Improved therapeutical guidelines and surveillance of multi-resistant gut bacteria with ESBL

Antimicrobial resistance is one of the greatest threats to human health according to WHO.  Multidrug resistant bacteria are increasing globally. Enterobacteriaceae producing Extended-Spectrum Beta-Lactamase (ESBL) are of particular concern as they are resistant to our most used antibiotics. Some are even resistant to carbapenems our last-resort broad-spectrum antibiotics, leaving very few treatment choices left in case of severe infections.

The ESBL resistance genes are generally carried on transmissible plasmids that can be easily forwarded from one bacterium to the next by conjugation and by this mechanism increase resistance development further. Enterobacteriaceae are common colonizers of the gut flora but are also our main human pathogen causing urinary tract infections (UTI) and blood stream infections (BSI).  

An increasing number of these bacteria are becoming multidrug resistant, especially E. coli and K. pneumoniae.  Enterobacteriaceae producing ESBL (EPE) are the most prevalent multidrug resistant bacteria globally and in Sweden, especially ESBL-producing E. coli (ESBL-E. coli). Severe infections with EPE is linked to higher morbidity and mortality as compared to their non-resistant counterparts. To halt this resistance development, especially within the health care sector, surveillance of EPE, proper infection control and antibiotic stewardship are needed. 

There is a global agreement that screening for EPE in the gut flora of patients is beneficial in minimizing transmission within the hospital setting from colonized patients recently hospitalized abroad in EPE high endemic settings. In Sweden, screening of recent travelers prior to hospitalization is also recommended.  In case of a severe infection in previously EPE colonized patients, the present guidelines recommend treating these patients with broad-spectrum antibiotics awaiting culture results. These screening recommendations as well as treatment guidelines can be questioned as they may cause unnecessary anxiety both from the patient and doctors’ point of view, and possibly lead to unnecessary broad-spectrum antibiotic use. 

Our aim is to identify both bacterial as well as patient related risk factors leading to an increased risk of EPE infection, especially recurrent infection with ESBL-E. coli. We have studied culture results from >3200 patients following a positive EPE-screen culture in stool at hospital admission (n=1400) or an EPE-positive clinical culture, due to UTI or BSI (n=1800) in the Gothenburg area between 2004-2014.  We found that those solely colonized in feces rarely (<6%) developed a subsequent EPE-infection in the upcoming year, whereas those with a previous culture positive infection developed a new EPE-infection in almost 30%, most within 6 months. Recurrent infections were more prevalent in the elderly and in men compared to women. Thus, broad-spectrum antibiotics in case of an infection in otherwise healthy patients only colonized by EPE in the gut may be questioned. In addition, patients developing EPE infection had rarely been screened according to the present guidelines. Our data further indicates that EPE- isolates colonizing the gut belong to less virulent bacterial strain types than those causing UTI.  

Presently, in collaboration with researcher at Chalmers Technical University who have developed a new method for detailed studies of plasmids, we are investigating if the feces isolates harbor the same ESBL-plasmids as the UTI-isolates.

On the other hand, and rarely considered in the present treatment guidelines, patients with a previous EPE-infection are a matter of concern in case of new infections. We have shown that recurrent EPE-infections in these patients almost always are caused by the same, that is the initial infecting EPE-strain, and that a certain globally well-known ESBL-E. coli clone tends to cause more recurrences than other clones. We have also shown, together with our colleagues at Chalmers, that ESBL-carrying plasmid transfer between Enterobacteriaceae of various species preceding a subsequent EPE-infection appears to be rare but can occasionally occur.

In ongoing collaborations with all clinical microbiology laboratories in Region Västra Götaland we are now comparing the bacterial properties of ESBL-E. coli isolates that have been prospectively collected for almost two years from >300 patients with UTI. Patients with sporadic UTI are compared to those with recurrent UTI to further elaborate our hypothesis that the initial infecting ESBL-E. coli strain is of importance for the subsequent risk of developing recurrent EPE-infections. If this is true, these strains should be routinely typed and monitored to foresee the upcoming risk of recurrent EPE-infection both to assure adequate treatment of patients but also to halt transmission of clones prone to cause recurrent EPE-infections.  None of this is done today and will be increasingly important with the emerge of carbapenem resistant EPE.