Javaudin François, Bémer Pascale, Batard Eric, Montassier Emmanuel
MiHAR Laboratary, EE1701, University of Nantes, 44200 Nantes, France.
Emergency Department, Nantes University Hospital, 44000 Nantes, France.
Microorganisms. 2021 Dec 13;9(12):2580. doi: 10.3390/microorganisms9122580.
The growing resistance of bacteria to antibiotics is a major global public health concern. An important reservoir of this resistance is the gut microbiota. However, limited data are available on the ability of phage therapy to reduce the digestive carriage of multidrug-resistant bacteria.
Four novel lytic phages were isolated in vitro for efficacy against an extended-spectrum beta-lactamase-producing (ESBL) strain also resistant to carbapenems through a carbapenemase OXA-48. The first step was to develop models of ESBL digestive carriage in mice. The second step was to test the efficacy of an oral and rectal phage therapy (a cocktail of four phages or microencapsulated phage) to reduce this carriage.
The two most intense models of digestive carriage were obtained by administering amoxicillin (0.5 g·L) continuously in the drinking water (Model 1) or pantoprazole (0.1 g·L) continuously in the drinking water, combined with amoxicillin (0.5 g·L), for the first 8 days (Model 2). Oral administration of the phage cocktail to Model 1 resulted in a transient reduction in the concentration of ESBL in the faeces 9 days after the bacterial challenge (median = 5.33 × 10 versus 2.76 × 10 CFU·g, = 0.02). In contrast, in Model 2, oral or oral + rectal administration of this cocktail did not alter the bacterial titre compared to the control (area under the curve, AUC, 3.49 × 10; 3.41 × 10 and 3.82 × 10 for the control, oral and oral + rectal groups, respectively; -value > 0.8 for each two-by-two group comparison), as well as the administration of an oral microencapsulated phage in Model 1 (AUC = 8.93 × 10 versus 9.04 × 10, = 0.81).
Oral treatment with amoxicillin promoted digestive carriage in mice, which was also the case for the addition of pantoprazole. However, our study confirms the difficulty of achieving efficacy with phage therapy to reduce multidrug-resistant bacterial digestive carriage in vivo.
细菌对抗生素的耐药性不断增强是全球主要的公共卫生问题。这种耐药性的一个重要来源是肠道微生物群。然而，关于噬菌体疗法降低多重耐药菌在消化道中携带的能力的数据有限。
体外分离出四种新型裂解性噬菌体，用于对抗一株产超广谱β-内酰胺酶（ESBL）且通过碳青霉烯酶OXA-48对碳青霉烯类耐药的菌株。第一步是建立小鼠ESBL消化道携带模型。第二步是测试口服和直肠噬菌体疗法（四种噬菌体的混合物或微囊化噬菌体）降低这种携带的效果。
通过在饮用水中持续给予阿莫西林（0.5 g·L）（模型1）或在饮用水中持续给予泮托拉唑（0.1 g·L）并在最初8天联合给予阿莫西林（0.5 g·L）（模型2），获得了两种最强烈的消化道携带模型。在模型1中，在细菌攻击后9天口服噬菌体混合物导致粪便中ESBL浓度短暂降低（中位数 = 5.33×10对2.76×10 CFU·g， = 0.02）。相比之下，在模型2中，与对照组相比，口服或口服 + 直肠给予这种混合物并未改变细菌滴度（曲线下面积，AUC，对照组、口服组和口服 + 直肠组分别为3.49×10；3.41×10和3.82×10；每组两两比较的 - 值>0.8），模型1中口服微囊化噬菌体的情况也是如此（AUC = 8.93×10对9.04×10， = 0.81）。
口服阿莫西林促进了小鼠消化道携带，添加泮托拉唑时也是如此。然而，我们的研究证实了在体内通过噬菌体疗法降低多重耐药菌消化道携带实现疗效的困难。
