Avoid Rounds of Treatment Interspersed with Pathogen Outgrowth

To this point in the chapter, we have focused on situations in which resistance arrives with the infecting pathogen, essentially from the outside. Emergence of resistance within a given person is a different issue. In some cases, such as treatment of syphilis with penicillin, resistance emerges rarely if at all, and one need dose only high enough to remove symptoms. In other situations, dosing strategies need to block mutant growth. For example, azithromycin was thought to be effective as a single-dose treatment with syphilis,290 but resistance to azithromycin is now a growing problem.291 With tuberculosis, half of the patients treated only with streptomycin or isoniazid develop drug-resistant infection. HIV-positive patients with tuberculosis develop rifapentine resistance, and those with MDR tuberculosis develop fluoroquinolone resistance. At the beginning of Chapter 5, “Emergence of Resistance,” we discussed a case of oxacillin-resistant, vancomycin-nonsusceptible S. aureus, and in Chapter 10, “Restricting Antibiotic Use and Optimizing Dosing,” we described patients who acquired rifampicin-resistant S. aureus when treated for tuberculosis. In the latter study, genetic analyses pointed strongly to susceptible bacterial populations becoming resistant in the patients during treatment. Other cases exist with fluoroquinolone-resistant pneumococci.104 Thus, the principles of mutant amplification apply to a broad range of pathogen-antibiotic combinations.

A key is to avoid treatment interspersed with periods of pathogen population expansion. With each successive treatment episode, the resistant fraction of the pathogen population increases. Eventually, the disease may become untreatable by that antibiotic. (In the laboratory, gradual enrichment of mutant subpopulations is easily seen after repeated treatment, dilution, growth of survivors, and retreatment.) In humans, mutant enrichment is common in patients with uncontrolled HIV infection who are treated for recurring bacterial and fungal infections. Gradual mutant enrichment is also seen during treatment of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. These bacteria cannot be completely removed, and eventually resistance emerges to one drug after another. With other diseases, enrichment of resistant mutants over many years of recurring infection is not well documented, but we may not have looked hard enough for it.

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