Repeated Exposition to Subinhibitory Concentrations of Antibiotic in vitro Readily Decreases Susceptibility of <i>Neisseria gonorrhoeae </i>to Rifampicin, but Not to New Cephalosporins and Penicillin G

Abstract

Repeated subcultivation of Neisseria gonorrhoeae in the presence of subinhibitory concentrations of antibiotic has turned out as a reliable model to predict the low potential for development of resistance with respect to the beta-lactam antibiotic penicillin. Before large-scale introduction of the new cephalosporins we exposed 5 N. gonorrhoeae strains of different susceptibility to penicillin repeatedly to subinhibitory concentrations of cefotiam, ceftizoxime, rifampicin and penicillin G incorporated into chocolate agar. Each time the most resistant representatives of a strain were propagated, on the whole 25 times. While resistance to rifampicin increased readily (all strains became relatively resistant, MIC = 4 μg/ml),the same was not true of the cephalosporins. Although their susceptibility decreased, too, no strain acquired partial or even total resistance (final MIC ≤0.128 with cefotiam and ceftizoxime). The cephalosporins thus rather parallelled penicillin G which hardly induced any increase of resistance. Thus, a quick loss of clinical efficacy need not be feared after large-scale introduction of the new cephalosporins into the therapy of gonorrhea.

The population dynamics of antimicrobial chemotherapy

“…where h(C) is defined to mean b Ϫ x Ϫ f(C), and all other variables are as stated in Theory. This prediction is consistent with the frequent observation that growth of bacteria in subinhibitory concentrations can select effectively for resistant mutants (5,6,16,23,30,32,52). The model predicts that such selection will be most efficient at an intermediate rate of antibiotic-mediated killing.…”

Impact of Antimicrobial Dosing Regimen on Evolution of Drug Resistance In Vivo: Fluconazole andCandida albicans

“…The association between dosing and resistance emergence observed in the current investigation is disparate from that described for antimicrobial compounds with cidal killing characteristics. The inhibitory or static antimicrobial activity of the triazole compounds may explain these differences.The rapid development and spread of antimicrobial resistance has become an increasingly serious public health problem in a wide range of infectious diseases (3,28,29,37,38,44,45,53,58). New drugs for the treatment of these resistant infections are unlikely to appear soon enough and in sufficient numbers to solve many of the resistance problems.…”

“…However, the relationship in the context of use pattern and resistance development is complex and remains, for the most part, undefined. One dosing regimen approach that has been shown to reduce the amplification of resistant strains involves the use of large, infrequent doses of antimicrobials to eliminate not only the susceptible populations but also any resistant mutants (7,13,15,18,25,26,28). The success of this dosing strategy has been demonstrated with a few antimicrobial drug class-organism combinations in which antimicrobial drugs exhibit extensive organism killing or "cidal" activity.…”