[468_TD$DIFF]Opinion Phagocytes, Antibiotics, and Self-Limiting Bacterial Infections Bruce R. Levin, 1,4, * Fernando Baquero, 2,4 Peter (Pierre) Ankomah, 3 and Ingrid C. McCall 1 Most antibiotic use in humans is to reduce the magnitude and term of mor- bidity of acute, community-acquired infections in immune competent patients, rather than to save lives. Thanks to phagocytic leucocytes and other host defenses, the vast majority of these infections are self-limiting. Never- theless, there has been a negligible amount of consideration of the contribu- tion of phagocytosis and other host defenses in the research for, and the design of, antibiotic treatment regimens, which hyper-emphasizes antibiotics as if they were the sole mechanism responsible for the clearance of infections. Here, we critically review this approach and its limitations. With the aid of a heuristic mathematical model, we postulate that if the rate of phagocytosis is great enough, for acute, normally self-limiting infections, then (i) antibiotics with different pharmacodynamic properties would be similarly effective, (ii) low doses of antibiotics can be as effective as high doses, and (iii) neither phenotypic nor inherited antibiotic resistance generated during therapy are likely to lead to treatment failure. Antibiotics as Life-Style Rather than Life-Saving Drugs The current concern about the future of antibiotic therapy due to the rampant evolution of antibiotic resistance in pathogenic bacteria and the dearth of drugs with novel targets [476_TD$DIFF][1–3] is well justified for life-threatening bacterial infections, particularly for those in immune-compro- mised patients in hospitals. We should not forget, however, that, in the developed world, some 90% of human use of antibiotics is in the community, not in hospitals (http://ecdc.europa.eu/), and is employed to treat common, normally self-limiting, acute bacterial infections in otherwise healthy, immune-competent, patients [4–6]. In the community, as well as in hospitals, we are continually confronted with bacteria capable of colonizing and replicating in or on human hosts, but, thanks to a variety of innate defenses [7], symptomatic infections with these bacteria that would prompt patients to seek medical attention are rare in immune-competent hosts. Particularly prominent among these innate defenses are the evolutionarily ancient ones: phagocytic cells that recognize invading microbes and engulf and destroy them [8–10]. In addition to this predatory response, the phagocytic leucocytes play a significant role in modulating the other host responses to infecting microbes and the homeostasis of the immune system [11]. Even when symptoms are apparent, in the vast majority of cases the innate immune defenses – responsible for maintaining the subclinical detente [7] between potentially invasive bacteria and humans – clear the infection. This applies to many common infections, including acute otitis Trends With a sufficiently high rate of phago- cytosis: antibiotics with very different pharmacodynamic properties, bacter- icidal and bacteriostatic, can be simi- larly effective; phenotypic resistance (persistence) will have little effect on the rate of clearance; minority popula- tions of genetically resistant bacteria will not ascend to dominance; and lower doses of antibiotics will be as effective as higher doses. As the rate of phagocytosis declines, bactericidal drugs will be increasingly more effective than bacteriostatic ones, persistence will play an increas- ingly important role in the course of therapy, minority populations of resis- tant bacteria will ascend to domi- nance, and higher doses of antibiotics will be more effective than lower doses. 1 Department of Biology, Emory University, Atlanta, GA, USA 2 Ramón y Cajal Institute for Health Research (IRYCIS), Ramón y Cajal University Hospital, CIBERESP, Madrid, Spain 3 Massachusetts General Hospital, Boston, MA, USA 4 Co-first authors *Correspondence: blevin@emory.edu (B.R. Levin). TIMI 1487 No. of Pages 15 Trends in Microbiology, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tim.2017.07.005 1 © 2017 Elsevier Ltd. All rights reserved.