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References

1. Tunkel AR, Scheld WM. Acute meningitis. In: Mandell GL,

Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennetts Principles

and Practices of Infectious Diseases. Philadelphia, PA: Elsevier, Inc.,

2005; 1083126.

2. Fong IW, Tomkins KB. Review of Pseudomonas aeruginosa

meningitis with special emphasis on treatment with ceftazidime. Rev

Infect Dis1985; 7: 60412.3. Carmeli Y, Troillet N, Eliopoulos GM et al . Emergence of

antibiotic-resistant Pseudomonas aeruginosa: comparison of risks

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Chemother1999; 43: 137982.

4. Tunkel AR, Kaufman BA. Cerebrospinal fluid shunt infections. In:

Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and

Bennetts Principles and Practices of Infectious Diseases. Philadelphia,

PA: Elsevier, Inc., 2005; 112632.

5. Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal

use of polymyxins in patients with Gram-negative meningitis: a sys-

tematic review of the available evidence. Int J Antimicrob Agents 2007;

29: 925.

6. Isaacs D, Slack MP, Wilkinson AR et al. Successful treatment of

Pseudomonas ventriculitis with ciprofloxacin. J Antimicrob Chemother1986; 17: 5358.

7. Matthews SJ, Lancaster JW. Doripenem monohydrate, a broad-

spectrum carbapenem antibiotic. Clin Ther2009; 31: 4263.

8. Mushtaq S, Ge Y, Livermore DM. Doripenem versus

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Antimicrob Agents Chemother2004; 48: 308692.

9. Sakyo S, Tomita H, Tanimoto K et al. Potency of carbapenems

for the prevention of carbapenem-resistant mutants of Pseudomonas

aeruginosa. J Antibiot (Tokyo)2006; 59: 2208.

10. Huynh HK, Biedenbach DJ, Jones RN. Delayed resistance

selection for doripenem when passaging Pseudomonas aeruginosa

isolates with doripenem plus an aminoglycoside. Diagn Microbiol Infect

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Journal of Antimicrobial Chemotherapydoi:10.1093/jac/dkp127

Advance Access publication 4 April 2009

Rhabdomyolysis and acute renal failure associated

with the co-administration of daptomycin and an

HMG-CoA reductase inhibitor

Randy O. Odero, Kerry O. Cleveland* and Michael

S. Gelfand

Division of Infectious Diseases, Department of Medicine,

University of Tennessee Health Science Center, Memphis,

TN 38104, USA

Keywords: interstitial nephritis, linezolid, simvastatin, creatine

phosphokinase

*Corresponding author. Tel: 1-901-448-5770;

Fax: 1-901-448-5940; E-mail: kcleveland@utmem.edu

Sir,

Daptomycin is a lipopeptide antibiotic approved for the

treatment of complicated skin and skin structure infections (cSSSIs)

due to specified organisms and the treatment of Staphylococcus

aureus bloodstream infections, including right-sided endocardi-

tis, caused by methicillin-susceptible S. aureus and methicillin-

resistant S. aureus.1

Although well tolerated in clinical trials and

use, there have been reports of elevations in serum creatine

phosphokinase (CPK) concentrations, occasionally with accom-

panying rhabdomyolysis and acute renal failure.25

Here, we

report this first case of CPK elevation with rhabdomyolysis and

acute renal failure that developed during the co-administration

of daptomycin and an HMG-CoA reductase inhibitor. Symptomsresolved after discontinuation of daptomycin.

A patient suffered a fall injury with a resulting fracture of the

femoral bone at the site of previous total hip arthroplasty.

Irrigation and debridement and removal of the prosthesis were

performed. Intravenous (iv) vancomycin (1 g every 24 h) and

cefepime (1 g every 12 h) were given post-operatively. Copious

amounts of purulence had been encountered at the arthroplasty

site, but no organisms grew from intraoperative cultures. For the

next 2 weeks, there was no fever, but the white blood cell

(WBC) count remained elevated (18000 23000 WBC/mm3

).

Vancomycin was discontinued and iv daptomycin was begun

(7.2 mg/kg daily). Serum creatinine was noted to be 1.5 mg/dL,

with a calculated creatinine clearance of 24.6 mL/min. Four days

later, the daptomycin dose was changed to 7.2 mg/kg every 48 h.On the 16th day of daptomycin treatment, the patient com-

plained of weakness and diffuse aches in the proximal thighs

and arms. Serum CPK concentration was found to be 8995 IU/L

(normal 38 234 IU/L). No prior CPK value was available.

Antibiotics were changed to oral linezolid 600 mg and ciproflox-

acin 500 mg, both twice daily. Vigorous iv fluids were adminis-

tered. The serum creatinine reached a peak of 3.4 mg/dL.

Urinalysis revealed 1 albumin and a urine Hansel stain showed

eosinophils. The patients usual medications included simvasta-

tin (80 mg each evening), extended-release niacin (500 mg each

evening) and esomeprazole (20 mg daily) and were continued

throughout her hospitalization.

Six days after stopping daptomycin, the serum creatinine

returned to baseline. Seven days after stopping daptomycin, the

CPK concentration had decreased to 125 IU/L.

A 4 week course of linezolid was completed, followed by

oral minocycline 100 mg twice daily. The arthroplasty was suc-

cessfully revised and the patient was discharged on long-term

suppressive minocycline therapy, continuing to do well after

1 year with no evidence of recurrent infection.

Few cases of daptomycin-induced rhabdomyolysis have been

described in the literature.25

In clinical trials, up to 6.7% of sub-

jects experienced an increase in CPK concentrations.6

In Phase 3

cSSSI studies, 0.2% of patients treated with daptomycin had

Research letters

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symptoms of muscle pain or weakness associated with CPK

elevations greater than four times the upper limits of normal.7

Dosing frequency appears to have a more direct relationship on

skeletal muscle than do peak plasma concentrations of daptomy-

cin.8

The mechanism behind adverse skeletal muscle effects may

involve leakage of intracellular CPK from affected myocytes in a

manner similar to the drugs ability to cause release of intracellular

ions from bacterial cells. It is thought that less frequent adminis-

tration of the drug allows additional repair time for damagedmyocytes.

In most prior reports of daptomycin toxicity, complaints

usually began within 1 week, occasionally after a single dose.25

This patient developed symptoms on the 16th day of treatment.

The patient was also receiving niacin and an HMG-CoA reductase

inhibitor, drugs that are known to increase the risk of rhabdomyo-

lysis when used alone or in combination.9,10

Both niacin and sim-

vastatin were continued, and the rhabdomyolysis resolved after

discontinuation of daptomycin. The temporal occurrence of rhab-

domyolysis seems to implicate daptomycin as the causative agent

rather than simvastatin and/or niacin, both of which had been well

tolerated before and after the course of daptomycin and episode

of rhabdomyolysis. Speculatively, any of these three agents could

have contributed to, or potentiated, the actions of the other agentor agents in causing the rhabdomyolysis.

Previous reports have not included the co-administration of

HMG-CoA reductase inhibitors with daptomycin.25

A literature

search at www.pubmed.com performed using the keywords

daptomycin, statin, rhabdomyolysis and/or reductase

inhibitor did not reveal a previous report of rhabdomyolysis in

a patient receiving daptomycin and concomitant statin therapy.

The eosinophiluria may have been due to interstitial nephri-

tis. While a number of medications, including cephalosporins

and proton pump inhibitors, can be associated with interstitial

nephritis, the other drugs have not been frequently implicated in

the literature as causes of rhabdomyolysis.

The elevation in the CPK concentration was sufficient

enough to potentially have had a detrimental effect on renalfunction. The complaints of myalgias and weakness were con-

sistent with a clinical impression of myopathy. The initial dose

and frequency of daptomycin used in this patient were based on

estimates by the prescribing physicians and were higher than

those recommended by the manufacturer.7

This may have led to

an increased risk of elevated CPK and associated problems.

In conclusion, this is the first case reporting reversible

rhabdomyolysis and renal failure after the co-administration of

daptomycin and an HMG-CoA reductase inhibitor. According

to the package insert for daptomycin, experience with co-

administration with HMG-CoA reductase inhibitors is limited,

and their use might need to be suspended during therapy with

daptomycin.7

Consistent with earlier experiences, this patients

renal dysfunction improved within 10 days after stopping

daptomycin.2,7

Additional clues to impending adverse effects of daptomycin

may be obtained by monitoring renal and hepatic function tests.

The current recommendation is to monitor the serum CPK con-

centration at least weekly, and more frequently if clinicalconditions warrant.

7

Funding

No financial support was received for this work.

Transparency declarations

None to declare.

References

1. http://www.fda.gov/CDER/drug/InfoSheets/patient/daptomycinPIS.

htm (9 November 2008, date last accessed).

2. Patel SJ, Samo TC, Suki WN. Early-onset rhabdomyolysis related

to daptomycin use. Int J Antimicrob Agents2007; 30: 4724.

3. Papdopoulos S, Ball AM, Liewer SE et al. Rhabdomyolysis during

therapy with daptomycin. Clin Infect Dis 2006; 42: e10810.

4. Kazory A, Dibadj K, Weiner ID. Rhabdomyolysis and acute renal

failure in a patient treated with daptomycin. J Antimicrob Chemother

2006; 57: 5789.

5. Edwards CM, King K, Garcia RJ. Early-onset rhabdomyolysis

associated with daptomycin. Infect Dis Clin Pract2006; 14: 3278.

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alone, and simvastatin alone (from the United States Food and Drug

Administration Adverse Event Reporting System). Am J Cardiol 2007;

99: 37981.

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