The parenterally administered cephalosporins are widely used as broad spectrum antibiotics for moderate-to-severe infections with susceptible organisms. Despite their widescale use, cases of drug induced liver disease from the cephalosporins are very rare, with only isolated case reports having been published.
Parenterally administered cephalosporins include cefazolin (Ancef: 1st generation), cefepime (Maxipime: 4th), cefoperazone (Cefobid: 3rd), cefotaxime (Claforan: 3rd), cefoxitin (Mefoxin: 2nd), ceftaroline (Teflaro: 5th), ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime: 3rd), ceftibuten (3rd), ceftizoxime (Cefizox: 3rd), ceftolozane/tazobactam (Zerbaxa: 5th), ceftriaxone (Rocephin: 3rd), cefuroxime (Zinacef: 2nd), and cephradine (1st); the latter two are also available in oral formulations. Most of these cephalosporins can be given either intravenously or intramuscularly and are indicated for therapy of moderate-to-severe bacterial infections caused by susceptible organisms. Typical dose regimens in adults range from 250 mg, 500 mg, 1 gram or 2 grams every 6 to 12 hours for 7 to 14 days. The parenteral cephalosporins are widely used in medicine for serious infections and can be safely given to patients with advanced liver disease, dose modifications being required mainly for renal insufficiency. Many of these agents are also approved for use in children.
Parenteral administration of cephalosporins can be associated with minor elevations in serum aminotransferase and alkaline phosphatase values, but these are generally mild, transient and not associated with symptoms or development of more severe liver injury. The frequency of these elevations is reported to be as high as 11%, but varies depending upon the frequency of monitoring, duration of therapy, and nature and severity of the underlying illness. Clinically apparent liver injury from parenteral cephalosporin administration is rare, and not all of the formulations have been linked to cases of liver injury. Cefazolin has been most frequently linked to cholestatic jaundice, but it is also one of the most frequently used cephalosporins. The clinical pattern of injury suggests that hepatotoxicity is largely a class effect from the cephalosporins, even though it is idiosyncratic and rare. The typical latency period is 1 to 4 weeks with an abrupt onset of liver injury. Symptoms and jaundice can arise after the course of antibiotics and typically consist of nausea, abdominal pain, pruritus and jaundice. The pattern of serum enzyme elevations is usually described as cholestatic, but mixed and hepatocellular instances have been reported. Liver injury is often accompanied by fever, rash and eosinophilia or other signs and symptoms of hypersensitivity. A history of penicillin allergy is not common, but the liver injury resembles that associated with penicillin hepatotoxicity.
Likelihood score: B (cephalosporins as a class are very likely but rare causes of clinically apparent liver injury, the association having been made largely with the most frequently used agents, such as cefazolin, cephalexin and ceftriaxone).
Mechanism of Injury
The mechanism of hepatic injury due to cephalosporins is unknown, but believed to be hypersensitivity, similar to that of other penicillins.
Outcome and Management
In most case reports, recovery has been rapid within 4 to 8 weeks, with residual injury or persistent serum enzyme elevations. Among the few cases reported, none have been fatal, although in some complicated cases the hepatic injury and cholestasis may have contributed to the mortality from the underlying illness.
References to the safety and potential hepatotoxicity of parenteral cephalosporins are provided in the introductory Overview section on Cephalosporins.
Drug Class: Antiinfective Agents, Cephalosporins
|Medication:||Cefazolin, 2 g iv at time of surgery|
|Pattern:||Mixed → cholestatic (R=2.2→0.9)|
|Severity:||3+ (jaundice and hospitalization)|
|Recovery:||Complete 8 weeks|
|Other medications:||Chronically, salbutamol and ibuprofen, perioperatively nitrous oxide, fentanyl, propofol, midazolam, dramamine, acetaminophen with codeine|
|Time After Starting||Time After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|Orthopedic surgery under nitrous oxide and propofol, and iv cefazolin (2 g)|
|7 days||6 days||194||309||5.7||10% eosinophils|
|8 days||7 days||192||240||5.3|
|11 days||10 days||193||358||4.4|
|2 weeks||13 days||116||385||4.3|
|3 weeks||20 days||92||373||2.9|
|4 weeks||27 days||92||293||1.4|
|2 months||2 months||62||97||0.8||No symptoms|
|8 months||8 months||20||60||0.6|
|DRUG||CAS REGISTRY NO||MOLECULAR FORMULA||STRUCTURE|