The liver toxicity of this antibacterial drug is ignored by 90% of doctors!

For medical professionals only

Are penicillin-like antimicrobials hepatotoxic?

In recent years, many prospective and retrospective studies have shown that anti-infective drugs are the most important drugs causing drug-induced liver injury [1]. This is closely related to the pharmacological effect of related drugs, the patient's genotype performance and liver function, of course, this is also inseparable from the widespread use of anti-infective drugs in the clinic.

When it comes to drug-induced hepatotoxicity, everyone is familiar with macrolides, tetracycline antibacterial drugs, anti-tuberculosis drugs and antifungal drugs, but they often ignore liver damage caused by β-lactam antibacterial drugs (penicillins, cephalosporins, carbapenems).

Before opening today's reading, order the liver damage of several generations of penicillin:

Next, Jie Xiao Yao summarized the characteristics of liver damage caused by penicillin antibacterial drugs in β-lactam antibacterial drugs to reveal the answer.

The incidence of drug-induced liver injury caused by penicillin-based antibacterial drugs is not high, and most of them are specific, manifested as transient, asymptomatic, and reversible elevated liver enzymes, but in rare cases, late-onset cholestatic hepatitis can also be caused.

Natural penicillin

Representative drug: Penicillin G[2]

▌ Liver toxicity

First-generation penicillin G can cause three different forms of liver damage:

1. Long-term, high-dose parenteral penicillin can lead to a transient and asymptomatic increase in serum aminotransferase levels, which can quickly resolve after stopping treatment or switching to another antibiotic, usually without jaundice, and normal or slightly elevated alkaline phosphatase.

2. Severe hypersensitivity reactions, such as Stevens-Johnson syndrome or allergic reactions, may be accompanied by liver damage and jaundice, it is not clear whether this is hepatotoxicity caused by penicillin, or a complication of hyperthermia, shock and systemic immune reactions.

3. Specific type, delayed cholestatic hepatitis, but very rare. Presents with symptoms of nausea, abdominal discomfort, jaundice, and pruritus, usually 1 to 4 weeks after initiation of treatment, and a few days or weeks after the completion of a course of treatment. Serum enzyme results usually show cholestasis, but may be mixed or hepatocellular if tested shortly after the onset of illness.

▌ Likelihood rating

C (Possible rare cause of clinically apparent liver damage).

▌ Results & Management

Treatment with high-dose penicillin causes an asymptomatic increase in serum aminotransferase levels, usually resolves quickly after penicillin is discontinued, and these patients can tolerate another form of penicillin without relapse.

In a small number of cases of cholestatic hepatitis, the prognosis is good despite slow recovery in some cases (2-6 months). Fatal cases of penicillin-related liver injury have been reported, but are often associated with hypersensitivity or severe allergic reactions (e.g., Stevens-Johnson syndrome).

Patients with penicillin-induced specific liver injury should not be exposed to other penicillins, and cephalosporins are given only after careful monitoring.

Semi-synthetic penicillin: aminopenicillin

Representative drugs: amoxicillin[3], amoxicillin clavulanate potassium[4]

Reports of amoxicillin-induced heterogeneous liver injury are rare and characterized by short incubation periods ranging from a few days to up to two weeks. Liver damage may occur after discontinuation of antibiotics.

Serum enzymes are manifested by significant elevations of aminotransferases (ALT) and aspartate aminotransferases (AST), minimal elevations of alkaline phosphatase, and rapid recovery after discontinuation.

Cholestatic liver injury with significantly elevated alkaline phosphatase has also been reported, some of which are associated with long-term cholestasis. Episodes of liver damage may be accompanied by allergic signs or symptoms such as eosinophilia, rash, and arthralgia, and in some cases toxic epidermal necrolysis or Stevens-Johnson syndrome.

It is important to note that typical cholestatic hepatitis, which occurs in combination preparations of amoxicillin clavulanate potassium, is more common than liver damage caused by amoxicillin alone.

It is also currently the most common cause of acute liver injury specific to the United States, Europe and Australia, which is often thought to be attributed to potassium clavulanate rather than amoxicillin.

The development of liver damage in amoxicillin clavulanate potassium is delayed and is easily overlooked. The onset is usually from a few days to up to 8 weeks after the start of treatment (about 3 weeks on average), usually accompanied by fatigue, low-grade fever, nausea, and abdominal pain, followed by itching and jaundice. Serum enzymes are predominantly cholestatic, with significant increases in alkaline phosphatase and γ-glutamyl transpeptidase.

In some cases, aminotransferase levels are significantly elevated, with mixed or hepatocellular forms, especially in younger patients with earlier injury. In children, amoxicillin clavulanate potassium hepatotoxicity is usually jaundice-free and manifests as nausea, vomiting, and abdominal pain rather than jaundice and pruritus. Elevated serum enzymes are more likely to be hepatocyte-damaging, but the course is usually benign.

Amoxicillin B (a highly probable but rare cause of clinically significant liver damage).

Amoxicillin clavulanate potassium A (a clear cause of clinically apparent liver damage).

Amoxicillin-induced cholestasis in cases recovers slowly (2-6 months), but recovers.

Acute liver failure reported by induced liver injury is rare, while there are several cases of absent bile duct syndrome. Corticosteroids are often used to treat allergic manifestations of penicillin-associated immunoallergic hepatitis; although fever and rash may improve rapidly, they have not been shown to be effective in improving concomitant liver disease.

Liver damage caused by potassium amoxicillin clavulanate is usually associated with jaundice and can be severe and long-lasting (jaundice lasts 4-24 weeks), but rarely leads to sustained injury or death.

Deaths from liver damage caused by potassium amoxicillin clavulanate have been reported, but occur mainly in patients with other comorbidities (including cirrhosis) or multiple doses. Cholestamine may help relieve symptoms, but may not accelerate recovery.

Because relapse can cause relapse and cross-sensitivity to liver damage with other penicillins and cephalosporins, patients with liver injury caused by treatment with aminopenicillin should avoid other aminopenicillins and use cephalosporins with caution.

Semi-synthetic penicillin: piperacillin

Representative drugs: piperacillin[5], piperacillin tazobactam[6]

Up to 12% of patients with intravenous piperacillin may experience transient and mild to moderate elevations in serum aminotransferases, but these data are of little clinical significance.

Rare cases of specific liver injury have been reported in people treated with piperacillin, usually with cholestasis within 1-6 weeks of initiating treatment. However, once piperacillin is discontinued, it usually presents self-limiting.

Liver damage with piperacillin tazobactam is more common in patients than with piperacillin alone. Elevated alanine is seen in 6% to 15% of patients receiving piperacillin tazobactam and elevated bilirubin in 3% to 5% of patients, but resolves rapidly after discontinuation.

The risk of hepatitis caused by cholestatic hepatitis by piperacillintazobactam does not increase significantly compared with monotherapy, appears 1-3 weeks after initiation of antibiotics, usually days or weeks after discontinuation of antibiotics.

Liver injury is usually self-limiting, but severe cases of cholestatic hepatitis can lead to prolonged jaundice or a slight alkaline phosphatase elevation lasting 6 to 12 months after clinical remission.

In addition, piperacillin tazobactam has resulted in more than 12 cases of drug eruptions with eosinophilia and hypersensitivity syndrome, usually after 2-3 weeks of long-term treatment, initially with rash and fever, followed by liver or renal insufficiency or both.

Liver injury is usually mixed or cholestatic, but hepatocyte damage has also been reported. In many cases, liver damage is mild and masked by systemic symptoms and rashes.

Piperacillin, piperacillintazobactam B (known rare cause of clinically apparent liver damage).

In a small number of cases of hepatitis with piperacillin with or without tazobactam, the patient recovered within a few weeks after discontinuation of the drug. Cases of DRESS syndrome tend to last longer, usually with corticosteroids to treat manifestations of fever and rash.

Whether corticosteroids also improve liver and kidney involvement is unclear, but it generally lasts at least 6 to 8 weeks. Reapply usually results in a more severe recurrence of the injury.

Patients with piperacillin-induced hepatitis should avoid re-exposure and use other penicillins and cephalosporins with caution. The role of tazobactam in liver injury is uncertain, but it is possible to cause hypersensitivity syndrome.

summary:

Elevated liver enzymes caused by penicillin-based antibacterial drugs are generally transient, mild, and self-limiting, and cholestasis is rare, but cases have also been reported. Some liver function impairments are associated with drug hypersensitivity reactions and allergic reactions. At the same time, clinicians and pharmacists should be concerned about liver damage caused by amoxicillin clavulanate potassium.

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Resources:

[1] Bj rnsson ES. Drug-induced liver injury due to antibiotics. Scand J Gastroenterol. 2017 Jun-Jul;52(6-7):617-623.

[2] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Penicillin G and V. [Updated 2020 Oct 20].

[3] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Amoxicillin. [Updated 2020 Oct 20].

[4] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Amoxicillin-Clavulanate. [Updated 2020 Oct 20].

[5] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Piperacillin. [Updated 2020 Oct 20].

[6] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Piperacillin-Tazobactam. [Updated 2020 Oct 20].

Source: Clinical Pharmacy Channel of the Medical Community

Author: Doraemon

Editor-in-charge: Tian Dongliang

Proofreader: Zang Hengjia

Plate making: Xue Jiao