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Letters
RESEARCH LETTER
Differences in Clinical Outcomes in Keratitis
Due to Fungus and Bacteria
Retrospective studies have suggested that, compared with bacterial keratitis, fungal keratitis has particularly poor outcomes.1
An unbiased analysis would ideally be performed in a prospective, standardized fashion. Herein, we compare clinical outcomes in ulcers due to bacteria and fungus using data collected from 2 similarly structured prospective clinical trials.2,3
Methods | The National Eye Institute–funded Steroids for Corneal Ulcers Trial3,4 (SCUT) and the pilot study for the National Eye Institute–funded Mycotic Ulcer Treatment Trial2
(MUTT pilot) were concurrent, randomized controlled trials
comparing outcomes in patients with bacterial (SCUT) and fungal (MUTT pilot) keratitis. Detailed methods have been previously reported.2,3 Outcomes for both trials included best spectacle-corrected visual acuity and infiltrate or scar size at 3
months from enrollment, time to re-epithelialization, and corneal perforation. The 2 trials were conducted at the Aravind
Eye Care System (Madurai, Pondicherry, Tirunelveli, and Coimbatore, India) by the same investigators; all measurements
were made by the same graders according to identical protocols. Patients were enrolled during overlapping periods (September 2006 through February 2010 for SCUT; December 2007
through May 2008 for MUTT pilot). Institutional review board
approval was obtained by the University of California, San Francisco Committee on Human Research and the Aravind Institutional Review Board, and written informed consent was obtained from each participant.
Table. Comparison of 3-Month Scar Size and Best Spectacle-Corrected
Visual Acuity in Patients with Bacterial and Fungal Keratitis by
Multivariate Linear Regressiona
Model
Coefficient (95% CI)
P Value
3-mo BSCVA, logMAR
Fungal vs bacterial
0.07 (−0.02 to 0.18)
.12
Vs enrollment BSCVA
0.65 (0.59 to 0.71)
<.001
Fungal vs bacterial
0.27 (0.11 to 0.43)
.001
Vs enrollment infiltrate
size
0.92 (0.89 to 0.96)
<.001
3-mo scar size,
geometric mean, mm
Perforation, No. (%)
Fungal
16/101 (16)
Bacterial
15/485 (3)
<.001
Abbreviation: BSCVA, best spectacle-corrected visual acuity.
a
1088
There were 443 patients with bacterial keratitis in the BSCVA model and 438
patients with bacterial keratitis in the scar size model. There were 89 patients
with fungal keratitis in both models.
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All culture-positive bacterial and fungal cases enrolled in
India were included in the analysis. Three-month best spectacle-corrected visual acuity and infiltrate or scar size between fungus and bacteria were analyzed by linear regression controlling for baseline characteristics (enrollment best
spectacle-corrected visual acuity or infiltrate or scar size). In
patients who had undergone corneal transplantation prior to
their 3-month visit, last observation carried forward or an assigned visual acuity of 1.7 was used, whichever was worse. For
infiltrate or scar size, last observation carried forward was used
in these patients. Time to re-epithelialization was analyzed with
a Cox proportional hazards model controlling for baseline epithelial defect size. Perforation was assessed using Fisher exact test.
Results | Of 500 cases enrolled in SCUT and 120 cases enrolled
in MUTT pilot, 485 cases in SCUT and 101 cases in MUTT pilot
were culture positive, enrolled in India, and included in the
analysis. Fungal keratitis cases were associated with approximately a 0.32-mm larger infiltrate or scar size compared with
bacterial keratitis cases at 3 months, correcting for enrollment infiltrate size (P < .001) (Table). There was no difference in best spectacle-corrected visual acuity at 3 months in
patients with fungal and bacterial keratitis (P = .12) (Table). Fungal keratitis cases re-epithelialized significantly more slowly
than bacterial keratitis cases (median, 15 vs 7.5 days, respectively; P < .001). There were more perforations in the fungal
keratitis group than in the bacterial keratitis group (16 of 101
[16%] vs 15 of 485 [3%], respectively; P < .001). Sensitivity
analyses restricting the bacterial cases to only those enrolled
during the same period as the fungal cases did not change the
results.
Discussion | Fungal keratitis is frequently considered more difficult to treat than bacterial keratitis and is thought to have
worse prognoses.1,5 Here, fungal keratitis cases had nearly 5
times as many corneal perforations, some of which led to therapeutic penetrating keratoplasty, and longer healing times. They
also had larger scars, although a difference of 0.32 mm may not
be clinically significant. However, there was no significant difference in visual acuity in the bacterial and fungal keratitis
groups, including patients with presumably the most severe
ulcers, some of whom underwent sight-improving keratoplasty.
While there are inherent challenges in combining data from
multiple clinical studies, these trials are a special case. The trials
were conducted concurrently by the same investigators, outcomes were measured according to identical protocols, and the
inclusion and exclusion criteria were nearly identical for both
trials. For fungal ulcers, the epithelium was removed to enhance drug penetration, and approximately half of the cases
received repeated scraping at 7 and 14 days because one of the
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primary aims of the trial was to assess whether repeated scraping improved outcomes. The result of longer healing times in
fungal ulcers may be influenced by this. Re-epithelialization
is a difficult end point to measure, particularly in fungal keratitis, so this result should be interpreted with some caution.
Other factors associated with fungal and bacterial keratitis
cases, such as geographic location of the patients, could act
as confounders in this study. Selection bias could occur because use of topical antibiotics prior to presentation is more
common than antifungal use, and culture-negative bacterial
ulcers may be milder. However, the results of this study suggest that fungal keratitis has a higher risk of perforation and
may have worse overall outcomes compared with bacterial
keratitis.
N. Venkatesh Prajna, MD
Muthiah Srinivasan, MD
Prajna Lalitha, MD
Tiruvengada Krishnan, MD
Revathi Rajaraman, MD
Meenakshi Ravindran, MD
Jeena Mascarenhas, MD
Catherine E. Oldenburg, MPH
Kathryn J. Ray, MA
Stephen D. McLeod, MD
Nisha R. Acharya, MD, MS
Thomas M. Lietman, MD
Author Affiliations: Aravind Eye Care System, Madurai, Tamil Nadu, India
(Prajna, Srinivasan, Lalitha, Mascarenhas); Aravind Eye Care System,
Pondicherry, India (Krishnan); Aravind Eye Care System, Coimbatore, Tamil
Nadu, India (Rajaraman); Aravind Eye Care System, Tirunelveli, Tamil Nadu,
India (Ravindran); Francis I. Proctor Foundation, University of California, San
Francisco (Oldenburg, Ray, McLeod, Acharya, Lietman).
Corresponding Author: Thomas M. Lietman, MD, Department of
Ophthalmology, Francis I. Proctor Foundation, University of California, San
Francisco School of Medicine, 513 Parnassus, S309, San Francisco, CA 94193
([email protected]).
Author Contributions: All authors had full access to all the data in the study
and take responsibility for the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Prajna, Srinivasan, Oldenburg, McLeod, Acharya,
Lietman.
Acquisition of data: Prajna, Lalitha, Krishnan, Rajaraman, Ravindran,
Mascarenhas, Oldenburg, Ray, McLeod.
Analysis and interpretation of data: Prajna, Srinivasan, Mascarenhas, Oldenburg,
Ray, McLeod, Acharya, Lietman.
Drafting of the manuscript: Ravindran, Oldenburg.
Critical revision of the manuscript for important intellectual content: Prajna,
Srinivasan, Lalitha, Krishnan, Rajaraman, Mascarenhas, Ray, McLeod, Acharya,
Lietman.
Statistical analysis: Srinivasan, Oldenburg, Ray.
Obtained funding: Lietman.
Administrative, technical, and material support: Prajna, Lalitha, Krishnan,
Rajaraman, Ravindran, Mascarenhas, Oldenburg, McLeod, Acharya.
Study supervision: Prajna, Srinivasan, Lalitha, Oldenburg, McLeod, Acharya,
Lietman.
Conflict of Interest Disclosures: None reported.
Funding/Support: The Steroids for Corneal Ulcers Trial was supported by grant
U10 EY015114 from the National Eye Institute. Acharya is supported by grant
K23EY017897 from the National Eye Institute and a Research to Prevent
Blindness Award. The Department of Ophthalmology, University of California,
San Francisco is supported by core grant EY02162 from the National Eye
Institute, by an unrestricted grant from Research to Prevent Blindness, and by
That Man May See, Inc. Alcon provided moxifloxacin (Vigamox) for the Steroids
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for Corneal Ulcers Trial. Alcon donated natamycin and Pfizer donated
voriconazole for the Mycotic Ulcer Treatment Trial pilot study.
Role of the Sponsor: The sponsors had no role in the design and conduct of the
study; collection, management, analysis, and interpretation of the data; or
preparation, review, or approval of the manuscript.
1. Wong TY, Ng TP, Fong KS, Tan DT. Risk factors and clinical outcomes between
fungal and bacterial keratitis: a comparative study. CLAO J. 1997;23(4):275-281.
2. Prajna NV, Mascarenhas J, Krishnan T, et al. Comparison of natamycin and
voriconazole for the treatment of fungal keratitis. Arch Ophthalmol.
2010;128(6):672-678.
3. Srinivasan M, Mascarenhas J, Rajaraman R, et al; Steroids for Corneal Ulcers
Trial Group. The Steroids for Corneal Ulcers Trial: study design and baseline
characteristics. Arch Ophthalmol. 2012;130(2):151-157.
4. Srinivasan M, Mascarenhas J, Rajaraman R, et al; Steroids for Corneal Ulcers
Trial Group. Corticosteroids for bacterial keratitis: the Steroids for Corneal
Ulcers Trial (SCUT). Arch Ophthalmol. 2012;130(2):143-150.
5. Lalitha P, Prajna NV, Kabra A, Mahadevan K, Srinivasan M. Risk factors for
treatment outcome in fungal keratitis. Ophthalmology. 2006;113(4):526-530.
Clinicopathological Findings in Persistent Corneal
Cowpox Infection
Cowpox viruses (CPXVs) belong to the genus Orthopoxvirus.1 Increasingly, CPXV infections have been reported in domestic cats,
rats, and exotic zoo animals, with humans potentially being infected through direct contact with these animals.1 Typically, a
CPXV infection becomes apparent through the development of
small skin lesions. Healing comes with scar formation and can
take several weeks. Complications and severe courses have been
reported in immunocompromised individuals.2
Report of a Case | In February 2009, a 49-year-old woman presented to a local clinic with a swollen eyelid and phlyctenular
changes of the cornea in her right eye. She received antibiotics and steroid eyedrops for 2 weeks, but she developed a corneal infiltration and marginal ulceration and her bestcorrected visual acuity (BCVA) decreased to 20/100.3 Because
of skin lesions on her shoulder that developed after direct contact with a rat suspected of being infected with CPXV, she was
also tested for a CPXV infection. That was confirmed by realtime polymerase chain reaction from conjunctival and skin
swab samples. The CPXV infection of the eye was probably
caused by smear infection. Involvement of Staphylococcus aureus was shown by a swab, so she was given cefuroxime sodium and local antibiotics. Corneal infiltration then resolved,
but limbal ulceration worsened. Four months after the initial
infection, conjunctival swabs were negative for CPXV. From
then on, she received steroid eyedrops to control inflammation, ofloxacin eyedrops because of subtotal erosion, and lubricants. From her general medical history, she solely reported a 22-year history of type 1 diabetes mellitus.
In March 2010, she presented at the University Eye Hospital Freiburg because of increasing corneal melting with persistent corneal erosion (Figure 1, A and B). Her BCVA was counting fingers. Penetrating limbokeratoplasty was performed.
Postoperatively, her BCVA was 10/200 (Figure 1C) and she received immunosuppressive treatment with mycophenolate
mofetil.4 Three weeks later, the patient presented with scleritis, transplant erosion, and ocular hypotension. Her BCVA was
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