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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Daptomycin

Last Update: December 4, 2017.

OVERVIEW

Introduction

Daptomycin is an intravenously administered, broad spectrum antibiotic used to treat complex skin and tissue infections, endocarditis and bacteremia. Daptomycin is associated with a low to modest rate of serum enzyme elevations during therapy, but is a very rare cause of clinically apparent liver injury.

Background

Daptomycin (dap" toe mye' sin) is a cyclic lipopeptide antibiotic that is poorly absorbed orally and must be given intravenously. Daptomycin appears to act by binding to bacterial membranes causing their depolarization and disruption and cell death. Daptomycin has been shown to be highly effective in treating severe gram-positive bacterial infections, including methicillin resistant Staphylococcal aureus (MRSA) and vancomycin resistant enterococcal (VRE) infections, and bacterial resistance is rare. Because of its value in treating multidrug resistant infections, daptomycin is usually limited for use in complicated infections in the hospital setting. Daptomycin was approved for use in 2006 and current indications include complicated skin and skin structure infections and severe bacteremia and endocarditis caused by susceptible organisms. Daptomycin is available in generic forms and under the brand name Cubicin in single use vials of 500 mg. The typical dose is 4 to 6 mg/kg once daily for 7 to 28 days, depending upon the type of infection and organism. Side effects may include restlessness, dizziness, headache, fever, abdominal pain, nausea, diarrhea and cough. Serum creatine kinase (CK) levels are often raised during intravenous daptomycin therapy, and many instances symptomatic myositis and of rhabdomyolysis have been reported, particularly with higher doses of therapy and in patients on concurrent statin medications. Rare complications include hypersensitivity reactions and interstitial pneumonitis.

Hepatotoxicity

Elevations in serum aminotransferase levels occur in 2% to 6% of patients receiving daptomycin, rates that are minimally higher than with placebo or comparator drugs. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. Isolated case reports of possible liver injury from daptomycin have been reported, but serum bilirubin was normal in most cases, and the serum aminotransferase elevations were mild-to-moderate and typically accompanied by severe muscle injury with marked CK elevations. Such cases without jaundice or alkaline phosphatase elevations are more likely due to muscle rather than liver injury. Nevertheless, a few case reports of mild jaundice with a hepatocellular pattern of serum enzyme elevations and normal CK levels has been published. The latency to onset was 5 weeks, immunoallergic and autoimmune features were not present, and resolution was slow with mild abnormalities still present 6 weeks later. Thus, clinically apparent liver injury from daptomycin probably occurs, but is quite rare.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Liver Injury

The mild-to-moderate serum aminotransferase elevations that occur during daptomycin therapy may represent muscle rather than liver injury and are likely due to direct toxicity to muscle. The rare instances of jaundice and hepatitis with daptomycin therapy probably represent idiosyncratic liver injury.

Outcome and Management

The severity of the liver injury linked to daptomycin therapy is usually mild and self-limited, and dose modification or discontinuation is rarely necessary. No instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been attributed to daptomycin therapy. The outcome of reexposure to daptomycin after liver or muscle injury has not been reported. Also, there is no information on cross sensitivity between daptomycin and other peptide antibiotics (such as the glycopeptides antibiotics, vancomycin and teicoplanin), but there is little reason to believe that such sensitivity exists.

Drug Class: Antiinfective Agents

CASE REPORT

Case 1. Mild liver injury arising during daptomycin therapy.

[Modified from: Abraham G, Finkelberg D, Spooner LM. Daptomycin-induced acute renal and hepatic toxicity without rhabdomyolysis. Ann Pharmacother 2008; 42: 719-21. PubMed Citation]

A 35 year old man with paraplegia and a decubitus ulcer with a methicillin resistant Staphylococcus aureus infection as well as a urinary tract infection with vancomycin resistant enterococci was treated at home with intravenous daptomycin in a dose of 4 mg/kg once daily. After 5 weeks of this treatment, he developed nausea and fatigue and was found to have abnormal liver tests. He had no history of liver disease and denied alcohol abuse and exposures to viral hepatitis. He had a history of drug allergy to penicillin (rash). Other medications included clonazepam for sleep, sertraline for depression, hydromorphone for pain, prochlorperazine for nausea, ferrous sulfate and vitamin C, all of which he had taken for more than a year. On examination, he was anicteric, afebrile and without findings indicative of acute or chronic liver disease. Laboratory tests showed bilirubin 2.0 mg/dL, ALT 8050 U/L, AST 6020 U/L, alkaline phosphatase 370 U/L, INR 1.2 and CK 111 U/L. Daptomycin was stopped and vancomycin and ciprofloxacin were begun. Tests for hepatitis A, B and C were negative and computed tomography of the abdomen showed no biliary dilatation or hepatic masses. Blood cultures grew Stenotrophomonas maltophilia which was sensitive to ciprofloxacin. Vancomycin was discontinued and he remained afebrile. Liver tests improved slowly and were near-normal six weeks later (Table).

Key Points

Medication:Daptomycin (325 mg daily)
Pattern:Hepatocellular (R=33)
Severity:3+ (bilirubin elevation and hospitalization)
Latency:5 weeks
Recovery:Almost complete at 6 weeks
Other medications:Clonazepam, sertraline, hydromorphone, prochlorperazine, ferrous sulfate, vitamin C

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
2 weeksPre20
5 weeks080503702.0Admission
6 weeks1 week819Discharge
12 weeks7 weeks81AST 51
Normal Values <40 <130 <1.2

Comment

The height of the serum aminotransferase levels and rapid fall with stopping daptomycin suggests a direct hepatic toxicity; the phenotype of acute hepatic necrosis. This pattern can also occur after an acute ischemic injury to the liver or acetaminophen (or cocaine) overdose. None of these possibilities seemed reasonable in this case report.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Daptomycin – Generic, Cubicin®

DRUG CLASS

Antiinfective Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Daptomycin 103060-53-3 C72-H101-N17-O26
Chemical structure for Daptomycin

ANNOTATED BIBLIOGRAPHY

References updated: 04 December 2017

Abbreviations: MRSA, methicillin resistant Staphylococcus aureus

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    (Expert review of hepatotoxicity published in 1999, does not discuss daptomycin).
  • Moseley RH. Daptomycin. Hepatotoxicity of antimicrobial and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 470.
    (Expert review of antibiotic induced liver injury, mentions rare reports of asymptomatic serum enzyme elevations in patients receiving daptomycin).
  • MacDougall C, Chambers HF. Daptomycin. Protein synthesis inhibitors and miscellaneous antibacterial agents. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1542-3.
    (Textbook of pharmacology and therapeutics; daptomycin is a cyclic lipopeptide antibiotic that was discovered 25 years ago, but developed clinically more recently because of the growing need for antibiotics effective against multidrug resistant bacteria).
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    (35 year old man developed fatigue and nausea 5 weeks after starting intravenous daptomycin for osteomyelitis [bilirubin 2.0 mg/dL, ALT 6020 U/L, Alk P 370 U/L, CK 111 U/L, creatinine 2.9 mg/dL, INR 1.2], with almost complete resolution 6 weeks after switching to vancomycin: Case 1).
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    (Among 52 Taiwanese adults treated with daptomycin, CK elevations occurred in 5 [10%] and ALT elevations in 2 [4%], but most were mild).
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    (Patient with chronic hepatitis C receiving peginterferon and ribavirin, was receiving antibiotics for a gluteal absess and developed muscle aches and fever after a second dose of daptomycin [CPK 12933 U/L rising to 45257 U/L, ALT 371 U/L, ALT 67 U/L, Alk P and bilirubin not given], resolving wihtin 10 days of stopping daptomycin).
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    (Safety analysis in 2263 patients given daptomycin for more than 14 days found only 3 patients with CK elevations and rare instances of nausea and rash; ALT elevations and hepatotoxicity not mentioned).
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    (Among 67 patients with severe infections treated with daptomycin, bone marrow suppression occurred in 70%, abnormal ALT levels in 29% and renal dysfunction in 20% of patients, but the abnormalities were usually due to the underlying illness rather than the antibiotic therapy).
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    (31 year old man with bacterial endocarditis due to MRSA, developing worsening liver tests within 5 days of starting daptomycin [bilirubin 0.6 rising to 1.8 mg/dL, ALT ~250 to 800 U/L, Alk P ~100 to 400 U/L], improving once daptomycin was stopped).
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    (44 year old African American women with osteomyelitis developed rhabdomyolysis a few days after starting daptomycin and ciprofloxacin [bilirubin normal, ALT 236 U/L, AST 750 U/L, Alk P 207 U/L, CPK 16710 U/L, creatinine 4.7 mg/dL], resolving within 1-2 months of stopping daptomycin).
  • Bland CM, Bookstaver PB, Lu ZK, Dunn BL, Rumley KF; Southeastern Research Group Endeavor (SERGE-45). Musculoskeletal safety outcomes of patients receiving daptomycin with HMG-CoA reductase inhibitors. Antimicrob Agents Chemother 2014; 58: 5726-31. [PMC free article: PMC4187944] [PubMed: 25022580]
    (Among 220 patients treated with daptomycin, the 49 who were also receiving statins were more likely to have mucle pains [6% vs 3%] and DPK elevations above 1000 U/L [10% vs 5%] than those who were not, but the differences were not statistically significant).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 2 were attributed to daptomycin).
  • Mo Y, Nehring F, Jung AH, Housman ST. Possible hepatotoxicity associated with daptomycin: a case report and literature review. J Pharm Pract 2016; 29: 253-6. [PubMed: 26763341]
    (49 year old woman with multiple medical problems developed jaundice while being treated for a MRSA infection with daptomycin in a dose of 300 mg intravenously once daily for 3 weeks [bilirubin 5.8 mg/dL, ALT 1449 U/L, Alk P 935 U/L, INR 4.15, CPK 45 U/L], with slow and incomplete recovery after stopping daptomycin).

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