Recognize and interpret common pharmacogenomic relationships that affect adverse events and efficacy of medications used in infectious diseases.
Discuss the clinical utility of pharmacogenomics in the management of infectious diseases, particularly antiprotozoal, antifungal, and antiviral agents.
Applying pharmacogenomics in infectious diseases requires consideration of the genomes of the pathogen (e.g., bacteria and virus) and the human host. The pathogen’s genome could be used to identify the antigen, specific infecting organism, and factors that could contribute to antimicrobial resistance. Development of diagnostic microbiology tools and effective vaccines could be enhanced by knowing the portions of a pathogen that are important antigenic determinants. For instance, important genes that confer resistance to antimicrobials can be detected with these assay tests. The information subsequently can be used to select the appropriate antimicrobial treatment for the infection.1 Similarly, the human host’s genome may have susceptibility genes and new drug targets that may be used in the treatment of infectious diseases. Genetic polymorphisms in the human immune system have also been associated with susceptibility to infections and response to antimicrobial treatments.2 Understanding human genomics could lead to informed infectious disease management by knowing how each individual’s genomic variation affects his or her response to the pathogen, antimicrobial agent, or vaccine.
Pharmacogenomics in infectious diseases could provide more accurate results than phenotypic assays that are subject to significant intrinsic variation caused by a large number of external factors that affect bacterial growth and the intrinsic biological variation in the organisms themselves.2 With regard to diagnostic tools, there are nucleic acid testing assays that directly detect resistant bacteria and viral pathogens from clinical samples.1 In infectious diseases, comparative genomics is used to determine the available genome sequences to perform either interspecies or intraspecies comparisons of bacterial genome content or to compare the human genome with those of other model organisms. Furthermore, comparative genomics includes the powerful tools of bioinformatics and microarray technology to identify virulence determinants, antimicrobial drug targets, vaccine targets, and new markers for diagnostics.2 For example, the study of the genome content of Bacillus Calmette-Guérin strains using Mycobacterium tuberculosis was achieved by using microarray-based comparative genomics.3
As was mentioned in Chapter 1, pharmacogenomics involves genes that encode drug-metabolizing enzymes, drug transporters, and drug targets—proteins that might influence drug response. Furthermore, variation in drug response and effects could be associated with pharmacokinetic (PK) factors that influence the concentration of a drug that will reach the therapeutic target. Among the PK factors, genetic variation in the expression and function of drug-metabolizing enzymes (primarily the cytochrome P450 system) can influence the plasma drug concentrations and therapeutic effects. Another genetic factor that may affect individual drug response is the variation in human leukocyte antigen genes,4 such as observed in individuals receiving abacavir, carbamazepine, phenytoin, and allopurinol. For the content of this chapter, only particular anti-infectives and antivirals will be discussed based on the ...