In recent decades, the use (and abuse) of antibiotics, especially of molecules with a broad spectrum of action, the administration of sub-optimal dosages and the first-line use of molecules with a high capacity to generate resistance, have led to the emergence of the antibiotic resistance. In recent years, in fact, antibiotics have been used on a massive scale, not only for therapies on humans, but also in livestock and animal husbandry and in food production, so much so that they have led to the selection of microbial strains that have acquired multiple resistances, i.e. directed towards many (if not all) antibiotic families.
When it comes to antibiotic resistance and multi-resistant bacteria, the dreaded "superbugs", one often thinks of new diseases and/or pandemics spreading out of control. In reality, the real threat is less glaring, but more insidious, as it lurks in the very places of care, in our hospitals.
Nosocomial infections resistant to all major antibiotic treatments are unfortunately increasing rapidly. The most recent CDC reports about 2 million patients who contract an infection, sustained by resistant bacteria, associated with healthcare, of which almost 23,000 die as a result of their infection. The pathogens involved, collected under the acronym 'ESKAPE' are Enterococcus faecium, Staphylococcus aureus, Klebsiella spp., Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp, but this list is certainly reductive and other microbial species are rapidly being added.
In the case of tuberculosis, multi-resistant bacterial strains already cause around 200,000 deaths a year, mainly in poor countries. The Neisseria gonorrhoeae, another micro-organism that has developed resistance to antibiotics, was originally sensitive to penicillin. When the efficacy of the latter began to decline, it was replaced by tetracyclines and then by fluoroquinolones and then by cephalosporins. At present, some strains are only sensitive to a combination of ceftriaxone (a cephalosporin) and azithromycin (an azalide).
If one then considers not only antibiotics, but also drugs against parasites, such as the malaria plasmodiumand viruses, such as theHIVthe problem multiplies, particularly in poor countries. For malaria the problem of resistance had already arisen in the past, but at the beginning of the new millennium the use of a new drug, artemisinin (see article), seemed to have marked a turning point. Unfortunately, however, new resistant strains are already appearing and so are the drug combinations used since the early 1990s as the first therapy against HIV. These resistant strains can currently be tackled with other drugs, kept in reserve for this purpose, but this makes therapy much more complex and expensive.
 The mechanisms of antibiotic resistance
Antibiotics in most cases kill bacteria by blocking the synthesis of new proteins or by interfering with the development of cell walls. Any mutation in the genome of bacteria that makes these actions of the drug less effective therefore benefits all bacteria that possess it, and consequently tends to spread throughout the population. The passage of the modified genes from one bacterium to another occurs very rapidly, through the plasmids, small circular strands of DNA that can be easily transferred not only from one individual to another, but also from species to species, and the same happens with genes that make a disease more virulent.
Among the mechanisms of antibiotic resistance are those that produce enzymes that hydrolyse beta-lactam antibiotics (beta-lactamases) or aminoglucosides (acetylating, adenylating and phosphorylating enzymes), but other systems such as efflux pumps, modification of molecular targets or activation of alternative metabolic pathways are also important. These mutations, however, entail a cost for the micro-organism in terms of energy and materials (even just copying the DNA of the resistance gene imposes a metabolic load!), which implies that resistance mechanisms are induced to develop only in the presence of an active stimulus, such as the presence of a drug, and, therefore, if the bacteria are exposed to less drug, resistance should decrease.
At this point, unfortunately, a important and widespread misunderstanding so there is a misconception that it is the person taking the drug that becomes resistant to its effects and not the microbes! Research published last year by the World Health Organisation (WHO) reported that three quarters of the population in middle and low-income countries misunderstood the problem in this way, and a survey conducted in 2015 by the Wellcome Trust reported the prevalence of a similar misconception in England. This erroneous belief has serious consequences on a practical level as only if one is convinced that resistance is an attribute of the bacterium, using drugs only as needed, but in a decisive manner, makes sense. If, on the other hand, one mistakenly believes that resistance is an attribute of people, one will have no qualms about taking antibiotics to the extent that they appear to have any effect and will have a tendency to discontinue them when symptoms subside, rather than prolonging their administration until the bacteria have been completely eradicated. These problems are particularly acute where antibiotics can be easily purchased as over-the-counter drugs.
To assume that campaigns aimed at raising public awareness can be decisive is downright optimistic. In 2013, a paper published in the Journal of Antimicrobial Chemotherapy estimated that about two-thirds of patients who should not have taken antibiotics had taken them anyway. There is also the phenomenon whereby the patient, once he or she has gone to the doctor, 'demands' (pester effect) to go away with some meaningful therapy, so if he has a sore throat, probably of viral origin, he will press for a (not actually necessary) antibiotic to prevent any possible complications.
Compounding the problem is the use of antibiotics in the farm animalsalso because (for reasons that are still not fully understood) it has been observed that cattle treated with antibiotics swell faster. Drugs mixed with animal feed pass through animal dung into the soil and waterways and this feeds resistance, mostly in non-human pathogens. However, as we have seen, resistance mechanisms can easily pass from these species to those capable of causing disease in humans. Among other things, farmers often administer the very antibiotics that doctors keep in reserve to treat resistant nosocomial infections, such as the colistin. This antibiotic is not widely used in humans because it can have damaging effects on the kidneys, but it constitutes the 'reserve cartridge' to be used against Acinetobacter, Pseudomonas aeruginosa, Klebsiella and Enterobacter. Last year, bacteria with colistin-resistant genes were isolated in hospital patients in China and it is thought that the cause is the use of colistin in agriculture.
The cost of banning the use of antibiotics as growth promoters altogether was estimated by a US government study to be less than 1% of product, and the European Union has already adopted this ban.
Meanwhile on the research front for new antibiotic agents, there is a pipeline of about 40 potentials new products in various stages of development, of which only a fraction will reach the market and still require substantial investment to complete the human clinical trial phase.
Some important recommendations that could be applied in the immediate future to contain resistance associated with nosocomial infections are:
1) Promoting prevention and control, limiting the misuse of antibiotics and improving practices of infection control;
2) adopt strict hand hygiene practices;
3) Maintaining a high level of vaccinations in populations;
4) Using microbiological diagnostics in prescribing the right antibiotic, at the right dosage and duration, in the right infection;
5) Introducing national plans to identify actions to monitor resistance;
6) Investing in diagnostic and therapeutic innovation.
Regarding the last point, interesting novelties lie ahead in terms of co-optation in the fight against infections of the viruses known as bacteriophagescapable of attacking bacteria and by an innovative gene editing tool the CRISPR/Cas9a gene 'editing' technique derived from bacteria. In fact, CRISPRs are part of the bacteria's immune system and are also 'gene editors' thanks to the Cas endonuclease that recognises the RNA into which the viral DNA translates in order to replicate. The Cas enzyme takes over that RNA, so it recognises exactly the pieces of viral DNA and eliminates them all. The correction remains in the bacterium's genome and is passed on to the daughter cells.
Dr. Carmelo Chines
Direttore responsabile
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