Tazilsun Mechanism of Action

Pharmacology: Piperacillin, a broad spectrum, semisynthetic penicillin active against many gram-positive and gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many β-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of tazobactam in the piperacillin/tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many β-lactamase producing bacteria normally resistant to it and other β-lactam antibiotics. Thus, piperacillin/tazobactam combines the properties of a broad spectrum antibiotic and a β-lactamase inhibitor.
Pharmacokinetics: Adults: Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of this product (piperacillin and tazobactam for injection). Piperacillin plasma concentrations, following a 30-minute infusion of this product (piperacillin and tazobactam for injection), were similar to those attained when equivalent doses of piperacillin were administered alone, with mean peak plasma concentrations of approximately 134 μg/mL and 298 μg/mL for the 2.25 g and 4.5 g of this product (piperacillin and tazobactam for injection) doses, respectively. The corresponding mean peak plasma concentrations of tazobactam were 15 μg/mL and 34 μg/mL, respectively.
Following a 30-minute I.V. infusion of 2.25 g and 4.5 g of this product (piperacillin and tazobactam for injection) every 6 hours, steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose. Steady-state plasma concentrations after 30-minute infusions every 6 hours are provided in Table 1.
Following single or multiple doses of this product 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.
Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. 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.
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.
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 this product are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of this product. (See Dosage & Administration for specific recommendations for the treatment of patients with renal insufficiency.)
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 & Administration.
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 this product due to hepatic cirrhosis. (See Table 1.)

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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 2-9 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.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or tazobactam.
Piperacillin/Tazobactam: Piperacillin/tazobactam was negative in microbial mutagenicity assays at concentrations up to 14.84/1.86 μg/plate. Piperacillin/tazobactam was negative in the unscheduled DNA synthesis (UDS) test at concentrations up to 5689/711 μg/mL. Piperacillin/tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell HPRT) assay at concentrations up to 8000/1000 μg/mL. Piperacillin/tazobactam was negative in a mammalian cell (BALB/c-3T3) transformation assay at concentrations up to 8/1 μg/mL. In vivo, piperacillin/tazobactam did not induce chromosomal aberrations in rats dosed I.V. with 1500/187.5 mg/kg; this dose is similar to the maximum recommended human daily dose on a body-surface-area basis (mg/m²).
Piperacillin: Piperacillin was negative in microbial mutagenicity assays at concentrations up to 50 μg/plate. There was no DNA damage in bacteria (Rec assay) exposed to piperacillin at concentrations up to 200 μg/disk. Piperacillin was negative in the UDS test at concentrations up to 10,000 μg/mL. 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 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 similar (rats) to 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 mice were administered piperacillin 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 a microbial mutagenicity assay. Bacteria injected into the peritoneal cavity of mice administered piperacillin at I.V. doses up to 2000 mg/kg/day did not show increased mutation frequencies.
Tazobactam: Tazobactam was negative in microbial mutagenicity assays at concentrations up to 333 μg/plate. Tazobactam was negative in the UDS test at concentrations up to 2000 μg/mL. Tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell HPRT) assay at concentrations up to 5000 μg/mL. In another mammalian point mutation (mouse lymphoma cells) assay, tazobactam was positive at concentrations ≥3000 μg/mL. Tazobactam was negative in a cell (BALB/c-3T3) transformation assay at concentrations up to 900 μg/mL. In an in vitro cytogenetics (Chinese hamster lung cells) assay, tazobactam was negative at concentrations up to 3000 μg/mL. In vivo, tazobactam did not induce chromosomal aberrations in rats at I.V. doses up to 5000 mg/kg, which is 23 times the maximum recommended human daily dose based on body surface area (mg/m²).
Microbiology: Piperacillin/tazobactam is highly active against piperacillin-susceptible microorganisms as well as many β-lactamase producing, piperacillin-resistant microorganisms.
Gram-negative bacteria: β-lactamase producing and non-β-lactamase producing strains of Escherichia coli, Citrobacter spp. (including C. farmeri, C. braakii), Klebsiella spp. (including K. oxytoca, K. pneumoniae), Enterobacter spp. (including E. cloacae, E. aerogenes), Proteus vulgaris, Proteus mirabilis, Providencia rettgeri, Providencia stuartii, Plesiomonas shigelloides, Morganella morganii, Serratia spp. (including S. marcescens, S. liquefaciens), Salmonella spp., Shigella spp., Pseudomonas aeruginosa and other Pseudomonas spp. (including P. cepacia, P. fluorescens), Xanthomonas maltophilia, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella spp. (including M. catarrhalis), Acinetobacter spp., Haemophilus influenzae, Haemophilus parainfluenzae, Pasteurella multocida, Yersinia spp., Campylobacter spp., Gardnerella vaginalis. The in vitro studies have shown that piperacillin/tazobactam acts synergistically with aminoglycosides against multiple-resistant Pseudomonas aeruginosa.
Gram-positive bacteria: β-lactamase producing and non-β-lactamase producing strains of Streptococci (S. pneumoniae, S. pyogenes, S. bovis, S. agalactiae, Group C, Group G, S. viridans), Enterococci (E. faecalis, E. faecium), Staphylococcus aureus (not methicillin-resistant S. aureus), S. saprophyticus, S. epidermidis (coagulase-negative staphylococci), Corynebacteria, Listeria monocytogenes, Nocardia spp.
Anaerobic bacteria: β-lactamase producing and non-β-lactamase producing anaerobes such as Bacteroides spp. (including B. bivius, B. disiens, B. capillosus, B. melaninogenicus, B. oralis), Bacteroides fragilis group (including B. fragilis, B. vulgatus, B. distasonis, B. ovatus, B. thetaiotaomicron, B. uniformis, B. asaccharolyticus), as well as Peptostreptococcus spp., Fusobacterium spp., Eubacterium group, Clostridium spp. (including C. difficile, C. perfringens), Veillonella spp., and Actinomyces spp.
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. MIC values should be determined using serial dilutions of piperacillin combined with a fixed concentration of 4 μg/mL tazobactam. The MIC values obtained should be interpreted according to criteria provided in Table 2.
Diffusion Technique: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure, requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100 μg of piperacillin and 10 μg of tazobactam to test the susceptibility of microorganisms to piperacillin/tazobactam. The disk diffusion interpreted criteria are provided in Table 3.
Anaerobic Techniques: For anaerobic bacteria, the susceptibility to piperacillin/tazobactam can be determined by the reference agar dilution method. (See Table 2.)

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Quality Control: Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the test procedures. Standard piperacillin/tazobactam powder should provide the following ranges of values noted in Table 3. Quality control microorganisms are specific strains of microorganisms 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. (See Table 3.)

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