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Medically reviewed by Militian Inessa Mesropovna, PharmD. Last updated on 10.04.2022
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Therapeutic: PIPRACIL (piperacillin sodium) is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below:
Intra-Abdominal Infections including hepatobiliary and surgical infections caused by E. coli, Pseudomonas aeruginosa, enterococci, Clostridium spp., anaerobic cocci, or Bacteroides spp., including B. fragilis.
Urinary Tract Infections caused by E. coli, Klebsiella spp., P. aeruginosa, Proteus spp., including P. mirabilis, or enterococci.
Gynecologic Infections including endometritis, pelvic inflammatory disease, pelvic cellulitis caused by Bacteroides spp., including B. fragilis, anaerobic cocci, Neisseria gonorrhoeae, or enterococci (E. faecalis).
Septicemia including bacteremia caused by E. coli, Klebsiella spp., Enterobacter spp., Serratia spp., P. mirabilis, S. pneumoniae, enterococci, P. aeruginosa, Bacteroides spp., or anaerobic cocci.
Lower Respiratory Tract Infections caused by E. coli, Klebsiella spp., Enterobacter spp., P. aeruginosa, Serratia spp., H. influenzae, Bacteroides spp., or anaerobic cocci. Although improvement has been noted in patients with cystic fibrosis, lasting bacterial eradication may not necessarily be achieved.
Skin and Skin Structure Infections caused by E. coli, Klebsiella spp., Serratia spp., Acinetobacter spp., Enterobacter spp., P. aeruginosa, Morganella morganii, Providencia rettgeri, Proteus vulgaris, P. mirabilis, Bacteroides spp., including B. fragilis, anaerobic cocci, or enterococci.
Bone and Joint Infections caused by P. aeruginosa, enterococci, Bacteroides spp., or anaerobic cocci.
Uncomplicated Gonococcal Urethritis caused by N. gonorrhoeae.
PIPRACIL (piperacillin sodium) has also been shown to be clinically effective for the treatment of infections at various sites caused by Streptococcus species including S. pyogenes and S. pneumoniae; however, infections caused by these organisms are ordinarily treated with more narrow spectrum penicillins. Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, PIPRACIL (piperacillin sodium) is particularly useful for the treatment of mixed infections and presumptive therapy prior to the identification of the causative organisms.
Also, PIPRACIL (piperacillin sodium) may be administered as single drug therapy in some situations where normally two antibiotics might be employed.
Piperacillin has been successfully used with aminoglycosides, especially in patients with impaired host defenses. Both drugs should be used in full therapeutic doses.
Appropriate cultures should be made for susceptibility testing before initiating therapy and therapy adjusted, if appropriate, once the results are known.
Prophylaxis: PIPRACIL (piperacillin sodium) is indicated for prophylactic use in surgery including intra-abdominal (gastrointestinal and biliary) procedures, vaginal hysterectomy, abdominal hysterectomy, and cesarean section. Effective prophylactic use depends on the time of administration; PIPRACIL (piperacillin sodium) should be given one-half to one hour before the operation so that effective levels can be achieved in the site prior to the procedure.
The prophylactic use of piperacillin should be stopped within 24 hours, since continuing administration of any antibiotic increases the possibility of adverse reactions, but in the majority of surgical procedures, does not reduce the incidence of subsequent infections. If there are signs of infection, specimens for culture and susceptibility testing should be obtained for identification of the causative microorganism so that appropriate therapy can be instituted.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of PIPRACIL (piperacillin sodium) and other antibacterial drugs, PIPRACIL (piperacillin sodium) should only be used 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.
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PIPRACIL (piperacillin sodium) may be administered by the intramuscular route (see NOTE) or intravenously as a three- to five-minute intravenous injection or as a 20- to 30-minute infusion. The usual dosage of PIPRACIL (piperacillin sodium) for serious infections is 3 to 4 g given every four to six hours as a 20- to 30-minute infusion. For serious infections, the intravenous route should be used.
PIPRACIL (piperacillin sodium) should not be mixed with an aminoglycoside in a syringe or infusion bottle since this can result in inactivation of the aminoglycoside.
The maximum daily dose for adults is usually 24 g/day, although higher doses have been used. Intramuscular injections (see NOTE) should be limited to 2 g per injection site. This route of administration has been used primarily in the treatment of patients with uncomplicated gonorrhea and urinary tract infections.
DOSAGE RECOMMENDATIONS
Type of Infection | Usual Total Daily Dose |
Serious infections such as septicemia, nosocomial pneumonia, intra-abdominal infections, aerobic and anaerobic gynecologic infections, and skin and soft tissue infections | 12 - 18 g/d I.V. (200 -300 mg/kg/d) in divided doses every 4 to 6 h |
Complicated urinary tract infections | 8 - 16 g/d I.V. (125 -200 mg/kg/d) in divided doses every 6 to 8 h |
Uncomplicated urinary tract infections and most community-acquired pneumonia | 6 - 8 g/d I.M. or I.V. (100 -125 mg/kg/d) in divided doses every 6 to 12 h |
Uncomplicated gonorrhea infections | 2 g I.M.† as a one-time dose |
† One g of probenecid should be given orally one-half hour prior to injection. |
The average duration of PIPRACIL (piperacillin sodium) treatment is from seven to ten days, except in the treatment of gynecologic infections, which is from three to ten days; the duration should be guided by the patient's clinical and bacteriological progress. For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. Antibiotic therapy for S. pyogenes infections should be maintained for at least ten days to reduce the risk of rheumatic fever.
When PIPRACIL (piperacillin sodium) is given concurrently with aminoglycosides, both drugs should be used in full therapeutic doses.
Renal Impairment
Dosage in Renal Impairment
Creatinine Clearance mL/min | Urinary Tract Infection (uncomplicated) | Urinary Tract Infection (complicated) | Serious Systemic Infection |
> 40 | No dosage adjustment necessary | ||
20-40 | No dosage adjustment necessary | 9 g/day 3 g every 8 h | 12 g/day 4 g every 8 h |
< 20 | 6 g/day 3 g every 12 h | 6 g/day 3 g every 12 h | 8 g/day 4 g every 12 h |
For patients on hemodialysis, the maximum daily dose is 6 g/day (2 g every 8 hours). In addition, because hemodialysis removes 30% to 50% of piperacillin in 4 hours, a 1-g additional dose should be administered following each dialysis period.
For patients with renal failure and hepatic insufficiency, measurement of serum levels of piperacillin will provide additional guidance for adjusting dosage.
Prophylaxis
When possible, PIPRACIL (piperacillin sodium) should be administered as a 20- to 30-minute infusion just prior to anesthesia. Administration while the patient is awake will facilitate identification of possible adverse reactions during drug infusion. (See PRECAUTION: DRUG INTERACTIONS.)
INDICATION | 1st Dose | 2nd Dose | 3rd Dose |
Intra-abdominal Surgery | 2 g I.V. just prior to surgery | 2 g during surgery | 2 g every 6 h Post-Op for no more than 24 h |
Vaginal Hysterectomy | 2 g I.V. just prior to surgery | 2 g 6 h after 1st dose | 2 g 12 h after 1st dose |
Cesarean Section | 2 g I.V. after cord is clamped | 2 g 4 h after 1st dose | 2 g 8 h after 1st dose |
Abdominal Hysterectomy | 2 g I.V. just prior to surgery | 2 g on return to recovery room | 2 g after 6 h |
Pediatric patients. Dosages in pediatric patients under 12 years of age have not been studied in adequate and well-controlled clinical trials (See CLINICAL PHARMACOLOGY).
PRODUCT RECONSTITUTION/DOSAGE PREPARATION
Conventional Vials: | |
Diluents for Reconstitution | |
Sterile Water for Injection | Sodium Chloride Injection |
Bacteriostatic¶ Water for Injection | Bacteriostatic¶ Sodium Chloride Injection Dextrose 5% in Water Dextrose 5% and 0.9% Sodium Chloride Lidocaine#HCl 0.5-1% (without epinephrine) |
¶Either Parabens or Benzyl Alcohol. #For Intramuscular Use Only. Lidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type. |
Conventional Vials: | |
Intravenous Solutions | Intravenous Admixtures |
Dextrose 5% in Water | Normal Saline [+ KCl 40 mEq] |
0.9% Sodium Chloride | 5% Dextrose in Water [+ KCl 40 mEq] |
Dextrose 5% and 0.9% Sodium Chloride | 5% Dextrose/Normal Saline [+ KCl 40 mEq] |
Lactated Ringer's Injection† † | Ringer's Injection [+ KCl 40 mEq] |
Dextran 6% in 0.9% Sodium Chloride | Lactated Ringer's Injection [+ KCl 40 mEq] † † |
† † When PIPRACIL® is further diluted with Lactated Ringer's Injection, the diluted solution must be administered within 2 hours. |
Intravenous Administration
Reconstitution Directions for Conventional Vials: Reconstitute each gram of PIPRACIL (piperacillin sodium) with at least 5 mL of a suitable diluent (except Lidocaine HCl 0.5%-1% without epinephrine) listed above. Shake well until dissolved. Reconstituted solution may be diluted to the desired volume (eg, 50 or 100 mL) in the above listed intravenous solutions and admixtures.
Directions for Administration
Intermittent IV Infusion
Infuse diluted solution over period of about 30 minutes. During infusion, it is desirable to discontinue the primary intravenous solution.
Intravenous Injection (Bolus)
Reconstituted solution should be injected slowly over a 3-to 5-minute period to help avoid vein irritation.
Intramuscular Administration
(Conventional Vials Only)
Reconstitution Directions: Reconstitute each gram of PIPRACIL (piperacillin sodium) with 2 mL of a suitable diluent listed above to achieve a concentration of 1 g per 2.5 mL. Shake well until dissolved.
Directions for Administration
When indicated by clinical and bacteriological findings, intramuscular administration of 6 to 8 g daily of PIPRACIL (piperacillin sodium) , in divided doses, may be utilized for initiation of therapy. In addition, intramuscular administration of the drug may be considered for maintenance therapy after clinical and bacteriologic improvement has been obtained with intravenous piperacillin sodium treatment. Intramuscular administration should not exceed 2 g per injection at any one site.
The preferred site is the upper outer quadrant of the buttock (ie, gluteus maximus).
The deltoid area should be used only if well-developed, and then only with caution to avoid radial nerve injury. Intramuscular injections should not be made into the lower or mid-third of the upper arm.
Stability of PIPRACIL (piperacillin sodium) Following Reconstitution
PIPRACIL (piperacillin sodium) is stable in both glass and plastic containers when reconstituted with recommended diluents and when diluted with the intravenous solutions and intravenous admixtures indicated above.
Pharmacy vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20° to 25°C [68° to 77°F]), or after 48 hours if stored at refrigerated temperature (2° to 8°C [36° to 46°F]). Vials should not be frozen after reconstitution.
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PIPRACIL (piperacillin sodium) is contraindicated in patients with a history of allergic reactions to any of the betalactams, including penicillins and/or cephalosporins.
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WARNINGS
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC/ANAPHYLACTOID) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH PIPRACIL (piperacillin sodium) , CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PIPRACIL (piperacillin sodium) SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC/ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including PIPRACIL (piperacillin sodium) , 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.
C. 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
PRECAUTIONS
General
Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics, 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, the antibiotic should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms which might cause superinfections should be kept in mind, particularly during prolonged treatment. If this occurs, appropriate measures should be taken.
As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.
PIPRACIL (piperacillin sodium) is a monosodium salt containing 1.85 mEq of Na+ per g (42.5 mg of Na+ per g). This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be made in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.
Leukopenia and neutropenia may occur during prolonged therapy.
As with other semisynthetic penicillins, PIPRACIL (piperacillin sodium) therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Prescribing PIPRACIL (piperacillin sodium) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Laboratory Tests
While piperacillin possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, during prolonged therapy is advisable.
All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with piperacillin should have a follow-up serologic test for syphilis after 3 months.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Mutagenesis
Piperacillin was negative in the Ames Salmonella reversion test at concentrations up to 10 μg/plate. There was no DNA damage in bacteria (Rec assay) exposed to piperacillin at concentrations up to 200 μg/disc. In a mammalian point mutation (mouse lymphoma cells) assay, piperacillin was positive at concentrations ≥ 2500 μg/mL. Piperacillin was negative in a cell (BALB/c-3T3) transformation assay at concentrations up to 3000 μg/mL. In vivo, piperacillin did not induce chromosomal aberrations in the bone marrow cells of mice at I.V. doses up to 2000 mg/kg/day or rats at I.V. doses up to 1500 mg/kg/day. These doses are half (mice) or three-fourths (rats) the maximum recommended human daily dose based on body-surface area (mg/m²). In another in vivo test, there was no dominant lethal effect when piperacillin was administered to rats at I.V. doses up to 2000 mg/kg/day, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m²). When piperacillin was administered to mice at I.V. doses up to 2000 mg/kg/day, which is half the maximum recommended human daily dose based on body-surface area (mg/m²), urine from these animals was not mutagenic when tested in the Ames assay using Salmonella strain TA-98 in the absence of β-glucuronidase.
Impairment of Fertility
Reproduction studies have been performed in mice (SQ) and rats (I.P.) and have revealed no evidence of impaired fertility due to piperacillin administered up to a dose which is half (mice) or similar (rats) to the maximum recommended human daily dose based on body-surface area (mg/m²). The plasma/serum concentrations at the highest daily dose administered to rats in reproduction studies were comparable to the maximum serum concentration seen in man, based on a toxicology study in rats in which similar doses of piperacillin (in combination with a beta-lactamase inhibitor, tazobactam) were administered I.P. and based on extrapolations from an animal pharmacokinetic study using lower doses of piperacillin alone.
Pregnancy
Teratogenic effects-Pregnancy Category B
Teratology studies have been performed in mice (I.V.) and rats (I.V., I.P. and SQ) and have revealed no evidence of harm to the fetus due to piperacillin administered up to a dose which is approximately half the maximum recommended human daily dose based on body-surface area (mg/m²). In pharmacokinetic studies in pregnant and nonpregnant rats, in which piperacillin was administered I.V. at a dose which is half the maximum daily dose administered in teratology studies, serum concentrations in rats were approximately 10 times the maximum serum concentration seen in man. In other studies in mice and rats, in which piperacillin (in combination with a beta-lactamase inhibitor, tazobactam) was administered I.V. at approximately half the maximum daily dose administered in teratology studies, plasma concentrations of piperacillin were approximately 2 times (mice) and 5 times (rats) the serum concentrations seen in man.
There are, however, no adequate and well-controlled studies with piperacillin in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Piperacillin is excreted in low concentrations in human milk. Caution should be exercised when PIPRACIL (piperacillin sodium) is administered to nursing mothers.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Data from published pharmacokinetics studies indicate that the elimination half-life of piperacillin in neonates is twofold to fourfold longer than that seen in pediatric patients 1 month of age and above as well as in adults. In infants, children, and adolescents, the elimination half-life of piperacillin is shorter than that observed in adults. As in adults, the elimination of piperacillin is decreased in pediatric patients with renal impairment. (See CLINICAL PHARMACOLOGY.)
Geriatric Use
Clinical studies of PIPRACIL (piperacillin sodium) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
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.
PIPRACIL (piperacillin sodium) contains 42.5 mg (1.85 mEq) of sodium per gram. At the usual recommended doses, patients would receive between 255 and 765 mg/day (11.1 and 33.3 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. The total sodium content from dietary and non-dietary sources may be clinically important with regard to such diseases as congestive heart failure.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
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PIPRACIL (piperacillin sodium) is generally well tolerated. The most common adverse reactions have been local in nature, following intravenous or intramuscular injection. The following adverse reactions may occur:
Local Reactions: In clinical trials thrombophlebitis was noted in 4% of patients. Pain, erythema, and/or induration at the injection site occurred in 2% of patients. Less frequent reactions including ecchymosis, deep vein thrombosis, and hematomas have also occurred.
Gastrointestinal: Diarrhea and loose stools were noted in 2% of patients. Other less frequent reactions included vomiting, nausea, increases in liver enzymes (LDH, AST, ALT), hyperbilirubinemia, cholestatic hepatitis, bloody diarrhea, and pseudomembranous colitis. The onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.)
Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions (some leading to shock and fatalities) have been reported. (See WARNINGS.)
Rash was noted in 1% of patients. Other less frequent findings included pruritus, vesicular eruptions, and positive Coombs tests.
Other dermatologic manifestations, such as erythema multiforme, urticaria, toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported.
Renal: Elevations of creatinine or BUN, renal failure and interstitial nephritis have been reported.
Central Nervous System: Headache, dizziness, fatigue, and seizures have been reported.
Hemic and Lymphatic: Hemolytic anemia, agranulocytosis, pancytopenia, prolonged bleeding time, reversible leukopenia, neutropenia, thrombocytopenia, and/or eosinophilia have been reported. As with other β-lactam antibiotics, reversible leukopenia (neutropenia) is more apt to occur in patients receiving prolonged therapy at high dosages or in association with drugs known to cause this reaction.
Serum Electrolytes: Individuals with liver disease or individuals receiving cytotoxic therapy or diuretics were reported to demonstrate a decrease in serum potassium concentrations with high doses of piperacillin. Hypokalemia has been reported.
Skeletal: Prolonged muscle relaxation (see PRECAUTIONS: DRUG INTERACTIONS).
Other: Fever, superinfection, including candidiasis; hemorrhagic manifestations have been reported.
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
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There is no specific information on overdose with PIPRACIL (piperacillin sodium). Other penicillin-class drugs in overdosage, however, have the potential to cause neuromuscular hyperirritability or convulsive seizures. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. Piperacillin can be removed by hemodialysis but not peritoneal dialysis.
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PIPRACIL (piperacillin sodium) is not absorbed when given orally. Peak serum concentrations are attained approximately 30 minutes after intramuscular injections and immediately after completion of intravenous injection or infusion. The serum half-life in healthy volunteers ranges from 36 minutes to one hour and 12 minutes. The mean elimination half-life of PIPRACIL (piperacillin sodium) in healthy adult volunteers is 54 minutes following administration of 2 g and 63 minutes following 6 g. As with other penicillins, PIPRACIL (piperacillin sodium) is eliminated primarily by glomerular filtration and tubular secretion; it is excreted rapidly as unchanged drug in high concentrations in the urine. Approximately 60% to 80% of the administered dose is excreted in the urine in the first 24 hours. Piperacillin urine concentrations, determined by microbioassay, are as high as 14,100 μg/mL following a 6-g intravenous dose and 8,500 μg/mL following a 4-g intravenous dose. These urine drug concentrations remain well above 1,000 μg/mL throughout the dosing interval.
Distribution
PIPRACIL (piperacillin sodium) binding to human serum proteins is 16%. The drug is widely distributed in human tissues and body fluids, including bone, prostate, and heart, and reaches high concentrations in bile. After a 4-g bolus injection, maximum biliary concentrations average 3,205 μg/mL. It penetrates into the cerebrospinal fluid in the presence of inflamed meninges.