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PubMed1997

Influence of piperacillin-tazobactam on pharmacokinetics of gentamicin given once daily.

The effect of piperacillin-tazobactam on the pharmacokinetics of gentamicin given once daily was studied. Healthy adult volunteers each received four drug regimens in randomized order: gentamicin 7 mg/kg i.v. once daily (1) by itself, (2) with piperacillin 4 g and tazobactam 0.5 g (both as the sodium salt) every six hours i.v., (3) with piperacillin 4 g and tazobactam 0.5 g i.v. every eight hours, and (4) with piperacillin 8 g and tazobactam 1 g by continuous i.v. infusion over 24 hours. All the gentamicin doses were infused over 30 minutes two hours after piperacillin-tazobactam. Blood samples were drawn before and at the end of each gentamicin infusion and at intervals up to 12 hours after the start of each gentamicin infusion. Samples were assayed for gentamicin concentration by an enzyme-multiplied immunoassay technique and for piperacillin and tazobactam concentrations by high-performance liquid chromatography. Six women and four men completed all four drug regimens. For the gentamicin-alone regimen, the mean +/- S.D. area under the concentration-versus-time curve was 78.06 +/- 10.28 micrograms/mL.hr, the mean +/- S.D. peak concentration (30 minutes after the end of an infusion) was 20.28 +/- 2.54 micrograms/mL, and the mean +/- S.D. half-life was 2.41 +/- 0.24 hours. The values for gentamicin alone did not differ significantly from those for gentamicin in any of the combination regimens. Coadministration of once-daily gentamicin and piperacillin-tazobactam in various i.v. infusion regimens did not affect the pharmacokinetics of once-daily gentamicin.

Adolescent↗
PubMed1986

Timentin versus piperacillin in the treatment of hospitalized patients with urinary tract infections.

The efficacy and safety of Timentin (ticarcillin plus potassium clavulanate) and piperacillin were compared in a clinical trial of 78 hospitalized patients with urinary tract infections. There were 37 evaluable patients in the Timentin-treated group and 39 in the piperacillin-treated group. The 43 infection sites in each group were primarily complicated pyelonephritis or complicated cystitis; six patients in the Timentin-treated group and four in the piperacillin-treated group also had septicaemia. Both ticarcillin (3 g) plus potassium clavulanate (200 mg) and piperacillin (125-200 mg/kg per day) were administered intravenously. The 43 most common pathogens in each treatment group were Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa from the urinary tract and E. coli from the blood. Nine pathogens in the Timentin-treated group and 11 in the piperacillin-treated group were resistant to ticarcillin in vitro. Eradication was achieved for 39 of the 43 (91%) pathogens in the Timentin group, including all six organisms isolated from the blood, and eight (89%) of the ticarcillin-resistant pathogens. In the piperacillin-treated group, 33 of the 43 (77%) pathogens were eradicated, including three of the four blood isolates, but only eight (73%) of the ticarcillin-resistant pathogens. Clinical cure or improvement occurred in 97% of the patients in each group. Mild and transient increases in levels of liver enzymes or eosinophils were reported for 11 patients in the Timentin group and seven in the piperacillin group. In one patient in the Timentin group, a drug-related rash and nausea developed, and treatment was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Susceptibility of Escherichia coli isolates with TEM-1 beta-lactamase to combinations of BRL42715, tazobactam or clavulanate with piperacillin or amoxycillin .

Production of TEM-1 beta-lactamase is the commonest cause of acquired resistance to amoxycillin and piperacillin in Escherichia coli, now occurring in c. 50% of isolates. Consecutive E. coli isolates producing TEM-1 beta-lactamase were collected at The London Hospital in 1982 (n = 50) and 1989 (n = 46). Enzyme quantities varied 150-fold amongst the isolates. Randomly-selected isolates from both years (n = 36; nine per quartile of the beta-lactamase activity distribution) were tested for susceptibility to combinations of amoxycillin or piperacillin with clavulanate or tazobactam or with BRL42715, a novel penem. The inhibitor concentrations needed to potentiate the penicillins related to the amount of beta-lactamase produced. BRL42715, at 1 mg/l, rendered all the isolates, including TEM-1 hyperproducers, susceptible to the recommended BSAC breakpoints of 8 mg amoxycillin/1 and 16 mg piperacillin/l. At 2 mg/l, BRL42715 almost always reduced amoxycillin and piperacillin MICs to the levels (1-2 mg/l) expected for E. coli isolates that lack TEM-1 enzyme. Tazobactam, at 1-2 mg/l, reduced piperacillin MICs to 1-2 mg/l for strains in the lower half of the beta-lactamase distribution, but greater than 8 mg tazobactam/l was required to reduce piperacillin MICs to 16 mg/l for one-third of the top quartile isolates. Clavulanate was a stronger potentiator of piperacillin than was tazobactam. On the other hand, amoxycillin was a more difficult substrate to potentiate than piperacillin, and isolates with enzyme levels in the top half of the distribution generally required greater than or equal to 8 mg clavulanate/l to reduce amoxycillin MICs to less than or equal to 8 mg/l.

Amoxicillin↗
PubMed2000

Surgery and intensive care procedures affect the target site distribution of piperacillin.

OBJECTIVE: Therapeutic failure of antibiotic therapy has been ascribed to pharmacokinetic alterations in compromised patient populations. The present study, therefore, aimed at examining the influences of cardiac surgery and intensive care procedures on the postoperative target site distribution of piperacillin. For this purpose, the penetration of piperacillin to the interstitial space fluid, the relevant target site for most bacterial infections, was compared between patients after aortic valve replacement and healthy volunteers. DESIGN: Comparative study in two study populations. SETTING: The intensive care unit and research ward of a university hospital. PATIENTS: The study population included six otherwise healthy patients scheduled to undergo aortic valve replacement and a control group of six healthy male volunteers. INTERVENTIONS: After the administration of a single i.v. infusion of 4.0 g piperacillin, free piperacillin concentrations were measured in the interstitium of skeletal muscle and subcutaneous tissue by in vivo microdialysis and in venous serum. Piperacillin concentrations were assayed with reversed phase high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Interstitial piperacillin concentrations in muscle and subcutaneous adipose tissue were significantly lower in patients compared with volunteers with the area under the curve for the interstitium/area under the curve for serum concentration ratios ranging from 0.25 to 0.27 and from 0.43 to 1.22 in patients and volunteers, respectively (p < .05 between groups). The terminal elimination half-life was markedly prolonged in patients, leading to a concomitant increase in t > minimal inhibitory concentration (MIC) values, the relevant surrogate for therapeutic success of therapy with beta-lactam antibiotics, for strains with MIC50 <4 microg/mL. For strains with MIC50 >20 microl/mL, however, inadequate target site concentrations were attained in the patient population. CONCLUSIONS: During the postoperative and intensive care periods, target site concentrations of piperacillin are markedly altered and decreased. This may also be true for other antibiotic agents and may have clinical implications in that current dosing guidelines may result in inadequate target site concentrations for high-MIC strains. Conceivably, this could lead to therapeutic failure in some patients.

Adult↗
PubMed1998

Penetration of piperacillin into the vitreous after intravenous administration.

PURPOSE: Penetration of piperacillin into the vitreous cavity after intravenous administration was investigated in humans. METHODS: Forty-five eyes undergoing vitrectomy between November 1993 and December 1994 were included. Each patient received a single intravenous dose of piperacillin 4 g 2 hours before ocular incision. A 0.2-mL vitreous sample was aspired at the beginning of vitrectomy, a blood sample was obtained, and piperacillin level was assessed. RESULTS: There were no detectable drug concentrations in 25 eyes. Mean vitreous drug concentration in the remaining evaluable eyes (n = 14) was 2.33 microg/mL (+/-0.76). We divided samples into two groups: 23 uninflamed (Group 1) and 16 inflamed (Group 2) eyes. Mean vitreous drug concentration was 0.42 microg/mL in Group 1 and 4.95 microg/mL in Group 2 (P < 0.2). Piperacillin concentration was higher than the minimum inhibitory concentration for gram-positive bacteria in 13% of uninflamed and 69% of inflamed eyes (P < 0.001). CONCLUSION: Studies show that intravenously administered piperacillin can penetrate the vitreous cavity in rabbits. Our study suggests that a single dose of piperacillin can produce intravitreal concentrations sufficient to kill gram-positive bacteria in inflamed eyes. The poor intraocular penetration of systemically administered piperacillin in uninflamed eyes raises questions about its usefulness as a prophylactic agent in ophthalmic surgery.

Adult↗
PubMed1992

[Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases].

Fourty-two febrile episodes of 32 patients with hematologic disease during neutropenia were treated with two randomly assigned antibiotic combinations of either piperacillin plus gentamicin or piperacillin plus aztreonam. Eleven of the 22 febrile episodes treated with piperacillin plus gentamicin and 12 of the 20 febrile episodes treated with piperacillin plus aztreonam responded. Addition of cefamandole to non-responders improved the outcome in 2 of the 16 febrile episodes. Mean nadir leucocyte count, age, sex, and underlying disease were not significantly different in both groups. Side effects were tolerable in both groups, although 1 patient treated with piperacillin plus gentamicin showed severe renal impairment. Piperacillin plus aztreonam is as effective as piperacillin plus gentamicin as an empiric antibiotic combination in the treatment of febrile episodes with hematologic disease during neutropenia.

Adolescent↗
PubMed1981

Clinical evaluation of piperacillin with observations on penetrability into cerebrospinal fluid.

Piperacillin, a new semisynthetic penicillin, was evaluated for efficacy and safety in 26 patients, most of whom had pneumonia. Included were four patients with gram-negative meningitis in whom the penetration of piperacillin into cerebrospinal fluid was determined. Cure was achieved in 11 of 17 patients with pneumonia; another 4 were improved. One relapse and one failure occurred among nine patients with gram-negative pneumonia. Cure or improvement occurred in seven of nine patients with gram-negative infection in various extrapulmonary sites. Piperacillin given by continuous infusion in a dosage ranging from 324 to 436 mg/kg of body weight per day to four patients with meningitis resulted in a mean cerebrospinal fluid level of 23 micrograms/ml at 24 h; the mean penetration of piperacillin into the cerebrospinal fluid was 32% at this interval. Levels of piperacillin in cerebrospinal fluid collected later during the course of therapy were also adequate. Adverse effects were noted in six patients, but only one episode of granulocytopenia was serious. Emergence of resistance to piperacillin did not occur, and only one superinfection was noted. Piperacillin appeared to be efficacious in the treatment of pneumonia. It penetrated well into the cerebrospinal fluid of patients with meningitis and may be useful for treatment of selected gram-negative infections in extrapulmonary sites.

Haemophilus Infections↗
PubMed1982

Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease.

Possible antibiotic inactivation was studied in 12 subjects with end-stage renal disease who were undergoing thrice-weekly hemodialysis. The study was a randomized three-way crossover. Subjects received (i) gentamicin as a single intravenous dose of 2 mg/kg, (ii) 4 g of piperacillin intravenously every 12 h for four doses or 2 g of carbenicillin intravenously every 8 h for six doses, and (iii) gentamicin as described in (i) plus piperacillin or carbenicillin as described in (ii). Subjects were studied on their off-dialysis days, and each treatment phase was separated by a 3-week wash-out period. Gentamicin was inactivated to a greater extent by carbenicillin than by piperacillin (P less than 0.05). In the six subjects in the carbenicillin group, the terminal elimination-phase half-life (t 1/2 beta) of gentamicin was 61.6 h when gentamicin was administered alone, and it was 19.4 h when gentamicin was administered with carbenicillin. In six subjects in the piperacillin group, the mean t 1/2 beta of gentamicin when gentamicin was given alone was 53.9 h, and it was 37.7 h when gentamicin was given with piperacillin. The inactivation rate constant (ki) of gentamicin was 0.0251/h for the carbenicillin group and 0.0064/h for the piperacillin group, demonstrating that carbenicillin inactivated gentamicin for time faster than did piperacillin. No inactivation of either beta-lactam could be measured. Control samples verified that no in vitro inactivation occurred.

Biotransformation↗
PubMed1982

Piperacillin distribution into bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue in surgical patients.

The concentrations of piperacillin in serum, bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue were measured simultaneously at various times after the intravenous administration of a single 5-g dose to each of 14 patients undergoing biliary tract surgery. Piperacillin concentrated in the bile with peak levels exceeding 4,000 micrograms/ml. In a single patient with cystic duct obstruction, trace gallbladder bile piperacillin levels were measured. Gallbladder wall concentrations of piperacillin tended to be higher than corresponding serum concentrations, with a correlation observed between tissue values and the degree of acute gallbladder inflammation and gallbladder bile piperacillin concentrations. Mean peak muscle and adipose tissue piperacillin concentrations of 31 and 27 micrograms/g, respectively, were reached at between 2 and 3 h after the start of infusion. These concentrations exceeded the minimum inhibitory concentration for a majority of susceptible organisms. A single 5-g dose of piperacillin achieved therapeutic levels in gallbladder wall, intraabdominal skeletal muscle, and adipose tissue and concentrated in the bile of patients with patent biliary tracts.

Abdominal Muscles↗
PubMed1983

Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections.

Piperacillin as a single agent was compared in a prospective randomized trial with carboxypenicillin-aminoglycoside combinations in empirical therapy of serious bacterial infections. The difference in the clinical response rates with piperacillin (77% of 26 infection episodes) and combination therapy (75% of 24 infection episodes) were not statistically significant. Fewer adverse effects occurred in the piperacillin-treated group (42%) than in the combination-treated group (71%) (P = 0.0399 by Fisher's exact test), although neither nephrotoxicity nor hypokalemia alone was significantly less frequent in patients receiving piperacillin. However, the emergence of resistant organisms during therapy was more frequent among patients receiving piperacillin alone (42% of patients) than among patients receiving combination therapy (17% of patients) (P = 0.465 by Fisher's exact test). Moreover, emergence of resistance accounted for 5 of 9 patients with treatment failure, superinfection, or both when piperacillin was used as a single agent, compared with 2 of 10 similar patients in the combination group (P = 0.1299 by Fisher's exact test). The use of piperacillin as a single agent in the treatment of serious bacterial infections is not advocated, and the addition of an aminoglycoside to prevent emergence of resistance during empirical therapy of such infections is strongly recommended.

Adult↗
PubMed1989

Protective effect of piperacillin against the nephrotoxicity of cisplatin in rats.

The protective effect of piperacillin against the nephrotoxicity of cisplatin was compared with that of fosfomycin in Fischer 344 rats. Blood urea nitrogen, serum creatinine, and morphological changes were evaluated as the renal toxicological parameters. Rats receiving 2 mg of cisplatin per kg of body weight for 5 days showed significant (P less than 0.01 by multiple-comparison test) elevation of blood urea nitrogen and serum creatinine concentrations compared with rats receiving saline alone and also exhibited development of cell lesions in the pars recta of the tubules in the outer stripe of the outer medulla. However, piperacillin (250 and 1,000 mg/kg) significantly (P less than 0.01 by multiple-comparison test) reduced these toxicological parameters in comparison with results for cisplatin alone. The protective effect of piperacillin was superior to that of fosfomycin, although platinum levels in the kidney were higher with the combination of cisplatin and piperacillin than with cisplatin plus fosfomycin. Although the nephrotoxicity of cisplatin was also reduced when cisplatin was administered concomitantly with sodium chloride in mole-equivalents to 250 and 1,000 mg of piperacillin per kg, its protective effect was less than that of the corresponding piperacillin dose. These results suggest that piperacillin may have a role as a protective agent against the nephrotoxicity of cisplatin.

Animals↗
PubMed1989

Comparative in vitro activities of piperacillin-tazobactam and ticarcillin-clavulanate.

The in vitro activities of ticarcillin, piperacillin, clavulanic acid, tazobactam, ticarcillin-clavulanate, and piperacillin-tazobactam against 819 bacterial isolates were compared. The two beta-lactamase inhibitors, clavulanic acid and tazobactam, had little useful antibacterial activity but enhanced the activities of the penicillins against beta-lactamase-producing strains of Haemophilus influenzae, Branhamella catarrhalis, and methicillin-susceptible Staphylococcus aureus; all strains were susceptible to both combinations. Both enzyme inhibitors also enhanced the activities of the penicillins against most strains of Escherichia coli, Klebsiella spp., Citrobacter diversus, Proteus spp., Providencia spp., and Bacteroides spp. and against occasional strains of Citrobacter freundii, Enterobacter spp., and Serratia marcescens. Clavulanic acid frequently enhanced the activity of ticarcillin against Xanthomonas maltophilia, and tazobactam frequently enhanced the activity of piperacillin against Morganella morganii. Enhancement was observed primarily with strains relatively resistant to the penicillins. In general, clavulanic acid was more effective than tazobactam in enhancing penicillin activity against Klebsiella spp., C. diversus, X. maltophilia, and Bacteroides spp., whereas tazobactam was more effective against Escherichia coli and Proteeae. There was little or no enhancement of activity against Enterococcus faecalis, Aeromonas hydrophila, Pseudomonas aeruginosa, Pseudomonas cepacia, or Acinetobacter anitratus. Clavulanic acid occasionally antagonized the activity of ticarcillin against ticarcillin-susceptible members of the family Enterobacteriaceae, but those strains were still considered susceptible to the combination. Tazobactam never antagonized the activity of piperacillin. In a direct comparison of the activities of ticarcillin-clavulanate and piperacillin-tazobactam, the two were equally active against H. influenzae, B. catarrhalis, and S. aureus; the latter was more active against E. faecalis. For relatively susceptible strains of members of the family Enterobacteriaceae, neither combination was predictably more active than the other, but relatively resistant strains were generally more susceptible to piperacillin-tazobactam. Piperacillin-tazobactam was more active than ticarcillin-clavulanate against A. hydrophila, P. aeruginosa, and P. cepacia, similar in activity against A. anitratus, and less active against X. maltophilia and Bacteroides spp.

Anti-Bacterial Agents↗
PubMed1990

Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease.

The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were biexponential. The terminal elimination half-life (t1/2 beta) of tobramycin was markedly reduced (59.62 +/- 25.18 [mean +/- standard deviation] versus 24.71 +/- 5.41 h) and total body clearance (CLP) was significantly increased in the presence of piperacillin (3.45 +/- 1.61 versus 7.16 +/- 1.64 ml/min). In contrast, the t1/2 beta (41.80 +/- 13.24 versus 40.07 +/- 10.37 h) and CLP (5.11 +/- 2.15 versus 5.55 +/- 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.

Adult↗
PubMed1992

Piperacillin-tazobactam versus imipenem-cilastatin for treatment of intra-abdominal infections.

In order to compare the clinical and microbiological efficacies and safety of piperacillin plus tazobactam with those of imipenem plus cilastatin, 134 patients with intra-abdominal infections (73 patients with appendicitis) participated in an open randomized comparative multicenter trial. A total of 40 men and 29 women (mean age, 53 years; age range, 18 to 92 years) were enrolled in the piperacillin-tazobactam group and 40 men and 25 women (mean age, 54 years; age range, 16 to 91 years) were enrolled in the imipenem-cilastatin group. The patients received either piperacillin (4 g) and tazobactam (500 mg) every 8 h or imipenem and cilastatin (500 mg each) every 8 h. Both regimens were given by intravenous infusion. A total of 113 patients were clinically evaluable. Of 55 patients who received piperacillin-tazobactam, 50 were clinically cured, while 40 of 58 patients in the imipenem-cilastatin group were clinically cured. The differences were significant (Wilcoxon test; P = 0.005). There were 4 failures or relapses in the piperacillin-tazobactam group and 18 failures or relapses in the imipenem-cilastatin group. The microorganisms isolated were eradicated in similar proportions in the two patient groups. Adverse reactions, mainly gastrointestinal disturbances and nausea, were noted in 13 patients who received piperacillin-tazobactam and in 14 patients who received imipenem-cilastatin. Results of the present study show that piperacillin-tazobactam is effective and safe for the treatment of intra-abdominal infections.

Abdomen↗
PubMed1994

Comparative activities of piperacillin and tazobactam against clinical isolates of Legionella spp.

We evaluated the in vitro activity of piperacillin alone or in combination with the beta-lactamase inhibitor tazobactam against clinical isolates of Legionella species. At an inoculum of approximately 10(4) CFU, tazobactam, piperacillin, and the 8:1 combination had equivalent activities against Legionella spp. At an approximately 10-fold higher inoculum, the following results were obtained, expressed as MICs for 50 and 90% of strains tested (MIC range): piperacillin, 4 and 16 (0.25 to 32) micrograms/ml; tazobactam, 0.5 and 1 (0.125 to 2) micrograms/ml; and piperacillin-tazobactam (expressed in terms of MIC of piperacillin) 0.5 and 1 (0.03 to 2) micrograms/ml. Tazobactam alone and the combination with piperacillin were more active than piperacillin alone at the higher inoculum.

Drug Synergism↗
PubMed1994

Single-dose pharmacokinetics of piperacillin and tazobactam in infants and children.

The pharmacokinetics of piperacillin and tazobactam were assessed after single-dose administration to 47 infants and children. Study subjects ranging in age from 2 months to 12 years were randomized to receive one of two different doses of a piperacillin-tazobactam combination (8:1): a low dose (n = 23) of 50 and 6.25 mg of piperacillin and tazobactam per kg of body weight, respectively, or a high dose (n = 24) of 100 and 12.5 mg, respectively. The pharmacokinetic behavior of tazobactam was very similar to that observed for piperacillin, supporting the use of these two agents in a fixed-dose combination. No differences in the pharmacokinetics of piperacillin or tazobactam were observed between the two doses administered. The elimination parameters half-life and total body clearance decreased and increased, respectively, with increasing age, whereas volume parameters (volume of distribution and steady-state volume of distribution) remained relatively constant for both compounds. The primary metabolite of tazobactam, metabolite M1, was measurable in the plasma of 18 of the 47 study subjects; 17 of these 18 subjects received the high doses. More than 70% of the administered piperacillin and tazobactam doses were excreted unchanged in the urine over a 6-h collection period. These data combined with the known in vitro susceptibilities of a broad range of pediatric bacterial pathogens indicate that a dose of 100 mg of piperacillin and 12.5 of mg tazobactam per kg of body weight administered as a fixed-dose combination every 6 to 8 h would be appropriate to initiate clinical efficacy studies in infants and children for the treatment of systemic infections arising outside of the central nervous system.

Child↗
PubMed1997

Mechanism of suppression of piperacillin resistance in enterobacteria by tazobactam.

Resistance to piperacillin in several isolates of Citrobacter freundii and Enterobacter cloacae was investigated and confirmed to occur at a frequency of 10(-7) to 10(-6). Development of resistance to piperacillin was significantly suppressed by tazobactam but not by clavulanic acid. To elucidate the mechanism by which resistance suppression occurs, the effect of piperacillin plus tazobactam on the induction of AmpC beta-lactamase was analyzed by monitoring the beta-galactosidase activity of an inducible ampC-lacZ gene fusion in Escherichia coli. The combination exerted no inhibitory effect on AmpC beta-lactamase induction. Tazobactam also had no effect on the accumulation of a key intermediate in the AmpC beta-lactamase induction pathway, 1,6-anhydromurotripeptide, in an ampD mutant strain of E. coli. However, the addition of tazobactam to liquid cultures of E. cloacae 40001 in the presence of piperacillin at four times the MIC caused a delay in the recovery of the culture to piperacillin-induced stress. At 16 times the MIC, a complete suppression of regrowth occurred. Analysis of culture viability on piperacillin plates showed that the culture recovery was due to growth by moderately resistant mutants preexisting in the cell population, which at 16 times the MIC became susceptible to the combination. Evidence from the kinetics of inhibition of the E. cloacae 40001 AmpC beta-lactamase by clavulanic acid, sulbactam, and tazobactam and from the effects of these drugs on the frequency of resistance to piperacillin suggests that the suppressive effect of tazobactam on the appearance of resistance is primarily mediated by the beta-lactamase inhibitory activity.

Chromatography, High Pressure Liquid↗
PubMed1997

Assessment of biliary excretion of piperacillin-tazobactam in humans.

Piperacillin-tazobactam concentrations in serum and bile were measured intraoperatively in 10 patients undergoing cholecystectomy (group 1) and 5 cholecystectomized patients provided with external bile duct drainage (group 2). Each patient received a single intravenous dose of piperacillin at 4 g plus tazobactam at 0.5 g over 30 min. Drug concentrations in both serum and bile were measured by high-performance liquid chromatography. In group 1 patients, serum and bile specimens and gallbladder wall fragments were collected at mean times of 70 and 83 min postinfusion, respectively. The mean concentrations of piperacillin and tazobactam were, respectively, 69.1 +/- 41.5 (standard deviation) and 9.9 +/- 5.1 microg/ml in serum, 630.4 microg/ml (range, 24.8 to 1,194 microg/ml) and 11.8 microg/ml (range, 3.6 to 22 microg/ml) in choledochal bile, 342.3 microg/ml (range, 1.1 to 1,149 microg/ml) and 7.7 microg/ml, (range, 0.2 to 23.1 microg/ml) in gallbladder bile, and 49.3 microg/g (range, 9.7 to 223 microg/g) and 2.9 microg/g (range, 0.1 to 5.9 microg/g) in the gallbladder wall. In group 2 patients, the amounts of drugs recovered in bile drainage obtained over 12 h were 28.4 +/- 18.0 and 1.0 +/- 0.5 mg for piperacillin and tazobactam, respectively. Peak piperacillin and tazobactam concentrations in bile reached 358 +/- 242 and 10.8 +/- 4.2 microg/ml, respectively. Comparison of drug levels in serum and bile suggests an underlying active secretion process for piperacillin elimination into the bile, unlike that of tazobactam. From a therapeutic viewpoint, given the concentrations of tazobactam recorded in bile fluid and tissue, the addition of this beta-lactamase inhibitor to piperacillin therapy might be of interest in the management of biliary tract infections, mostly in patients at risk of mixed aerobic-anaerobic infections due to beta-lactamase-producing organisms.

Adult↗