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Pronunciation
(pi PER a sil in)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of susceptible infections such as septicemia, acute and chronic respiratory tract infections, skin and soft tissue infections, and urinary tract infections due to susceptible strains of Pseudomonas, Proteus, and Escherichia coli and Enterobacter; active against some streptococci and some anaerobic bacteria; febrile neutropenia (as part of combination regimen)
Pregnancy Risk Factor
B
Pregnancy Considerations
Adverse events have not been observed in animal studies; therefore, piperacillin is classified as pregnancy category B. Piperacillin crosses the placenta and distributes into the amniotic fluid. Due to pregnancy induced physiologic changes, some pharmacokinetic parameters of piperacillin may be altered. At term, the apparent volume of distribution of piperacillin is increased and peak concentrations are significantly lower. Total clearance is normal to increased at term. These changes continue into the early postpartum period.
Lactation
Enters breast milk/compatible
Breast-Feeding Considerations
Small amounts of piperacillin are excreted in breast milk. The manufacturer recommends that caution be exercised when administering piperacillin to nursing women. Other penicillins are considered safe for use during breast-feeding. Nondose-related effects could include modification of bowel flora.
Contraindications
Hypersensitivity to piperacillin, other beta-lactam antibiotics (penicillins or cephalosporins), or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients.
• Bleeding disorders: Particularly in patients with renal impairment, bleeding disorders have been observed; discontinue if thrombocytopenia or bleeding occurs.
• Leukopenia/neutropenia: During prolonged use, leukopenia and neutropenia have been reported.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns:
• Cystic fibrosis: An increased frequency of fever and rash has been reported in patients with cystic fibrosis.
• Renal impairment: Use with caution in patients with renal impairment, due to sodium load and adverse effects (anemia, neuropsychological changes); dosage adjustment recommended.
• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.
Adverse Reactions
Frequency not defined.
Central nervous system: Confusion, convulsions, drowsiness, fever, Jarisch-Herxheimer reaction
Dermatologic: Rash, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Electrolyte imbalance, hypokalemia
Hematologic: Abnormal platelet aggregation and prolonged PT (high doses), agranulocytosis, Coombs' reaction (positive), hemolytic anemia, pancytopenia
Local: Thrombophlebitis
Neuromuscular & skeletal: Myoclonus
Renal: Acute interstitial nephritis, acute renal failure
Miscellaneous: Anaphylaxis, hypersensitivity reactions
Metabolism/Transport Effects
None known.
Drug Interactions
Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Risk D: Consider therapy modification
BCG: Antibiotics may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Fusidic Acid: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Methotrexate: Penicillins may decrease the excretion of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 24 hours after cessation of antibacterial agents. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Storage
Reconstituted solution is stable (I.V. infusion) in NS or D5W for 24 hours at room temperature, 7 days when refrigerated, or 4 weeks when frozen. After freezing, thawed solution is stable for 24 hours at room temperature or 48 hours when refrigerated. 40 g bulk vial should not be frozen after reconstitution.
Compatibility
Stable in dextran 6% in NS, D5NS, D5W, LR, NS, SWFI, bacteriostatic water; variable stability (consult detailed reference) in peritoneal dialysis solutions.
Y-site administration: Compatible: Acyclovir, aldesleukin, allopurinol, amifostine, aztreonam, bivalirudin, ciprofloxacin, cyclophosphamide, cyclosporine, dexmedetomidine, diltiazem, docetaxel, doxorubicin liposome, enalaprilat, esmolol, etoposide phosphate, famotidine, fenoldopam, fludarabine, foscarnet, gallium nitrate, granisetron, heparin, hetastarch in lactate electrolyte injection (Hextend®), hydromorphone, IL-2, labetalol, linezolid, lorazepam, magnesium sulfate, melphalan, meperidine, midazolam, milrinone, morphine, multiple vitamins, nicardipine, oxytocin, pantoprazole, propofol, ranitidine, remifentanil, tacrolimus, teniposide, theophylline, thiotepa, verapamil, zidovudine. Incompatible: Amiodarone, amphotericin B cholesteryl sulfate complex, filgrastim, gemcitabine, sargramostim, tobramycin, vinorelbine. Variable (consult detailed reference): Anakinra, cisatracurium, fluconazole, ondansetron, vancomycin.
Compatibility in syringe: Compatible: Dimenhydrinate, heparin, pantoprazole.
Mechanism of Action
Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs); which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.
Pharmacodynamics/Kinetics
Absorption: I.M.: 70% to 80%
Protein binding: ~16%
Bioavailability: Not well absorbed when given orally
Half-life elimination (dose dependent; prolonged with moderately severe renal or hepatic impairment):
Neonates: 1-5 days old: 3.6 hours; >6 days old: 2.1-2.7 hours
Children: 1-6 months: 0.79 hour; 6 months to 12 years: 0.39-0.5 hour
Adults: 36-80 minutes
Time to peak, serum: I.M.: 30-50 minutes
Excretion: Primarily urine; partially feces
Dosage
Usual dosage range:
Infants and Children: I.M., I.V.: 200-300 mg/kg/day in divided doses every 4-6 hours
Adults: I.M., I.V.: 2-4 g/dose every 4-6 hours (maximum: 24 g/day)
Indication-specific dosing:
Children: I.M., I.V.:
Cystic fibrosis: 350-500 mg/kg/day in divided doses every 4-6 hours
Adults:
Burn wound sepsis: I.V.: 4 g every 4 hours with vancomycin and amikacin
Cholangitis, acute: I.V.: 4 g every 6 hours
Keratitis
(Pseudomonas):
Ophthalmic: 6-12 mg/mL every 15-60 minutes around the clock for 24-72 hours, then slow reduction
Malignant otitis externa: I.V.: 4-6 g every 4-6 hours with tobramycin
Moderate infections: I.M., I.V.: 2-3 g/dose every 6-12 hours (maximum: 2 g I.M./site)
Prosthetic joint
(Pseudomonas):
I.V.: 3 g every 6 hours with aminoglycoside
Pseudomonas
infections: I.V.: 4 g every 4 hours
Severe infections: I.M., I.V.: 3-4 g/dose every 4-6 hours (maximum: 24 g/24 hours)
Urinary tract infections: I.V.: 2-3 g/dose every 6-12 hours
Uncomplicated gonorrhea: I.M.: 2 g in a single dose accompanied by 1 g probenecid 30 minutes prior to injection
Dosing adjustment in renal impairment: Adults: I.V.:
Clcr 20-40 mL/minute: Administer 3-4 g every 8 hours
Clcr <20 mL/minute: Administer 3-4 g every 12 hours
Moderately dialyzable (20% to 50%)
Continuous arteriovenous or venovenous hemodiafiltration effects: Dose as for Clcr 10-50 mL/minute
Administration: I.M.
Do not administer more than 2 g per injection site.
Administration: I.V.
Administer around-the-clock to promote less variation in peak and trough serum levels. Give at least 1 hour apart from aminoglycosides. Rapid administration can lead to seizures. Administer direct I.V. over 3-5 minutes. Intermittently infusion over 30 minutes.
Some penicillins (eg, carbenicillin, ticarcillin and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
Administration: I.V. Detail
pH: 5.5-7.5
Monitoring Parameters
Observe for signs and symptoms of anaphylaxis during first dose
Test Interactions
May interfere with urinary glucose tests using cupric sulfate (Benedict's solution, Clinitest®); false-positive urinary and serum proteins, positive Coombs' test [direct]. False-positive Platelia® Aspergillus EIA test (Bio-Rad Laboratories) has been reported.
Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro, leading to a potential underestimation of aminoglycoside serum concentration.
Dietary Considerations
Sodium content of 1 g: 1.85 mEq
Patient Education
This drug can only be given by injection or infusion. Report immediately any redness, swelling, burning, or pain at infusion/injection site or any signs of allergic reaction (eg, respiratory difficulty or swallowing, chest tightness, rash, hives, swelling of lips or mouth). Maintain adequate hydration unless instructed to restrict fluid intake. May cause confusion or drowsiness. Report chest pain, palpitations, or irregular heartbeat; unusual confusion, pain, swelling, or heat in legs; changes in urinary pattern; signs of an opportunistic infection (fever, chills, unhealed sores, white plaques in mouth or vagina, purulent vaginal discharge); and persistent diarrhea.
Geriatric Considerations
Because of piperacillin's lower sodium content, it is preferred over ticarcillin in patients with a history of heart failure and/or renal or hepatic disease. Adjust dose for renal function.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Prolonged use of penicillins may lead to development of oral candidiasis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Infectious Diseases Comment
A well-documented reaction can occur between beta-lactam and aminoglycoside antibiotics in vitro, leading to complexation, opening of the beta-lactam ring and presumably, loss of antibacterial activity for one or both agents. However, the conditions under which this reaction occurs are variable and influenced by (but not limited to) assay methodology, sampling time and storage, and drug selection and concentration. In general, many of the in vitro studies employed artificial conditions that tested high concentrations of the penicillin derivative (equating to serum levels most likely observed only in severe renal impairment) in combination with gentamicin or tobramycin. Incubation of the agents at conditions of 37°C for up to 48 hours has definitely demonstrated inactivation and loss of bactericidal activity. However, some of these studies permitted a considerable time lapse prior to assaying the medium, or stored the samples at higher temperatures (-20°C or greater), which may have allowed continued chemical degradation prior to assay. In general, amikacin was the most resistant to penicillin-mediated chemical degradation, and cephalosporins were much less likely than penicillins to inactivate the aminoglycosides.
The more robust studies have been those which evaluated in vivo effects via rapid and frequent blood sampling during concomitant dosing. In vivo, there are a number of studies documenting significant changes in the half-life of gentamicin in combination with primarily ticarcillin and carbenicillin, but usually only in the setting of end-stage renal disease. A number of literature reports suggest that despite documented changes in gentamicin kinetics, this is not likely to lead to clinically significant differences in outcomes in patients with normal renal function. Furthermore, there are no published, prospective, outcomes-based studies that provide compelling evidence of changes in rates of clinical or microbiological response as a function of dosing separation.
Based on the weight of evidence to date, coadministration of (but not coadmixture of) a penicillin or cephalosporin antibiotic with an aminoglycoside should not pose a significant concern in patients with even mild renal impairment. However, specific circumstances exist in which this approach should be undertaken with caution. Concurrent administration of either gentamicin or tobramycin with piperacillin, carbenicillin, or ticarcillin (including combinations with beta-lactamase inhibitors), particularly in the face of moderate-to-severe renal failure, would warrant careful monitoring of aminoglycoside serum levels, CBCs and clinical response to avoid potentially reduced efficacy due to chemical inactivation.
Mental Health: Effects on Mental Status
May cause drowsiness or confusion; penicillins reported to cause apprehension, illusions, hallucinations, depersonalization, agitation, encephalopathy, and insomnia
Mental Health: Effects on Psychiatric Treatment
May cause leukopenia, neutropenia, pancytopenia, and agranulocytosis; monitor patients receiving clozapine, carbamazepine, or valproic acid therapy.
Nursing: Physical Assessment/Monitoring
Assess results of culture and sensitivity tests and patient's allergy history prior to starting therapy. Use caution with impaired renal function and history of seizure activity. Monitor for hypersensitivity reactions, opportunistic infection (fever, chills, unhealed sores, white plaques in mouth or vagina, purulent vaginal discharge), confusion, rash, thrombophlebitis, and renal failure.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injection, powder for reconstitution: 2 g [DSC], 3 g [DSC], 4 g [DSC], 40 g [DSC]
References
Capellier G, Cornette C, Boillot A, et al, “Removal of Piperacillin in Critically Ill Patients Undergoing Continuous Veno-Venous Hemofiltration,” Crit Care Med, 1998, 26(1):88-91.
Chow MS, Quintiliani, and Nightingale CH, "In Vivo Inactivation of Tobramycin by Ticarcillin. A Case Report," JAMA, 1982, 247(5):658-9.
Daly JS, Dodge RA, Glew RH, et al, "Effect of Time and Temperature on Inactivation of Aminoglycosides by Ampicillin at Neonatal Dosages," J Perinatol, 1997, 17(1):42-5.
Donowitz GR and Mandell GL, “Beta-Lactam Antibiotics,” N Engl J Med, 1988, 318(7):419-26 and 318(8):490-500.
Dowell JA, Korth-Bradley J, Milisci M, et al, "Evaluating Possible Pharmacokinetic Interactions Between Tobramycin, Piperacillin, and a Combination of Piperacillin and Tazobactam in Patients With Various Degrees of Renal Impairment," J Clin Pharmacol, 2001, 41:979-86.
Farchione LA, "Inactivation of Aminoglycosides by Penicillins," J Antimicrob Chemother, 1982, 8(Suppl A):27-36.
Fuchs PC, Stickel S, Anderson PH, et al, "In Vitro Inactivation of Aminoglycosides by Sulbactam, Other Beta-Lactams, and Sulbactam-Beta-Lactam Combinations," Antimicrob Agents Chemother, 1991, 35(1):182-4.
Halstenson CE, Wong MO, Herman CS, et al, "Effect of Concomitant Administration of Piperacillin on the Dispositions on Isepamicin and Gentamicin in Patients With End-Stage Renal Disease," Antimicrob Agents Chemother, 1992, 36(9):1832-36.
Hitt CM, Patel KB, Nicolau DP, et al, "Influence of Piperacillin-Tazobactam on Pharmacokinetics of Gentamicin Given Once Daily," Am J Health Syst Pharm, 1997, 54(23):2704-8.
Keller E, Bohler J, Busse-Grawitz A, et al, “Single Dose Kinetics of Piperacillin During Continuous Arteriovenous Hemodialysis in Intensive Care Patients,” Clin Nephrol, 1995, 43(Suppl 1):20-3.
Konishi H, Goto M, Nakamoto Y, et al, "Tobramycin Inactivation by Carbenicillin, Ticarcillin, and Piperacillin," Antimicrob Agents Chemother, 1983, 23(5):653-57.
Lau A, Lee M, Flascha S, et al, "Effect of Piperacillin on Tobramycin Pharmacokinetics in Patients with Normal Renal Function," Antimicrob Agents Chemother, 1983, 24(4):533-37.
Placzek M, Whitelaw A, Want S, et al, “Piperacillin in Early Neonatal Infection,” Arch Dis Child, 1983, 58(12):1006-9.
Prince AS and Neu HC, “Use of Piperacillin, A Semisynthetic Penicillin, in the Therapy of Acute Exacerbations of Pulmonary Disease in Patients With Cystic Fibrosis,” J Pediatr, 1980, 97(1):148-51.
Russoe ME and Atkins-Thor E, "Gentamicin and Ticarcillin in Subjects With End-Stage Renal Disease. Comparison of Two Assay Methods and Evaluation of Inactivation Rate," Clin Nephrol, 1981, 15(4):175-80.
Tan JS and File TM Jr, “Antipseudomonal Penicillins,” Med Clin North Am, 1995, 79(4):679-93.
Thirumoorthi MC, Asmar BI, Buckley JA, et al, “Pharmacokinetics of Intravenously Administered Piperacillin in Preadolescent Children,” J Pediatr, 1983, 102(6):941-6.
Thompson MIB, Russo ME, Saxon BJ, et al, "Gentamicin Inactivation by Piperacillin or Carbenicillin in Patients With End-Stage Renal Disease," Antimicrob Agents Chemother, 1982, 21(2):268-73.
Viollier AF, Standiford HC, Drusano GL, et al, "Comparative Pharmacokinetics and Serum Bactericidal Activity of Mezlocillin, Ticarcillin and Piperacillin, With and Without Gentamicin," J Antimicrob Chemother, 1985, 15(5):597-606.
Walterspiel JN, Feldman S, Van R, et al, "Comparative Inactivation of Isepamicin, Amikacin, and Gentamicin by Nine Beta-Lactams and Two Beta-Lactamase Inhibitors, Cilastatin and Heparin," Antimicrob Agents Chemother, 1991, 35(9):1875-8.
Wright AJ, “The Penicillins,” Mayo Clin Proc, 1999, 74(3):290-307.
Yoshikawa TT, “Antimicrobial Therapy for the Elderly Patient,” J Am Geriatr Soc, 1990, 38(12):1353-72.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2011
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