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in resource - rich settings , echinocandins are the antifungal agents of choice for invasive infections caused by candida glabrata due to the relative resistance of this species to azole antifungals .
anidulafungin , caspofungin and micafungin disrupt the synthesis of -1,3-d - glucan , an essential fungal cell wall component , by inhibiting -1,3-d - glucan synthase .
-1,3-d - glucan synthase is an enzyme complex comprised of two subunits : fksp , a catalytic subunit and rho1p , a regulatory subunit .
it is thought that the echinocandins bind to fksp , which is encoded by three related genes : fks1 , fks2 and fks3 . reduced susceptibility to echinocandins is associated with amino acid substitutions in two highly - conserved hot - spot regions of the fks genes . for c. glabrata ,
a variety of amino acid changes in the hotspot regions of fks1 and fks2 confer resistance to the echinocandins , .
here we describe the first two south african c. glabrata isolates with echinocandin resistance mediated by mutations in the fks2 gene .
both isolates were cultured from urine specimens of patients treated in the private health sector .
the first patient was a 29-year - old female with osteogenesis imperfecta who was re - admitted in october 2014 to the intensive care unit ( icu ) of a private hospital in johannesburg in septic shock ( day 0 ) .
the patient was admitted one week after a prior prolonged icu admission for severe pneumonia and was treated with empiric antibiotics and fluids .
klebsiella pneumoniae and enterococcus faecalis were isolated from re - admission blood cultures . c. glabrata was cultured from a urine specimen on day + 46 and this isolate
was submitted to a reference laboratory for confirmation of species - level identification and antifungal susceptibility testing . despite an initial improvement in her condition ,
the patient deteriorated and she died approximately two months after re - admission ( day + 60 ) . at the diagnostic laboratory , the isolate was initially identified as c. glabrata using the maldi - tof ms instrument ( biomrieux , marcy etoile , france ) and minimum inhibitory concentrations ( mics )
were determined using pre - prepared sensititre yeastone microbroth dilution panels ( thermo fisher scientific , cleveland , ohio , usa ) : 8  g / ml for fluconazole , 0.5  g / ml for voriconazole , 0.25  g / ml for caspofungin and 0.5  g / ml for anidulafungin .
identification of the isolate was confirmed by sequencing of the internal transcribed spacer ( its ) region of the ribosomal rna gene at the reference laboratory .
mics were then confirmed using the same microbroth dilution panels ( thermo fisher scientific , cleveland , ohio , usa ) and by etest ( biomrieux , marcy etoile , france ) on rpmi 1640 plates containing 2% glucose ( diagnostic media products , nhls , south africa ) , as recommended by the manufacturer .
echinocandin mics generated by the sensititre yeastone method are comparable to those generated using the clinical and laboratory standards institute ( clsi ) m27-a3 method .three reference laboratory personnel performed susceptibility tests independently and in duplicate .
the quality control ( qc ) strains , candida parapsilosis atcc 22019 and candida krusei atcc 6258 were run simultaneously and mics were within expected qc ranges .
the broth microdilution mic ranges were 0.51  g / ml ( clsi m27-s4 resistance breakpoint 0.5  g / ml ) for anidulafungin , 0.25  g / ml for micafungin ( clsi resistance breakpoint 0.25  g / ml ) and 16  g / ml for fluconazole ( clsi resistance breakpoint 64  g / ml ) ( table 1 ) . the etest mic ranges were 0.50.75  g / ml and 0.190.25  g / ml for anidulafungin and micafungin respectively and 3  8  g / ml for fluconazole . published epidemiologic cut - off values ( ecvs ) determined by multiple laboratories for the sensititre yeastone method were also applied to the mic of each tested antifungal agent to determine whether the isolate was wild type or a mutant ( table 1 ) , , .
a mutation was detected in the hotspot 1 region of the fks2 gene where serine was replaced by phenylalanine at position 663 ( s663f ) . in september 2015 , a second c. glabrata strain from another patient was submitted to the reference laboratory for confirmatory tests ( private - sector patient ; urine specimen ; clinical details unavailable ) .
the anidulafungin and micafungin mics were both 2  g / ml by the sensititre yeastone method and a change from arginine to lysine at amino acid position 1377 ( r1377k ) was identified by sequencing the fks2 hotspot 2 region .
this is the first report of echinocandin - resistant c. glabrata isolates from south africa , mediated by fks2 gene mutations , and isolated from the urine of two patients in the private sector .
the echinocandins have increasingly been used for first - line management of candidaemia , especially in the private sector , since 2007 when caspofungin was registered .
anidulafungin and micafungin have since also been registered . in a national surveillance study conducted in south africa in 2009 and 2010 ,
only ten of 1252 ( 0.8% ) bloodstream candida isolates had resistant/ intermediate micafungin or anidulafungin mic values and were considered to be non - susceptible to the echinocandins .
however , fks gene sequencing of the ten isolates , including three c. glabrata isolates , yielded no mutations in the hotspot regions . as a result of poor in - vivo glomerular filtration or tubular secretion
we hypothesize that exposure of the c. glabrata strains to sub - therapeutic echinocandin concentrations may have led to emergence of resistance in the two cases that we report here .
a travel history was not available for either patient ; therefore , it is not known if these mutant strains were acquired .
the s663f mutation has not been described as often as the serine to proline replacement at the same amino acid position . in a us population - based surveillance study , of 490 bloodstream c. glabrata isolates , 16 ( 3% ) had elevated echinocandin mics and an fks mutation
. of 11 isolates with mutations in fks2 hotspot 1 at amino acid position 663 , only one had the serine to phenyalanine replacement that we describe here . in another us study ,
77 of 1032 ( 7% ) isolates had echinocandin mics in the intermediate or resistant categories , 51 of which had fks mutations ; two isolates had the s663f mutation .
previously , a nonsense mutation at fks 2 hotspot 2 has been described where arginine was replaced with a stop codon at amino acid position 1377 .
caspofungin mics are an unreliable indicator of echinocandin resistance owing to inter - laboratory variation of mic readings especially for c. glabrata ; instead , anidulafungin or micafungin mics have been recommended to predict susceptibility to the class , . in conclusion , we have described the first two cases of echinocandin - resistant c. glabrata isolates in south africa .
systematic active laboratory surveys , including isolates from cases of non - invasive candida infection , are needed to determine if echinocandin resistance has become more widespread in south africa .
for unrelated work , nelesh p. govender has received speaker honoraria from pfizer , astellas and msd ( pty ) ltd , has received travel grants from msd ( pty ) ltd , has provided educational materials for terranova and has acted as a temporary consultant for fujifilm pharmaceuticals . for the remaining authors ,
echinocandins are recommended as first - line agents to treat invasive infections caused by candida glabrata since this organism is inherently less susceptible to azoles . 
 however , resistance to echinocandins has been described in c. glabrata due to amino acid changes in the hotspot regions of the fks1 and fks2 genes . in this report 
 , we describe the first two south african c. glabrata isolates with echinocandin resistance mediated by mutations in the fks2 gene . 
 both isolates were cultured from urine specimens from private - sector patients .