Discussion
Throughout this analysis, one can perceive colistin resistance as an extremely complex matter. Perhaps, the most relevant question to be asked afterwards is: is resistance to colistin a public health issue, nowadays?
Regarding the definition, public health is defined by Charles-Edward Amory Winslow, a public health expert, as “the science and art of preventing disease, prolonging life, and promoting health through the organized efforts and informed choices of society, organizations, public and private communities, and individuals”.1 Therefore, a public health issue would be an existing threatening factor to public health.
Different epidemics and pandemics have been defined as public health issues in the past and are carefully surveilled by WHO, such as, the virus Influenza and obesity. The subject to question is – does resistance to colistin have the same relevance to public health as any of those matters?
Firstly, it is important to keep in mind that colistin resistance has plenty of influencing variants and cannot be seen as a simple problem. From different origins, to different mechanisms, the resistance to this antibiotic becomes a more complex problem day by day. A very recent example of this matter is how the plasmid-mediated resistance to colistin successively increased from one gene-type to eight gene-types in three years.
There is no doubt that the use of this antibiotic in livestock increased the spreading of resistance significantly over the years, but according to recent data, other determinants have also been crucial. For example, international travel has several times proven to be associated with the dissemination of resistance genes from endemic zones to practically non-affected areas, using individuals as vehicles; another example are migratory birds, also proven to be carriers of these genes, just as pet animals in endemic zones such as China.
This leads us to a new interrogation – up to what point is exactly known the dissemination of colistin resistance?
Just as referred above, the “new genes” have actually been present in the environment and animal samples for decades, they just were undetected, for they were
not sampled or typed in the target samples. Possessing such ubiquitous hosts as Enterobacteriaceae, for instance, it is unlikely that the real dissemination rates are ever exactly known and are probably being underestimated at the present day.
This is a particular problem in nosocomial settings where, besides detection being a complicated part of the process, targeting for the detection might be more difficult, since resistance determinants are only tested in suspected cases of colistin resistance and not in every bacterium.
Detection is, thus, a vital part of the study on colistin resistance, since poor detection methods might add to the underestimation of the dissemination of this gene. New methods of analysis are under development, like, for instance, the Multiplex PCR for detection of plasmid-mediated colistin resistance determinants, which already optimised for food, animal and environmental samples.2
Public health is, then, threatened from different fronts, which is already noted through the increase of reports of human cases. Hampering this situation is the problematic of MDR bacteria, already proven to be capable of coexistence with colistin resistance genes. In spite of the fitness cost regarding plasmid-mediated resistance discussed at the time of its discovery, several examples and outbreaks of MDR and colistin resistant bacteria have been reported in the last few years, for example, combinations of ESBLs or carbapenemases (like NDM-1) and colistin resistance genes, not only from chromosomal origin, but also from plasmid-mediated resistance, just as combinations of several mcr types in one bacterial strain.3–5
Health professionals can consider this another front of attack, since this makes the treatment of difficult infections even more problematic. Regardless of the control in monotherapy or combination therapy regimens, they face lack of access to one of the last-resort antibiotics, which continues to unpredictably modify paradigms on modern treatment regimens, especially due to the genetic adaptations which do not exclusively dependent on selective pressure from surrounding environments (having been found bacteria that “casually” were porters of colistin resistance genes).
Particular examples of complicated, and probably unexpected, cases are the ones referred prior to discussion – MDR and colistin resistant E. coli and K.
pneumoniae, which still astound worldwide health professionals concerning their easy spread and fatality.
Looking upon this information, resistance to colistin seems to oblige to what is considered a public health threat.
Moreover, another social-effecting determinant is represented by the costs implied by this situation. The existence of “untreatable infections” leads to bigger expenses in the healthcare field, not only regarding the investigation of new therapeutic alternatives, but also recalling every cost involved in the hospitalisation of patients and their successive attempts of treatment. This will also affect the individuals’ quality of life, which nowadays is a major concern regarding the healthcare field.
Weighing all these factors, we can conclude that resistance to colistin is, at the present day, a public health issue.
The question to ask next is – how can we reach public health in this reality? Or is it even possible?
New treatment options (alternatives to colistin) have already started to be discussed and studied, such as pentamidine, a widely used drug, in the treatment of fungal and parasitic infections, but not bacterial infections. Recent studies concluded that it destabilizes the membrane of Gram-negative bacterial cells, demonstrating synergic effects when associated with other antibiotics, such as rifampicin. The same studies also concluded that this combination is effective in cases of mcr-1 resistance, which suggests even though the antibiotics culminate in the same effect, their mechanism of action is different, making pentamidine a possible successful alternative to colistin. It is, however, important to highlight that data regarding the effects on human cells is still necessary, even though Stokes et al. proved this activity to exist in vivo (using mice).6,7
An interesting strategy to overcome this resistance would also be to deepen the study of genetics on its mechanisms. The study of MRR involving colistin-resistance genes could enlighten the primary causes of its transmission and, perhaps, guide to a way to predict it and prevent it. Every sequence and genetic variant registered in GenBank may be helpful, working as a foundation to the studies, which is already globally accepted.
Nevertheless, it is also important to define a strategy to overcome the spread of this pandemic. There is no doubt that the action should start within the veterinary field, since most samples and variants emerge from this environment. Even so, action in healthcare facilities and promoted by healthcare professionals is another very important part of a future containment plan, since they are the primarily informed individuals and can implement preventive measures and invest in the surveillance of these situations and current resistance cases.
The future depends on what we do in the present.