Determination of free interstitial concentrations of piperacillin-tazobactam combinations by microdialysis.
(1/458)
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. (+info)
Clavulanate induces expression of the Pseudomonas aeruginosa AmpC cephalosporinase at physiologically relevant concentrations and antagonizes the antibacterial activity of ticarcillin.
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Although previous studies have indicated that clavulanate may induce AmpC expression in isolates of Pseudomonas aeruginosa, the impact of this inducer activity on the antibacterial activity of ticarcillin at clinically relevant concentrations has not been investigated. Therefore, a study was designed to determine if the inducer activity of clavulanate was associated with in vitro antagonism of ticarcillin at pharmacokinetically relevant concentrations. By the disk approximation methodology, clavulanate induction of AmpC expression was observed with 8 of 10 clinical isolates of P. aeruginosa. Quantitative studies demonstrated a significant induction of AmpC when clavulanate-inducible strains were exposed to the peak concentrations of clavulanate achieved in human serum with the 3.2- and 3.1-g doses of ticarcillin-clavulanate. In studies with three clavulanate-inducible strains in an in vitro pharmacodynamic model, antagonism of the bactericidal effect of ticarcillin was observed in some tests with regimens simulating a 3.1-g dose of ticarcillin-clavulanate and in all tests with regimens simulating a 3.2-g dose of ticarcillin-clavulanate. No antagonism was observed in studies with two clavulanate-noninducible strains. In contrast to clavulanate. No antagonism was observed in studies with two clavulanate-noninducible strains. In contrast to clavulanate, tazobactam failed to induce AmpC expression in any strains, and the pharmacodynamics of piperacillin-tazobactam were somewhat enhanced over those of piperacillin alone against all strains studied. Overall, the data collected from the pharmacodynamic model suggested that induction per se was not always associated with reduced killing but that a certain minimal level of induction by clavulanate was required before antagonism of the antibacterial activity of its companion drug occurred. Nevertheless, since clinically relevant concentrations of clavulanate can antagonize the bactericidal activity of ticarcillin, the combination of ticarcillin-clavulanate should be avoided when selecting an antipseudomonal beta-lactam for the treatment of P. aeruginosa infections, particularly in immunocompromised patients. For piperacillin-tazobactam, induction is not an issue in the context of treating this pathogen. (+info)
Randomized prospective study comparing cost-effectiveness of teicoplanin and vancomycin as second-line empiric therapy for infection in neutropenic patients.
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BACKGROUND AND OBJECTIVE: The current health-care philosophy dictates that new therapies should always be evaluated for their economic impact. Along with acquisition cost, the cost of delivery, monitoring, adverse effects and treatment failure must also be considered when determining the total cost of therapy. These auxiliary costs can be significant and greatly alter the overall cost of a drug treatment. We conducted a prospective randomized study to evaluate the efficacy, safety and cost of vancomycin and teicoplanin therapy in patients with neutropenia, after the failure of empirical treatment with a combination of piperacillin/tazobactam and amikacin. DESIGN AND METHODS: Seventy-six febrile episodes from 66 patients with hematologic malignancies under treatment, neutropenia (neutrophils <500/mm3) and fever (38 degrees C twice or 38.5 degrees C once) resistant to the combination piperacillin/tazobactam and amikacin were included in the study. RESULTS: Primary success of second-line therapy was obtained in 35 cases (46%) with no significant difference between vancomycin (17/38) and teicoplanin arms (18/38). No difference in renal or hepatic toxicity related to the antibiotic therapy was observed. The average cost per patient according to glycopeptide used was $450+/-180 for the teicoplanin group and $473+/-347 for the vancomycin group. Interestingly, in the teicoplanin arm, drug acquisition accounted for 97% of the total cost, while in the vancomycin arm administration and monitoring play an important role in overall costs. INTERPRETATION AND CONCLUSIONS: In conclusion, our pharmacoeconomic analysis demonstrates that teicoplanin and vancomycin can be administered in neutropenic hematologic patients with similar efficacy and direct costs. (+info)
Piperacillin and tazobactam exhibit linear pharmacokinetics after multiple standard clinical doses.
(4/458)
A population pharmacokinetic (PK) analysis was conducted to determine if piperacillin and tazobactam exhibited linear or nonlinear PKs and if incremental changes in the daily dosage of piperacillin affected tazobactam PKs. Four dosage groups were evaluated after multiple dosing regimens. Concentrations of drug in plasma and amounts in urine were best fitted by using a linear two-compartment PK model. No significant difference between dosing groups was seen for any piperacillin or tazobactam PK parameters. Both drugs exhibited linear PKs when given at usual clinical doses. Tazobactam PKs did not appear to be affected by the different dosing regimens of piperacillin. (+info)
Efficacy of beta-lactam and inhibitor combinations in a diffusion chamber model in rabbits.
(5/458)
Using a diffusion chamber in rabbits, we evaluated therapy with the combination of ceftriaxone plus the beta-lactamase inhibitor tazobactam in comparison with ceftriaxone alone. One sensitive and one resistant strain of Escherichia coli, Enterobacter cloacae and Klebsiella pneumoniae were inoculated into one of the six diffusion chambers, implanted in the same animal. In order to simulate pharmacokinetics in humans, both substances were administered in decreasing doses. Ceftriaxone was given 0, 2, 4 and 6 h after infection in dosages of 45, 35, 25 and 15 mg/kg of body weight, while tazobactam was administered either in one dose at 0 h, or divided into two doses at 0 and 1 h or 0 and 4 h, or divided into three doses at 0, 1 and 4 h after infection. The ratio of ceftriaxone:tazobactam was fixed at 8:1. Ceftriaxone, in combination with tazobactam, given in one dose immediately after infection showed a significant reduction in bacterial count. All other combinations of ceftriaxone and tazobactam did not differ from ceftriaxone in monotherapy. Co-administration of the beta-lactamase inhibitor tazobactam significantly enhanced the activity of ceftriaxone against all three tested species. (+info)
Aspartic acid for asparagine substitution at position 276 reduces susceptibility to mechanism-based inhibitors in SHV-1 and SHV-5 beta-lactamases.
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In SHV-type beta-actamases, position 276 (in Ambler's numbering scheme) is occupied by an asparagine (Asn) residue. The effect on SHV-1 beta-lactamase and its extended-spectrum derivative SHV-5 of substituting an aspartic acid (Asp) residue for Asn276 was studied. Mutations were introduced by a PCR-based site-directed mutagenesis procedure. Wild-type SHV-1 and -5 beta-lactamases and their respective Asn276-->Asp mutants were expressed under isogenic conditions by cloning the respective bla genes into the pBCSK(+) plasmid and transforming Escherichia coli DH5alpha. Determination of IC50 showed that SHV-1(Asn276-->Asp), compared with SHV-1, was inhibited by 8- and 8.8-fold higher concentrations of clavulanate and tazobactam respectively. Replacement of Asn276 by Asp in SHV-5 beta-lactamase caused a ten-fold increase in the IC50 of clavulanate; the increases in the IC50s of tazobactam and sulbactam were 10- and 5.5-fold, respectively. Beta-lactam susceptibility testing showed that both Asn276-->Asp mutant enzymes, compared with the parental beta-lactamases, conferred slightly lower levels of resistance to penicillins (amoxycillin, ticarcillin and piperacillin), cephalosporins (cephalothin and cefprozil) and some of the expanded-spectrum oxyimino beta-lactams tested (cefotaxime, ceftriaxone and aztreonam). The MICs of ceftazidime remained unaltered, while those of cefepime and cefpirome were slightly elevated in the clones producing the mutant beta-lactamases. The latter clones were also less susceptible to penicillin-inhibitor combinations. Asn276-->Asp mutation was associated with changes in the substrate profiles of SHV-1 and SHV-5 enzymes. Based on the structure of TEM-1 beta-lactamase, the potential effects of the introduced mutation on SHV-1 and SHV-5 are discussed. (+info)
In-vitro susceptibilities of species of the Bacteroides fragilis group to newer beta-lactam agents.
(7/458)
The in-vitro activities of imipenem and four beta-lactam-beta-lactamase inhibitor combinations were tested against 816 strains of the Bacteroides fragilis group, and compared with other anti-anaerobic agents. None of the strains was resistant to metronidazole, and only one was resistant to chloramphenicol. Mezlocillin and piperacillin were moderately active, while clindamycin was the least active. Rates of resistance varied between various species. The new beta-lactam agents tested showed excellent activity; piperacillin-tazobactam and imipenem were the most active. The emergence of strains that are resistant to these agents, observed in this study, suggests there is a need to perform periodic antimicrobial susceptibility tests. (+info)
In vitro and in vivo activities of Syn2190, a novel beta-lactamase inhibitor.
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Syn2190, a monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1 beta-lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 microM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 beta-lactamase-producing strains, such as Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Morganella morganii. However, against beta-lactamase-derepressed mutants of P. aeruginosa, the MICs of ceftazidime plus Syn2190 were not affected by the amount of beta-lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC(50)s) of ceftazidime plus Syn2190 were 2- to 16-fold lower than those of ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC(50)s of cefpirome plus Syn2190 were two- to eightfold lower for cefpirome-resistant clinical isolates. The synergies of Syn2190 plus ceftazidime or cefpirome observed in vitro were also reflected in vivo. Syn2190 improved the efficacies of both cephalosporins in both a murine systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant P. aeruginosa. (+info)