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Table 1.  
Comparison of Fold Change in MIC Between Pretreated and Nonpretreated Fungal Ulcers
Comparison of Fold Change in MIC Between Pretreated and Nonpretreated Fungal Ulcers
Table 2.  
Effect of Pretreatment on Natamycin and Voriconazole MICa
Effect of Pretreatment on Natamycin and Voriconazole MICa
1.
Ray  KJ, Prajna  L, Srinivasan  M,  et al.  Fluoroquinolone treatment and susceptibility of isolates from bacterial keratitis. JAMA Ophthalmol. 2013;131(3):310-313.
PubMedArticle
2.
Pfaller  MA.  Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012;125(1)(suppl):S3-S13.
PubMedArticle
3.
Kanafani  ZA, Perfect  JR.  Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis. 2008;46(1):120-128.
PubMedArticle
4.
Prajna  NV, Krishnan  T, Mascarenhas  J,  et al; Mycotic Ulcer Treatment Trial Group.  The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422-429.
PubMedArticle
5.
Lalitha  P, Prajna  NV, Oldenburg  CE,  et al.  Organism, minimum inhibitory concentration, and outcome in a fungal corneal ulcer clinical trial. Cornea. 2012;31(6):662-667.
PubMedArticle
6.
Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard. 3rd ed. Wayne, PA: Clinical & Laboratory Standards Institute; 2008.
Research Letter
October 2015

Association of Pretreatment With Antifungal Medication and Fungal Resistance in the Mycotic Ulcer Treatment Trial I

Author Affiliations
  • 1Aravind Eye Care System, Madurai, India
  • 2Francis I. Proctor Foundation, University of California, San Francisco
  • 3Department of Epidemiology and Biostatistics, University of California, San Francisco
  • 4Department of Ophthalmology, University of California, San Francisco
  • 5Department of Optometry, University of California, Berkeley
JAMA Ophthalmol. 2015;133(10):1210-1211. doi:10.1001/jamaophthalmol.2015.2040

Treatment with topical antibiotics has been shown to select for antibiotic resistance in bacterial ulcers.1 Topical antifungal medications may similarly select for resistant fungi. Resistance among invasive fungal species has now been recognized as an important clinical concern.2,3 The Mycotic Ulcer Treatment Trial I (MUTT I) was a randomized, controlled, double-masked trial that found topical natamycin to be superior to voriconazole in the treatment of filamentous fungal ulcers.4 Herein, we evaluate the effect of pretreatment with antifungal medications on natamycin and voriconazole minimum inhibitory concentration (MIC) from baseline cultures collected during MUTT I.

Methods

Detailed methods for the clinical trial and for handling of microbiological specimens have been published previously.4,5 In brief, corneal scrapings and cultures were obtained from all patients at enrollment. Patients were eligible for inclusion if fungus was found on potassium hydroxide wet mount preparation and Gram staining was negative for bacteria. All culture-positive specimens underwent susceptibility testing using the standards set by the Clinical and Laboratory Standards Institute.6 A t test was used to analyze the association between pretreatment with antifungal medications and baseline log2-transformed natamycin and voriconazole MICs for Aspergillus, Fusarium, and all other ulcers.

Ethical approval for the study was obtained from the Aravind Eye Care System Institutional Review Board, the University of California, San Francisco Committee on Human Research, and the Dartmouth-Hitchcock Medical Center Committee for the Protection of Human Subjects. Written informed consent was obtained from all participants, and the trial conformed to the Declaration of Helsinki.

Results

Baseline culture and MIC data were available for 221 of 323 study participants (68%) and were included in the analysis. Eighty-eight participants (40%) were female and the median age was 46 years (interquartile range, 38-55 years). A difference was not identified in the pretreated vs nonpretreated groups regarding age or sex. Table 1 outlines pretreatment drugs and duration as well as fold change in MICs between groups. Among the 90 patients who were pretreated, 42 (47%) were pretreated with natamycin alone, 14 (16%) with an azole, and 34 (38%) with both an azole and natamycin. The mean duration of pretreatment was 5.7 days for natamycin and 3.8 days for azole alone. The azole was topical in 45 participants (94%), oral in 6 (12%), and both in 3 (6%).

Of the 126 Fusarium ulcers, 58 (46%) were pretreated. Fusarium isolates showed 0.89-fold (lower) natamycin MICs (95% CI, 0.70- to 1.11-fold; P = .30) when pretreated with natamycin alone and 1.12-fold voriconazole MICs (95% CI, 0.62- to 2.03-fold; P = .70) when pretreated with an azole alone compared with no pretreatment. When pretreated in combination, they had 0.75-fold natamycin MICs (95% CI, 0.51- to 1.09-fold; P = .12) and 0.90-fold voriconazole MICs (95% CI, 0.63- to 1.28-fold; P = .55) compared with no pretreatment.

Of the 52 Aspergillus ulcers, 22 (42%) were pretreated. Aspergillus isolates showed 1.64-fold (higher) natamycin MICs (95% CI, 0.77- to 3.48-fold; P = .19) when pretreated with natamycin alone and demonstrated 1.16-fold voriconazole MICs (95% CI, 0.48- to 2.81-fold; P = .73) when pretreated with an azole alone compared with no pretreatment. When treated in combination, they had 1.91-fold natamycin MICs (95% CI, 0.57- to 6.36-fold; P = .28) and 0.82-fold voriconazole MICs (95% CI, 0.33- to 2.03-fold; P = .66) compared with no pretreatment.

Among the 43 remaining ulcers, 10 (23%) were pretreated. Non-Fusarium, non-Aspergillus isolates showed 0.57-fold natamycin MICs (95% CI, 0.35- to 0.93-fold; P = .03) when treated with natamycin alone and 1.02-fold voriconazole MICs (95% CI, 0.50- to 4.14-fold; P = .98) when treated with an azole alone compared with no pretreatment. When pretreated in combination, they had 1.26-fold natamycin MICs (95% CI, 0.70- to 2.28-fold; P = .44) and 2.57-fold voriconazole MICs (95% CI, 0.46- to 14.32-fold; P = .27) compared with no pretreatment.

Table 2 shows median and 90th percentile MIC data for Fusarium, Aspergillus, and all other organisms by pretreatment status.

Discussion

We found no association between pretreatment with antifungal medications and fungal resistance as measured by MIC from baseline cultures collected at enrollment in MUTT I. Prior reports in the literature indicate that resistance develops only after prolonged treatment with antifungal medications.2,3 While these data suggest that antifungal treatment does not select for resistant strains, 5 days may not be enough time to show emerging resistance patterns. It may be sufficient to detect any clinically relevant resistance in corneal ulcer treatment.

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Article Information

Corresponding Author: Jennifer Rose-Nussbaumer, MD, Francis I. Proctor Foundation, University of California, San Francisco, 513 Parnassus Ave, S334, San Francisco, CA 94143 (jennifer.rose@ucsf.edu).

Published Online: June 25, 2015. doi:10.1001/jamaophthalmol.2015.2040.

Author Contributions: Drs Lietman and Rose-Nussbaumer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Rose-Nussbaumer.

Critical revision of the manuscript for important intellectual content: N. V. Prajna, L. Prajna, O’Brien, Sun, Acharya, Lietman.

Statistical analysis: Sun, Rose-Nussbaumer.

Obtained funding: Acharya, Lietman.

Administrative, technical, or material support: N. V. Prajna, O’Brien, Acharya.

Study supervision: N. V. Prajna, Lietman.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was supported by grant U10-EY018573-01A1 from the National Eye Institute in conjunction with the National Eye Institute–sponsored Mycotic Ulcer Treatment Trial (principal investigator, Dr Lietman). Dr Rose-Nussbaumer was supported by an unrestricted grant from the Peirles Foundation.

Role of the Funder/Sponsor: The National Eye Institute supported design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The Peirles Foundation supported analysis and interpretation of the data and preparation of the manuscript.

Trial Registration: clinicaltrials.gov Identifier: NCT00996736

Group Information: The Mycotic Ulcer Treatment Trial Group includes the following members: Aravind Eye Hospital, Madurai, India: N. Venkatesh Prajna, MD (principal investigator), Lalitha Prajna, MD, Jeena Mascarenhas, MD, Muthiah Srinivasan, MD, FRCOphth, MA, Rajarathinam Karpagam, Malaiyandi Rajkumar, S. R. Sumithra, and C. Sundar; Aravind Eye Hospital, Coimbatore, India: Revathi Rajaraman, MD (site director), Anita Raghavan, MD, P. Manikandan, MPhil; Aravind Eye Hospital, Pondicherry, India: K. Tiruvengada Krishnan, MD (site director), and N. Shivananda; Francis I. Proctor Foundation, University of California, San Francisco: Thomas M. Lietman, MD (principal investigator), Nisha Acharya, MD (principal investigator), Stephen D. McLeod, MD, John P. Whitcher, MD, MPH, Salena Lee, OD, Vicky Cevallos, MT(ASCP), Brett L. Shapiro, MD, Catherine E. Oldenburg, MPH, Kieran S. O’Brien, MPH, and Kevin C. Hong, BA; Data and Safety Monitoring Committee: Marian Fisher, PhD (chair), Anthony Aldave, MD, Donald F. Everett, MA, Jacqueline Glover, PhD, K. Ananda Kannan, MD, Steven Kymes, PhD, and Ivan Schwab, MD; Coordinating Center, Francis I. Proctor Foundation, University of California, San Francisco: Thomas M. Lietman, MD (principal investigator), Nisha Acharya, MD (principal investigator), David Glidden, PhD, Stephen D. McLeod, MD, John P. Whitcher, MD, MPH, Salena Lee, OD, Kathryn Ray, MA, Vicky Cevallos, MT(ASCP), Brett L. Shapiro, MD, Catherine E. Oldenburg, MPH, Kevin C. Hong, BA, and Kieran S. O’Brien, MPH; Project Office, National Eye Institute, Rockville, Maryland: Donald F. Everett, MA; and Photography Reading Center, Dartmouth Medical School, Lebanon, New Hampshire: Michael E. Zegans, MD, and Christine M. Kidd, PhD.

References
1.
Ray  KJ, Prajna  L, Srinivasan  M,  et al.  Fluoroquinolone treatment and susceptibility of isolates from bacterial keratitis. JAMA Ophthalmol. 2013;131(3):310-313.
PubMedArticle
2.
Pfaller  MA.  Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012;125(1)(suppl):S3-S13.
PubMedArticle
3.
Kanafani  ZA, Perfect  JR.  Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis. 2008;46(1):120-128.
PubMedArticle
4.
Prajna  NV, Krishnan  T, Mascarenhas  J,  et al; Mycotic Ulcer Treatment Trial Group.  The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422-429.
PubMedArticle
5.
Lalitha  P, Prajna  NV, Oldenburg  CE,  et al.  Organism, minimum inhibitory concentration, and outcome in a fungal corneal ulcer clinical trial. Cornea. 2012;31(6):662-667.
PubMedArticle
6.
Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard. 3rd ed. Wayne, PA: Clinical & Laboratory Standards Institute; 2008.
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