What to do with elevated Alanine Transaminase (ALT) levels in a patient on clindamycin and rifampicin?

From the Guidelines

For a patient on clindamycin and rifampicin with an ALT level of 141, I strongly recommend temporarily discontinuing both medications and consulting with the prescribing physician immediately to minimize the risk of liver injury and ensure the best possible outcome in terms of morbidity, mortality, and quality of life. The patient's ALT level is approximately 2-3 times the upper limit of normal (ULN), considering the normal range for ALT is typically around 0-40 U/L. According to the guidelines for detection, assessment, and management of suspected acute drug-induced liver injury 1, discontinuation of the study drug should be considered in any one of the following conditions: (a) ALT or AST ≥8× ULN; (b) ALT or AST ≥5× ULN for more than 2 weeks; (3) ALT or AST ≥3× ULN with TBL ≥2× ULN or INR>1.5; (4) ALT or AST ≥3× ULN with symptoms such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, or rash. Although the current ALT level does not meet the criteria for immediate discontinuation based on the ULN, the guidelines suggest that in patients with elevated ALT at baseline, discontinuation rules should be determined as multiples of baseline rather than multiples of ULN 1. Given the potential for clindamycin and rifampicin to cause drug-induced liver injury, with rifampicin being more commonly associated with hepatotoxicity, it is prudent to err on the side of caution and discontinue both medications to prevent further liver damage. After stopping the medications, comprehensive liver function tests should be ordered, including AST, bilirubin, alkaline phosphatase, and GGT to assess the extent of liver dysfunction. The patient should be monitored closely with follow-up liver tests within 1-2 weeks. If ALT levels normalize after discontinuation, a careful rechallenge with alternative antibiotics may be considered based on the original indication. Rifampicin particularly affects liver enzymes through induction of cytochrome P450, which can increase the metabolism of many drugs and potentially cause hepatocellular injury 1. During this period, adequate hydration should be maintained, and alcohol and hepatotoxic medications (including acetaminophen) should be avoided. If the original infection still requires treatment, alternative antibiotics with lower hepatotoxicity profiles should be selected based on culture sensitivity results and the specific infection being treated. It is also important to note that the management of elevated ALT levels in patients on immune checkpoint inhibitors, as outlined in the guidelines for detection, assessment, and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development 1, may not be directly applicable to this scenario, as the patient is on clindamycin and rifampicin, not immune checkpoint inhibitors. However, the general principles of monitoring and managing liver injury can still be applied, and the patient's condition should be closely monitored to prevent any further liver damage.

From the FDA Drug Label

In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary However, periodic liver enzyme determinations should be made when treating patients with severe liver disease.

The management of elevated ALT levels in a patient on clindamycin and rifampicin involves:

• Monitoring liver enzyme levels periodically, especially in patients with severe liver disease
• Considering the potential interaction between clindamycin and rifampicin, as rifampicin is a strong CYP3A4 inducer that may reduce clindamycin plasma concentrations 2
• No specific dosage modification is recommended for clindamycin in patients with liver disease, but caution is advised when using clindamycin in patients with moderate to severe liver disease.

From the Research

Management of Elevated ALT Levels

If a patient's Alanine Transaminase (ALT) level increases to 141 while on clindamycin and rifampicin, the following steps can be considered:

• Monitor liver function tests regularly, as the elevation of ALT levels may indicate hepatocellular injury 3
• Investigate the cause of elevated ALT levels, which may include testing for viral hepatitis, nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and hemochromatosis 3
• Consider the potential hepatotoxic effects of clindamycin and rifampicin, although the risk is relatively low 4, 5
• Assess the patient's adherence to the prescribed treatment and clinic visits, as poor adherence may contribute to hepatotoxicity 5

Potential Hepatotoxicity of Clindamycin and Rifampicin

• Clindamycin is not commonly associated with hepatotoxicity, but it can cause liver injury in rare cases 4
• Rifampicin has been linked to hepatotoxicity, particularly in patients with baseline hepatic dysfunction 5
• The combination of clindamycin and rifampicin has been used effectively in the treatment of staphylococcal osteoarticular infections, with no reported cases of hepatotoxicity 6

Clinical Considerations

• The normal ALT level ranges from 29 to 33 IU/L in males and 19 to 25 IU/L in females 3
• Elevated ALT levels may require further investigations, including testing for viral hepatitis and other liver diseases 3
• The utility of transaminases, including ALT, is evident in the assessment of liver disease outcome and prognostic evaluation 3