A number of new fluoroquinolone antibacterials have been released for clinical use in recent years. These new agents exhibit enhanced activity against Gram-positive organisms while retaining much of the Gram-negative activity of the earlier agents within the same class. The pharmacokinetics of most of these agents are well described including serum pharmacokinetics, tissue and fluid distribution, and pharmacokinetics in renal and hepatic disease. When compared with earlier agents within this class (i.e. ciprofloxacin), the newer agents retain the wide distribution characteristics; however, they exhibit a more prolonged elimination, which, in part, supports single daily administration for these agents. Based on their predominant renal elimination, dosage adjustment is necessary in the presence of renal disease for ciprofloxacin, levofloxacin, gatifloxacin and sitafloxacin. Drug interactions, particularly with multivalent cations (calcium/aluminium-containing antacids and iron products), remain a problem for the newer agents, resulting in reduced absorption requiring separate administration times to maximise bioavailability. However, the newer agents do not appear to interfere significantly with the cytochrome P450 system, thus minimising the potential for interactions with other drugs metabolised by this system. The pharmacodynamic properties of the fluoroquinolones have been well described. The bactericidal activity is maximised when the ratios of peak plasma drug concentration (Cmax): minimum inhibitory concentrations (MIC) or area under the concentration-time curve (AUC): MIC exceed specific threshold values. Knowledge of the pharmacodynamic relationships allows for appropriate drug selection and enables design of dosage regimens to maximise the bactericidal activity. Therapeutic drug monitoring of the fluoroquinolones may provide a means of optimising the dosage regimen in certain clinical situations (that is, meningitis and hospitalised pneumonias) with the goals of achieving a more predictable therapeutic response and minimising the potential for the development of resistance.

Aminoglycosides are often prescribed as part of the treatment regimen for acute pulmonary exacerbations due to their potent activity and low potential for development of resistance. Preliminary evidence from randomized controlled trials in patients with cystic fibrosis (CF) suggests that once-daily administration of aminoglycosides results in similar efficacy and a low risk for toxicity compared with traditional dosing. The pharmacokinetics of aminoglycosides administered once daily in CF patients are currently not well described. In this study we compare the distribution and elimination patterns of traditional dosing (3.3 mg/kg q8h) versus once-daily dosing (10 mg/kg q24h) of tobramycin in six adult patients with CF. The pharmacokinetics of tobramycin administered either once daily or every 8 h were best described by a two-compartment model. No statistically significant differences in any of the pharmacokinetic parameter values between regimens were noted. The distribution phase half-lives of 32 and 24 min following the q8h and q24h regimens were longer than expected. The use of a one-compartment model requires clinical peak levels to be drawn 2 h after initiation of either a 30 min infusion for multiple daily dosing or a 60 min infusion with once-daily dosing, to ensure completion of the distribution phase. Our data indicate that a dose of 10 mg/kg/day provides post-distributional phase peak concentrations that achieve the desired goal for susceptible organisms (>20 mg/L) and AUC(24) values at the upper end of the desired range (70-100 mg.h/L).

Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC ratio of >125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one-and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained Acute pulmonary exacerbations requiring antibiotic and airway clearance therapy are the most frequent complication of cystic fibrosis (CF). Acute exacerbations occur as a result of a flare-up of the chronic infection within the lower airways. In this scenario, the therapeutic goals include reduction of bacterial density and improvement of pulmonary function and nutritional status (16). Therefore, the primary therapeutic approach is institution of antimicrobial therapy directed against the most commonly encountered pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae.Ciprofloxacin is a second-generation fluoroquinolone with a broad spectrum of activity. It possesses potent bactericidal activity against P. aeruginosa isolates from CF patients (1, 18). In addition, ciprofloxacin has consistently demonstrated synergistic activity with other antipseudomonal agents against multiple-drug-resistant P. aeruginosa isolates obtained from CF patients (18). With these attributes, it is not surprising that ciprofloxacin is frequently prescribed for the treatment of pulmonary exacerbations in CF patients.The pharmacokinetics of ciprofloxacin have been extensively evaluated in stable CF patients (4,9,11,14,17,20,23). Results of these studies indicate no significant alterations in pharmacokinetics when patients are compared with normal healthy volunteers. In contrast, data on the pharmacokinetics of ciprofloxacin during acute pulmonary exacerbations are limited (2, 21). In addition, none of these studies performed compartmental pharmacokinetic analysis, which would permit dosage individualization for the patient. Studies performed in non-CF patients with nosocomially acquired lower respiratory tract infections demonstrated that optimal clinical and bacteriological outcomes are associated with achievement of specific threshold values of pharmacodynamic variables, such as the area under the concentration time curve from 0 to 24 h (AUC 0-24 )/MIC ratio and peak/MIC ratio (6, 15). Specifically, Forrest et al. demonstrated that optimal clinical and bacteriological responses in non-CF patients with lower respiratory tract infections are associated with the abili...

High-dose ibuprofen therapy has demonstrated to slow deterioration in pulmonary function in children with cystic fibrosis with mild lung disease. Therapeutic drug monitoring has been recommended to maintain peak concentrations within the range of 50 to 100 mg/L to ensure efficacy. Current methods for dosage individualization are based on dose proportionality using visual inspection of the peak concentration; however, because of interpatient variability in the absorption of the various formulations this method may result in incorrect assessments of the peak concentration achieved. Maximum a posteriori Bayesian analysis (MAP-B) has proven to be a useful and precise method of individualizing the dose of aminoglycosides but requires a description of the structural model. In this study we performed parametric population modeling analysis on plasma concentrations of ibuprofen after single doses of 20 to 30-mg/kg tablet or suspension in children with cystic fibrosis. Patients evaluated in this study were part of a single dose pharmacokinetic study that has been published previously. A one-compartment model with first order absorption and a lag time best described the data. The pharmacokinetic parameters differed significantly depending on the formulation administered. D-optimal sampling times for the suspension and tablet formulations are 0, 0.25 to 0.5, 1, and 3 to 4 hours and 0, 0.25 to 0.5, 1 to 1.5, and 5 hours respectively. Use of MAP-B analysis performed with the 4 d-optimal sampling strategy resulted in accurate and precise estimates of the pharmacokinetic parameters when compared with maximum likelihood analysis using the complete plasma concentrations data set. Further studies are needed to evaluate the performance of these models and the impact on patient outcomes.