Innovation in antimicrobial development

Not only is it critical to identify new antimicrobics but also to incorporate them into a reliable testing device to accurately negotiate optimum patient treatment.

From the isolation of an antibiotic-producing species of Cephalosporium in a sewage outfall in Sardinia back in 19451, a novel  antibiotic was isolated and characterised as demonstrating increased resistance to hydrolysis by a penicillinase. The subsequent development efforts, spanning 5 generations (classified based on spectrum of coverage and temporal discovery), saw cephalosporins stand firm against the relentless evolution of bacteria. But in recent history, bacteria with enzymes capable of breaking down the unique beta-lactam ring for which cephalosporins were originally so stable against, are now adept at being able to hydrolyze the majority of β-lactams  that are currently in use. Together these enzymes constitute the most important resistance mechanism of Gram-negative rods2 , and are known as extended-spectrum beta-lactamases  (ESBLs).

The addition of a beta-lactamase inhibitor e.g. avibactam with a cephalosporin as in the case of ceftazidime-avibactam, has seen success against many ESBLs, as much as 99.7% 3, as well as AmpC, Klebsiella pnuemoniae carbapenemase (KPC) and OXA-48- producing Enterobacterales4, over the last couple of years. This successful pairing has another member in the form of ceftolozane-tazobactam.  Unfortunately these beta-lactam/beta-lactamase inhibitor combinations do not offer treatment against infections caused by metallo-beta-lactamase Gram-negative organisms for which the mortality rate ranges from 18 – 67% and the incidence is growing worldwide5. Enter cefiderocol. 

Cefiderocol is a first-in-class siderophore cephalosporin and is the first treatment to provide coverage against all Gram-negative pathogens considered of critical priority by the World Health Organisation (WHO) – carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales – all of which are associated with high mortality rates6. Amongst these priority organisms are metallo-beta-lactamase organisms for which cefiderocol offers an alternative treatment option instead of colistin, the last resort drug with toxic, life-threatening side-effects7

Cefiderocol is the world’s first siderophore cephalosporin antibiotic. It binds to the pathogen’s own iron uptake system, meaning it is pulled through the outer membrane and into the cell with the essential nutrient as it is absorbed. Researchers have likened this innovative mode of action to a Trojan horse.8

Innovative products, however, are only part of the solution. To ensure this first-in-class antibiotic can be introduced seamlessly into routine clinical practice, we also need to provide laboratories with the tools they need to play their essential role in the diagnostic pathway, and guide treatment decisions.

So far, many suppliers have struggled to add reliable cefiderocol testing solutions to their existing, routine testing ancillaries.

But Thermo Fisher Scientific has invested in research and development (R&D) efforts to deliver a testing plate that can be used with the same broth as the rest of the growing portfolio of EUCAST/CLSI compliant Clinical Thermo Scientific™ Sensititre™ Plates.

Laboratories understand the importance of antibiotic susceptibility testing (AST) and minimum inhibitory concentration (MIC) screening in the global AMR stewardship effort.  They are well versed in this arena but cefiderocol’s unique mode of action requires a unique method of MIC – one that requires different testing conditions than those used for existing treatment options.

Through the challenging development of cefiderocol, Thermo Fisher Scientific’s R&D team has negated the need for laboratories to unnecessarily invest in time, resource and money.  Cefiderocol is now available in the US (product codes: MDRGN2F, MDRGNX2F) and Europe (EUMDROXF) on both standard (off the shelf) and custom formats enabling laboratories to carry out routine phenotypic AST testing, as they have done, many times before.

Included with cefiderocol on the latest European format (EUMDROXF) are imipenem/relebactam, meropenem/vaborbactam and eravacycline. These new antibiotics represent the latest treatment options for complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAI) and for hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP respectively). It is now possible to report and interpret MIC results according to EUCAST breakpoints for the latest antimicrobials.

References

 

  1. https://pubmed.ncbi.nlm.nih.gov/3319494/ 
  2. https://www.sciencedirect.com/science/article/pii/S1198743X14640490 
  3. https://doc.rero.ch/record/326990/files/nor_erc.pdf 
  4. https://pubmed.ncbi.nlm.nih.gov/29671219/ 
  5. https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-018-3581-z#:~:text=Gram-negative%20isolates-,Verona%20integron%20Metallo%20beta-lactamase%20(VIM)%20was%20the%20most,1.5%25)%20(Table%204). 
  6. https://www.businesswire.com/news/home/20200914005049/en/Shionogi-Launches-FETCROJA%C2%AE-cefiderocol-in-the-United-Kingdom-for-the-Treatment-of-Infections-Due-to-Aerobic-Gram-Negative-Bacteria-in-Adults-With-Limited-Treatment-Options 
  7. https://www.researchgate.net/publication/51637851_Renal_and_neurological_side_effects_of_colistin_in_critically_ill_patients 
  8. https://pubmed.ncbi.nlm.nih.gov/27773991/ 

 

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