daptomycin 10 mg/kg once daily were initiated. The patient’s treatment regimen is shown in table 2. Daptomycin and rosuvastatin were discontinued on the 23rd day of treatment because of the blood CPK elevation (2416 U/L), and linezolid 600 mg twice daily was started instead of daptomycin.

Table 2.

Antibiotic regimen

Days	Antibiotics
Day 1–4	Gentamicin + vancomycin
Day 5–7	Linezolid + ceftriaxone
Day 8–23	Ampicillin-sulbactam + daptomycin
Day 24–39	Ampicillin-sulbactam + linezolid

Outcome and follow-up

We closely monitored the serum CPK and creatinine of the patient receiving daptomycin and rosuvastatin. Baseline (day 8) serum CPK and creatinine were 22 U/L and 1.50 mg/dL, respectively. Systemic muscle pain and fatigue, along with elevated CPK values, occurred in the patient after receiving daptomycin and rosuvastatin for 16 days. There was no significant change in creatinine (1.60 mg/dL). Both drugs that could cause myopathy were stopped and linezolid was started. Six days after discontinuation of daptomycin and rosuvastatin, CPK levels returned to normal range (figure 1). As the CPK values decreased, the patient's symptoms began to improve. After receiving linezolid and ampicillin-sulbactam for 7 days, the patient underwent transoesophageal echocardiography and the echocardiogram showed vegetation and aortic and mitral regurgitation. Therefore, it was decided to perform aortic and mitral valve replacement. The patient was followed up in the intensive care unit after surgery. Warfarin and aspirin were initiated 24 hours after surgery. Linezolid and ampicillin-sulbactam were stopped 3 days after surgery. The patient was discharged after being followed up in the intensive care unit for 11 days.

Figure 1.

Blood creatine phosphokinase (CK) concentrations over treatment period.

Discussion

Although daptomycin therapy is generally well tolerated in studies evaluating its safety,^{6 7} daptomycin-associated myopathy has been observed in 2–10% of patients.^8–10 Cases of myotoxicity, which can progress to rhabdomyolysis with daptomycin treatment, have also been reported.^{11 12} Creatine kinase should be measured at least once a week (more frequently in patients with renal insufficiency).¹

The adverse effects of statins include myositis, myalgia, elevated liver function tests, rhabdomyolysis (rarely) and acute renal failure. Risk factors that increase the adverse effects of statins include high-dose statin use, older age, interactions between statins and other drugs, female gender, hepatic insufficiency, renal insufficiency, Asian race, alcohol use, diabetes mellitus, hypertension and hypothyroidism.¹³

In a study using a computer-based search engine, adverse reaction reports in which rosuvastatin was suspected were examined. Atorvastatin, simvastatin, pravastatin and cerivastatin were used for comparison. Post-marketing security data were used for comparison of the statins. As a result of this study, concerns about the safety of rosuvastatin emerged at the commonly used doses of the drug.¹⁴

In a cell culture study comparing the cytotoxicities of statins with lipid lowering activities, it was observed that hydrophilic statins, especially pravastatin and rosuvastatin, had less myotoxic effects than lipophilic statins.¹⁵ Although there is no clear evidence that lipophilicity is associated with myotoxicity, switching to a less lipid-soluble statin may be an alternative when statin-induced rhabdomyolysis cases are observed.¹⁶

Concomitant use of daptomycin and statins has been considered as a risk factor for myopathy. Rhabdomyolysis was observed with rosuvastatin treatment, although the risk of rhabdomyolysis was highest with pravastatin treatment.⁵ There are also many cases of myotoxicity observed with rosuvastatin treatment.^{17 18}

Parra-Ruiz et al conducted a two-centre, retrospective, cohort study evaluating the safety of concomitant statin (average daptomycin dose 8.1 mg/kg/day) and high-dose daptomycin against daptomycin monotherapy (average daptomycin dose 7.8 mg/kg/day). In the daptomycin monotherapy group, creatine kinase elevations were higher than the group receiving the daptomycin-statin combination (10% vs 8%), but this difference was not statistically significant.²

Golightly et al conducted a study comparing the incidence of clinical myopathy in patients receiving concomitant daptomycin-rosuvastatin or simvastatin therapy to those receiving statin only. This study was carried out by examining the medical records of patients who received daptomycin and statin. If there was evidence of myalgia in the records and there was a secondary mobility limitation due to elevated serum CPK values, it was considered as treatment-related muscle damage. These data were compared with those of other hospitalised patients receiving statin therapy only. The authors concluded that there was no statistically significant increase in the incidence of clinical myopathy as a result of concomitant use of daptomycin and statin.³

In a multicentre, retrospective study by Bland et al, myotoxic adverse effects of daptomycin monotherapy against concomitant daptomycin and statin therapy were compared. Patients who received daptomycin treatment for ≥7 days were divided into the daptomycin group or the concomitant daptomycin-statin treatment group. The statins used in treatment were simvastatin, atorvastatin, pravastatin, rosuvastatin and lovastatin. Three primary safety outcomes were evaluated in the study: (1) CPK level >1000 U/L, (2) myalgia or related muscle pain, and (3) the number of patients requiring discontinuation of therapy. There was no significant difference between the daptomycin monotherapy group and the concomitant daptomycin-statin treatment group in terms of elevated CPK values (>1000 U/L) (10.2% vs 5.3%, p=0.32). There were no significant differences in musculoskeletal adverse effects between the two groups (6.12% vs 2.92%, p=0.38). Likewise, no statistically significant difference was found between the two groups in terms of the number of patients requiring discontinuation of treatment (3.51% vs 6.12%, p=0.42).⁴

A recent study drew attention to the risk of myopathy caused by concomitant use of statin-daptomycin. A single-centre, retrospective, matched case–control risk factor analysis was performed in adult and paediatric patients. The patient group that developed myopathy and the control group that did not were matched 1:1. As a result of multivariate analysis, the concomitant use of statin and daptomycin was found to be an independent risk factor for the development of myopathy and rhabdomyolysis.⁵ The authors recommended monitoring CPK twice a week or temporarily stopping statin treatment during co-administration. Since this study was a matched case–control study, it had a lower level evidence compared with other cohort studies.^{2 4} However, the number of patients included in the study was higher than other cohort studies.^{2 4}

To the best of our knowledge, myotoxicity has not been reported with other drugs administered to our patient, except rosuvastatin and daptomycin. Although myotoxicity can be seen with both drugs alone, the risk of myotoxicity increases with concurrent daptomycin and statin therapy.⁵ Therefore, it was considered that CPK elevation was more likely to be caused by concomitant daptomycin-statin treatment in our patient.

CPK levels decreased dramatically after discontinuation of daptomycin and rosuvastatin treatment. No life-threatening adverse effects were observed as a result of concomitant daptomycin and rosuvastatin treatment. As soon as daptomycin treatment was started, we monitored CPK twice a week in the patient, who was at high risk of a cardiovascular event. We selected this approach, instead of temporarily stopping rosuvastatin, because of the patient’s high atherosclerotic cardiovascular event risk. As a result of CPK monitoring, we stopped both drugs and prevented serious conditions (such as rhabdomyolysis) developing in the patient.

Learning points.

• When daptomycin and statin are concomitantly used, serum CPK levels should be monitored twice a week or this combination should be avoided and the statin should be temporarily discontinued.

• Clinicians and pharmacists should carefully monitor patients receiving a daptomycin-statin combination and be alert to the risk of myopathy.

• As can be seen from this case presentation, pharmacist–clinician collaboration plays an extremely important role in the management of drug interactions.

Ethics statements

Patient consent for publication

Obtained.