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 at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

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.

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.

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) 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

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.

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.

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) 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 (eg, 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 (ie, 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.

Side Effects by Body System

General

In general, side effects have been described as transient and mild to moderate. In clinical trials, piperacillin-tazobactam was discontinued 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 post-marketing experience a similar safety profile was reported in pediatric patients that is seen in adults.

Gastrointestinal

Diarrhea associated with piperacillin-tazobactam is usually self-limited. There are case reports of pseudomembranous colitis in patients receiving piperacillin-tazobactam.

Gastrointestinal side effects have included diarrhea (11.3%), constipation (7.7%), nausea (6.9%), vomiting (3.3%), dyspepsia (3.3%), stool changes (2.4%), abdominal pain (1.3%), flatulence (1.3%), anorexia (1.3%), and duodenal ulcer (1.3%). Melena, hemorrhage, gastritis, hiccough, ileus, taste perversion, ulcerative 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.

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.

Dermatologic side effects have included rash (4.2%), including maculopapular, bullous, urticarial, and eczematoid rash, erythematous rash (3.9%), and pruritus (3.1%). Erythema multiforme, exanthemous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have also been reported.

Hypersensitivity

Hypersensitivity reactions generally include urticarial rash, but rare reports of severe reactions, including Stevens-Johnson syndrome, dyspnea, and edema have been reported. There are small studies showing an increased incidence of unexplained fever in patients with cystic fibrosis who are given piperacillin.

Hypersensitivity reactions, including fever, rash, and eosinophilia, occur in approximately 1% to 5% of patients. Severe hypersensitivity reactions to piperacillin-tazobactam are rare, and may include anaphylaxis, edema, hypotension, and dyspnea. Anaphylactic/anaphylactoid reactions resulting in shock and fatalities have been reported with piperacillin.

Local

Local reactions have included injection site reactions (0.5%), pain (0.2%), inflammation (0.2%), phlebitis (1.3%), thrombophlebitis (0.2%), and edema (0,1%).

Cardiovascular

Cardiovascular side effects have included hypertension (1.6%) and edema (1.2%). Tachycardia, supraventricular tachycardia, ventricular tachycardia, bradycardia, arrhythmia, atrial fibrillation, ventricular fibrillation, cardiac arrest, cardiac failure, circulatory failure, myocardial infarction, angina, and flushing have been reported in 1% or fewer patients.

Endocrine

Endocrine side effects have included diaphoresis in 1% or fewer patients.

Genitourinary

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

Hematologic

Hematologic side effects have included thrombophlebitis (1.3%) and decreased hemoglobin and hematocrit, thrombocytopenia, increased platelet count, eosinophilia, leukopenia, neutropenia, positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time. Leukopenia/neutropenia has frequently been associated with prolonged therapy (>21 days) and appears to be reversible. Mesenteric embolism, purpura, epistaxis, pulmonary embolism, ecchymosis, hemoptysis, and hemolytic anemia have been reported in 1% or fewer patients. Hemolytic anemia, anemia, thrombocytosis, agranulocytosis, and pancytopenia have also been reported. Leukopenia has been reported in 23% of patients with liver disease receiving beta-lactam antibiotics.

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 transient elevations of alkaline phosphatase, AST (SGOT), ALT (SGPT), and bilirubin, and hepatitis and cholestatic jaundice.

Metabolic

Metabolic side effects have included symptomatic hypoglycemia, thirst, gout, vitamin B12 deficiency anemia, increased and decreased sodium, potassium, calcium, hyperglycemia, decreased total protein or albumin. Hypomagnesemia and hypophosphatemia have also been reported.

Musculoskeletal

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

Nervous system

Nervous system side effects have included headache (7.7%), insomnia (6.6%), agitation (2.1%), dizziness (1.4%), and anxiety (1.2%). Tremor, convulsions, vertigo, syncope, cerebrovascular accident, tinnitus, and combativeness have been reported in 1% or fewer patients. Somnolence, confusion, and tonic-clonic seizure have also been reported.

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.

Ocular

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

Other

Other side effects have included rigors, back pain, malaise, asthenia, chest pain, and candidal superinfections.

Psychiatric

Psychiatric side effects have included confusion, hallucination, and depression in 1% or fewer patients.

Renal

Renal side effects have included increased serum creatinine and blood urea nitrogen. Acute interstitial nephritis and renal failure have also been reported.

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 patients symptoms improved to baseline after 21 days of prednisone.

Respiratory

Respiratory side effects have included rhinitis (1.2%) and dyspnea (1.1%). Pharyngitis, pulmonary edema, bronchospasm, coughing, atelectasis, and hypoxia have been reported in 1% or fewer patients.

Other

The use of piperacillin-tazobactam has been associated with false-positive tests for Aspergillus galactomannan antigenemia.

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