![]() Such nonreplicating “persisters” can survive exposure to otherwise lethal antibiotic concentrations. Some bacteria might stop replication either because of stochastic internal processes or in response to external triggers. Third, pathogen heterogeneity has been suggested as a major cause of treatment failures ( 1, 2, 20– 22). Moreover, limited nutrient supply and stress conditions can slow bacterial proliferation, which increases tolerance to most antibiotics ( 14– 18), in some conditions due to low ATP levels ( 19). Such tolerant states might be triggered by stresses imposed on the pathogen by the host immune system ( 7– 13). Second, bacteria might adopt physiological states in host tissues that enable them to tolerate antibiotic exposure. First, antimicrobials might not reach all bacterial cells in sufficient amounts because anatomical permeation barriers limit drug access to bacteria in certain tissue areas ( 5, 6). Various mechanisms have been proposed to explain pathogen persistence during antimicrobial chemotherapy. These results identify uneven Salmonella tissue colonization and spatiotemporal inflammation dynamics as main causes of Salmonella persistence and establish a powerful approach to investigate scarce but impactful pathogen subsets in complex host environments.ĭevelopment of effective treatments requires a detailed understanding of the underlying mechanisms. However, adjunctive therapies sustaining inflammatory support enabled effective clearance. Neutrophil densities declined further during treatment in response to receding Salmonella loads, resulting in insufficient support for Salmonella clearance from the white pulp and eradication failure. Instead, antimicrobial clearance required support of Salmonella-killing neutrophils and monocytes, and the density of such cells was lower in the white pulp than in other spleen compartments containing higher Salmonella loads. Previous models could not explain these findings: drug exposure was adequate, Salmonella continued to replicate, and host stresses induced only limited Salmonella drug tolerance. Chemotherapy cleared >99.5% of the Salmonella but was inefficient against a small Salmonella subset in the white pulp. Here, we localized and characterized rare surviving Salmonella in mouse spleen using high-resolution whole-organ tomography. In vitro studies suggest various mechanisms of antibiotic persistence, but their in vivo relevance remains unclear because of the difficulty of studying scarce pathogen survivors in complex host tissues. ![]() Persisting pathogens can subsequently cause relapsing diseases. Antimicrobial chemotherapy can fail to eradicate the pathogen, even in the absence of antimicrobial resistance. ![]()
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January 2023
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