Stealth an­tibi­otic will only go so far in fight against re­sis­tance

The Irish Times - Tuesday - Health - - Health Lifestyle - Muiris Hous­ton

The dis­cov­ery of a new an­tibi­otic is a rare event. Es­pe­cially one that works in a novel way. Ce­fide­ro­col, in a trial pub­lished re­cently in The Lancet In­fec­tious Dis­eases, has been shown to be ef­fec­tive in the treat­ment of kid­ney and uri­nary tract in­fec­tions. The new an­tibi­otic em­ploys a neat trick to in­fil­trate bac­te­ria – it pig­gy­backs onto iron, which is taken up in in­creased amounts by bac­te­ria. Dur­ing an acute in­fec­tion, one of our nat­u­ral re­sponses is to cre­ate an iron-poor en­vi­ron­ment. Bac­te­ria in­crease their iron in­take in re­sponse. The new an­tibi­otic, ce­fide­ro­col, binds to iron, so that bac­te­ria trans­port it past their de­fences and in­side their cells.

The de­fin­i­tive mech­a­nism of ac­tion of ce­fide­ro­col is not novel: once in­side the bac­te­rial cell, it in­ter­rupts the syn­the­sis of a key com­po­nent of the bac­te­rial cell wall. What is new is its man­ner of get­ting in­side to do the job. The com­bi­na­tion of such a clever en­try de­sign and an un­der­ly­ing mech­a­nism of ac­tion that is tried and tested has ex­perts en­thused.

How­ever, this was a phase two trial, and while en­cour­ag­ing – the com­pound has the broad­est gram-neg­a­tive spec­trum of any agent cur­rently in the pipe­line – the re­sults can­not be used to es­tab­lish con­clu­sions about the clin­i­cal ef­fi­cacy or safety of ce­fide­ro­col. A phase three trial is now un­der way.

As we grap­ple with ris­ing rates of an­tibi­otic re­sis­tance and the emer­gence of in­fec­tions that are ef­fec­tively un­treat­able, the fo­cus has nat­u­rally been on an­tibi­otic stew­ard­ship – dis­cour­ag­ing in­ap­pro­pri­ate use and be­ing highly se­lec­tive in pre­scrib­ing the drugs. But a pipe­line of new an­tibi­otics, which we can hus­band more care­fully than ex­ist­ing drugs, would help smooth the other side of the an­tibi­otic re­sis­tance equa­tion.

An anal­y­sis of an­tibac­te­rial drugs that are be­ing de­vel­oped as of July 1st this year was also pub­lished in The Lancet In­fec­tious Dis­eases. A World Health Or­gan­i­sa­tion (WHO) ad­vi­sory group iden­ti­fied 30 new chem­i­cal en­tity (NCE) an­tibac­te­rial drugs, 10 NCEs against tu­ber­cu­lo­sis, and four NCEs against C dif­fi­cile were iden­ti­fied. But the clin­i­cal pipe­line is dom­i­nated by de­riv­a­tives of es­tab­lished drug classes and most an­tibi­otics in de­vel­op­ment are based on lim­ited in­no­va­tion. The ad­vi­sory group clas­si­fied each drug on the ba­sis of how ef­fec­tive it would be on bugs la­belled by the WHO as a source of con­cern – given the avail­abil­ity of lim­ited or no-treat­ment op­tions (Pseu­domonas aerug­i­nosa, En­ter­obac­te­ri­aceae, for ex­am­ple).

A fea­ture of the list of new an­tibac­te­rial drugs in the clin­i­cal pipe­line is the pres­ence of very few oral an­tibi­otics. These are valu­able in many set­tings but are es­pe­cially needed for the treat­ment of com­mon com­mu­nity-ac­quired in­fec­tions. The mainly in­tra­venous drugs in de­vel­op­ment, will, by their very na­ture, be suit­able for sicker, hos­pi­talised pa­tients.

The de­vel­op­ment of new an­ti­tu­ber­cu­lo­sis drugs faces spe­cific chal­lenges, in­clud­ing the need to treat tu­ber­cu­lo­sis with a com­bi­na­tion of at least three dif­fer­ent an­tibac­te­rial drugs. Pa­tients with drug-re­sis­tant TB re­quire treat­ment reg­i­mens which are longer, less ef­fec­tive, and less ac­ces­si­ble than first-line reg­i­mens. At the same time, they are gen­er­ally more costly, toxic, and com­pli­cated to de­liver.

The clin­i­cal pipe­line of new

The clin­i­cal pipe­line of new an­tibi­otics is dom­i­nated by de­riv­a­tives of old classes, re­flect­ing the lower re­search and de­vel­op­ment risk

an­tibi­otics is dom­i­nated by de­riv­a­tives of old classes, re­flect­ing the lower re­search and de­vel­op­ment risk, the short-term hori­zon of in­vest­ments, and the sci­en­tific chal­lenges of pur­su­ing in­no­va­tive ap­proaches. It means that what­ever new drugs emerge, they are less likely to be able to block the de­vel­op­ment of an­tibac­te­rial re­sis­tance.

So, in this World An­tibi­otic Aware­ness Week (No­vem­ber 12th-18th) the em­pha­sis once again will be on in­creas­ing global aware­ness of an­tibi­otic re­sis­tance and at­tempt­ing to avoid the fur­ther emer­gence and spread of an­tibi­otic re­sis­tant bugs. Next Sun­day is Eu­ro­pean An­tibi­otic Aware­ness Day, an an­nual Eu­ro­pean pub­lic-health ini­tia­tive to raise aware­ness about the threat to pub­lic health of an­tibi­otic-re­sis­tance.

This year’s theme is pru­dent an­tibi­otic use: to stop re­sis­tant bac­te­ria from de­vel­op­ing and help keep an­tibi­otics ef­fec­tive for fu­ture gen­er­a­tions.

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