Antimicrobial Resistance Mechanisms

Antimicrobial resistance is the ability of a microorganism to grow at drug concentrations that would normally inhibit it. It is intrinsic when a species lacks the drug target or cannot take up the drug (for example Enterococcus and cephalosporins, Klebsiella and ampicillin, Pseudomonas aeruginosa and ceftriaxone). It is acquired when a normally susceptible organism gains a resistance trait by mutation or by horizontal gene transfer.

Genetic routes. Mutation under selection (rpoB for rifampicin, gyrA and parC for fluoroquinolones); transfer of plasmids, transposons and integrons by conjugation, which carry several genes at once (ESBL, aminoglycoside, fluoroquinolone and sulphonamide resistance together); transformation and transduction. Selection pressure from any antibiotic, in humans, animals and the environment, favours resistant strains.

Biochemical mechanisms. Enzymatic destruction or modification of the drug; alteration or replacement of the target; reduced entry through porin loss; active efflux; target protection; metabolic bypass of the inhibited step.

Related phenomena. Heteroresistance (a resistant subpopulation within a susceptible isolate), tolerance (survival without a rise in MIC), persisters, and biofilm protection all cause treatment failure without a resistant test result.

Using resistance knowledge.

• Read the local antibiogram before choosing empirical therapy; resistance varies by hospital, ward, community and country.
• Know intrinsic resistance so that a reported susceptible result for an intrinsically resistant pair is not trusted.
• Use phenotypic tests as signals: a positive D-test (erythromycin-induced clindamycin resistance), cefoxitin resistance in S. aureus (MRSA), ceftriaxone resistance in E. coli or Klebsiella (suspect ESBL), carbapenem non-susceptibility (test for carbapenemase type).
• Inducible AmpC organisms (Enterobacter cloacae complex, Klebsiella aerogenes, Citrobacter freundii, Serratia, Morganella) can become resistant to third generation cephalosporins during treatment even if reported susceptible initially.
• Use targeted or rapid molecular testing for carbapenemase genes (KPC, NDM, OXA-48, VIM, IMP), because the choice of drug depends on the enzyme.

Containing resistance. Hand hygiene, contact precautions for MRSA, VRE, CRE and CRAB, screening of high-risk patients, antimicrobial stewardship with the shortest effective course, narrowest effective drug, and prompt de-escalation.

Drivers. Unnecessary or prolonged prescribing, under-dosing, over-the-counter sale, falsified or substandard products, poor sanitation and water, crowded hospitals, agricultural use, and international travel. In East Africa several of these coexist, and local surveillance data should drive empirical choices.

Consequences. Longer illness, treatment failure, higher mortality, use of more toxic or costly drugs (colistin, aminoglycosides), and loss of prophylaxis for surgery and chemotherapy.

Monitoring. Culture and susceptibility results interpreted with the clinical picture; surveillance antibiograms updated yearly; screening swabs in outbreaks and for transfer from high-prevalence settings; review of therapy at 48 to 72 hours.

Special groups. Neonates, immunosuppressed patients and patients in intensive care are most exposed to resistant organisms and need early culture and rapid de-escalation. Pregnant and breastfeeding patients are limited to fewer options, so resistance restricts treatment more sharply.