Candida auris: old but new treatment

 A recent article found that the combination of lopinavir with an azole antifungal (itraconazole) may effectively treat multidrug-resistant Candida species, including C. auris, which has recently come to light as a huge potential problem (see candida auris lopinavir plus azole works antimicagentchemo2020 in dropbox, or DOI: 10.1128/AAC.00684-20) 

 

Details: 

-- this is basically a laboratory study, so I will not go into lots of detail 

-- they assessed fluconazole chemosensitization  by 1,547 FDA approved drugs and clinical molecules against azole-resistant C. aureus 

 

Results: 

--lopinavir exhibited potent synergistic interactions with azole drugs, especially with itraconazole but also with fluconazole and voriconazole (lopinavir's combination with itraconazole worked on all C. auris clades, fluconazole only on clade 1, and voriconazole worked only on clades 1 and 4) 

    -- though lopinavir by itself had no antifungal activity 

-- in nematodes, this combination reduced the fungal burden by 88.5% for several medically important Candida species, including C. auris, C. albicans, C. tropicalis, C. krusei, and C. parapsilosis (though not C. glabrata)

-- for C. auris, lopinavir was found to significantly interfere with fungal glucose utilization, ATP synthesis, and the efflux ability of C. auris and thereby increase susceptibility to azole drugs [i.e., azole-resistance was related to the fact that when azoles invaded the C. auris, the azoles were kicked out of the fungal cells and therefore unable to kill them; lopinavir blocked this fungal ability to evict the azoles so that the fungi were no longer resistant to them] 

 

Commentary: 

-- Candida auris has been involved in many global outbreaks of serious invasive infections with very high mortality (40 to 60%) and is resistant to the standard antifungal agents 

-- there are specific groups of C. auris (clades 1, 2, and 4) which have a higher propensity for invasive infections and are more resistant to antifungal drugs, are able to withstand commonly used disinfectants, have the ability to persist on surfaces for extended periods, and have efficient transmissibility among patients 

    -- hyperactivity of the membrane efflux transporters has been found in C. auris of the above clades 

-- about 90% of C. auris are resistant to azoles 

-- a pretty recent blog detailed cases in the US of this highly resistant species, that spreads easily in hospitals and is very hard to eradicate, with some hospitals needing special cleaning equipment and ripping out some the ceilings and floor tiles to eradicate it: see http://gmodestmedblogs.blogspot.com/2019/04/antibiotic-resistant-fungi-c-auris.html 

-- this organism's resistance has evolved largely related to monoculture farming (diversity in farming tends to limit the spread of disease), with multidrug resistance likely related to the fact that antifungal agents are commonly used in agriculture 

-- the CDC in 2019 listed C. auris as an “urgent threat”  (see http://gmodestmedblogs.blogspot.com/2019/11/cdc-updated-threats-of-antibiotic.html )

 

-- I do find it satisfying and efficient to be able to repurpose older medications (e.g. lopinavir), which has gone through some iterations from a primary HIV medication, to one that may have some effect on SARS-CoV-2 (not used now...), and now to perhaps a clinical benefit for C. auris.  And, it is a potentially game-changing to find a potential benefit from co-administering lopinavir with azoles, the old standby antifungal agents which are cheap, oral, and well-tolerated

--and, I do find that the mechanism of action is appealing: lopinavir effectively counteracts the way fungi have developed resistance to azoles by decreasing their efflux from cells. This is very similar to using amoxicillin in patients with clarithromycin-resistant H pylori infections, where pretreating the bacteria with amoxicillin changes the structure of the bacterial cell membrane, effectively disrupting the efflux channels in the cell walls of clarithromycin-resistant H pylori, thereby allowing the clarithromycin to do its destruction. the result is that there is an 89% eradication of clarithromycin-resistant strains responding to clarithromycin after pretreatment with amoxicillin vs 29% with standard clarithromycin-based therapy  (see http://gmodestmedblogs.blogspot.com/2016/10/h-pylori-regimens-stratified-by.html)

 

limitations:
-- most obvious limitation is that this is a bench research study, with some clinical evidence of effectiveness found in nematodes 

 

So, there may be some real clinical efficacy for this drug combination in otherwise largely untreatable infections with multidrug resistant Candida auris. Maybe even with the very difficult process of disinfecting contaminated hospital rooms. And, lopinavir makes yet another appearance on the scene, repurposed this time as a sensitizer to the antifungal agent itraconazole. This clearly is a potential treatment regimen that should be assessed in humans, for what could be a spreading scourge….

and, i want to use this example as another of many stressing the baseline importance of fundamental changes necessary in industrial farming to avoid current and future development of multidrug resistant microbes, some without any effective antibiotic therapy (as with c. auris) (see http://gmodestmedblogs.blogspot.com/2017/03/antibiotic-resistant-bacteria-of-concern.html )

geoff

 

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