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Published: September 2012

Antibiotics and Liver Injury - Be Suspicious!

Prescriber Update 33(3): 26–27
September 2012

Prescribers are advised to be aware of the risk of liver injury associated with antibiotic treatment. Early recognition is essential as withdrawal of the causative antibiotic is the most effective treatment1. Specialist advice should be sought in all cases of severe liver injury and in patients who fail to improve despite withdrawal of the antibiotic.

Drug-induced liver injury

Drug-induced liver injury (DILI) can be classified as hepatocellular, cholestatic or mixed depending on the specific liver function test abnormalities that occur. DILI has an estimated incidence of 1 in 10,000 to 1 in 100,000. As with other liver diseases, DILI can present with jaundice, malaise, abdominal pain, unexplained nausea and anorexia. There are no specific signs, symptoms or tests that can confirm a diagnosis of DILI.

Antibiotic-associated DILI

Antibiotics are a common cause of DILI, probably because of the high rate of exposure in the community. Most cases are idiosyncratic and are therefore rare, unpredictable (from the pharmacology of the antibiotic) and largely dose-independent1, 2. The characteristics of DILI associated with specific antibiotics are summarised below (Table 1).

Table 1: Estimated frequency and characteristics of DILI associated with selected antibiotics2

Antibiotic Incidence and liver injury Onset Time to recovery
Flucloxacillin 1.8-3.6 per 100,000 prescriptions
Cholestatic
Can be early (1-9 weeks after starting) or delayed after treatment has stopped Usually within 12 weeks of stopping. 30% have a protracted course
Amoxicillin/
Clavulanic acid
1-17 per 100,000 prescriptions
Hepatocellular, cholestatic or mixed
Within 4 weeks of starting but typically after stopping Within 16 weeks of stopping therapy
Ceftriaxone Up to 25% adults and 40% children develop cholelithiasis After 9-11 days of treatment Within 2-3 weeks of stopping
Erythromycin < 4 cases per 100,000 prescriptions
Cholestatic
Within 10-20 days of starting Within 8 weeks of stopping
(Trimethoprim/
Sulfamethoxazole)
Cotrimoxazole
< 2 per 10,000 prescriptions
Cholestatic or mixed
Unknown Within a few weeks of stopping
Doxycycline < 1 per 18 million daily doses
Cholestatic
Long latency of over 1 year Variable. Most recover on stopping
Ciprofloxacin Isolated cases only
Hepatocellular and cholestatic
Unknown Unknown


Risk factors

Genetic variability is considered to be the most important risk factor, although specific genetic markers have not yet been elucidated for most antibiotics1. Other potential risk factors include1:

An important exception are tetracyclines, where high doses seem to be a predictor of liver injury2.

Diagnosis and treatment

Diagnosis requires a temporal association with antibiotic use and exclusion of other causes of acute liver injury (eg, alcohol, viral hepatitis, autoimmune liver disease, metabolic liver disease, ischaemic hepatitis and extra-hepatic biliary obstruction)3. The pattern of liver injury may also aid diagnosis (Table 1).

Treatment consists primarily of withdrawal of the causative antibiotic and supportive care if required. Most cases are mild and self-limiting1. However, rare cases of acute liver failure and death have been reported1. Chronic liver disease is a very rare complication but is more likely to develop if the antibiotic is continued despite evidence of liver injury.

New Zealand case reports

The Centre for Adverse Reactions Monitoring (CARM) has received a total of 360 reports of liver injury associated with the use of non-tuberculosis antibiotics since January 2000. Most reports were in adults aged over 50 years (71%), with 13 reports in patients aged less than 20 years. Seven reports (2%) involved a fatality.

The majority of CARM reports of liver injury were associated with β-lactam penicillins (Figure 1). Amoxicillin/clavulanic acid, flucloxacillin and erythromycin were the antibiotics most often implicated in the development of liver injury in New Zealand.

Figure 1

Figure 1: Classes of non-tuberculosis antibiotics associated with liver injury in New Zealand

Key Messages

  • Antibiotics are a common cause of drug-induced liver injury.
  • Most cases of antibiotic-induced liver injury are idiosyncratic, unpredictable and largely dose-independent.
  • In New Zealand, the antibiotics most often implicated with liver injury are amoxicillin/clavulanic acid, flucloxacillin and erythromycin.
  • Withdrawal of the causative antibiotic is the most effective treatment.
References
  1. Polson JE. 2007. Hepatotoxicity due to antibiotics. Clinics in Liver Disease 11: 549-61, vi.
  2. Andrade RJ, Tulkens PM. 2011. Hepatic safety of antibiotics used in primary care. Journal of Antimicrobial Chemotherapy 66: 1431-46.
  3. Hussaini SH, Farrington EA. 2007. Idiosyncratic drug-induced liver injury: an overview. Expert Opinion on Drug Safety 6: 673-84.

 

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