Rodrigues Maria E, Lopes Susana P, Pereira Cláudia R, Azevedo Nuno F, Lourenço Anália, Henriques Mariana, Pereira Maria O
Centre of Biological Engineering, LIBRO-Laboratório de Investigação em Biofilmes Rosário Oliveira, University of Minho, Campus de Gualtar, Braga, Portugal.
LEPABE-Dep. of Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, Porto, Portugal.
PLoS One. 2017 Jan 23;12(1):e0170433. doi: 10.1371/journal.pone.0170433. eCollection 2017.
The polymicrobial nature of ventilator-associated pneumonia (VAP) is now evident, with mixed bacterial-fungal biofilms colonizing the VAP endotracheal tube (ETT) surface. The microbial interplay within this infection may contribute for enhanced pathogenesis and exert impact towards antimicrobial therapy. Consequently, the high mortality/morbidity rates associated to VAP and the worldwide increase in antibiotic resistance has promoted the search for novel therapeutic strategies to fight VAP polymicrobial infections. Under this scope, this work aimed to assess the activity of mono- vs combinational antimicrobial therapy using one antibiotic (Polymyxin B; PolyB) and one antifungal (Amphotericin B; AmB) agent against polymicrobial biofilms of Pseudomonas aeruginosa and Candida albicans. The action of isolated antimicrobials was firstly evaluated in single- and polymicrobial cultures, with AmB being more effective against C. albicans and PolyB against P. aeruginosa. Mixed planktonic cultures required equal or higher antimicrobial concentrations. In biofilms, only PolyB at relatively high concentrations could reduce P. aeruginosa in both monospecies and polymicrobial populations, with C. albicans displaying only punctual disturbances. PolyB and AmB exhibited a synergistic effect against P. aeruginosa and C. albicans mixed planktonic cultures, but only high doses (256 mg L-1) of PolyB were able to eradicate polymicrobial biofilms, with P. aeruginosa showing loss of cultivability (but not viability) at 2 h post-treatment, whilst C. albicans only started to be inhibited after 14 h. In conclusion, combination therapy involving an antibiotic and an antifungal agent holds an attractive therapeutic option to treat severe bacterial-fungal polymicrobial infections. Nevertheless, optimization of antimicrobial doses and further clinical pharmacokinetics/pharmacodynamics and toxicodynamics studies underpinning the optimal use of these drugs are urgently required to improve therapy effectiveness and avoid reinfection.
呼吸机相关性肺炎（VAP）的多微生物性质现已明确，混合细菌-真菌生物膜定植于VAP气管内导管（ETT）表面。这种感染中的微生物相互作用可能会促进发病机制的增强，并对抗菌治疗产生影响。因此，与VAP相关的高死亡率/发病率以及全球抗生素耐药性的增加，促使人们寻找对抗VAP多微生物感染的新治疗策略。在此背景下，本研究旨在评估使用一种抗生素（多粘菌素B；PolyB）和一种抗真菌药（两性霉素B；AmB）的单一疗法与联合疗法对铜绿假单胞菌和白色念珠菌多微生物生物膜的活性。首先在单微生物和多微生物培养物中评估了单一抗菌药物的作用，结果显示AmB对白色念珠菌更有效，而PolyB对铜绿假单胞菌更有效。混合浮游培养物需要同等或更高的抗菌浓度。在生物膜中，只有相对高浓度的PolyB才能减少单物种和多微生物群体中的铜绿假单胞菌，白色念珠菌仅表现出局部干扰。PolyB和AmB对铜绿假单胞菌和白色念珠菌混合浮游培养物表现出协同作用，但只有高剂量（256 mg L-1）的PolyB能够根除多微生物生物膜，铜绿假单胞菌在治疗后2小时显示出可培养性丧失（但不是活力丧失），而白色念珠菌在14小时后才开始受到抑制。总之，涉及抗生素和抗真菌剂的联合疗法是治疗严重细菌-真菌多微生物感染的一种有吸引力的治疗选择。然而，迫切需要优化抗菌药物剂量，并开展进一步的临床药代动力学/药效学和毒代动力学研究，以支持这些药物的最佳使用，从而提高治疗效果并避免再次感染。
