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Fitness Landscape of the Immune Compromised Favors the Emergence of Antibiotic Resistance Elisa Margolis† and Jason W. Rosch*,†
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Department of Infectious Diseases, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States ABSTRACT: Antibiotic resistance can come at a high cost, both in terms of fitness for the pathogen and poorer outcomes for patients. The fitness landscape encountered by bacterial pathogens varies greatly throughout patient populations in terms of host immunity as well as the duration and spectrum of antibiotics encountered. Severely immunocompromised patients present a favorable environment for antibiotic resistance to emerge due to lack of immune-mediated competition and increased opportunities to evolve both on-target and compensatory mutations. Such patients may present unique pathways for antibiotic resistance to emerge.
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bacteria in these hosts.2 Treatment with antibiotics can also alter mucosal innate immune defenses, allowing for outgrowth of antibiotic-resistant organisms that would otherwise be kept in check.3 Moreover, hosts that are immunocompromised may present a less complex adaptive landscape, which could hasten the emergence of the most beneficial drug-resistant mutation within the infecting bacterial population.4 This less complex landscape encompasses not only direct killing mechanisms but also altered host metabolite withholding mechanisms. In addition to direct immune clearance mechanisms, altered pharmacokinetics and pharmacodynamics in neutropenic patients can result in suboptimal antibiotic exposures which do not reach indicated therapeutic targets.5 These altered antibiotic kinetics may also provide additional opportunities for resistance development. For all of these reasons, severely immune deficient patients may be particularly prone to the emergence of resistant bacterial populations during the course of infection. Increased exposure to antibiotics, often in the form of prolonged antibiotic prophylaxis, in the immune-compromised patients may also play a role in the emergence of novel antibiotic resistance mechanisms. The most obvious mechanism is the on-target mutations that directly arise as a result of the antimicrobial therapy for the reasons stated previously. Prolonged antibiotic exposure may also significantly enhance the mutational frequency of the bacteria being targeted, accelerating the rate by which advantageous mutations arise in a population.6 As such, these patient populations may provide a unique environment that favors emergence of resistance both due to a lowered fitness threshold coupled with heightened mutagenic potential. Lack of innate immune clearance may also allow for the preservation and emergence of bacterial populations with enhanced tolerance to antibiotic exposure. In healthy individuals, the relatively small populations of bacteria recalcitrant to antibiotic mediated killing and nonreplicating
he widespread and unchecked emergence of pathogenic bacteria that are antibiotic-resistant is an ongoing and critical threat for modern medicine. Despite extensive knowledge of the clinically relevant mutations that confer antibiotic resistance, the factors that determine which mutations will arise and disseminate in pathogenic bacterial populations are less well understood. Conventionally, volume of antibiotic use and mutational frequency have been considered major determinants in the rate of antibiotic resistance in bacterial populations. Refinements have included considering fitness cost imposed by resistance and compensatory evolution that ameliorates this cost. Still underappreciated are aspects of host biology that shape these fitness considerations, as well as antibiotic efficacy and mutation rates for many pathogenic bacteria populations in vivo. One of most prominent features of host biology that imposes strong selective constraints during infection is the immune system; thus, evolutionary trajectories of antibiotic resistance in patients with impaired immunity may be distinct from the general population. Why might patients with compromised immune systems be ideal hosts for the emergence of antibiotic resistance mechanisms? For one, due to lack of innate immune clearance, larger bacterial populations in host tissues can be reached. A large bacterial population provides more opportunities for the evolution or pre-existence of an advantageous mutation conferring antibiotic resistance. Lack of innate immune clearance may also allow for a reduction in the immunemediated competition between antibiotic-resistant and antibiotic-sensitive cells. In healthy individuals, broadly crossreactive phagocytic cells cause interference competition between bacteria variants.1 In contrast, in severely immune compromised individuals, lack of clonal interference would be more permissive for bacteria to acquire on-target mutations, even if they are deleterious. This extends to the acquisition of compensatory mutations, even if they are only slightly advantageous. Impaired innate immunity also widens the window of antibiotic concentrations that antibiotic mutants are selected. This is in part due to reduced immune killing requiring higher antibiotic concentration to kill resistant © XXXX American Chemical Society
Received: July 3, 2018
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DOI: 10.1021/acsinfecdis.8b00158 ACS Infect. Dis. XXXX, XXX, XXX−XXX
ACS Infectious Diseases
Viewpoint
Figure 1. Immunodeficiency shifts the infection risk of bacteria in a given bacterial population through both direct fitness effects on the bacteria and impact on antibiotic clearance in the host. (A) Lack of immune pressure increases the relative proportion of high-risk bacterial strains and reduces the proportion of low-risk strains in terms of their pathogenic potential. High risk bacterial populations are indicated in red, intermediate by gray, and low-risk in green. (B) Differences in bacterial population bottlenecks imparted by immune enables infections by a greater proportion of the bacterial population in immune-compromised individuals pressure (R = high risk/resistant, I = intermediate, S = low risk/resistant) compared to the general population.
resistance mechanisms to arise (Figure 1). Extensive antibiotic exposure from both prophylaxis and treatment alters the native microbial flora and facilitates outgrowth of nonsusceptible bacterial populations. The lack of immune pressures and the potential for prolonged periods of infection can facilitate the emergence of such pathways and likely lead to pathways that are specific for immune compromised individuals. These unique features make such patient populations a fertile ground for antibiotic resistance to develop. The resistance mechanisms observed in such patients may be harbingers of the future of antibiotic resistance.
bacteria have a propensity for being eliminated by innate phagocytic cells. In contrast, severely immune compromised individuals lack such mechanisms for elimination of these bacterial populations that persist following antibiotic exposure, allowing for subsequent pathogen outgrowth and a more permissive window for both on-target and compensatory mutations to be acquired. Based on this permissive terrain, it would be expected that unique pathways conferring antibiotic tolerance may also selectively emerge in the context of immune suppression. There is limited clinical evidence that immune-compromised individuals may be a reservoir for novel resistance and tolerance mechanisms to emerge, though specific examples provide insight into what pathways may arise in such populations. In response to a limited and relatively brief eight-day exposure to quinolone antibiotics in neutropenic patients, resistant populations of viridans group streptococci emerged after commencing prophylaxis. 7 Similar rapid emergence and prolonged persistence of resistant bacterial pathogens have been observed in other patients with neutropenia following chemotherapy.8 In one case of persistent vancomycin-resistant enterococcal bacteremia in a neutropenic patient, mutations arose in relA that resulted in constitutive activation of the stringent response which in turn conferred high-level antibiotic tolerance during biofilm growth.9 In persistently infected hospitalized patients, other mutations can arise in S. aureus agr quorum sensing pathways that enhance tolerance under antimicrobial stress conditions with no discernible alterations in antimicrobial resistance profiles.10 Bacterial isolates from cancer patients in some instances were the first to demonstrate resistance to vancomycin and linezolid in certain regions.11 These data indicate persistently infected and immune-compromised patients may allow for the emergence of novel resistance and tolerance pathways that facilitate bacterial evasion of antimicrobial therapy. Patients with severe immune deficiencies present a unique set of challenges both from a treatment perspective as well as for the potential for unique tolerance and antimicrobial
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AUTHOR INFORMATION
Corresponding Author
*Phone: 901-595-3408; E-mail:
[email protected]. Author Contributions †
Both authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS J.W.R. is supported by Grants 1U01AI124302 and 1RO1AI110618. J.W.R. and E.M. are funded by ALSAC. REFERENCES
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DOI: 10.1021/acsinfecdis.8b00158 ACS Infect. Dis. XXXX, XXX, XXX−XXX
ACS Infectious Diseases
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DOI: 10.1021/acsinfecdis.8b00158 ACS Infect. Dis. XXXX, XXX, XXX−XXX
