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PubMed2006

Use of in vitro critical inhibitory concentration, a novel approach to predict in vivo synergistic bactericidal effect of combined amikacin and piperacillin against Pseudomonas aeruginosa in a systemic rat infection model.

PURPOSE: This study was undertaken to explore the use of in vitro critical inhibitory concentration (CIC) as a surrogate marker relating the pharmacokinetic (PK) parameters to in vivo bactericidal synergistic effect [pharmacodynamic (PD)] of amikacin + piperacillin combination against Pseudomonas aeruginosa in a systemic rat infection model. METHODS: The in vitro antibacterial activities of amikacin and piperacillin, alone and in combinations at various ratios of the concentrations, were tested against a standard [5 x 10(5) colony-forming units (CFU)/ml] and a large (1.5 x 10(8) CFU/ml) inoculum of P. aeruginosa ATCC 9027 using a modified survival-time method. The CIC of each individual antibiotic for the different combinations was determined using a cup-plate method. In vivo studies were performed on Sprague-Dawley rats using a systemic model of infection with P. aeruginosa ATCC 9027. PK profiles and in vivo killing effects of the combination at different dosing ratios were studied. RESULTS: An inoculum effect was observed with the antibiotics studied. Synergy was seen against both the inocula at the following concentration ratios: 70% C(ami) + 30% C(pip) and 75% C(ami) + 25% C(pip), where C(ami) and C(pip) are the concentrations of amikacin and piperacillin to produce a 1000-fold decrease in bacterial population over 5 h, respectively. The CIC values determined corroborated with the order of in vitro bacterial killing observed for the antibiotic combinations. The dosing ratio of 12.6 mg/kg amikacin + 36 mg/kg piperacillin (a 70:30 ratio of the individual doses) exhibited the greatest killing in vivo when compared to the other ratios. The PK-PD relationships were described by simple, linear regression equations using the area under the in vivo killing curve as a PD marker and the AUCIC(ami)/CIC(ami) + AUCIC(pip)/CIC(pip), AUC(ami)/CIC(ami) + AUC(pip)/CIC(pip), C(max,ami)/CIC(ami) + C(max,pip)/CIC(pip), and AUCIC(ami)/MIC(ami) + AUCIC(pip)/MIC(pip) as PK markers for the amikacin + piperacillin combination. CONCLUSION: The combination of amikacin and piperacillin exhibited synergistic killing effect on P. aeruginosa that could be modeled using CIC as a surrogate marker relating the PK parameters to in vivo bactericidal effect.

Amikacin↗
PubMed1984

Moxalactam plus piperacillin versus moxalactam plus amikacin in febrile granulocytopenic patients.

In a prospective randomized trial, febrile granulocytopenic patients received either moxalactam plus piperacillin or moxalactam plus amikacin as initial empiric antimicrobial therapy. Most patients were also given prophylactic vitamin K. The overall response rates for the two regimens were similar (105 of 136, or 77 percent, for moxalactam plus piperacillin versus 107 of 136, or 79 percent, for moxalactam plus amikacin). For Pseudomonas aeruginosa infections, the response rate was better in patients receiving moxalactam plus amikacin (seven of nine versus one of five, p = 0.06); two patients treated with moxalactam plus piperacillin experienced relapse of P. aeruginosa bacteremia in association with the emergence of beta-lactam-resistant P. aeruginosa isolates. On the other hand, bacteremic enterococcal superinfections occurred in seven patients receiving moxalactam plus amikacin but in none given moxalactam plus piperacillin (p = 0.02). Serious side-effects were minimal with both regimens, and nephrotoxicity was less common in patients receiving moxalactam plus piperacillin (two of 136 versus six of 136, p = 0.28). There was no antibiotic-related hemorrhage. These results suggest that the overall efficacy and toxicity of moxalactam plus piperacillin and moxalactam plus amikacin are similar. Moxalactam/piperacillin therapy may be limited in certain patients by the emergence of beta-lactam-resistant P. aeruginosa, whereas enterococcal superinfections may complicate moxalactam/amikacin therapy.

Adolescent↗
PubMed1995

Infection after colorectal surgery: a randomized trial of prophylaxis with piperacillin versus sulbactam/piperacillin. West of Scotland Surgical Infection Study Group.

Antibiotics used for prophylaxis in elective colorectal surgery should be effective against the organisms contaminating the soft tissues and isolated from postoperative infections. These are usually the enterobacteriaceae commensal to the colon. However, staphylococcal and anaerobic infections are not uncommon. Piperacillin has been used as antibiotic prophylaxis and been shown to be as efficacious as an aminoglycoside with metronidazole. Piperacillin is susceptible to many beta-lactamases and we have therefore conducted a study to assess the efficacy of adding sulbactam, a beta-lactamase inhibitor, to piperacillin for prophylaxis in elective colorectal surgery. Three hundred and seventy-nine patients were randomized to receive a single dose of piperacillin 4 g intravenously (iv) (group P, n = 192) or piperacillin 4 g with sulbactam 2 g iv (group SP n = 187). Fifty-three patients were withdrawn from analysis leaving 168 evaluable patients in group P and 158 patients in group SP. Postoperative infective complications occurred in 91 (28%) patients, 55 (33%) in group P and 36 (23%) in group SP (chi 2 = 4.0 P < 0.05). Surprisingly Staphylococcus aureus was isolated from wound infections in 22 patients (12 in group P and 10 in group SP) which represents 24% of those patients who developed infective morbidity. We conclude that sulbactam improves the efficacy of piperacillin as prophylaxis in elective colorectal surgery but does little to protect against staphylococcal wound infection.

Adolescent↗
PubMed1996

High-performance liquid chromatographic determination of tazobactam and piperacillin in human plasma and urine.

A high-performance liquid chromatographic (HPLC) method with ultraviolet (UV) absorbance was developed for the analysis of piperacillin-tazobactam (tazocillin), in plasma and urine. The detection was performed at 218 nm for tazobactam and 222 nm for piperacillin. The procedure for assay of these two compounds in plasma and of piperacillin in urine involves the addition of an internal standard (ceftazidime for tazobactam and benzylpenicillin for piperacillin) followed by a treatment of the samples with acetonitrile and chloroform. To quantify tazobactam in urine, diluted samples were analysed using a column-switching technique without internal standard. The HPLC column, LiChrosorb RP-select B, was equilibrated with an eluent mixture composed of acetonitrile-ammonium acetate (pH 5). The proposed technique is reproducible, selective, and reliable. The method has been validated, and stability tests under various conditions have been performed. Linear detector responses were observed for the calibration curve standards in the ranges 5-60 micrograms/ml for tazobactam, and 1-100 micrograms/ml for piperacillin and spans what is currently though to be the clinically relevant range for tazocillin concentrations in body fluids. The limit of quantification was 3 micrograms/ml for tazobactam and 0.5 microgram/ml for piperacillin in plasma and urine. Extraction recoveries from plasma proved to be more than 85%. Precision, expressed as C.V., was in the range 0.4-18%.

Chromatography, High Pressure Liquid↗
PubMed1994

Prediction of piperacillin-tazobactam susceptibility among Enterobacteriaceae, Pseudomonas aeruginosa, and other bacteria using ticarcillin-clavulanic acid, ceftazidime, and other broad-spectrum antimicrobial in vitro test results.

The ability of various in vitro beta-lactam susceptibility test results to predict the susceptibility of piperacillin-tazobactam (a new beta-lactam-beta-lactamase inhibitor combination) was assessed using more than 46,000 recent clinical isolates. The organisms were tested by reference-quality National Committee for Clinical Laboratory Standards (NCCLS) broth microdilution procedures and interpreted by the currently published NCCLS criteria. The recommended antimicrobial tests that would accurately predict the piperacillin-tazobactam in vitro efficacy had an overall very major, false-susceptible rate of only 0.6% (< or = 1.5% is acceptable). The following drug tests can be used to judge piperacillin-tazobactam activity and spectrum (low patient risk) conservatively: for Enterobacteriaceae use ticarcillin-clavulanic acid results (0.6% very major error); for Pseudomonas aeruginosa use piperacillin (0.1%) results; for enterococci use ampicillin or ampicillin-sulbactam (1.8%) results; for Haemophilus influenzae and Moraxella catarrhalis use cefotaxime or cefuroxime or ceftriaxone (1.5%); and for staphylococci use oxacillin by NCCLS recommendations. When the piperacillin-tazobactam testing reagents become available, the direct testing of this combination should be applied to relevant clinical isolates. The piperacillin-tazobactam break points should be reassessed as indicated by the cited minimum inhibitory concentration population analysis to improve predictive accuracy; H. influenzae susceptibility modified to < or = 2/4 micrograms/ml and Enterococcus species susceptibility tested at < or = 16/4 micrograms.

Anti-Bacterial Agents↗
PubMed2006

In vitro activities of various piperacillin and sulbactam combinations against bacterial pathogens isolated from Intensive Care Units in Taiwan: SMART 2004 programme data.

We investigated the in vitro activity of various piperacillin and sulbactam combinations against Gram-negative bacterial isolates from Intensive Care Units (ICUs) in Taiwan. Antimicrobial susceptibility testing of 1030 bacterial isolates recovered from ICUs of nine major teaching hospitals was performed using the agar dilution method. Sulbactam was added to piperacillin either at a fixed sulbactam concentration of 4 mg/L and 8 mg/L or at a piperacillin:sulbactam ratio of 2:1 and 4:1. Piperacillin/sulbactam at a ratio of 2:1 or a fixed 8 mg/L concentration of sulbactam had better activities against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Serratia marcescens than other piperacillin/sulbactam formulations. For Pseudomonas aeruginosa, piperacillin/sulbactam (2:1 or 4:1 ratios) had MIC(90) values (minimum inhibitory concentration for 90% of the organisms) of 64 mg/L (>90% susceptibility) compared with 64 mg/L for cefoperazone/sulbactam (68% susceptibility) and 128 mg/L for piperacillin/tazobactam (82% susceptibility). For Acinetobacter baumannii, both piperacillin/sulbactam (either 2:1 ratio or a fixed 8 mg/L sulbactam) and cefoperazone/sulbactam were the most potent agents. Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa (53-57% in either 2:1 or 4:1 ratios) and A. baumannii (38-46% in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam) isolates. Results of susceptibility tests with piperacillin/sulbactam are dependent on the method used. Piperacillin/sulbactam combinations possessed better in vitro activities than piperacillin alone or piperacillin/tazobactam against P. aeruginosa and A. baumannii.

Bacteria↗
PubMed2003

Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis.

OBJECTIVES: The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma. PATIENTS AND METHODS: The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam. RESULTS: The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed. CONCLUSION: This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.

Adult↗
PubMed2005

Piperacillin-resistant Escherichia coli bacteraemia: relation to empiric therapy and clinical outcome.

Escherichia coli is a leading cause of bacteraemia. The aim of this study was to evaluate all E. coli positive blood cultures collected during a 4-y period in a haematological department using piperacillin plus netilmicin for empiric treatment of febrile episodes. We measured the incidence of piperacillin-resistant E. coli bacteraemia among haematological and non-haematological patients, described the importance of previous antibiotic treatment for resistance development in E. coli and evaluated the impact of piperacillin resistance on the clinical outcome of E. coli bacteraemia. 114 episodes of E. coli bacteraemia in 104 patients were recorded and 98 episodes in 88 patients (42 males and 46 females) with a median age of 64 y (range 19-85 y) were evaluated. In 81.6% of the episodes the patients had a haematological disorder, dominated by acute leukaemia (41.3%), chronic leukaemia (16.3%) and lymphoma (10%). The proportion of piperacillin-resistant E. coli was higher among haematological patients than non-haematological patients (25% vs 0%, p=0.02) and resistance was associated with piperacillin therapy during the previous month (p=0.05). No difference in clinical outcome was found between haematological patients infected with piperacillin-susceptible or -resistant E. coli (intensive care 12% vs 15%; mortality 22% vs 25%).

Adult↗
PubMed1989

In vitro and in vivo efficacy of YTR-830H and piperacillin combinations versus beta-lactamase-producing bacteria.

YTR-830H, a beta-lactamase inhibitor, is a non-amino penicillanic sulfone. In vitro synergistic activity with piperacillin was determined for 226 beta-lactamase producing clinical cultures. Combination of piperacillin: YTR in ratios of 2:1, 4:1, and 8:1 were highly effective vs Escherichia coli, Proteus, Providencia, Morganella, Staphylococcus, and Bacteroides. Minimum inhibitory concentrations (MICs) of piperacillin were reduced from the resistant to susceptible range. The higher ratios were less effective vs Enterobacter, Serratia, and Citrobacter. YTR-830H was not antagonistic with piperacillin. Combinations of 2:1, 4:1, and 8:1 increased the therapeutic effectiveness of piperacillin 8 - to 36 - fold against acute lethal infections produced in mice with piperacillin-resistant Escherichia coli, Klebsiella pneumoniae, Morganella morganii, and Staphylococcus aureus.

Animals↗
PubMed1991

Synergy with cefsulodin or piperacillin and three aminoglycosides or aztreonam against aminoglycoside resistant strains of Pseudomonas aeruginosa.

Fifty-one strains of Pseudomonas aeruginosa, with resistance to one or more amino-glycosides, were tested for synergy with cefsulodin or piperacillin plus amikacin, tobramycin, gentamicin or aztreonam by the agar dilution technique. Cefsulodin plus any one of the three aminoglycosides regardless of the degree of resistance to the aminoglycoside was synergistic against P. aeruginosa for two thirds of the isolates. In contrast, synergy rates with piperacillin were much less uniform. The highest rate of synergy with piperacillin (90.0%) was observed with gentamicin for the gentamicin resistant strains. The lowest rate of synergy was observed with piperacillin plus amikacin (32.2%) for isolates with moderate resistance to amikacin. Synergy for strains with moderate resistance to amikacin was observed more commonly with cefsulodin than with piperacillin. Synergy for strains with a known mechanism of resistance to amikacin was more common with cefsulodin regardless of the mechanism of resistance. Cefsulodin or piperacillin in combination with aztreonam was rarely synergistic (less than 12%).

Aminoglycosides↗
PubMed1998

Determination of free interstitial concentrations of piperacillin-tazobactam combinations by microdialysis.

The investigation of tissue penetration and distribution of antibiotics is of great importance, since infections occur mostly in the tissues. The aim of this study was to investigate the pharmacokinetics of piperacillin and tazobactam, alone and in combination, by measuring total plasma and free interstitial concentrations, and to examine the relationship between free levels of both drugs in blood and those in the extracellular space. Piperacillin and tazobactam were administered, alone and in combination, to anaesthetized rats as a single iv bolus dose. Total plasma concentrations and free extracellular concentrations were quantified by HPLC. In-vivo microdialysis sampling was used to study the free tissue distribution patterns of both drugs. The pharmacokinetics of piperacillin and tazobactam in plasma were consistent with a two-compartment body model. Piperacillin pharmacokinetics were not influenced by co-administration of tazobactam. Tazobactam's volumes of distribution and clearance were decreased by the co-administration of piperacillin and the area under the curve was significantly increased. Comparisons between calculated free concentrations in the peripheral compartment for both drugs and measured free extracellular concentrations revealed excellent agreement. For piperacillin and tazobactam, alone and in combination, predictions of the concentration-time profiles of free drug in the peripheral compartment can be made on the basis of plasma data.

Animals↗
PubMed2003

Penicillin-binding proteins involved in high-level piperacillin resistance in Veillonella spp.

OBJECTIVES: To investigate high-level piperacillin resistance in Veillonella spp. in the absence of beta-lactamase activity. METHODS: Penicillin-binding protein (PBP) competition studies were conducted in Veillonella strains, with piperacillin MICs ranging from 0.5 to >128 mg/L and ampicillin MICs from 0.125 to 4 mg/L. Whole cell lysates were pre-incubated with piperacillin or ampicillin and post-labelled with [3H]benzylpenicillin. RESULTS: PBP competition studies showed that the PBP with greatest affinity for penicillin and ampicillin had a molecular weight of approximately 66 kDa, and exhibited reduced binding of piperacillin in resistant strains. CONCLUSIONS: This unusual focusing of different penicillins on one PBP may be the cause of selective mutants resulting from piperacillin MICs > 128 mg/L. In the absence of beta-lactamases, alterations in penicillin-binding were seen to be major contributors to high-level piperacillin resistance development.

Ampicillin↗
PubMed2006

In vitro and in vivo determination of piperacillin metabolism in humans.

Piperacillin metabolism and biliary excretion are different between humans and preclinical species. In the present study, piperacillin metabolites were characterized in bile and urine of healthy humans and compared with metabolites formed in vitro. Volunteers were administered 2 g of piperacillin IV; blood, urine, and duodenal aspirates (obtained via a custom-made oroenteric catheter) were collected. The metabolism of piperacillin in humans also was investigated in vitro using pooled human liver microsomes and sandwich-cultured human hepatocytes. Piperacillin and metabolites were estimated by high-performance liquid chromatography with tandem mass spectrometry detection. Piperacillin, desethylpiperacillin, and desethylpiperacillin glucuronide were detected in bile, urine, and human liver microsomal incubates. Similar to the in vivo results, desethylpiperacillin was formed and excreted into bile canaliculi of sandwich-cultured human hepatocytes. This is the first report of glucuronidation of desethylpiperacillin in vitro or in vivo. The clinical method employed in this study to determine biliary clearance of drugs also facilitates bile collection as soon as bile is excreted from the gallbladder, thereby minimizing the exposure of labile metabolites to the intestinal environment. This study exemplifies how a combination of in vitro and in vivo tools can aid in the identification of metabolites unique to the human species.

Anti-Bacterial Agents↗
PubMed1978

In vitro activity of piperacillin, a new semisynthetic penicillin with an unusually broad spectrum of activity.

The in vitro activity of piperacillin (T-1220), a new semisynthetic derivative of aminobenzylpenicillin, was investigated. The majority of streptococci and pneumococci were inhibited by 0.12 micrograms/ml; the staphylococci and enterococci were inhibited by 2 micrograms/ml. Piperacillin was slightly more active against Neisseria and Haemophilus influenzae than was ampicillin. Piperacillin was active against all members of the Enterobacteriaceae including the Klebsiella, 58% of which were inhibited by 8 micrograms/ml. The activity of piperacillin was at least equivalent, but generally superior, to that of ampicillin or carbenicillin on species susceptible to these drugs. Most striking was its activity on Pseudomonas aeruginosa: 50% were inhibited by 2 micrograms/ml, and 83% were inhibited by 4 micrograms/ml. The minimum bactericidal concentrations were very close to the minimum inhibitory concentrations, and in most species only a slight inoculum effect was observed on the minimum bacterial values except for certain P. aeruginosa strains. A complete parallel resistance exists between piperacillin and ampicillin or carbenicillin. However, the clinical importance of this is largely mitigated by the intrinsically higher activity of piperacillin.

Enterobacteriaceae↗
PubMed1978

Susceptibility of cephalothin-resistant gram-negative bacilli to piperacillin, cefuroxime, and other selected antibiotics.

The in vitro antibacterial activity of piperacillin and cefuroxime against 180 isolates of cephalothin-resistant Enterobacteriaceae and of piperacillin against 46 isolates of Pseudomonas aeruginosa was determined. Amikacin, gentamicin, carbenicillin, cefoxitin, and cefamandole were included for comparison. The activities of piperacillin and carbenicillin against Enterobacteriaceae were comparable. Piperacillin was appreciably more active against Pseudomonas than carbenicillin and was equivalent in activity to amikacin on a weight basis. The following beta-lactam agents were the most active against the indicated organisms (in parentheses): cefoxitin (indole-positive Proteus spp.), cefuroxime and cefoxitin, (Klebsiella spp.), piperacillin (Enterobacter spp.), cefuroxime and cefoxitin (E. coli), piperacillin and cefoxitin (Serratia spp.), and cefoxitin (Providencia spp.). Amikacin inhibited 98% of Enterobacteriaceae at clinically achievable serum levels.

Amikacin↗
PubMed1982

Comparison of piperacillin and penicillin in the treatment of uncomplicated gonorrhea.

A total of 120 men with uncomplicated infections caused by beta-lactamase-negative, highly penicillin-susceptible strains of Neisseria gonorrhoeae were included in this study. They were randomly assigned to regimens of either piperacillin (2.0 g) or procaine penicillin G (4.8 X 10(6) U) intramuscularly, both delivered concomitantly with an oral dose of 1.0 g probenecid. A total of 103 patients completed the study, providing data from 112 infected sites: for the penicillin regimen--urethra, 46; pharynx, 5; and rectum, 4; for the piperacillin regimen--urethra, 53; pharynx, 3; and rectum, 1. In the penicillin group, there were no failures at any of the infected sites. In the piperacillin group, all except one pharyngeal infection were cured. Also, in the piperacillin group, four men visit, whereas no cases of this type occurred in the penicillin group. No major side effects were noted in either group. Clinically, piperacillin was as effective as procaine penicillin G in the treatment of gonococcal urethritis in men. Pharyngeal infection may be refractory to piperacillin therapy.

Gonorrhea↗
PubMed1983

Pharmacokinetics of piperacillin in subjects with various degrees of renal function.

The pharmacokinetics of piperacillin were examined after single intravenous doses to three groups of male patients with creatinine clearances of greater than or equal to 60 (group I), greater than or equal to 20 but less than 60 (group II), and less than 20 (group III) ml/min per 1.73 m2. Each of 32 patients received either 1 or 4 g of piperacillin as a bolus injection. Three patients received both doses. After a rapid 0.5- to 1-h distribution phase, antibiotic levels in serum declined monoexponentially. After the 1-g dose, mean peak piperacillin levels in serum were 60, 103, and 67 micrograms/ml and the beta phase elimination half-lives were 1.0, 1.6, and 3.9 h in groups I, II, and III, respectively. After the 4-g dose, the respective mean peak piperacillin levels in serum were 329, 232, and 262 micrograms/ml and beta phase half-lives were 1.4, 2.3, and 2.6 h in the three groups. There was no clear evidence of significant dose-dependent effects on any pharmacokinetic parameters in any of the groups. Piperacillin levels in urine were far higher than those in serum, generally exceeding the minimal inhibitory concentrations for susceptible organisms during the 24 h after both the 1- and the 4-g dose. Piperacillin dosage modification is required only in patients with severe renal impairment.

Aged↗
PubMed1984

Comparative pharmacokinetics of apalcillin and piperacillin.

The pharmacokinetics of apalcillin and piperacillin, each administered intravenously as a single 2-g dose, were compared in 10 volunteers in a randomized study of crossover design using bioassay and high-pressure liquid chromatographic procedures. The concentrations of both penicillins in serum were determined over a period of 12 h and in urine over 24 h. Concentrations of apalcillin and piperacillin at the end of the 15-min infusion were similar; however, at 8 h, concentrations of piperacillin were below measurable levels, whereas concentrations of apalcillin were still measurable at 10 h. Pharmacokinetic parameters were calculated according to a two-compartment open model. The area under the curve and the half-life for apalcillin were larger than for piperacillin. On the other hand, renal clearance of piperacillin was substantially greater than that of apalcillin. Of the apalcillin excreted via the kidneys, approximately one-fifth was eliminated as two microbiologically inactive penicilloic acid derivatives. The nonrenal clearance of apalcillin was 79% of total clearance. Binding of apalcillin to serum protein was almost twice that of piperacillin.

Adult↗