Fosfomycin is an orally available, broad spectrum antibiotic used largely for treatment of uncomplicated urinary tract infections. Fosfomycin is associated with a low rate of transient serum enzyme during therapy and with rare cases of clinically apparent acute liver injury with jaundice.
Fosfomycin (fos' foe mye. sin) is an oral, broad spectrum bactericidal antibiotic that is typically used as a single, large oral dose to treat acute cystitis. Fosfomycin (also known as phosphomycin) is a natural product of Streptomyces fradiae that acts by inactivation of a bacterial enzyme necessary for cell wall synthesis. Fosfomycin has a unique structure (an analogue of phosphoenolpyruvate) and is structurally unrelated to other antibiotics. It has activity against both gram-positive and gram-negative bacteria and is excreted largely unchanged and in its active form in the urine, making it useful for treatment of urinary tract infections. Antibacterial resistance is, however, frequent with prolonged use. Fosfomycin was approved for use in the United States in 1997 and current indications are for uncomplicated urinary tract infections caused by susceptible organisms. Fosfomycin is available under the commercial name Monurol in a sachet of 3 grams and is recommended as a single dose. Intravenous formulations of fosfomycin have been used in combination with carbapenems or aminoglycosides as therapy of multidrug resistant bacterial organisms such as methicillin-resistant Staphyloccocus aureus (MRSA), but it has yet to be approved for this use in the United States. The intravenous formulation is generally given in 1 to 2 gram amounts every 6 hours for 3 to 28 days. Oral fosfomycin is well tolerated; common side effects may include diarrhea, nausea, headache and fungal vaginitis. Rare, but potentially serious adverse events include allergic reactions, anaphylaxis and toxic megacolon.
Serum aminotransferase elevations occur in a small proportion of patients after a single oral dose of fosfomycin (1-2%), but at rates similar to those with comparator antibiotics. Nevertheless, serum enzyme elevations are mentioned as potential adverse events in the product label for fosfomycin. In addition, a small number of cases of clinically apparent liver injury attributed to fosfomycin have been published. The time to onset has been short, within one week of a single oral dose or within the first week of intravenous therapy, and the pattern of liver enzyme elevations has been mixed or hepatocellular. The injury has typically been mild and self-limited, and no cases of fatal acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been convincingly linked to fosfomycin. The number of cases described has been too few to establish a typical clinical pattern, but immunoallergic features and autoimmune markers appear to be uncommon.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
The cause of the liver injury due to fosfomycin is unknown, but is likely to be immunologically mediated. Fosfomycin has minimal hepatic metabolism (mostly glucuronidation), and drug-drug interactions with it are not expected.
Outcome and Management
The severity of the liver injury linked to fosfomycin has ranged from transient, asymptomatic serum enzyme elevations to clinically apparent hepatitis. Severe but not fatal instances of acute hepatitis have been reported. In one publication, reexposure to fosfomycin after clinically apparent liver injury led to a rapid recurrence. Fosfomycin has a unique chemical structure unlike other antibiotics, and there is evidence for cross sensitivity to hepatic injury between fosfomycin and other antimicrobial agents.
Case 1. Acute hepatitis attributed to fosfomycin.
[Modified from: Matsumori A, Yoneda S, Kobayashi Y, Takeda K, Andoh M, Yamane Y, Nishimura K, et al. [A case of acute severe hepatitis induced by fosfomycin]. Nihon Shokakibyo Gakkai Zasshi 2005; 102: 1207-11. Japanese. PubMed Citation]
A 30 year old, previously healthy man with an upper respiratory infection developed fever, fatigue, and jaundice a few days after a single, oral dose of fosfomycin. He had no history of liver disease, alcohol abuse or drug allergies. He was not taking other medications except for cold remedies. He had fever, but no rash or lymphadenopathy. Laboratory tests showed a total bilirubin of 6.5 mg/dL (direct 3.5 mg/dL), ALT 558 U/L, AST 442 U/L, alkaline phosphatase 649 U/L, GGT 192 U/L and a prothrombin index of 44% (roughly equivalent to an INR of 1.7). He was admitted for observation and management (Table). Tests for hepatitis A, B and C were negative as were tests for CMV and EBV infection. ANA and AMA were negative and IgG levels were minimally elevated (1714 mg/dL). An abdominal ultrasound and enhanced CT showed evidence of severe liver necrosis with atrophy. Within the next few days, he developed asterixis with a worsening of prothrombin time and hyperammonemia (112
μg/dL). He was treated with plasma exchange given infusions of glucagon and insulin, whereupon he began to improve. A liver biopsy done 6 weeks after presentation showed spotty necrosis, inflammation and regeneration. He was discharged after 42 days in the hospital. All laboratory tests were normal when he was seen in follow up, 4 months after onset.
||Fosfomycin, single oral dose
|| Mixed (R=~2.8)|
||4+ (jaundice, hospitalization and features of hepatic failure)
||Within 4 months
|Other medications:||Over-the-counter cold remedies|
|Time After Starting/Stopping
|6 days||540||40%||6.5||Plasma exchange|
|8 days||480||35%||6.4||Plasma exchange|
|11 days||220||30%||3.5||Plasma exchange|
|42 days||50||80%||1.2||Liver biopsy, discharged|
*Values estimated from Figure 3.
A young man developed a severe hepatitis a few days after receipt of a single, large oral dose of fosfomycin for a suspected upper respiratory infection. The pattern of liver enzyme elevations was "mixed", but the course resembled acute liver failure. Other causes of liver disease were adequately ruled out, although tests for hepatitis E and a few rare opportunistic viral infections were not done. Evidence of hepatic failure included prolongation of prothrombin time, hyperammonemia, asterixis and CT and ultrasound evidence of severe hepatic necrosis. The few other reported cases of clinically apparent liver injury from fosfomycin have been self-limited, with mild jaundice and a hepatocellular pattern of serum enzyme elevations. Fosfomycin has been used extensively abroad, in Europe and Asia, but has had limited use in the United States. As might be expected, cases of drug induced liver injury from fosfomycin have been reported from Japan, China and Europe, but not the United States. [Help in the translation of this case report was kindly provided by Dr. Saturo Saito.]
REPRESENTATIVE TRADE NAMES
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 06 February 2018
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