Antibiotic resistance: where are we going?
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Ann Ig 2018; 30 (Suppl. 1): 52-57 doi:10.7416/ai.2018.2235
Antibiotic resistance: where are we going?
V. La Fauci1, V. Alessi2
Key words: Antibiotic resistance, MDRO, carbapenem-resistant, ESBL
Parole chiave: Antibiotico resistenza, MDRO, resistenza ai Carbapenemi, ESBL
Abstract
Antibiotic resistance represents the greatest threat in the field of infectious diseases today, due to the sharp
increase of this event both in Europe and the World. The presence of these multidrug-resistant microorga-
nisms in hospitals is associated with many risks, including the increased likelihood of treatment failure, an
increased risk of morbidity and mortality, longer hospital stay, higher hospitalization costs and more legal
disputes. The epidemiology of multidrug-resistant microorganisms infections varies from year to year, by
geographical area, by hospital and by ward or department. Italy lies in fifth place among European countries
regarding the use of antibiotics in human and veterinary clinical practice. Unfortunately, antibiotic resistance
remains one of the highest in Europe and is consistently above the European average for both Gram nega-
tive and positive bacteria. The appearance and the growth of resistance to Carbapenems has been rapid,
alarming and dramatic in Italy so much that the country is now classified as hyperendemic. It is important
to highlight the known and emerging risk factors to define multidrug-resistant microorganisms prevention
and control measures, both at individual and community level.
Antibiotic resistance represents today the is developed upon exposure to the drug itself.
greatest threat in the area of infectious It is one of the mechanisms of biological
diseases, due to the great epidemiological competition between microorganisms based
and economic impact of this phenomenon on the production of antimicrobials. The
(1). According to WHO data, it causes about latter are natural molecules produced by
700,000 deaths each year, reaching 10 microbes to defend themselves from other
million worldwide by 2050, unless effective microbes. The use of antibiotics in human
measures are implemented. In Europe alone, and veterinary clinical practice has generated
there have been about 25,000 deaths in just further selective pressure in these
one year, with a cost in terms of health and environments, favoring the selection of
productivity loss of nearly € 1.5 billion a resistant microorganisms and the acquisition
year (2). Antibiotic resistance is determined of resistant genes carried by mobile genetic
by a natural evolutionary mechanism caused elements such as plasmids. These help
by mutations in the genetic makeup that spread resistance among pathogenic bacteria,
protects the bacteria from drug action, which via forms of horizontal exchange, and are
1
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, A.O.U. Policlinico
“G. Martino”, Biological tour 1° Floor, Messina, Italy
2
Postgraduate Medical School in Hygiene and Preventive Medicine, University of Messina, Messina, ItalyAntibiotic resistance: where are we going? 53 further facilitated by poor environmental priority: Streptococcus pneumoniae management and maintenance. The resistant (penicillin-non-susceptible), Haemophilus pathogens thereby selected are in turn influenzae (ampicillin-resistant), Shigella released into the environment and may also spp (fluoroquinolone-resistant) (4). The contaminate the food chain. Antibiotic WHO (5) has also defined other risk factors resistance is multifactorial and may be in addition to the excessive use of antibiotic favored by inappropriately prescribed drugs, such as poor hygiene conditions in antibiotics or due to erroneous dosages, by hospitals, poor hygiene in the food supply empirical therapies in which broad-spectrum chain and lack of awareness among citizens, antibiotics are used in the absence of so much that 57% of European citizens are adequate diagnostics procedures, from the unaware that antibiotics are ineffective increasingly marked use in hospitals on against viruses and 44% do not know that patients in already critical condition, the they have no effect on colds and flu. The increased incidence of infections related to presence of these multiresistant micro- care and also antibiotics being added to organisms in hospitals is associated with animal feed. Hence, there is a need for a One many risks, including the increased likelihood Health approach that includes a range of of treatment failure, an increased risk of measures, including guidelines for the morbidity and mortality, longer hospital prevention of infections and the prudent use stays, higher health costs and more legal of antibiotics, the adoption of new directives disputes. The same definition of Multi-Drug on veterinary medicines and medicated feed, Resistant Organisms (MDRO) defines the encouraging the search for new antibiotics characteristics of these germs that are often and rapid diagnostic tests to detect bacterial resistant to all antibiotics except for one or infections (3). The World Health Organization two antimicrobials on the market (6). The (WHO) has identified the most important epidemiology of MDRO infections varies resistant bacteria worldwide for which there not only from year to year, but also by is an urgent need for new treatments. The geographical area, by hospital and by aim is to help countries to manage measures department. It is therefore essential to be of national surveillance, control, research aware of the local epidemiological data and development. Microbes have been provided by the Annual Reports from the classified based on their level of pathogenicity, European Centre for Disease Control and ranked according to priority as follows: (ECDC). MDROs include Extended critical priority: Acinetobacter Baumannii Spectrum Beta-Lactamases (ESBLs), (carbapenem-resistant), Pseudomonas resulting from the emergence of new Gram- aeruginosa (carbapenem-resistant), Entero- negative bacteria producing β-Lactamase. bacteriaceae including Klebsiella, E.coli, ESBLs are enzymes able to neutralize the Serratia, and Proteus (carbapenem-resistant, β-lactam ring of the antibiotic and thus ESBL-producing); high priority: Entero- render it ineffective. Beta-lactam antibiotics coccus faecium (vancomycin- resistant); are a class of broad-spectrum antibiotics that Staphylococcus aureus (methicillin -resistant, includes Penicillin, Cephalosporin, vancomycin-intermediate and resistant), Cephamycin, Monobactam and Carbapenem. Helicobacter pylori (clarithromycin- The latter are among the most widely used resistant), Campylobacter spp. (fluoro- antibiotics and the rate at which resistance quinolone-resistant), Salmonellaa spp has emerged has been particularly rapid and (fluoroquinolone-resistant), Neisseria is therefore a cause for concern, deserving gonorrhoeae (fluoroquinolone-resistant and attention at global level. Carbapenems, in cephalosporin-resistant); and medium particular Imipenem, Meropenem,
54 V. La Fauci et al. Ertapenem, Doripenem, have a broad 5,331 bacteraemias from Carbapenem- spectrum of action, are stable to many resistant and/or carbapenemases-producing inhibitors (7-8) and often represent the last enterobacteria. However, it should be noted therapeutic resort in the treatment of that the number of reports and incidence infections caused by multi-drug resistant differ substantially between Italian Regions, gram-negative bacteria. The loss of ranging from 946 reports from Latium to 0 effectiveness of this class of antibiotics has from Molise (perhaps due to under-reporting). limited the therapeutic interventions available In 84% of cases the patients were in hospital and led to combinations of antibiotics being at the onset of the bacteraemia and the used that include molecules which have not reports come mainly from the intensive care been used for many years and which are units and general medicine wards of hospitals relatively toxic (9-10). This causes an in northern Italy. Finally, 96.8% of reported increase in the mortality rate due to delayed cases were caused by Klebsiella pneumoniae administration of an effective therapy and and only 3.2% by E. coli. The rates stratified the fewer therapeutic options available, that by age group for the three-year period 2014- require the use of less effective and/or more 2016 show that the age group most affected toxic antibiotics (11-12). In its annual by CPE bacteraemia is placed between 65 Reports, the ECDC provides data regarding and 84 years of age; 62% being males, with Europe on the average and for the individual an average age of 65.4 years. The cases were states. The data for 2017, concerning reported above all by regions in northern carbapenem-resistant germs such as Italy (2,758 cases, 51.7%), followed by Acinetobacter spp, show the European central regions (1,364 cases, 25.8%), the percentage of resistant strains at 50% in south (761 cases, 14.1%) and the islands 2015, with Italy alone reporting 78%; for the (448 cases, 8.4%). It is to be hoped that local Pseudomonas aeruginosa the European and regional Health Authorities will be more average of resistant strains was 17.8%, with closely involved in National Surveillance, Italy reporting a worse rate of 23%; data on which will allow longer term monitoring not carbapenem-resistant E. coli report a only the changing rates of CPE bacteraemia percentage of resistant strains in Europe of but also the assessment of the impact of the 0.1%, with Italy at a rate of 0.2%, with control and prevention measures implemented slightly increased rate from 2012 to (14). Apart from the resistance to carbapenems 2015,which then remained the same; finally of some bacteria under surveillance, such as carbapenem-resistant Klebsiella pneumonia Klebsiella pneumoniae and Escherichia coli, (13) fluctuated between 2006 and 2015 with another concern is (15) their resistance to an increase in resistant strains, in Europe this third generation Cephalosporins, to increased from 6.2% in 2012 to 8.1% in Aminoglycosides and Fluoroquinolone. 2015. Since 2013 Italy has been called an Often the resistances combine generating “endemic country” as regards these resistant multiresistant bacterias causing infections germs, due to their continuous dramatic that are difficult to treat. Looking at the increase, so much that in 2015 it reached strains resistant to 3rd generation 34% of resistance, thereby becoming a Cephalosporins, the percentage of resistant “hyperendemic country”. National Klebsiella pneumoniae in Europe increased surveillance data from 1 April 2013 to 31 from 25.8% in 2012 to 30.3% in 2015, with July 2016 show that in Italy the incidence of Italy alone recording a percentage of 55.9%. all Carbapenemase-producing The strains of resistant E. coli also rose from Enterobacteriaceae (CPE) infections is the 11.9% in 2012 to 13.1% in 2015, reaching second highest in Europe, after Greece, with 30.1% in Italy in 2015. With regard to
Antibiotic resistance: where are we going? 55
aminoglycosides-resistant Klebsiella control of multiresistant bacterial infections
pneumoniae, the European average increased with measures targeted on all healthcare
only slightly from 21.5% in 2012 to 22.5% sectors (hospitals, long-term care facilities,
in 2015. From the latest reports, the etc) and in communities, through the
prevalence of resistant strains in Italy is appropriate use of antibiotics in human
higher than the European average of 34%. medicine and veterinary strategies. It is also
For E. coli resistant to this class of antibiotics necessary to develop national policies to
there was an annual average of 10.4% in tackle the problems that are in line with the
2015, while Italy had a rate almost double. WHO global action plan on antimicrobial
The fluoroquinolone-resistant Klebsiella resistance. In addition, the approach taken
pneumoniae strains show an increasing trend by hospitals and their policies concerning
in Europe, rising from 25.3% in 2012 to antibiotics should be based on scientific data.
29.7% in 2015, in Italy the rates were Antimicrobial resistance cannot be solved
definitely worse, going from 20% in 2009 to solely by continuous producing new
46.0% in 2011 and 53.7% in 2015.For E. antibiotics. Healthcare professionals and
coli strains resistant to the same class of citizens must be informed about the problem
antibiotics, the European average in 2015 of antimicrobial resistance through better
stood at 28.8%, while in Italy the situation information and education (18). It is
worsened from 36% in 2009 to 41% in 2011 therefore necessary for everyone to
and to 44% in 2015. As regards the resistance collaborate: citizens should take antibiotics
of Gram-positive bacteria, the Italian only under prescription of their doctors, and
situation is fluctuating. If we take into only at the dose indicated and for the
consideration the methicillin-resistant prescribed duration (and not for longer or
Staphylococcus aureus, the European shorter periods), doctors should apply the
average went from 18.8% in 2012 to 16.8% measures for the prevention and control of
in 2015; Italy remained one of the eight infections, prescribe antibiotics only when
European countries above 25%, with a rate necessary and in an appropriate manner,
of 37% in 2009, 38% in 2011 and 36% in administrators should strengthen surveillance
2015 (16-17). The Vancomycin-resistant systems and laboratory efficiency and
Enterococcus faecium strains in Europe implement programs to ensure appropriate
increased only slightly, from 8.1% in 2012 antibiotic prescription, the pharmaceutical
to 8.3% in 2015, while Italy remained below industry should invest in the development of
the average in 2009 and in 2011 at 4%, but new tools for the diagnosis and treatment of
exceeded the average in 2015, reaching 9%. infections (19).
For Macrolides resistance of Streptococcus
pneumoniae strains, the European data
fluctuated just as for Italy, where it went Riassunto
from 21% in 2009 to 27% in 2011, falling Antibiotico resistenza: dove stiamo andando?
to 21% in 2015 (13). To conclude, among
the European countries, Italy occupies the L’antibiotico resistenza rappresenta oggi la più Grande
fifth place as regards antibiotics use for Minaccia nell’ambito delle malattie infettive a causa del
human health nationwide and antibiotic notevole incremento dell’antibiotico resistenza in Europa
resistance remains unfortunately among the e nel Mondo. La presenza di questi microrganismi mul-
tiresistenti in ospedale si correla a moltissimi rischi, tra
highest in Europe and is consistently above cui l’aumento della probabilità di fallimento terapeutico,
the European average. It is possible to l’aumento del rischio di morbilità e mortalità, l’aumento
control antimicrobial resistance only by della durata della degenza ospedaliera, l’aumento dei
combining measures for the prevention and costi sanitari e dei contenziosi. L’epidemiologia delle56 V. La Fauci et al.
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Correspondending author: Prof. Vincenza La Fauci, orcid.org/0000-0002-5038-8811
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, A.O.U.
Policlinico “G. Martino”, Biological tour 1° Floor, Via Consolare Valeria, 98125 Messina, Italy
e-mail: vlafauci@unime.itYou can also read
