In this survey, respondents overwhelmingly preferred combination therapy to monotherapy for treatment of acanthamoeba keratitis, although considerable uncertainty remained regarding this choice. This preference for combination therapy mirrors many of the recent case series that describe combination treatment for acanthamoeba keratitis.11–14
This preference is also consistent with case reports of acanthamoeba keratitis that failed monotherapy but subsequently responded to multiple agents.15
Traditionally, combination therapy has been advocated due to the belief that multiple agents were more effective, and selected for less resistance.2
In general, survey respondents agreed with this assessment. However, combination therapy has the potential disadvantages of epithelial toxicity, cost, and compliance,16, 17
all of which were commonly identified as reasons why survey respondents would refrain from using combination therapy. Given the excellent in vitro
susceptibility profile of the biguanide medications for acanthamoeba, monotherapy with one of these medications could be sufficiently effective while avoiding the disadvantages of combination therapy.18
The lack of randomized clinical trials comparing combination therapy with monotherapy for acanthamoeba keratitis makes an evidenced-based decision difficult. Nonetheless, concern for poor outcomes, regardless of which particular treatment is used, may lead some clinicians to use more rather than fewer medications, even if the evidence base for this decision is limited.
Although respondents favored combination therapy over monotherapy, almost half had used monotherapy in the past, with the most popular choice being PHMB, followed by chlorhexidine. Likewise, if asked to choose an ideal medication for use as monotherapy, over half would choose PHMB, and over three-quarters would choose either PHMB or chlorhexidine. This preference is not surprising, given in vitro
and clinical studies of the various medications for acanthamoeba keratitis. Reports have shown that both PHMB and chlorhexidine have in vitro
minimum cysticidal concentrations (MCCs) of roughly 2-3 μg/mL, much lower than the concentrations usually used in clinical practice (0.02% for each).18
Case reports and series have suggested that single-agent treatment with chlorhexidine19, 20
may be successful. A clinical trial comparing chlorhexidine monotherapy with PHMB monotherapy found that these two treatments had similar efficacy for acanthamoeba keratitis, with visual acuity improving in the majority of patients taking each medication.4
Monotherapy with other agents has been even less well characterized, although it is has been well established that the in vitro
susceptibility profile of the diamidines, neomycin, and azoles is inferior to that of the biguanides.11, 18, 24, 25
While the vast majority of respondents used combination therapy, there was little consensus on exactly which agents to use. The most common combination, PHMB and propamidine, accounted for only 11% of all reported regimens of combination therapy. There was broader consensus on classes of medications, with over 65% of reported combinations including a biguanide and diamidine. This is consistent with many recent reports advocating the use of these two classes of medications, with or without other agents.3, 11–13
Choices of combination therapy regimens in an ideal world were not substantially different. This may indicate that clinicians generally have adequate access to their choices of mediations, or alternately could reflect the lack of comparative research regarding acanthamoeba treatment. Over one-third of respondents would include neomycin and/or an azole in their ideal choice of combination therapy, despite in vitro
evidence that these medications have poor activity against acanthamoeba18, 25
and the potential for corneal toxicity.26, 27
The continued use of these agents may be influenced more by their wide availability than by their perceived effectiveness.
Respondents were divided on the use of corticosteroids, with little over half of respondents using corticosteroids in the treatment of acanthamoeba keratitis. The use of steroids in the management of acanthamoeba keratitis is controversial. Animal models have shown that in the absence of anti-acanthamoebal therapy, corticosteroids promote excystment of acanthamoeba cysts and proliferation of trophozoites.28
While some authors have recommended against using corticosteroids during active infection,29, 30
others believe steroid therapy may be useful for control of pain and inflammation when given in combination with adequate anti-acanthamoebal therapy.3, 7, 10
More than 75% of respondents viewed keratoplasty as a viable treatment modality for acanthamoeba keratitis, but most clinicians would only perform keratoplasty after medical treatment had failed. This is consistent with most reports of therapeutic keratoplasty for acanthamoeba, which have found acceptable cure rates, but often in the setting of multiple surgeries and poor visual outcomes.16, 31–35
Almost half of respondents reported using confocal microscopy for the diagnosis of acanthamoeba keratitis, although almost all who did so also used more traditional methods such as smear and culture. Some reports have suggested a favorable sensitivity and specificity of confocal microscopy when compared to culture and smear.36, 37
Nonetheless, this survey suggests that respondents who do use confocal microscopy have not used it as a replacement for smear and culture, but instead are using confocal microscopy as an additional testing modality for a disease that remains difficult to diagnose.
We suspected that respondents may be uncertain about some of their opinions, given the lack of evidence. Eliciting both an estimate and the confidence in that estimate allowed us to assess the uncertainty of the group, as a distribution (). We observed relatively wide distributions for each of the two questions, indicating a high level of uncertainty. These distributions suggest the equipoise necessary for a clinical trial to be considered, and also could be considered as the prior distributions for a Bayesian analysis of a future clinical trial.38–40
This study was limited by factors common to many surveys: low response rate, possibility of recall bias, focus solely on specialists, and unclear generalizability to the underlying study sample. However, we believe the number of respondents was adequate to gauge the preferences of practicing cornea specialists, who likely provide treatment for the majority of patients with acanthamoeba keratitis. The survey asked general questions by design, and did not specify definitions for all terms used. For example, terms like “treatment failure” and “clinical resolution” were left to the judgment of the respondent. Nearly 60% of respondents had seen 10 or fewer cases of acanthamoeba keratitis in the past 5 years. Given the low volume of cases, some respondents may never have encountered a case that failed monotherapy or required steroids, which could alter their practice patterns.
In conclusion, surveyed cornea specialists who treat acanthamoeba keratitis used combination therapy more commonly than single-agent therapy, despite uncertainty about the relative effectiveness of the two. The actual and ideal preferred regimens of both monotherapy and combination therapy for acanthamoeba keratitis were similar. PHMB was the most widely-prescribed medication used in both monotherapy and combination therapy regimens, and the biguanide-diamidine combination was the most common component of combination therapy. Most clinicians believed that corticosteroids and keratoplasty play a role in acanthamoeba keratitis treatment. Adjunctive use of confocal microscopy was commonly used for diagnosing acanthamoeba keratitis. Clinicians expressed a great deal of uncertainty regarding the benefit of combination therapy and the use of corticosteroids, a finding which is not surprising given that acanthamoeba keratitis is a relatively rare event that does not lend itself to comparative effectiveness studies or clinical trials. Nonetheless, the beliefs and practices of cornea specialists are helpful in identifying areas of acanthamoeba keratitis treatment which are still controversial, and in need of further study.