Cephalosporin caused by drug liver damage, these 5 points you have to know!

For medical professionals only

Introduction to hepatotoxicity caused by the β-lactam family

Written by | Doraemon

Source | Clinical Pharmacy Channel of the Medical Community

In this period, we will look at the characteristics of hepatotoxicity caused by β-lactam family and other two major categories in the family of cephalosporins and carbapenem antibacterial drugs.

Cephalosporins

Cephalosporins are similar to penicillin adverse reactions, commonly drug allergies and hypersensitivity reactions.

In general, cephalosporins have little hepatotoxicity, with only rare cases of liver damage caused by such drugs being reported and varying from case to case.

Typical cases of liver injury caused by cephalosporins are a type of self-limiting cholestatic hepatitis with mild immune allergic features 1-3 weeks after the start of treatment, sometimes after a single parenteral administration.

In cephalosporins, ceftriaxone is a special case, and when administered extraintestinally, cholestasis may occur with symptoms of cholecystitis and cholestatic jaundice.

Therefore, in addition to ceftriaxone, cephalosporins are often discussed as a large class.

Cephalosporins other than ceftriaxone[1-2]

1. Hepatotoxicity

With cephalosporins, serum aminotransferase and alkaline phosphatase values may be slightly elevated, but these are usually mild and transient.

Clinically apparent liver injury is rare, only individual case reports have been published, and not all preparations have been associated with cases of liver injury.

Typical cases have an incubation period of 1 to 4 weeks, and symptoms develop after antibiotics, usually including nausea, abdominal pain, itching, and jaundice.

Elevated serum enzymes are predominantly cholestasis, but mixed and hepatocellular cases have been reported. Liver injury is often accompanied by fever, rash, and eosinophilia or other allergic signs and symptoms.

The course of the disease is usually self-limiting and the mortality rate is low.

2. Likelihood score

B (Cephalosporins are likely to be a rare cause of clinically apparent liver damage, mainly associated with the most commonly used drugs, such as cefazoline and cefotaxin).

3. Results and management

In most case reports, recovering quickly within 4 to 8 weeks, the presence of cross-sensitivity to liver damage due to cephalosporins is unclear.

In many published cases, patients switch to another cephalosporin does not cause damage again, but switching to another class of drugs other than cephalosporins is still recommended.

Similarly, patients with a history of penicillin allergy have a higher incidence of hypersensitivity to cephalosporins and should be avoided or used under careful monitoring.

Ceftriaxone[3]

Ceftriaxone is given parenterally, and sediment-like stones occur in about 3% to 46% of patients.

The incidence in children may be higher than in adults and is associated with higher doses and longer courses of treatment and may be associated with fasting or dehydration.

The syndrome is called "pseudolithiasis", the main component of the stone is ceftriaxone calcium, after discontinuation of the drug will resolve spontaneously, generally do not require surgical intervention, most cases asymptomatic.

Usually, serum enzyme and bilirubin levels remain normal even if they develop biliary colic, but in rare cases, severe cholestatic jaundice or cholelithic pancreatitis may occur and require surgical intervention.

Symptoms of sludge in the gallbladder and gallbladder disease may appear within a few days after initiation of treatment, usually resolve rapidly after ceftriaxone is stopped, and there are also cases of bile mud and gallstones that can be detected by ultrasound within a few months.

Ceftriaxone can also cause immunoallergic cholestatic hepatitis, a manifestation consistent with other cephalosporins, but very rarely.

Symptoms of abdominal pain, nausea, itching, and jaundice appear within 1 to 4 weeks of initiation of treatment and may worsen by 1 to 2 weeks after discontinuation of antibiotics.

Elevated serum enzymes are predominantly cholestasis, and clinical symptoms are common as immune allergic features of fever, rash, and eosinophilia. Injuries are usually mild and self-limiting.

B (Ceftriaxone is most likely the cause of clinically apparent liver damage, as well as the appearance of ceftriaxone calcium in the gallbladder or bile duct tree, bile mud and "pseudolithia" caused by crystallization in the bile).

In most case reports, recovery is rapid within 1-2 weeks, but some patients require cholecystectomy during acute illness, and stones or bile mud may last for up to several months.

Immune allergic forms of cholestatic hepatitis usually resolve rapidly and are not associated with acute liver failure or chronic injury.

Carbapenems——

Imipenem, Meropenem[4-5]

Most carbapenems have been reported to cause transient, mild to moderate, and asymptomatic elevations in serum aminotransferase levels, although this increase resolves quickly once treatment is stopped.

In addition, the development of cholestatic liver injury during or shortly after treatment with carbapenems has been rarely reported, usually in patients with multiple other medical problems and other causes of liver disease (parenteral nutrition, sepsis).

Carbapenems are mainly excreted from the urine in their prototype form, and the liver metabolism is minimal, so it is rare to cause severe hepatotoxicity.

In large clinical trials, about 6% of patients experienced a transient and asymptomatic increase in serum transaminases levels after 5-14 days of imipenem application.

However, there are generally no clinical symptoms and no dose adjustment is required. Cholestatic jaundice has also been reported during or shortly after treatment, with an incubation period of 1 to 3 weeks, and the serum enzyme is usually elevated in the form of cholestasis.

It has been reported that after receiving intravenous meropenem for up to 14 days, 1% to 6% of recipients had elevated serum aminotransferases. These elevations are usually transient, mild, and asymptomatic, and dose adjustment is rarely required.

Meropenem has also been linked to rare cholestatic jaundice, which usually appears after 1-3 weeks of treatment.

Carbapenems may present with immune allergy features, but autoantibodies are rare. Imipenem and meropenem have been reported to cause bile duct disappearance syndrome, and there have been no reports of acute liver failure caused by imipenem and meropenem.

Imipenem, meropenem D (possible rare cause of clinically apparent liver injury).

Liver damage caused by carbapenems is usually mild and self-limiting. Cholestatic hepatitis, which can be caused by carbapenems, is also usually self-limiting and does not require treatment or intervention.

In patients with absent bile duct syndrome, corticosteroids are often used but have not been shown to be beneficial and are best avoided. Some patients may benefit from the symptomatic treatment of antihistamines, cholestamines, and pruritus associated with cholestasis.

There is little information about the cross-sensitivity that different β-lactam antibiotics may have for liver injury, but patients with one carbapenem causing clinically significant liver damage should avoid other carbapenems.

summary

Although the incidence of cyclolide antibacterial drugs, antituberculous drugs, and azole antifungal drugs caused by liver damage caused by β-lactam antibacterial drugs is low, the rare hepatotoxicity cannot be ignored.

Clinical practice should standardize the use of antibacterial drugs, strengthen the monitoring of liver and kidney function of patients, and ensure the safety of medication.

bibliography:

[1] LiverTox:Clinical and Research Information on Drug-Induced Liver Injury[Internet]. Bethesda(MD):National Institute of Diabetes and Digestive and Kidney Diseases;2012-. Cephalosporins,Oral. [Updated 2021 Dec 20].

Available from:https://www.ncbi.nlm.nih.gov/books/NBK548358/

[2] LiverTox:Clinical and Research Information on Drug-Induced Liver Injury[Internet]. Bethesda(MD):National Institute of Diabetes and Digestive and Kidney Diseases;2012-. Cephalosporins,Parenteral. [Updated 2021 Dec 20].

Available from:https://www.ncbi.nlm.nih.gov/books/NBK547862/

[3] LiverTox:Clinical and Research Information on Drug-Induced Liver Injury[Internet]. Bethesda(MD):National Institute of Diabetes and Digestive and Kidney Diseases;2012-. Ceftriaxone. [Updated 2021 Dec 20].

Available from:https://www.ncbi.nlm.nih.gov/books/NBK548258/

[4] LiverTox:Clinical and Research Information on Drug-Induced Liver Injury[Internet]. Bethesda(MD):National Institute of Diabetes and Digestive and Kidney Diseases;2012-. Imipenem-Cilastatin. [Updated 2017 Jan 17].

Available from:https://www.ncbi.nlm.nih.gov/books/NBK548708/

[5] LiverTox:Clinical and Research Information on Drug-Induced Liver Injury[Internet]. Bethesda(MD):National Institute of Diabetes and Digestive and Kidney Diseases;2012-. Meropenem. [Updated 2017 Jan 17].

Available from:https://www.ncbi.nlm.nih.gov/books/NBK547861/

Source: Clinical Pharmacy Channel of the Medical Community

Author: Doraemon

Editor-in-charge: Tian Dongliang

Proofreader: Zang Hengjia

Plate making: Xue Jiao