abstract

Antibiotic and antiviral resistance represents a major and continually evolving challenge to infectious disease management. The progressive reduction in antimicrobial effectiveness is associated with genetic variation, selective pressure, inappropriate antimicrobial exposure, pathogen adaptation, transmission of resistant organisms and viruses, and limitations in the development of new therapeutic agents. Although individual antimicrobial agents remain essential components of modern medicine, their prolonged use can provide opportunities for resistant subpopulations to emerge and expand. Combination therapy has therefore attracted considerable attention as a strategy for increasing therapeutic effectiveness while potentially reducing the probability and speed of resistance development.

The present paper examines combination therapy as a resistance-management strategy across bacterial and viral infections, with particular emphasis on molecular mechanisms, therapeutic potential and implications for antimicrobial drug development. The study integrates evidence from antimicrobial pharmacology, molecular microbiology, virology, drug-discovery research and resistance biology. The analysis considers several mechanisms through which combinations may produce beneficial effects, including simultaneous inhibition of independent targets, sequential blockade of a biological pathway, enhancement of intracellular drug accumulation, inhibition of resistance enzymes, interference with compensatory pathways, and reduction of the probability that a pathogen can simultaneously acquire multiple resistance determinants. Combination therapy is also considered in relation to pharmacodynamic synergy, antagonism, additive activity, collateral sensitivity and evolutionary selection.

For antibiotics, combinations involving agents with complementary mechanisms may be particularly useful against multidrug-resistant bacteria, although inappropriate combinations can produce antagonism, toxicity or unnecessary selection pressure. In antiviral therapy, combinations can inhibit different stages of the viral life cycle or target distinct viral proteins, thereby limiting the opportunity for a single mutation to confer clinically meaningful resistance. The paper further examines the incorporation of combination strategies into modern drug-development pipelines through target selection, in-vitro synergy testing, pharmacokinetic/pharmacodynamic modelling, molecular docking, artificial intelligence, resistance forecasting and genomic surveillance.