The Role of the Microbiome in Infection Control
The disruption of the human microbiome through use of antimicrobials is a topic of growing interest among healthcare epidemiologists, not only because it is a major risk factor for C. difficile infection (CDI), but also because it could be a driving force behind the introduction and proliferation of multidrug-resistant organisms (MDROs) in healthcare settings. A greater understanding of the protective role of the microbiome could have major implications for the future direction of infection control. The speakers in this video review the current understanding of the role of microbiome disruption in the epidemiology of diseases such as CDI and MDRO colonization and transmission, and what the future may hold with regard to intervention.
Michael Schmidt, Medical Univ. of South Carolina, Charleston, SC
Cliff McDonald, Centers for Disease Control and Prevention, Atlanta, GA
Alan Walker, Wellcome Trust Sanger Inst., Cambridge, United Kingdom
EMBARGOED UNTIL: Wednesday, September 11, 3:00 PM MDT
(Session 110, Paper K-879)
CDC, Atlanta, GA, United States
Microbiologists and infection control professionals should prepare for the day they will monitor for the risk of colonization or infection with multidrug-resistant organisms (MDROs) through sampling patient’s native microbiota and manipulating these microbial communities as an infection prevention strategy. Hopefully soon the current ‘scorched microbial earth’ approach to fighting infection will yield to a more strategic and sustainable approach of ‘tending the human microbiome’.
The human microbiome consists of the collective genome of all microbiota living in or on a person, consisting of approximately 1014 microorganisms, or 10X the number of cells in a person and 100X the number of genes. Using metagenomic methods, descriptions of the relative abundances of the thousands of species constituting the human microbiome are becoming readily available. In the most microbially rich human body site, the large intestine, only about 20% of species have ever before been successfully cultured in vitro. This human intestinal microbiome establishes itself in the first years of life and while several factors including human genetics, surrounding environment (i.e. other microbe sources), and diet all impact the intestinal microbiome, there is increasing evidence that medications and particularly antibiotics produce among the most profound and long-lasting impacts.
Meanwhile in healthcare we stand on the precipice of a post-antibiotic era as MDROs threaten to overtake our hospitals. Major recognized threats include methicillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae, vancomycin-resistant enterococci (VRE), and Clostridium difficile. Each of these MDROs shares certain characteristics: direct and indirect contact transmission between patients, a larger number of asymptomatically colonized in addition to actively infected patients, and colonization that usually precedes infection. This colonization occurs primarily at sites of ‘pathologic biofilms’ (e.g. indwelling devices, chronic wounds, and other devitalized tissue) or sites normally colonized by human microbiota. Current strategies to prevent the spread of MDROs are focused on interrupting transmission of MDR strains, as well as their transferrable resistance determinants, and antibiotic stewardship. However, as the number and prevalence of MDROs continue to increase, interrupting transmission will become increasingly difficult and will only slow but not stop the spread of emerging resistance. Meanwhile, in understanding the impact of antibiotic use on resistance, we have focused for too long on the role of antibiotics in selecting for genetic mutation, recombination, transfer, and expression of resistance in individual microbial species rather than on the role of antibiotics in promoting colonization, expansion, and eventual domination the human microbiome by resistance determinants.
For example, in the case of addressing VRE in the 1990s, particular concern was given to limiting vancomycin use long after VRE’s emergence and regional spread, leading to, among other things, recommendations to avoid oral vancomycin for treating C. difficile infection. However, it is now known that drugs with anti-anaerobic activity including some cephalosporins and metronidazazole were more responsible for predisposing patients to colonization and domination of their microbiomes by VRE and therefore probably more responsible for its global spread. A turning point in our battle with MDROs will come with a shift in perspective in the field of infectious diseases that ‘antibiotic selective pressure’ mediates its greatest public health impact through ‘pressure on the human microbiome’ by promoting colonization, expansion, and domination by particular MDROs or their transferrable resistance determinant(s).
Although there is great protective effect of an unperturbed, intact human microbiome in resisting colonization and domination by MDROs, because antibiotics are so widely used and their effects so cumulative and enduring, the association between antibiotic exposure and risk of MDRO colonization is often obscured. Nonetheless, both the very low rates of MDRO colonization among healthy healthcare personnel, despite ample opportunity for transmission, and the near absolute pre-requisite of antibiotic priming to promote MDRO colonization in animal models, support the important role of colonization resistance afforded by an intact microbiome. Furthermore, an intact microbiome impacts infection outcomes; recent findings suggest bacterial dominance with an MDRO often precedes bloodstream infection and dominance occurs only in the setting of a highly perturbed microbiome. Finally, early evidence in animals suggest antibiotic-induced perturbations of the microbiome may unleash ‘pathobionts’ (i.e. normal members of the microbiota that are normally held in check by other members of the microbiota) to cause sepsis, raising the specter that antibiotic exposures in and of themselves could be a heretofore unrecognized risk for occult sepsis in severely ill patients.
Opportunities to intervene include preserving the micriobiome by refocusing antibiotic stewardship based on better understanding of the effects of different agents and combinations on the microbiome. Along this line, CDC is working with FDA and other partners to define and standardize metrics around an ‘Antibiotic or Microbiome Disruption Index’. This is conceptualized as a set of standards for use in possibly both animal and human models to quantitate the degree to which a medication perturbs the microbiome and correlating such perturbations to human health outcomes such as C. difficile infection and other types of MDRO colonization, domination, and infection.
Another opportunity to intervene is the use of intestinal microbiota transplantation to prevent not only recurrent C. difficile infection but also other forms of MDRO colonization, domination, or infection. A corollary to this will be to harvest microbiome samples, freeze, and later auto-transplant them back into patients after their microbiome has become perturbed from exposure to antibiotics and other medications. More aesthetic and easier to manage will be future use of advanced probiotics or pre-biotics (i.e. specialized dietary supplements that promote outgrowth of one part of a perturbed microbiome over another) with the aim of either restoring a patient’s microbiome to a protected state or to ‘replace’ a dominant, virulent MDRO with a less virulent, susceptible native or bioengineered member of the microbiota. Finally, it is likely that new molecular therapeutics will be developed that exploit our growing knowledge of the protective effects of an intact microbiome, whether these are natural antibacterial substances or up-regulators of mucosal immune host responses that are usually expressed through the ‘cross-talk’ of an intact microbiome with human host.
Regardless of the exact rate of development in each of these intervention areas, we should look forward to and prepare for the day that microbiologists and infection control professionals will team up to ‘tend’ the human microbiome as a principal means of controlling MDROs in healthcare.
The findings and conclusions in this report are those of the author and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.