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DRUG RECORD

 

MEROPENEM

OVERVIEW
Meropenem

 

Meropenem is a carbapenem antibiotic with broad spectrum of activity that is administered intravenously and used for severe bacterial infections due to sensitive agents. Meropenem is a common cause of mild transient aminotransferase elevations and can rarely result in clinically apparent, cholestatic liver injury.

 

Background

Meropenem (mer" oh pen' em) is a broad-spectrum, beta lactam carbapenem antibiotic that acts by binding to the penicillin binding proteins and disrupting bacterial cell wall integrity and synthesis. Meropenem has a broad spectrum of activity against many aerobic and anaerobic gram-positive and gram-negative organisms, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis and Peptostreptococcus species.   Meropenem was approved for use in the United States in 1996 and is currently indicated for the treatment of severe or complicated skin, tissue, intra-abdominal and urogenital infections as well as sepsis due to susceptible organisms. Its use is generally reserved for severe infections in hospitalized patients.  The recommended dosage is 0.5 to 1 gram given intravenously every 8 hours with dose adjustment for renal impairment. Meropenem is available in vials of 500 mg or 1 gram of lyophilized powder for injection in generic forms and under the brand name Merrem. The most common side effects are diarrhea, nausea and vomiting, skin rash and pruritus.

 

Hepatotoxicity

Serum aminotransferase elevations have been reported in 1 to 6% of recipients of intravenous meropenem when given for up to 14 days. These elevations are usually transient, mild and asymptomatic; and rarely require dose adjustment.   Meropenem has also been linked to rare cases of cholestatic jaundice that usually arises after 1 to 3 weeks of therapy.  Immunoallergic features may be present but are rarely prominent.  Autoantibodies are rare.  Most cases are mild and self-limited, but at least one instance of vanishing bile duct syndrome related to meropenem therapy has been published (Case 1).  Meropenem has not been reported to cause acute liver failure.

 

Mechanism of Liver Injury

The cause of the mild, transient serum enzyme elevations during meropenem therapy is not know.  The cholestatic hepatitis attributed to the carbapenems is probably immunoallergic and resembles the rare clinically apparent liver injury that has been linked to penicillins and cephalosporins. 


Outcome and Management

The liver injury due to the meropenem is usually mild and self-limited.  Rarely, meropenem and other carbapenems can cause a clinically apparent and protracted cholestatic hepatitis that is usually self-limiting but can lead to vanishing bile duct syndrome.  In patients with vanishing bile duct syndrome, corticosteroids are often used but have not been shown to be beneficial and are best avoided.  Some patients may benefit from symptomatic therapy of the pruritus associated with cholestasis using antihistamines, ursodiol or cholestyramine.  There is little information on possible cross-sensitivity to liver injury among the different betalactam antibiotics, but patients with clinically apparent liver injury due to meropenem should probably avoid re-exposure as well as other carbapenems.

 

Drug Class: Carbapenems

Other drugs within this class: Ertapenem, Imipenem

 

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CASE REPORT
Meropenem

Case 1. Cholestatic hepatitis and vanishing bile duct syndrome due to meropenem
(Modified from: Schumaker AL, Okulicz JF. Meropenem-induced vanishing bile duct syndrome. Pharmacotherapy 2010; 30: 335e-338e. PubMed Citation)
.

 

A 60 year old woman developed jaundice and pruritus 3 weeks after starting treatment with intravenous meropenem (1 gm twice daily) for a brain abscess .  Her medical history included type 2 diabetes, diabetic neprhopathy, hypertension and hyperlipidemia for which she was taking glipizide (5 mg daily), atorvastatin (40 mg daily), telmistartan (80 mg daily), and calcium acetate (667 mg thrice daily) long term.  Two months before presentation with jaundice she developed a brain abscess thought to be a complication of otitis media.  Cultures were negative and she was initially treated with ceftriaxone and metronidazole.  Levetiracetam (250 mg twice daily) was started for control of seizures.  Because of antibiotic induced leukopenia, her antibiotic regimen was changed to merepenem which was continued for 3 weeks and discontinued promptly when she developed jaundice.  At that time, examination revealed jaundice, but no fever, rash, lymphadenopathy, splenomegaly or hepatomegaly. Laboratory results showed a serum bilirubin of 11.2 mg/dL (direct 9.9 mg/dL), ALT 83 U/L, AST 238 U/L, alkaline phosphatase 1467 U/L and GGT 230 U/L.  These values had been normal before she started meropenem (Table).  The prothrombin time was 15.6 seconds and blood counts were normal.  Serum creatinine was mildly elevated but stable (2.4 mg/dL).  Tests for hepatitis B and C were negative as were routine autoantibodies.  Abdominal ultrasound followed by ERCP showed no abnormalities of the gallbladder or bile ducts.  A liver biopsy showed marked cholestasis, mild inflammation and paucity of bile ducts in portal areas.  She was treated with ursodiol and followed without other specific therapy.  Her liver tests gradually improved, but she was still jaundiced 5 months later. 

 

Key Points

 

Medication:

Meropenem

Pattern:

Cholestatic (R = 0.2)

Severity:

4+ (Prolonged Jaundice)

Latency:

3 weeks

Recovery:

Incomplete at 5 months

Other medications:

Glipizide, atorvastatin, telmistartan, calcium, ceftriaxone, metronidazole, levetiracetam

Time After Starting

Time After Stopping

ALT* (U/L)

Alk P* (U/L)

Bilirubin* (mg/dL)

Other

Pre   25 100 0.5
0   25 100 0.5 Meropenem started
1 week   25 100 0.5
3 weeks 0 83 1320 11.2 Meropenem stopped
4 weeks 1 week 180 1467 16 ERCP
5 weeks 2 weeks 130 1350 22 Liver biopsy
6 weeks 3 weeks 110 1020 27
7 weeks 4 weeks 90 625 22
8 weeks 5 weeks 100 500 23
10 weeks 7 weeks 90 320 19
14 weeks 11 weeks 50 400 13
18 weeks 15 weeks 30 280 11
19 weeks 16 weeks 50 250 8

Normal Values

<40

<148

<1.2

* Values estimated from Figure 1

 

Comment

While the carbapenems can commonly cause asymptomatic serum enzyme elevations, clinically apparent liver injury from their use is quite rare.  The few case reports in the literature suggest that the carbapenems cause a cholestatic hepatitis much like occurs with the penicillins and cephalosporins with a latency of 1 to 3 weeks and a mild, self-limiting course.  The current report, however, demonstrates that severe cholestatic liver injury can result in bile duct damage and loss and, if sufficiently severe, can lead to prolonged cholestasis and jaundice and even end-stage liver disease. While penicillin- and carbapenem-induced cholestatic liver injury is believed to be immunologically mediated, patients do not always have immunoallergic features, such as rash, fever, facial edema and eosinophilia. 

 

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PRODUCT INFORMATION
Meropenem

 

REPRESENTATIVE TRADE NAMES
Merrem®


DRUG CLASS
Anti-Infective Agents

 

COMPLETE LABELING

FDA Product labeling at DailyMed, National Library of Medicine, NIH
Merrem® (meropenem) Injection Product Labeling, AstraZeneca Pharmaceuticals.


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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Meropenem 119478-56-7 C17-H25-N3-O5-S.H2-O Meropenem  chemical structure

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  1. PubMed logoRecent References on Meropenem

  2. Clinical Trials logoTrials on Meropenem

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