Doxycycline is a semisynthetic tetracycline-related, bacteriostatic antibiotic that has been linked to rare instances of acute cholestatic liver injury.
Doxycycline (dox" i sye' kleen) is a semisynthetic tetracycline that is used for mild-to-moderate infections due to susceptible organisms. Doxycycline, like other tetracyclines, is active against a wide spectrum of gram-positive and gram-negative bacteria as well as against several rickettsia, spirochetes, chlamydia and mycoplasma. Unlike tetracycline and oxytetracycline, doxycycline has excellent oral availability and wide tissue penetration. Indications include upper respiratory, skin, or soft tissue infections due to susceptible bacteria, gonorrhea and syphilis in penicillin-allergic patients, non-gonococcal urethritis, acute pelvic inflammatory disease, epididymitis, oorchitis, Lyme disease, and as prophylaxis against traveler’s diarrhea. Doxycycline is also used chronically as treatment of acne. Doxycycline was approved for use in the United States in 1967 and is still widely used, with more than 11 million prescriptions filled yearly. Doxycycline is available in multiple generic forms in capsules and tablets ranging from 20 to 100 mg, and as oral suspensions for pediatric use. Typical adult doses are 100 to 200 mg twice daily for 7 to 30 days. Parenteral forms for intravenous or intramuscular administration are also available. Trade names for doxycycline include Vibramycin, Oracea, Adoxa, Monodox and Doxycin. Common side effects include headache, dizziness, nausea, gastrointestinal upset, skin and tooth discoloration and rash.
Doxycycline has been associated with rare instances of hepatic injury, generally arising within 1 to 2 weeks of starting therapy, sometimes with a history of previous administration of the agent without injury. The pattern of injury ranges from hepatocellular to cholestatic and is probably most commonly mixed. The onset is often abrupt and can be accompanied by signs of hypersensitivity, such as fever, rash and eosinophilia (DRESS syndrome). Recovery is usually rapid and usually complete within 4 to 6 weeks. However, instances of severe and prolonged cholestatic liver injury have been reported with oral doxycycline. The autoimmune-like hepatitis that has been described with minocycline has not been linked to doxycycline, despite similarities in chemical structure and similar indications and uses, perhaps because it is used less frequency in a low dose, long term regimen. High dose intravenous doxycycline can cause acute fatty liver typical of that caused by intravenous tetracycline, particularly in susceptible patients such as pregnant women. This type of injury is, however, quite rare. Nevertheless, for these reasons, the duration and dose of parenteral doxycycline therapy should be minimized.
Likelihood score: C (probable cause of clinically apparent liver injury).
Mechanism of Injury
The cause of the idiosyncratic liver injury associated with doxycycline is unknown, but several features (short latency, recurrence with reexposure) suggest an immunoallergic etiology.
Outcome and Management
Recovery after withdrawal of doxycycline is usually rapid, but in instances with severe cholestasis, can require 2 to 6 months. No case of acute liver failure has been reported due to doxycycline, but rare instances of vanishing bile duct syndrome have been linked to its use. Cross sensitivity to hepatic injury between minocycline and doxycycline has not been shown, but both can cause a short incubation period acute hepatitis with immunoallergic features, so that some degree of cross reactivity may occur.
References to doxycycline induced liver injury are provided in the introductory Overview section on the Tetracyclines.
Drug Class: Antiinfective Agents, Tetracyclines
Case 1. Cholestatic hepatitis attributed to doxycycline therapy.
|Medication:||Doxycycline (200 mg once daily for 8 days)|
|Pattern:||Mixed (R=3.9), later hepatocellular (R=10)|
|Severity:||3+ (jaundice and hospitalization)|
|Latency:||1 day to symptoms, 8 days to jaundice|
|Other medications:||None mentioned|
|Time After Starting||Time After Stopping||ALT* (U/L)||Alk P* (U/L)||Bilirubin* (mg/dL)||Other|
|Doxycycline given for 8 days for suspected pneumonia|
|1 day||0||NA||NA||NA||Rash and nausea|
|8 days||0||173||130||4.4||Doxycycline stopped|
|11 days||3 days||194||112||5.0||Negative viral markers|
|36 days||28 days||431||104||8.1|
|53 days||45 days||442||91||7.1||Liver biopsy|
|56 days||48 days||474||104||7.2|
|2 months||2 months||743||100||4.6|
|3 months||3 months||388||87||3.1|
|4 months||4 months||32||61||0.8|
|DRUG||CAS REGISTRY NO||MOLECULAR FORMULA||STRUCTURE|