There are no agents approved for the treatment of AK in any country. In recent years combinations of unlicensed anti-amoebic agents such as biguanides and diamidines have greatly improved the treatment outcome of Acanthamoeba keratitis. They have shown some efficacy but the treatment regimens and the concentrations of active agents are based on empirical safety and efficacy data (Dart et al. 2009). The ODAK project will address this issue by developing the first approved drug of AK and providing a well researched evidence base for safe effective future treatment regimens.
The use of biguanides has revolutionized the treatment of early cases of Acanthamoeba keratitis: relief of pain is rapid and active infection is usually eradicated after 4 weeks as opposed, to 4 months or longer, with propamidine and neomycin. The Acanthamoeba cysts can withstand a wide variety of physical conditions and drugs and this makes the medical treatment both difficult and protracted. Failure to eradicate the viable cysts results in reoccurrence of the disease. The only available and consistently cysticidal agents are the biguanides PHMB and Chlorhexidine. Typically treatment involves a biguanide (PHMB 0.02% or chlorhexidine 0.02%) and a diamidine (propamidine 0.1% or hexaidine 0.1%) although there is no clinical data indicating this association is more effective than monotherapy with PHMB. The dosage regimen has not been standardized and a significant statistical evaluation is lacking.
Treatment is now effective in most cases using biguanides (PHMB or chlorhexidine) either as monotherapy or combined with propamidine by inactivating trophozoites and cysts in Acanthamoeba keratitis in the majority of patients (90%) (Seal D. 2003). In a multicentre study in the UK the average duration of medical therapy was 6 months (Range 0.5-29 months; 218 patients). Late presenting cases, (infection established > 3 months) remain difficult to treat, requiring prolonged drug therapy as well as graft surgery.
Dart et al. (2009) highlighted the lack of information on biguanides for the treatment of AK which raises concerns about potential local toxicity. The article states that a major step forward in the treatment of AK would be the licensing of either PHMB or chlorhexidine as an orphan medicine such that associated data on toxicity, antimicrobial efficacy and pharmacokinetics would result. In addition, a recent international survey of 82 ophthalmologists and vision scientists highlighted the lack of sufficiently powered comparative effectiveness clinical trials, making evidence based decision making for AK difficult. This study identified PHMB as the most common “ideal choice” for monotherapy and 94% used a biguanide in combination therapy, the more experienced clinicians were most likely to choose PHMB (Oldenbrg et al 2011).
Typical Treatment Regimen
Treatment typically starts with 0.02% (200 µg/ml) PHMB or chorhexidine digluconate in physiological saline and propamidine isethionate 0.1% (1000 µg/ml) in physiological saline. Hexamidine (Desmodine) can be used as an alternative, commercially available diamidine drug instead of propamidine.
Usually these drugs are given every hour, day and night for the first 3 days, reducing to 2-hourly by day only. Adjunctive therapy includes oral flurbiprofen for both non-steroidal anti-inflammatory and analgesic effects and topical mydriatic. If diagnosed early, medical cure is possible with complete recovery of vision. One week after starting therapy, however, there may be a corneal reaction to antigens or toxins from lysis of dead amoebae, with localized stromal oedema and anterior chamber activity, which lasts up to 3 weeks. Although this may be suppressed with corticosteroids, their use is not encouraged. Corticosteroids suppress the activity of the macrophage, which is essential in scavenging and destroying amoeba. In general, it is recommended to delay and limit steroid use as much as possible, utilizing it in combination with antiamoebic agents and only in those patients with severe pain, scleritis or severe anterior chamber inflammation.
In some late-presenting cases with deep stromal infection Acanthamoeba can persist causing an active infection despite treatment with PHMB or chlorhexidine, but when isolated and cultured, the organism is found to be sensitive to these compounds. It is not understood why the biguanide can be ineffective in vivo. Further studies are necessary in this situation (Seal D. 2003).
Cyst sensitivity to PHMB is higher than to propamidine (Larkin DF et al., 1992; Seal D. 1996). For such reasons, some feel that the combination therapy with propamidine is outdated and recommend intensive monotherapy with PHMB (or chlorhexidine) alone (Seal D. 2003; Mathers W. 2006).