The Day-1 Treatment Regimen For 0.3% Ciprofloxacin And 0.3% Ofloxacin In Bacterial Keratitis: Do The Guidelines Need To Be Revised?

Available Day-1 drop regimen guidelines for the topical fluoroquinolones 0.3% ciprofloxacin and 0.3% ofloxacin (2FQ) for  treating  bacterial keratitis (BK) vary greatly, and few are referenced to a clinical trial. We examined the issue by: 1) an analysis of published clinical trials to derive evidence based drop regimen; and 2) analysing published 2FQ corneal concentrations and the Minimum Inhibitory Concentration₉₀ (MIC₉₀) of BK isolates. Both approaches indicated much higher numbers of drops on Day-1 for each FQ than most published guidelines. We show that guidelines proposing different regimen for mild, moderate and severe BK are not evidence based, and the same Day-1 regimen should be used for all BK presentations.

As academics training health professionals in optometry and ophthalmology, we discovered that many published guidelines for the Day-1 treatment of BK with the 2FQs did not provide an evidence base for their guidelines. We reviewed the clinical trials and pharmacodynamic literature (DOI:10.1016/j.clae.2022.101725; DOI:10.1089/jop.2022.0110) and also examined the case for different drop regimen based on categorisation. (DOI:10.1016/j.curtheres.2023.100729) to create an evidence based approach. 

Large-scale literature reviews using PubMed, Google and other search engines were used to provide information for three publications summarised here. Day-1 is defined as the 24-hour period following the diagnosis of BK and the initiation of treatment. For the clinical trial review, 11 studies which utilised the 2FQ which met the inclusion criteria were included. MIC₉₀ refers to the lowest concentration required to inhibit growth in 90% of bacteria. For the study of corneal concentrations of ciprofloxacin and ofloxacin, animal and human cadaver studies were excluded. The BK ulcer size categorisation study reviewed 31 publications. Articles other than those in English were excluded.

Analysis of the six 0.3% ciprofloxacin trials found that lower drop numbers on Day-1 were associated with higher treatment failure rates (p < 0.002). To achieve the median failure rate of 0.3% ofloxacin (5 trials, median drops on Day-1, 24) 47.2 drops on Day-1 were required. This reflects the disparity in the manufacturers Day-1 recommendations (0.3% ciprofloxacin 120 drops and 0.3% ofloxacin 34 to 68 drops). To achieve maximum corneal 2FQ concentrations, the manufacturers’ recommended drop regimen for both 2FQ are the most pharmacodynamically appropriate. No clinical trial had categorised BK ulcers as mild, moderate or severe or by size. Thus, there is no evidence that any BK ulcers should be treated differently to any other with the 2FQ.

Collectively, the evidence from our three published papers indicates that the manufacturers’ Day-1 regimen for bacterial keratitis using either 0.3% ciprofloxacin or 0.3% ofloxacin are the most appropriate treatment protocol.  Many published guidelines suggest much less stringent Day-1 drop regimen. Our analysis of the published papers related to the use of 0.3% ciprofloxacin and 0.3% ofloxacin indicate that lower drop recommendations may be associated with higher treatment failure rates. Aspects of these findings may also be applicable to the other topical antibiotics used to treat BK. Providers of BK treatment guidelines that are not referenced to either our published papers or a specific clinical trial should review those guidelines.