Introduction

Omadacycline is an oral, tetracycline-like antibiotic used to treat moderate-to-severe infections including community-acquired pneumonia and acute bacterial skin and skin structure infections caused by susceptible organisms. Oral omadacycline use has been associated with serum enzyme elevations during therapy but has not been implicated in cases of clinically apparent acute liver injury.

Background

Omadacycline (oh mad" a sye' kleen) is an oral, broad spectrum tetracycline like antibiotic with potent activity against both aerobic and anaerobic gram-positive and gram-negative organisms. Omadacyline is a semisynthetic derivative of minocycline that is classified as an aminomethylcycline. It has a broader spectrum of activity than standard tetracyclines including activity against tetracycline-resistant organisms and methicillin resistant Staphylococcus aureus (MRSA). Omadacyline also has excellent oral absorption and both intravenous and oral preparations have been developed. In multiple clinical trials, omadacycline was found to be effective in community acquired pneumonia and serious acute skin and skin structure associated infections (cellulitis, abscess, deep tissue infections). The tetracyclines act by inhibition of protein synthesis by binding to the 30S subunit of microbial ribosomes. Human cells are less susceptible to this inhibition. Omadacycline was approved for use in community acquired pneumonia and skin and skin structure infections in 2018. It is available as 100 mg of lyophilized power in single dose vials for reconstitution and intravenous use as well as 150 mg tablets for oral use under the brand name Nuzyra. Omadacycline is generally given as a loading dose initially, followed by a daily intravenous or oral maintenance dose for a total of 7 to 14 days. Side effects of omadacycline include gastrointestinal upset, nausea and diarrhea, and more rarely, rash and hypersensitivity reactions. Tetracyclines can cause vertigo and tinnitus, skin photosensitivity reactions, and staining of developing teeth (in children or when taken by a pregnant mother) for which reason the tetracyclines should not be used in pregnant women or in children below the age of nine.

Hepatotoxicity

In clinical trials of omadacycline usually conducted in critically ill patients with major infections, serum aminotransferase elevations arose in 4% of patients and to above 5 times ULN in 1.5%. Nevertheless, the abnormalities were generally transient and asymptomatic and were no more frequent than with comparator antibiotic treated subjects. Nevertheless, other tetracycline antibiotics are well known causes of drug induced liver injury. In particular, high doses of intravenous tetracycline are known to cause severe hepatic microvesicular steatosis with lactic acidosis and severe hepatic dysfunction (LASH syndrome) for which reason intravenous tetracycline has been withdrawn from use. This complication has not been reported with intravenous omadacycline, eravacycline or tigecycline. The tetracyclines have also been linked to idiosyncratic liver injury with autoimmune features that generally arise with long term use and has most commonly been associated with minocycline. This complication also has not been reported with omadacycline, eravacycline or tigecycline.

Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which omadacycline might cause liver injury is unknown. Omadacycline is not metabolized in the liver to an appreciable extent which may explain its relative lack of hepatotoxicity. It does not appear to interact with cytochrome P450 enzymes and has not been reported to cause significant drug-drug interactions.

Outcome and Management

Patients on intravenous omadacycline who develop serum aminotransferase elevations that rise above 5 times the upper limit of normal or are accompanied by jaundice or symptoms should have omadacycline discontinued. Whether there is cross sensitivity to hepatic injury among the various tetracyclines is not known but switching to another class of antibiotics would be more appropriate than changing to another tetracycline-like agent in patients who develop significant hepatic injury while receiving omadacycline.

Drug Class: Antiinfective Agents, Tetracyclines