Henrichfreise Beate, Wiegand Irith, Luhmer-Becker Ingeborg, Wiedemann Bernd
Pharmaceutical Microbiology Unit, Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Meckenheimer Allee 168, 53115, Bonn, Germany.
Antimicrob Agents Chemother. 2007 Oct;51(10):3642-9. doi: 10.1128/AAC.00160-07. Epub 2007 Aug 6.
In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.
在本研究中，我们调查了抗生素药代动力学特征与野生型及超突变型铜绿假单胞菌菌株中突变介导的耐药性发展之间的相互作用。我们使用体外模型模拟常用治疗药物美罗培南和头孢他啶的特征，这两种具有高水平抗假单胞菌活性的药物据说是具有不同刺激耐药性发展潜力的药物。在头孢他啶治疗野生型菌株（PAO1）期间，迅速选择了过量产生AmpC的完全耐药突变体，并且它们在群体中完全取代了野生型细胞。在用美罗培南治疗期间，PAO1的突变体没有被如此迅速地选择，并且由于OprD的缺失仅表现出中度耐药性。这些突变体在群体中也取代了亲本菌株。在用美罗培南治疗突变型铜绿假单胞菌菌株期间，缓慢选择的突变体没有积累多种耐药机制，而只是失去了OprD，并且在群体中没有完全取代亲本菌株。我们的结果表明，美罗培南和头孢他啶的常用给药方案无法避免野生型和超突变型铜绿假单胞菌菌株突变体的选择。对于治疗结果，包括预防耐药性发展，抗生素浓度比目前方案中更长时间地保持在突变预防浓度以上将是有益的。
