Fun­gal in­fec­tion im­mune to drugs qui­etly sweeps globe

The Buffalo News - - FRONT PAGE - By Matt Richtel and An­drew Ja­cobs

In May 2018, an el­derly man was ad­mit­ted to the Brook­lyn branch of Mount Si­nai Hospi­tal for ab­dom­i­nal surgery. A blood test re­vealed that he was in­fected with a newly dis­cov­ered germ as deadly as it was mys­te­ri­ous.

The germ, a fun­gus called Can­dida au­ris, preys on peo­ple with weak­ened im­mune sys­tems, and it is qui­etly spread­ing across the globe. Re­cently C. au­ris reached New York, New Jersey and Illi­nois, lead­ing the fed­eral Cen­ters for Dis­ease Con­trol and Pre­ven­tion to add it to a list of germs deemed “ur­gent threats.”

The man at Mount Si­nai died af­ter 90 days in the hospi­tal, but C. au­ris did not. Tests showed it was every­where in his

room, so in­va­sive that the hospi­tal needed spe­cial clean­ing equip­ment and had to rip out some of the ceil­ing and floor tiles to erad­i­cate it.

C. au­ris is so tena­cious, in part, be­cause it is im­per­vi­ous to ma­jor an­ti­fun­gal med­i­ca­tions, mak­ing it a new ex­am­ple of one of the world’s most in­tractable health threats: the rise of drug-re­sis­tant in­fec­tions.

For decades, pub­lic health ex­perts have warned that the overuse of an­tibi­otics was re­duc­ing the ef­fec­tive­ness of drugs that have length­ened life spans by cur­ing bac­te­rial in­fec­tions once com­monly fa­tal. But lately, there has been an ex­plo­sion of re­sis­tant fungi as well.

“It’s an enor­mous prob­lem,” said Matthew Fisher, a pro­fes­sor of fun­gal epi­demi­ol­ogy at Im­pe­rial Col­lege Lon­don. “We de­pend on be­ing able to treat those pa­tients with an­ti­fun­gals.”

Sim­ply put, fungi, just like bac­te­ria, are evolv­ing de­fenses to sur­vive mod­ern medicines. A study the British gov­ern­ment funded projects that if poli­cies are not put in place to slow the rise of drug re­sis­tance, 10 mil­lion peo­ple could die world­wide of all such in­fec­tions in 2050, eclips­ing the 8 mil­lion ex­pected to die that year from can­cer.

An­tibi­otics and an­ti­fun­gals are es­sen­tial to com­bat in­fec­tions in peo­ple, but an­tibi­otics are also used widely to pre­vent dis­ease in farm an­i­mals, and an­ti­fun­gals are also ap­plied to pre­vent agri­cul­tural plants from rot­ting. Some sci­en­tists cite ev­i­dence that ram­pant use of fungi­cides on crops is con­tribut­ing to the surge in dru­gre­sis­tant fungi in­fect­ing hu­mans.

Yet as the prob­lem grows, it is lit­tle un­der­stood by the pub­lic – in part be­cause the very ex­is­tence of re­sis­tant in­fec­tions is of­ten cloaked in se­crecy. With bac­te­ria and fungi alike, hos­pi­tals and lo­cal gov­ern­ments are reluc­tant to dis­close out­breaks for fear of be­ing seen as in­fec­tion hubs.

C. au­ris, which in­fected the man at Mount Si­nai, is one of dozens of dan­ger­ous bac­te­ria and fungi that have de­vel­oped re­sis­tance. Yet, like most of them, it is a threat that is vir­tu­ally un­known to the pub­lic.

Other prom­i­nent strains of the fun­gus Can­dida – one of the most com­mon causes of blood­stream in­fec­tions in hos­pi­tals – have not de­vel­oped sig­nif­i­cant re­sis­tance to drugs, but more than 90 per­cent of C. au­ris in­fec­tions are re­sis­tant to at least one drug, and 30 per­cent are re­sis­tant to two or more drugs, the CDC said.

Nearly half of pa­tients who con­tract C. au­ris die within 90 days, ac­cord­ing to the CDC. Yet the world’s ex­perts have not nailed down where it came from in the first place.

“It is a crea­ture from the black la­goon,” said Dr. Tom Chiller, who heads the fun­gal branch at the CDC. “It bub­bled up and now it is every­where.”

‘No need’ to tell pub­lic

In late 2015, Dr. Johanna Rhodes, an in­fec­tious dis­ease ex­pert at Im­pe­rial Col­lege Lon­don, got a pan­icked call from the Royal Brompton Hospi­tal out­side Lon­don. C. au­ris had taken root there months ear­lier, and the hospi­tal couldn’t clear it.

“We have no idea where it’s com­ing from. We’ve never heard of it. It’s just spread like wildfire,” Rhodes said she was told. She agreed to help the hospi­tal iden­tify the fun­gus’ ge­netic pro­file and clean it from rooms.

It was spread­ing, but word of it was not. The hospi­tal, a spe­cialty lung and heart cen­ter that draws wealthy pa­tients from the Mid­dle East and around Europe, alerted the British gov­ern­ment and told in­fected pa­tients, but made no pub­lic an­nounce­ment.

This hushed panic is play­ing out in hos­pi­tals around the world. In­di­vid­ual in­sti­tu­tions and na­tional, state and lo­cal gov­ern­ments have been reluc­tant to pub­li­cize out­breaks of re­sis­tant in­fec­tions, ar­gu­ing there is no point in scar­ing pa­tients – or prospec­tive ones.

Dr. Silke Sche­lenz, Royal Brompton’s in­fec­tious dis­ease spe­cial­ist, found the lack of ur­gency from the gov­ern­ment and hospi­tal in the early stages of the out­break “very, very frus­trat­ing.”

“They ob­vi­ously didn’t want to lose rep­u­ta­tion,” Sche­lenz said. “It hadn’t im­pacted our sur­gi­cal out­comes.”

By the end of June 2016, a sci­en­tific pa­per re­ported “an on­go­ing out­break of 50 C. au­ris cases” at Royal Brompton, and the hospi­tal took an ex­tra­or­di­nary step: It shut down its ICU for 11 days, again with no an­nounce­ment.

Days later the hospi­tal fi­nally ac­knowl­edged to a news­pa­per that it had a prob­lem. A head­line in the Daily Tele­graph warned, “In­ten­sive Care Unit Closed Af­ter Deadly New Su­per­bug Emerges in the U.K.”

Yet the is­sue re­mained lit­tle known in­ter­na­tion­ally, while an even big­ger out­break had be­gun in Va­len­cia, Spain, at the Hospi­tal Univer­si­tari i Po­litec­nic La Fe. As with Royal Brompton, the hospi­tal in Spain did not make any pub­lic an­nounce­ment. It still has not.

The se­crecy in­fu­ri­ates pa­tient ad­vo­cates, who say peo­ple have a right to know if there is an out­break.

“Why the heck are we read­ing about an out­break al­most a year and a half later – and not have it front-page news the day af­ter it hap­pens?” said Dr. Kevin Ka­vanagh, chair­man of Health Watch USA, a non­profit pa­tient ad­vo­cacy group.

Health of­fi­cials say that dis­clos­ing out­breaks fright­ens pa­tients about a sit­u­a­tion they can do noth­ing about, par­tic­u­larly when the risks are un­clear.

“It’s hard enough with th­ese or­gan­isms for health care providers to wrap their heads around it,” said Dr. Anna Yaf­fee, a for­mer CDC out­break in­ves­ti­ga­tor. “It’s re­ally im­pos­si­ble to mes­sage to the pub­lic.”

Of­fi­cials in Lon­don did alert the CDC to the Royal Brompton out­break while it was oc­cur­ring. And the CDC re­al­ized it needed to get the word to U.S. hos­pi­tals.

On June 24, 2016, the CDC blasted a na­tion­wide warn­ing and set up an email ad­dress, can­di­daau­[email protected], to field queries. Dr. Snigdha Vallabhaneni, a key mem­ber of the fun­gal team, ex­pected to get a trickle – “maybe a mes­sage every month.”

In­stead, within weeks, her in­box ex­ploded. In the United States, 587 cases of peo­ple hav­ing con­tracted C. au­ris have been re­ported, ac­cord­ing to the CDC. The symp­toms – fever, aches and fa­tigue – are seem­ingly or­di­nary, but when a per­son gets in­fected, par­tic­u­larly some­one al­ready un­healthy, such com­mon­place symp­toms can be fa­tal.

The role of pes­ti­cides

As the CDC works to limit the spread of drug-re­sis­tant C. au­ris, its in­ves­ti­ga­tors have been try­ing to answer the vex­ing ques­tion: Where in the world did it come from?

The first time doc­tors en­coun­tered C. au­ris was in the ear of a woman in Japan in 2009 (au­ris is Latin for ear). It seemed in­nocu­ous at the time, a cousin of com­mon, eas­ily treated fun­gal in­fec­tions. Three years later, it ap­peared in an un­usual test re­sult in the lab of Dr. Jac­ques Meis, a mi­cro­bi­ol­o­gist in Ni­jmegen, Nether­lands, who was an­a­lyz­ing a blood­stream in­fec­tion in 18 pa­tients from four hos­pi­tals in In­dia. Soon, new clus­ters of C. au­ris seemed to emerge with each pass­ing month in dif­fer­ent parts of the world.

When the CDC in­ves­ti­ga­tors com­pared the en­tire genome of au­ris sam­ples from In­dia and Pak­istan, Venezuela, South Africa and Japan, they found that its ori­gin was not a sin­gle place, and there was not a sin­gle au­ris strain. The genome se­quenc­ing showed that there were four dis­tinc­tive ver­sions of the fun­gus, with dif­fer­ences so pro­found that they sug­gested that th­ese strains had di­verged thou­sands of years ago and emerged as re­sis­tant pathogens from harm­less en­vi­ron­men­tal strains in four dif­fer­ent places at the same time.

“Some­how, it made a jump al­most seem­ingly si­mul­ta­ne­ously, and seemed to spread and it is drug-re­sis­tant, which is re­ally mind-bog­gling,” Vallabhaneni said.

There are dif­fer­ent the­o­ries as to what hap­pened with C. au­ris. Meis, the Dutch re­searcher, said he be­lieved that drug-re­sis­tant fungi were de­vel­op­ing, thanks to heavy use of fungi­cides on crops.

Meis be­came in­trigued by re­sis­tant fungi when he heard about the case of a 63-year-old pa­tient in the Nether­lands who died in 2005 from a fun­gus called Aspergillus. It proved re­sis­tant to a front-line an­ti­fun­gal treat­ment called itra­cona­zole. That drug is a vir­tual copy of the azole pes­ti­cides that are used to dust crops the world over.

Chiller of the CDC the­o­rizes that C. au­ris may have ben­e­fited from the heavy use of fungi­cides. His idea is that C. au­ris ac­tu­ally has ex­isted for thou­sands of years, a not par­tic­u­larly ag­gres­sive bug. But as azoles be­gan de­stroy­ing more preva­lent fungi, an op­por­tu­nity ar­rived for C. au­ris to en­ter the breach.

The mys­tery of C. au­ris’ emer­gence re­mains un­solved, and its ori­gin seems, for the mo­ment, to be less im­por­tant than stopping its spread.

Cen­ters for Dis­ease Con­trol and Pre­ven­tion via The New York Times

Cul­tured Can­dida au­ris in a petri dish. Re­sis­tant to many anti-fun­gal med­i­ca­tions, C. au­ris can cause dan­ger­ous in­fec­tions that can be life-threat­en­ing.

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