Does Zosyn (piperacillin and tazobactam) cause side effects?

Zosyn (piperacillin and tazobactam) is an injectable combination of two antibiotics with broad spectrum activity used to treat a variety of bacterial infections, including pneumonia, appendicitis, pelvic inflammatory disease, E. coli infection, cellulitis, and postpartum endometriosis.

Piperacillin is an extended-spectrum penicillin antibiotic, but it can be destroyed by an enzyme produced by bacteria called beta lactamase. Tazobactam inhibits beta lactamase and prevents the destruction of piperacillin so it is given with piperacillin to enhance the activity of piperacillin in eradicating bacterial infections.

Piperacillin kills bacteria by inhibiting the synthesis of bacterial cell walls. It binds preferentially to specific penicillin-binding proteins (PBPs) located inside bacterial cell walls.

PBPs vary among bacterial species, and thus susceptibility to piperacillin depends on the ability of piperacillin to bind to each species' specific PBPs. In-vitro studies of piperacillin and tazobactam have shown that the combination has activity against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria.

Common side effects of Zosyn include

Serious side effects of Zosyn include

Drug interactions of Zosyn include probenecid, which may inhibit the renal tubular secretion (elimination via the kidneys) of Zosyn and cause higher, prolonged blood levels of Zosyn.

  • Zosyn may inhibit platelet aggregation (formation of a blood clot) which may increase the risk for bleeding.
  • Co-administration with blood-thinning agents such as warfarin requires close monitoring for signs or symptoms of bleeding.
  • Zosyn may prolong the neuromuscular blockade of vecuronium.
  • Zosyn may decrease the renal (kidney) elimination of methotrexate which can result in methotrexate toxicity.

Zosyn is known to cross the placenta. Zosyn is approved to treat postpartum infections. As with all medications, Zosyn should be used cautiously in pregnancy. Potential benefits of treatment should be weighed against any potential risk to the fetus.

Piperacillin is excreted into human milk in small amounts. Excretion of tazobactam in human milk has not been studied. Due to the lack of safety data, Zosyn should be used cautiously in females who are breastfeeding.

What are the side effects of Zosyn (piperacillin and tazobactam)?

Common side effects associated with piperacillin/tazobactam include:

Rare side effects occurring with a frequency of less than 1% are:

  • agranulocytosis,
  • hypersensitivity type reactions,
  • anemia,
  • canker sores,
  • atrial fibrillation,
  • bradycardia,
  • cardiac arrest,
  • cardiac arrhythmia,
  • heart failure, and
  • Clostridium difficile associated diarrhea.

Zosyn (piperacillin and tazobactam) side effects list for healthcare professionals

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During the initial clinical investigations, 2621 patients worldwide were treated with Zosyn in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, Zosyn was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%).

Table 3: Adverse Reactions from Zosyn Monotherapy Clinical Trials

System Organ Class/ Adverse Reaction
Gastrointestinal disorders
  Abdominal pain(1.3%)
General disorders and administration site conditions
  Injection site reaction( ≤ 1%)
  Rigors( ≤ 1%)
Immune system disorders
  Anaphylaxis( ≤ 1%)
Infections and infestations
  Pseudomembranous colitis( ≤ 1%)
Metabolism and nutrition disorders
  Hypoglycemia( ≤ 1%)
Musculoskeletal and connective tissue disorders
  Myalgia( ≤ 1%)
  Arthralgia( ≤ 1%)
Nervous system disorders
Psychiatric disorders
Skin and subcutaneous tissue disorders
  Rash including maculopapular, bullous, and urticarial(4.2%)
  Purpura( ≤ 1%)
Vascular disorders
  Thrombophlebitis( ≤ 1%)
  Hypotension( ≤ 1%)
  Flushing( ≤ 1%)
Respiratory, thoracic and mediastinal disorders
  Epistaxis( ≤ 1%)

Nosocomial Pneumonia Trials

Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with Zosyn in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg q6h) in combination with an aminoglycoside.

In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin/tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin/tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event.

The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside.

Table 4: Adverse Reactions from Zosyn Plus Aminoglycoside Clinical Trialsa

System Organ Class Adverse Reaction
Blood and lymphatic system disorders
  Anemia( ≤ 1%)
  Thrombocytopenia( ≤ 1%)
  Eosinophilia( ≤ 1%)
Gastrointestinal disorders
  Abdominal pain(1.8%)
  Stomatitis( ≤ 1%)
General disorders and administration site conditions
  Injection site reaction( ≤ 1%)
Infections and infestations
  Oral candidiasis(3.9%)
  BUN increased(1.8%)
  Blood creatinine increased(1.8%)
  Liver function test abnormal(1.4%)
  Alkaline phosphatase increased( < 1%)
  Aspartate aminotransferase increased( ≤ 1%)
  Alanine aminotransferase increased( ≤ 1%)
Metabolism and nutrition disorders
  Hypoglycemia( ≤ 1%)
  Hypokalemia( ≤ 1%)
Nervous system disorders
Psychiatric disorders
Renal and urinary disorders
  Renal failure( ≤ 1%)
Skin and subcutaneous tissue disorders
Vascular disorders
a For adverse drug reactions that appeared in both studies the higher frequency is presented.

Other Trials: Nephrotoxicity

In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin/tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other betalactam antibacterial drugs.


Studies of Zosyn in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with Zosyn (112.5 mg/kg every 8 hours) and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the Zosyn group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the Zosyn group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.

Adverse Laboratory Events (Seen During Clinical Trials)

Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of Zosyn was used in combination with an aminoglycoside, changes in laboratory parameters include:

Hematologic - decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills)

Coagulation - positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time

Hepatic - transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin

Renal - increases in serum creatinine, blood urea nitrogen

Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged.

Post-Marketing Experience

In addition to the adverse drug reactions identified in clinical trials in Table 3 and Table 4, the following adverse reactions have been identified during post-approval use of Zosyn. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary - hepatitis, jaundice

Hematologic - hemolytic anemia, agranulocytosis, pancytopenia

Immune - hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock)

Renal - interstitial nephritis

Respiratory - eosinophilic pneumonia

Skin and Appendages - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative

Additional Experience With piperacillin

The following adverse reaction has also been reported for piperacillin for injection:

Skeletal - prolonged muscle relaxation.

Post-marketing experience with Zosyn in pediatric patients suggests a similar safety profile to that seen in adults.

What drugs interact with Zosyn (piperacillin and tazobactam)?


Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides.

In Vivo Inactivation

When aminoglycosides are administered in conjunction with piperacillin to patients with endstage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored.

Sequential administration of Zosyn and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary.

In Vitro Inactivation

Due to the in vitro inactivation of aminoglycosides by piperacillin, Zosyn and aminoglycosides are recommended for separate administration. Zosyn and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. Zosyn, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. Zosyn is not compatible with tobramycin for simultaneous Y-site infusion.


Probenecid administered concomitantly with Zosyn prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with Zosyn unless the benefit outweighs the risk.


Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone.

Monitor kidney function in patients concomitantly administered with piperacillin/tazobactam and vancomycin.

No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.


Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.


Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Zosyn could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing muscle relaxants could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (See package insert for vecuronium bromide).


Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.

Effects On Laboratory Tests

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin/tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.

As with other penicillins, the administration of Zosyn may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST®). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Treatment & Diagnosis

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Medically Reviewed on 7/17/2020
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Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.