In Vitro Resistance Selection in Shigella flexneri by Azithromycin, Ceftriaxone, Ciprofloxacin, Levofloxacin, and Moxifloxacin

Abstract

Shigella flexneri continues to be a major cause of diarrhea-associated illness, and increasing resistance to first-line antimicrobials complicates the treatment of infections caused by this pathogen. We investigated the pharmacodynamics of current antimicrobial treatments for shigellosis to determine the likelihood of resistance promotion with continued global antimicrobial use. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, ciprofloxacin, levofloxacin, and moxifloxacin against a wildtype strain of S. flexneri (ATCC 12022) and an isogenic gyrA mutant (m-12022). Timekill assays were performed to determine antimicrobial killing. Concentrations of approved doses of ciprofloxacin, levofloxacin, and moxifloxacin are predicted to surpass the MPC for a majority of the dosage interval against ATCC 12022. However, against m-12022, concentrations of all fluoroquinolones are predicted to fall below the MPC and remain in the MSW for a majority of the dosage interval. Concentrations of ceftriaxone fall within the MSW for the majority of the dosage interval for both strains. All agents other than azithromycin displayed bactericidal activity in time-kill assays. Results of pharmacodynamic analyses suggest that all tested fluoroquinolones would achieve a favorable area under the concentration-time curve (AUC)/MPC ratio for ATCC 12022 and would restrict selective enrichment of mutants but that mutant selection in m-12022 would be likely if ciprofloxacin were used. Based on pharmacodynamic analyses, azithromycin and ceftriaxone are predicted to promote mutant selection in both strains. Confirmation of these findings and examination of novel treatment regimens using in vivo studies are warranted.KEYWORDS Shigella flexneri, mutant prevention concentration, mutant selection window T he pathogenic bacterium Shigella flexneri is a major cause of dysentery and related morbidity and mortality worldwide, particularly in children less than 5 years of age in developing countries and travelers returning from tropical areas. In the 1990s, the number of annual cases of shigellosis worldwide was approximately 164.7 million, with 1.1 million resulting in death (1). Data from 2014 demonstrated an average of 5.81 cases per 100,000 individuals in the United States (2). The treatment of shigellosis has been complicated by the emergence of strains of S. flexneri that are resistant to many antimicrobials, including former first-line treatment options such as ampicillin, chloramphenicol, tetracyclines, and trimethoprim-sulfamethoxazole (SXT) (1). Current treatment guidelines for infectious diarrhea from the Infectious Diseases Society of America, published in 2001, recommend SXT, a fluoroquinolone (ofloxacin, norfloxacin, or ciprofloxacin), ceftriaxone, or azithromycin (3). In guidelines published by the WHO in 2005, ciprofloxacin was considered the first-line treatment for shigellosis, with ceftriaxone and azithromycin considered to be alternative therapies (4). Howe...

Drug Combinations to Prevent Antimicrobial Resistance: Some Correlations, Rules and Laws, and a Preliminary Scheme

“…These data pairs include the MIC and the corresponding MPC, of various antimicrobial agents with different classes against representative pathogenic bacteria, and shown in Table S5. After this, using another forty-six data pairs (MIC, MPC) (Table S6) reported from other papers [38][39][40][41][42], this correlation was further verified by comparison the calculated MPC with the tested one.…”

“…Thereby, we can simultaneously use equations ( 7) and ( 8), or other equations established like similar method, to quickly and complementarily predict the rough MPCs from the MIC as references when need. This was further verified by another forty-six data pairs (MIC, MPC) (Table S6) from another five papers [38][39][40][41][42], with an acceptable probability of 91.3%. Conversely, the larger prediction accuracy further confirmed that the MPC of an antimicrobial agent can be roughly calculated from its corresponding MIC.…”

Drug Combinations to Prevent Antimicrobial Resistance: Some Correlations and Laws, and their Verifications, thus Proposing Some Principles and a Preliminary Scheme

“…Thereby, we can simultaneously use equations ( 7) and (8), or other equations established like similar method, to quickly and complementarily predict the rough MPCs from the MIC as references when need. This was further verified by another forty-six data pairs (MIC, MPC) (Table S7) from another five papers [42][43][44][45][46], with an acceptable probability of 91.3%. Conversely, the larger prediction accuracy further confirmed that the MPC of an antimicrobial agent can be roughly calculated from its corresponding MIC.…”

Evaluation of Shigella Species Azithromycin CLSI Epidemiological Cutoff Values and Macrolide Resistance Genes

“…It has been recommended by the American Academy of Pediatrics for treatment of shigellosis in children and by the World Health Organization as a second-line treatment in adults. However, recent reports have suggested that there are Shigella isolates that are not susceptible to azithromycin (4,9,10).…”