Re: noninherited resistance

[Guest guest]

Also:

http://jac.oxfordjournals.org/cgi/content/abstract/59/2/254

The results here with E coli and rifampin are markedly different than

what you'd see with MTB. Rifampin at clinical concentrations is a

potent killer of nongrowing MTB.

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Antibiotic treatment in vitro of phenotypically tolerant bacterial

populations

Camilla Wiuff* and Dan I. Andersson

Department of Medical Biochemistry and Microbiology, Uppsala

University Box 582, S-751 23 Uppsala, Sweden

Received 2 August 2006; returned 4 October 2006; revised 19 October

2006; accepted 21 October 2006

*Correspondence address. Health Protection Scotland, Section for HAI &

IC, 1 Cadogan Square, Cadogan Street, Glasgow G2 7HF, UK. Tel:

+44-141-2822927; Fax: +44-141-8470399; E-mail:

camilla.wiuff@...

Objectives: Most pharmacodynamic models used for design of treatment

regimens are based on time–kill data obtained with normal cells in the

susceptible state without taking into account the killing kinetics of

the antibiotic-tolerant cells in the population. We compared the

microbiological efficacy of six antibiotics against tolerant cells and

by mathematical modelling explored the potential clinical implications

of tolerance.

Methods: Tolerant cells were obtained by filtration of bacterial

cultures of Escherichia coli MG1655 after antibiotic exposure. Killing

kinetics of the tolerant cells was compared with that of exponentially

growing naive cells. To examine the nutrient dependency of the

reversion from the tolerant state to the susceptible state, tolerant

cells were re-suspended in Luria–Bertani and PBS and re-exposed to

antibiotics. A mathematical model was used to explore the clinical

implications of antibiotic tolerance.

Results: Streptomycin was the most efficient drug against tolerant

cells. Ciprofloxacin and ampicillin had intermediate activity against

tolerant cells while rifampicin, tetracycline and erythromycin had

poor activity against tolerant cells. No correlation could be

established between the microbiological efficacies against susceptible

and tolerant cells. Reversion from tolerance to susceptibility was

dependent on the presence of nutrients and growth. Computer

simulations demonstrated that the efficacy of antibiotics against

tolerant cell populations has a large influence on treatment outcome.

Conclusions: The in vitro killing kinetics of tolerant cells is

antibiotic-dependent and different from that of cells in the

susceptible state. This difference in efficacy could have an influence

on treatment outcome and tolerance should therefore be studied further

in vivo.