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.
Hyatt
J M
JM
The Clinical Pharmacokinetics Laboratory, Millard Fillmore Health System, Buffalo, New York, USA.
Luzier
A B
AB
Forrest
A
A
Ballow
C H
CH
Schentag
J J
JJ
D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015281:Cefmenoxime / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D011237:Predictive Value of Tests; D012044:Regression Analysis; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D002511:Cephalosporins; D002939:Ciprofloxacin; D002442:Ceftazidime; D015281:Cefmenoxime