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Antibiotics and Innate Immunity: a Cooperative Effort Toward The applyparastyle “fig//caption/p[1]” parastyle “FigCapt” Open Forum Infectious Diseases PERSPECTIVES Antibiotics and Innate Immunity: A Cooperative Effort Toward the Successful Treatment of Infections Andrew Berti,1,2 Warren Rose,3, Victor Nizet,4,5 and George Sakoulas4 1Department of Pharmacy Practice, Wayne State University College of Pharmacy and Health Sciences, Detroit, Michigan, USA, 2Department of Biochemistry, Microbiology and Immunology, Wayne State University College of Medicine, Detroit, Michigan, USA, 3School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA, 4Collaborative to Halt Antimicrobial Resistant Microbes, University of California San Diego School of Medicine, La Jolla, California, USA, and 5Skaggs School of Pharmacy, University of California San Diego, La Jolla, California, USA Despite the common ancestry of antimicrobial and immunological science, a divergence driven by artificially construed paradigms in microbiology has placed limits on how we understand the mechanisms of antibiotics in vivo. We summarize recent updates on Downloaded from https://academic.oup.com/ofid/article/7/8/ofaa302/5873654 by guest on 26 August 2020 data that shed light on how antibiotics interact with components of innate immunity. Keywords. antibiotic; antimicrobial peptides; innate immunity, mechanism. Despite common roots of antimicro- species, suggesting that antibiotics them- Institute. This assay consists of collecting bial therapy and immunology in the re- selves may represent primeval precursors patient blood samples, ideally during search efforts of legendary pioneers like of the immune systems of higher organ- serum peak and trough concentrations Louis Pasteur and Paul Ehrlich, our di- isms. Along those lines, the mechanisms of the antibiotic, combining equally with vergent and hyperspecialized evolution of action of some current “exogenous” bacterial growth medium and testing the of medicine has largely separated the natural product antibiotics used in clin- bactericidal titer concentration against pharmacology of antibiotics adminis- ical medicine overlap considerably with the patient’s bacterial isolate. A high SBT tered to patients from the functions of the “endogenous” antimicrobial pep- may indicate that the dose chosen for the patient’s innate immune system [1]. tides of the mammalian innate immune the patient is sufficient for treatment [6]. Ehrlich’s work in immunology won him system [3]. This process has implications However, significant variability in the the 1908 Nobel Prize in Medicine; his for antimicrobial susceptibility, as the medium, diluent, inoculum, incubation, contributions to antimicrobial chemo- presence of host defense peptides in vivo and controls has impeded the widespread therapy with salvarsan, an arsphenamine during chronic infection is sufficient to clinical application of SBT testing. In ad- compound that was the first treatment select for cross-resistance to daptomycin, dition, use of only the serum excludes for syphilis, should not be forgotten [2]. even in the treatment-naïve patient [4, 5]. other critical components of the patient The great majority of current antibiotics innate immune system, for example, are natural products produced by actino- ENDOGENOUS AND EXOGENOUS leukocytes, and this may fail to recapit- ANTIBIOTICS mycetes, fungi, or other microorganisms ulate the full interaction of antibiotics used in niche competition against other There is abundant literature examining with host immune defenses. For example, the pharmacodynamic relationships of macrolide antibiotics induce formation exogenous antibiotics with one another, of neutrophil extracellular traps (NETs) Received 30 April 2020; editorial decision 6 July 2020; defining synergy, additivity, indifference, containing antimicrobial peptides and accepted 15 July 2020. and antagonism. Conversely, studies of histones that can ensnare bacteria and Correspondence: George Sakoulas, MD, Center for Immunity, Infection & Inflammation, UCSD School of Medicine the pharmacodynamics of innate im- attract other immune cells [7], while Biomedical Research Facility II, Room 4114, 9500 Gilman mune components and antibiotics are beta-lactams sensitize bacteria to neutro- Drive, Mail Code 0760, La Jolla, CA 92093-0760 (gsakoulas@ scarce and have been difficult to imple- phils [8]. Anthropocentric debates about health.ucsd.edu). Open Forum Infectious Diseases® ment and replicate in the patient care set- “monotherapy” vs “combination therapy” © The Author(s) 2020. Published by Oxford University Press ting. Serum inhibitory and bactericidal in the treatment of infection fail to con- on behalf of Infectious Diseases Society of America. This titers (SBTs) were devised as an investi- sider the fact that the net antimicrobial is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial- gational test to evaluate the bactericidal effect in a patient receiving antibiotic NoDerivs licence (http://creativecommons.org/licenses/ properties of antibiotic therapy in a more pharmacotherapy is the collective sum- by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided physiological context, namely the serum mation of exogenous pharmacotherapy the original work is not altered or transformed in any of the patient. Specifics for the perfor- and innate immune defense factors. way, and that the work is properly cited. For commercial re-use, please contact [email protected] mance of SBT testing have been published “Monotherapy” never really exists in a DOI: 10.1093/ofid/ofaa302 by the Clinical and Laboratory Standards pure form. PERSPECTIVES • OFID • 1 CONVENTIONAL BACTERIOLOGIC treated in animal models of endocar- beta-lactams like nafcillin and oxacillin MEDIA: AN OBSTACLE TO OUR ditis with beta-lactam monotherapy [11, has been successfully deployed as adjunc- COMPLETE UNDERSTANDING OF ANTIMICROBIAL ACTIVITY 13]. Azithromycin efficacy against mul- tive salvage therapy to successfully clear tiple gram-negative bacterial species refractory MRSA bacteremia [18, 19]. The conceptual divergence of antibiotic (eg, Acinetobacter baumannii, Klebsiella Ampicillin has been used in an analogous pharmacology and immunology dis- pneumoniae) depends on bicarbonate, fashion to clear persistent bacteremia ciplines may have been aggravated by and this activity translates to in vivo ef- due to ampicillin-resistant, vancomycin- the historical choice of media used to ficacy in murine infection models [14, resistant Enterococcus faecium (VRE) cultivate and examine microorganism 15]. MHB lacks bicarbonate buffer; thus [20]. In both cases, concentrations well susceptibility and resistance. From the standard clinical AST testing declares below the MIC rendered MRSA and VRE beginnings of the human antibiotic era, azithromycin inactive against these hypersusceptible to cationic antimicro- antimicrobial susceptibility testing (AST) pathogens. Another recent study shows bial peptides, a property completely of pathogens has focused exclusively on how hyperphysiological concentrations missed in standard AST testing, which Downloaded from https://academic.oup.com/ofid/article/7/8/ofaa302/5873654 by guest on 26 August 2020 media optimized for microbial growth, of zinc in MHB render metallo-beta- may serve a critical role in the resolution with the addition of antibiotics up to the lactamase-producing Enterobacteriaceae of severe infection. Synergy with anti- point of growth inhibition defining the resistant to carbapenems in such media. microbial peptides has also been shown “minimum inhibitory concentration” However, these organisms are susceptible for ceftaroline against Streptococcus (MIC), which serves as the centerpiece to carbapenems in vivo, where nutritional pneumoniae [21] and ceftriaxone against of clinical microbiology [9]. AST para- immunity restricts zinc concentrations to Salmonella enterica [22]. The cationic de- digms have somewhat arbitrarily con- much lower levels. Removal of zinc from fense peptide cathelicidin is a key host verged on Mueller-Hinton broth (MHB) MHB broth more reliably predicts in vivo defense against systemic infection and for most assays in the clinical microbi- activity of carbapenems against these or- bacterial meningitis. Antimicrobial syn- ology lab. This medium, first developed ganisms [16]. Rigid continuation of AST ergy with cathelicidin may be an im- 1941 for isolating pathogenic strains of paradigms utilizing only standard bac- portant factor driving better clinical Neisseria spp. [10], does not recapitulate teriological media overlooks potential outcomes [22]. in vitro the in vivo environment relevant useful activities of the currently available This enhancement between antibiotics for infection, nor is it a medium in which antibiotics against multidrug-resistant and immune response extends beyond host antimicrobial peptide activity can bacteria [14], but it also hinders the tran- beta-lactams. Azithromycin, a macro- be reliably assayed [9]. Recent work has sition of pharmacodynamic analysis of lide antibiotic, demonstrates synergy shown considerable differences in MICs innate immunity synergy with antibiotics with host antimicrobial peptides against between standard bacteriological media to a more clinical mainstream. Pseudomonas and Acinetobacter [14]. and more physiological media such as Even certain beta-lactamase inhibitors, mammalian tissue culture media [11, 12]. BACTERICIDAL VS conceptually deployed to
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