Mathematical Examination of Dual Individualization Principles (II): The Rate of Bacterial Eradication at the Same Area under the Inhibitory Curve is More Rapid for Ciprofloxacin Than for Cefmenoxime

Abstract

OBJECTIVE: To compare two antibiotics at equal ranges of area under the inhibitory curve (AUIC) exposure to determine if the rate of bacterial eradication differed between these antibiotics. DESIGN: Retrospective comparison of two previously collected studies of similar patients with nosocomial pneumonia. SETTING: Hospitalized patients, most intubated in critical care units with nosocomial pneumonia. PARTICIPANTS: Patients treated with either iv ciprofloxacin (n=74) or the iv third-generation cephalosporin cefmenoxime (n=43) were compared for their length of treatment required to eradicate bacterial pathogens from their respective infection sites, using serial cultures from the site of infection. All patients were also assessed for clinical outcomes. Serum samples were obtained to evaluate individual patient antibiotic pharmacokinetics, which were used to model pharmacodynamics of response. The HPLC assay used for each antibiotic had interday coefficients of variation <10 percent. Serum concentration versus time profiles were fit using the computer program ADAPT II to determine pharmacokinetic parameters for each patient. The primary drug exposure measure that related to response was the AUIC, calculated as steady-state AUC0–24/minimum inhibitory concentration. RESULTS: AUIC values in the patients ranged from 6.0 to more than 7000, yet the AUIC value was highly predictive of time to bacterial eradication (p<0.OO 1). Although more than 75 percent of patients eventually achieved eradication of pathogens from tracheal aspirate cultures, ciprofloxacin and cefmenoxime differed significantly in the time required to sterilize these cultures. At appropriate AUIC values (>250) for ciprofloxacin, the median time to eradication was two days, while cefmenoxime (also at AUIC values >250) required six days to achieve the same result. CONCLUSIONS: We conclude that the more rapid in vitro bacterial killing, which is characteristic of ciprofloxacin at optimal AUIC values, can manifest in vivo as more rapid clearance of bacteria from the respiratory tract of patients, even when both agents are controlled for initial antibacterial exposure (i.e., same AUIC).