Drug Resistance Types and Classification
Drug resistance is fundamentally classified into two main categories based on timing of development: acquired resistance (developing during treatment due to suboptimal drug exposure or poor adherence) and primary/transmitted resistance (infection with already-resistant organisms), with additional recognition of pre-treatment resistance and naturally occurring resistance in certain pathogen variants.
Core Classification Framework
Primary Classification by Mechanism of Development
Acquired Drug Resistance (ADR): Resistance that emerges in an individual receiving antimicrobial drugs (either as therapy or prevention) with suboptimal dosing or poor adherence, resulting from selection pressure on the pathogen during treatment 1
Primary Resistance: Resistance present in a patient who develops active infection following transmission of drug-resistant organisms, occurring before any drug exposure 1
Transmitted Drug Resistance (TDR): Resistance that occurs when a drug-naïve individual is infected with a drug-resistant pathogen from another person 1
Pre-Treatment Drug Resistance (PDR): Resistance detected at the time of treatment initiation or re-initiation, which may represent either transmitted or acquired resistance (or both), and is particularly concerning from a public health perspective as it exists in individuals who may not know their status and continue transmission 1
Natural/Intrinsic Resistance: Resistance due to pre-existing polymorphisms conferring innate resistance to certain drug classes, such as HIV-2 and HIV-1 groups N and O having natural resistance to first-generation NNRTIs, thymidine analogues, and/or integrase inhibitors 1, 2
Classification by Extent of Resistance
Multidrug Resistance (MDR): Non-susceptibility to at least one agent in three or more antimicrobial categories 3. For tuberculosis specifically, MDR is defined as resistance to both isoniazid and rifampicin, the two most powerful first-line drugs 1, 4
Extensively Drug-Resistant (XDR): Non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (isolates remain susceptible to only one or two categories) 3. For tuberculosis, XDR is defined as resistance to rifampicin, plus any fluoroquinolone, plus at least one priority A drug (bedaquiline or linezolid) 4
Pre-XDR: For tuberculosis, this is MDR-TB with additional resistance to any fluoroquinolone 4
Pandrug Resistance (PDR): Non-susceptibility to all agents in all antimicrobial categories 3
Mechanistic Classification
Six Distinct Molecular Mechanisms
Drug Inactivation: Enzymatic modification or degradation of the antimicrobial agent before it reaches its target 5, 6
Drug Target Alteration: Mutations in the target site that prevent drug binding while maintaining essential function, such as mutations in DNA gyrase or topoisomerase IV (Quinolone-Resistance Determining Regions) for fluoroquinolones 7, 5, 6
Drug Efflux: Active pumping of drugs out of cells through efflux pumps, reducing intracellular drug concentrations 7, 5, 6
DNA Damage Repair: Enhanced repair mechanisms that counteract drug-induced DNA damage 5, 6
Cell Death Inhibition: Alterations in apoptotic pathways that prevent programmed cell death despite drug presence 5, 6
Epithelial-Mesenchymal Transition: Phenotypic changes in cancer cells that confer resistance properties 6
Clinical Context-Specific Classifications
Timing-Based Surveillance Categories
Resistance at Start of Treatment: The proportion of cases whose organisms are resistant to a drug or combination at treatment initiation, calculated separately for previously treated versus treatment-naïve patients 1
Previous Treatment Status: Patients with ≥1 month of combination antimicrobial therapy (excluding preventive chemotherapy) versus those never treated 1
Critical Clinical Pitfalls
Cross-resistance patterns: Resistance mechanisms may confer resistance to multiple drugs within the same class or even across classes, though fluoroquinolones differ structurally from aminoglycosides, macrolides, and β-lactams and may remain active against organisms resistant to these other classes 7
Spontaneous mutation rates: Resistance development through spontaneous mutation is rare (10⁻⁹ to 10⁻¹⁰ for fluoroquinolones), but selection pressure from suboptimal therapy dramatically increases resistance emergence 7
Natural polymorphisms: HIV-2 contains natural polymorphisms conferring innate resistance to first-generation NNRTIs, making resistance testing interpretation algorithms developed for HIV-1 inapplicable 2
Heteroresistance: Tumor cell heterogeneity means that resistant subpopulations may exist before treatment, leading to treatment failure even with initially sensitive disease 6