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Relationships between pharmacodynamic indices (PI), such as the area under the concentration-time curve (AUC)/MIC ratio and time > MIC (T(>MIC)), and efficacy have been described for antimicrobial drugs. The use of these quantitative relationships may increase the power to demonstrate significant effects of drugs, obviating the need to include large numbers in comparative trials. Patients with cystic fibrosis (CF) hospitalized for treatment of an infectious exacerbation due to Pseudomonas aeruginosa were eligible for the study. They received tobramycin 3.3 mg/kg tid as initial therapy in combination with ticarcillin 125 mg/kg qid. Blood samples were drawn at t = 0-8 h after infusion. Pharmocokinetic parameters and PI were calculated for every individual and correlated to the relative improvement in forced expiratory volume during the first second (FEV1) and forced vital capacity (FVC) between pretreatment and days 9-11 as a measure of efficacy. The 3 PI fAUC/MIC, f Peak/MIC, and T(>MIC) of tobramycin showed a significant correlation with effect and was the highest for the fAUC/MIC relationships with FEV1 and FVC as determined both by the Emax model as well as Spearman correlations (r = 0.77, P = 0.002 and 0.58, P = 0.036 for FEV1 and FVC). Pharmacokinetic parameters AUC and Peak as such showed no significant correlation with effect, nor did the MIC values. There is a significant relationship between PI of aminoglycosides and efficacy parameter (increase in FEV1 and FVC) in patients with CF. This study demonstrates the applicability of pharmacodynamic relationships in determining efficacy of antimicrobial therapy, by demonstrating a strong PI-effect relationship in a group of only 13 patients.

Antibacterials play a central role in the medical management of patients with cystic fibrosis (CF). Administration of adequate dosages of antibacterials results in pronounced beneficial effects on the morbidity and mortality of this patient group. The dosage of the antibacterial that is needed for optimal treatment depends on the individual patient's pharmacokinetics and the pharmacokinetic-pharmacodynamic effect on the micro-organism of relevance in the host. In general, the disposition of antibacterial drugs in patients with CF is not as 'atypical' as once thought. Recent research with adequately matched controls demonstrated that, for a few beta-lactam antibacterials only, a CF-specific increase of the total body clearance seems to exist and that the large volumes of distribution observed are the result of malnutrition and the relative lack of adipose tissue. Pharmacokinetic-pharmacodynamic relationships in patients with CF are less well studied. Apart from the pharmacokinetics, there is a need for optimisation of antibacterial therapy. For the aminoglycosides, pharmacokinetic optimisation based on measured serum drug concentrations is common practice. The Sawchuk-Zaske method based on peak and trough drug concentrations is widely used. A more sophisticated approach is the 'goal-oriented model-based Bayesian adaptive control' method, where integration of mathematically determined optimally (D-optimally) sampled serum drug concentrations and a population model results in the most likely set of individual pharmacokinetic parameter values suitable for further pharmacokinetic optimisation of the therapy. A future development is the integration of changing serum drug concentrations and killing rates of the target micro-organism to a pharmacokinetic-pharmacodynamic surrogate relationship to optimise drug therapy. The latter approach may be extremely useful in deciding on the frequency of aminoglycoside administration as well as the optimal use of the beta-lactam antibacterials and fluoroquinolones.

We investigated the emergence of resistance to 15 anti-pseudomonal antibiotics amongst Pseudomonas aeruginosa isolates from 34 chronically colonized patients with cystic fibrosis by comparing the susceptibilities of strains isolated before 1987 and after 1989 from the same patients. Strains obtained after 1989 from a further 19 patients who were newly colonized served as controls. The 34 pairs of isolates demonstrated a marked increase in resistance which could not be accounted for by a general increase in resistance during the intervening years since the susceptibility patterns of strains isolated before 1987 were similar to those of strains isolated from patients in the control group. There was a strong correlation between this increase in resistance and both the frequency of admissions to and the number of days spent in hospital. Cluster analysis of the changes in susceptibility for individual antibiotics revealed four distinct patterns of resistance: the fluoroquinolones, with the exception of ofloxacin; the aminoglycosides; the ureidopenicillins and aztreonam; and the cephalosporins, carbapenems, carboxypenicillins and ofloxacin. We conclude that the long-term administration of anti-pseudomonal antibiotics to patients who are chronically colonized with P. aeruginosa is associated with the development of resistance.

The occurrence of various Pseudomonas aeruginosa strains in the sputum of 15 patients with cystic fibrosis (CF) was monitored over periods ranging from 2 to 60 months. Isolates of P. aeruginosa were typed by four different techniques, namely serotyping, active and passive pyocin typing, and phage typing. The maximum number of different serotypes found in the patients was three (one serotype in nine patients; two serotypes in five patients; three serotypes in one patient). Pyocin and phage typing showed no marked differences between strains of the same serotype in individual patients. Exacerbations of chronic respiratory infection were not associated with changes in the sputum flora, the composition of P. aeruginosa strains in which remains constant over long periods in patients with CF.

The pharmacokinetics of tobramycin were evaluated in 15 patients (8 to 22 years of age) with cystic fibrosis (CF). A dose of 3.0 to 3.3 mg/kg of body weight was given intravenously over 20 minutes, and concentrations in serum were followed up to eight hours after initiation of the infusion. In the calculation of pharmacokinetic parameters, a two-compartment open model was used. The elimination half-life of the drug was highly inversely correlated with age (p less than 0.0004), and body weight (p less than 0.00002). Total body clearance (TBC), and volume of distribution at steady state (VDSS) were directly correlated with age and body weight. However, when TBC and VDSS were corrected for BSA, no correlation could be demonstrated. The mean one-hour and eight-hour serum concentrations of tobramycin were 5.40 and 0.45 microgram X ml-1, respectively. Between patients, considerable differences were found in the time after administration at which the serum concentration decreased below 1 microgram X ml-1. This interpatient variation has clinical implications for tobramycin therapy in CF, in particular for the dosing interval.

Patients with cystic fibrosis (CF) show abnormal aminoglycoside pharmacokinetics. After a conventional dose, the serum concentrations in CF patients are lower than those in nonCF patients. The lower serum concentrations in CF might be explained by increased total body clearance and/or a larger volume of distribution. The therapeutic range of aminoglycosides is narrow due to oto- and nephrotoxicity. The changed pharmacokinetics and the narrow therapeutic range make it difficult to ensure that patients with CF are adequately and safely treated with aminoglycosides. The mode of administration of aminoglycosides influences the antibacterial effect of these agents on Pseudomonas aeruginosa and the development of possible side effects. The therapeutic implications of these facts are discussed.

The efficacy of the dosing regimen of tobramycin was investigated in 28 patients with cystic fibrosis who had an acute exacerbation of chronic pulmonary infection with Pseudomonas aeruginosa. The initial dose of tobramycin was 3.3 mg/kg of body weight three times daily (ie, 10 mg/kg/day). A highly significant relationship was found between the serum concentration of tobramycin before the dose and the change in the forced expiratory volume in one second (FEV1), both measured on the tenth day of treatment (rs = 0.75; p less than 0.001). In nine of the 16 patients who had a six-hour serum concentration of 1 mg/L or less on the tenth day of treatment, the eight-hour dosing interval of tobramycin was shortened to achieve a serum concentration of tobramycin of about 1 mg/L before the dose. In the other seven patients, the dosage of tobramycin was not changed. On the 20th day, seven of the nine patients in whom the dosing interval was shortened exhibited an increase in FEV1 of 20 percent or more. Such an increase was observed only in one of the seven patients in whom the dosing interval was not reduced (p less than 0.05). We conclude that individualizing the dosage of tobramycin in patients with cystic fibrosis results in a better clinical outcome.