Classification of mechanisms of drug resistance

Many organisms and cell types have been shown to be able to develop resistance towards chemicals. A few typical examples are:

• Parasites resistant against anti-parasitic drugs
• Mosquitoes resistant against insecticides
• Bacteria resistant against antibiotics
• Cancer cells resistant against anti-cancer drugs

Extensive studies on the underlying mechanisms of drug resistance have shown that the following mechanisms can be involved.

• Drug target unchanged
  
  • Resistance by exclusion
    • loss of drug accumulation mechanism (decreased import)
    • increased drug elimination (increases export) (e.g. multidrug resistance in cancer cells)
  • Resistance by metabolism
    • active drug converted to an inactive form (e.g. penicillinase, insecticide resistance)
    • prodrug no longer converted to its active form (e.g. resistance to purine analogues in cancer cells)
      
• Alterations in drug target
  • elimination of target (e.g. induction of alternative pathway)
  • alteration of targets' affinity for the drug
  • overproduction of target (e.g. gene amplification)
  • accumulation of metabolite antagonistic to drug (e.g. PABA overproduction by pneumococci)
    

In general development of drug resistance occurs gradually or in several discrete steps. When organisms or cells are exposed to suboptimal and thus sublethal levels of a drug they tend to respond to the stress situation by adaptation involving one or more of the above mentioned mechanisms. In addition to resistance to a single drug, multiple drug resistant malaria is becoming wide spread. The exposure to sub-optimal drug levels through self medication in the management of fever in developing countries is probably one of the most important reasons for the presence of (multiple) drug resistant malaria.

To reduce the risks of development of drug resistance in malaria, chemoprophylaxis and treatment using more than one different drugs, such as the sulphadoxine / pyrimethamine combination of Fansidar, or the combination of chloroquine / paludrine, is absolutely essential. New drugs are not given anymore alon, but only in combination with another one.