Vademecum

PIPERACILINA

Description: Piperacillin is a parenteral, semisynthetic, extended-spectrum acylureidopenicillin. Extended-spectrum penicillins, such as piperacillin, are used mainly in the treatment of serious, gram-negative infections and in combination with an aminoglycoside to treat systemic Pseudomonas infections. Clinically, piperacillin is used to treat intra-abdominal infections, respiratory and urinary tract infections, skin and soft-tissue infections, and other infections caused by susceptible organisms. Piperacillin was approved by the FDA in 1981. Its patent expired in September 1995. Mechanism of Action: Piperacillin is a beta-lactam antibiotic and is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinisic activity of piperacillin, as well as the other penicillins, against a particular organism depends on its ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, piperacillin's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor. Piperacillin is active against many bacteria, but it is susceptible to the beta-lactamases produced by many gram-positive and gram-negative bacteria. The extended-spectrum penicillins are not used in the treatment of infections caused by gram-positive bacteria because penicillin G and ampicillin are more potent against these organisms. In general, the extended-spectrum penicillins have greater activity than other penicillins against gram-negative bacteria (especially Pseudomonas and Proteus) due to enhanced penetration through the cell wall of these bacteria. This activity is due, in part, to the presence of a large polar group in the side chains of these antibiotics. Piperacillin is the most potent of the extended-spectrum penicillins against Pseudomonas, and, among these agents, the relative potency against Pseudomonas is as follows: piperacillin > mezlocillin = ticarcillin > carbenicillin. In addition to Pseudomonas, piperacillin's gram-negative spectrum includes Enterobacter species, E. coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia, Serratia, and N. gonorrhoeae. Its anaerobic spectrum includes the Peptococcus and Peptostreptococcus species, Clostridium perfringes, Clostridium tetani, and Bacteroides including many strains of B. fragilis. Piperacillin in combination with an aminoglycoside is synergistic in treating gram-negative infections, especially Pseudomonas lung infections. Clinicians are advised to consult susceptibility data at the institution in which they practice to determine piperacillin's activity. Pharmacokinetics: Piperacillin is administered parenterally. Peak serum levels of piperacillin occur within 30�50 minutes following an IM dose. Approximately 16�22% of the circulating drug is protein-bound. It is distributed into the kidneys; heart; gallbladder; bone; bile; urine; and peritoneal, pleural, and synovial fluids. It reaches minimal levels within the CSF when the meninges are uninflamed; these levels increase in the presence of inflammation. The drug crosses the placenta. Piperacillin does not appear to be appreciably metabolized, although its exact metabolic fate is not known. The majority of the drug is excreted into the urine primarily via tubular secretion and glomerular filtration. Approximately 10�20% of a dose is excreted via biliary excretion. A small percentage is excreted in breast milk. In patients with normal renal function, the elimination half-life of piperacillin is 30�90 minutes. The elimination half-life increases to up to 2�6 hours in patients with end-stage renal disease. In patients with combined renal and hepatic dysfunction, the elimination half-life increases to 11�32 hours. Dosages need to be adjusted accordingly.

Indications...Dosage The following organisms are generally considered susceptible to piperacillin in vitro; however, safety and effectiveness in treating clinical infections due to these microorganisms may not be established: Acinetobacter sp.; Actinomyces sp.; Bacteroides fragilis; Prevotella melaninogenica; Bacteroides sp.; Bacteroides vulgatus; Bifidobacterium sp.; Brevundimonas vesicularis; Burkholderia cepacia; Citrobacter diversus; Citrobacter freundii; Citrobacter sp.; Clostridium difficile; Clostridium perfringens; Clostridium sp.; Eikenella corrodens; Enterobacter aerogenes; Enterobacter cloacae; Enterobacter sp.; Enterococcus faecalis; Enterococcus faecium; Escherichia coli; Eubacterium sp.; Flavobacterium sp.; Fusobacterium sp.; Haemophilus influenzae (beta-lactamase negative); Haemophilus parainfluenzae; Klebsiella pneumoniae; Klebsiella sp.; Lactobacillus sp.; Moraxella sp.; Morganella morganii; Neisseria meningitidis; Peptococcus sp.; Peptostreptococcus sp.; Propionibacterium sp.; Proteus mirabilis; Proteus vulgaris; Providencia rettgeri; Providencia stuartii; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pseudomonas stutzeri; Salmonella sp.; Serratia liquefaciens; Serratia marcescens; Serratia sp.; Shigella sp.; Stenotrophomonas maltophilia; Streptococcus agalactiae (group B streptococci); Streptococcus dysgalactiae; Streptococcus pneumoniae; Streptococcus pyogenes (group A beta-hemolytic streptococci); Veillonella sp.; Viridans streptococci; Yersinia sp. For the treatment of moderate to severe bacterial infection including lower respiratory tract infections (e.g. pneumonia), skin and skin structure infections (e.g. cellulitis, diabetic foot ulcer), bone and joint infections (e.g. osteomyelitis, infectious arthritis), intraabdominal infections, gynecologic infections (e.g. endometritis, pelvic cellulitis) including pelvic inflammatory disease (PID), bacteremia or septicemia, caused by susceptible bacterial organisms and for empiric anti-infective management of febrile neutropenia: Parenteral dosage: Adults and adolescents: The recommended dose is 12�18 g/day IV (200�300 mg/kg/day) in divided doses every 4�6 hours. Maximum daily dose is 24 g/day. IM injections should be limited to 2 g/injection site and are used for uncomplicated infections. When administered in combination with ciprofloxacin for the treatment of febrile neutropenia, the recommended piperacillin dosage is 50 mg/kg IV every 4 hours (not to exceed 24 g/day) for 7�14 days. Children and infants�: Doses of 200�300 mg/kg/day IV in divided doses every 4�6 hours have been used. The maximum dose is 24 g/day. Neonates > 7 days�: A dose of 200 mg/kg/day IV in divided doses every 6 hours has been used. Neonates < 7 days�: A dose of 150 mg/kg/day IV in divided doses every 8 hours has been used. �for the treatment of community acquired pneumonia: Parenteral dosage: Adults: The recommended dose is 6�8 g/day IV or IM (100�125 mg/kg/day) in divided doses every 6�12 hours. �for the treatment of pulmonary infection secondary to complications of cystic fibrosis (e.g. bronchiectasis, pneumonia) caused by susceptible bacterial organisms: Intravenous dosage: Adults and children: The recommended dose is 350�450 mg/kg/day IV in divided doses. For the treatment of meningitis� caused by susceptible bacterial organisms: Parenteral dosage: Adults and adolescents: A dose of 4 g IV every 4 hours or 75 mg/kg IV every 6 hours has been used. Children and infants�: Doses of 200�300 mg/kg/day IV in divided doses every 4�6 hours have been used. The maximum dose is 24 g/day. Neonates > 7 days weighing >= 2000 g�: A dose of 50 mg/kg IV or IM every 6 hours has been used. Neonates > 7 days weighing < 2000 g�: A dose of 50 mg/kg IV or IM every 8 hours has been used. Neonates < 7 days weighing >= 2000 g�: A dose of 50 mg/kg IV or IM every 8 hours has been used. Neonates < 7 days weighing < 2000 g�: A dose of 50 mg/kg IV or IM every 12 hours has been used. For the treatment of endocarditis� due to Pseudomonas aeruginosa or Serratia sp.: Intravenous dosage: Adults: Although the optimal dosage has not been established, large doses (e.g., 18�24 g/day IV in divided doses every 4�6 hours) are usually necessary to achieve adequate bactericidal concentrations within vegetations. Piperacillin should generally be administered in combination with therapeutic doses of an aminoglycoside for this condition. For the treatment of urinary tract infection (UTI): �for the treatment of uncomplicated urinary tract infection (UTI): Parenteral dosage: Adults: The recommended dose is 6�8 g/day IV or IM (100�125 mg/kg/day) in divided doses every 6�12 hours. �for the treatment of complicated urinary tract infection (UTI): Intravenous dosage: Adults: The recommended dose is 3�4 g IV every 6�8 hours. For the treatment of uncomplicated gonorrhea due to Neisseria gonorrhoeae when the infecting strain has been tested and found to be susceptible to piperacillin: NOTE: Piperacillin is not included in current CDC recommendations for the treatment of gonorrhea,[1632] however, the manufacturer's product literature offers the following dosage: Intramuscular dosage: Adults: The recommended dose is 2 g IM as a single dose with 1 g PO probenecid given 30 minutes prior to injection. For surgical prophylaxis in contaminated or potentially contaminated procedures: �for surgical prophylaxis during intra-abdominal (gastrointestinal and biliary) procedures: Intravenous dosage: Adults: The recommended dose is 2 g IV 30�60 minutes prior to surgery, 2 g IV during surgery, and 2 g IV every 6 hours post-op for no more than 24 hours. �for surgical prophylaxis during vaginal hysterectomy: Intravenous dosage: Adults: The recommended dose is 2 g IV 30�60 minutes prior to surgery, then 2 g IV six hours and twelve hours after the first dose. �for surgical prophylaxis during cesarean section: Intravenous dosage: Adults: The recommended dose is 2 g IV after the cord is clamped, then 2 g IV four hours and eight hours after the first dose. �for surgical prophylaxis during abdominal hysterectomy: Intravenous dosage: Adults: The recommended dose is 2 g IV just prior to surgery, then 2 g IV on return to the recovery room, then 2 g IV 6 hours later. Patients with renal impairment: CrCl > 40 ml/min: No dosage adjustment needed. CrCl 20�40 ml/min: Extend dosing interval to every 8 hours. CrCl <20 ml/min: Extend dosing interval to every 12 hours. Intermittent hemodialysis: About 30�50% of a dose of piperacillin is removed during a standard intermittent hemodialysis session. The manufacturer recommends a maximum dosage of 2 g IV every 8 hours and an additional 1 g IV dose after each standard dialysis session. Continuous hemodialysis (CAVHD, CVVHD): Definitive dosage recommendations have not been established. Piperacillin is significantly removed by CAVHD or CVVHD. A daily dose 1.5 times that used for anuric nondialyzed patients has been recommended, assuming a combined dialysis and ultrafiltrate flow rate of 1.5 L/hr.[1493] Peritoneal dialysis: Extend dosing interval to every 12 hours.

Administration Parenteral Administration �Piperacillin is administered parenterally. �Solutions prepared from ADD-Vantage� vials or pharmacy bulk packages are for IV infusion only and should not be used for direct IV injection or IM. �Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Intramuscular injection: �IM injections should not exceed 2 g at any one site. �Reconstitute each gram with at least 2 ml of sterile or bacteriostatic water for injection, sterile or bacteriostatic sodium chloride injection, or 0.5 or 1% lidocaine HCl injection (without epinephrine). Vigorous agitation immediately after adding diluent will facilitate dissolution. The resulting IM solutions contain 400 mg/ml of piperacillin. �Withdraw appropriate dose and inject into the gluteus maximus; the deltoid area should only be used if well-developed and with caution to avoid injury to the radial nerve. Injections should not be made into the lower or mid-third of the upper arm. Aspirate prior to injection to avoid injection into a blood vessel. Direct intermittent IV injection: �Reconstitute each gram with at least 5 ml of sterile water for injection, sodium chloride injection, D5W injection, D5NS, or bacteriostatic water (containing parabens or benzyl alcohol). Vigorous agitation may be necessary to dissolve the drug. �Inject appropriate dose directly into a vein over 3�5 minutes. Intermittent IV infusion: �Vials: Further dilute reconstituted solution to at least 50 ml with a compatible IV solution. �ADD-Vantage� vials: Reconstitute according to manufacturer's instructions. �Pharmacy bulk packages: Reconstitute the 40 g vial with 172 ml of a compatible IV infusion solution (except lidocaine 0.5�1% without epinephrine). The resultant IV solution contains 200 mg/ml. Dilute as above for vials. �Infuse appropriate dose IV over 30 minutes.

Contraindications Piperacillin should be used with caution in patients with renal disease or renal impairment since the drug is eliminated via renal mechanisms. Because the sodium content of piperacillin is lower than that of ticarcillin and carbenicillin, however, it may be more advantageous to use piperacillin in these patients. Piperacillin is partially excreted unchanged in the bile. Excretion may be reduced in patients with hepatic disease such as common bile duct obstruction. Because piperacillin can cause hypokalemia, it should be used with caution in patients who already have hypokalemia or who may have low potassium stores. Serum electrolytes may need to be monitored in all patients receiving the drug. Piperacillin is a penicillin, and should not be used in patients with penicillin hypersensitivity. Due to piperacillin's structural similarity to the cephalosporins, it should be used cautiously in patients with cephalosporin hypersensitivity or imipenem hypersensitivity, because they are more susceptible to cross-hypersensitivity reactions. Patients with allergies or allergic conditions including asthma, eczema, hives, or hay fever may have a greater risk for hypersensitivity reactions to penicillins. Piperacillin is relatively contraindicated in patients with a coagulopathy (e.g., hemophilia) because the drug can inhibit platelet aggregation. Its use in these patients or in patients with other bleeding disorders can increase the risk of bleeding. Antibiotic therapy can result in superinfection or suprainfection with nonsusceptible organisms. Overgrowth of Candida, Serratia, Klebsiella, or P. aeruginosa can occur with extended-spectrum penicillin therapy. Patients should be monitored closely during therapy. Penicillins should be used with caution in patients with a history of GI disease, especially colitis, because the adverse GI effects associated with penicillin therapy can exacerbate the condition. Also, patients who develop diarrhea while taking or soon after taking penicillins should be considered for differential diagnosis of antibiotic-associated pseudomembranous colitis. Penicillins are excreted in breast milk. Penicillins may cause diarrhea, candidiasis, and skin rash in breast-feeding infants. The potential risk to the infant should be considered versus the potential benefit in the mother. A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins and using Benedict's solution, Fehling's solution, and Clinitest� tablets. However, this reaction has not been observed with Tes-tape� (glucose Enzymatic Test Strip, USP, Lilly).

Interactions Probenecid inhibits renal tubular secretion of piperacillin, causing higher, prolonged serum levels of the drug. In general, this pharmacokinetic interaction is not harmful and, in some patients, may be desirable. Clinicians should note, however, that high concentrations of penicillin have been associated with seizures, although this effect usually occurs in patients with renal impairment who receive large, IV doses of penicillin. Concomitant use of some beta-lactam antibiotics with aminoglycosides can provide additive or synergistic activity against some bacteria. Combination therapy with a penicillin and an aminoglycoside is usually recommended against enterococci. The combination of piperacillin with an aminoglycoside can be additive or synergistic against some gram-negative organisms such as Pseudomonas aeruginosa, E. coli, Klebsiella, Citrobacter, Enterobacter, Serratia, and Proteus mirabilis. In general, this drug combination is not harmful, but some penicillins are chemically and physically incompatible with aminoglycosides and can inactivate the aminoglycoside when mixed. Concomitant use of clavulanic acid with piperacillin improves the activity of piperacillin against some beta-lactamase-producing bacteria. Piperacillin in large doses inhibits renal tubular secretion of methotrexate, causing higher, prolonged serum levels of methotrexate. Because of the toxicity of methotrexate, these two drugs should not be administered together.

Adverse Reactions A local injection site reaction, including phlebitis, can occur during therapy with piperacillin. Hypersensitivity reactions are among the most frequent adverse reactions to the penicillins. These effects range from rash to anaphylactic shock. The more severe anaphylactoid reactions occur less frequently with the extended-spectrum penicillins than with the natural penicillins. Interstitial nephritis, a hypersensitivity reaction, with renal tubular necrosis and nephrotic syndrome has been reported. Dermatologic adverse effects can occur with penicillins. These include maculopapular rash, urticaria, purpura, bullous rash, vasculitis, erythema nodosum, and exfoliative dermatitis. Other skin reactions which occur infrequently, but can be serious, include Stevens-Johnson syndrome and toxic epidermal necrolysis. Seizures have been reported when large doses of penicillins were administered to patients with renal impairment.[545] Appropriate dosage adjustments should be observed in these patients. Diarrhea is a commonly reported adverse reaction to piperacillin. Pseudomembranous colitis can occur during use of or following discontinuance of piperacillin, but this effect is rare. Other reported but rare adverse reactions include elevated hepatic enzymes. Hypokalemia has been reported during therapy with piperacillin. Serum electrolytes may need to be monitored in patients receiving large doses of piperacillin. Platelet dysfunction occurs to varying degrees with the extended-spectrum penicillins. It occurs more frequently with the carboxypenicillins (ticarcillin and carbenicillin) than with the acylureidopenicillins (mezlocillin and piperacillin). The drug can bind to platelets to prevent aggregation, which causes increased bleeding time. Clinically significant bleeding, however, is rare. Antibiotic therapy can result in superinfection or suprainfection with nonsusceptible organisms. Overgrowth of Candida, Serratia, Klebsiella, or P. aeruginosa can occur with extended-spectrum penicillin therapy. Patients should be monitored closely during therapy.

Piperacillin Pipracil�

1493. Reetze-Bonorden P, Bohler J, Keller E. Drug dosage in patients during continuous renal replacement therapy. Clin Pharmacokinet 1993;24:362�79.