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318 AndesTABLE 1 Amphotericin B PharmacokineticsFormulation Carrier %AmB Dose C max AUC t1/2 Spleen Lung KidneyAmB Deoxycholate 34 0.6 1.1 17 24 80 15 82ABLC DMPC 35 5 1.7 14 173 3008 77 44– DMPG – – – – – – – –ABCD Cholesterol 50 5 3.1 43 30 850 27 87– Sulfate – – – – – – – –L-AmB HSPC 10 5 83 555 24 765 31 74– DSPG – – – – – – – –Dose mg/kg, AUC mg*hr/L, t1/2 hours, organ concentration mg/L.Abbreviations: DMPC, dimyristoyl phospitidylcholine; DMPG, dimyristoyl phospitidylcglycerol; HSPC, hydrogenatedsoy phosphatidylcholine; DSPG, distearoyl phosphitidylcholine; AmB, amphotericin B; ABLC, AmB lipidcomplex; ABCD, AmB colloidal dispersion; AUC, area under the curve.method, both experimental models in vitro and in vivo and clinical trial data havebeen able to demonstrate a correlation between drug dose, the minimum inhibitoryconcentration (MIC), and outcome (34–37). These investigations have beenimportant for describing the relative potencies of these antifungal drugs against anumber of relevant pathogens. Further characterization of the pharmacodynamicsof the polyenes soon followed.Time Course ActivityThe field of antimicrobial pharmacodynamics examines the relationship betweendrug exposure and antimicrobial activity or host toxicity (38). There are two majorfactors, which are used to define the relationship between drug concentration andmicrobiologic activity over time. The first is whether organism killing is enhancedby increasing drug concentration. The second is the presence and duration ofantimicrobial effects that persist following brief drug exposure (postantibiotic orpostantifungal effects) (39).In VitroQuantitation of the impact of AmB concentrations on antifungal activity has beenexamined in a number of time kill in vitro studies (40–44). These studies havedemonstrated that as the concentration of AmB is increased, both the rate and theextent of antifungal killing are enhanced. For example, Di Bonaventura et al.examined the activity of several antifungals including AmB deoxycholate in anin vitro time kill model against nonalbicans Candida species (45). Followingexposure to AmB concentrations 0.125 to 8 times the MIC, viable counts weredetermined every 2 to 16 hours over a 24-hour period. More than a 4 log reductionin organism burden was observed within two hours and maximal killing wasnoted with AmB concentration only twofold in excess of the MIC. Similarly,Klepser et al. used an in vitro time kill model to characterize the impact of doseescalation of AmB against C. albicans and C. neoformans (41,42). These investigatorsalso observed maximal killing of organisms with AmB concentrations two to fourtimes the MIC. Klepser et al. also noted that the rate of organism killing increasedas the drug concentration was escalated from 0.125 times the MIC to 4 times theMIC. The concentration-dependent effects of AmB have also been demonstratedagainst filamentous fungal pathogens. Lewis et al. observed enhanced activityagainst Aspergillus, Fusarium, and Scedosporium species with escalating AmBconcentrations using a hyphal viability assay (43).