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Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model.
J Antimicrob Chemother. 2011 Jul; 66(7):1537-46.JA

Abstract

OBJECTIVES

Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI.

METHODS

MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations.

RESULTS

Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing.

CONCLUSIONS

Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid.

Authors+Show Affiliations

Microbiology, University of Leeds and Leeds Teaching Hospitals, Leeds General Infirmary, Old Medical School, Leeds LS1 3EX, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21504940

Citation

Baines, Simon D., et al. "Evaluation of Linezolid for the Treatment of Clostridium Difficile Infection Caused By Epidemic Strains Using an in Vitro Human Gut Model." The Journal of Antimicrobial Chemotherapy, vol. 66, no. 7, 2011, pp. 1537-46.
Baines SD, Noel AR, Huscroft GS, et al. Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model. J Antimicrob Chemother. 2011;66(7):1537-46.
Baines, S. D., Noel, A. R., Huscroft, G. S., Todhunter, S. L., O'Connor, R., Hobbs, J. K., Freeman, J., Lovering, A. M., & Wilcox, M. H. (2011). Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model. The Journal of Antimicrobial Chemotherapy, 66(7), 1537-46. https://doi.org/10.1093/jac/dkr155
Baines SD, et al. Evaluation of Linezolid for the Treatment of Clostridium Difficile Infection Caused By Epidemic Strains Using an in Vitro Human Gut Model. J Antimicrob Chemother. 2011;66(7):1537-46. PubMed PMID: 21504940.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model. AU - Baines,Simon D, AU - Noel,Alan R, AU - Huscroft,Grace S, AU - Todhunter,Sharie L, AU - O'Connor,Rachael, AU - Hobbs,Joanne K, AU - Freeman,Jane, AU - Lovering,Andy M, AU - Wilcox,Mark H, Y1 - 2011/04/18/ PY - 2011/4/21/entrez PY - 2011/4/21/pubmed PY - 2011/9/29/medline SP - 1537 EP - 46 JF - The Journal of antimicrobial chemotherapy JO - J Antimicrob Chemother VL - 66 IS - 7 N2 - OBJECTIVES: Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI. METHODS: MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations. RESULTS: Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing. CONCLUSIONS: Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/21504940/Evaluation_of_linezolid_for_the_treatment_of_Clostridium_difficile_infection_caused_by_epidemic_strains_using_an_in_vitro_human_gut_model_ L2 - https://academic.oup.com/jac/article-lookup/doi/10.1093/jac/dkr155 DB - PRIME DP - Unbound Medicine ER -