Propamidine 0.1% eye drops

INTRODUCTION: Acanthamoeba keratitis (AK) was first identified in 1972 and the first patient cured with propamidine was reported in 1985. Treatment outcomes, before the advent of the first effective anti-amoebic treatment, were known to be poor and often required therapeutic keratoplasty (TK) but have not been evaluated in detail. Analysis of these outcomes has value for several reasons: it gives an historical perspective, describes the natural history of AK when the disease was minimally modified by the early treatments and provides a benchmark against which current treatments can be compared and how these have changed the therapeutic results. METHODS: We conducted a systematic literature review for the period 1970-1995 using PRISMA guidelines. The population of interest comprised patients with AK treated without products having established anti-amoebic activity against both trophozoites and cysts (biguanides or diamidines). The outcomes of interest were medical cure, TK and enucleation. Proportions and 95% confidence intervals were estimated. RESULTS: Fifty-six case reports were eligible. Risk factors for AK were reported in 44/56 patients: contact lens wear in 30/44 (68.2%) and trauma in 14/44 (31.8%). The mean time from presentation to diagnosis was 7.3 weeks (standard deviation 9.3 weeks); 13/56 (23.2%) were diagnosed within 4 weeks. Topical treatments given to patients included corticosteroids (85.2%), antibiotics (85.2%), antivirals (72.2%) and antifungals (51.8%). Final visual acuity was ≥ 20/40 in 17/33 (51.5%) patients with no missing data. Medical cures were reported in 11/56 patients (19.6%), TK in 38/56 (67.9%), other surgery in 4/56 (7.1%) and enucleation in 3/56 (5.4%). CONCLUSION: This study suggests that, before the availability of propamidine as the first effective treatment for AK, the clinical outcome of these patients was poor with only a few patients cured without surgery. These findings should be interpreted with caution because they rely on case reports and series that are subject to inherent bias.

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PURPOSE: To compare topical PHMB (polihexanide) 0.02% (0.2 mg/ml)+ propamidine 0.1% (1 mg/ml) with PHMB 0.08% (0.8 mg/ml)+ placebo (PHMB 0.08%) for Acanthamoeba keratitis (AK) treatment. DESIGN: Prospective, randomized, double-masked, active-controlled, multicenter phase 3 study (ClinicalTrials.gov identifier, NCT03274895). PARTICIPANTS: One hundred thirty-five patients treated at 6 European centers. METHODS: Principal inclusion criteria were 12 years of age or older and in vivo confocal microscopy with clinical findings consistent with AK. Also included were participants with concurrent bacterial keratitis who were using topical steroids and antiviral and antifungal drugs before randomization. Principal exclusion criteria were concurrent herpes or fungal keratitis and use of antiamebic therapy (AAT). Patients were randomized 1:1 using a computer-generated block size of 4. This was a superiority trial having a predefined noninferiority margin. The sample size of 130 participants gave approximately 80% power to detect 20-percentage point superiority for PHMB 0.08% for the primary outcome of the medical cure rate (MCR; without surgery or change of AAT) within 12 months, cure defined by clinical criteria 90 days after discontinuing anti-inflammatory agents and AAT. A prespecified multivariable analysis adjusted for baseline imbalances in risk factors affecting outcomes. MAIN OUTCOME MEASURES: The main outcome measure was MCR within 12 months, with secondary outcomes including best-corrected visual acuity and treatment failure rates. Safety outcomes included adverse event rates. RESULTS: One hundred thirty-five participants were randomized, providing 127 in the full-analysis subset (61 receiving PHMB 0.02%+ propamidine and 66 receiving PHMB 0.08%) and 134 in the safety analysis subset. The adjusted MCR within 12 months was 86.6% (unadjusted, 88.5%) for PHMB 0.02%+ propamidine and 86.7% (unadjusted, 84.9%) for PHMB 0.08%; the noninferiority requirement for PHMB 0.08% was met (adjusted difference, 0.1 percentage points; lower one-sided 95% confidence limit, -8.3 percentage points). Secondary outcomes were similar for both treatments and were not analyzed statistically: median best-corrected visual acuity of 20/20 and an overall treatment failure rate of 17 of 127 patients (13.4%), of whom 8 of 127 patients (6.3%) required therapeutic keratoplasty. No serious drug-related adverse events occurred. CONCLUSIONS: PHMB 0.08% monotherapy may be as effective (or at worse only 8 percentage points less effective) as dual therapy with PHMB 0.02%+ propamidine (a widely used therapy) with medical cure rates of more than 86%, when used with the trial treatment delivery protocol in populations with AK with similar disease severity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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BACKGROUND/AIMS: keratitis is a rare, severe corneal infection. Until the recent approval of polihexanide (PHMB) 0.08% by the European Medicines Agency, there were no licensed medical therapies and current treatments relied on off-label or compounded products. The purpose of this study is to estimate the relative efficacy of PHMB 0.08% compared with current treatments. METHODS: A patient-level indirect treatment comparison (ITC) compared data from a pivotal trial of PHMB 0.08% and a retrospective real-world study of current treatments: (1) any anti-amoebic treatment (AAT), (2) PHMB 0.02% plus a diamidine (propamidine or hexamidine) 0.1% and (3) chlorhexidine (CXL) 0.02% alone or in combination with a diamidine. The primary outcome was the clinical resolution rate (CRR) without surgery within 12 months. ITCs were implemented using propensity scoring analysis with overlap weighting and adjustment for covariates (age, sex, disease stage, treatment delay, prior use of corticosteroid or antiviral). RESULTS: The CRR was 84.8% for PHMB 0.08% (n=66), 43.6% for any AAT (n=227), 55.0% for PHMB 0.02% plus a diamidine (n=111) and 40.0% for CXL 0.02% with or without a diamidine (n=35). In the unweighted analysis, the absolute difference (95% CI) in favour of PHMB 0.08% was 41.2% (28.8%, 51.2%; p<0.001) compared with any AAT, 29.9% (14.5%, 42.1%; p<0.001) compared with PHMB 0.02% plus a diamidine and 44.8% (23.9%, 62.3%; p<0.001) compared with CXL 0.02% with or without a diamidine. Similar results were observed in the weighted analyses. CONCLUSIONS: These results suggest that PHMB 0.08% when delivered with the recommended protocol is significantly more effective than currently used treatments in achieving clinical resolution without surgery. The study limitations include differences in recruitment periods, diagnostic criteria and drug delivery methodology, as well as limitations of the ITC adjustment measures which can lead to residual confounding.

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Acanthamoeba keratitis is the most dangerous ocular-infection that can cause blindness. The propamidine-isethionate (PI) 0.1% eye-drops are used in the treatment, but they have low-bioavailability due to precorneal loss parameters. In-situ-gels are administered as drops into the eye and changed into gel in the cul-de-sac, which may be able to solve these issues. In this study, we demonstrate different nano-ocular delivery-systems formulations of 0.1%PI loaded in-situ-gels using the ideas of pH & temperature-stimulated in-situ-gelation. Pluronic F-127 a thermosensitive-polymer with chitosan as a pH-sensitive polymer that also enhances permeability was utilized as a gelling-agent. Several in-vitro pharmaceutical and antiprotozoal assessments on Acanthamoeba keratitis were assessed for the developed formulations. It was observed that the created PI-chitosan nanoparticles in-situ-gel formulation showed smaller particle-size, higher zeta with a higher %inhibition of amoebae after 24-h incubation compared to other formulations with continuous drug release for 24-h. The PI-CSNPs in-situ-gel formulation offers an effective substitute for traditional BROLENE eye-drops in the management of Acanthamebae, around double the effect based on % amebae inhibition, reached 92%. It can reach the clinical-stage & is appropriate for sustained-ocular-administration for the treatment of Acanthamoeba keratitis.

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