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Plasma levels of piperacillin and vancomycin used as prophylaxis in liver transplant patients.

The pharmacokinetics of piperacillin and vancomycin used intravenously as antibioprophylaxis were measured in the plasma and bile during orthotopic liver transplantation. Piperacillin (4 g and then 2 g every 4 h) and vancomycin (1 g and then 0.5 g every 6 h) were infused in 10 patients. During vascular clamping without venovenous bypass, clearance of both antibiotics decreased in relation to renal insufficiency. During the surgical procedure, volume of distribution of both drugs increased because of fluid redistribution. The peaks of piperacillin after first, second and third administrations were respectively 314, 265 and 210 mg.l-1, while trough levels were 46.5, 55.2 and 54.5 mg.l-1. The peaks of vancomycin were 54.4, 49.6 and 40.9 mg.l-1, while first and second trough levels were 9.5 and 12 mg.l-1. These plasma concentrations were quite similar to levels reported in healthy subjects despite large blood loss and fluid replacement. However, piperacillin trough concentrations (< 64 mg/l) were too low in relation to its concentration-dependent antibacterial activity and vancomycin peak concentrations (> or = 40 mg/l) were slightly too high in relation to its toxicity.

Adolescent↗

Moxalactam and piperacillin: a study of in vitro characteristics and pharmacokinetics in cancer patients.

We evaluated the microbiologic characteristics including MIC determinations, synergy plate assays and serum bactericidal activity for two regimens being examined as empiric antibiotic therapy for febrile granulocytopenic cancer patients. The regimens consisted of moxalactam (4 g.i.v. q12h) plus piperacillin (75 mg/kg i.v. q6h) or moxalactam (as above) plus amikacin (levels adjusted to one hour post-infusion levels of 25 mg/l and troughs of 6-8 mg/l). Detailed pharmacokinetics were ascertained for the beta lactams. All drugs were active against a panel of 11 strains each of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. The pharmacokinetic profile showed serum levels sufficient to provide good antimicrobial activity throughout the dosing interval. Both regimens displayed synergistic or partially synergistic activity in the main for the test organisms; moxalactam plus piperacillin produced good results against S. aureus and P. aeruginosa. In the serum bactericidal assays, the moxalactam-piperacillin combination produced significantly higher mean titers at both peak and trough when compared to the moxalactam-amikacin regimen. This may be because moxalactam acts as a beta lactamase inhibitor for both staphylococcal beta lactamase, as well as the Sabath-Abraham Id type beta lactamase carried by P. aeruginosa (among others). Moxalactam-piperacillin deserves extensive evaluation as empiric therapy for the febrile neutropenic cancer patients.

Amikacin↗

Empiric antimicrobial therapy in febrile granulocytopenic patients. Randomized prospective comparison of amikacin plus piperacillin with or without parenteral trimethoprim/sulphamethoxazole.

In a prospective randomized trial parenteral trimethoprim/sulphamethoxazole was added to amikacin plus piperacillin in order to compare triple-drug antibiotic combination with a standard regimen as empiric therapy of fever in patients with granulocytopenia. One hundred and sixty-one episodes were evaluated; 74 episodes with amikacin plus piperacillin and 87 episodes with amikacin plus piperacillin plus trimethoprim/sulphamethoxazole. The overall response to therapy (63% vs. 84%) as well as the response of microbiologically documented infections (60% vs. 82%) was significantly better in patients treated with the triple-drug combination (p less than 0.05). However, no statistically significant differences in response to antibiotics at different infection sites or with regard to any single pathogen was found between the two groups. Trimethoprim/sulphamethoxazole seemed to be responsible for additional toxicity (nausea and vomiting) when added to amikacin plus piperacillin, but these side-effects were clearly related to the rate of infusion of trimethoprim/sulphamethoxazole. The findings of this study support the use of a three-drug versus a two-drug combination as empiric antibiotic regimen in febrile granulocytopenic patients.

Adolescent↗

A randomized study of imipenem compared to cefotaxime plus piperacillin as initial therapy of infections in granulocytopenic patients.

The objective of the presented, randomized study was to compare the efficacy of antimicrobial monotherapy with imipenem (3 x 0.5g/d) to a combination therapy with cefotaxime (3 x 2g/d) plus piperacillin (3 x 4g/d) for empirical treatment of infections in neutropenic patients. In 165 patients, 237 infectious episodes were evaluable. The overall response rate of patients treated with cefotaxime plus piperacillin was 67/115 (58%), of those treated with imipenem 66/122 (54%). In patients not responding to the initial therapy regimen within 2 or 3 days, the antimicrobial therapy was modified. After therapy modification 85/100 patients were cured. Fever of unknown origin (FUO) showed the most favourable course compared to other infection types, with a response in 46/59 (78%) and in 35/50 (70%) cases, respectively. In comparison, pneumonias were successfully treated in only 3/21 (14%) and 7/37 (19%) cases. Even including patients with modified therapy, only 66% (21/32) of pneumonia episodes responded. The unfavourable results in pneumonias is mainly due to the high rate of 13 systemic mycoses in this group (22%). Overall, a similar response was observed in patients treated with cefotaxime plus piperacillin in comparison with imipenem. In primary bacteremias however, an advantage was observed in patients treated with imipenem (20/27; 74%) compared with cefotaxime plus piperacillin (11/23; 48%).

Adolescent↗

Problems in interpretation of piperacillin susceptibility of TEM-1 producing Escherichia coli in the disk diffusion test.

The susceptibility of 455 Escherichia coli blood culture isolate to piperacillin was tested with the disk diffusion test. The presence of different beta-lactamase genes in these strains was also studied using DNA hybridization. Of the TEM beta-lactamase producing isolates, 64% (61/95) were interpreted as intermediately susceptible to piperacillin. Because piperacillin is hydrolyzed by TEM-type beta-lactamases, we suggest that the intermediate susceptibility category should be reduced or omitted in testing piperacillin susceptibility of Escherichia coli isolates.

Drug Resistance, Microbial↗

Effect of increasing doses of amikacin with or without piperacillin in the serum bactericidal test.

To determine whether high doses of amikacin would prevent the development of resistance in clinical isolates, the serum bactericidal activity and killing rate of conventional and high doses of amikacin and piperacillin alone and in combination were measured in volunteer sera against a series of ten strains each of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Amikacin serum levels were 24.9 +/- 6.0 mg/l 1 h after infusion of the 7.5 mg/kg dose and 44.8 +/- 5.0 mg/l after the two-fold dose. Median serum bactericidal titers for low dose piperacillin + amikacin were 1:8-1:64 and for high-dose piperacillin + amikacin 1:16-1:128. Both were satisfactory, except against piperacillin-resistant Pseudomonas aeruginosa (median bactericidal titers less than or equal to 1:2), and both combinations had equivalent killing rates.

Adult↗

Electrochemical behavior and differential pulse polarographic determination of piperacillin sodium.

In an aqueous piperacillin sodium solution, a well-defined single wave or single peak was observed by direct current (DC) polarography or differential pulse polarography (DPP). The peak potential change per pH unit was -54 mV in the phosphate buffer at 18 degrees C, which indicated that protons were involved in the electrochemical reduction of the 2,3-dioxopiperazine moiety of piperacillin sodium with a H+/e- ratio of one. Using a phosphate buffer of pH 4.3, the 1.0 x 10(-7) M piperacillin sodium single peak could be determined by DPP with relative standard deviation of 1.6% (n=3). Piperacillin sodium could be analyzed without interference from penicillin G-potassium, which enabled the employment of DPP as a fast and simple technique for monitoring the synthetic process of the antibiotic.

Calibration↗

Pharmacokinetic parameters of netilmicin and protective effect of piperacillin regarding nephrotoxicity caused by netilmicin.

The pharmacokinetic interaction of Netilmicin and Piperacillin has been studied as well as the potential protective effect that Piperacillin exert on nephrotoxicity caused by Netilmicin, when both antibiotics are administered to rabbits by single and multiple dosage regimens. Netilmicin was administered at a dose of 7 mg/kg and 12 h interval, which allometrically correspond to 5 mg/kg at 24 h interval for men. Piperacillin was administered at a dose of 280 mg/kg at 12 h interval (the total number of doses of both antibiotics was 20). After single and multiple dose regimens plasma level curves of Netilmicin and renal concentration were determined using an HPLC technique. Besides that, an histologic study was carried out by electronic microscopy to determine the renal damage. A significant variation of some pharmacokinetic parameters of Netilmicin such as Vc and t(1/2) was observed when Netilmicin is administered together with Piperacillin; a similar modification in the renal accumulation and renal damage caused by Netilmicin was shown.

Animals↗

Comparative pharmacokinetics of 14C-piperacillin following intravenous and intraperitoneal administration in pregnant and non-pregnant rats.

14C-piperacillin (Pipracil) at a dose level of 1000 mg/kg was administered intravenously or intraperitoneally to pregnant and non-pregnant female rats. Rats were sacrificed at predetermined time intervals, and 14C-piperacillin concentrations determined in serum, amniotic fluid, placenta, and fetus. The piperacillin serum levels in both pregnant and nonpregnant rats following intravenous administration were comparable; however, following intraperitoneal administration, the serum drug levels in the pregnant rats as compared to the nonpregnant rats were lower. The fetal drug levels, however, were higher following intraperitoneal administration than following intravenous administration. The total area under the fetal drug concentration-time curve following intraperitoneal administration was about two times the corresponding area under the curve following intravenous administration. The data indicate that the fetal exposure to piperacillin was greater following intraperitoneal administration.

Amniotic Fluid↗

Piperacillin levels in human tears and aqueous humor.

Thirty patients scheduled to undergo elective intraocular surgery were each given 4 g of piperacillin intravenously. Specimens of serum, tears, and aqueous humor were collected from zero to nine hours after infusion and assayed for piperacillin content by high pressure liquid chromatography. In noninflamed eyes piperacillin sodium distributed into tears and aqueous humor in concentrations exceeding the minimum inhibitory concentration required for many gram-positive and gram-negative organisms. Higher levels of piperacillin were anticipated in patients with inflamed eyes who possessed an altered blood-aqueous barrier, and in patients receiving serial doses of this agent.

Adult↗

Clinical comparison of piperacillin and cefamandole in treatment of complicated urinary tract infections.

The efficacy and safety of piperacillin were compared with those of cefamandole in 72 patients (mean age: 63 years) with complicated urinary tract infections. Efficacy was evaluable in 25/34 piperacillin-treated patients (12 Gm/day) and in 23/38 cefamandole-treated patients (6 Gm/day). Clinical cure or improvement was noted in all patients who were given piperacillin and in 96 per cent (22/23) of those who received cefamandole. Seventy-one per cent (41/58) of the organisms cultured pretherapy were gram-negative aerobic bacteria. Escherichia coli was the most frequently isolated organism (15/58, or 26%), followed by Pseudomonas species (8/58, or 14%), and Proteus species (8/58, or 14%). Adverse clinical experiences were few, and none was directly attributed to therapy with either antibiotic. The changes noted in the results of laboratory tests were considered to be unrelated to the antibiotics administered. Thus, both piperacillin and cefamandole were safe and effective in the treatment of patients with complicated urinary tract infections.

Cefamandole↗

Multicenter evaluation of the in vitro activity of piperacillin-tazobactam compared with eleven selected beta-lactam antibiotics and ciprofloxacin against more than 42,000 aerobic gram-positive and gram-negative bacteria. In Vitro Susceptibility Surveillance Group.

The in vitro activities of piperacillin-tazobactam, 11 other beta-lactam antibiotics, and ciprofloxacin were evaluated in a large multicenter study. A total of 42,208 organisms, collected from 79 listed medical centers and large community hospitals, were tested using the National Committee for Clinical Laboratory Standards broth microdilution procedure. Imipenem (94.7% inhibition), ciprofloxacin (93.8%), and ceftazidime (90.8%) were the most active antibiotics against 31,426 Gram-negative bacilli. Piperacillin-tazobactam (88.8%) and ticarcillin-clavulanate (86.4%) were the most active combination antibiotics against these organisms. Ampicillin-sulbactam (97.8%), piperacillin-tazobactam (96.4%), and imipenem (96.9%) were the most active antibiotics against 10,782 Gram-positive cocci. Overall, the most active antibiotics against all organisms tested were imipenem (95.2%), ciprofloxacin (91.0%), and piperacillin-tazobactam (90.8%).

Anti-Bacterial Agents↗

Pharmacodynamics of piperacillin in severely ill patients evaluated by using a PK/PD model.

Penetration of antiinfective drugs into soft tissues is essential for antimicrobial killing at the target site, but is substantially lower in severely ill patients compared with healthy subjects. The present study was conducted to assess the antimicrobial effect of piperacillin in severely ill patients. Strains of Staphylococcus aureus and Pseudomonas aeruginosa were exposed in vitro to concentrations of piperacillin, simulating the pharmacokinetic profiles measured in soft tissue of patients and healthy subjects. The simulation for patients resulted in effective killing, whereas bacterial regrowth was detected for healthy subjects. Our in vitro simulation showed that bacterial killing may be effective in severely ill patients despite relatively low concentrations of piperacillin at the target site. This finding is due to impaired renal function and subsequently prolonged tissue and plasma half-lives of piperacillin in intensive care patients.

Colony Count, Microbial↗

Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients.

Since the bactericidal effects of beta-lactam antibiotics are time dependent, the optimum strategy for their administration could be continuous infusion. In this prospective, randomised controlled trial to evaluate the clinical efficacy of continuous infusion therapy, we evaluated the outcomes for 40 septic critically ill patients who received piperacillin either continuously (2 g intravenously (i.v.) over 0.5 h as a loading dose followed by 8 g i.v. daily over 24 h (n=20)) or as an intermittent infusion (3 g i.v. every 6h over 0.5 h (n=20)). Results from our study demonstrated that the clinical efficacy of piperacillin as a continuous infusion is superior to intermittent administration in critically ill patients. Change in APACHE II scores from baseline at the end of the second, third and fourth days, respectively, were 4.1, 5.1 and 5.2 for continuous infusion and 2.0, 2.6 and 2.8 for intermittent infusion (P< or =0.04). Considering minimum inhibitory concentrations (MICs) of 16 microg/mL and 32 microg/mL, the percentage of time for which piperacillin plasma concentrations were higher than the MIC (%T>MIC) was calculated for each patient in the two groups. For MICs of 16 microg/mL and 32 microg/mL, %T>MIC in the continuous infusion group was 100% and 65% of the dosing interval, respectively; in the intermittent infusion group, %T>MIC was only 62% and 39% of the dosing interval. There was a significant relationship between clinical results and laboratory data. It was shown that the superiority of the clinical efficacy of continuous infusion could be related to piperacillin pharmacodynamics. Continuous infusion significantly reduced the severity of illness as demonstrated by APACHE II scores during therapy.

APACHE↗

Antiendotoxin activity of protegrin analog IB-367 alone or in combination with piperacillin in different animal models of septic shock.

The therapeutic efficacy of protegrin peptide IB-367 was investigated in three rat models of septic shock: (i) rats injected intraperitoneally with 1mg Escherichia coli 0111:B4 lipopolysaccharide, (ii) rats given an intraperitoneal injection of 2 X 10(10) CFU of E. coli ATCC 25922, and (iii) rats in which intra-abdominal sepsis was induced via cecal ligation and puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1mg/kg of IB-367, 60mg/kg piperacillin and 1mg/kg of IB-367 plus 60mg/kg piperacillin. The peptide demonstrated lower level of antimicrobial activity than piperacillin, nevertheless it exhibited the dual properties of antimicrobial and antiendotoxin agent. Finally IB-367 and piperacillin association showed to be the most effective therapeutic approach.

Animals↗

Single-dose versus multiple-dose piperacillin prophylaxis in primary cesarean operation.

A prospective, randomized double-blind study was undertaken to determine the safety and efficacy of single-dose versus multiple-dose piperacillin for primary cesarean operation prophylaxis. After informed consent was obtained, patients received either 4 gm of piperacillin intravenously as a single dose or three 2 gm doses of piperacillin intravenously 4 hours apart. One hundred sixteen patients were evaluated for response; postoperative infection at the operative site was prevented in 52/60 (86.6%) who received the single dose and 53/56 (94.6%) who received multiple doses. The types of postoperative infections that occurred were similar in those patients in each group who developed infection and all responded well to therapeutic drugs. No adverse reactions to piperacillin were noted. Demographic characteristics and risk factors for infection were comparable for the two groups. These data support the efficacy of single-dose prophylaxis with an appropriate antibiotic agent.

Adult↗

Pharmacokinetics of intravenously administered piperacillin in preadolescent children.

We studied the pharmacokinetics of piperacillin in 37 preadolescent children (mean age 52 months, range 1 month to 11 years) after 50 mg/kg IV doses. Pharmacokinetic parameters were determined after the initial dose in 18 instances and after subsequent doses in 32 instances. There were no significant differences between the initial doses and the subsequent doses in the plasma piperacillin concentrations at comparable times, the elimination rate constants, the elimination-phase plasma half-lives, the total body clearances, the apparent volumes of distribution, or the areas under the concentration curves. At the end of a 30-minute infusion of the drug, the plasma concentration was 166.2 +/- 42.2 mg/L (mean +/- SD) and ranged from 91.6 to 268.3 mg/L. The mean half-life was 31.0 +/- 9.4 minutes. The half-life of piperacillin in children 1 to 6 months of age (47.2 minutes) was significantly longer than in older children (28.8 minutes) (P less than 0.05). Likewise, the total body clearance of the drug in the younger age group (71.7 ml/min/m2) was significantly lower than in the older children (130.8 ml/min/m2) (P less than 0.05). The mean renal clearance of the drug was only 63% (range 39% to 85%) of the total body clearance, suggesting a variable but substantial nonrenal route of elimination. The intravenous administration of 50 mg/kg piperacillin every four hours results in adequate plasma concentrations for the treatment of most infections caused by gram-negative and gram-positive organisms.

Bacterial Infections↗

High-performance liquid chromatographic determination of a new beta-lactamase inhibitor and its metabolite in combination therapy with piperacillin in biological materials.

[2S-(2 alpha,3 beta,5 alpha)]-3-Methyl-7-oxo-3-(1H-1,2,3-triazol-1-yl- methyl)-4-thia-1-azabicyclo [3.2.0]-heptane-2-carboxylic acid 4,4-dioxide (YTR-830H) is a new beta-lactamase inhibitor and the combination therapy of this compound with piperacillin is now under study. For the determination of the beta-lactamase inhibitor and piperacillin in biological materials, plasma and visceral tissue homogenates were deproteinized, whereas diluted urine and filtered faeces homogenates were treated with a Sep-Pak C18 cartridge. In order to assay the inactive metabolite of beta-lactamase inhibitor, each sample was treated with a Sep-Pak C18 cartridge. Aliquots of each preparation were chromatographed using ion-pair and reversed-phase chromatographic techniques on a high-performance liquid chromatograph equipped with a UV detector, set at 220 nm. The detection limits of beta-lactamase inhibitor and piperacillin were 0.2 microgram/ml in plasma, 2.5-5.0 micrograms/ml in urine and 0.2-0.5 microgram/g in visceral tissue and faeces. Those of the metabolite were 1.0 microgram/ml in plasma, 2.5-5.0 micrograms/ml in urine and 1.0 microgram/g in visceral tissue and faeces. A precise and sensitive assay for the determination of the beta-lactamase inhibitor, its metabolite and piperacillin is described, and their stabilities in several media are reported.

Animals↗