Definition and significance of antibiotic resistances

Since the first antibiotic, penicillin, was invented in 1928 and then successfully applied in 1942, many lives have been saved due to antibiotics transforming modern medicine (Sengupta et al., 2013). Antibiotics have not only helped to save lives but had a major role in medical and surgical advances as well as in extending the expected life spans by reducing the severity of bacterial infections outcomes. Nevertheless, resistance to anti-biotics has become a prominent clinical problem. The resistance to penicillin became apparent already during the work on finalizing the drug and by 1950 became the threat to many prior medical advances. Many new antibiotics have been introduced over the years to fight the resistance problem, however, by now resistance has been seen in almost all discovered antibiotics. It is claimed that the main reasons for antibiotic re-sistance are the overuse and misuse of antibiotics, and the shortage/failure of new anti-biotics development due to low economic incentives and demanding regulations (Ven-tola, 2015). According to the European Centre for Disease Prevention and Control

(ECDC), around 33 000 people die each year in Europe due to infections caused by antibiotic-resistant bacteria (THL, 2018).

The evolution of bacterial resistance to antibiotics poses a major threat to global health as infectious diseases that have long been considered curable have become dangerous again (Morel et al., 2016). Currently, one of the major clinical threats, and the interest of this thesis, is carbapenemase resistant enterobacteriaceae (CRE) which is a group of bacteria that became resistant to ‘all or nearly all’ antibiotics, including carbapenems that are seen as the ‘treatment of last resort’ against the drug-resistant pathogens (Ventola, 2015). As carbapenems are seen as the most reliable drugs in treatment of bacterial infections, the emergence and highly increasing spread of resistance to these antibiotics is a major public health concern (Meletis, 2016).

Carbapenem resistance restricts treatment options and is associated with adverse clini-cal and economic outcomes including delay in administration of effective therapy, in-creased patient morbidity, attributable mortality, inin-creased length of stay, and inin-creased costs of health care (Mariappan et al., 2017; Moloney et al., 2019). Since the first report on a carbapenem-resistant isolate in 1996, CRE has already spread globally and some countries, like Greece or Italy, are already considered endemic for some CRE strains (Magiorakos et al., 2017). Figure 43 presents the most current situation regarding car-bapenem resistance in Europe.

Carbapenem resistance in Europe (ECDC, 2019).

As Figure 43 shows, carbapenem resistance is already a major problem in some of the European countries where CRE prevalence levels reach above 10%. Simplifying, if CRE prevalence in a country is 10%, it means that on average 10% of the patients that are admitted to the hospital are likely to be CRE carriers. There are still many countries in

Prevalence level

which prevalence of CRE is relatively low. However, as the cross-border transmission of bacteria is possible (people travel abroad and are treated in hospitals abroad), the hos-pitals in countries with low prevalence are also cautions about the CRE. Also, the case company’s representative said:

“In the low prevalence countries, they want to keep it low. They want to ensure that there are no patients released that would spread the CRE in the community and in result increase the prevalence. Also, the antibiotics to treat those with re-sistances are much more expensive. This is why these countries have incentive to screen patients, too.”

CRE is readily transmissible in healthcare as well as community settings (Nordmann et al., 2016), especially elderly and people with many comorbidities, i.e., having another disease or suffering due to other health conditions, are at risk of CRE acquisition. Hence, CRE poses extreme risk especially in healthcare facilities such as hospital and long-term care facilities, for example elderly nursing homes. There are several modes of CRE transmission in the hospital environment such as:

• patient-to-patient transmission

• healthcare worker-to-patient transmission

• medical devices-to-patient transmission

• hospital environment-to-patient transmission

First, patients might be either colonized or infected by CRE. In the case of colonization, CRE bacteria live harmlessly in the parts of the human ingestion system or on the skin, and the person does not display any symptoms of CRE bacteria carriage (Moloney et al., 2019). However, if the bacteria enter different areas such as bladder or bloodstream, they can cause illness that may result in severe morbidities leading even to death (Molo-ney et al., 2019). Furthermore, both infected and colonized patients are seen as the main reservoirs for CRE transmission to other patients resulting in the wider-spread carriage, further infections, and possible outbreaks (Magiorakos et al., 2017). Especially asymp-tomatic patients are a significant threat to the transmission of bacteria from patient to patient, as well as to healthcare workers and the environment; hence active screening of patients, potentially at risk of CRE carriage, is of utmost importance.

Second, CRE can be transmitted through contaminated hands of healthcare workers (HCWs). Being in contact with colonized patients, HCWs may pick up bacteria on their hands during various activities such as touching a patient or patient’s clothing,

bedmak-ing, toileting activities, or even while administering medications to the patients (Sander-son and Weissler, 1992). Despite strict work hygiene policies in healthcare, the average compliance with proper hand hygiene of HWCs remains at around 40% (Tacconelli et al., 2014). Then bacteria being present on hands and as a result, also on the clothing of HWCs can be cross transmitted to other patients.

Third, inadequately decontaminated medical devices and tools that were used for exam-ination of colonized patients or were touched by contaminated hands of HWCs pose yet another mode for transmission of infectious diseases, and antimicrobial resistance (Tac-conelli et al., 2014). According to study of Epstein et al. (2014), 39 patients who were exposed to duodenoscope, a medical device that is inserted into human’s small intestine to perform for example biopsy, were later found colonized with the same CRE strain found also on the device.

Last, the transmission of CRE may happen via a broadly understood hospital environ-ment. Surfaces, sinks, drains, and toilets in patent rooms may be contaminated and bac-teria are able to survive in these places for a significant amount of time. The latest study by van Beek et al. (2019) confirmed epidemiological links between patients who were staying in the same rooms but whose stays were not overlapping. Environmental screen-ing of surfaces, sinks, drains, and toilets in those rooms proved positive for CRE despite proper terminal cleaning and decontamination of the patient’s rooms and bathrooms.

Beside different transmission modes, there exists a positive correlation between certain factors that increase the risk of colonization followed by an infection. Those factors are so-called risk factors, and in the case of CRE, those risk factors are prolonged hospital-ization, severe underlying hospitalhospital-ization, presence of invasive medical devices and an-tibiotics use (Mariappan et al., 2017; Magiorakos et al, 2017). There is an overall 16,5%

risk that a colonized patient will become infected (Tischendorf et al., 2016), that risk var-ies between 7,6 to 89% depending on the severity of the patient’s illness (McConville et al. 2017; Ambretti et al. 2019) and between those patients, 10-75% are likely to die due to CRE (Tischendorf et al., 2016).