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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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Doxycycline

Last Update: January 23, 2019.

OVERVIEW

Introduction

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.

Likelihood score: B (highly likely but rare 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. The injury is similar to what has been described much more frequency with minocycline which has been linked to HLA-B*35:01, although only in a minority of cases.

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.

Drug Class: Antiinfective Agents, Tetracyclines

CASE REPORT

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 StartingTime After StoppingALT* (U/L)Alk P* (U/L)Bilirubin* (mg/dL)Other
Doxycycline given for 8 days for suspected pneumonia
1 day0NANANARash and nausea
8 days01731304.4Doxycycline stopped
11 days3 days1941125.0Negative viral markers
36 days28 days4311048.1
53 days45 days442917.1Liver biopsy
56 days48 days4741047.2
2 months2 months7431004.6
3 months3 months388873.1
4 months4 months32610.8
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.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Doxycycline – Generic, Monodox®, Vibramycin®

DRUG CLASS

Antiinfective Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Doxycycline Monohydrate17086-28-1C22-H24-N2-O8.H2-O
2D chemical structure of 17086-28-1

ANNOTATED BIBLIOGRAPHY

References updated: 23 January 2019

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    (29 year old African American man developed jaundice 14 days after starting bupropion and doxycycline [bilirubin 19.9 mg/dL, ALT 888 U/L, Alk P 234 U/L, INR 3.0, eosinophils 5%] with resolution within 2 months on prednisone, the authors suggesting that bupropion was the most likely cause).
  • Urban TJ, Nicoletti P, Chalasani N, Serrano J, Stolz A, Daly AK, Aithal GP, et al; Drug-Induced Liver Injury Network (DILIN); Pharmacogenetics of Drug-Induced Liver Injury group (DILIGEN); International Serious Adverse Events Consortium (iSAEC). Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗35:02 as a risk factor. J Hepatol 2017; 67: 137-44. [PMC free article: PMC5634615] [PubMed: 28323125]
    (The uncommon HLA allele B*35:02 was found in 4 of 25 [16%] of patients with minocycline hepatotoxicity vs 0.6% in a population control group; those with and without this allele did not different in clinical features or outcome).

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