CLINICAL PHARMACOLOGY
Intravenous Administration:
In healthy adult volunteers, mean serum piperacillin concentrations immediately after a two‑to three‑minute intravenous injection of 2, 4, or 6 g were 305, 412, and 775 μg/mL, respectively. Serum concentrations lack dose proportionality.
| PIPERACILLIN SERUM CONCENTRATIONS IN ADULTS (μ g/mL) AFTER A TWO- TO THREE-MINUTE I.V. INJECTION |
| DOSE | 0 | 10 min | 20 min | 30 min | 1 h | 1.5 h | 2 h | 3 h | 4 h | 6 h | 8 h | |
| 2 | 305
(159-
615) | 202
(164-
225) | 156
(52-
165) | 67
(41-
88) | 40
(25-
57) | 24
(18-
31) | 20
(14-
24) | 8
(3-
11) | 3
(2-
4) | 2
(≤0.6-
3) | —
| |
| 4 | 412
(389-
484) | 344
(315-
379) | 295
(269-
330) | 117
(98-
138) | 93
(78-
110) | 60
(50-
67) | 36
(26-
51) | 20
(17-
24) | 8
(7-
11) | 4
(3.7-
4.1) | 0.9
(0.7-
1) | |
| 6 | 775
(695-
849) | 609
(530-
670) | 563
(492-
630) | 325
(292-
363) | 208
(180-
239) | 138
(115-
175) | 90
(71-
113) | 38
(29-
53) | 33
(25-
44) | 8
(3-
19) | 3.2
(<2-
6) | |
| PIPERACILLIN SERUM CONCENTRATIONS IN ADULTS (μ g/mL) AFTER A 30-MINUTE I.V. INFUSION |
| DOSE | 0 | 5 min | 10 min | 15 min | 30 min | 45 min | 1 h | 1.5 h | 2 h | 4 h | 6 h | 7.5 h |
| 4 | 244
(155-
298) | 215
(169-
247) | 186
(140-
209) | 177
(142-
213) | 141
(122-156) | 146
(110-
265) | 105
(85-
133) | 72
(53-
105) | 53
(36-
69) | 15
(6-
24) | 4
(1-
9) | 2
(0.5-
3) |
| 6 | 353
(324-
371) | 298
(242-
339) | 298
(232-
331) | 272
(219-314) | 229
(185-
249) | 180
(144-
209) | 149
(117-
171) | 104
(89-
113) | 73
(66-
94) | 22
(12-
39) | 16
(5-
49) | —
— |
A 30-minute infusion of 6 g every 6 h gave, on the fourth day, a mean peak serum concentration of 420 μg/mL.
Intramuscular Administration:
PIPRACIL is rapidly absorbed after intramuscular injection. In healthy volunteers, the mean peak serum concentration occurs approximately 30 minutes after a single dose of 2 g and is about 36 μg/mL. The oral administration of 1 g probenecid before injection produces an increase in piperacillin peak serum level of about 30%. The area under the curve (AUC) is increased by approximately 60%.
Pharmacokinetics:
PIPRACIL is not absorbed when given orally. Peak serum concentrations are attained approximately 30 minutes after intramuscular injections and immediately after completion of intravenous injection or infusion. The serum half-life in healthy volunteers ranges from 36 minutes to one hour and 12 minutes. The mean elimination half-life of PIPRACIL in healthy adult volunteers is 54 minutes following administration of 2 g and 63 minutes following 6 g. As with other penicillins, PIPRACIL is eliminated primarily by glomerular filtration and tubular secretion; it is excreted rapidly as unchanged drug in high concentrations in the urine. Approximately 60% to 80% of the administered dose is excreted in the urine in the first 24 hours. Piperacillin urine concentrations, determined by microbioassay, are as high as 14,100 μg/mL following a 6-g intravenous dose and 8,500 μg/mL following a 4-g intravenous dose. These urine drug concentrations remain well above 1,000 μg/mL throughout the dosing interval.
Distribution:
PIPRACIL binding to human serum proteins is 16%. The drug is widely distributed in human tissues and body fluids, including bone, prostate, and heart, and reaches high concentrations in bile. After a 4-g bolus injection, maximum biliary concentrations average 3,205 μg/mL. It penetrates into the cerebrospinal fluid in the presence of inflamed meninges.
Special Populations:
Renal Insufficiency: The elimination half-life is increased twofold in mild to moderate renal impairment and fivefold to sixfold in severe impairment. Because PIPRACIL is excreted by the biliary route as well as by the renal route, it can be used safely in appropriate dosage in patients with severely restricted kidney function. (See DOSAGE AND ADMINISTRATION.)
Pediatric Patients: After intravenous administration of 50 mg/kg (5-minute infusion) in neonates, the mean plasma concentration of piperacillin extrapolated to time zero was 141 μg/mL, and the apparent volume of distribution averaged 101 mL/kg.
In premature neonates, the mean elimination half-life has been reported to range from 147 to 258 minutes following administration of a single intravenous dose of 75 mg/kg, the half‑life decreasing with increasing postnatal age. The changes in half-life appeared to be caused by an immature renal system during the first weeks of life. In one study in neonates, the mean elimination half-life ranged from 127 to 217 minutes following a single intravenous dose of 50 mg/kg. As in premature neonates, the half-life in neonates decreased with increasing postnatal age. The mean total body clearance in neonates has been reported to range from 32 to 41 mL/min/1.73 m2 after an intravenous dose of 50 mg/kg.
Following administration of an intravenous dose of 50 mg/kg in older pediatric patients (from 1 month up to 15 years of age), the mean elimination half-life has been reported to range from 31 to 37 minutes, and the mean total body clearance has been reported to range from 124 to 160 mL/min/1.73 m2.
As in adults, PIPRACIL elimination tends to be prolonged in pediatric patients with renal impairment. In one study in pediatric patients (age range, 3.3 to 14.3 years), the mean elimination half-life in patients with decreased renal function was approximately 60 minutes versus 37 minutes in patients with normal renal function. The elimination half-life has been reported to range from 3.5 to 14 hours in neonates with severe renal impairment.
Pharmacokinetic data have indicated that among pediatric patients below 12 years of age, those with cystic fibrosis have increased bioavailability, lower serum concentrations, and increased total body clearance of piperacillin compared to young, healthy pediatric volunteers under 12 years of age.
MICROBIOLOGY
Piperacillin is an antibiotic which exerts its bactericidal activity by inhibiting both septum and cell wall synthesis. It is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Piperacillin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic gram-positive microorganisms
Enterococci, including Enterococcus faecalis
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Acinetobacter species
Enterobacter species
Escherichia coli
Haemophilus influenzae (non-β-lactamase-producing strains)
Klebsiella species
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Pseudomonas aeruginosa
Serratia species
Anaerobic gram-positive microorganisms
Anaerobic cocci
Clostridium species
Anaerobic gram-negative microorganisms
Bacteroides species, including Bacteroides fragilis
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. However, the safety and effectiveness of piperacillin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Streptococcus agalactiae
Streptococcus bovis
Viridans group streptococci
Aerobic gram-negative microorganisms
Burkholderia cepacia
Citrobacter diversus
Citrobacter freundii
Pseudomonas fluorescens
Stenotrophomonas maltophilia
Yersinia enterocolitica
Anaerobic gram-positive microorganisms
Actinomyces species
Eubacterium species
Anaerobic gram-negative microorganisms
Fusobacterium necrophorum
Fusobacterium nucleatum
Porphyromonas asaccharolytica
Prevotella melaninogenica
Veillonella species
Susceptibility Testing Methods
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 1,2 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of piperacillin powder. The MIC values should be interpreted according to the following criteria:
For testing Enterobacteriaceae and Acinetobacter species:
| MIC (μg/mL) | Interpretation |
≤ 16
32-64
≥ 128 | Susceptible (S)
Intermediate (I)
Resistant (R) |
For testing Pseudomonas aeruginosa:
| MIC (μg/mL) | Interpretation |
≤ 64
≥ 128 | Susceptible (S)
Resistant (R) |
For testing Enterococcus faecalis a:
| MIC (μg/mL) | Interpretation |
|
a Penicillin susceptibility may be used to predict the susceptibility to piperacillin. 1,2
|
≤ 8
≥ 16 | Susceptible (S)
Resistant (R) |
Haemophilus species are considered susceptible if the MIC of piperacillin is≤ to 1 μg/mL.*
* Dilution methods such as those described in the International Collaborative Study (Acta Pathol Microbiol Scand [B] 1971; suppl 217) have been used to determine susceptibility of organisms to piperacillin.
Dilution (MICs) susceptibility test methods and interpretative criteria for assessing the susceptibility of Neisseria gonorrhoeae to piperacillin have not been established. However,β‑lactamase testing will detect one form of penicillin resistance in Neisseria gonorrhoeae and is recommended. 1,2
Dilution (MICs) susceptibility test methods and interpretative criteria for assessing the susceptibility of Streptococcus pneumoniae and Streptococcus pyogenes to piperacillin have not been established. 1,2
A report of“Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result 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 “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Quality Control:
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard piperacillin powder should provide the following MIC values:
| Microorganism | | MIC (μg/mL) |
Enterococcus faecalis
Escherichia coli
Pseudomonas aeruginosa | ATCC 29212
ATCC 25922
ATCC 27853 | 1-4
1-4
1-8 |
Diffusion Techniques:
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100μg of piperacillin to test the susceptibility of microorganisms to piperacillin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 100 μg piperacillin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae and Acinetobacter species:
| Zone Diameter (mm) | Interpretation |
≥ 21
18-20
≤ 17 | Susceptible (S)
Intermediate (I)
Resistant (R) |
For testing Pseudomonas aeruginosa:
| Zone Diameter (mm) | Interpretation |
≥ 18
≤ 17 | Susceptible (S)
Resistant (R) |
For testing Enterococcus faecalis b:
| Zone Diameter (mm) | Interpretation |
|
b Penicillin susceptibility may be used to predict the susceptibility to piperacillin. 2,3
|
≥ 15
≤ 14 | Susceptible (S)
Resistant (R) |
Haemophilus species which give zones of ≥ 29 mm are susceptible; resistant strains give zones of ≤ 28 mm. The above interpretive criteria are based on the use of the standardized procedure. Antibiotic susceptibility testing requires carefully prescribed procedures. Susceptibility tests are biased to a considerable degree when different methods are used.
NCCLS Approved Standard; M2-A2 (Formerly ASM-2) Performance Standards for Antimicrobic Disk Susceptibility Tests, Second Edition, available from the National Committee of Clinical Laboratory Standards.
Disk diffusion (zone diameters) susceptibility test methods and interpretative criteria for assessing the susceptibility of Neisseria gonorrhoeae to piperacillin have not been established. However, β-lactamase testing to penicillin is recommended. It will detect one form of penicillin resistance, chromosomally mediated resistance, in Neisseria gonorrhoeae. In addition, gonococci with 10-unit penicillin disk zone diameters of ≤ 19 mm are likely to be β-lactamase producing strains (plasmid-mediated penicillin resistance). 2,3
Disk diffusion (zone diameters) susceptibility test methods and interpretative criteria for assessing the susceptibility of Streptococcus pneumoniae and Streptococcus pyogenes to piperacillin have not been established. 2,3
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for piperacillin.
Quality Control:
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 100-μg piperacillin disk should provide the following zone diameters in these laboratory test quality control strains:
| Microorganism | | Zone Diameter (mm) |
Escherichia coli
Pseudomonas aeruginosa | ATCC 25922
ATCC 27853 | 24-30
25-33 |
Anaerobic Techniques:
For anaerobic bacteria, the susceptibility to piperacillin as MICs can be determined by standardized test methods. 4 The MIC values obtained should be interpreted according to the following criteria:
| MIC (μg/mL) | Interpretation |
≤ 32
64
≥ 128 | Susceptible (S)
Intermediate (I)
Resistant (R) |
Interpretation is identical to that stated above for results using dilution techniques.
As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized piperacillin powder should provide the following MIC values:
| Microorganism | | MIC (μg/mL) |
|
c This quality control range is applicable only to tests performed using either Brucella blood agar or Wilkins-Chalgren agar with the Reference Agar Dilution Method. 4
d This quality range is applicable only to tests performed in the broth formulation of Wilkins-Chalgren agar with the Broth microdilution method. 4
|
Bacteroides fragilis c
Bacteroides thetaiotaomicron d | ATCC 25285
ATCC 29741 | 2-8
8-32 |
|
