Abstract
Background:The glycylcycline antibiotic tigecycline may have a relatively low propensity to promote Clostridium difficile infection in part because it causes less disruption of the indigenous intestinal microbiota than other broad-spectrum antibiotics. We used a mouse model to compare the effects of tigecycline versus other commonly used antibiotics on colonization resistance to C. difficile and on the metabolic functions of the intestinal microbiota.Methods:To assess in vivo colonization resistance to C. difficile, mice were challenged with oral C. difficile spores 1, 7, or 12 days after completion of 3 days of treatment with subcutaneous saline, tigecycline, ceftriaxone, piperacillin-tazobactam, or linezolid. Levels of bacterial metabolites in fecal specimens of mice treated with the same antibiotics were analyzed using non-targeted metabolic profiling by gas chromatograph (GC)/mass spectrometry (MS) and ultra-high performance liquid chromatography-tandem MS (UPLC-MS/MS).Results:All of the antibiotics disrupted colonization resistance to C. difficile when challenge occurred 2 days after treatment. Only piperacillin/tazobactam mice had disturbed colonization resistance at 7 days after treatment. All of the antibiotics altered fecal metabolites in comparison to controls, but tigecycline caused significantly less alteration than the other antibiotics, including less suppression of multiple amino acids, bile acids, and lipid metabolites.Conclusions:Tigecycline, linezolid, and ceftriaxone caused transient disruption of colonization resistance to C. difficile, whereas piperacillin/tazobactam caused disruption that persisted for 7 days post-treatment. Tigecycline caused less profound alteration of fecal bacterial metabolites than the other antibiotics, suggesting that the relatively short period of disruption of colonization resistance might be related in part to reduced alteration of the metabolic functions of the micro-biota.
Highlights
Antimicrobial therapy plays a central role in the pathogenesis of Clostridium difficile infection (CDI)
We demonstrated that recovery of colonization resistance to C. difficile after clindamycin or piperacillin/tazobactam treatment coincided with restoration of pretreatment levels of several fecal bacterial metabolites [9]
Mouse model of in vivo colonization resistance to C. difficile Figure 1 shows the effect of antibiotic treatment on the establishment of colonization with C. difficile when mice were challenged 2 or 7 days after the last antibiotic dose
Summary
Antimicrobial therapy plays a central role in the pathogenesis of Clostridium difficile infection (CDI). Piperacillin/tazobactam inhibits colonization by C. difficile in mice during treatment, but promotes growth and toxin production if exposure occurs during the period of recovery of the anaerobic microbiota [1]. It is plausible that tigecycline might have a relatively low propensity to promote CDI in comparison to other broad-spectrum antibiotics. In a human gut model, tigecycline inhibited growth and toxin production by C. difficile [5]. There is some evidence that tigecycline may cause relatively limited disruption of the indigenous microbiota of the colon, with sparing of Bacteroides spp. The glycylcycline antibiotic tigecycline may have a relatively low propensity to promote Clostridium difficile infection in part because it causes less disruption of the indigenous intestinal microbiota than other broad-spectrum antibiotics. We used a mouse model to compare the effects of tigecycline versus other commonly used antibiotics on colonization resistance to C. difficile and on the metabolic functions of the intestinal microbiota
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