A retrospective analysis of pharmacokinetic-pharmacodynamic parameters as indicators of the clinical efficacy of ceftizoxime.

OBJECTIVE: To analyse the relationship between a series of estimated pharmacokinetic-pharmacodynamic parameters and the reported efficacy of ceftizoxime. DESIGN: Retrospective literature search and analysis using different correlation models. METHODS: The following parameters were calculated for each group of patients included in the study from the simulated plasma concentration curves corresponding to the dosage regimen administered: (i) peak concentration at steady state divided by the minimum inhibitory concentration (CmaxSS/MIC); (ii) the time that the plasma drug concentration exceeded the MIC scaled to 24 hours at steady state [(tSS)24h > MIC]; (iii) the total area under the concentration-time curve over 24 hours at steady state divided by the MIC [(AUC(SS))24h/MIC]; and (iv) the AUC at steady state for the period of time that the concentration is above the MIC over a period of 24 hours divided by the MIC [(AUIC(SS))24h]. A univariate correlation analysis was performed considering efficacy [rate (%) of clinical cure or bacterial eradication] as the dependent variable and the pharmacokinetic-pharmacodynamic parameter as the independent variable, using linear and nonlinear models. RESULTS: (tSS)24h > MIC was the only parameter that was statistically correlated with efficacy, the linear model being the best choice among the 4 relationship approaches tested. A biased frequency distribution of reported efficacy data constricts the correlation analysis to a narrow range of efficacy and hinders interpretation of the results. CONCLUSIONS: The reporting of cases with low efficacy rates as well as those with high efficacy rates, including information on patient idiosyncrasies and the infecting organisms, would be of great help in performing retrospective analyses of the use of antimicrobial agents, leading to the optimisation of therapy with this type of drug in clinical practice.

A retrospective analysis of pharmacokinetic/pharmacodynamic indices as indicators of the clinical efficacy of ciprofloxacin.

A retrospective analysis of the relationship between estimated pharmacokinetic/pharmacodynamic indices and the reported efficacy of ciprofloxacin has been carried out using different correlation models. f1.gif" BORDER="0">, T(ss) > MIC, f2.gif" BORDER="0"> and AUIC(ss) were calculated for each clinical case included in the study, from simulated plasma level curves corresponding to the dosage regimen administered. A univariate correlation analysis was performed considering efficacy (%) as the dependent variable and indices as the independent variables according to linear and non-linear pharmacokinetic-pharmacodynamic models (PK-PD models). The results prove that log-transformation of the independent variable improves the data fitting to linear model. The four estimated indices show a log-linear relationship with outcome, T(ss) > MIC and AUIC(ss) being the parameters best correlated with percentage efficacy. The E(max) model with intrinsic response is an additional correlation strategy for T(ss) > MIC, leading to estimated values of E(max) and E(0) of 100.34 +/- 25.09% and 24.40 +/- 11.7%, respectively. The wide range of bacteria responsible for the infections considered, including Gram-positive pathogens such as staphylococci, might explain the good correlation between T(ss) > MIC and percentage efficacy found for ciprofloxacin in this study.

Influence of dose on the distribution kinetics of ciprofloxacin and ofloxacin in the isolated hindlimb of the rat.

The aim of this study was to determine whether the dose influences the distribution kinetics of ciprofloxacin and ofloxacin in muscle- bone- and skin-tissues included in the isolated hindlimb of the rat. Experiments were carried out in the isolated perfused hindlimb of the rat, administering a single dose of 45, 450 or 900 microg of each quinolone as a bolus injection. Outflow perfusate samples were collected for 20 min and drug levels were determined by an HPLC technique. The mean transit time (MTT) and the distribution volume of ciprofloxacin significantly increased with the dose injected (MTT=1.47+/-0.69, 8.74+/-0.27 and 9.52+/-2.95 min for 45, 450 and 900 microg, respectively). A similar situation was observed with ofloxacin, although the increase in these parameters was less pronounced (MTT=3.65+/-0.86, 7.92+/-2.03 and 8.32+/-1.70 min for 45, 450 and 900 microg, respectively). The distribution of ciprofloxacin and ofloxacin in the rat hindlimb appears to be a dose-dependent process, at least for the dose range considered in this study. This might explain the high variability in the distribution coefficients reported for these drugs in literature.

A comparative study of ofloxacin and ciprofloxacin erythrocyte distribution.

The present work deals with the in vitro and in vivo distribution of ofloxacin and ciprofloxacin in erythrocytes. In vitro studies were carried out in standard solutions prepared using fresh blood for a concentration range between 100 and 0.25 micrograms mL-1. A 5 mg kg-1 bolus dose was administered to rabbits and erythrocyte and plasma kinetics were determined over 8 h. A linear model was used to establish the relationship between plasma and erythrocyte concentrations of both quinolones in vitro. The mean partition coefficient values obtained were 1.04 +/- 0.02 and 1.32 +/- 0.03 for ofloxacin and ciprofloxacin, respectively. A decrease in the ciprofloxacin partition coefficient was observed at higher concentrations. Values ranged between 2.54 +/- 0.40 and 1.38 +/- 0.15 as the concentrations increased. The partition coefficients obtained from the linear relationship between plasma and erythrocyte concentrations established from the in vivo data were 0.80 +/- 0.58 for ofloxacin and 0.61 +/- 0.30 for ciprofloxacin. In vivo plasma and erythrocyte data analysis was performed by a deconvolution method and the theoretical transfer curves in erythrocytes were estimated. The distribution of both quinolones to erythrocytes is very rapid, probably due to a high permeability of erythrocyte membranes to these drugs. This was also confirmed by the parallelism between plasma and erythrocyte kinetics.

Sequential intravenous-oral ciprofloxacin plus amoxycillin/clavulanic acid shortens hospital stay in infected non severe neutropenic patients.

The objective of this study was to determine the efficacy and safety of the combination ciprofloxacin plus amoxicillin/clavulanic acid as an empirical treatment of infection in hematologic patients without severe neutropenia. These drugs allowed us to carry out a sequential therapy, first intravenously and later orally, so that the patient could be discharged as soon as there was a response. Serum concentrations of ciprofloxacin were monitored in this study. Forty seven of the sixty-six patients included (71%) responded to the treatment with no differences between the dosages of ciprofloxacin employed (600-900 mg daily in two or three divided doses). In the patients who responded, the signs and symptoms of infection lasted only three days, which could allow a short hospital stay (median of six days). In the first pre and post-dose serum samples, ciprofloxacin concentrations were significantly higher when the drug was administered every 8 h. Nevertheless, 72 h after the beginning of treatment, they had leveled out in either 8 and 12 h schemes. The toxicity of the treatment was very light, with only four cases with adverse effects, grades I and II. This data suggests that the employed combination is effective and safe and can considerably decrease costs incurred through the admission of hematologic patients with serious infections but without severe neutropenia.

Study on pharmacokinetics and nephrotoxicity of netilmicin in rabbits using a new dosage regimen.

The potential nephrotoxicity and pharmacokinetic parameters of netilmicin were investigated in rabbits after single and multiple dosage regimens (7 mg/kg/12 h) allometrically equivalent to a once-daily regimen of 5 mg/kg/24 h in man. Netilmicin was determined in plasma and renal tissue by a high-performance liquid chromatography (HPLC) technique with fluorescence detection and precolumn derivatization. The renal toxicity was determined by electron microscopy. Statistical comparison between animals that received a single dose and those that received a multiple dosage regimen showed that the only parameter significantly different was the elimination constant K10. The histological study revealed a high interindividual variability in the nephrotoxicity induced by prolonged treatment with netilmicin: 50% of the animals experienced tubular necrosis and the remaining did not. Although plasma concentration time curves did not show significant differences between both groups of animals, the concentrations of netilmicin in renal cortex were higher in the group with tubular necrosis. In conclusion, even though netilmicin was administered in a dosage regimen equivalent to once-daily administration in man, it induced tubular necrosis which was probably related to the duration of treatment. The results also showed that there was no correlation between plasma concentrations of the drug and its potential nephrotoxicity.

Open-loop feedback control of serum bentazepam concentrations and Bayesian estimation in multiple dosage regimens in patients.

The time course of serum levels of bentazepam was studied in 10 patients receiving anxiolytic agent orally at a dose of 25 mg on multiple dosage regimens with dosage intervals of 8 and 12 h. Using the methods of "open-loop feedback control", no linear regression programs and Bayesian estimation, it was possible to establish the best estimates of the pharmacokinetic parameters corresponding to the single-compartment model for each patient from all their data relating to the serum levels obtained after the first dose and after multiple dosing with different regimens. The application of the Kruskal Wallis test showed that there were only statistical differences for the absorption constant, determined with and without Bayesian estimation. However, no statistically significant differences were found on comparing the experimentally obtained serum levels with the corresponding theoretical values calculated independently for each patient from the parameters established with and without Bayesian estimation. As population pharmacokinetic parameters of bentazepam, the following were established: Ka = 2.330 +/- 0.665 l/h; Vd = 1.209 +/- 0.546 l/Kg and Ke = 0.160 +/- 0.118 l/h, corresponding to a mean value for the elimination half-life of 4.33 h.