PHARMACODYNAMICS OF INTRAVENOUS CIPROFLOXACIN IN SERIOUSLY ILL-PATIENTS

Seventy-four acutely ill patients were treated with intravenous ciprof loxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating dr ug exposure (and other factors) to infectious outcome was performed. P lasma samples were obtained and assayed for ciprofloxacin by high-perf ormance liquid chromatography. Samples from patients were frequently c ultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versu s the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradic ation by proportional hazards regression. The independent variables co nsidered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trou gh/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/ MIC ratio (AUIC), presence of other active antibacterial agents, and p atient characteristics. The most important predictor for all three mea sures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 1 25 SIT-1 . h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinic al and microbiologic cures. At an AUIC below 125 (19 patients), the pe rcent probabilities of clinical and microbiologic cures were 42 and 26 %, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were tw o significant breakpoints in the time-to-bacterial-eradication data. A t an AUIC below 125 (21 patients), the median time to eradication exce eded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradicat ion was 6.6 days; and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findi ngs, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dos age of intravenous ciprofloxacin to individual patients' pharmacokinet ics and their bacterial pathogens' susceptibilities. An a priori dosin g algorithm (based on MIC, patient creatinine clearance and weight, an d the clinician-specified AUIC target) was developed. This approach wa s shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical re sponses to ciprofloxacin, as a consequence of targeting the AUIC.