In Vitro Activity of Chlorhexidine Compared with Seven Antifungal Agents against 98 Fusarium Isolates Recovered from Fungal Keratitis Patients

Abstract

Fungal keratitis is a common but severe eye infection in tropical and subtropical areas of the world. In regions with a temperate climate, the frequency of infection is rising in patients with contact lenses and following trauma. Early and adequate therapy is important to prevent disease progression and loss of vision. The management of Fusarium keratitis is complex, and the optimal treatment is not well defined. We investigated the in vitro activity of chlorhexidine and seven antifungal agents against a well-characterized collection of Fusarium isolates recovered from patients with Fusarium keratitis. The fungus culture collection of the Center of Expertise in Mycology Radboudumc/CWZ was searched for Fusarium isolates that were cultured from cornea scrapings, ocular biopsy specimens, eye swabs, and contact lens fluid containers from patients with suspected keratitis. The Fusarium isolates that were cultured from patients with confirmed keratitis were all identified using conventional and molecular techniques. Antifungal susceptibility testing was performed according to the EUCAST broth microdilution reference method. The antifungal agents tested included amphotericin B, voriconazole, posaconazole, miconazole, natamycin, 5-fluorocytosine, and caspofungin. In addition, the activity of chlorhexidine was determined. The fungal culture collection contained 98 Fusarium isolates of confirmed fungal keratitis cases from 83 Dutch patients and 15 Tanzanian patients. The isolates were collected between 2007 and 2017. Fusarium oxysporum (n = 24, 24.5%) was the most frequently isolated species followed by Fusarium solani sensu stricto (n = 18, 18.4%) and Fusarium petroliphilum (n = 11, 11.2%). Amphotericin B showed the most favorable in vitro inhibition of Fusarium species followed by natamycin, voriconazole, and chlorhexidine, while 5-fluorocytosine, posaconazole, miconazole, and caspofungin showed no relevant inhibiting effect. However, chlorhexidine showed fungicidal activity against 90% of F. oxysporum strains and 100% of the F. solani strains. Our study supports the clinical efficacy of chlorhexidine and therefore warrants its further clinical evaluation for primary therapy of fungal keratitis, particularly in low and middle income countries where fungal keratitis is much more frequent and, currently, antifungal eye drops are often unavailable.

Chlorhexidine for the Treatment of Fusarium Keratitis: A Case Series and Mini Review

“…Our susceptibility data suggest that the standard chlorhexidine concentration used for the treatment of Acanthamoeba keratitis (0.02%) may also be effective for the treatment of fungal keratitis. This is also supported by published in vitro data [ 16 , 17 , 18 ]. The main difficulties with topical antifungal treatment of ocular infections are poor ocular penetration and local bioavailability, the limited number of preparations, and drug toxicity.…”

Epidemiology and Clinical Management of Fusarium keratitis in the Netherlands, 2005–2016

“…There is increasing evidence that chlorhexidine may be effective for the treatment of Fusarium keratitis, supported by both clinical trials and in vitro studies (Rahman et al, 1997(Rahman et al, , 1998. We recently showed that chlorhexidine exhibited fungicidal activity against a broad range of filamentous fungi including Fusarium species, at concentrations that could be readily achieved clinically (Oliveira dos Santos et al, 2019). The activity of chlorhexidine against Acanthamoeba and bacteria makes it a very attractive agent for local treatment of keratitis.…”

“…Rational treatment choices are also hampered by the lack of correlation between MIC and drug efficacy. The most frequently isolated Fusarium species complexes (FSSC, FOSC and FFSC) are generally multidrug resistant in vitro and any activity is at best fungistatic (Oliveira dos Santos et al, 2019). The use of MICs to guide treatment choices is limited due to the fact that through topical therapy the fungus is exposed to very high drug concentrations and thus may respond despite a high in vitro MIC.…”

The combined utilization of Chlorhexidine and Voriconazole or Natamycin to combat Fusarium infections

“…There are several studies showing that CHL exhibits in vitro antifungal activity against Fusarium spp. Oliveira et al found that CHL exhibited fungicidal activity against 90% of tested F. oxysporum strains and 100% of tested F. solani strains when evaluating 98 strains isolated from fungal keratitis patients [ 11 ]. Xu et al found that the MIC range for CHL is 8–32 μg/mL, while the MIC 90 value of chlorhexidine was 32 μg/mL for 24 F. solani strains [ 12 ].…”