Silent pan­demic

Covid-19 has reignited con­cerns about an­tibi­otic re­sis­tance. Is the mar­ket for new drugs in need of re­form?

Geographical - - WORLD­WATCH -

An in­con­ve­nient truth: as the Covid-19 pan­demic ploughs on, a slower-act­ing pan­demic may fol­low closely be­hind. Prior to the emer­gence of the novel coro­n­avirus, the de­vel­op­ment of an­tibi­otic re­sis­tance – in which in­fec­tious dis­eases be­come re­sis­tant to our arsenal of an­tibi­otics – was re­ferred to as the ‘silent pan­demic’. Many clin­i­cians are now con­cerned that the num­ber of pa­tients with Covid-19 be­ing treated with an­tibi­otics could ex­ac­er­bate re­sis­tance, lead­ing to more dif­fi­cult-totreat in­fec­tions in the fu­ture.

Stud­ies show that one in seven pa­tients hos­pi­talised with Covid-19 have ac­quired a dan­ger­ous se­condary bac­te­rial in­fec­tion on top of their in­fec­tion with SARSCoV-2. The need to treat these se­condary in­fec­tions is para­mount: half of those who have died with Covid-19 have car­ried them. How­ever, emerg­ing data show that an­tibi­otics might be be­ing pre­scribed too read­ily, lead­ing to mis­use that could drive an­tibi­otic re­sis­tance. An early study of Covid-19 pa­tients treated in Wuhan – the cen­tre of the ini­tial out­break – found that 95 per cent were treated with an­tibi­otics. A more re­cent clin­i­cal re­view shows that while 72 per cent of Covid-19 pa­tients have re­ceived an­tibi­otics, only eight per cent demon­strated bac­te­rial or fun­gal in­fec­tions. ‘In the early stages of the pan­demic, doc­tors were ap­pro­pri­ately cau­tious be­cause they didn’t want peo­ple to sur­vive the virus, but die from se­condary bac­te­rial in­fec­tions,’ ex­plains Kevin Out­ter­son, an­tibi­otics ex­pert and ex­ec­u­tive di­rec­tor of CARB-X, an an­tibi­otics in­no­va­tion fund. ‘You would need to have been a physi­cian at their hos­pi­tal, in the con­text of a pan­demic, to be in a po­si­tion to judge their think­ing. But, with­out a doubt, there have been a lot of pa­tients who have taken an­tibi­otics, who in ret­ro­spect did not need them – and that is guar­an­teed to drive an­tibi­otic re­sis­tance.’

As the world’s at­ten­tion is gripped by the Covid-19 pan­demic, top-tier clin­i­cians are urg­ing us not to lose sight of the silent pan­demic. ‘The chal­lenge of an­tibi­otic re­sis­tance could be­come an enor­mous force of ad­di­tional sick­ness and death across our health sys­tem as the toll of coro­n­avirus-re­lated pneu­mo­nia stretches crit­i­cal-care units be­yond their ca­pac­ity,’ wrote

Julie Ger­berd­ing, a physi­cian who was di­rec­tor of the US Cen­ters for Dis­ease Con­trol and Preven­tion dur­ing the Ge­orge W Bush ad­min­is­tra­tion, in an open plea pub­lished on 23 March.

Her warn­ing be­came a call to re­form the an­tibi­otic de­vel­op­ment process: ‘To fight these su­per­bugs, we des­per­ately need new an­tibi­otics. An im­por­tant ques­tion pol­i­cy­mak­ers should be ask­ing them­selves is: why don’t we have pow­er­ful an­tibi­otics on hand when we need them the most?’

To­day, an­tibi­otic-re­sis­tant in­fec­tions cause 700,000 deaths per year – a fig­ure that the World Health Or­ga­ni­za­tion es­ti­mates will rise to 10 mil­lion per year by 2050 at cur­rent tra­jec­to­ries. The num­ber of re­sis­tant in­fec­tions is grow­ing world­wide. An un­prece­dented epi­demic of an­tibi­otic-re­sis­tant typhoid caused by Sal­mo­nella en­ter­ica has oc­curred in parts of Asia and Africa; 5,274 peo­ple were in­fected with an­tibi­otic-re­sis­tant typhoid dur­ing an out­break in Sindh Prov­ince in Pak­istan be­tween 2016 and 2018.

In a 2017 report, DRIVE-AB – an an­tibi­otics re­search in­vest­ment ini­tia­tive – pre­dicted that deaths from res­pi­ra­tory pathogens (in­clud­ing those known to cause se­condary in­fec­tions in Covid-19 pa­tients), such as Kleb­siella pneu­mo­niae, may dou­ble by 2050.

The prob­lem is that clin­i­cians are faced with a bar­ren phar­ma­ceu­ti­cal pipe­line – no new an­tibi­otic classes have been dis­cov­ered since the 1970s. New an­tibi­otics that have entered the mar­ket have been de­riv­a­tives of es­tab­lished drugs. A frag­ile com­mer­cial en­vi­ron­ment with ex­tremely high de­vel­op­ment costs and very low re­turns on in­vest­ment is largely to blame. ‘The sci­ence of an­tibi­otics is not the prob­lem here. It’s the eco­nomics that are bro­ken,’ says Out­ter­son. Achao­gen, the com­pany that man­u­fac­tured Pla­zomicin, de­clared bank­ruptcy in 2019 af­ter the first year of sales of the new an­tibi­otic to­talled less than US$1 mil­lion. It wasn’t alone. In fact, four of the last 14 an­tibi­otics ap­proved by the FDA went into bank­ruptcy in 2019. There were 18 global phar­ma­ceu­ti­cal com­pa­nies de­vel­op­ing an­tibi­otics in 1990 – to­day there are five.

Phar­ma­ceu­ti­cal com­pa­nies are dis­in­cen­tivised to de­velop an­tibi­otics be­cause they are taken for short pe­ri­ods of time, un­like med­i­ca­tion for chronic con­di­tions such as di­a­betes or arthri­tis. Com­pa­nies aren’t will­ing to take on the fi­nan­cial risks of clin­i­cal de­vel­op­ment, which can take a min­i­mum of nine years and US$1 bil­lion up­front.

If we’re to stop our­selves from be­ing cast back into the pre-an­tibi­otic era of health­care, Out­ter­son thinks we must fix these bro­ken eco­nomics. ‘There’s no other sec­tors of the econ­omy where the most in­no­va­tive prod­uct is ac­tively dis­cour­aged from be­ing de­vel­oped. If this was the case with mo­bile phones, we’d still be talk­ing on bricks. We need a dif­fer­ent way to re­im­burse an­tibi­otics de­vel­op­ment to en­cour­age in­no­va­tion.’ In­cen­tive ini­tia­tives are emerg­ing. CARB-X is a part­ner­ship be­tween gov­ern­ments and phil­an­thropic or­gan­i­sa­tions that pulls funds to­gether to help phar­ma­ceu­ti­cal com­pa­nies push new an­tibi­otics through early clin­i­cal de­vel­op­ment. So far, CARB-X has in­vested more than US$240 mil­lion across 64 projects, yield­ing 16 po­ten­tial new classes of an­tibi­otics. Sim­i­larly, the AMR Ac­tion Fund is a nearly US$1 bil­lion fund put for­ward by 23 ma­jor play­ers in the phar­ma­ceu­ti­cal in­dus­try. By help­ing to fund the ex­pen­sive lat­ter stages of clin­i­cal de­vel­op­ment, they aim to bring two to four new an­tibi­otics to mar­ket by 2030.

At the post-ap­proval stage of clin­i­cal de­vel­op­ment, a new pay­ment model could trans­form re­im­burse­ment. ‘A sub­scrip­tion pay­ment model could mean that an­tibi­otics get re­im­bursed based on their value to so­ci­ety, rather than the vol­ume pre­scribed and sold,’ says Out­ter­son. The UK is al­ready im­ple­ment­ing this strat­egy: on 17 June, the UK gov­ern­ment an­nounced that the NHS will be of­fer­ing two con­tracts to pay phar­ma­ceu­ti­cal com­pa­nies us­ing a ‘sub­scrip­tion-style’ pay­ment model. ‘Covid-19 has taught us a lot about how dam­ag­ing it is to be un­der­pre­pared,’ says Out­ter­son. ‘The costs are astro­nom­i­cal. We need to fix the bro­ken eco­nomics of an­tibi­otics by tak­ing ap­pro­pri­ate ac­tion and mak­ing small in­vest­ments, so that my grand­chil­dren don’t con­tin­u­ally live through what we’re liv­ing through right now with Covid-19.’

From March, lock­downs across the globe saw streets be­come ghost-like relics of fa­mil­iar, bustling cen­tres of com­merce. Travel re­stric­tions grounded air­planes, train travel screeched to a halt and the sound of car en­gines was largely si­lenced. The pe­cu­liar­i­ties of this time are man­i­fold and run deep. Seis­mol­o­gists have dis­cov­ered that lock­downs across the world re­sulted in the long­est and most pro­nounced quiet pe­riod of ‘seis­mic noise’ in recorded his­tory.

To de­tect earth­quakes, geo­sci­en­tists use seis­mome­ters to eaves­drop on the seis­mic noise emit­ted from tec­tonic shifts that rip­ple through the Earth. How­ever, hu­man ac­tiv­ity on the sur­face also causes vi­bra­tions that prop­a­gate into the ground as high-fre­quency seis­mic waves. ‘Whether we drive our car, catch the train, or touch­down on an air­port run­way, each of us con­trib­utes to an­thro­pogenic seis­mic noise,’ ex­plains Stephen Hicks, a seis­mol­o­gist at Im­pe­rial Col­lege London.

The Royal Ob­ser­va­tory of Bel­gium, along with five aca­demic in­sti­tu­tions, in­clud­ing Im­pe­rial, have gath­ered seis­mic noise data from a global net­work of 268 seis­mic sta­tions in 117 coun­tries. Dur­ing lock­downs, they recorded a global me­dian re­duc­tion in seis­mic noise of up to 50 per cent – lead­ing some re­searchers to coin the term ‘an­thropause’. Pre­dictably, the strong­est re­duc­tions in seis­mic noise oc­curred in pop­u­lated en­vi­ron­ments: a 50 per cent re­duc­tion was recorded as tourism was grounded in Bar­ba­dos and the Sri Lankan city of Kandy; while a 33 per cent re­duc­tion was seen in Brussels, where lock­downs were en­forced from 18 March.

The pro­nounced pe­riod of quiet has its uses. The mut­ing of an­thro­pogenic noise al­lows sci­en­tists to fo­cus on nat­u­ral tec­tonic sounds. ‘An­thro­pogenic noise has al­ways been an un­wanted arte­fact on seismograp­hs. Smaller sig­nals from nat­u­ral tec­tonic sources can get lost in noise re­sult­ing from the an­thro­pogenic ac­tiv­ity oc­cur­ring at the sur­face,’ says Hicks.

Large-mag­ni­tude earth­quakes are gen­er­ally ac­com­pa­nied by smaller sig­na­tures of tec­tonic sounds that are of­ten ob­scured by the hub­bub of an­thro­pogenic ac­tiv­ity. Lock­downs present the best op­por­tu­nity to date for seis­mol­o­gists to pin­point these small sig­na­tures. ‘If we can de­tect the sig­na­tures of

The un­prece­dented pause in hu­man ac­tiv­ity that took place dur­ing global lock­downs has pro­vided seis­mol­o­gists with a unique op­por­tu­nity

smaller earth­quakes that oc­curred dur­ing lock­down, we might be able to go back through the ar­chives of seis­mo­graph data and find sim­i­lar sig­na­tures that might, for ex­am­ple, ac­com­pany larger earth­quakes,’ says Hicks.

Dis­cov­er­ies are al­ready be­ing made. Dur­ing lock­down, a mag­ni­tude-five earth­quake oc­curred south­west of Pe­tatlán, Mex­ico. Due to the re­duc­tion in an­thro­pogenic noise, seis­mol­o­gists were able to hear its tec­tonic sound sig­na­tures more clearly. The newly iden­ti­fied sig­nals could be used as tem­plates to mon­i­tor tec­tonic un­rest in the fu­ture, po­ten­tially has­ten­ing earth­quake-pre­dic­tion meth­ods.

Hicks ex­plains that lock­downs have pro­vided a rare op­por­tu­nity for his field. ‘With grow­ing ur­ban pop­u­la­tions in tec­ton­i­cally ac­tive ar­eas, such as Tokyo, San Fran­cisco, or San­ti­ago, an­thro­pogenic noise is go­ing to in­crease,’ he says. ‘With ur­ban­i­sa­tion, it’s be­com­ing more im­por­tant that we un­der­stand the small tec­tonic sound sig­na­tures, so that we can bet­ter forecast large-mag­ni­tude earth­quakes. We’ve never re­ally been able to qui­eten an­thro­pogenic noise be­cause we’ve never had a co­her­ent shut­down – now, new av­enues of re­search are open­ing up.’

The un­nat­u­rally empty streets of London

Newspapers in English

Newspapers from UK

© PressReader. All rights reserved.