Piperacillin/Tazobactam Actions

• Actions of Piperacillin/Tazobactam in details
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Actions of Piperacillin/Tazobactam in details

Pharmacotherapeutic Group: Antibacterials for systemic use, combinations of penicillins including β-lactamase inhibitors. ATC Code: J01C R05.

Pharmacology: Pharmacodynamics: Mode of Action: Piperacillin/Tazobactam (sterile piperacillin sodium/tazobactam sodium) is an injectable antibacterial combination consisting of the semisynthetic antibiotic piperacillin sodium and the β‑lactamase inhibitor tazobactam sodium for intravenous administration. Thus, Piperacillin/Tazobactam combines the properties of a broad‑spectrum antibiotic and a β‑lactamase inhibitor.

Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis. Piperacillin and other β‑lactam antibiotics block the terminal transpeptidation step of cell wall peptidoglycan biosynthesis in susceptible organisms by interacting with penicillin-binding proteins (PBPs), the bacterial enzymes that carry out this reaction. In vitro, piperacillin is active against a variety of gram‑positive and gram‑negative aerobic and anaerobic bacteria.

Piperacillin has reduced activity against bacteria harboring certain β‑lactamase enzymes, which chemically inactivate piperacillin and other β‑lactam antibiotics. Tazobactam sodium, which has very little intrinsic antimicrobial activity, due to its low affinity for PBPs, can restore or enhance the activity of piperacillin against many of these resistant organisms. Tazobactam is a potent inhibitor of many class A β‑lactamases (penicillinases, cephalosporinases and extended spectrum enzymes). It has variable activity against class A carbapenemases and class D β‑lactamases. It is not active against most class C cephalosporinases and inactive against Class B metallo‑β‑lactamases.

Two features of Piperacillin/Tazobactam lead to increased activity against some organisms harboring β‑lactamases that, when tested as enzyme preparations, are less inhibited by tazobactam and other inhibitors: tazobactam does not induce chromosomally mediated β‑lactamases at tazobactam levels achieved with the recommended dosing regimen and piperacillin is relatively refractory to the action of some β‑lactamases.

Like other β‑lactam antibiotics, piperacillin, with or without tazobactam, demonstrates time-dependent bactericidal activity against susceptible organisms.

Pharmacokinetics: Adults: Peak plasma concentrations of Piperacillin/Tazobactam are attained immediately after completion of an intravenous infusion of Piperacillin/Tazobactam. Piperacillin plasma concentrations, following a 30-minute infusion of Piperacillin/Tazobactam, were similar to those attained when equivalent doses of piperacillin were administered alone, with mean peak plasma concentrations of approximately 134, 242 and 298 μg/mL for the 2.25 g, 3.375 g and 4.5 g Piperacillin/Tazobactam (Piperacillin/Tazobactam) doses, respectively. The corresponding mean peak plasma concentrations of tazobactam were 15, 24 and 34 μg/mL, respectively.

Following a 30-minute I.V. infusion of 3.375 g Piperacillin/Tazobactam every 6 hours, steady-state plasma concentrations of Piperacillin/Tazobactam were similar to those attained after the first dose. In like manner, steady-state plasma concentrations were not different from those attained after the first dose when 2.25 g or 4.5 g doses of Piperacillin/Tazobactam were administered via 30-minute infusions every 6 hours. Steady-state plasma concentrations after 30-minute infusions every 6 hours are provided in the table as follows.

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

Metabolism: Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that has been found to be microbiologically inactive.

Elimination: Both Piperacillin/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 appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose appearing as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile.

Following administration of single or multiple Piperacillin/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. The elimination half-lives of both Piperacillin/Tazobactam are increased with decreasing renal clearance.

There are no significant changes in the pharmacokinetics of piperacillin due to tazobactam. Piperacillin appears to reduce the rate of elimination of tazobactam.

Special Populations: The half-lives of piperacillin and of tazobactam increase 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/Tazobactam due to hepatic cirrhosis.

The half-lives of Piperacillin/Tazobactam increase with decreasing creatinine clearance.

The increase in half-life is two-fold and four-fold for Piperacillin/Tazobactam, respectively, at creatinine clearance below 20 mL/min compared to patients with normal renal function.

Hemodialysis removes 30% to 50% of Piperacillin/Tazobactam with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the Piperacillin/Tazobactam doses, respectively, with up to 18% of the tazobactam dose removed as the tazobactam metabolite.

Toxicology: Preclinical Safety Data: Carcinogenicity: Carcinogenicity studies have not been conducted with piperacillin, tazobactam, or the combination.

Mutagenicity: Piperacillin/Tazobactam was negative in microbial mutagenicity assays.

Piperacillin/Tazobactam was negative in the unscheduled DNA synthesis (UDS) test.

Piperacillin/Tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell hypoxanthine phosphoribosyltransferase [HPRT]) assay. Piperacillin/Tazobactam was negative in a mammalian cell (BALB/c-3T3) transformation assay. In vivo, Piperacillin/Tazobactam did not induce chromosomal aberrations in rats dosed intravenously.

Piperacillin was negative in microbial mutagenicity assays. There was no DNA damage in bacteria (Rec assay) exposed to piperacillin. Piperacillin was negative in the UDS test. In a mammalian point mutation (mouse lymphoma cells) assay, piperacillin was positive.

Piperacillin was negative in a cell (BALB/c-3T3) transformation assay. In vivo, piperacillin did not induce chromosomal aberrations in mice dosed intravenously.

Tazobactam was negative in microbial mutagenicity assays. Tazobactam was negative in the UDS test.

Tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell HPRT) assay. In another mammalian point mutation (mouse lymphoma cells) assay, tazobactam was positive. Tazobactam was negative in a cell (BALB/c-3T3) transformation assay. In an in vitro cytogenetics (Chinese hamster lung cells) assay, tazobactam was negative. In vivo, tazobactam did not induce chromosomal aberrations in rats dosed intravenously.

Reproductive Toxicity: In embryo-fetal development studies there was no evidence of teratogenicity following intravenous administration of tazobactam or the Piperacillin/Tazobactam combination; however, in rats there were slight reductions in fetal body weight at maternally toxic doses.

Intraperitoneal administration of Piperacillin/Tazobactam was associated with slight reductions in litter size and an increased incidence of minor skeletal anomalies (delays in bone ossification) at doses that produced maternal toxicity. Peri-/post-natal development was impaired (reduced pup weights, increase in still birth, increase in pup mortality) concurrent with maternal toxicity.

Impairment of Fertility: Reproduction studies in rats revealed no evidence of impaired fertility due to tazobactam or Piperacillin/Tazobactam when administered intraperitoneally.

Mechanism of Resistance: There are three major mechanisms of resistance to β‑lactam antibiotics: Changes in the target PBPs resulting in reduced affinity for the antibiotics, destruction of the antibiotics by bacterial β‑lactamases, and low intracellular antibiotic levels due to reduced uptake or active efflux of the antibiotics.

In gram‑positive bacteria, changes in PBPs are the primary mechanism of resistance to β‑lactam antibiotics, including Piperacillin/Tazobactam. This mechanism is responsible for methicillin resistance in staphylococci and penicillin resistance in Streptococcus pneumoniae and viridans group streptococci.

Resistance caused by changes in PBPs also occurs in fastidious gram‑negative species, such as Haemophilus influenzae and Neisseria gonorrhoeae. Piperacillin/Tazobactam is not active against strains in which resistance to β‑lactam antibiotics is determined by altered PBPs. As indicated above, there are some β‑lactamases that are not inhibited by tazobactam.

Methodology for Determining the In Vitro Susceptibility of Bacteria to Piperacillin/Tazobactam: Susceptibility testing should be conducted using standardized laboratory methods, such as those described by the Clinical and Laboratory Standards Institute (CLSI). These include dilution methods (minimal inhibitory concentration, [MIC], determination) and disk susceptibility methods. Both CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) provide susceptibility interpretive criteria for some bacterial species based on these methods. It should be noted that for the disk diffusion method, CLSI and EUCAST use disks with different drug contents. The CLSI interpretive criteria for susceptibility testing for Piperacillin/Tazobactam are listed in table 2.

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Quality control microorganisms are specific strains with intrinsic biological properties relating to resistance mechanisms and their genetic expression within the microorganism; the specific strains used for susceptibility test quality control are not clinically significant.

Organisms and quality control ranges for Piperacillin/Tazobactam to be utilized with CLSI methodology and susceptibility test interpretive criteria are listed in the table as follows:

EUCAST has also established clinical breakpoints for Piperacillin/Tazobactam against some organisms. Like CLSI, the EUCAST MIC susceptibility criteria are based on a fixed concentration of 4 mg/L of tazobactam. However, for inhibition zone determination, the disks contain 30 µg of piperacillin and 6 µg of tazobactam. The EUCAST rationale document for Piperacillin/Tazobactam states that breakpoints for Pseudomonas aeruginosa apply to dosages of 4 g, 4 times daily, whereas the breakpoints for other organisms are based on 4 g, 3 times daily. The EUCAST breakpoints for Piperacillin/Tazobactam are listed in the following table.

Per EUCAST, for species without Piperacillin/Tazobactam breakpoints, susceptibility in staphylococci is inferred from cefoxitin/oxacillin susceptibility. For groups A, B, C and G streptococci and Streptococcus pneumoniae, susceptibility is inferred from benzylpenicillin susceptibility. For other streptococci, enterococci, and β‑lactamase-negative Haemophilus influenzae, susceptibility is inferred from amoxicillin-clavulanate susceptibility. There are no EUCAST breakpoints for Acinetobacter. The EUCAST rationale document for Piperacillin/Tazobactam states that in endocarditis caused by streptococci other than groups A, B, C and G and S. pneumoniae, national or international guidelines should be referred to.

Quality control ranges for EUCAST susceptibility breakpoints are listed in the following table.

MICs are determined using a fixed concentration of 4 mg/L Tazobactam.

Piperacillin/Tazobactam is highly active against piperacillin-sensitive micro-organisms as well as many beta-lactamase producing, piperacillin-resistant microorganisms.

Gram-Negative Bacteria: Most plasmid mediated β-lactamase producing and non-β-lactamase producing strains of Escherichia coli, Shigella spp., Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella spp. (including M. catarrhalis), Haemophilus spp. (including H. influenzae, H. parainfluenzae), Pasteurella multocida, Yersinia spp., Campylobacter spp., Gardnerella vaginalis. Many chromosomally mediated β-lactamase producing and non-β-lactamase producing strains of Enterobacter spp. (including E. cloacae, E. aerogenes), Citrobacter spp. (including C. freundii, C. diversus), Providencia spp., Morganella morganii, Serratia spp. (including S. marcescens, S. liquefaciens), Pseudomonas aeruginosa and other Pseudomonas spp. (including P. cepacia, P. fluorescens), Xanthomonas maltophilia, Acinetobacter spp.

Gram-Positive Bacteria: β-lactamase producing and non-β-lactamase producing strains of streptococci (S. pneumoniae, S. pyogenes, S. bovis, S. agalactiae, S. viridans, Group C, Group G), enterococci (E. faecalis), 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), the 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, Clostridia spp. (including C. difficile, C. perfringens), Vellonella spp., and Actinomyces spp.

How should I take Piperacillin/Tazobactam?

A nurse or other trained health professional will give you or your child Piperacillin/Tazobactam. Piperacillin/Tazobactam is given through a needle placed in one of your veins. The medicine must be injected slowly, so your IV tube will need to stay in place for 30 minutes.

Piperacillin/Tazobactam administration

IV: Administer by IV infusion over 30 minutes. For extended infusion administration (off-label method), administer over 4 hours (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

Piperacillin/Tazobactam pharmacology

Mechanism of Action

Piperacillin/Tazobactam for injection is an antibacterial drug.

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/Tazobactam after multiple intravenous doses are summarized in Table 6.

Table 6: Mean (CV%) Piperacillin/Tazobactam PK Parameters

* Piperacillin/Tazobactam were given in combination, infused over 30 minutes. † Numbers in parentheses are coefficients of variation (CV%).
		Piperacillin
Piperacillin/ Tazobactam Dose*	Cmax mcg/mL	AUC† mcg•h/mL	CL mL/min	V L	T1/2 h	CLR mL/min
2.25g	134	131 (4)	257	17.4	0.79	-
3.375g	242	242 (10)	207	15.1	0.84	140
4.5g	298	322 (16)	210	15.4	0.84	-
		Tazobactam
Piperacillin/ Tazobactam Dose*	Cmaxmcg/mL	AUC† mcg•h/mL	CL mL/min	V L	T 1/2 h	CLR mL/min
2.25g	15	16 (21)	258	17	0.77	-
3.375g	24	25 (8)	251	14.8	0.68	166
4.5g	34	39.8 (15)	206	14.7	0.82	-

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

Distribution

Both Piperacillin/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/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/Tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.

Table 7: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of Piperacillin/Tazobactam for Injection

* Each subject provided a single sample. † Time from the start of the infusion
Tissue or Fluid	N*	Sampling period† (h)	Mean PIP Concentration Range (mg/L)	Tissue: Plasma Range	Tazo Concentration Range (mg/L)	Tazo Tissue:Plasma Range
Skin	35	0.5 to 4.5	34.8 to 94.2	0.60 to 1.1	4 to 7.7	0.49 to 0.93
Fatty Tissue	37	0.5 to 4.5	4 to 10.1	0.097 to 0.115	0.7 to 1.5	0.10 to 0.13
Muscle	36	0.5 to 4.5	9.4 to 23.3	0.29 to 0.18	1.4 to 2.7	0.18 to 0.30
Proximal Intestinal Mucosa	7	1.5 to 2.5	31.4	0.55	10.3	1.15
Distal Intestinal Mucosa	7	1.5 to 2.5	31.2	0.59	14.5	2.1
Appendix	22	0.5 to 2.5	26.5 to 64.1	0.43 to 0.53	91 to 18.6	0.80 to 1.35

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/Tazobactam for injection 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/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/Tazobactam for injection are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of Piperacillin/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/Tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis.

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/Tazobactam for injection due to hepatic cirrhosis.

Pediatrics

Piperacillin/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/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/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/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/Tazobactam for injection and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated.

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.

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

aThese 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/Tazobactam powders1,2. 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 method4.

Table 8: Susceptibility Interpretive Criteria for Piperacillin/Tazobactam

* These interpretive criteria for Haemophilus influenzae are applicable only to tests performed using Haemophilus Test Medium inoculated with a direct colony suspension and incubated at 35°C in ambient air for 20 to 24 hours.
	Susceptibility Test Result Interpretive Criteria
	Minimal Inhibitory Concentration (MIC in mcg/mL)			Disk Diffusion (Zone Diameter in mm)
Pathogen	S	I	R	S	I	R
Enterobacteriaceae	≤ 16	32 to 64	≥ 128	≥ 21	18 to 20	≤17
Acinetobacter baumanii	≤ 16	32 to 64	≥ 128	≥ 21	18 to 20	≤17
Haemophilus influenzae*	≤ 1	-	≥2	≥ 21	-	-
Pseudomonas aeruginosa	≤ 16	32 to 64	≥ 128	≥ 21	15 to 20	≤ 14
Bacteroides fragilis group	≤ 32	64	≥ 128	-	-	-

Note: Susceptibility of staphylococci to Piperacillin/Tazobactam may be deduced from testing only penicillin and either cefoxitin or oxacillin.

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.

Table 9. Acceptable Quality Control Ranges for Piperacillin/Tazobactam to be Used in Validation of Susceptibility Test Results

* This quality control range for Haemophilus influenzae is applicable only to tests performed using Haemophilus Test Medium inoculated with a direct colony suspension and incubated at 35°C in ambient air for 20 to 24 hours. † The quality control ranges for Bacteroides fragilis and Bacteroides thetaiotaomicron are applicable only to tests performed using the agar dilution method.
	Acceptable Quality Control Ranges
QC Strain	Minimum Inhibitory Concentration Range (MIC in mcg/mL)	Disk Diffusion Zone Diameter Ranges in mm
Escherichia coli ATCC 25922	1 to 4	24 to 30
Escherichia coli ATCC 35218	0.5 to 2	24 to 30
Pseudomonas aeruginosa ATCC 27853	1 to 8	25 to 33
Haemophilus influenzae* ATCC 49247	0.06 to 0.5	33 to 38
Staphylococcus aureus ATCC 29213	0.25 to 2	-
Staphylococcus aureus ATCC 25923	-	27 to 36
Bacteroides fragilis† ATCC 25285	0.12 to 0.5	-
Bacteroides thetaiotamicron† ATCC 29741	4 to 16	-
Clostridium difficile† ATCC 700057	4 to 16	-
Eubacterium lentum† ATCC 43055	4 to 16	-

References

1. NCIt. "Tazobactam: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
2. NCIt. "Piperacillin Anhydrous: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
3. EPA DSStox. "Tazobactam: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

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Information checked by Dr. Sachin Kumar, MD Pharmacology