Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure

Abstract

Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host–pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

Ability of Bicarbonate Supplementation to Sensitize Selected Methicillin-ResistantStaphylococcus aureus(MRSA) Strains to β-Lactam Antibiotics in anEx VivoSimulated Endocardial Vegetation Model

“…The current study extends our previous work on the ability of NaHCO 3 supplementation of standard MRSA in vitro media to identify a sub-set of MRSA strains that may, in fact, exhibit β-lactam susceptibility (14, 22, 23). The notion of employing alternative media for antibiotic susceptibility screening is not new; however, the biological basis and clinical utility of this approach has substantially increased in the last few years.…”

“…For example, Kubicek-Sutherland et al mimicked the intracellular conditions of the macrophage phagosome in which Salmonella resides, using a mildly acidic and phosphate/magnesium-poor culture medium. Their study revealed that when Salmonella were grown in this media, antimicrobial susceptibility profiles emerging from this scenario were better predictors of treatment outcomes in murine bacteremia models than more traditional susceptibility testing strategies (23). Similar studies using Acinetobacter and staphylococci grown in Dulbecco Modified Eagles Medium (DMEM) or RPMI were better predictors of in vivo treatment outcomes, when compared to standard susceptibility testing modalities (13, 15).…”

Antimicrobial peptide exposure selects forStaphylococcus aureusresistance to human defence peptides

“…56,57 The host–pathogen interactions involved in the transition of S. aureus from a commensal organism to an invasive pathogen are complex and not yet fully characterized. It is known that host AMPs provide a significant barrier to S. aureus colonization in humans.…”

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…All of these components modulate various pathways and are mainly causative for the altered in vivo efficiency of antibiotics. [69,[71][72][73][74] Efforts were made to mimic in vivo conditions during in vitro AST to account for this contextual antibiotic susceptibility.Astraightforward and very effective approach is the substitution of common rich laboratory medium with minimal medium. [75,76] Ar ecent study by Ersoy et al revealed that the antibiotic susceptibility of various clinical isolates strongly depends on the medium used for in vitro cultivation.…”