Abstract
An obstacle to drug development, particularly in this era of multiple drug resistance, is the under-appreciation for the role the host environment plays in microbial response to drugs. With the rise in fungal infection and drug resistance, particularly in individuals with co-morbidities, the influence serum and its components have on antimicrobial susceptibility requires assessment. This study examined the impact of physiologically relevant glucose and insulin levels in the presence and absence of 50 % human plasma on MICs for clinical isolates of Candida lusitaniae, Candida parapsilosis, Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei and Cryptococcus neoformans. The addition of insulin or glucose at physiologic levels in RPMI medium alone altered the MIC in either a positive or negative fashion, depending on the organisms and drug tested, with C. glabrata most significantly altered with a 40, >32- and 46-fold increase in MIC for amphotericin B, itraconazole and miconazole, respectively. The addition of candida-antibody negative plasma also affected MIC, with the addition of glucose and insulin having a tandem effect on MIC. These findings indicate that phenotypic resistance of Candida and Cryptococcus can vary depending on the presence of insulin with glucose and plasma. This modulation of resistance may help explain treatment failures in the diabetic population and facilitate the development of stable drug-resistant strains. Furthermore, these findings indicate the need for a precision approach in the choice of drug treatment and drug development.
Highlights
Phenotypic response to environmental shifts is essential for microbial survival and is of particular importance with respect to changes that occur in vivo, which affect response to antimicrobial agents
The testing of fungal susceptibility in the presence of plasma with and without the supplements glucose and/or insulin to simulate type II diabetes appears warranted in light of their sometimes adverse effect on the Minimum e inhibitory concentrations (MIC) of the antifungal agents
While multiple in vitro studies show that glucose induces phenotypic resistance, the organism is always exposed to glucose in the presence of insulin in vivo [27,30,31]
Summary
Phenotypic response to environmental shifts is essential for microbial survival and is of particular importance with respect to changes that occur in vivo, which affect response to antimicrobial agents. The potential changes in response to drugs upon growth within the host could both be responsible for treatment failures and provide the potential for novel drug development. It is essential to define these phenotypic responses to host factors, and metabolic conditions, to predict effective drug design and utility. A common metabolic condition associated with increased risks for infections is type II diabetes.
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