Аннотация
С целью проверки гипотезы о существовании диапазона концентраций, в пределах которого наиболее вероятна селекция устойчивых мутантов (mutant selection window - MSW), изучали изменения чувствительности метициллинорезистентного штамма Staphylococcus aureus при моделировании in vitro фармакокинетических профилей моксифлоксацина (МОК), левофлоксацина (ЛЕВ) и ципрофлоксацина (ЦИП). Во всех случаях имитировался многократный прием МОК, ЛЕВ (оба - один раз в сутки) и ЦИП (2 раза в сутки), при котором снижение уровней хинолонов было моноэкспоненциальным с периодом полувыведения 12; 6,8 и 4 ч соответственно. Моделируемые значения максимальной концентрации (Cmax) были равны или ниже МПК, выше МПК, но ниже концентрации, предотвращающей образование устойчивых мутантов (mutant prevention concentration - МРС), или выше МРС. Соответствующие значения Cmax/МПК находились в интервале от 1,3 до 24. Для всех трех хинолонов наиболее значительное повышение МПК наблюдалось при значениях Cmax/МПК, составлявших от 2 до 6, когда уровни МОК, ЛЕВ и ЦИП находились внутри MSW на протяжении большей части интервала дозирования. Никаких изменений в МПК не наблюдалось при минимальных значениях Cmax/МПК (<1,5), а также при максимальных значениях Cmax/МПК (18-24), когда уровни хинолонов были выше МРС на протяжении большей части интервала дозирования. Пороговые значения Cmax/МПК, которые предотвращают селекцию резистентных мутантов, соответствуют суточной дозе МОК, которая составляет 66% от клинической, и суточным дозам левофлоксацина и ципрофлоксацина, составляющим 220 и 640% от клинических доз соответственно. Таким образом, МОК способен предотвратить селекцию устойчивых стафилококков, а ЛЕВ и ЦИП - нет. Полученные данные подтверждают концепцию MSW.
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