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ARTICLE

Synergy Between Antibiotics and The Innate Immune System

MAR 09, 2020 | ANDREW BERTI, PHARMD; WARREN ROSE, PHARMD; GEORGE SAKOULAS, MD
The activities of antibiotics against bacteria have traditionally been considered only in terms of their direct inhibition and killing properties in isolation. However, growing evidence suggests that antimicrobials also interact with host innate immunity to provide potent indirect effects which enhance bacterial clearance and may result in more rapid and complete effects, thereby reducing the likelihood of emergence of resistance among residual bacteria, and other positive clinical outcomes. Innate endogenous host defense peptides, evolved to protect the host by preventing establishment of infection from pathogenic organisms and have similar antimicrobial mechanisms of action to peptide antimicrobials delivered to patients such as daptomycin and colistin.1

Scientific literature abounds with research examining the pharmacodynamics relationship of antibiotics, defining synergy, additivity, indifference, and antagonism, but studies of the pharmacodynamics of innate immune components with antibiotics are scarce. The monotherapy versus combination therapy debates for the treatment of infections fail to consider the potential additional value of the patient immune system on antibiotic pharmacotherapy (Illustration). 

The recommendations for antimicrobial susceptibly testing from Clinical Laboratory Standards Institute include the use of standard bacterial medium to establish the minimum inhibitory concentration.2 This is commonly defined by the lowest level of drug that inhibits bacterial growth, juxtaposed by the fact that it is determined in media designed to optimize bacterial growth. Therefore, the interpretation of the “true” MIC and its translation to the patient treated with an antimicrobial can be a controversial and moving target.

More recent research has explored the effect of different media types, commonly more host-mimicking media such as cell culture media (RPMI) and bacterial media buffered in more host physiologic ions such as bicarbonate.3,4 These media types may offer other advantages in that these are preferred for analyzing the antimicrobial effects of host defense peptides as well. These studies have found significant discrepancies in the antibiotic susceptibility between host-mimicking media and bacterial growth media. Strikingly, some antibiotics showing resistance in standard bacterial growth media (Mueller-Hinton) are susceptible in RPMI and other host-mimicking media. This includes azithromycin activity against Acinetobacter baumannii and Pseudomonas aeruginosa and recently nafcillin and cefazolin susceptibility against select MRSA strains.3,5 This has translated to in vivo efficacy in animal models and has demonstrated successful approaches in patients when there are discordant susceptibility results between standard and alternative media types.4,5  

There remains much debate over the clinical benefit of bactericidal versus bacteriostatic antibiotics.6 The occasionally observed similar efficacy of bacteriostatic antibiotics, as determined by traditional medium, may be because some are in fact bactericidal in the host environment.5 Since some bacteria use elements of traditional bacterial growth media to counteract antibiotics, there has been exploration of specific media types to better test individual antibiotics. Recently, carbapenems were shown to be active against metallo-beta-lactamase producing gram-negative organisms when studied in zinc-depleted Muller-Hinton broth, and susceptible strains in this media correlated with in vivo efficacy.7 This approach has now been translated into clinic testing for the new antibiotic cefiderocol, which requires iron-depleted media to prevent bacteria from artificially overcoming the antibiotic mechanism of siderophore-mimetic uptake of the cephalosporin molecule.8 There is a clear need for further studies to screen antibiotics in alternative media to improve the translation of pharmacodynamics to the bedside.  Increasingly, studies suggest that this may be a unique screening approach tailored to individual organism and antibiotic types.

While we might consider the direct, in vitro mechanism of action of an antibiotic to drive its antimicrobial efficacy, additional effects of antibiotics on bacteria have shown improved host clearance and immune optimization. This includes the ability for antibiotics to alter virulence factors and other mechanisms, which can modify host response. Clinical practice guidelines already recognize the benefit of affecting virulence factor production in the treatment of severe necrotizing fasciitis.9 Recently the influence on host immune responses with antibiotics was found with increased IL-1β and lower IL-10 production in patients treated with β-lactam adjunctive therapy combined with standard antibiotics in MRSA bacteremia.10 Although previous vaccine attempts against S. aureus have failed, new immunologic-based therapies show promise when combining virulence factor antibodies with traditional therapeutics.11 Each of these approaches for antibiotic- immune synergy would be missed with standard media.

Looking towards the future, it appears that our focus of antimicrobial pharmacology to the exclusion of host immunology has resulted in an outdated understanding of antimicrobial therapy. More objective examinations of immune system and antibiotic cooperativity through use of alternative media types, analysis of host cytokine responses, mathematical modeling and computer simulation will hopefully help transition this field into a more tangible science. Steps must be taken to reunite the understanding of innate immunity-antibiotic relationships in order to improve treatments, better appreciate antibiotic therapy, slow the development of resistance, and discover new therapeutic approaches.



Rose is an associate professor of pharmacy at the University of Wisconsin-Madison. His translational research interests and expertise in acute bacterial infections include antimicrobial pharmacology, resistance and virulence, and host-pathogen interactions. 

Berti is an assistant professor of pharmacy and medicine at Wayne State University in Detroit, Michigan. His research investigates how combining antibiotics in a deliberate and rational manner can improve outcomes for patients with challenging bacterial infections. By integrating pharmacokinetics, bacteriology, molecular biology and recombinant genetics, his group examines when therapies are appropriate, why they provide benefit and how best to administer them.

Sakoulas is a clinical infectious disease physician at Sharp Rees-Stealy Medical Group in San Diego, California. He also is an associate adjunct professor at the University of California San Diego School of Medicine, where he participates in the Collaborative to Halt Antibiotic-Resistant Microbes. 



References:
  1. Hancock REW, Haney EF, Gill EE. 2016. The immunology of host defence peptides: beyond antimicrobial activity. Nat Rev Immunol 16:321-334.
  2. Clinical and Laboratory Standards Institute. 2019. Performance standards for antimicrobial susceptibility testing. CLSI document M100-ED29; Clinical and Laboratory Standards Institute, Wayne, PA.
  3. Ersoy SC, Heithoff DM, Barnes LV et al. 2017. Correcting a fundamental flaw in the paradigm for antimicrobial susceptibility testing. EBioMed 20:173-181.
  4. Ersoy SC, Abdelhady W, Li L, Chambers HF, Xiong YQ, Bayer AS. 2019. Bicarbonate resensitization of methicillin-resistant Staphylococcus aureus to β-lactam antibiotics. Antimicrob Agents Chemother 63:e00496-19.
  5. Lin L, Nonejuie P, Munguia J et al. 2015. Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens. EBioMed 2:690-698.
  6. Wald-Dickler N, Holtom P, Spellberg B. 2018. Busting the myth of “static vs cidal”: a systemic literature review. Clin Infect Dis 66:1470-1474.
  7. Asempa TE, Abdelraouf K, Nicolau DP. 2020. Metallo-β-lactamase resistance in Enterobacteriaceae is an artefact of currently utilized antimicrobial susceptibility testing methods. J Antimicrob Chemother pii:dkz32.
  8. Zhanef GG, Golden AR, Zelenitsky S et al. 2019. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant gram-negative bacilli. Drugs 79:271-289.
  9. Stevens DL, Bisno AL, Chamber HF et al. 2014. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 59:e10-e52.
  10. Volk CF, Burgdorf S, Edwerdson G, Nizet V, Sakoulas G, Rose WE. 2019. Interleukin (IL)-1β and IL-10 host responses in patients with Staphylococcus aureus bacteremia determined by antimicrobial therapy. Clin Infect Dis pii:ciz686.
  11. Miller LS, Fowler VG, Shukla SK, Rose WE, Proctor RA. 2020. Development of a vaccine against Staphylococcus aureus invasive infections: Evidence based on human immunity, genetics and bacterial evasion mechanisms. FEMS Microbiol Rev 44:123-153.
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