Purpose
To evaluate the efficacy of 0.02% polyhexamethylene biguanide (PHMB) in the treatment of keratoconjunctivitis caused by microsporidia.
Design
Prospective, double-masked, randomized, placebo-controlled clinical trial.
Methods
One hundred forty-five patients in a single-center, institutional setting were recruited. Patients with superficial keratoconjunctivitis and corneal scrapings with positive results for microsporidial spores were included. Patients with any known allergy to PHMB, and clinically suspected bacterial, viral, or fungal infection were excluded from the study. One hundred forty-five patients were treated at 4-hour intervals with either topical 0.02% PHMB (n = 72) or placebo (n = 73). The patients were followed-up on day 3 ± 1, day 7 ± 1, and weekly thereafter, until complete resolution of the corneal lesions. Patients with deterioration of clinical symptoms and signs were removed from the study and were treated with PHMB. Main outcome measures included resolution time, cure time, and final visual outcome.
Results
Resolution time was defined as the amount of time until disappearance of corneal epithelial infiltrates. Cure time was defined as the interval until absence of conjunctival congestion, corneal epithelial lesion, and superficial punctate keratitis. Baseline characteristics showed no relevant difference between the groups. The mean resolution time was 4.9 ± 2.2 days and 4.6 ± 2.3 days in the PHMB and placebo groups, respectively ( P = .49). The mean time for cure was 13.5 ± 6.6 days and 9.4 ± 5.1 days in PHMB and placebo groups, respectively ( P = .004). There was no significant difference in the final visual outcome between the groups ( P = .10). No serious adverse effects were noted.
Conclusions
Treatment of microsporidial keratoconjunctivitis with PHMB does not offer any significant advantage over placebo, suggesting self-limiting nature of the disease.
Microsporidia are small, obligate, spore-forming, intracellular living eukaryotes that infect a broad range of vertebrates and invertebrates. In humans, microsporidia are opportunistic pathogens that are reported to cause gastrointestinal, sinus, pulmonary, muscular, renal, and ocular disease. The ocular manifestations include superficial keratoconjunctivitis and stromal keratitis. The early reports of microsporidial keratoconjunctivitis involved immunocompromised patients. However, these pathogens seem to be increasingly prevalent in immunocompetent patients. We have reported an epidemic of keratoconjunctivitis caused by microsporidia.
The management of microsporidial keratoconjunctivitis is challenging because no definitive treatment exists. Anecdotal reports of specific treatment include the use of albendazole, broad-spectrum antibiotics, itraconazole, propamidine isoethionate, fumagillin, chlorhexidine, polyhexameththylene biguanide, and lubricants. In all studies, epithelial keratoconjunctivitis has been reported to resolve in a varying period without significantly affecting visual acuity. The present study was designed to determine the clinical efficacy of 0.02% polyhexameththylene biguanide (PHMB) in the treatment of keratoconjunctivitis caused by microsporidia.
Methods
This single-center, double-masked, randomized, placebo-controlled clinical trial examined 145 patients. Informed written consent was obtained from each participant before inclusion in the study.
Inclusion and Exclusion Criteria
Patients with superficial epithelial keratitis or keratoconjunctivitis and whose corneal scrapings showed positive results for microsporidia spores were included in the study. The patients needed to have the ability to understand and sign an informed consent form. For patients younger than 18 years, the informed consent was required to be understood and signed by the parent or guardian. The exclusion criteria included known allergy to PHMB and clinically suspected bacterial, viral, or fungal infection of the cornea.
Sample Size, Randomization, and Masking
A computer-generated randomized number was assigned to each patient at the time of initiation of treatment. Both the patient and the physician were masked to the drug. Identical eye drop bottles containing either 0.02% PHMB or the placebo were dispensed to the patients by the pharmacist. A sample size of 45 in each group was considered sufficient to detect a grouped difference of 3 ± 5 days with 80% power and 5% level of significance. However, expecting a drop-out of 30% owing to the mild nature of the disease, 145 patients were recruited, with 72 in the PHMB group and 73 in the placebo group. Based on previous experience, a standard deviation of 5 days was considered and a difference of more than 10% was considered clinically relevant.
Primary and Secondary Outcome Measures
The patients were asked to return for follow-up once weekly. The primary outcome was the time taken for resolution of corneal infiltrate in each group. The secondary outcomes were: (1) final visual acuity, (2) clinical outcome, and (3) adverse event, if any.
Procedures
At the baseline (i.e., day 0), demographic information and detailed medical history was obtained from each patient. Visual acuity was measured using a Snellen chart, and a slit-lamp examination was performed on all patients. A corneal scraping was obtained from all patients who exhibited clinical features of microsporidial keratoconjunctivitis, such as diffuse, multifocal, coarse, raised, punctate, round to oval epithelial lesions in the cornea on slit-lamp examination. The corneal scraping was carried out with the help of a sterile no. 15 blade on a Bard-Parker handle (Sharp Edge Industries, Ahmedabad, India) after instillation of topical anesthesia (0.5% proparacaine hydrochloride). The scraping was smeared on 2 glass slides and was subjected to direct smear examination after being stained with 10% potassium hydroxide with 0.1% calcofluor white (fluorescence microscopy) and gram, Giemsa, or modified acid fast (1% H 2 SO 4 ) stain. The material also was inoculated onto 1 culture medium (chocolate agar/blood agar) that was incubated at 37 C for 2 weeks.
Medication and Dosing Regimen
Although 0.02% PHMB was prepared by dilution with artificial tear (hydroxymethyl cellulose, Foods, Drugs and Chemicals) under sterile conditions, the placebo was artificial tear (hydroxymethyl cellulose, Foods, Drugs and Chemicals). Patients were instructed to use the medication at 4-hour intervals in the affected eye. The patients were examined on day 3 ± 1, day 7 ± 1, and thereafter at weekly intervals until the clinical symptoms and signs had resolved completely. For patients whose corneal scraping culture showed significant bacterial growth, 0.3% ciprofloxacin eye drops were added every 6 hours for 1 week at the second visit. Thirty-two eyes had clinical features of anterior uveitis at follow-up (0.02% PHMB, 16; placebo, 16). A topical steroid was used in 12 eyes (features of uveitis, 8 eyes; corneal scar, 4 eyes; 0.02% PHMB used in 5, and placebo used in 7). In all eyes, the steroid was started after resolution. In case of worsening, that is, deterioration of clinical symptoms and signs, especially where there was an increase in the number of corneal lesions, patients were removed from the study and started on 0.02% PHMB.
Statistical Analysis
Baseline characteristics were compared using the unpaired t test. The chi-square test was used to compare proportions. To compare the time for resolution and intergroup visual acuity in the 2 groups, the unpaired t test was used.
Results
Patient Disposition and Demographics
One hundred forty-five eyes of 145 patients (0.02% PHMB, 72; placebo, 73) were recruited. Of these, 99 completed the study (47 in the PHMB group and 52 in the placebo group). The reasons for excluding 46 patients from the analyses were (1) loss to follow-up after day 0 and failure to adhere to advised follow-up visit (n = 41), and (2) adverse event (n = 5; Figure 1 ). Baseline characteristics (age, gender, duration of symptoms, clinical features) showed no relevant difference between the 2 groups ( Table 1 ). Thirty-five patients had a history of presumed trauma. Corneal scrapings of all patients showed the presence of microsporidial spores in (1) 10% potassium hydroxide with 0.1% calcofluor white under a fluorescence microscope, (2) gram, Giemsa, or modified acid-fast (1% H 2 SO 4 ) stain under the light microscope, or (3) both. Bacterial growth ( Corynebacterium species, 4; Pseudomonas species, 5; Acinetobacter baumannii , 1) in significant numbers (>10 colonies) was seen in 10 (7.2%) of 138 corneal scrapings (culture not carried out in 7 cases). The culture was sterile in the rest of the cases after 2 weeks of incubation.
| PHMB (0.02%) Group | Placebo Group | P Value | |
|---|---|---|---|
| Age (yrs) | .55 | ||
| Mean (SD) | 35.5 (13.9) | 36.9 (14.6) | |
| Range | 7 to 78 | 13 to 80 | |
| Gender (male-to-female) | 50:22 | 52:21 | .96 |
| Eye (right-to-left) | 38:34 | 37:36 | .93 |
| Duration of symptoms | .68 | ||
| No. | 72 | 73 | |
| Mean (SD) | 7.9 (4.0) | 8.3 (7.3) | |
| Range | 1 to 20 | 2 to 60 | |
| 95% CI | 6.96 to 8.84 | 6.60 to 10.0 |
Treatment Outcome ( Table 2 )
Resolution and Cure Time
We defined resolution time as the time required for the corneal epithelial infiltrates to disappear completely (no infiltrates visible on slit-lamp examination). The mean time required for resolution was 4.9 ± 2.2 days and 4.6 ± 2.3 days in the 0.02% PHMB and placebo groups, respectively ( P = .49). Cure time was defined as disappearance of conjunctival congestion, corneal epithelial lesions, and superficial punctate keratitis. The mean time required for cure was 13.5 ± 6.6 days and 9.4 ± 5.1 days in the 0.02% PHMB and placebo group, respectively ( P = .004).
| PHMB (0.02%) Group | Placebo Group | P Value | |
|---|---|---|---|
| VA at presentation (logMAR) | .29 | ||
| No. | 72 | 73 | |
| Mean (SD) | 0.34 (0.56) | 0.26 (0.34) | |
| 95% CI | 0.21 to 0.47 | 0.18 to 0.34 | |
| Resolution time (excluding worsening patient) | .49 | ||
| No. | 47 | 52 | |
| Mean (SD) | 4.9 (2.2) | 4.6 (2.3) | |
| Range | 3 to 11 | 2 to 14 | |
| 95% CI | 4.29 to 5.51 | 3.95 to 5.25 | |
| Time for cure (excluding worsening patient) | .0045 | ||
| No. | 35 | 36 | |
| Mean (SD) | 13.5 (6.6) | 9.4 (5.1) | |
| Range | 3 to 33 | 3 to 24 | |
| 95% CI | 11.23 to 15.77 | 7.67 to 11.13 | |
| Clear cornea | 25 (of 35) | 17 (of 36) | .067 |
| Final VA (logMAR; excluding worsening patient) | .10 | ||
| No. | 35 | 36 | |
| Mean (SD) | 0.27 (0.71) | 0.07 (0.13) | |
| 95% CI | 0.03 to 0.51 | 0.03 to 0.11 | |
| Final VA (logMAR; including worsening patient; one of the worsening patients in the placebo group was lost to follow-up) | .12 | ||
| No. | 36 | 39 | |
| Mean (SD) | 0.27 (0.70) | 0.09 (0.17) | |
| 95% CI | 0.03 to 0.51 | 0.03 to 0.14 |
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