MILLER K, O'NEILL AJ, CHOPRA I; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. C1-965.
Antimicrobial Research Centre, Leeds, United Kingdom
BACKGROUND: Hypermutable sub-populations exhibiting up to 1000-fold increase in mutation frequency occur in several bacterial pathogens, including Escherichia coli and Pseudomonas aeruginosa. Emergence of resistance during chemotherapy is likely to be greatest at trough (C[min]) drug concentrations. Using E. coli as a model we determined whether hypermutators have increased potential to develop antibiotic resistance when drug concentrations fall to C[min] during therapy. E. coli hypermutators were exposed to various drugs used to treat UTIs at estimated C[min] concentrations achieved within man. METHODS: Mutation frequencies were determined for a parental E. coli K-12 strain and uvrD, mutS and mutH derivatives in MH agar containing expected serum and urine C[min] drug concentrations for healthy patients and those with renal failure (RF). Mutation frequencies were determined aerobically and anaerobically to trimethoprim (TMP), sulfamethoxazole (SMX), cefotaxime (CTX), tetracycline (TET) and gentamicin (GNT). RESULTS: Mutation frequencies to TMP and GNT were ~ 30x higher in hypermutators than in the parent at expected serum C[min] in healthy and RF patients under aerobic conditions, increasing to 150x higher for TMP anaerobically. Mutants were selected aerobically at expected CTX urinary C[min] in RF patients and anaerobically for GNT at urinary C[min] in healthy patients. However, mutation frequencies for resistance to these drugs were not elevated in hypermutable hosts. Antibiotic-resistant mutants were not recovered from any strain for the other drugs (TET, SMX) at expected serum or urinary C[min] in healthy or RF patients. CONCLUSIONS: At expected serum C[min] for GNT and TMP, hypermutable strains are at an advantage since drug-resistant mutants are selected at higher frequencies than in non-hypermutable hosts. However, for other antibiotics a hypermutable phenotype produces no significant increase in resistant mutants at drug concentrations achievable within the body, even at the C[min].
Publication Types:
Keywords:
- Anti-Bacterial Agents
- Cefotaxime
- Chromosomes
- Escherichia coli
- Escherichia coli Infections
- Humans
- Male
- Mutation
- Pseudomonas aeruginosa
- Selection (Genetics)
- Sulfamethoxazole
- Trimethoprim
- Urinary Tract Infections
- genetics
- microbiology
Other ID:
UI: 102267041
From Meeting Abstracts