Determination of free interstitial concentrations of piperacillin-tazobactam combinations by microdialysis.
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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/tazobactam plus tobramycin versus ceftazidime plus tobramycin for the treatment of patients with nosocomial lower respiratory tract infection. Piperacillin/tazobactam Nosocomial Pneumonia Study Group.
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An open-label, randomized, comparative, multi-centre study was conducted at 25 centres in the USA and Canada to compare the safety and efficacy of piperacillin/tazobactam plus tobramycin with ceftazidime plus tobramycin in patients with lower respiratory tract infections. Piperacillin/tazobactam (3 g/375 mg) every 4 h or ceftazidime (2 g) every 8 h were administered i.v. for a minimum of 5 days. Tobramycin (5 mg/kg/day) given in divided doses every 8 h was administered to all patients. Patients with Pseudomonas aeruginosa isolated from respiratory secretions at baseline were to continue tobramycin for the duration of the study. Tobramycin could be discontinued in other patients after the baseline culture results were known. A total of 300 patients was randomized, 155 into the piperacillin/tazobactam group and 145 into the ceftazidime group. Of these, 136 patients (78 in the piperacillin/tazobactam group and 58 in the ceftazidime group) were considered clinically evaluable. Both groups were comparable for age, sex, duration of treatment and other demographic features. The clinical success rate in evaluable patients was significantly greater (P = 0.006) in the piperacillin/tazobactam treatment group (58/78; 74%) than in the ceftazidime group (29/58; 50%). Eradication of the baseline pathogen was significantly greater (P = 0.003) in the piperacillin/tazobactam group (66%) than in the ceftazidime group (38%). The clinical and bacteriological responses of those patients with nosocomial pneumonia were similar to the overall results. Twelve (7.7%) piperacillin/tazobactam-treated patients and 24 (17%) ceftazidime-treated patients died during the study (P = 0.03). Seven of the 24 deaths in the ceftazidime treatment group but only one of the 12 deaths in the piperacillin/tazobactam treatment group were directly related to failure to control infection. The majority of adverse events were thought by the investigator to be attributable to the patients' underlying disease and not drug related. In this study, piperacillin/tazobactam plus tobramycin was shown to be more effective and as safe as ceftazidime plus tobramycin in the treatment of patients with nosocomial LRTI. (+info)
Antibiotic dosing issues in lower respiratory tract infection: population-derived area under inhibitory curve is predictive of efficacy.
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Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC; AUIC). The AUIC values in these studies were based on measured MICs and measured serum concentrations. This study evaluates AUIC estimates made using population pharmacokinetic parameters, and MICs from an automated microbiological susceptibility testing system. A computer database review over 2 years yielded 81 patients at Millard Fillmore Hospital with a culture-documented gram-negative LRTI who had been treated with piperacillin and an aminoglycoside, ceftazidime, ciprofloxacin or imipenem. Their AUIC values were estimated using renal function, drug dosages and MIC values. Outcome groups (clinical and microbiological cures and failures) were related to the AUIC values using Kruskal-Wallis ANOVA, linear regression and classification and regression tree (CART) analysis. A significant breakpoint for clinical cures was an AUIC value at least 72 SIT(-1) x 24 h (inverse serum inhibitory titre integrated over time). All antibiotics performed significantly better above this value than below it. Clinical cure was well described by a Hill-type equation. Within the piperacillin/aminoglycoside regimen, most of the activity came from the piperacillin, which had a higher overall AUIC value than the aminoglycoside. AUIC estimations based upon MIC values derived from the automated susceptibility testing method differed from NCCLS breakpoint data and from tube dilution derived values in this hospital by as much as three tube dilutions. These automated methods probably overestimated the MIC values of extremely susceptible organisms. The lack of precise MIC estimates in automated clinical microbiology methods impairs the use of AUIC to prospectively optimize microbiological outcome. Even ignoring this limitation and using the values as they are reported, the results of this analysis suggest that AUIC targets between 72 and 275 SIT(-1) x 24 h are useful in predicting clinical outcome. (+info)
Piperacillin and tazobactam exhibit linear pharmacokinetics after multiple standard clinical doses.
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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)
Fresh vs aged benzylpenicillin on non-IgE responses in mice.
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AIM: To study whether or not the freshly prepared benzylpenicillin could induce different non-IgE antibody response from aged benzylpenicillin. METHODS: Antibody response was determined by enzyme-linked immunosorbent assay (ELISA). Antigen molecules recognized by antibodies and antigenic cross reactions were tested by hapten inhibition assay. RESULTS: Isotypes of specific non-IgE antibodies induced by freshly prepared benzylpenicillin were mainly IgM, and then IgG and IgA. Some parts of specific antibodies recognized benzylpenicillin molecule and major parts combined with degraded or transforming products. Isotypes of antibodies responsible for cross reaction were mainly IgG between benzylpenicillin and ampicillin and IgM between benzylpenicillin and piperacillin. CONCLUSION: Freshly prepared and aged benzylpenicillin induced different non-IgE antibody response. (+info)
In-vitro susceptibilities of species of the Bacteroides fragilis group to newer beta-lactam agents.
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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)