Piperacillin for Injection - Scientific Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Bone infection (Osteomyelitis), Burns, External, Cholangitis, Endometritis, Epididymitis, Gonorrhea (Gonococcal Infection, Uncomplicated), Gonococcal Infection, Joint Infection, Meningitis, Peritonitis, Pneumonia, Pyelonephritis (Kidney Infections), Postoperative Infection, Sepsis, Septicemia, Skin Infection (Skin or Soft Tissue Infection), Skin Infection, bacterial (Bacterial Skin Infection), Skin or Soft Tissue Infection, Surgical Prophylaxis, Streptococcal Infection, Urinary Tract Infection|
|Form:||Intravenous (IV), Powder|
|Common Name:||piperacillin sodium|
|Chemical Name:||6-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino] phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, monosodium salt.|
|Description:||Piperacillin sodium is a white to off-white hygroscopic, crystalline powder which is readily soluble in water and gives a colourless to pale-yellow solution. The pH of the aqueous solution is 5.5 to 7.5. The melting point is about 185 °C to 187 °C. It is very soluble in water, slightly soluble in ethanol, very slightly soluble in acetone, and practically insoluble in chloroform and in ether.|
|Composition:||Vials contain piperacillin sodium equivalent to the labelled amount of piperacillin. The sodium content (Na+), based on the molecular weight is 1.85 mEq/g (42.5 mg/g). |
Piperacillin for Injection 2 g/vial: each vial contains piperacillin sodium equivalent to piperacillin 2 g.
Piperacillin for Injection 3 g/vial: each vial contains piperacillin sodium equivalent to piperacillin 3 g.
Piperacillin for Injection 4 g/vial: each vial contains piperacillin sodium equivalent to piperacillin 4 g.
Piperacillin for Injection 40 g/vial: each vial contains piperacillin sodium equivalent to piperacillin 40 g.
Stability and Storage Recommendations
Piperacillin for Injection vials should be stored at controlled room temperature, between 15 °C and 30 °C.
Piperacillin for Injection 2 g/vial, 3 g/vial and 4 g/vial are single-use vials. Discard unused portion.
Piperacillin for Injection 40 g/vial is a Pharmacy Bulk Vial intended for multiple dispensing for Intravenous Use Only, employing a single puncture. Use reconstituted stock solutions within 8 hours.
For Intramuscular Use
Solutions for Reconstitution
Sterile Water for Injection, USP
|Vial Size||Volume to be Added||Approximate|
|2 g||4.0 mL||5.0 mL||0.4 g/mL|
|3 g||6.0 mL||7.5 mL||0.4 g/mL|
|4 g||8.0 mL||10.0 mL||0.4 g/mL|
Shake well until dissolved.
|Note:||Intramuscular injections should be limited to 2 g per injection site. Injection should be given into the upper outer quadrant of the buttock (i.e., gluteus maximus).|
For Intravenous Injection or Infusion
For intravenous injection or infusion, reconstitute Piperacillin for Injection with Sterile Water for Injection, USP.
|Vial Size||Volume to be Added||Approximate|
|2 g||10 mL||11 mL||0.18 g/mL|
|3 g||15 mL||17 mL||0.18 g/mL|
|4 g||20 mL||22 mL||0.18 g/mL|
Shake well until dissolved.
The prepared solution may be further diluted to the desired volume (at least 15 mL/g for infusion) with any Intravenous Solutions listed below.
|Vial Size||Volume to be Added||Approximate|
|40 g||172 mL||200 mL||0.20 g/mL|
Pharmacy Bulk Vial
THE AVAILABILITY OF THE PHARMACY BULK VIAL IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.
Directions for Dispensing from Pharmacy Bulk Vial
The Pharmacy Bulk Vial is intended for multiple dispensing for Intravenous use only, employing a single puncture. Following reconstitution, the solution should be further diluted to the desired volume in any appropriate intravenous solution of Intravenous Admixture listed below. Use reconstituted stock solutions within 8 hours and further diluted solutions within 24 hours at room temperature or 72 hours if refrigerated.
5% Dextrose Injection, USP (D5W)
0.9% Sodium Chloride Injection, USP (NORMAL SALINE) [NS]
5% Dextrose and 0.9% Sodium Chloride Injection, USP (D5NS)
Lactated Ringer's Injection, USP
|Note:||Because of chemical instability, Piperacillin for Injection should not be used for intravenous administration with solutions containing only sodium bicarbonate. (See INCOMPATIBILITY section.)|
Stability of Solutions
Stability studies have demonstrated chemical stability (pH, potency and clarity) through 24 hours at room temperature and up to 72 hours refrigerated.
Piperacillin for Injection is stable in PVC containers when reconstituted with recommended diluents and further diluted with the indicated intravenous solutions.
Piperacillin for Injection should not be added to blood products. Because of chemical instability, Piperacillin for Injection should not be used for intravenous administration with solutions containing only sodium bicarbonate.
As with all parenteral products, intravenous admixtures should be inspected for clarity of solutions, particulate matter, precipitate, discolouration, and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.
Availability of Dosage Forms
Piperacillin for Injection (sterile piperacillin sodium) is available in vials containing amounts of piperacillin sodium equivalent to 2, 3 and 4 grams of piperacillin. Available in boxes of 10 vials. Also available in a pharmacy bulk vial containing piperacillin sodium equivalent to 40 g of piperacillin. Available in boxes of single-use vials.
|8685||10 x 2 g single-use vials|
|8690||10 x 3 g single-use vials|
|8695||10 x 4 g single-use vials|
|8698||1 x 40 g Pharmacy Bulk Vial|
Vial stoppers do not contain natural rubber latex.
Piperacillin is a bactericidal, semi-synthetic penicillin with a broad spectrum of activity, encompassing both gram-negative and gram-positive anaerobic and aerobic organisms. TABLE 1 lists the minimal inhibitory concentrations (MICs) of Piperacillin for Injection for 47,119 clinical isolates tested in vitro.
|No. of Isolates Tested||% of Isolates Inhibited by (µq/mL)|
|Neisseria gonorrhoeae (β-lac)||44||100||100|
|Proteus (indole) spp.||2747||79||83||88||92||95|
*Includes strains of both β-lactamase positive and negative bacteria
** Values at 1 mcg/mL given only for those species for which this is the recommended breakpoint.
Several investigators have shown that, for about 80% of clinical isolates of both gram-negative and gram-positive bacteria that were tested, the minimum bactericidal concentration (MBC) of piperacillin was equal to or at most twice the MIC. For the majority of the remaining 20% of isolates, the MBC/MIC ratio is 4/1. Overall, the MBC/MIC ratio of piperacillin is similar to that of the aminoglycosides. Piperacillin kills isolates of Pseudomonas at about the same rate as cefoperazone and is 2- to 4- fold more active than moxalactam.
Table 2 lists the susceptibility of 9,725 clinical isolates of gram-negative aerobic and anaerobic isolates to piperacillin. The data were obtained during 1988 from 11 geographically distinct hospital laboratories throughout the United States. Susceptibility studies of gram-positive pathogens to piperacillin were not included in this study.
|ORGANISMS||Percent of Isolates|
|≤ 16 mcg/mL||32 ‒ 64 mcg/mL||≥ 128 mcg/mL|
* S = Susceptible, I = Intermediate, R = Resistant
In vitro, piperacillin is active against most strains of clinical isolates of the following microorganisms:
Aerobic and Facultatively Anaerobic Organisms
Morganella morganii* (formerly Proteus morganii)
Providencia rettgeri* (formerly Proteus rettgeri)
Serratia spp. including S. marcescens* and S. Liquefaciens*
Enterobacter spp. including E. aerogenes* and E. cloacae*
Citrobacter spp. including C. freundii* and C. diversus*
Pseudomonas spp. including P. cepacia*, P. maltophilia*, P. fluorescens*
Acinetobacter spp. (formerly Mima-Herellea)
Haemophilus influenzae (non-β-lactamase-producing strains)
Yersinia spp.* (formerly Pasteurella)
Group D Streptococci including Enterococci (streptococcus faecalis, S. faecium*)
β-hemolytic streptococci including
Group A Streptococcus (S. pyogenes*)
Group B Streptococcus (S. agalactiae*)
Staphylococcus aureus (non-penicillinase-producing)*
Staphylococcus epidermidis (non-penicillinase-producing)*
Bacteroides spp. including B. fragilis group (B. fragilis, B. vulgatus*)
Non-B fragilis group (B. melaninogenicus*)
Clostridium spp. including C. perfringens* and C. difficile*
Fusobacterium spp. * including F. necleatum* and F. necrophorum*
* Piperacillin has been shown to be active in vitro against these organisms; however, clinical efficacy has not been established.
Piperacillin can be inactivated in vitro by (β-lactamases produced by some strains of gram- negative and staphylococcal bacteria, however, it was found to be active against β-lactamase- producing gonococci.
In vitro testing of piperacillin combinations with gentamicin, tobramycin or amikacin shows a high incidence of synergistic action against strains of Pseudomonas, Serratia, Klebsiella, Proteus (indole-positive), Providencia and Staphylococcus species. Against other organisms, including strains of Enterobacter and Acinetobacter, partial synergy or indifference was noted. Overall, the data suggest that such combinations have clinical potential in the treatment of severe infections caused by these organisms.
Combinations of piperacillin with cephalosporin antibiotics may result in synergistic, additive, indifferent, or antagonistic effects. The effect appears to depend on the cephalosporin and the type of organism tested. Against strains of Klebsiella, Escherichia coli, Acinetobacter, Proteus mirabilis, Salmonella, enterococci, and Staphylococcus aureus, combinations of piperacillin with cefamandole or cefoxitin had synergistic, additive, or indifferent but no antagonistic effects. However, against Pseudomonas, Enterobacter, Serratia, and indole-positive Proteus strains, combinations of piperacillin with cefoxitin had a high frequency of antagonistic effects; combinations of piperacillin with cefamandole had additive or indifferent effects and a low frequency of antagonism.
Tests in mice reflect the in vitro observations. Piperacillin combinations with moxalactam, cefotaxime or cefoperazone have shown some limited in vitro synergy (18 ‒ 25 % of isolates tested) against Pseudomonas aeruginosa and Serratia marcescens.
The data indicate that piperacillin-cephalosporin combinations may have clinical advantages but that susceptibility tests should be conducted.
The use of a 100 mcg piperacillin disc with susceptibility test methods which measure zone diameter gives an accurate estimation of in vitro susceptibility of organisms to piperacillin. The following standard procedure has been recommended for use with discs for testing antimicrobials.* Piperacillin 100 mcg discs should be used for the determination of the susceptibility of organisms to piperacillin. With this type of procedure, a report of "susceptible" from the laboratory indicates that the infecting organism is likely to respond to therapy.
A report of “intermediate susceptibility” suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissue and fluids (e.g., bile, urine) in which high antibiotic levels are obtained. A report of "resistant" indicates that the infecting organism is not likely to respond to therapy.
With the piperacillin disc, a zone of 18 mm or greater indicates susceptibility, zone sizes of 14 mm or less indicate resistance, and zone sizes of 15 to 17 mm indicate intermediate susceptibility. (See TABLE 3.)
* NCCLS Approved Standard: M2-A3 (Formerly ASM-2) Performance Standards for Antimicrobial Disc Susceptibility Tests, Third Edition.
Haemophilus, Neisseria and Staphylococcus species which give zones of ≥ 29 mm are susceptible; resistant strains give zones of ≤ 28 mm. The above interpretive criteria is 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.
The standardized procedure requires the use of control organisms. The 100 mcg piperacillin disc should give zone diameters between 24 and 30 mm for Escherichia coli ATCC No. 25922 and between 25 and 33 mm for Pseudomonas aeruginosa ATCC No. 27853.
Dilution methods such as those described in the International Collaboration Study+ and the NCCLS Approved Standard++ have been used to determine susceptibility of the following organisms: Enterobacteriaceae, Pseudomonas species and Acinetobacter species are considered susceptible if the minimal inhibitory concentration of piperacillin (MIC) is no greater than 16 mcg/mL, and are considered resistant if the MIC is greater than 128 mcg/mL.
Haemophilus and Neisseria species are considered susceptible if the MIC of piperacillin is less than or equal to 1 mcg/mL. Staphylococcus species are considered susceptible if the MIC of piperacillin is less than or equal to 0.12 mcg/mL. (See TABLE 4.)
When anaerobic organisms are isolated from infection sites, it is recommended that other tests such as the modified Broth-Disk+++ method be used to determine the antibiotic susceptibility of these slowly-growing organisms.
+ Acta Pathologica et Microbiologica Scandinavica, Section B Suppl. 217, 1971.
++ NCCLS Approved Standards: M7-A Methods for Dilution, Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, December, 1985.
+++ Wilkins, T.D., and Thiel, T. Antimicrob. Agents Chemother. 3:350-356 (March) 1973.
|BACTERIA||PIPERACILLIN DISCS 100 mcg Zone Diameter (Millimeters)|
|All fast-growing bacteria except those listed below||≥ 18||15 ‒ 17||≤ 14|
|≥ 29||≤ 28|
When minimal inhibitory concentrations (MIC) are determined by standard dilution methods+, the guidelines given in TABLE 4 are suggested.
+ Acta Pathologica et Microbiologica Scandinavica, Section B Suppl. 217, 1971.
|BACTERIA||PIPERACILLIN: MIC (mcg/mL)|
|All bacteria, except those listed below||≤ 6||32 – 64||≥ 128|
|≤ 1||≥ 1|
|Staphylococcus spp.||≤ 0.12||≥ 0.25|
Peak serum concentrations of piperacillin are attained approximately 30 minutes after intramuscular injection and immediately after intravenous injection or infusion. The serum half- life in healthy volunteers ranges from 36 minutes to 1 hour and 12 minutes. Serum levels after intravenous administration (see Table 5) and renal clearance do not show dose proportionality because of saturation of the renal secretory mechanism.
|ROUTE||2 ‒ 3 min||30 min||1 hr||2 hrs||4 hrs||6 hrs|
|Note:||Following a 30 minute infusion of 6 g every 6 hours, on the fourth day, mean peak serum concentrations were 420 mcg/mL.|
(see Table 5 above)
Piperacillin for Injection 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 mcg/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%.
The substitution of 0.5% lidocaine for Sterile Water as a diluent in a intramuscular pharmacokinetic study showed no significant difference in the area under the serum concentration curve, peak serum concentration or cumulative urine excretion of piperacillin. However, the serum half-lives were prolonged from 67 to 70 minutes at 3 g/day, 56 to 68 minutes at 4 g/day and 52 to 59 minutes at 6 g/day.
(see Table 5 above)
In healthy adult volunteers, mean serum levels immediately after a two to three minute intravenous injection of 2, 4 or 6 g were 305, 412 and 775 mcg/mL. Serum levels lack dose proportionality.
Piperacillin binding to human serum proteins is 16%.
Piperacillin is widely distributed in human tissues and body fluids, including bone, prostate, and heart and reaches high concentrations in bile (see TABLE 6). After a 4 gram bolus, maximum biliary concentrations averaged 3,205 mcg/mL. It penetrates into the cerebrospinal fluid in the presence of inflamed meninges. Because Piperacillin for Injection is excreted by the biliary route (10 ‒ 20%) as well as by the renal route, it can be used safely in appropriate dosages (see DOSAGE AND ADMINISTRATION) in patients with mild to severe renal impairment and can be used in treatment of hepato-biliary infections.
|Type of Tissue or|
|Tissue or Fluid|
Level (mcg/mL or mcg/g)
|Bone, diseased||25||at surgery||300 mg/kg|
|Cardiac muscle||113.5||10 ‒ 20 mins.||100 mg/kg i.v. bolus||500|
|Gallbladder||26||1 hour||2 g i.v.||166|
|Intestinal wall (colon)||9.3||1½ hr||2 g i.v.||12.3|
|Kidney, cortex||23.0 ‒ 115.0||at surgery||4 g i.v.||NG*|
|Kidney, medulla||4.0 ‒ 46.0||at surgery||4 g i.v.||NG*|
|Prostatic tissue||71.5||45 mins.||4 g|
|Subcutaneous tissue||120||1 hr.||4 g i.v.||140|
|Synovial tissue||135||NG*||300 mg/kg|
|Wound tissue||7||1 hr.||2 g i.v.||30|
|Bile||3247||1a hrs||4 g i.v.||86.7|
|Bronchial secretions||31.4||30 ‒ 45 mins.||4 g|
|Cerebrospinal fluid (meningitis patients)||6.7||4¾ hrs|
on day 2
|Peritoneal fluid||35.5||2 hrs||50 mg/kg|
|Sputum||10||NG*||4 ‒ 16 g/day|
i.v. or i.m.
|Urine||10000||1 hr||2 g i.m.||36.4|
* NOT GIVEN
As with other penicillins, piperacillin 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, were as high as 14,100 mcg/mL following a 6 g intravenous dose and 8,500 mcg/mL following a 4 g intravenous dose. These urine drug concentrations remained well above 1,000 mcg/mL throughout the dosing interval.
The elimination half-life is increased two-fold in mild to moderate renal impairment and five-to- six-fold in severe impairment.
The mean elimination half-life of piperacillin in healthy adult volunteers is 54 minutes following administration of 2 g and 63 minutes following 6 g.
Pharmacokinetic characteristics in patients with cystic fibrosis are somewhat different than in normal subjects in that, in the former, piperacillin has a shorter half-life, a decreased volume of distribution and an increase in clearance. These differences suggest the need for either increased dosages or shortened dosage intervals in patients with cystic fibrosis.
While piperacillin reduces platelet aggregation, these effects are less than those caused by ticarcillin or carbenicillin at equivalent therapeutic dosage.
There was no significant inactivation of amikacin, gentamicin or tobramycin in serum when the aminoglycoside was administered concomitantly with carbenicillin or piperacillin to subjects with normal renal function. In the urine, lowering of the concentration of tobramycin, and gentamicin to a lesser degree, by the presence of carbenicillin or piperacillin was observed. This possible inactivation effect was greater with carbenicillin than with piperacillin. No urinary inactivation of amikacin by either of these penicillins was observed. The clinical significance of these observations is unknown.
A follow-up study was conducted in patients with end-stage renal failure stabilized on chronic intermittent hemodialysis. No inactivation of piperacillin or carbenicillin in these patients was observed when gentamicin was administered concomitantly with either of these penicillins.
Carbenicillin and piperacillin, however, inactivated gentamicin in these patients. Gentamicin was inactivated 4 times faster by carbenicillin than by piperacillin.
The acute median lethal dose (LD50) in rats was 2 ‒ 3 g/kg (i.v.), 7 ‒ 10 g/kg (i.p.), > 10 g/kg (s.c.) in 6 and 12 week old rats, and 9 g/kg (s.c.) in 1 week old rats; in mice, the LD50 was 5 g/kg (i.v.), > 10 g/kg (s.c.) and 10 g/kg (i.p.). Single intravenous doses of 2 and 4 g/kg were well tolerated in the dog with no changes in biochemical or hematological parameters. Signs of toxicity at 6 g/kg (i.v.) included emesis, diarrhea, salivation, and lacrimation. Slight to moderate increases in SGOT and SGPT values, white blood cell counts, and neutrophil-to-lymphocyte ratios were noted 1 day after dosing. A single 4 g/kg intravenous dose in the monkey produced similar biochemical and hematological changes and, in addition, moderate increase in lactic dehydrogenase and decreases in red blood cell counts.
Subacute and Chronic Toxicity
Rats given daily intraperitoneal doses of piperacillin (0.5 ‒ 2 g/kg/day for 6 months and 1 ‒ 4 g/kg/day for 1 month) showed no toxic effects except for reduced body weight gain in females at 4 g/kg/day only and in males at all dose levels.
Similar findings, plus evidence of renal damage, were seen in rats given ampicillin (2 g/kg/day for 1 month). In rats given 1, 2 or 4 g/kg twice daily intraperitoneally for 6 months, all showed an increase in lymphocytes at 4 and 6 months. At post-mortem all animals had unilateral hydronephrosis and some had urinary bladder urothelial hyperplasia, probably due to local irritation.
Dogs were given piperacillin for 1 month (up to 1 g/kg/day) i.m. (compared with ampicillin) and i.v. (alone and with gentamicin) and for 6 months (up to 2 g/kg/day i.v.). Transient increases in blood serum enzyme values, increases in kidney and liver weights, and mild local irritation at the injection site were seen in the 1-month i.m. study in both piperacillin- and ampicillin-treated dogs. No other toxic effects were seen in the adult dog studies and there was no synergistic toxicity when piperacillin was combined with gentamicin.
Special Toxicitv Studies
Daily intravenous administration of 0.5 ‒ 1 g/kg/day for 1 month in the rat did not cause loss of pinna reflex (as a measurement of ototoxic effect) at any frequency from 200 ‒ 20,000 Hz.
In 4 dogs, daily administration of 2 g/kg intravenously for 1 month resulted in no drug-induced changes in liver or kidney on electron microscopic examination. The same animals showed no eye abnormalities observable by gross examination or direct ophthalmoscopy.
Reproduction and Teratology
Subcutaneous or intravenous administration of piperacillin sodium (0.5, 1 or 2 g/kg) to mice prior to mating (and in females extending into early gestation), during the period of organogenesis, or during late gestation and through the lactation period, had no adverse effect on reproductive success or the development of offspring. Survival rates, weaning rates and body weights were higher in offspring of treated dams than controls.
In rats, with the possible exception of a slight decrease in the survival rate of pups of high-dose dams, subcutaneous administration of 0.25 ‒ 1 g/kg of piperacillin sodium during the period of organogenesis had no adverse effects on reproductive success or the development of offspring.
Intraperitoneal doses of 0.5, 1.0, and 2.0 g/kg/day, given to rats (males for 9 weeks prior to mating and females for 2 weeks prior to mating and until the offsprings were weaned) had no adverse effects except at the 2 g/kg/day dose level where longer precoital time and a lower pregnancy rate were noted; no firm conclusions can be drawn. In the offspring of these animals, no adverse effects regarding early neonatal development, fertility and reproductive performance attributable to treatment of the parents with piperacillin sodium were demonstrated.
In rabbit teratology range finding studies, intravenous doses of 0.25 to 1 g/kg/day of piperacillin sodium from day 6 to 18 of gestation produced marked decreases in food intake and body weight. Maternal mortality and intrauterine deaths were high in all treatment groups; however, fetuses which did survive had no external morphologic abnormalities. Similar results were seen in dams dosed with 1 g/kg/day (single dose or 0.5 g/kg b.i.d.) from day 6 to 8 of gestation.
Piperacillin was non-mutagenic in in vivo cytogenetics, Ames Test, Host-Mediated (mouse) assay, Induction of Unscheduled DNA Synthesis, and Dominant Lethal test systems.
An injection of 0.05 mL of 250 ‒ 500 mg/mL piperacillin given intracutaneously in the rat produced local reaction similar to ampicillin and carbenicillin.
In the rabbit eye, a single 0.1mL instillation of 500 mg/mL piperacillin produced no changes at 24 or 72 hours. Single or multiple intramuscular injections of piperacillin 25, 35 or 40% in Sterile Water were similar to or less irritating than carbenicillin in rabbits.
Single or multiple injections of piperacillin 25 or 40% solutions in either saline (with and without lidocaine) or Sterile Water (with and without lidocaine) were generally well tolerated, though aqueous solutions were better tolerated than saline solutions.
Single injections of piperacillin 40% solution in saline or Sterile Water solution with lidocaine were better tolerated than 2.5% solutions of tetracycline HCl. In another rabbit study 0.05 mL of a 200 mg/mL solution was injected into an occluded auricular vein for 3 minutes, three times daily for three days. Piperacillin was somewhat less irritating than the carbenicillin or ampicillin controls when incidence, onset or length of thrombus were compared.
Effects on Blood
Concentrations up to 500 mg/mL piperacillin sodium did not produce hemolysis of rabbit erythrocytes in vitro; using human erythrocytes hemolysis was produced at concentrations higher than 240 mg/mL. Ampicillin and carbenicillin produced hemolysis at concentrations of 200 mg/mL and higher with human erythrocytes.
Bleeding time in mice was unchanged at i.v. doses of 250 mg/kg piperacillin sodium, but increased at doses of 500 and 1,000 mg/kg. Increases were seen with 1,000 mg/kg of ampicillin and carbenicillin.
Neither piperacillin sodium, ampicillin nor carbenicillin affected rabbit blood prothrombin and partial thromboplastin time in vitro at 10-5 to 10-3 g/mL; all compounds prolonged PT and PTT at 10-2 g/mL.
IV doses of 0.5 or 1.0 g/kg of the same compounds did not affect PT but decreased PTT.
Concentrations of piperacillin sodium, ampicillin and carbenicillin from 10-5 to 10-3 g/mL did not affect platelet aggregation induced by adenosine diphosphate or collagen; all compounds inhibited aggregation at a concentration of 10-2 g/mL.
Possible Immune Responses
No skin sensitization occurred with doses of 1, 5, and 10 mg/0.5 mL of piperacillin sodium in guinea pigs. No signs of anaphylaxis were seen in guinea pigs at doses of 3 to 150 mg/kg.
Protein conjugates of piperacillin sodium produced only slightly positive Arthus reactions after subcutaneous injection in rabbits. Cross reactivity (passive cutaneous anaphylaxis) of piperacillin sodium with ampicillin or penicillin G was weak, displaying 1/8 and 1/16 of the titers from the homologous antigen-antibody systems.