Shigella flexneri, the etiological agent responsible for dysentery, exerts a significant global impact. While antimicrobials such as ampicillin, chloramphenicol and TMP-SMX have been used to treat this infection in the past, their efficacy has been diminished by resistance. 2001 IDSA guidelines recommended TMP-SMX, fluoroquinolones, ceftriaxone or azithromycin for treatment; however the susceptibility profiles continue to evolve as resistance to third generation cephalosporins increases. Therefore a study to evaluate the pharmacodynamics of current antimicrobials against Shigella－all the while maintaining efficacy without development of resistance－to ensure optimal treatment regimens was performed,

The antimicrobials tested included three fluoroquinolones (levofloxacin, ciprofloxacin, moxifloxacin) as well as azithromycin, and ceftriaxone. The mutant prevention concentration (MPC), and mutant selection window (MSW) were measured against a wild-type strain of S. flexneri (ATCC-12022) and a gyrA mutant (m-12022). When antimicrobial concentrations are found within the MSW range it indicates promotion of resistance. Time-kill assays were also performed against ATC 12022 as well as against a gyrA mutant selected through levofloxacin exposure.

Results confirmed that according to CLSI standards, both Shigella strains were susceptible to levofloxacin, ciprofloxacin and ceftriaxone. In regard to the pharmacodynamic evaluation, azithromycin was the only agent tested that did not achieve concentrations above the MIC. Ceftriaxone concentrations were within the MSW 69% of the time for ATC-12022 and 98% for the m-12022. Ciprofloxacin, moxifloxacin and levofloxacin exceeded MPC against the ATC-12022 for 100, 100, 87% of the dosage interval, respectively. However, against the resistant mutant m-12022, concentrations of all fluoroquinolones fell below the MPC and were within the MSW for the majority of the dosage interval. Only levofloxacin and moxifloxacin achieved AUC/MPC values predicting prevention of resistance development.

Based on these results azithromycin and ceftriaxone are predicted to promote mutant selection in both strains. Researchers noted that if a 750 mg dose of levofloxacin was used, an AUC/MPC ratio of 125 and 31 would be achieved for ATC-12022 and m-12022 respectively. This lower risk of resistance selection against both strains indicates a need to investigate levofloxacin administration in patients with shigellosis.

PMID: 28483960

Antimicrob Agents Chemother. 2017 Jun 27;61(7). pii: e00086-17. doi: 10.1128/AAC.00086-17. Print 2017 Jul.

Source: https://www.ncbi.nlm.nih.gov/pubmed/28483960?dopt=Abstract