Burgess D S, Hastings R W
College of Pharmacy, The University of Texas at Austin and Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-6220, USA.
Diagn Microbiol Infect Dis. 2000 Oct;38(2):87-93. doi: 10.1016/s0732-8893(00)00173-5.
This study evaluated the in vitro pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans. MICs were determined for three clinical isolates according to NCCLS guidelines (M27). Time-kill studies were performed using antifungal concentrations of 0.25-32 x MIC and inocula of 10(3) and 10(5) CFU/ml. At predetermined time points over 72 hours, samples of each inoculum/drug combination were withdrawn and plated using a spiral plater. Colony counts were determined after incubation at 35 degrees C for 48 hours. Area under the kill curves (AUKCs) were plotted versus the AUC/MIC ratios. Inoculum effect was evaluated by calculating an estimated AUKC for the low inoculum then comparing it to the measured low inoculum using the unpaired Student's t-test. The MICs of fluconazole and itraconazole for isolate 97-1199, 97-1061, and 97-585 were 2, 4, 32 microg/ml and 0.03, 0.06, 0. 5 microg/ml, respectively. For amphotericin B, the MIC was 0. 25 microg/ml for each isolate. The triazoles demonstrated fungistatic activity against each isolate at both inocula with the exception of itraconazole against C. neoformans 97-585. Maximal suppression was noted at concentrations 8-16 x MIC correlating with an AUC/MIC of 192 for both inocula. Conversely, amphotericin B was fungicidal and displayed concentration-dependent activity against each isolate at both inocula. Maximal killing was observed at concentrations >4 x MIC for the low inoculum and >8 x MIC for the high inoculum for each isolate. No statistically significant differences were detected between the measured and estimated AUKCs for each antifungal agent. In conclusion, our results suggest that the triazoles were most effective against C. neoformans when concentrations were maintained at 8-16 x MIC. Amphotericin B, on the other hand, was concentration-dependent; thus, greater activity was exerted at higher concentrations.
本研究评估了氟康唑、伊曲康唑和两性霉素B对新型隐球菌的体外药效学。根据美国国家临床实验室标准化委员会（NCCLS）指南（M27）测定了三株临床分离株的最低抑菌浓度（MIC）。使用0.25 - 32倍MIC的抗真菌浓度以及10³和10⁵CFU/ml的接种量进行时间杀菌研究。在72小时内的预定时间点，取出每种接种物/药物组合的样本，并用螺旋接种仪接种平板。在35℃孵育48小时后测定菌落计数。绘制杀菌曲线下面积（AUKC）与AUC/MIC比值的关系图。通过计算低接种量的估计AUKC，然后使用未配对的学生t检验将其与测量的低接种量进行比较，评估接种物效应。氟康唑和伊曲康唑对分离株97 - 1199、97 - 1061和97 - 585的MIC分别为2、4、32μg/ml和0.03、0.06、0.5μg/ml。对于两性霉素B，每株分离株的MIC均为0.25μg/ml。三唑类药物对两种接种量的每种分离株均表现出抑菌活性，但伊曲康唑对新型隐球菌97 - 585除外。在8 - 16倍MIC浓度下观察到最大抑制作用（两种接种量的AUC/MIC均为192）。相反，两性霉素B具有杀菌作用，并且对两种接种量的每种分离株均表现出浓度依赖性活性。对于每种分离株，低接种量在浓度>4倍MIC时观察到最大杀菌效果，高接种量在浓度>8倍MIC时观察到最大杀菌效果。每种抗真菌药物的测量AUKC和估计AUKC之间未检测到统计学显著差异。总之，我们的结果表明，当浓度维持在8 - 16倍MIC时，三唑类药物对新型隐球菌最有效。另一方面，两性霉素B具有浓度依赖性；因此，在较高浓度下发挥更大的活性。
