The clinical impression of inordinate selection of resistant mutants to nalidixic acid cannot be substantiated on close scrutiny when sensitive infections are treated at a full dosage of 4 gm/day. When 27 consecutive patients were treated with 4 gm of nalidixic acid per day, resistance developed in the bacteriuric population in only 7%. Moreover, resistance in the fecal reservoir was surprisingly minimal and much less than that reported for sulfonamides, tetracyclines, and ampicillin. The observation is important because multiply-resistant Enterobacteriaceae maintain their sensitivity to nalidixic acid since extrachromosomal R-factor resistance to nalidixic acid has never been demonstrated and cannot be transferred from one organism to another. In vitro data on 100 sensitive strains of Enterobacteriaceae show that the development of resistance to nalidixic acid is inversely proportional to the concentration of nalidixic acid regardless of whether the inoculum size is 105 or 108 bacteria per milliliter. Underdosage (< 4 gm/day) with nalidixic acid is the probable cause of excessive resistance.
(JAMA 236:1857-1860, 1976)
Stamey TA. Resistance to Nalidixic AcidA Misconception Due to Underdosage. JAMA. 1976;236(16):1857-1860. doi:10.1001/jama.1976.03270170023019