Resistance to antimicrobial agents is a growing and worrying phenomenon. Extensively drug-resistant bacteria, or XDR bacteria, are a type of multidrug-resistant organisms that are resistant to almost all or all approved antimicrobial agents.
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The term was first coined in response to Mycobacterium tuberculosis that was resistant to first-line agents (isoniazid and rifampicin), a fluoroquinolone, and to one or more second-line parenteral drugs (amikacin, kanamycin, and capreomycin). This was later expanded to include other bacteria that were resistant to most standard antimicrobial treatments.
Defining XDR bacteria
XDR bacteria are different from multidrug-resistant bacteria and pan-drug resistant bacteria. The difference is mainly interpreted as to what extent the bacteria are drug-resistant, with multidrug-resistant bacteria being unsusceptible to one or more antimicrobial agents and pan-drug resistant bacteria being unsusceptible to all antimicrobial agents.
Therefore, XDR bacteria rest somewhere in between these two categories. Occasionally, definitions are based on broader categories of antimicrobials rather than agents, which therefore narrows the bacteria fitting the description. However, this system is often seen as more informative by healthcare professionals treating afflicted patients with various antimicrobial classes.
Prevalence of XDR bacteria
The exact prevalence of XDR bacteria can be hard to estimate. Studies looking at hospitals in central India found that 13.8% of bacterial strains were XDR bacteria, and another 37.1% were multidrug-resistant bacteria. Of patients, 1.6% had XDR bacterial infections, and 4.2% had multidrug-resistant bacteria. However, given that the study was carried out in a tertiary care center, the levels may be higher than average.
This same study found that there were more Gram-positive than Gram-negative bacterial strains. The majority of XDR strains were found in the surgery section of the hospital, and overall most XDR bacteria were coagulase-positive staphylococci or Pseudomonas aeruginosa species. A similar trend has been found in studies in Riyadh, Saudi Arabia.
Studies in Europe have shown that strains of Klebsiella pneumonia, which is also found in the central Indian hospitals, are spreading and developing into XDR bacteria. The resistance was mainly due to the acquisition of carbapenemase, which makes carbapenem redundant, and β-lactam resistance. The study also found that the resistance developed in several separate lineages, thereby showing the risk of random XDR development.
The spread of the XDR bacteria across European hospitals was found to be influenced by its degree of resistance and by whether the strain’s resistance was due to carbapenemase acquisition, in which case transmission was increased.
How can XDR bacterial infections be cured?
Increases in antimicrobial resistance, coupled with an increase in the occurrence of infectious diseases, presents a serious health hazard and has even suggested to lower public health standards to pre-antibiotic era levels in some countries.
Lacking sufficient knowledge can also make the problem worse. If XDR bacteria are present, and patients are treated insufficiently, treatment can cause increasing levels of resistance to be developed.
Some combinations of drugs have been discovered that can be used to treat XDR bacteria. One of these is neuroleptic thioridazine. This drug, in combination with antibiotic agents, has shown success in curing XDR tuberculosis when administered by an experienced physician.
Thioridazine works by disrupting calcium inside the cell. For XDR tuberculosis bacteria, this means the main method through which antibiotic resistance is achieved, which is through efflux pumps that are overexpressed, is disrupted as the drug causes inhibition of potassium and calcium efflux pumps.
An additional key benefit of thioridazine is that it is not patent-protected, meaning it can be distributed at low cost to those in need.
Sources
- Magiorakos A.P. et al. (2012). Multidrug resistant, extensively drug resistant and pandrug resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clinical Microbiology and Infection. https://doi.org/10.1111/j.1469-0691.2011.03570.x
- Basak, S. et al. (2016). Multidrug resistant and extensively drug resistant bacteria: a study. Journal of Pathogens. https://doi.org/10.1155/2016/4065603
- Amaral, L. and Viveiros, M. (2012). Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections. International Journal of Antimicrobial Agents. https://doi.org/10.1016/j.ijantimicag.2012.01.012
- David, S. et al. (2019). Epidemic of carbapenem resistant Klebsiella pneumonia in Europe is driven by nosocomial spread. Nature Microbiology. https://doi.org/10.1038/s41564-019-0492-8
Further Reading
Novel antibacterial discovery: Umbrella toxin particles secreted by Streptomyces