Fig 5.

Comparative antimicrobial susceptibility profiles of hypermutators and normomutators in Patient 1 (A) and Patient 2 (B) as measured by zone of inhibition in a standard disc diffusion assay highlight increased sensitivities and resistance levels by hypermutators. (A) In Patient 1, hypermutators were significantly more resistant to amikacin (U = 315.5, P = 0.00013), piperacillin-tazobactam (U = 457.5, P = 0.023), and ceftazidime (U = 428, P = 0.0095) than normomutators, although there was no significant difference in the resistance profiles of hyper- and normomutators in regard to meropenem (U = 630, P = 0.69). Hypermutator isolates in Patient 1 displayed ZOI values that were on average 10 times larger for ciprofloxacin (U = 218, P < 0.00001) and >13 times larger for tobramycin (U = 379.5, P = 0.0018) than normomutators, and isolates with both DNA MMR mutations in this population additionally presented ZOI values that were 36 times larger than normomutators for tobramycin (U = 172.5, P < 0.00001), indicating increased sensitivity displayed by hypermutators. (B) In Patient 2, hypermutators displayed increased susceptibility to amikacin (U = 479, P = 0.029), meropenem (U = 194, P < 0.00001), piperacillin-tazobactam (U = 121.5, P < 0.00001), and ciprofloxacin (U = 213.5, P < 0.00001) relative to normomutators. Hypermutators in Patient 2 were more resistant to ceftazidime (U = 417.5, P = 0.0045). There was no statistically significant difference between the tobramycin susceptibility profiles of hyper- and normomutators in this population (U = 634.5, P = 0.61). (*) indicates P ≤ 0.05, (**) indicates P ≤ 0.01, (***) indicates P ≤ 0.001, and (****) indicates P < 0.0001 in a Mann-Whitney U test. Clinical thresholds for resistance to amikacin, meropenem, piperacillin-tazobactam, ciprofloxacin, tobramycin, and ceftazidime as determined by the CLSI are 14, 15, 14, 18, 12, and 14 mm, respectively. Clinical thresholds for sensitivity to these antimicrobials are 17, 19, 21, 25, 15, and 18 mm, respectively.