Zosyn Side Effects

Please note - some side effects for Zosyn may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Zosyn - for the Consumer

Zosyn

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Zosyn:

Agitation; constipation; diarrhea; dizziness; headache; indigestion; nausea; pain, swelling, or redness at the injection site; sleeplessness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Zosyn:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody stools; chest pain; decreased urination; depression; fainting; fast, slow, or irregular heartbeat; fever, chills, or sore throat; hallucination; inflammation at the injection site; prolonged muscle relaxation; red, swollen, or blistered skin; seizures; severe diarrhea, vomiting, or stomach pain; shortness of breath; swelling of the hands, ankles, or feet; tremor; unusual bleeding or bruising; unusual tiredness or weakness; vaginal irritation or discharge; vein inflammation or tenderness; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Zosyn Side Effects - for the Professional

Zosyn

Adverse Events From Clinical Trials

During the initial clinical investigations, 2621 patients worldwide were treated with Zosyn (piperacillin and tazobactam for injection, USP) in phase 3 trials. In the key North American 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%).

Adverse local reactions that were reported, irrespective of relationship to therapy with Zosyn, were phlebitis (1.3%), injection site reaction (0.5%), pain (0.2%), inflammation (0.2%), thrombophlebitis (0.2%), and edema (0.1%).

Based on patients from the North American trials (n=1063), the events with the highest incidence in patients, irrespective of relationship to Zosyn therapy, were diarrhea (11.3%); headache (7.7%); constipation (7.7%); nausea (6.9%); insomnia (6.6%); rash (4.2%), including maculopapular, bullous, urticarial, and eczematoid; vomiting (3.3%); dyspepsia (3.3%); pruritus (3.1%); stool changes (2.4%); fever (2.4%); agitation (2.1%); pain (1.7%); moniliasis (1.6%); hypertension (1.6%); dizziness (1.4%); abdominal pain (1.3%); chest pain (1.3%); edema (1.2%); anxiety (1.2%); rhinitis (1.2%); and dyspnea (1.1%).

Additional adverse systemic clinical events reported in 1.0% or less of the patients in the initial North American trials are listed below within each body system.

Autonomic Nervous System—hypotension, ileus, syncope

Body as a whole—rigors, back pain, malaise

Cardiovascular—tachycardia, including supraventricular and ventricular; bradycardia; arrhythmia, including atrial fibrillation, ventricular fibrillation, cardiac arrest, cardiac failure, circulatory failure, myocardial infarction

Central Nervous System—tremor, convulsions, vertigo

Gastrointestinal—melena, flatulence, hemorrhage, gastritis, hiccough, ulcerative stomatitis

Pseudomembranous colitis was reported in one patient during the clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment.

Hearing and Vestibular System—tinnitus

Hypersensitivity—anaphylaxis

Metabolic and Nutritional—symptomatic hypoglycemia, thirst

Musculoskeletal—myalgia, arthralgia

Platelets, Bleeding, Clotting—mesenteric embolism, purpura, epistaxis, pulmonary embolism.

Psychiatric—confusion, hallucination, depression

Reproductive, Female—leukorrhea, vaginitis

Respiratory—pharyngitis, pulmonary edema, bronchospasm, coughing

Skin and Appendages—genital pruritus, diaphoresis

Special senses—taste perversion

Urinary—retention, dysuria, oliguria, hematuria, incontinence

Vision—photophobia

Vascular (extracardiac)—flushing

Nosocomial Pneumonia Trials

In a completed study of nosocomial lower respiratory tract infections, 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.

In this study of Zosyn in combination with an aminoglycoside, adverse events that occurred in more than 1% of patients and were considered by the investigator to be drug-related were: diarrhea (17.6%), fever (2.7%), vomiting (2.7%), urinary tract infection (2.7%), rash (2.3%), abdominal pain (1.8%), generalized edema (1.8%), moniliasis (1.8%), nausea (1.8%), oral moniliasis (1.8%), BUN increased (1.8%), creatinine increased (1.8%), peripheral edema (1.8%), abdomen enlarged (1.4%), headache (1.4%), constipation (1.4%), liver function tests abnormal (1.4%), thrombocythemia (1.4%), excoriations (1.4%), and sweating (1.4%).

Drug-related adverse events reported in 1% or less of patients in the nosocomial pneumonia study of Zosyn with an aminoglycoside were: acidosis, acute kidney failure, agitation, alkaline phosphatase increased, anemia, asthenia, atrial fibrillation, chest pain, CNS depression, colitis, confusion, convulsion, cough increased, thrombocytopenia, dehydration, depression, diplopia, drug level decreased, dry mouth, dyspepsia, dysphagia, dyspnea, dysuria, eosinophilia, fungal dermatitis, gastritis, glossitis, grand mal convulsion, hematuria, hyperglycemia, hypernatremia, hypertension, hypertonia, hyperventilation, hypochromic anemia, hypoglycemia, hypokalemia, hyponatremia, hypophosphatemia, hypoxia, ileus, injection site edema, injection site pain, injection site reaction, kidney function abnormal, leukocytosis, leukopenia, local reaction to procedure, melena, pain, prothrombin decreased, pruritus, respiratory disorder, SGOT increased, SGPT increased, sinus bradycardia, somnolence, stomatitis, stupor, tremor, tachycardia, ventricular extrasystoles, and ventricular tachycardia.

In a previous nosocomial pneumonia study conducted with a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside, the following adverse events, irrespective of drug relationship, were observed: diarrhea (20%); constipation (8.4%); agitation (7.1%); nausea (5.8%); headache (4.5%); insomnia (4.5%); oral thrush (3.9%); erythematous rash (3.9%); anxiety (3.2%); fever (3.2%); pain (3.2%); pruritus (3.2%); hiccough (2.6%); vomiting (2.6%); dyspepsia (1.9%); edema (1.9%); fluid overload (1.9%); stool changes (1.9%); anorexia (1.3%); cardiac arrest (1.3%); confusion (1.3%); diaphoresis (1.3%); duodenal ulcer (1.3%); flatulence (1.3%); hypertension (1.3%); hypotension (1.3%); inflammation at injection site (1.3%); pleural effusion (1.3%); pneumothorax (1.3%); rash, not otherwise specified (1.3%); supraventricular tachycardia (1.3%); thrombophlebitis (1.3%); and urinary incontinence (1.3%).

Adverse events irrespective of drug relationship observed in 1% or less of patients in the above study with Zosyn and an aminoglycoside included: aggressive reaction (combative), angina, asthenia, atelectasis, balanoposthitis, cerebrovascular accident, chest pain, conjunctivitis, deafness, dyspnea, earache, ecchymosis, fecal incontinence, gastric ulcer, gout, hemoptysis, hypoxia, pancreatitis, perineal irritation/pain, urinary tract infection with trichomonas, vitamin B12 deficiency anemia, xerosis, and yeast in urine.

Pediatrics

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.

In this study, adverse events that were reported in more than 1% of patients, irrespective of relationship to therapy with Zosyn, were: diarrhea (7.0%), fever (4.8%), vomiting (3.7%), local reaction (3.3%), abscess (2.2%), sepsis (2.2%), abdominal pain (1.8%), infection (1.8%), bloody diarrhea (1.1%), pharyngitis (1.5%), constipation (1.1%), and SGOT increase (1.1%).

Adverse events reported in 1% or less of pediatric patients receiving Zosyn are consistent with adverse events reported in adults.

Additional controlled studies in pediatric patients showed a similar safety profile as that described above.

Post-Marketing Experience

Additional adverse events reported from worldwide marketing experience with Zosyn, occurring under circumstances where causal relationship to Zosyn is uncertain:

Gastrointestinal—hepatitis, cholestatic jaundice

Hematologic—hemolytic anemia, anemia, thrombocytosis, agranulocytosis, pancytopenia

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

Infections—candidal superinfections

Renal—interstitial nephritis, renal failure

Skin and Appendages—erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

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

Adverse Laboratory Events

Of the studies reported, including that of nosocomial lower respiratory tract infections in which a higher dose of Zosyn (piperacillin and tazobactam for injection, USP) was used in combination with an aminoglycoside, changes in laboratory parameters, without regard to drug relationship, include:

Hematologic—decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. The leukopenia/neutropenia associated with Zosyn administration appears to be reversible and most frequently associated with prolonged administration, i.e., ≥21 days of therapy. 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

Urinalysis—proteinuria, hematuria, pyuria

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.

The following adverse reaction has also been reported for PIPRACIL® (piperacillin for injection):

Skeletal—prolonged muscle relaxation

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

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Side Effects by Body System - for Healthcare Professionals

General

In general, side effects have been described as transient and mild to moderate. In clinical trials, piperacillin-tazobactam was discontinued in 3.2% of patients due to dermatologic effects (including rash and pruritus; 1.3%), gastrointestinal effects (including diarrhea, nausea, and vomiting; 0.9%), and allergic reactions (0.5%). In nosocomial pneumonia trials, 11% of patients discontinued piperacillin-tazobactam due to a side effect.

Gastrointestinal

Gastrointestinal side effects have included diarrhea (up to 20%), constipation (up to 8.4%), nausea (up to 6.9%), oral thrush/moniliasis (up to 3.9%), vomiting (up to 3.3%), dyspepsia (up to 3.3%), hiccough (up to 2.6%), stool changes (up to 2.4%), abdominal pain (up to 1.8%), enlarged abdomen (1.4%), flatulence (up to 1.3%), anorexia (1.3%), and duodenal ulcer (1.3%). Melena, gastrointestinal hemorrhage, gastritis, ileus, taste perversion, ulcerative stomatitis, colitis, dry mouth, dysphagia, glossitis, stomatitis, fecal incontinence, gastric ulcer, pancreatitis, and pseudomembranous colitis have been reported in 1% or fewer patients. Clostridium difficile-associated diarrhea has also been reported.

Diarrhea associated with piperacillin-tazobactam is usually self-limited. There are case reports of pseudomembranous colitis in patients receiving piperacillin-tazobactam. The onset of pseudomembranous colitis symptoms may develop during or after antibacterial therapy.

Nervous system

Piperacillin may have neuromuscular blocking properties, and has been noted to enhance the effect of neuromuscular blocking agents.

Patients with renal insufficiency may be at greater risk of developing seizures, even with adjusted dosages.

Nervous system side effects have included headache (up to 7.7%), insomnia (up to 6.6%), agitation (up to 7.1%), and dizziness (1.4%). Tremor, convulsions, vertigo, syncope, central nervous system depression, grand mal convulsion, cerebrovascular accident, somnolence, tinnitus, hypertonia, stupor, and deafness have been reported in 1% or fewer patients. Tonic-clonic seizure has also been reported. Neurotoxicity has been reported with piperacillin.

Dermatologic

A patient with mononucleosis developed a nonallergic rash after 3 weeks of treatment with piperacillin-tazobactam for osteomyelitis. He had no history of penicillin allergy. His Epstein-Barr virus IgG and IgM antibodies were positive. The rash resolved quickly after discontinuation of the piperacillin-tazobactam.

Piperacillin therapy has been associated with an increased incidence of rash in cystic fibrosis patients.

Dermatologic side effects have included rash (including maculopapular, bullous, urticarial, and eczematoid; up to 4.2%), erythematous rash (3.9%), pruritus (up to 3.2%), excoriations (1.4%), sweating (1.4%), and diaphoresis (up to 1.3%). Fungal dermatitis (1% or less), exanthemous pustulosis, and drug-induced petechial rash have been reported. Petechial rash or purpura due to thrombocytopenia, exanthematous pustulosis, bullous dermatosis, erythema nodosum, exanthems, exfoliative dermatitis, urticaria, pruritus, vesiculation, Jarisch-Herxheimer reaction, Stevens-Johnson syndrome, purpura, and vasculitis have been reported with piperacillin. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported during postmarketing experience.

Other

Piperacillin therapy has been associated with an increased incidence of fever in patients with cystic fibrosis.

Other side effects have included fever (up to 3.2%), pain (up to 3.2%), edema (up to 1.9%), generalized edema (1.8%), peripheral edema (1.8%), moniliasis (up to 1.8%), and chest pain (up to 1.3%). Rigors, back pain, malaise, flushing, asthenia, earache, xerosis, and decreased drug level have been reported in 1% or fewer patients. The use of piperacillin-tazobactam has been associated with false-positive tests for Aspergillus galactomannan antigenemia. Candidal superinfections have been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects have included hypertension (up to 1.6%), cardiac arrest (up to 1.3%), supraventricular tachycardia (up to 1.3%), thrombophlebitis (1.3%), and hypotension (up to 1.3%). Tachycardia, ventricular tachycardia, bradycardia, arrhythmia, atrial fibrillation, ventricular fibrillation, cardiac failure, circulatory failure, myocardial infarction, angina, sinus bradycardia, ventricular extrasystoles, and mesenteric embolism have been reported in 1% or fewer patients.

Psychiatric

Psychiatric side effects have included anxiety (up to 3.2%) and confusion (up to 1.3%). Hallucination, aggressive reaction (combative), and depression have been reported in 1% or fewer patients.

Genitourinary

Genitourinary side effects have included urinary tract infection (2.7%) and urinary incontinence (1.3%). Genital pruritus, balanoposthitis, leukorrhea, vaginitis, perineal irritation/pain, urinary retention, dysuria, oliguria, hematuria, urinary incontinence, urinary tract infection with trichomonas, and yeast in urine have been reported in 1% or fewer patients. Proteinuria and pyuria have also been reported.

Metabolic

Metabolic side effects have included fluid overload (1.9%). Symptomatic hypoglycemia, thirst, acidosis, increased alkaline phosphatase, dehydration, gout, vitamin B12 deficiency anemia, hypernatremia, hypokalemia, hyponatremia, hypophosphatemia, hyperglycemia, and hypoglycemia have been reported in 1% or fewer patients. Decreased total protein or albumin, hypomagnesemia, abnormalities in electrolytes (i.e., increased and decreased sodium, potassium, and calcium), decreased blood glucose, and transient elevations of alkaline phosphatase have also been reported. Electrolyte and acid-base disturbances have been reported with piperacillin.

Renal

Renal side effects have included increased serum creatinine and blood urea nitrogen in 1.8% of patients. Acute kidney failure and abnormal kidney function have been reported in 1% or fewer patients. Acute onset of renal dysfunction (with elevated serum creatinine, lumbar pain, rash, fever, arthralgias, and eosinophiluria) has been reported. Interstitial nephritis and renal failure have been reported during postmarketing experience.

A 51-year-old woman developed an acute onset of renal dysfunction after 6 days of therapy with piperacillin-tazobactam. The patient also had an elevated serum creatinine, lumbar pain, rash, fever, arthralgias, and eosinophiluria. The piperacillin-tazobactam was discontinued and the patient's symptoms improved to baseline after 21 days of prednisone.

Hematologic

Hematologic side effects have included thrombocythemia (1.4%). Anemia, thrombocytopenia, eosinophilia, leukopenia, purpura, hypochromic anemia, leukocytosis, decreased prothrombin, and ecchymosis have been reported in 1% or fewer patients. Decreased hemoglobin and hematocrit, increased platelet count, neutropenia, positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time, reversible bone marrow suppression, and prolonged bleeding time have been reported. Leukopenia/neutropenia has frequently been associated with prolonged therapy (i.e., 21 days or longer) and appears to be reversible. Bleeding disorders, neutropenia, thrombocytopenia, and hemolytic anemia have been reported with piperacillin. Leukopenia has been reported in 23% of patients with liver disease receiving beta-lactam antibiotics. Hemolytic anemia, anemia, thrombocytosis, agranulocytosis, and pancytopenia have been reported during postmarketing experience.

Reversible bone marrow suppression is rare, and usually limited to prolonged therapy with piperacillin.

Risk factors for increased bleeding time with piperacillin include age over 60 years, cytotoxic chemotherapy, thrombocytopenia, azotemia, doses of 12 grams per day or more, and therapy for 6 days or more.

Hepatic

Hepatic side effects have included abnormal liver function tests (1.4%). Increased SGOT and SGPT have been reported in 1% or fewer patients. Transient elevations of AST (SGOT), ALT (SGPT), and bilirubin and increased gamma-glutamyltransferase have been reported. Hepatotoxicity has been reported with piperacillin. Hepatitis and cholestatic jaundice have been reported during postmarketing experience.

Respiratory

Respiratory side effects have included pleural effusion (1.3%), pneumothorax (1.3%), rhinitis (1.2%), and dyspnea (up to 1.1%). Pharyngitis, pulmonary edema, bronchospasm, coughing, epistaxis, pulmonary embolism, hyperventilation, respiratory disorder, increased cough, atelectasis, hemoptysis, and hypoxia have been reported in 1% or fewer patients.

Hypersensitivity

Hypersensitivity side effects have included anaphylaxis (1% or less) and allergic reactions. Hypersensitivity reactions have generally included urticarial rash, but rare reports of severe reactions, including anaphylaxis, Stevens-Johnson syndrome, dyspnea, hypotension, and edema, have been reported. Hypersensitivity reactions, including fever, rash, and eosinophilia, have been reported. Hypersensitivity reactions and anaphylactic/anaphylactoid reactions (resulting in shock and fatalities) have been reported with piperacillin. Hypersensitivity reactions and anaphylactic/anaphylactoid reactions (including shock) have also been reported during postmarketing experience.

Local

Local side effects have included phlebitis (1.3%), inflammation at injection site (up to 1.3%), and thrombophlebitis (0.2%). Injection site edema, injection site pain, injection site reaction, and local reaction to procedure have been reported in 1% or fewer patients.

Musculoskeletal

Musculoskeletal side effects have included myalgia and arthralgia in 1% or fewer patients. Prolonged muscle relaxation has been reported with piperacillin.

Ocular

Ocular side effects have included photophobia, diplopia, and conjunctivitis in 1% or fewer patients.

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