Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice

Abstract

Acinetobacter baumannii is increasingly refractory to antibiotic treatment in healthcare settings. As is true of most human pathogens, the genetic path to antimicrobial resistance (AMR) and the role that the immune system plays in modulating AMR during disease are poorly understood. Here we reproduced several routes to fluoroquinolone resistance, performing evolution experiments using sequential lung infections in mice that are replete with or depleted of neutrophils, providing two key insights into the evolution of drug resistance. First, neutropenic hosts acted as reservoirs for the accumulation of drug resistance during drug treatment. Selection for variants with altered drug sensitivity profiles arose readily in the absence of neutrophils, while immunocompetent animals restricted the appearance of these variants. Secondly, antibiotic treatment failure in the immunocompromised host was shown to occur without clinically defined resistance, an unexpected result that provides a model for how antibiotic failure occurs clinically in the absence of AMR. The genetic mechanism underlying both these results is initiated by mutations activating the drug egress pump regulator AdeL, which drives persistence in the presence of antibiotic. Therefore, antibiotic persistence mutations present a two-pronged risk during disease, causing drug treatment failure in the immunocompromised host while simultaneously increasing the emergence of high-level AMR.

Clinical and Genomic Evolution of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections over Two Time Periods at a Tertiary Care Hospital in South India: A Prospective Cohort Study

“…Censoring was not required as all study participants were followed up until death or 30 days. We used STATA 16…”

“…In addition, patients in C2 with CRKp had new risk factors, including chronic liver disease and recent surgery. Recent data support severe immunosuppression, including neutropenia, to promote antimicrobial resistance [16][17][18]. Significant antibiotic pressure in these patients and immunosuppression promotes the survival of persistent bacteria, enabling the development of multidrug resistance.…”

High prevalence of fluconazole resistant Candida tropicalis among candiduria samples in China: An ignored matter of concern

“…Second, azoles were still widely used in clinical treatment of fungal infections and as prophylaxis for highrisk populations (Vardakas et al, 2006;Hicheri et al, 2012;Coussement et al, 2021). Previous study indicated that immunosuppression coupled with antimicrobial stress could result in rapid selection of resistance and expansion of antimicrobialresistant populations in the respiratory tract (Huo et al, 2022). Fluconazole is primarily renal cleared and has high urinary concentration (Lazar and Wilner, 1990), which could become a selective pressure for resistant isolates.…”

Antibiotic Tolerance Indicative of Persistence Is Pervasive among Clinical Streptococcus pneumoniae Isolates and Shows Strong Condition Dependence

“…Clearly, persisters constitute a viable pool that facilitates resistance development by prolonging the presence of viable bacteria during antibiotic treatment ( 26 , 27 ), but various other mechanisms have been suggested ( 6 , 8 , 10 , 26 , 28 ). For example, Windels et al and Huo et al identified that the increased mutation rate in highly persistent strains promotes evolution toward antibiotic resistance ( 6 , 29 ), and Levin-Reisman et al indicated the role of epistasis between antibiotic persistence and resistance mutations ( 28 ).…”