The theory behind AMR

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1. Background of AMR

What is antibiotic resistance and how does it develop?

2. Mechanisms of bacterial resistance to antibiotics

A summary of the type of resistance and a detailed description of the mechanisms that can be detected by the AMRDetecTool

3. Spread of resistance

Spread of resistance from bacteria to bacteria & from patient to patient & and how to avoid or reduce this

4. Multiresistant bacteria that can be detected by the device

ESBLs: CTXM – MULTI, Carbapenemases: KPC, OXA, VIM, IMP, NDM, VAN A/B, OXA-Ab, 3GC

5. The detection of resistance

The current possible methods and why LFIA is good

Background of AMR

Antibiotic resistance is the ability of bacteria to defeat the drugs designed to kill them. The increase and spreading of resistance can compromise the treatment of infectious diseases and other advanced therapeutic procedures as transplantation or anti-cancer therapy that involve immunosuppression and thus require robust anti-infective preventive therapies.

Bacteria change when exposed to antibiotics: using antibiotics may exert on bacteria a selective pressure leading to an increase in the prevalence of resistance.

The development of resistance is a natural phenomenon, but if antibiotics are not used properly, this process will speed up.

The source of the genes causing resistance to antimicrobials was the environmental microbiota, and the pathogenic bacteria acquired R-factors (resistance plasmids) from them. And what happened next? You can watch it in this excellent video:

Mechanisms of bacterial resistance to antibiotic

  • Change(s) in the antibiotic target sites – e.g. Vancomycin resistance
  • Decrease of the membrane permeability – various antibiotics (e.g. aminoglycosides, fluoroquinolones, tetracycline)
  • Efflux: the bacteria pump the antibiotics out – various antibiotics (beta-lactams, novobiocin,
    erythromycin, fluoroquinolones, tetracycline, chloramphenicol, linezolid)
  • Antibiotic degradation: e.g beta-lactamase production

Vancomycin resistance:

https://jcm.asm.org/content/54/10/2436

 

Spread of resistance

From bacteria to bacteria:

From patient to patient:

In case of inadequate hygiene, bacteria may spread from person to person through contact with colonized people and contaminated devices.
Bacteria may cause hospital-acquired infections: pneumonia, bloodstream infection, urogenital infection, skin and soft tissue infection, etc.

Multiresistant bacteria that can be detected by the device

ESBL-s: CTX-M MULTI

ESBL (extended-spectrum beta-lactamase) production is becoming more common among Enterobacteriales.

The CTX-M-type extended-spectrum β-lactamase variants are the most frequently identified ESBLs.

ESBLs hydrolyze:

  • penicillins
  • 2nd, 3rd and 4th generation cephalosporins
  • aztreonam
  • (not cephamycins and carbapenems)

Carbapenemases: KPC, OXA, VIM, IMP, NDM

Carbapenemase production is more and more commonly reported in K. pneumoniae and has also been identified in other gram-negative pathogens including Pseudomonas aeruginosa.

Carbapenemases are beta-lactamases with versatile hydrolytic capacities.

Carbapenemases hydrolyze:

  • penicillins
  • cephalosporins
  • monobactams
  • carbapenems

Klebsiella with plasmid-mediated carbapenem resistance is a significant risk to hospitalized patients. The transfer of these resistance plasmids into E. coli is a significant public health threat because resistant E. coli may become part of the normal gut flora and thereby would be a source of infections in healthcare settings and the community. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086234/)

VAN A/B: vancomycin-resistant Enterococci

Enterococci tend to persist in hospital environments, allowing for dissemination of resistance elements.

They are common colonizers.

Infections usually occur in immunosuppressed patients who have received multiple antibiotic treatments in the past.

Typically infection may be caused by enterococci:

  • urinary tract infections
  • intra-abdominal and pelvic infections
  • skin and skin structure infections
  • endocarditis
  • central nervous system infections (rarely)

High risk of infection:

  • chronic dialysis treatment
  • severe underlying disease
  • immunosuppressed condition
  • use of invasive devices
  • long hospital care
  • previous or current antibiotic therapy

Van A is responsible for most of the human cases of VRE around the world and is mostly carried by E. faecium. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521680/)

Enterococci carriers of VAN A gene are resistant to vancomycin and also teicoplanin, but the carriers of VAN B can be susceptible to teicoplanin.

OXA-Ab: OXA-type carbapenemases in Acinetobacter sp.

Acinetobacter species are significant pathogens in hospital-acquired and healthcare-associated infections worldwide.

Acinetobacter spp. may cause:

  • ventilator-associated pneumonia
  • bloodstream infection
  • wound infection
  • urinary tract infection

A. baumannii can develop resistance to multiple classes of antimicrobial agents.
The bacterium can be found anywhere in the hospital environment, can survive on dry surfaces for prolonged periods, often causes protracted outbreaks.

Risks of infection:

  • stay in intensive care units
  • burn injuries
  • traumatology patients
  • ventilated patients
  • immunosuppressed condition
  • serious underlying disease (chronic lung disease or diabetes mellitus)

3GC: third-generation cephalosporin resistance

3GC device for detection of determinants conferring third-generation cephalosporinase resistance (ESBLs (VEB, PER, GES, TEM, SHV), plasmid-encoded cephalosporinases (CMY, DHA)

Cephalosporins allow treating a variety of bacterial infections. Cephalosporin allergy is rare, and they generally cause few side effects. But the resistance against them is increasing continuously.

 

      The detection of resistance

      PCR

      LAMP

      MALDI-TOF MS

      The AMR DetecTool detects the enzymes directly from the patient’s sample, shortening the workflow for the detection of multidrug-resistant bacteria to 30 minutes.

      LFIA: Lateral Flow ImmunoAssay

      The sample is applied at the end of the strip (sample pad), then migrates into the detection zone.
      If the target is present in the sample, the antibodies will bind to it, recognising the test line and a control line, and coloured bands will appear.

      Carba5 principle:

      source: https://academic.oup.com/jac/article/73/4/909/4819243

       

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