Abstract/Text: To date, the majority of pharmacokinetic/pharmacodynamic (PK/PD) discussions have focused on PK/PD relationships evaluated at steady-state drug concentrations. However, a concern with reliance upon steady-state drug concentrations is that it ignores events occurring while the pathogen is exposed to intermittent suboptimal systemic drug concentrations prior to the attainment of a steady state. Suboptimal (inadequate) exposure can produce amplification of resistant bacteria. This minireview provides an overview of published evidence supporting the positions that, in most situations, it is the exposure achieved during the first dose that is relevant for determining the therapeutic outcome of an infection, therapeutic intervention should be initiated as soon as possible to minimize the size of the bacterial burden at the infection site, and the duration of drug administration should be kept as brief as clinically appropriate to reduce the risk of selecting for resistant (or phenotypically nonresponsive) microbial strains. To support these recommendations, we briefly discuss data on inoculum effects, persister cells, and the concept of time within some defined mutation selection window.

Abstract/Text: Minimum inhibitory and bactericidal concentrations do not describe the time course of a drug's antimicrobial activity against bacteria. Some antimicrobials exhibit concentration dependent killing over a wide range of concentrations (e.g. aminoglycosides and quinolones), while others show maximal killing at concentrations near the MIC (e.g. beta-lactams and glycopeptides). The aminoglycosides and quinolones can require high drug concentrations (about 10-fold higher than the MIC) to prevent the selection of resistant subpopulations of bacteria. Persistent suppression of bacterial growth after antimicrobial exposure is called the 'postantibiotic effect' (PAE) and varies in duration depending on the drug-organism combination, as well as the concentration and duration of drug exposure. Antimicrobials which are inhibitors of protein and nucleic acid synthesis exhibit prolonged PAEs with a large variety of bacteria. While beta-lactam antibiotics demonstrate PAEs with Gram-positive cocci, very short or no PAEs are observed with these drugs with Gram-negative bacilli. The only exception is that penem antibiotics can induce PAEs with some strains of Gram-negative bacilli, primarily Pseudomonas aeruginosa. Thus, the pharmacodynamic activity of an antimicrobial can vary markedly depending on the microorganism and the class of drug and its concentration.

Abstract/Text: Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured 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) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1.h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent 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 two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication 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 findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.