Pharmacokinetic/pharmacodynamic predictors of time to clinical resolution in patients with acute bacterial exacerbations of chronic bronchitis treated with a fluoroquinolone.

Forty nine subjects with acute bacterial exacerbations of chronic bronchitis (ABECB) treated with grepafloxacin were evaluated for parameters predictive of clinical outcome. Signs and symptoms associated with ABECB were serially collected and evaluated for changes. Coughs per day, sputum volume and the percentage of sputum neutrophils were associated with clinical outcome. A by groups analysis, based on clinical success was performed using Cox regression analysis to determine factors associated with time to clinical success and time to reduction in sputum volume, coughs per day and sputum neutrophil percent. Factors evaluated included AUIC (AUC/MIC), isolate species, years and type of underlying lung disease, alcohol use, smoking history and number of ABECB within the previous 12 months. AUIC<276 (mg h/l)/mg/l (P<0.03) and or the presence of mild bronchiectasis (P<0.01) were associated with longer time to clinical success. In addition a relationship was found between AUIC>212 (mg h/l)/mg/l (P<0.01) and AUIC>576 (mg h/l)/mg/l (P<0.02) and decreasing days to sputum volume reduction and coughs per day, respectively. A diagnosis of mild bronchiectasis prolonged the time to reduce coughs per day (P<0.03) and neutrophil percentage (P<0.01). Patients with mild bronchiectasis were found to have an increase in the time to clinical success, coughs per day improvement and sputum neutrophil percent improvement. AUIC is an important PK/PD parameter predictive of successful outcome in ABECB, even in subjects with mild bronchiectasis. Grepafloxicin has been withdrawn from sale since these studies were carried out. This work is published to illustrate the relationship between pharmacodynamics and clinical efficacy and the use of AUIC as a valuable predictive parameter for fluoroquinolones.

Comparison of the abilities of grepafloxacin and clarithromycin to eradicate potential bacterial pathogens from the sputa of patients with chronic bronchitis: influence of pharmacokinetic and pharmacodynamic variables.

A randomized open-label study was conducted to compare the pharmacokinetics and pharmacodynamics of grepafloxacin with those of clarithromycin in patients with chronic bronchitis whose sputa were colonized with potential bacterial pathogens. Patients received oral grepafloxacin 400 mg od for 10 days (n = 15) or oral clarithromycin 500 mg bd for 10 days (n = 10). Sputum samples were collected before the first dose, 1, 4 and 8 h after a dose on day 1 and then before a dose on days 2, 3, 5, 7 and 10 to determine the time to eradication (T(erad)) of the potential bacterial pathogens. Blood samples for measurement of grepafloxacin or clarithromycin and 14-hydroxyclarithromycin concentrations were obtained before a dose and 1, 2, 4, 8 and 12 h after doses on days 1 and 5. The area under the inhibitory serum concentration-time curve over 24 h (AUIC(24)), peak serum concentration:MIC ratio (C(max):MIC) and the percentage of the dosing interval during which the serum concentration exceeded the MIC (%tau >MIC) were calculated and serum inhibitory titres (SITs) were determined. Haemophilus spp. were the predominant potential bacterial pathogens and were recovered from the sputa of 24 patients. Strains of Streptococcus pneumoniae were isolated from two patients in the grepafloxacin group and a strain of Moraxella catarrhalis was isolated from one patient in the clarithromycin group. Haemophilus spp. isolates were eradicated from the sputa of 13 of 14 (93%) patients given grepafloxacin, but from only two of 10 (20%) patients given clarithromycin (P < 0.05). In the other eight (80%) patients who received clarithromycin, the sputum cultures remained positive throughout the 10 day course. Grepafloxacin eliminated potential bacterial pathogens more quickly than clarithromycin (median T(erad) 4 h versus 76 h). The S. pneumoniae strains were eradicated by grepafloxacin within 4 h and the single M. catarrhalis strain was eradicated by clarithromycin within 1 h. The greater efficacy of grepafloxacin, compared with that of clarithromycin, in terms of the incidence and speed of eradication of the Haemophilus spp. isolates, was associated with higher median values of AUIC(24) (169 SIT(-1)*h versus 8.1 SIT(-1)*h), C(max):MIC ratio (23.6 versus 0.7) and %tau >MIC (100% versus 0%). A Hill-type model adequately described the relationship between the percentage probability of eradicating potential bacterial pathogens from sputa and the plasma grepafloxacin concentration.

Pharmacodynamic modeling of risk factors for ciprofloxacin resistance in Pseudomonas aeruginosa.

OBJECTIVE: To determine risk factors for ciprofloxacin resistance in Pseudomonas aeruginosa. METHODS: Patients with cultures (any site) positive for P aeruginosa, susceptible to ciprofloxacin, between January 1993 and December 1996 were identified using a computerized database. Factors predictive of emergence of ciprofloxacin resistance in P aeruginosa strains isolated from the same cultured site, within 21 days of the initial culture, were determined. Factors considered included length of stay prior to initial P aeruginosa culture, isolation site, initial minimum inhibitory concentration (MIC), antibiotic area under the 24-hour concentration curve (AUC24), total area under the 24-hour inhibitory concentration curve ([AUIC24] AUC24/MIC summed for all active drugs), antibiotic(s) used as dichotomous variables (yes/no), and use of monotherapy or combination therapy. RESULTS: Of 635 patients, 43 (7%) subsequently had ciprofloxacin-resistant P aeruginosa isolated. Four significantly differing patient groups were identified: group 1, P aeruginosa isolates from all sites other than the respiratory tract, treated with any drugs; group 2, respiratory tract isolates treated with drugs other than ciprofloxacin; group 3, respiratory tract isolates treated with ciprofloxacin at AUIC24 >110 (microg x h/mL)/microg/mL; and group 4, respiratory tract isolates treated with ciprofloxacin at AUIC24 < or =110 (microg x h/mL)/microg/mL. The observed percentage resistant was a continuous function of prior length of stay in all four groups. Respiratory tract isolates had higher rates of ciprofloxacin resistance (12%) than isolates from other infection sites (4%). Respiratory tract isolates exposed to ciprofloxacin at AUIC24 < or =110 (microg x h/mL)/microg/mL had the highest resistance (17%). At AUIC24 >110 (microg x h/mL)/microg/mL, resistance was decreased to 11%, a rate similar to that seen in respiratory isolates not exposed to ciprofloxacin (7%). CONCLUSIONS: Application of pharmacokinetic and pharmacodynamic principles to dosing of ciprofloxacin may reduce the risk of ciprofloxacin resistance to the level seen in isolates exposed to other agents.

Modeling the response of pneumonia to antimicrobial therapy.

The response to antimicrobial therapy in patients with pneumonia was assessed by using a previously developed pneumonia scoring system. Patients from two different clinical trials were evaluated. The first group (n = 22) was treated with cefmenoxime. For these patients, doses were adjusted to achieve an area under the plasma concentration-versus-time curve (AUC) above the MIC of 140 microg x h/ml and pneumonia response scores were evaluated retrospectively. The second group (n = 21) were treated with either ciprofloxacin (CIP) or ceftazidime (TAZ) in a randomized clinical trial. Here, doses were adjusted to achieve AUC from 0 to 24 h/MIC values that were > 250 SIT(-1) x h (estimate of the area under the curve of inverse serum inhibitory titer versus time) and pneumonia response scoring was concurrent. In both studies eradication of the pathogen was determined by serial endotracheal cultures and clinical parameters were scored daily. A decrease in total score was indicative of an improving clinical condition. The percent change in clinical daily score was determined for each day of treatment. The rate of clinical response was determined by linear regression of the percent change in daily clinical score versus time during the course of antimicrobial therapy. Factors predictive of time to eradication were explored by interval analysis. Logistic regression was used to determine the earliest time point in therapy at which treatment scores predicted outcome. Kruskal-Wallis analysis of variance was used for statistical analysis, and significance was accepted at P < 0.05. There were no differences in baseline scores at day one for the patients treated with different antibiotics (P = 0.58). For patients with pathogen eradication, a significant difference between the two studies in time to eradication was found: 4.8 days for cefmenoxime-treated patients and 1.4 days for CIP- or TAZ-treated patients (P < 0.001). For patients experiencing bacterial eradication, the rates of clinical change for cefmenoxime and CIP or TAZ treatment were similar (P = 0.77). For patients with organisms that were not eradicated, the rates of change were similar (P = 0.14). There was a significant difference in the rate of change for patients experiencing eradication compared with that for patients in which the organism persisted (P << 0.01). Both treatment group and rate were found to be predictive of days to eradication. There was a significant difference in the percent change in clinical score on day 3 of therapy for patients with bacteria that were eradicated versus those with persistent organisms (P < 0.01). The percent change was more predictive of outcome with each subsequent day. Patients who demonstrated a > or = 10% reduction in clinical score after 72 h of treatment had an 88% probability of bacterial eradication. The clinical scoring system is a useful tool for modeling the response of pneumonia to antimicrobial therapy. The ability to predict outcome relatively early in therapy, by using a scoring system of clinical parameters which can be routinely monitored, will aid in assessing the response to antimicrobial therapy in clinical as well as in research settings.