Pipracil (Piperacillin Sodium)

PIPRACIL®

Wyeth-Ayerst

Piperacillin Sodium

Antibiotic

Action And Clinical Pharmacology: Piperacillin is a third-generation, broad-spectrum, semisynthetic penicillin. Piperacillin is bactericidal and exerts its antibacterial action by inhibiting both septum and cell wall synthesis in the bacterial cell.

The bactericidal action of b-lactam antibiotics is related to their ability to reach and bind target proteins, the penicillin sensitive enzymes within the cytoplasmic membranes of the bacteria. These enzymes are involved in reactions essential to cell division and to maintenance of the integrity of the cell structure.

Piperacillin has been shown to have ready accessibility to target enzymes within the bacteria that mediate septum and cell wall synthesis and high inhibitory activity for cell wall enzymes. Piperacillin induces the formation of elongated forms with defective cell walls.

Pharmacokinetics: Piperacillin can be administered either i.m. or i.v. It is not absorbed when given orally. Piperacillin is rapidly absorbed after i.m. injection. In healthy volunteers, the mean peak serum concentration occurs approximately 30 minutes after a single dose of 2 g and is about 36 µg/mL. Peak serum concentrations are attained immediately after completion of i.v. injection or infusion. Serum levels after i.v. administration and renal clearance do not show dose proportionality because of saturation of the renal secretory mechanism. The serum half-life in healthy volunteers ranges from 36 minutes to 1 hour and 12 minutes.

The mean elimination half-life of piperacillin in healthy adult volunteers is 54 minutes following administration of 2 g and 68 minutes following 6 g. With concurrent administration of probenecid higher and more prolonged serum levels are reached. The oral administration of 1 g probenecid before injection produces an increase in piperacillin peak serum level of about 30%. The area under the curve (AUC) is increased by approximately 60%. Piperacillin binding to human serum proteins is low (16%). The substitution of 0.5% lidocaine for Sterile Water as a diluent in an i.m. pharmacokinetic study showed no significant difference in the area under the serum concentration curve, peak serum concentration or cumulative urine excretion of piperacillin. The serum half-lives were prolonged from 67 to 70 minutes at 3 g/day, 56 to 68 minutes at 4 g/day and 52 to 59 minutes at 6 g/day, however.

As with other penicillins, piperacillin is eliminated primarily by glomerular filtration and tubular secretion. It is rapidly excreted as unchanged drug in urine, reaching high concentrations after a single 2 g i.m. dose. In man, urinary excretion accounted for 42 to 62% of 1 to 6 g i.v. doses within 2 hours and 54 to 79% within 4 hours. Mean urinary recovery in 24 hours was 74 to 89% for i.v. doses and 57 to 59% for i.m. doses. Piperacillin urine concentrations, determined by microbioassay, were as high as 14 100 µg/mL following a 6 g i.v. dose and 8 500 µg/mL following a 4 g i.v. dose. These urine drug concentrations remained well above 1 000 µg/mL throughout the dosing interval. The elimination half-life is increased 2-fold in mild to moderate renal impairment and 5-to-6-fold in severe impairment.

Because piperacillin is excreted by the biliary route (10 to 20%) as well as the renal route, it can be used safely in appropriate dosage (see Dosage) in patients with mild to severe renal impairment and can be used in treatment of hepatobiliary infections.

Pharmacokinetic characteristics were similar for normal subjects compared to patients with cystic fibrosis, whether or not the latter received concomitant treatment with pancreatic enzymes and vitamins.

While piperacillin reduces platelet aggregation, these effects are less than those caused by ticarcillin or carbenicillin at equivalent therapeutic dosage.

There was no significant inactivation of amikacin, gentamicin or tobramycin in serum when the aminoglycoside was administered concomitantly with carbenicillin or piperacillin to subjects with normal renal function. In the urine, lowering of the concentration of tobramycin, and gentamicin to a lesser degree, by the presence of carbenicillin or piperacillin was observed. This possible inactivation effect was greater with carbenicillin than with piperacillin. No urinary inactivation of amikacin by either of these penicillins was observed. The clinical significance of these observations is unknown.

A follow-up study was conducted in patients with end-stage renal failure stabilized on chronic intermittent hemodialysis. No inactivation of piperacillin or carbenicillin in these patients was observed when gentamicin was administered concomitantly with either of these penicillins. Carbenicillin and piperacillin, however, inactivated gentamicin in these patients. Gentamicin was inactivated 4 times faster by carbenicillin than by piperacillin.

Indications And Clinical Uses: The treatment of systemic and local infections due to susceptible strains of gram-negative and gram-positive aerobic and anaerobic bacteria listed below. Because of its broad spectrum of activity, piperacillin is also suitable for the therapy of mixed infections, and the presumptive therapy of serious infections, when piperacillin-sensitive pathogens are suspected as the cause of disease.

Intra-abdominal infections including hepato-biliary and surgical infections caused by E. coli, P. aeruginosa, enterococci, Clostridium spp., anaerobic cocci, and Bacteroides spp., including B. fragilis.

Urinary tract infections (complicated and uncomplicated) caused by E. coli, Klebsiella spp., P. aeruginosa, P. mirabilis and enterococci.

Gynecological infections including endometritis and pelvic inflammatory disease caused by Bacteroides spp., including B. fragilis, anaerobic cocci, N. gonorrhoeae, and enterococci (S. faecalis).

Septicemia including bacteremia caused by E. coli, Klebsiella spp., Serratia spp., P. mirabilis, S. pneumoniae, enterococci, P. aeruginosa, Bacteroides spp., and anaerobic cocci.

Lower respiratory tract infections caused by E. coli, Klebsiella spp., Enterobacter spp., P. aeruginosa, Serratia spp., H. influenzae, Bacteroides species and anaerobic cocci. Although improvement has been noted in patients with cystic fibrosis, lasting bacterial eradication may not be achieved.

Skin and skin structure infections caused by E. coli, Klebsiella spp., Serratia spp., Acinetobacter spp., Enterobacter spp., P. aeruginosa, indole-positive Proteus spp., P. mirabilis, Bacteroides spp., including B. fragilis, anaerobic cocci and enterococci.

Bone and joint infections caused by P. aeruginosa, enterococci, Bacteroides spp., and anaerobic cocci.

Uncomplicated urethritis caused by N. gonorrhoeae.

Appropriate cultures should be made before initiating treatment. Presumptive therapy may be started while awaiting results of susceptibility tests. Treatment should be adjusted, if necessary, when results of these tests become available.

Mixed Infections: Piperacillin has also been shown to be clinically effective for the treatment of infections at various sites caused by streptococcus species, including Group A beta-hemolytic Streptococcus and S. pneumoniae. While infections caused solely by these organisms are ordinarily treated with narrower spectrum penicillins, mixed infections involving the above, and other organisms susceptible to piperacillin, may be effectively treated by the latter.

Piperacillin may be administered as single drug therapy in some situations where normally 2 antibiotics might be employed.

General: The efficacy of piperacillin has been demonstrated in infections produced by organisms resistant to other penicillins, some aminoglycosides and cephalosporins.

Combined Therapy with Other Antibiotics: In vitro synergism has been shown between piperacillin and some aminoglycosides in some bacterial strains. Piperacillin has been used clinically with aminoglycosides, especially in patients with impaired host defenses. Both drugs were used in full therapeutic doses.

Piperacillin can be used safely in combination with penicillinase-resistant penicillins, e.g. oxacillin, in mixed infections when beta-lactamase-positive S. aureus is isolated along with piperacillin-susceptible organisms.

Piperacillin may be administered concomitantly with a cephalosoporin, provided that an additive or synergistic antibacterial action of the 2 antibiotics is ascertained through in vitro tests. Based on in vitro data, cefoxitin should not be given with piperacillin when infections caused by organisms producing inducible b-lactamases are suspected or confirmed.

Contra-Indications: A history of allergic reactions to any of the penicillins and/or cephalosporins.

Piperacillin when reconstituted with lidocaine for i.m. use is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type.

Manufacturers’ Warnings In Clinical States: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with penicillins. These reactions are more apt to occur in persons with a history of sensitivity to multiple allergens.

Cross-sensitivity of patients to penicillins and cephalosporins has been reported. Before initiating therapy with piperacillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins and other allergens.

If an allergic reaction occurs, the antibiotic should be discontinued. The usual agents (antihistamines, pressor amines and corticosteroids) should be readily available.

Serious anaphylactoid reactions require immediate emergency treatment with epinephrine. Oxygen, i.v. steroids, airway management, including intubation, should also be administered as necessary.

Antibiotic-associated pseudomembranous colitis has been reported with nearly all antibacterial agents, including piperacillin, and may range in severity from mild to life-threatening. It is important to consider this diagnosis if significant diarrhea or colitis occurs during therapy. Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases, management with fluids and electrolytes, protein supplementation and treatment with an oral antibacterial drug effective against C. difficile (e.g., oral vancomycin) should be considered.

Precautions: While piperacillin possesses the characteristic low toxicity of the penicillin group of antibiotics, it is advisable to check periodically for organ dysfunction (including renal, hepatic and hematopoietic) during prolonged therapy.

Bleeding manifestations have occurred in some patients receiving beta-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 or significant leukopenia occur, piperacillin should be discontinued and appropriate therapy instituted.

The possibility of the emergence of resistant organisms and the development of 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 i.v.

Since piperacillin is excreted not only renally but also by the biliary route, it can be used at reduced dosage (see Dosage) in patients with severely restricted kidney function and in those who have had nephrotoxic reactions to other drugs.

Piperacillin is a monosodium compound containing 1.85 mEq (42.5 mg) of Nag based on molecular weight. 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, receiving cytotoxic therapy or diuretics. Electrolyte and cardiac status should also be monitored during prolonged treatment in patients with impaired cardiac function.

Antimicrobials used in high doses for short periods to treat gonorrhea may mask or delay the symptoms of incubating syphilis. Therefore, prior to treatment, patients with gonorrhea should also be evaluated for syphilis. Specimens for darkfield examination should be obtained from patients with any suspected primary lesion, and serologic tests should be performed. In all cases where concomitant syphilis is suspected, monthly serological tests should be made for a minimum of 4 months. The use of some penicillins (ampicillin, amoxicillin) has been associated with morbilliform rashes in some cases of infectious mononucleosis. Piperacillin should be used with caution, therefore, in the treatment of infections caused by susceptible organisms in patients with infectious mononucleosis.

As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Because of chemical instability, piperacillin should not be used for i.v. administration with solutions containing only sodium bicarbonate (see Dosage, Incompatability).

Piperacillin should not be added to blood products.

Drug Interactions: The mixing of piperacillin with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycosides.

Concurrent administration of probenecid results in higher and more prolonged serum levels of piperacillin.

Whenever piperacillin is administered concurrently with another antibiotic the drugs should not be mixed in the same solution but must be administered separately.

Piperacillin, when used clinically in the early postoperative period, has been implicated in the prolongation of the neuromuscular blockage of vecuronium. In a controlled clinical study, the ureidopenicillins, including piperacillin, have been reported to prolong the action of vecuronium. Caution is indicated when piperacillin is used perioperatively with vecuronium and similar neuromuscular blocking agents.

Pregnancy and Lactation: Although reproduction studies in mice and rats performed at doses up to 4 times the human dose have shown no evidence of impaired fertility or harm to the fetus, safety of piperacillin use in pregnant women has not been determined. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. It has been found to cross the placenta in rats.

Caution should be exercised when piperacillin is administered to nursing mothers. It is excreted in low concentrations in milk.

Children: Dosages for children under the age of 12 have not been established.

Adverse Reactions: Piperacillin is generally well tolerated. The most common adverse reactions have been local in nature, following i.v. or i.m. injection. The following adverse reactions may occur:

Local: In adult clinical trials thrombophlebitis was noted in 2.5% of patients. It is more likely to occur when an insufficiently diluted solution is injected into the vein. Pain, erythema, and/or induration at the injection site occurred in 1.0% of patients. Less frequent reactions, including ecchymosis, deep vein thrombosis and hematomas, have also occurred.

Hypersensitivity: Rash and/or pruritus was noted in 2.3% of patients. Drug fever was 2% (Note: The incidence of rash and fever is higher in patients with cystic fibrosis). Other less frequent findings included vesicular eruptions, positive Coombs’ tests. Anaphylactoid reactions have been reported rarely (see Warnings). Other dermatologic manifestations such as erythema multiforme and Stevens-Johnson syndrome have been reported rarely.

Gastrointestinal: Diarrhea and loose stools were noted in 3% of patients. Other less frequent reactions included vomiting, nausea, bloody diarrhea. Pseudomembranous colitis has been reported rarely.

Hepatic: increases in liver enzymes (LDH, AST, ALT), hyperbilirubinemia. Rarely, cholestatic hepatitis.

Renal: elevations of creatinine or BUN. Rarely, interstitial nephritis.

CNS: headache, dizziness, fatigue. Convulsions with high doses.

Hemic and Lymphatic: reversible leukopenia, neutropenia, thrombocytopenia and/or eosinophilia, bleeding and decreases in prothrombin time have been reported. As with other beta-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 rarely to demonstrate a decrease in serum potassium concentrations with high doses of piperacillin.

Musculoskeletal: rarely, prolonged muscle relaxation.

Other: superinfection, including candidiasis and hemorrhagic manifestations.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Other than general supportive treatment, no specific antidote is known. Excessive serum levels of piperacillin may be reduced by hemodialysis. As with other penicillins, neuromuscular excitability or convulsions have occurred following large i.v. doses. General supportive measures, including administration of phenytoin and barbiturates or other anticonvulsant drugs may be considered. Daily doses of piperacillin of at least 24 g have been administered in man without observation of adverse effects.

For treatment of hypersensitivity reactions, see Warnings.

Dosage And Administration: Piperacillin may be administered i.m. or i.v. (either in a 3 to 5 minute injection or by infusion). Dosage and route of administration should be determined by the severity of the infection and condition of the patient. The usual dosage of piperacillin for serious infections is 3 to 4 g given every 4 to 6 hours as a 20- to 30-minute infusion. For serious infections the i.v. route should be used. See Table I.

The maximum daily dose usually administered to adults is 24 g/day, although higher doses have been used.

Infants and Children: Dosages in infants and children under 12 years of age have not been established.

Duration of therapy: The average duration of piperacillin treatment is from 7 to 10 days, except in the treatment of gynecologic infections, in which it is from 3 to 10 days; the duration should be guided by the patient’s clinical and bacteriological progress. Some infections such as osteomyelitis may require significantly longer periods of therapy. For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. Antibiotic therapy for Group A beta-hemolytic streptococcal infections should be maintained for at least 10 days to reduce the risk of rheumatic fever or glomerulonephritis.

Reconstitution and Administration: I.M. injection: I.M. injections 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. Injection should be given into the upper outer quadrant of the buttock (i.e., gluteus maximus).

When indicated by clinical and bacteriological findings, i.m. administration of 6 to 8 g daily of piperacillin, in divided doses, may be utilized for initiation of therapy. In addition, i.m. administration of the drug may be considered for maintenance therapy after clinical and bacteriological improvement has been obtained with i.v. piperacillin treatment.

The deltoid area should be used only if well-developed, and then only with caution to avoid radial nerve injury. I.M. injections should not be made into the lower or mid-third of the upper arm.

Solutions for Reconstitution: Sterile water for injection or 0.5 to 1.0% lidocaine HCl (without epinephrine) in sterile water for injection. (Lidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type).

The Pharmacy Bulk Vial is intended for multiple dispensing for i.v. use only, employing a single puncture. Following reconstitution (see Table IV), the solution should be further diluted to the desired volume in any appropriate i.v. solution or i.v. admixture listed below.

Any unused reconstituted solution should be discarded after 8 hours.

I.V. Solutions: Dextrose 5% in Water (D5W), 0.9% sodium chloride (Normal Saline) [NS], dextrose 5% and 0.9% sodium chloride (D5NS), Lactated Ringer’s Injection, USP, dextran 6% in 0.9% sodium chloride.

I.V. Admixtures: Normal saline [+KCl 40 mEq/500 mL], 5% dextrose in water (D5W) [+KCl 40 mEq/500 mL], Ringer’s Injection, USP [+KCl 40 mEq/500 mL], 5% Dextrose/Normal Saline (D5Ns) [+KCl 40 mEq/500 mL], Lactated Ringer’s Injection, USP [+KCl 40 mEq/500 mL].

Note: Because of chemical instability, piperacillin should not be used for i.v. administered with solutions containing only sodium bicarbonate (see Incompatibility).

Stability of Solutions: Stability studies have demonstrated chemical stability (pH, potency and clarity) through 24 hours at room temperature and up to 72 hours refrigerated. Appropriate consideration of aseptic technique recommends discarding unused portions after storage for 24 hours at room temperature or 48 hours refrigerated.

Piperacillin is stable in both glass and plastic containers when reconstituted with recommended diluents and further diluted with the indicated i.v. solutions and i.v. admixtures.

Incompatibility: Piperacillin should not be added to blood products.

Because of chemical instability, piperacillin should not be used for i.v. administration with solutions containing sodium bicarbonate alone. It may be used with i.v. admixtures containing other ingredients as well as sodium bicarbonate for up to 24 hours at room temperature and 48 hours refrigerated.

Solutions containing piperacillin and protein hydrolysates or amino acids should be used within 12 hours if stored at room temperature and 24 hours if refrigerated.

Availability And Storage: 2 g: Each vial contains: sterile piperacillin sodium lyophilized powder equivalent to 2 g of piperacillin. Tartrazine-free. Boxes of 10.

3 g: Each vial contains: sterile piperacillin sodium lyophilized powder equivalent to 3 g of piperacillin. Tartrazine-free. Boxes of 10.

4 g: Each vial contains: sterile piperacillin sodium lyophilized powder equivalent to 4 g of piperacillin. Tartrazine-free. Boxes of 10.

40 g: Each vial contains: sterile piperacillin sodium lyophilized powder equivalent to 40 g of piperacillin. Tartrazine-free. Single vials of 40 g.

Store at controlled room temperatures 15 to 30°C.

PIPRACIL® Wyeth-Ayerst Piperacillin Sodium Antibiotic

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