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DRUG RECORD

 

DOXYCYCLINE

OVERVIEW
Doxycycline

 

Doxycycline is a semisynthetic tetracycline-related bacteriostatic antibiotic that has been linked to rare instances of acute cholestatic liver injury.

 

Background

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. 

 

Hepatotoxicity

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.

 

Mechanism of Injury

The cause of the idiosyncratic liver injury associated with doxycycline is unknown, but several features (short latency, recurrence with re-exposure) 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 and 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: Tetracyclines

 

 

 

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CASE REPORT
Doxycycline

 

Case 1. Cholestatic hepatitis attributed to doxycycline therapy.
[Modified from: Björnsson E, Lindberg J, Olsson R. Liver reactions to oral low-dose tetracyclines. Scand J Gastroenterol 1997; 32: 390-5.]

A 32 year old man with fever and cough was treated with doxycycline for suspected pneumonitis and developed skin rash, abdominal pain and dark urine one day later. Symptoms of fatigue, nausea and pruritus arose and doxycycline was stopped after 8 days of therapy. His serum enzymes were elevated and he was mildly jaundiced with a total bilirubin of 4.4 mg/dL (Table). He also had eosinophilia (13.5%). He tested negative for antibodies to hepatitis A, B, and C as well as markers of acute CMV and Epstein Barr infection. Autoantibodies were negative, and an abdominal ultrasound was normal. He remained jaundiced for several months and underwent a liver biopsy that showed intrahepatic cholestasis with mild inflammatory changes suggestive of drug-induced liver injury. In follow-up at 3 and again at 18 months, all liver tests had returned to normal.

 

Key Points

 

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
Recovery: 3 Months
Other medications: None mentioned

 

Laboratory Values

 

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
Normal Values <40 <115 <1.2

* Estimated from Figure 1 and converted from µkat/l and µmol/L.

 

Comment

A convincing history, presentation, biochemical pattern and course for drug-induced liver disease with a rapid onset, mixed followed by hepatocellular pattern of enzyme elevations and fairly prolonged jaundice. The only medication taken was doxycycline which the patient had received at least twice in the past. The short latency to onset suggests previous sensitization.  Recovery was slow but complete. Thus, the overall presentation is quite convincing as immunoallergic drug-induced liver injury due to doxycycline. Future exposures to doxycycline as well as other tetracyclines should be avoided.

 

 

CASE REPORTS SUBMITTED TO LiverTox
Doxycycline

 

Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available to review. Most cases are from the Drug-Induced Liver Injury Network but others are from users of LiverTox who have submitted data from an actual clinical case. All have been reviewed and cleared of personal identifiers and a brief comment is added from the LiverTox editors.

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PRODUCT INFORMATION
Doxycycline

REPRESENTATIVE TRADE NAMES
Doxycycline – Monodox®, Vibramycin®

DRUG CLASS
Anti-Infective Agents

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH
Vibramycin® (doxycycline hyclate) Product Labeling, Pfizer Labs.

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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Doxycycline Hyclate 24390-14-5 C22-H24-N2-O8.Cl-H.1/2C2-H6-O.H2-O
Doxycycline  chemical structure

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OTHER REFERENCE LINKS
Doxycycline

 

  1. PubMed logoRecent References on Doxycycline

  2. Clinical Trials logoTrials on Doxycycline

  3. TOXLINE logoTOXLINE Citations on Doxycycline


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