Publication Details



Piperacillin is parenterally administered, extended-spectrum ureidopenicillin which, when combined with the beta-lactamase inhibitor tazobactam, is used to treat moderate-to-severe infectious due to susceptible organisms including lactamase producing penicillin-resistant bacteria. Piperacillin-tazobactam has been linked with idiosyncratic liver injury, including cases of DRESS and cholestatic liver injury that can be prolonged and even fatal.


Piperacillin-tazobactam is the combination of a fourth generation, extended-spectrum penicillin and a beta-lactamase inhibitor that is used for moderate-to-severe infections caused by susceptible agents, such as (but not limited to) Escherichia coli, many Bacteroides and Klebsiella species, Staphylococcus aureus, and Hemophilus influenzae. The combination of piperacillin with tazobactam provides broad activity against beta-lactamase producing penicillin-resistant bacterial species. This combination was approved for use in the United States in 1985 and is generally reserved for severe infections requiring parenteral therapy. Piperacillin-tazobactam is available in parenteral form for intravenous use in generic forms and under the trade name Zosyn. Recommended doses are 3 to 4.5 grams of piperacillin with 0.375 to 0.5 grams of tazobactam every 6 to 8 hours for 7 to 14 days. Common side effects include headache, dizziness, nausea, diarrhea, constipation, skin rash and hypersensitivity reactions. Rare but potentially severe adverse events include anaphylactic and hypersensitivity reactions, Stevens Johnson syndrome and toxic epidermal necrolysis.


In large clinical trials, ALT elevations were reported in 6% to 15% and bilirubin elevations in 3% to 5% of patients receiving piperacillin-tazobactam, with considerably lower rates in patients receiving comparator antibiotics (such as imipenim-cilastatin) and lower rates reported with piperacillin alone. These abnormalities were reported to resolve quickly with stopping therapy. Rare instances of idiosyncratic liver injury have been reported in persons receiving the piperacillin without tazobactam and a similar pattern of injury has been reported with the combination. The injury is typically cholestatic or mixed and arises 1 to 3 weeks after starting and often days or weeks after stopping the antibiotic. The liver injury is usually self-limited but severe cases of cholestatic hepatitis can lead to prolonged jaundice or persistence of minor alkaline phosphatase elevations for 6 to 12 months after clinical resolution. Immunoallergic features may be present but are generally mild.

In addition, the combination of piperacillin and tazobactam has been implicated in more than a dozen cases of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, usually arising after 2 to 3 weeks of long term therapy initially with rash and fever followed by liver or renal dysfunction or both. The liver injury is usually mixed or cholestatic but hepatocellular instances have also been reported. In many cases the liver injury is mild and overshadowed by the systemic symptoms and rash. Piperacillin-tazobactam has also been linked to instances of Stevens Johnson syndrome, although in most cases, other drugs known to be associated with the syndrome were being taken. These forms of hypersensitivity with liver involvement have not been reported with piperacillin alone. Because piperacillin-tazobactam is used for serious infections, patients are often taking multiple medications including other antibiotics such as vancomycin, azithromycin or ciprofloxacin, making the causality assessment challenging.

Likelihood score: B (likely rare cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the liver injury associated with piperacillin use is probably hypersensitivity or allergy. Cases of reoccurrence on reexposure have been reported. The role of tazobactam in the injury is uncertain, but it appears to be important in cases of DRESS syndrome.

Outcome and Management

In the few cases of delayed cholestatic hepatitis that have been described with piperacillin with or without tazobactam, patients have recovered within a few weeks of stopping. Cases with DRESS syndrome tend to be more prolonged and are usually treated with corticosteroids for the manifestations of fever and rash. Whether corticosteroids also improve the liver and renal involvement is not clear, but they are generally continued for at least 6 to 8 weeks. Rechallenge is usually followed by recurrence of injury which can be more severe. Patients with piperacillin induced hepatitis should avoid reexposure and should take other penicillins and cephalosporins with caution.

Drug Class: Antiinfective Agents, Penicillins (Fourth Generation)

Other Drugs in the Class: Piperacillin, Ticarcillin, Ticarcillin-Clavulanate



Piperacillin-Tazobactam – Generic, Zosyn®


Antiinfective Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 20 October 2020

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