Display options
Cite
Chesdachai S, Rajasingham R, Nicol MR, et al. Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model. Open Forum Infect Dis. 2019;6(10)doi: 10.1093/ofid/ofz369.
Chesdachai, S., Rajasingham, R., Nicol, M. R., Meya, D. B., Bongomin, F., Abassi, M., Skipper, C., Kwizera, R., Rhein, J., & Boulware, D. R. (2019). Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model. Open forum infectious diseases, 6(10), . https://doi.org/10.1093/ofid/ofz369
Chesdachai, Supavit, et al. "Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model." Open forum infectious diseases vol. 6,10 (2019). doi: https://doi.org/10.1093/ofid/ofz369
Chesdachai S, Rajasingham R, Nicol MR, Meya DB, Bongomin F, Abassi M, Skipper C, Kwizera R, Rhein J, Boulware DR. Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model. Open Forum Infect Dis. 2019 Oct 01;6(10). doi: 10.1093/ofid/ofz369. PMID: 31420668; PMCID: PMC6767974.
Copy Download .nbib Format: NLM
Share it on

Open Forum Infect Dis. 2019 Oct 01;6(10). doi: 10.1093/ofid/ofz369.

Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model.

Open forum infectious diseases

Supavit Chesdachai, Radha Rajasingham, Melanie R Nicol, David B Meya, Felix Bongomin, Mahsa Abassi, Caleb Skipper, Richard Kwizera, Joshua Rhein, David R Boulware

Affiliations

  1. Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
  2. College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
  3. Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.
  4. Department of Medical Microbiology and Immunology, Faculty of Medicine, Gulu University, Gulu, Uganda.

PMID: 31420668 PMCID: PMC6767974 DOI: 10.1093/ofid/ofz369

Abstract

BACKGROUND: Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100mg to 2000mg/day have been used. Prevalence of fluconazole non-susceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentration and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy.

METHODS: First, we conducted a systematic review using MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Second, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg/day coupled with fluconazole's known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100mg to 2000mg via linear regression. Third, the fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review.

RESULTS: We summarized 21 studies with 11,049 clinical Cryptococcus isolates. MICs were normally distributed with geometric mean of 3.4 μg/mL, median (MIC50) of 4 μg/mL, and 90th percentile (MIC90) of 16 μg/mL. The median MIC50 trended upwards from 4 μg/mL in 2000-2012 to 8 μg/mL in 2014-2018. Predicted sub-therapeutic fluconazole concentrations (below MIC) would occur in 40% with 100mg, 21% with 200mg, and 9% with 400mg. AUC/MIC ratio >100 would occur in 53% for 400mg, 74% for 800mg, 83% for 1200mg, and 88% for 1600mg.

CONCLUSIONS: Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.

© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Keywords: Cryptococcus ; Cryptococcal meningitis; Fluconazole; Fungal drug resistance; Systematic review

References

  1. N Engl J Med. 2014 Jun 26;370(26):2487-98 - PubMed
  2. Med Mycol. 2008 Jun;46(4):393-5 - PubMed
  3. N Engl J Med. 1997 Jul 3;337(1):15-21 - PubMed
  4. Mycoses. 2007 Jan;50(1):25-30 - PubMed
  5. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):e101-8 - PubMed
  6. Jpn J Antibiot. 1989 Jan;42(1):17-30 - PubMed
  7. HIV Med. 2010 Apr;11(4):276-81 - PubMed
  8. PLoS Med. 2010 Dec 21;7(12):e1000384 - PubMed
  9. AIDS. 2013 Aug 24;27(13):2089-99 - PubMed
  10. J Infect Dis. 1995 Aug;172(2):599-602 - PubMed
  11. Mycoses. 2016 Jun;59(6):351-6 - PubMed
  12. Lancet Infect Dis. 2016 Jul;16(7):809-818 - PubMed
  13. Diagn Microbiol Infect Dis. 2011 Nov;71(3):252-9 - PubMed
  14. Clin Infect Dis. 2014 Mar;58(5):736-45 - PubMed
  15. Med Mycol. 2013 Apr;51(3):261-9 - PubMed
  16. Antimicrob Agents Chemother. 2013 Jun;57(6):2793-800 - PubMed
  17. J Med Microbiol. 2018 Jan;67(1):87-96 - PubMed
  18. Lancet Infect Dis. 2019 Aug;19(8):843-851 - PubMed
  19. Clin Pharmacokinet. 1993 Jan;24(1):10-27 - PubMed
  20. Clin Infect Dis. 1999 Feb;28(2):291-6 - PubMed
  21. J Antimicrob Chemother. 2016 Dec;71(12):3599-3606 - PubMed
  22. PLoS Med. 2012;9(9):e1001316 - PubMed
  23. BMC Infect Dis. 2018 Dec 12;18(1):643 - PubMed
  24. Lancet Infect Dis. 2016 Oct;16(10):1111-1112 - PubMed
  25. Mycoses. 2018 May;61(5):290-297 - PubMed
  26. Antimicrob Agents Chemother. 2017 Dec 21;62(1): - PubMed
  27. Clin Infect Dis. 2010 Feb 1;50(3):291-322 - PubMed
  28. Antimicrob Agents Chemother. 2018 Aug 27;62(9): - PubMed
  29. HIV Med. 2018 Jul;19(6):e64-e65 - PubMed
  30. Antimicrob Agents Chemother. 1985 Nov;28(5):648-53 - PubMed
  31. Antimicrob Agents Chemother. 2000 Jun;44(6):1544-8 - PubMed
  32. Mycoses. 2017 Jan;60(1):40-50 - PubMed
  33. J Antimicrob Chemother. 2019 Mar 1;74(3):768-771 - PubMed
  34. J Clin Microbiol. 2010 Feb;48(2):539-44 - PubMed
  35. Antimicrob Agents Chemother. 2012 Nov;56(11):5898-906 - PubMed
  36. Med Mycol. 2018 Nov 1;56(8):963-971 - PubMed
  37. Clin Infect Dis. 1996 Feb;22(2):322-8 - PubMed
  38. Open Forum Infect Dis. 2015 Dec 28;2(4):ofv157 - PubMed
  39. Mycoses. 2011 Sep;54(5):e438-42 - PubMed
  40. Antimicrob Agents Chemother. 1993 Jun;37(6):1383-6 - PubMed
  41. N Engl J Med. 2018 Mar 15;378(11):1004-1017 - PubMed
  42. Med Mycol. 2017 Aug 1;55(6):680-685 - PubMed
  43. Antimicrob Agents Chemother. 2015 Dec;59(12):7197-204 - PubMed
  44. Antimicrob Agents Chemother. 2011 Jun;55(6):2606-11 - PubMed
  45. Lancet Infect Dis. 2017 Aug;17(8):873-881 - PubMed
  46. Antimicrob Agents Chemother. 2005 Jul;49(7):2994-6 - PubMed
  47. Rev Inst Med Trop Sao Paulo. 2007 Jan-Feb;49(1):41-7 - PubMed
  48. Pharm Res. 2018 Apr 27;35(7):132 - PubMed
  49. J Clin Microbiol. 2014 Jun;52(6):1921-31 - PubMed
  50. Clin Infect Dis. 2017 Nov 29;65(12):2126-2129 - PubMed
  51. Med Mycol. 2014 Jan;52(1):90-8 - PubMed
  52. Antimicrob Agents Chemother. 2001 Nov;45(11):3065-9 - PubMed
  53. J Clin Microbiol. 2005 May;43(5):2163-7 - PubMed

Publication Types

Grant support