Piperacillin/Tazobactam-Fresenius

/ Neopharm

This drug should be administered by intravenous infusion over 30 minutes. Neutropenic patients with signs of infection (e.g. fever) should receive immediate empirical antibiotic therapy before laboratory results are available.
Adults and adolescents (over 12 years): The usual dosage for adults and juveniles with normal renal function is 4 g piperacillin / 0.5 g tazobactam given every eight hours.  For nosocomial pneumonia and bacterial infections in neutropenic patients, the recommended dose is 4 g piperacillin/ 0.5 tazobactam administered every 6 hours. This regimen may also be applicable to treat patients with other indicated infections when particularly severe. Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with Piperacillin / Tazobactam at a dosage of 4 g piperacillin / 0.5 g tazobactam every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam). Treatment with the aminoglycoside should be continued in patients from whom Pseudomonas aeruginosa is isolated. If Pseudomonas aeruginosa is not isolated, the aminoglycoside may be discontinued at the discretion of the treating physician. Due to the in vitro inactivation of the aminoglycoside by beta-lactam antibiotics, and the aminoglycoside are recommended for separate administration. Piperacillin / Tazobactam and the aminoglycoside should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated.The dose and frequency depends on the severity and localisation of the infection and expected pathogens.
Frequency and the recommended dose for adult and adolescent patients by indication or condition: Severe pneumonia, Neutropenic adults with fever suspected to be due to a bacterial infection: every 6 hours. Complicated urinary tract infections (including pyelonephritis), complicated intra-abdominal infections, Skin and soft tissue infections (including diabetic foot infections): every 8 hours. In patients with renal insufficiency (Creatinine Clearance ≤ 40 mL/min), the intravenous dose should be adjusted to the degree of actual renal function impairment and each patient must be monitored closely for signs of substance toxicity; medicinal product dose and interval should be adjusted accordingly. In patients with nosocomial pneumonia receiving concomitant aminoglycoside therapy, the aminoglycoside dosage should be adjusted according to the recommendations of the manufacturer for the recommended daily doses – for patients with renal insufficiency: See prescribing information for full details.
Duration of therapy: The usual duration treatment for most indications is in the range of 5-14 days. However, the recommended treatment of nosocomial pneumonia is 7 to 14 days. In all conditions, the duration of therapy should be guided by the severity of the infection and the patient’s clinical and bacteriological progress.
Patients with hepatic impairment: Dosage adjustment is not warranted in patients with hepatic cirrhosis.
Elderly patients: Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
One vial of Piperacillin / Tazobactam 2 g / 0.25 g contains 4.7 mmol (108 mg) of sodium and one vial of Piperacillin / Tazobactam 4 g / 0.5 g contains 9.4 mmol (216 mg) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.
Pediatric Patients (2-12 years of age): For children with appendicitis older than 2 years and/or peritonitis, weighing up to 40 kg, and with normal renal function, the recommended Piperacillin / Tazobactam – is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.
Neutropenic children with fever suspected to be due to bacterial infections*: 80 mg Piperacillin / 10 mg Tazobactam per kg body weight / every 6 hours.
Complicated intra-abdominal infections*: 100 mg Piperacillin / 12.5 mg Tazobactam per kg body weight / every 8 hours.
(* Not to exceed the maximum 4 g / 0.5 g per dose over 30 minutes.)
For pediatric dosage in renal impairment: See prescribing information for full details.

Treatment of systemic and/or local infections caused by susceptible organisms. In combination with an aminoglycoside is indicated for the treatment of suspected bacterial infections in neutropenic adults and children above 2 years. Appendicitis complicated by rupture with peritonitis and/or abscess formation in children aged 2-12 years. Piperacillin/tazobactam is indicated for the treatment of the following infections in adults  and adolescents:
1. Severe pneumonia including hospital-acquired and ventilator-associated pneumonia.
2. Complicated urinary tract infections (including pyelonephritis).
3. Complicated intra-abdominal infections.
4. Complicated skin and soft tissue infections (including diabetic foot infections). this drug may be used in the management of neutropenic patients with fever suspected to be due to a bacterial infection. Appropriate culture and susceptibility tests should be performed before treatment in order to identify organisms causing infections and to determine their susceptibilities to  it.  Because of its broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic organisms as listed above, it is particularly useful in the treatment of mixed infections and in presumptive therapy prior to the availability of the results of sensitivity tests. Therapy with this drug may, however, be initiated before results of such test are known. Modification of the treatment may be required once these results become available or if there is no clinical response. In serious infections presumptive therapy  may be initiated before susceptibility test results are available. This drug acts synergistically with aminoglycosides against certain strains of Pseudomonas aeruginosa. Combined therapy has been successful, especially in patients with impaired host defenses. Both drugs should be used in full therapeutic doses. As soon as results of culture and susceptibility test become available, antimicrobial therapy should be adjusted. To reduce the development of drug-resistant bacteria and maintain the effectiveness of it and other antibacterial drugs, Piperacillin / Tazobactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

A history of allergic reactions to any of the penicillins, cephalosporins, beta-lactam active substances, (e.g. monobactam or carbapenem) or β-lactamase inhibitors. Hypersensitivity to the active substances or to any of intravenous solvent.

Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with Piperacillin / Tazobactam. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, monobactam or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with Piperacillin / Tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Piperacillin / Tazobactam should be discontinued and appropriate therapy instituted. It may require administration of epinephrine and other emergency measures.
Serious Skin Reactions: Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving Piperacillin / Tazobactam. If patients develop a skin rash they should be monitored closely and Piperacillin / Tazobactam – discontinued if lesions progress.
Clostridium difficile Associated Diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Piperacillin / Tazobactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Hematologic Effects: Bleeding manifestations have occurred in some patients receiving β-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, Piperacillin / Tazobactam should be discontinued and appropriate therapy instituted. The leukopenia/neutropenia associated with Piperacillin/ Tazobactam administration appears to be reversible and most frequently associated with prolonged administration. Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥ 21 days.
See prescribing information for full details.

Diarrhea, vomiting, nausea, rash.
See prescribing information for full details.

Aminoglycosides: 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 end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of piperacillin / tazobactam 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, piperacillin / tazobactam and aminoglycosides are recommended for separate administration. piperacillin / tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated.
Probenecid: Probenecid administered concomitantly with piperacillin / tazobactam 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 piperacillin / tazobactam unless the benefit outweighs the risk.
Anticoagulants: 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.
Vecuronium: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. piperacillin / tazobactam 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.
Methotrexate: 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.
Vancomycin: No pharmacokinetic interactions have been noted between piperacillin / tazobactam and vancomycin.
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 piperacillin / tazobactam may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
See prescribing information for full details.

Pregnancy: There are no or a limited amount of data from the use of Piperacillin/Tazobactam in pregnant women.
Lactation: Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Caution should be exercised and women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.
See prescribing information for details.

Symptoms: There have been postmarketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Treatment: In the event of an overdose, piperacillin / tazobactam treatment should be discontinued. No specific antidote is known. Treatment should be supportive and symptomatic according the patient’s clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin/tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively.
See prescribing information for full details.