Piperacillin and tazobactam

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe stomach pain, diarrhea that is watery or bloody;

• a seizure (convulsions);

• low white blood cell counts--fever, swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough, trouble breathing;

• low potassium--leg cramps, constipation, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling;

• signs of inflammation in your body--swollen glands, flu symptoms, easy bruising or bleeding, severe tingling or numbness, muscle weakness, upper stomach pain, jaundice (yellowing of the skin or eyes), chest pain, new or worsening cough with fever, trouble breathing; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• diarrhea, constipation;

• nausea;

• headache; or

• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Tell all of your health care providers that you take piperacillin and tazobactam. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• Do not use longer than you have been told. A second infection may happen.
• If you have high blood sugar (diabetes), do not use Clinitest®. Use some other urine glucose testing like Clinistix® or Tes-Tape®.
• Very bad and sometimes deadly allergic side effects have rarely happened. Talk with your doctor.
• Some patients may get low white blood cell counts. Tell the doctor right away about any fever, sore throat, or other signs of infection.
• If you are on a low-sodium or sodium-free diet, talk with your doctor. Some of these products have sodium.
• Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom when taking piperacillin and tazobactam.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using piperacillin and tazobactam while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

• If you need to store piperacillin and tazobactam at home, talk with your doctor, nurse, or pharmacist about how to store it.

Piperacillin and Tazobactam for injection is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a β-lactamase inhibitor, tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of the designated bacteria in the conditions listed below.

Intra-abdominal Infections

Appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. The individual members of this group were studied in fewer than 10 cases.

Skin and Skin Structure Infections

Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by β-lactamase producing isolates of Staphylococcus aureus.

Female Pelvic Infections

Postpartum endometritis or pelvic inflammatory disease caused by β-lactamase producing isolates of Escherichia coli.

Community-acquired Pneumonia

Community-acquired pneumonia (moderate severity only) caused by β-lactamase producing isolates of Haemophilus influenzae.

Nosocomial Pneumonia

Nosocomial pneumonia (moderate to severe) caused by β-lactamase producing isolates of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside) [see Dosage and Administration (2)].

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin and Tazobactam for injection and other antibacterial drugs, Piperacillin and Tazobactam for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by 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.

Mechanism of Action

Piperacillin and Tazobactam is an antibacterial drug [see Microbiology (12.4)].

Pharmacodynamics

The pharmacodynamic parameter for piperacillin/tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC.

Pharmacokinetics

The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of Piperacillin and Tazobactam after multiple intravenous doses are summarized in Table 6. 

Peak plasma concentrations of Piperacillin and Tazobactam are attained immediately after completion of an intravenous infusion of Piperacillin and Tazobactam. Piperacillin plasma concentrations, following a 30-minute infusion of Piperacillin and Tazobactam, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of Piperacillin and Tazobactam were similar to those attained after the first dose due to the short half-lives of Piperacillin and Tazobactam.

Distribution

Both Piperacillin and Tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.

Piperacillin and Tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of Piperacillin and Tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 7). 

Metabolism

Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.

Excretion

Following single or multiple Piperacillin and Tazobactam doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.

Both Piperacillin and Tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile.

Specific Populations

Renal Impairment

After the administration of single doses of piperacillin/tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for Piperacillin and Tazobactam are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of Piperacillin and Tazobactam for injection. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal-­impairment.

Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the Piperacillin and Tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2)].

Hepatic Impairment

The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of Piperacillin and Tazobactam due to hepatic cirrhosis.

Pediatrics

Piperacillin and Tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults.

In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 to 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin distribution volume is 0.243 (0.011) L/kg and is independent of age.

Geriatrics

The impact of age on the pharmacokinetics of Piperacillin and Tazobactam was evaluated in healthy male subjects, aged 18 to 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for Piperacillin and Tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance.

Race

The effect of race on Piperacillin and Tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses.

Drug Interactions

The potential for pharmacokinetic drug interactions between Piperacillin and Tazobactam and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7)].

Microbiology

Mechanism of Action

Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of Gram-positive and Gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a β-lactamase inhibitor of the Molecular class A enzymes, including Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally­-mediated β-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

Spectrum of Activity

Piperacillin/tazobactam has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-positive bacteria:

Staphylococcus aureus (methicillin susceptible isolates only)

Gram-negative bacteria:

Acinetobacter baumannii
Escherichia coli
Haemophilus influenzae (excluding β-lactamase negative, ampicillin-resistant isolates)
Klebsiella pneumoniae
Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible)
 

Anaerobic bacteria:

Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus)

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam. However, the safety and effectiveness of piperacillin/tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria:

Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin susceptible isolates only)
Streptococcus agalactiae†
Streptococcus pneumoniae† (penicillin-susceptible isolates only)
Streptococcus pyogenes†
Viridans group streptococci†

Gram-negative bacteria:

Citrobacter koseri
Moraxella catarrhalis
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Serratia marcescens
Providencia stuartii
Providencia rettgeri
Salmonella enterica

Anaerobic bacteria:

Clostridium perfringens
Bacteroides distasonis
Prevotella melaninogenica

† These are not β-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

Susceptibility Testing Methods

As is recommended with all antimicrobials, the results of in vitro susceptibility tests, when available, should be provided to the physician as periodic reports, which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Piperacillin and Tazobactam powders.1,2 MIC values should be determined using serial dilutions of piperacillin combined with a fixed concentration of 4 mcg/mL tazobactam. The MIC values obtained should be interpreted according to criteria provided in Table 8.

Diffusion Technique:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method1,3 and requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100 mcg of piperacillin and 10 mcg of tazobactam to test the susceptibility of microorganisms to piperacillin/tazobactam. The disk diffusion interpreted criteria are provided in Table 8.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to piperacillin/tazobactam can be determined by the reference agar dilution method.4

A report of S (“Susceptible”) indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of I (“Intermediate”) indicates that the results should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of R (“Resistant”) indicates that the pathogen is not likely to be inhibited even if the antimicrobial compound in the blood reaches the concentration usually achievable at the infection site; other therapy should be considered.

Quality Control

Standardized susceptibility test procedures require the use of quality controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test procedures.1,2,3,4 Standard piperacillin/tazobactam powder should provide the following ranges of values noted in Table 9. Quality control bacteria are specific strains of bacteria with intrinsic biological properties relating to resistance mechanisms and their genetic expression within the microorganism; the specific strains used for microbiological quality control are not clinically significant.

NDC 55150-120-30
Piperacillin
and Tazobactam
for Injection, USP
3.375 grams per vial
For Intravenous Use Only
Single-Dose Vial
Rx only
AUROMEDICS

• Piperacillin and Tazobactam Sodium
• Piperacillin Sodium and Tazobactam Sodium
• Piperacillin Sodium/Tazobactam
• Piperacillin/Tazobactam Sod
• Tazobactam and Piperacillin

Piperacillin 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. Piperacillin exhibits time-dependent killing. Tazobactam inhibits many beta-lactamases, including staphylococcal penicillinase and Richmond-Sykes types 2, 3, 4, and 5, including extended spectrum enzymes; it has only limited activity against class 1 beta-lactamases other than class 1C types.

Distribution

Well into lungs, intestinal mucosa, uterus, ovary, fallopian tube, interstitial fluid, gallbladder, and bile; penetration into CSF is low in subjects with noninflamed meninges; Vd: Children and Adults: 0.243 L/kg

Metabolism

Piperacillin: 6% to 9% to desethyl metabolite (weak activity)

Tazobactam: ~22% to inactive metabolite

Excretion

Clearance of both piperacillin and tazobactam are directly proportional to renal function; Infants and Children 9 months to 12 years: 5.64 mL/minute/kg

Piperacillin: Urine (68% as unchanged drug); feces (10% to 20%)

Tazobactam: Urine (80% as unchanged drug; remainder as inactive metabolite)

Time to Peak

Immediately following completion of 30-minute infusion

Half-Life Elimination

Note: Pediatric data: Reed 1994

Piperacillin:

Infants 2 to 5 months: 1.4 hours

Infants and Children 6 to 23 months: 0.9 hour

Children 2 to 12 years: 0.7 hour

Adults: 0.7 to 1.2 hours

Metabolite: 1 to 1.5 hours

Tazobactam:

Infants 2 to 5 months: 1.6 hours

Infants and Children 6 to 23 months: 1 hour

Children 2 to 12 years: 0.8 to 0.9 hour

Adults: 0.7 to 0.9 hour

Protein Binding

Piperacillin: ~26% to 33%; Tazobactam: 31% to 32%

Half-life increases 2-fold for piperacillin and 4-fold for tazobactam in patients with CrCl <20 mL/minute.

Administer by IV infusion over 30 minutes. For extended infusion administration (off-label dosing), administer over 3-4 hours (Kim 2007; Shea 2009).

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. Note: Reformulated Zosyn containing EDTA has been shown to be compatible in vitro for Y-site infusion with amikacin and gentamicin diluted in NS or D5W (applies only to specific concentrations and varies by product; consult manufacturer’s labeling). Reformulated Zosyn containing EDTA is not compatible with tobramycin.

Some products may contain sodium.

Vials: Store intact vials at 20°C to 25°C (68°F to 77°F). Use single-dose or bulk vials immediately after reconstitution. Discard any unused portion after 24 hours if stored at 20°C to 25°C (68°F to 77°F) or after 48 hours if stored at 2°C to 8°C (36°F to 46°F). Do not freeze vials after reconstitution. Stability in D5W or NS has been demonstrated for up to 24 hours at room temperature and up to 1 week at refrigerated temperature. Stability in an ambulatory IV infusion pump has been demonstrated for a period of 12 hours at room temperature.

Galaxy containers: Store at or below -20°C (-4°F). The thawed solution is stable for 14 days at 2°C to 8°C (36°F to 46°F) or 24 hours at 20°C to 25°C (68°F to 77°F). Do not refreeze.

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic/anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity or history of sensitivity to multiple allergens. Discontinue treatment and institute appropriate therapy if an allergic reaction occurs.

• Dermatologic effects: Serious skin reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), acute exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. If a skin rash develops, monitor closely. Discontinue if lesions progress.

• Electrolyte abnormalities: Sodium content (2.84 mEq per gram of piperacillin) should be considered in patients requiring sodium restriction. Assess electrolytes periodically in patients with low potassium reserves, especially those receiving cytotoxic therapy or diuretics.

• Hematologic effects: Prothrombin time, platelet aggregation, and clotting time abnormalities have been reported with piperacillin and particularly in patients with renal impairment. Discontinue if thrombocytopenia or bleeding occurs. Leukopenia/neutropenia may occur; appears to be reversible and most frequently associated with prolonged administration. Assess hematologic parameters periodically, especially with prolonged (≥21 days) use.

• Superinfection: 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 receiving piperacillin.

• Renal impairment: Use with caution in patients with renal impairment or in hemodialysis patients. 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.

Special populations:

• Critically ill patients: Use of piperacillin and tazobactam in critically ill patients may delay renal recovery as compared to other beta-lactam antibacterial drugs; consider alternative treatment options in critically ill patients. If alternative treatment options are inadequate or unavailable, closely monitor renal function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

3.375 g IV every 6 hours
Usual duration of therapy: 7 to 10 days

Use: For the treatment of uncomplicated and complicated skin and skin structure infections (including cellulitis, cutaneous abscesses, ischemic/diabetic foot infections) due to beta-lactamase-producing isolates of Staphylococcus aureus

IDSA Recommendations:
-Incisional surgical site infection: 3.375 g IV every 6 hours or 4.5 g IV every 8 hours
-Necrotizing infections of the skin, fascia, and muscle: 3.375 g IV every 6 to 8 hours
-Infection after animal bite: 3.375 g IV every 6 to 8 hours

Comments:
-Recommended as a single-drug regimen for treatment of incisional surgical site infections after intestinal or genitourinary tract surgery
-With vancomycin, recommended as a preferred regimen for the treatment of necrotizing infections of the skin, fascia, and muscle due to mixed infections
-Infection after animal bite: This drug does not provide coverage for methicillin-resistant S aureus (MRSA).
-Current guidelines should be consulted for additional information.

4.5 g IV every 6 hours
Duration of therapy: 7 to 14 days

Comments:
-Initial presumptive therapy should start with this drug plus an aminoglycoside.
-Aminoglycoside therapy should be continued if P aeruginosa is isolated.

Use: For the treatment of moderate to severe nosocomial pneumonia due to beta-lactamase-producing isolates of S aureus and by piperacillin-tazobactam-susceptible Acinetobacter baumannii, H influenzae, Klebsiella pneumoniae, and P aeruginosa

IDSA and American Thoracic Society Recommendations: 4.5 g IV every 6 hours
Duration of therapy: 7 days

Comments:
-Recommended as an empiric treatment regimen for clinically suspected ventilator-associated pneumonia in units where such coverage is appropriate
-Recommended as initial empiric therapy for hospital-acquired pneumonia (non-ventilator-associated pneumonia)
-Current guidelines should be consulted for additional information.

American Heart Association Recommendations:
Children and adolescents: 240 mg/kg/day (piperacillin component) IV in divided doses every 8 hours
Maximum dose: 18 g/day (based on piperacillin component)
Duration of therapy: At least 6 weeks

Comments:
-With an aminoglycoside, recommended as an alternative regimen for the treatment of infective endocarditis due to gram-negative enteric bacilli
-Current guidelines should be consulted for additional information.

Adults:
CrCl greater than 40 mL/min: No adjustment recommended.

CrCl 20 to 40 mL/min:
-Nosocomial pneumonia: 3.375 g IV every 6 hours
-Other indications: 2.25 g IV every 6 hours

CrCl less than 20 mL/min:
-Nosocomial pneumonia: 2.25 g IV every 6 hours
-Other indications: 2.25 g IV every 8 hours

Pediatric patients: Data not available