Normalization of creatine kinase values in a case of rhabdomyolysis during daptomycin treatment.

A 41-year-old woman presented in the Emergency Department with suspected compartment syndrome of lower left leg (creatine kinase [CK]: 12,502 IU/L, Cr: 4.31 mg/dL). Fasciotomy of the four limb compartments was conducted. By day 2, the patient presented oliguria during previous 24 h, so daily intermittent dialysis was carried out. On day 12, the patient presented an episode of bacteremia due to Staphylococcus hominis. Treatment with vancomycin was initiated and was changed after 4 days to daptomycin due to unsatisfactory clinical progression (6 mg/kg every 48 h, according to renal function and patient's weight) (CK: 2,972 IU/L). After 15 days of treatment, the dose of daptomycin was increased to 6 mg/kg every 24 h (CrCL: 46 mL/min, CK: 83 IU/L). The antibiotic was continued for another 4 days. Fourteen days later, the patient was discharged (CK: 26 IU/L). Daptomycin could be prescribed in some patients with elevated CK values. A cut-off value of baseline CK for use of daptomycin needs to be determined.

Introduction

Daptomycin is an antibiotic which is active against a majority of Gram-positive micro-organisms, including those which are multi-drug resistant.[1] It may cause rhabdomyolysis, which may require discontinuation of the drug.[1] Close monitoring of creatine kinase (CK) levels is therefore recommended in patients who have been prescribed this drug.[1]

Case Report

The authors report a case of rhabdomyolysis in a patient with compartment syndrome in which normal CK values were gradually restored during treatment with daptomycin. A 41-year-old woman presented in Emergency Department with intense pain in lower left leg, fever and marked asthenia 48 h, after falling at home. The patient remained several hours on the floor after the fall as she was unable to get up by herself. She was classified as morbidly obese (weight: 120 kg; body mass index: 52 kg/m2) and schizophrenic. Other comorbidities were not present. Patient did not take statins or any other medication that could possibly affect CK levels. She was on risperidone, quetiapine, valproic acid, topiramate and clorazepate dipotassium.

Physical examination revealed generalised erythema and swelling of left lower limb, absence of a distal pulse, intense pain on palpation of calf muscles and locally high temperature. Distal sensory alterations were not noted and acute venous or arterial disease was ruled out. The blood analysis revealed CK: 12,502 IU/L (reference values: 20-170 IU/L), creatinine: 4.31 mg/dL, urea: 119 mg/dL (reference values: 10-50 mg/dL), potassium: 5.30 mmol/L (reference values: 3.5-5.1 mmol/L), phosphate: 4.6 mg/dL (reference values: 2.5-4.8 mg/dL), magnesium: 2.1 (reference values: 1.6-2.5 mg/dL), C-reactive protein (CRP): 9.8 mg/dL (reference values: 0-0.8 mg/dL) and red blood cells count in urine: 2 (reference values: 0-5).

Normal saline infusion and urine alkalinization with sodium bicarbonate were started. A central venous pressure line was inserted to monitor the intravascular volume. With suspected compartment syndrome of left lower limb, a fasciotomy of the four limb compartments was carried out.

By day 2, the patient presented oliguria, with diuresis of 5-10 mL/h, so daily intermittent dialysis was initiated via jugular catheter. On day 5, serum electrolytes were in the normal range and serum urea was of 67 mg/dL. Furthermore, Enterobacter cloacae and Pseudomonas aeruginosa were isolated on surgical wound cultures. The blood cultures were negative. In accordance with the antibiogram, ciprofloxacin was started. Wounds were also surgically debrided. Patient continued to be febrile (38.7°C) despite treatment. Blood test on day 9 showed a procalcitonin value of 4.6 ng/mL (reference values: 0-0.05 ng/mL) and CRP of 5.8 mg/dL, so new blood cultures and catheter culture were ordered. A carbapenem was added to the antibiotic regime. The patient continued to be febrile over the following days. On day 12, the patient suffered an episode of bacteremia due to Staphylococcus hominis (minimum inhibitory concentration (MIC) vancomycin = 1 mg/L, MIC linezolid ≤ 2 mg/L). Treatment with vancomycin was initiated with dose of 15 mg/kg every 3 days. Vancomycin blood levels showed a trough concentration of 20 mg/mL. The treatment was changed after 4 days to daptomycin due to unsatisfactory clinical progress. Daptomycin was initiated at 6 mg/kg every 48 h and adjusted according to renal function and in accordance with patient's weight.[23] At this point, her CK had decreased at 2,972 IU/L.

The internal jugular central line and the haemodialysis catheter were removed and a triple-lumen haemodialysis catheter inserted. After 15 days of treatment, the daptomycin dose was increased to 6 mg/kg every 24 h due to recovery of renal function (Cockroft-Gault creatinine clearance: 46 mL/min). By this time, the CK value had fallen to 83 IU/L. The antibiotic was continued for another 4 days, (total duration of 20 days). The patient progressed favourably and the blood culture and wound culture were negative. Fourteen days afterwards, the patient was discharged with CK values of 26 IU/L.

Discussion

With compartment syndrome, the contents of muscle cells (myoglobin, CK, potassium and calcium) leak into the blood.[4] CK levels are estimated to increase to between 1,000 IU/L and 5,000 IU/L, with the need for haemodialysis in some cases. Fasciotomy is the usual treatment for compartment syndrome. Although animal studies have described a variable progression of CK values following fasciotomy,[5] it was later shown in humans that prompt performance of this surgical technique reduced the values of these enzymes.[6] Rhabdomyolysis has been identified as one of the most important adverse effects of daptomycin. Animal studies have shown that daptomycin-induced myopathy is specific for skeletal muscle and unlike other myopathies.[7]

The leakage of CK from the myocytes seems to be mediated via membrane perturbations, consistent with the lipophilic nature of daptomycin, its mechanism of action and its inability to penetrate the cell membrane.[8]

Phase III clinical trials have shown a CK increase in 2.8% of patients who received daptomycin 4 mg/kg/daily for skin and soft tissue infections and in up to 7% of those who received a dose of 6 mg/kg/daily for bacteraemia and/or endocarditis. A similar incidence has been reported in subsequent studies.[910] A Europe-wide study of patients from 118 institutions reported a CK increase of more than 5-10 times the upper limit of normal (ULN) and CK of more than 10 times the ULN in 3% and 4%, respectively, of the 1,127 patients recruited between January 2006 and August 2008.[10] This led to the discontinuation of treatment in 6 (0.53%) of the total number of patients included.

A study that analysed the safety of administering high doses of daptomycin (mean 8.9 mg/kg/daily (interquartile range [IQR]: 8-10 mg/kg/daily) in 250 patients revealed CK values superior to 200 IU/L in 10 (8.5%) of the 117 patients with this value at the end of the treatment (median CK at the end of the treatment: 39 U/L [IQR 26-67]).[11] None of them required discontinuation of the drug. No significant correlation could be established between the dose of daptomycin and the highest CK value observed (rs = 0.042, P = 0.63).

However, an increase of daptomycin trough concentration over 24.3 mg/L[12] and the presence of renal impairment[1] have been associated with a greater risk of increase in CK. For this reason, Food and Drug Administration (FDA) recommends close monitoring of this analytical parameter and discontinuation of treatment if this increases and/or in the case of muscle pain or weakness.[1]

In this case, the patient presented with rhabdomyolysis due to compartment syndrome which led to renal failure, even requiring haemodialysis. The patient was then put on daptomycin with the dose adjusted to renal function.

The treatment with daptomycin was initiated with a baseline CK value that was 17 times above the ULN. Majority of the reported studies use a CK value of more than 10 times above the ULN as a cut-off point. In this patient, who presented compartment syndrome, the CK value was within the normal limits 15 days after initiating daptomycin. However, the observations in this patient should not be extrapolated to other patients with similar conditions, as more study is required to determine the cut-off value of baseline CK, for prescribing this antibiotic.