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DRUG RECORD

 

CLINDAMYCIN

OVERVIEW
Clindamycin

 

Clindamycin is a broad-spectrum antibiotic used orally, topically and parenterally for bacterial infections due to sensitive organisms.  Clindamycin has been linked to rare instances of acute liver injury.

 

Background

Clindamycin (klin" da mye' sin) is a lincomycin derivative with activity against many aerobic gram-positive cocci as well as many anaerobic gram-negative and gram-positive organisms. It has special activity against Bacteroides fragilis and some activity against Toxoplasma gondii and Pneumocystis jiroveci. Clindamycin acts by its binding to the 50S ribosomal subunit of bacteria, thus inhibiting protein synthesis.  Clindamycin was approved for use in the United States in 1970 and is still in wide use with more than 7 million prescriptions being filled yearly.  Current indications include moderate-to-severe bacterial infections caused by sensitive agents. It is also used topically for acne and bacterial vaginosis. Clindamycin is available generically in oral and parenteral forms and as gels, foam, lotion and creams for topical use. Capsules of 75, 150 and 300 mg are available in generic forms and under the commercial name of Cleocin. Clindamycin is also available in suspension for pediatric use. The typical adult dose is 600 to 2700 mg im or iv daily (in two divided doses) or 150 to 450 mg orally every 6 hours for 5 to 14 days depending upon the type and severity of infection.   Common side effects include nausea, diarrhea, headache and skin rash. 

 

Hepatotoxicity

Clindamycin has been linked to two forms of hepatotoxicity: transient serum aminotransferase elevations usually occurring after several days of high intravenous doses and an acute, idiosyncratic liver injury that arises within 1 to 3 weeks of starting therapy and is typically mild and self-limited.  High doses of intravenous clindamycin can be accompanied by elevations in serum ALT in the range of 2 to 10 times the upper limit of normal starting after 5 to 15 days of therapy in a manner similar to what occurs with intravenous oxacillin therapy (Case 1). Symptoms, jaundice, and alkaline phosphatase elevations are mild if they occur at all and aminotransferase levels rapidly fall into the normal range (in 1 to 2 weeks) with discontinuation of clindamycin or switch to lower doses, particularly in oral formulations with which it rarely occurs.

Clindamycin therapy has also been linked to a clinically apparent acute hepatitis that arises between 1 to 3 weeks after starting either oral or parenteral therapy.  The pattern of serum enzyme elevations is typically hepatocellular or mixed, but can be cholestatic.  Allergic manifestations such as rash, fever and eosinophilia are typical but often are not prominent and are not present in all cases.  Autoantibodies are generally not present. The acute liver injury may accompany other signs of hypersensitivity such as Stevens Johnson syndrome.  The liver injury is usually mild-to-moderate in severity and resolves rapidly with stopping.

 

Mechanism of Injury

The cause of ALT elevations during high-dose clindamycin therapy is not known, but may be due to a direct but mild injury to the liver. Liver biopsy during these episodes generally shows minimal cell injury. The idiosyncratic reaction to clindamycin resembles the immunoallergic types of hepatitis that occur after many types of antibiotics including the penicillins and cephalosporins.

 

Outcome and Management

The serum aminotransferase elevations that appear during high-dose intravenous therapy with clindamycin are usually benign, minimally symptomatic and resolve rapidly with stopping therapy or switching to oral forms of clindamycin. The acute hepatitis that occurs very rarely can be symptomatic and prolonged and has been linked to once case of vanishing bile duct syndrome, but not with acute liver failure. Ordinarily, recovery can be expected in 4 to 8 weeks. Prednisone is not recommended. Patients should be told to avoid re-exposure to clindamycin, and other lincomycin derivatives.

 

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CASE REPORT
Clindamycin

 

Case 1. Serum aminotransferase elevations during intravenous therapy with clindamycin.

(Modified from case #3: Hinthorn DR, Baker LH, Romig DA, Voth DW, Liu C. Endocarditis treated with clindamycin: relapse and liver dysfunction. South Med J 1977; 70: 823-6. PubMed Citation)

A 57 year old man with rheumatic heart disease and Staphylococcal endocarditis was treated with clindamycin (300 mg every 8 hours) and developed elevations in serum aminotransferase levels starting during the first week of therapy. Clindamycin was stopped at day 16 because of continuing rises in ALT which promptly began to fall when he was switched to cephalothin (Table). While blood cultures became negative on therapy, he subsequently died of E. coli sepsis.

 

Key Points

 

Medication: Clindamycin, 300 mg IV every 8 hours
Pattern: Probably hepatocellular
Severity: 1+ (No jaundice)
Latency: 5 Days to AST elevations
Recovery: Incomplete
Other medications: None mentioned

 

Laboratory Values

 

Days After Starting Days After Stopping

ALT

(U/L)

AST

(U/L)

LDH

(U/L)

Other
Pre 10 700
0 Clindamycin started (300 mg IV q 8 hr)
5 55 70 1020
9 310 320 1400
16 510 600 2100
  0 Clindamycin stopped: cephalothin started
24 8 230 125 1420
Normal Values <40 <40 Not given

* Values estimated from Figure 1.

 

 

Comment

A typical pattern of serum aminotransferase elevations during intravenous clindamycin therapy that can be seen with several antibiotics, most typically with oxacillin. The liver injury usually arises after 4-6 days and is minimally symptomatic, anicteric and resolves rapidly when clindamycin is stopped.  The injury is probably dose related.

 

Case 2. Acute hepatitis arising during intravenous therapy with clindamycin.

(Modified from: Elmore M, Rissing JP, Rink L, Brooks GF. Clindamycin-associated hepatotoxicity. Am J Med 1974; 57: 627-30. PubMed Citation)

An 18 year old man with acute bacterial endocarditis related to injection drug use developed elevated serum aminotransferases and then jaundice during intravenous clindamycin therapy. The patient had been treated with high doses of cephalothin and vancomycin for over two months with an inadequate response during which time his liver tests were normal. Blood cultures revealed Staphylococcus aureus sensitive to clindamycin, and he was started on intravenous clindamycin (3.6 g/day) with a rapid clinical improvement. After a week, however, serum AST levels began to rise. The dose of clindamycin was cut in half, but he subsequently developed urticaria, recurrence of fever, jaundice and rising AST levels (Table). Tests for hepatitis B were negative, and liver biopsy showed acute hepatitis without fibrosis compatible with a drug-induced liver injury. Clindamycin was stopped and the rash, fever and jaundice promptly resolved. Follow up blood cultures were negative and serum AST levels were normal when tested one month later.

 

Key Points

 

Medication: Clindamycin, 3.6 g iv daily for 30 days
Pattern: Hepatocellular (R=9.1)
Severity: 3+ (Jaundiced and hospitalization prolonged)
Latency: 8 days to AST elevations, 22 days to jaundice
Recovery: Within one month
Other medications: None mentioned

 

Laboratory Values

 

Time After Starting Time After Stopping AST* (U/L) Alk P*   (U/L) Bilirubin* (mg/dL) Other
Clindamycin (3.6 gm IV daily) started for endocarditis
Pre 30 59 0.8
5 days   40
8 days   110
10 days   310
14 days 480 1.5
16 days 710 Reduced dose
3 weeks 750 80 3.5
4 weeks 80 1.8 Liver biopsy
  Fever and urticaria: clindamycin stopped
5 weeks 4 days 50
6 weeks 10 days 80 1.1
7 weeks 18 days 160 Normal
2 months 1 month 30 0.9
Normal Values <40 <40 <1.2

*Values estimated from Figure 1.

 

 

Comment

A typical pattern of serum aminotransferase elevations arising after a week of intravenous clindamycin therapy. The clindamycin dose was decreased because of the rising AST levels, but fever and urticaria arose, and clindamycin was stopped, whereupon the liver injury resolved rapidly. This example suggests that the asymptomatic elevations in serum aminotransferase levels during intravenous clindamycin therapy can evolve into the immunoallergic and icteric form of liver injury if therapy is continued. This report pre-dated the availability of tests for hepatitis C, which may have been at least partially responsible for the liver injury in this patient.

 

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REPRESENTATIVE TRADE NAMES
Cleocin®, Generic (Various)

DRUG CLASS
Anti-Infective Agents

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH
Clindamycin Hydrochloride Product Labeling, TEVA Pharmaceuticals USA.


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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Clindamycin 18323-44-9 C18-H33-Cl-N2-O5-S Clindamycin  chemical structure

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REFERENCES
Clindamycin

 

References Last Updated: 12 November 2013

  1. Zimmerman HJ. Clindamycin.  Hepatic injury from antimicrobial agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, p. 592.  (Expert review of liver injury published in 1999 mentions that ALT elevations are common during clindamycin therapy and 2 cases of hepatocellular jaundice due to clindamycin have been published).

  2. Moseley RH. Clindamycin. Hepatotoxicity of antimicrobials 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 that clindamycin has been rarely reported to cause hepatotoxicity).

  3. MacDougall C, Chambers HF.  Lincosamides (Clindamycin).  Protein synthesis inhibitors and miscellaneous antibacterial agents.  In, Brunton LL, Cchabner BA, Knollman BA, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1534-5.  (Textbook of pharmacology and therapeutics).

  4. Elmore MF, Rink LD, Rissing JP. Clindamycin, endocarditis, hepatotoxicity. Ann Intern Med 1973; 78: 779-80. PubMed Citation  (Letter to editor describing 18 year old injection drug user with acute bacterial endocarditis who developed marked AST elevation [710 U/L] after 18 days of iv clindamycin, resolving rapidly with stopping; 2 biopsies, first during therapy showed mild hepatitis, second during recovery showed resolution).

  5. Fass RJ, Scholand JF, Hodges GR, Saslaw S. Clindamycin in the treatment of serious anaerobic infections. Ann Intern Med 1973; 78: 853-9. PubMed Citation  (Analysis of responses to parenteral clindamycin in 19 adults with serious infections, 8 of who developed mild, transient ALT and AST or Alk P elevations, but none required discontinuation or developed jaundice).   

  6. Craig JA. Jaundice in acute pustular psoriasis. Br Med J 1974; 3: 43. PubMed Citation  (62 year old woman developed jaundice 3 days after starting clindamycin therapy of sepsis [bilirubin 12.2 mg/dL, ALT normal]; likely due to sepsis rather than clindamycin).

  7. Elmore M, Rissing JP, Rink L, Brooks GF. Clindamycin-associated hepatotoxicity. Am J Med 1974; 57: 627-30. PubMed Citation  (18 year old injection drug use with acute bacterial endocarditis developed jaundice [3.5 mg/dL] and AST elevations [710 U/L] after 21 days of iv clindamycin, resolving rapidly once therapy was stopped; two biopsies done, first during therapy showed mild hepatitis, second during recovery showed resolution: Case 2).

  8. Levison ME, Bran JL, Ries K. Treatment of anaerobic bacterial infections with clindamycin-2-phosphate. Antimicrob Agents Chemother 1974; 5: 276-80. PubMed Citation  (Among 35 patients treated with clindamycin im or iv for severe bacterial infections, mild elevations in ALT, AST and Alk P were common, one patient developed hepatitis 1 day after stopping 12-day course of clindamycin [bilirubin 5.6 mg/dL, ALT 680 U/L, Alk P 460 U/L], resolving within 3-4 months of stopping).

  9. Williams DN, Crossley K, Hoffman C, Sabath LD. Parenteral clindamycin phosphate: pharmacology with normal and abnormal liver function and effect on nasal staphylococci. Antimicrob Agents Chemother 1975; 7: 153-8. PubMed Citation  (Open label study of parenteral clindamycin therapy in 41 patients including 24 with pre-existing liver disease; AST levels rose in 5 patients with liver disease and improved in others; among 17 patients without liver disease, AST levels rose in 4 [52, 57, 60 and 270 U/L] but elevations were self-limited and resolved spontaneously).

  10. Hinthorn DR, Baker LH, Romig DA, Voth DW, Liu C. Endocarditis treated with clindamycin: relapse and liver dysfunction. South Med J 1977; 70: 823-6. PubMed Citation  (Among 6 patients treated for endocarditis with low rate of response, 2 developed ALT [~200 and 550 U/L], AST and LDH elevations after 8-18 days without jaundice or symptoms, resolving within 2 weeks of discontinuation: Case 1).

  11. Kobayasi A, Sato S, Ito T, Utsumi T, Kikuchi N. [Therapy for severe anaerobic infections with clindamycin (author's transl)] Jpn J Antibiot 1977; 30: 13-21. Japanese. PubMed Citation  (From abstract: Among 11 patients given oral clindamycin for up to 49 days, one developed transient ALT elevations).

  12. Prospective, randomized comparison of metronidazole and clindamycin, each with gentamicin, for the treatment of serious intra-abdominal infection. Surgery 1983; 93 (1 Pt 2): 221-9. PubMed Citation  (Multicenter study comparing clindamycin to metronidazole in 186 patients with severe infections; similar efficacy, AST elevations in 18% vs 10% but no frank hepatitis or discontinuation for liver injury).

  13. Altraif I, Lilly L, Wanless IR, Heathcote J. Cholestatic liver disease with ductopenia (vanishing bile duct syndrome) after administration of clindamycin and trimethoprim-sulfamethoxazole. Am J Gastroenterol 1994; 89: 1230-4. PubMed Citation  (Two cases of vanishing bile duct syndrome, one due to clindamycin: a 67 year old man with jaundice arising 1 week after completion of a 10-day course [bilirubin 14.6 mg/dL, ALT 315 U/L, Alk P 271 U/L, GGT 468 U/L], followed by prolonged jaundice for 2-4 years [bilirubin 4.2 mg/dL, Alk P 179 U/L, ALT 67 U/L], liver biopsies showing progressive loss of bile ducts; Ampicillin caused sudden worsening).

  14. Maraqa NF, Gomez MM, Rathore MH, Alvarez AM. Higher occurrence of hepatotoxicity and rash in patients treated with oxacillin, compared with those treated with nafcillin and other commonly used antimicrobials. Clin Infect Dis 2002; 34: 50-4. PubMed Citation  (Retrospective review of 222 children receiving outpatient parenteral antibiotics; 22% receiving oxacillin but only 1 of 72 receiving clindamycin developed “hepatitis” [at 17 days: bilirubin 0.6 mg/dL, ALT 183 U/L, AP normal]).

  15. Biesel-Desthieux MN, Tissières P, Belli DC, Le Coultre C, Gervaix A, Masserey Spicher V. Fulminant liver failure in a child with invasive group A streptococcal infection. Eur J Pediatr 2003; 162: 245-7. PubMed Citation  (No mention of clindamycin; 2 year old boy developed severe liver injury and encephalopathy after 3 days of acetaminophen [48 mg/kg/day] [bilirubin 3.1 mg/dL, ALT 5928 U/L, protime 12%]; also had streptococcal bacteremia responding rapidly to ceftriaxone).

  16. De Valle MB, Av Klinteberg V, Alem N, Olsson R, Björnsson E. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 2006; 24: 1187-95. PubMed Citation  (Survey of 77 cases of drug-induced liver injury seen over 10 years, found 2 cases of clindamycin related injury, both hepatocellular, with onset after 7 and 35 days, resolution in 2 weeks and 6 months).

  17. Aygun C, Kocaman O, Gurbuz Y, Senturk O, Hulagu S. Clindamycin-induced acute cholestatic hepatitis. World J Gastroenterol 2007; 13: 5408-10. PubMed Citation  (42 year old woman developed jaundice and pruritus after 6 days of oral clindamycin [bilirubin 4.1 mg/dL, ALT 1795 U/L, Alk P 339 U/L], resolving within 8 weeks of stopping).

  18. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation.  (Among 300 cases of drug-induced liver disease in the U.S. collected from 2004 to 2008, clindamycin was implicated in one case).

  19. Flores Sahagun JE, Ortiz Soto JA, Mendez T, Cardenas Ochoa EC, Hernandez Flores G.  [Stevens Johsnon Syndrome and clindamycin-or chlorpheniramine-induced intrahepatic cholestatis].  Dermatology Online J 2009; 15: 12. PubMed Citation  48 year old womann developed jaundice at the end of an 8-day course of clindamycin and chlorpheniramine [bilirubin 3.5 mg/dL, ALT 1105 U/L, Alk P 444 U/L], and rash that spread to mouth, palms and soles, responding to corticosteroids with rapid recovery within weeks).

  20. Leitner JM, Graninger W, Thalhammer F. Hepatotoxicity of antibacterials: Pathomechanisms and clinical. Infection 2010; 38: 3-11. PubMed Citation(Review of frequency and cause of antibiotic-induced liver injury, rates range from 0.2 [moxifloxacin] to 17 [amoxicillin/ clavulanate] per 100,000 prescriptions for different commonly implicated agents; mentions that clindamycin most frequency causes asymptomatic increases in ALT).

  21. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug-induced liver injury, including 31 due to antibiotics, but none were attributed to clindamycin).

  22. Bawany MZ, Bhutto B, Youssef WI, Nawras A, Sodeman T. Acute Liver Failure: An Uncommon Complication of Commonly Used Medication. Am J Ther 2011 Jun 3. [Epub ahead of print] PubMed Citation(73 year old man developed jaundice 7 days after starting clindamycin [bilirubin 6.9 mg/dL, ALT 1076 U/L, Alk P 203 U/L, INR 2.1], liver tests improved on stopping but patient developed respiratory followed by multiorgan failure and died soon thereafter). 

  23. Miller Quidley A, Bookstaver PB, Gainey AB, Gainey MD. Fatal clindamycin-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Pharmacotherapy 2012; 32: e387-92. PubMed Citation. (63 year old woman developed nausea and a generalized erythematous rash 4 days after starting a course of clindamycin with subsequent fever, eosinophilia [24%], lymphadenopathy, renal dysfunction, pancreatitis, and liver injury [bilirubin 4.3 mg/dL, ALT 67 U/L, Alk P 1010 U/L] with progressive multiorgan failure and death 16 days after presentation).

  24. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 114: 1419-25. PubMed Citation.   (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2-year period of which none were attributed to clindamycin).   

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  1. PubMed logoRecent References on Clindamycin

  2. ClinicalTrials.gov logoTrials on Clindamycin

  3. TOXLINE logoTOXLINE Citations on Clindamycin

 

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