How to balance between the antibiotic drug resistance AND drug related adverse effects during anti-infective therapy. Is there any role for Pharmacogenetics ?

Antibiotics are generally associated with side effects, that are usually tolerated because of higher benefit than that of risk. Resistance to antibiotic drugs has been dramatically increased in the last two decades and remains a concern of patient safety specially in patients in the intensive care unit. Few micro-organisms were found to have intrinsic ability to develop high levels of resistance or may even spread in patients as a result of poor practices in infection control. In the microorganism there could be genes of polygenetic origin which may vary a lot and acts as resistance gene when exposed to antibiotics. It is unrealistic to think of removal of this gene pool. A major reason for the resistance to antimicrobial is the irrational use of antibiotics. Fundamentally, the antimicrobial resistance development may often be considered as an adverse drug event. Increase in antimicrobial resistance may cause the exacerbation of the severe infection and associated adverse events. Evidence indicated that the different environment in the host and antibiotic treatment in the host can increase the resistance to antibiotics causing the ineffective treatment; for example the mutant Pseudomonas aeruginosa from the patients suffering from systic fibrosis (Oliver et al., 2000). Further, the evaluation of resistance to specific antimicrobial agent may often accompanied by the resistance to other multiple antimicrobial agents causing collateral hypersensitivity and ineffectiveness of the treatment. In this context, microbiological testing of antibiotic resistance by segregating the bacterial strains into categories of non-treatable and treatable gives guidance to practitioners with respect to the potential use of therapeutic agents in patient treatments. By this mean, unnecessary exposure of microbes towards the antibiotics is stopped. -------------------------------------------------------------------------------------------------------------------- In developed countries, antibiotic stewardship programs aiming for the improvement of the appropriate utilization of antibiotics and reduce antibiotic resistance, have also been shown to be effective in hospital settings. In Australia, utilization of antibiotics in hospitals is monitored by the federally-funded National Antimicrobial Utilisation Surveillance Program (McKenzie et al., 2013). Data generated from the surveillance report helps to analyse the trend of antibiotic usage. Recent progress on the bacterial ecogenetics and pharmacogenetics in combination with bioinformatics and system biology may play a bigger role for understanding the resistance mechanism and eventually reducing the adverse events caused by the antibiotics. Pharmacogenetic and basic research revealed new antimicrobial peptides and gave options for breaking the resistance using the old drug in new ways. The host-directed targeting of drug emerge to avoid the resistance (Dandekar and Dandekar, 2010). One of the finest examples of pharmacogenetic or pharmacogenomic application is the explanation of the ototoxicity in chronic use of aminoglycosides which is caused by genetic mutation among other contributing factors. It was found that the mutation of mitochondrial 12sRNA was associated with aminoglycoside-induced sensorineural deafness (Aung et al., 2014). This information helped the clinicians to decide the use of aminoglycoside in case there is any family history of hearing loss. It is worth to mention that the pharmacogenetic application has led the clinician to choose the appropriate proton pump inhibitor and right dosing strategy for eradication of H. pylori by overcoming the effect of CYP2C19 genotype. Therefore, there could be enormous opportunities in pharmacogenetic domain to understand the pathogenesis of infections, interactions between the host and microbes, for antibiotics that are efficacious, circumvent to resistance and also with lesser adverse events. -------------------------------------------------------------------------------------------------------------------- AUNG, A. K., HAAS, D. W., HULGAN, T. & PHILLIPS, E. J. 2014. Pharmacogenomics of antimicrobial agents. Pharmacogenomics, 15, 1903-1930. DANDEKAR, T. & DANDEKAR, G. 2010. Pharmacogenomic strategies against microbial resistance: from bright to bleak to innovative. Pharmacogenomics, 11, 1193-6. MCKENZIE, D., RAWLINS, M. & DEL MAR, C. 2013. Antimicrobial stewardship: what’s it all about? OLIVER, A., CANTÓN, R., CAMPO, P., BAQUERO, F. & BLÁZQUEZ, J. 2000. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science, 288, 1251-1253.

Posted On:12/11/2019

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