Et nyoppdaget antibiotikum følger en unik mekanisme for å bekjempe medisinresistente bakterier som er ansvarlige for UVI.
Antibiotika resistance is a major global threat to healthcare. Antibiotika resistance occurs when bacteria modify themselves in some manner which then either reduces or completely removes the effectiveness of an antibiotic drug which were originally developed and designed to prevent or cure infections caused by this bacterium. The ‘changed’ bacteria survive and continue to grow/multiply and same drugs now become ineffective on them. Many existing antibiotika are no longer able to combat most bacterial infections after developing high resistance against them. With time many different strains of bacteria have become or are becoming resistant to antibiotika. Misuse and uncontrolled overuse of antibiotika had further compounded this problem. Few new antibiotika which have been made available in the last several years or the ones which are currently undergoing trials rely on existing mechanisms of killing bacteria clearly indicating that most bacteria might already be resistant to them. World Health Organisation (WHO) has labelled gram-negative bacteria like Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae – carbapenem-resistant strains- as responsible for difficult-to-treat infections in clinical care and they are in the highest resistance category and are hardest to treat. For such bacterial strains no alternative antibiotika are available and the ones available have serious and drastic side effects.There is an urgent need for new strategies and novel antibiotika which will have unique modes of action.
Et nytt antibiotikum
Et nytt antibiotikum har blitt oppdaget som er svært effektivt i behandling av komplekse og avanserte urinveisinfeksjon (UTI) som er forårsaket av mange gram-negative bakterier som er resistente mot flere medikamenter. Denne studien, en fase II randomisert klinisk studie, har blitt ledet av forskere ved et farmasøytisk selskap Shionogi Inc i Japan og har blitt publisert i The Lancet Infeksiøse sykdommer. Antibiotikumet kalt cefiderocol is a siderophore-based drug which can eradicate higher levels of ‘stubborn’ bacteria (pathogen) and is seen to be not only very similar to standard antibiotika clinically used called imipenem-cilastatin but the new drug outperforms its effects.
Forsøket ble gjennomført med 448 voksne innlagt på sykehus på grunn av en komplisert ICU infeksjon eller nyrebetennelse på grunn av alvorlig bakteriell infeksjon. Flertallet av pasientene var infisert med bakterier E. coli, klebsiella og andre gram-negative gruppe bakterier som er sterkt resistente mot mange standard antibiotika. 300 voksne fikk tre daglige doser cefiderocol og 148 voksne fikk standardbehandling med imipenem-cilastatin i totalt 14 dager. Dette nye stoffet er veldig unikt i sin tilnærming til å bekjempe antibiotikaresistens brukt av gram-negative bakterie in comparison to all therapies known so far. It targets main three mechanisms (or barriers) which are used by bacteria to cause strong resistance to antibiotika in the first place. The drug succeeds in bypassing all defence mechanisms of the bacteria. The barriers are firstly, two outer membranes of the bacteria that create difficulty for antibiotika to infiltrate the bacterial cell. Secondly, porin channels which readily acclimatize blocking entry of antibiotika and thirdly, efflux pump of the bacteria which expels the antibiotic out of the bacterial cell rendering the antibiotic drug ineffective.
En smart mekanisme
Når en bakteriell infeksjon skjer i kroppen vår, reagerer immunsystemet vårt ved å skape et miljø med lite jern, som deretter kan hemme bakteriers evne til å vokse. Bakteriene er også smarte, for eksempel E Coli., da de reagerer med å samle opp så mye jern de kan. Dette nyoppdagede antibiotikumet bruker en unik mekanisme for å komme inn i bakteriene ved å utnytte denne helt egen mekanismen for bakterier som prøver å få jern for å overleve. For det første binder stoffet seg til jern og blir intelligent transportert gjennom den ytre membranen av bakterienes egne jerntransportkanaler inn i cellene hvor det deretter kan forstyrre og ødelegge bakterien. Disse jerntransportkanalene gjør det også mulig for stoffet å omgå porinkanalene til bakteriene som motvirker bakterienes andre barrieremekanisme. Dette scenariet hjelper stoffet til å få gjentatt tilgang selv i nærvær av utstrømningspumper.
The adverse effects of this new drug cefiderocol were similar to earlier therapies and most common symptoms were nausea, diarrhoea, constipation and abdominal pain. The drug was found to be effective, safe and well tolerated especially in older patients who were multi-drug resistant and had serious urinary tract or kidney infections. Cefiderocol was as effective as the standard antibiotic but whilst showing a sustained and superior antibacterial activity. Further clinical trials are ongoing to evaluate this new drug in patients suffering from hospital-acquired pneumonia and ventilator-associated pneumonia which is a common infection problem in healthcare settings. Authors stated that patients with carbapenem-resistant infections were not included in the current study because carbapenem was a comparator and this is being considered as one critical limitation of the study. This study has brought immense hope in fighting drug resistance and is seen as an initial first important step towards creating novel antibiotika.
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Source (s)
Portsmouth S et al. 2018. Cefiderocol versus imipenem-cilastatin for behandling av kompliserte urinveisinfeksjoner forårsaket av gramnegative uropatogener: en fase 2, randomisert, dobbeltblind, ikke-inferioritetsstudie. The Lancet Infectious Diseases. https://doi.org/10.1016/S1473-3099(18)30554-1
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