Extended Spectrum βeta Lactamase producing bacteria: an increasing source of causative infections

Beskrivning

Doktorandprojekt finansierat av HKR. Lina insikten vid Lund Universitet,

Kort sammanfattning:
Antibiotics have served as essential treatment of bacterial infections for several decades, and there is a global increase of antibiotic resistant bacteria causing severe infections in humans and animals. In the recent decade there has been a push for the implementation of antimicrobial stewardship, a set of strategies and plans to reduce the emergence and spread of resistant pathogens and to use existing antimicrobials more effectively by the World Health Organization (WHO). These includes to monitor the presence of multi resistant bacteria, and to encourage development of new diagnostic tools. Rapid, accurate and cost-effective susceptibility testing plays a key role in antimicrobial stewardship by reserving drugs of last resort to those cases in which they are warranted. An increasing number of infections are caused by resistant bacteria such as extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, resistant to penicillin’s, 2nd and 3rd generations cephalosporins, and in some cases also to carbapenems.

Traditional antimicrobial susceptibility tests include the disk diffusion test, E-test gradient diffusion test and broth dilution susceptibility tests. Although the tests are robust, they each rely on the growth of the bacteria to a dense culture while being exposed to the antibiotic panel. The identification of the causative pathogens takes at least five hours, and final antibiotic susceptibility results are generated in 18-36 hours. Due to the long time required to deliver test results compared to the tempo of infection, patients are often treated “empirically” with broader-spectrum regimens under the assumption that the infection could be drug-resistant. Thus, the faster the information is available, the faster the patient´s treatment can be optimized, potentially saving patient lives, reducing irreversible long-term side effects, as well as minimizing antibiotic toxicity, the risk of developing antibiotic resistance, and use of costly pharmaceuticals.

To improve susceptibility testing times there are currently a few rapid platforms gaining acceptance in the clinical laboratories such as polymerase chain reaction (PCR). PCR can be useful but provides only genetic information on the presence or absence of specific resistance-related genes, which not always mirror the complete resistance activity. Additionally, several hundred genes can cause extended spectrum β-lactamase (ESBL) production in Enterobacteriaceae and providing PCR-assays for all of these genes are currently expensive and time consuming, a fact that has restricted their general use. The detected gene fragments in PCR-systems might even originate from pathogens already suppressed or killed by antibiotics, and fragments whose origin is unknown.

In Sweden, the annual incidence of clinical infections caused by ESBL-producing bacteria, have yearly increased since 2000 with around 2.5%. In 2015 it became obligatory for the clinical microbiology laboratories to report incidences to the Swedish Public Health Agency. The most commonly reported clinical ESBL-producing bacterial species in 2018 was E. coli (87%) followed by K. pneumoniae (9%).

Both antibiotics and antibiotic resistant bacteria end up in wastewater treatment plants and are further transported into surface waters. This leads to an emerging number of resistant bacteria in the water environments that possess different routes of transmission back to the society. In European waters, as in the clinic, ESBL-related genes belonging to the blaCTX-M group are the most common, and they have rapidly replaced blaTEM and blaSHV as the dominant ESBL gene. blaCTX-M15 has become the dominant gene variant world-wide and seems to have a strong connection to Gram-negative bacteria infecting humans. In Sweden the governmental control on the usage of antibiotics for humans and animals is strictly enforced. Despite this, studies on environmental E. coli have shown that isolates with increased antibiotic resistance can be found in Swedish water systems as well as in animals.

Period	2014-jan.-01 → 2025-maj-30