The discovery of antibiotics in the middle of the last century is deservedly considered as one of the most important discoveries in medicine. This event allowed humans to be confident that it was possible to combat bacterial infections. For several decades antibiotics were effective, safe, relatively inexpensive and abundant. But as soon as antibiotics began to be used to treat infections the disease-causing bacteria began to fight back. Antimicrobial resistance (AMR) is not a new phenomenon. S. aureus resistant strains were reported less then one year after the mass production and use of the first antibiotic penicillin. Now, more than 75 years after the discovery of penicillin, resistant S. aureus strains in the community are exceeding 80% and over 95% in the hospital setting. Different bacteria have demonstrated astonishingly effective and complex survival mechanisms that are constantly changing thus challenging scientists to find more inventive ways to control infection. At the end of the century it became evident that antibiotics had become the victim of their own success. In the past decade resistance to existing antibiotics has become widespread making it imperative to find new classes of medicines and effective methods to limit the spread of resistance.
The emergence of the “superbugs” with their fearsome ability to resist antibiotics is well reported. All disease-causing bacteria have been reported to be resistant to at least one antibiotic and every antibiotic is subject to resistance. We are now witnessing the emergence of multiresistance; bacteria are considered multiresistant when they are resistant to 3 different groups of antibiotics.
The relationship between antibiotic use and antibiotic resistance is confirmed by experimental, clinical and population-based studies. No human group or society can survive without antibiotics but unnecessary and excessive use should be avoided in order to curb the emergence and spread of resistance. These statements are presented in various national and international reports and guidelines including the WHO Global Strategy for Containment of Antimicrobial Resistance(1) and the European Council recommendations (2,3) in which a comprehensive set of public health actions is provided.
The surveillance of antimicrobial resistance and control of antimicrobial agents use is a priority in both documents.
The aim of this article is to give an overview of antibiotic use and antibiotic resistance with a focus on the situation in the Baltic Sea Region (BSR) including the Baltic States (Lithuania, Latvia, Estonia) and Nordic countries (Finland, Norway, Sweden, Denmark). These countries have different histories and experiences in combating AMR. Basically, the Nordic countries developed their first national AMR programs in late 1960s-1970s that have demonstrated good results while the Baltic States are beginners and have started the activities in recent years.
Data from two European networks: the European Surveillance of Antimicrobial Сonsumption (ESAC) and the European Antimicrobial Resistance Surveillance System (EARSS) were used to give an overview of antimicrobial use and AMR. The ESAC project started at the end of 2001 with the aim to develop a data collection system that would produce comprehensive national data on the extent of antibiotic use in ambulatory and hospital care (4). It was funded by European Commission (DG SANCO), and developed and maintained a continuous, comprehensive and comparable database on antibiotic use in Europe. Currently the project is in the third phase and is funded by the European Centre for Disease Prevention and Control (ECDC).
Data on antimicrobial use in hospitals are not available in all European countries. Therefore, the use of ATC (Anatomical Therapeutic Chemical Classification System) class J01 antimicrobial agents among inpatients was analysed and is presented in this report. For Lithuania only data for the total use of antibiotics in 2006 are available and are presented with the outpatient data for 2005 for the rest of the countries. Antibiotic use is presented as defined daily doses (DDD) per 1000 inhabitants.
ЕARSS is also a publicly funded network. AMR in Europe is monitored by a network of national centers in 31 countries working according to standard protocols (5). Seven bacteria were selected for monitoring of the resistance. According to the EARSS protocol only invasive isolates, i. e. isolated from blood or cerebrospinal fluid (CSF) are included. Resistance trends can be obtained for five bacteria (Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecium, Enteroccocus faecalis and Escherichia coli) because they have been monitored for several years. Pseudomonas aeruginosa and Klebsiella pneumonia have recently been added to the protocol. No data for Pseudomonas aeurginosa and Enterococci resistance in 2006 in Denmark were available.
Although the relationship between antibiotic use and resistance is complex there is no doubt that increased antibiotic use is leading to higher levels of resistance. ESAC has confirmed that there are great variations in overall antibiotic use and the use of specific drug classes. There is more and more evidence that antibiotic use varies according to patient characteristics and other factors such as health systems, reimbursement schemes, delivery of primary care, cultural expectations, etc. These factors can have different effects on antibiotic use in outpatient and inpatient settings.
According to the ESAC database, antibiotic use in 24 countries varies from 11 to 35 DDD (median 19 DDD). Three countries have reported statistically significant increasing trends during 1998-2005 while 6 countries have observed decreasing trends.
The overview of antibiotic use in the Baltic Sea Region
The use of antibiotics in the BSR in ambulant care varies from 11.7 DDD (in Estonia) to 18 DDD (in Finland) (Fig. 1), both of which are lower than the EU median.
Fig. 1. Consumption of antibacterial agents (ATC class J01) in outpatient setting in the Baltic Sea Region countries
* - data correspond to total use (outpatients and inpatients in hospitals), as separate outpatient data not available in Lithuania
The proportion of different antibiotic classes used varies considerably between the regions and countries. Penicillins are more predominantly used in Denmark and Lithuania where they constitute more that 50% of all antibiotics prescribed (EU median approximately 45%). In Finland (31%) and Estonia (38%) penicillins are not the antibiotic of choice. The use of tetracyclines is lowest in Denmark (1.3 DDD) and highest in Finland (4 DDD) and Sweden (3.2 DDD) that both exceed the EU median (2.3 DDD). The use of macrolides and fluorquinolones in the BSR countries is lower than the EU median with very low level use of macrolides in Sweden (0.9 DDD) and fluorquinolones in Denmark (0.3 DDD).
Resistance to antimicrobials is a natural biological occurrence among all living microorganisms. The introduction of every antimicrobial agent into clinical practice has been followed by the detection of resistant strains. All antimicrobial agents have the potential to select drug resistant subpopulations of microorganisms. The prevalence of resistance varies between geographical regions and over time. While it is difficult to quantify the total impact of resistance on health, published data clearly indicate that morbidity and mortality are increased due to delays in administering effective treatment for infections caused by resistant pathogens. Surveillance of resistance is essential in providing information on the magnitude of the problem and trends.
All the bacteria included in the EARSS network may be conditionally divided into two groups: resistant bacteria observed in the hospital setting (S. aureus, Enteroccoci, K. pneumoniae, P. aeruginosa) and resistant bacteria more frequently detected in the community (S. pneumoniae, E. coli).
An overview of the current resistance situation in the BSR
S. aureus colonizes the anterior nares of about 30% of healthy humans. Although mainly a harmless coloniser, S. aureus can cause severe infections. The oxacillin-resistant form (methicillin-resistant S. aureus, MRSA) is the most important cause of antibiotic-resistant health care-associated infections worldwide. Since health care-associated MRSA infections add to the number of infections caused by methicillin-susceptible S. aureus, a high incidence of MRSA adds to the overall burden of infections caused by this species in hospitals. Moreover, infections with MRSA may result in prolonged hospitalizations and in higher mortality due to the increased toxicity and limited effectiveness of alternative treatment regimens. MRSA is currently the most commonly identified antibiotic-resistant pathogen in hospitals in many parts of the world, including Europe, the Americas, North Africa and the Middle- and Far-East.
According to the EARSS data, the MRSA prevalence among invasive isolates in Europe during 2006 varied from 1% to 67% (median 21%). It is evident that the Nordic countries and Estonia show the lowest rates of MRSA (Fig. 2). Lithuania and Latvia have the highest rates of MRSA in the BSR but are still below the EU median resistance rate.
Fig. 2. Resistance to methicillin of invasive Staphylococcus aureus in BSR countries, 2006 (Source: EARSS data. Available at: http://www.earss.rivm.nl)
Enterococcus species are responsible for wound, blood, urinary tract, heart and other life-threatening hospital-acquired infections. The first-line antibiotic treatment for some species is vancomycin. According to the CDC, by 2002 27% of the Enterococcus samples tested in the US were vancomycin-resistant.
Resistance of E. feacalis to vancomycin is very low in Europe and ranges from zero to 6% (median 0). E. feacium are more resistant to vancomycin and the proportion of resistant infections varies from zero to 44% (median <1). The BSR countries did not report cases of vancomycin-resistant E. feacalis (Sweden) and E. feacium (Sweden and Finland). However, the situation regarding aminoglycoside resistance is not so favourable (Fig. 3). The Baltic States are reporting significantly higher rates that exceed the EU median and represent the top levels in Europe with the resistance of E. feacalis ranging from 15-58% and E. feacium from 12-85%.
Fig. 3. Resistance of invasive (blood) enterococci to aminoglycosides in BSR countries, 2006 (Source: EARSS data. Available at: http://www.earss.rivm.nl)
Pseudomonas aeruginosa is a particularly nasty bug that causes urinary tract infections, lung infections, wound and other infections common in intensive care units and surgical departments. Flourquinolone is one of the most effective antibiotic classes to treat P. aeruginosa. CDC figures from 2002 reported that over 33% of tested samples were resistant (6).
Resistance of P. aeruginosa to 5 groups of antibiotics has been investigated by the EARSS and found to vary from 2-3% to up to 42-48% for different antibiotics in different countries. The situation in the BSR countries is heterogeneous. The Baltic States and especially Lithuania and Latvia show considerably higher resistance rates (Fig. 4). Estonia reports the highest rates of carbapenem resistance in the region (29%), while flourquinolone resistance in Lithuania (46%) almost reaches the top EU level (48%).
Fig. 4. Resistance of invasive (blood) Pseudomonas aeruginosa in BSR countries, 2006 (Source: EARSS data. Available at: http://www.earss.rivm.nl)
Klebsiella pneumoniae is clinically the most important member of the Klebsiella genus found in the normal flora of the mouth, skin and intestines. It is a pathogen associated with nosocomial infections, infections in compromised hosts causing severe pneumonia as well as blood stream and urinary tract infections. Due to high resistance reported worldwide K. pneumoniae has become one of the most important pathogens to fight in hospitals.
While resistance to carbapenems varies between zero and 33% in Europe, few countries in the BSR have reported single cases (Sweden, Norway and Finland). K. pneumoniae resistance to third generation cephalosporins, aminoglycosides and fluorquinolones is similar to that observed with other pathogens (Fig. 5). Resistance to all these groups of antibiotics in the Nordic countries is minimal and lower than EU median. The Baltic States report higher rates especially in Lithuania and Latvia (with the exception of fluorquinolone resistance in Lithuania). It is worth mentioning that even with these high rates, the Baltic States are still clearly below the top levels in Europe (third generation of cephalosporins 94%, aminoglycosides 91% and fluorquinolones 50%).
Fig. 5. Resistance of invasive (blood) Klebsiella pneumoniae in BSR countries, 2006 (Source: EARSS data. Available at: http://www.earss.rivm.nl)
S. pneumoniae is one of the lethal bacteria, the single most important cause of community-acquired pneumonia and the cause of childhood ear infections, meningitis and sinusitis. Some years ago the CDC reported up to 40 % resistance to at least one drug and 15 % resistance to three or more drugs. In Europe during 2006 the proportion of penicillin-resistant pneumococci varied from zero to 39 % with a median value of 7%. The situation concerning S. pneumoniae in the BSR is quite favourable; most countries have very low resistance except Lithuania (16%) and Finland (12%) where resistance is high (Fig. 6). Pneumocoсci resistance to macrolides (erythromycin) is increasing worldwide. In 2006 the proportion of erythromycin-resistant S. pneumoniae varied from zero to 47% (median 16%). The proportion of resistant isolates in the BSR, with the exception of Finland (24%) and Norway (12%), is 4-5 times lower that EU median.
Fig. 6. Resistance of invasive (blood and CSF) Stretococcus pneumoniae in BSR countries, 2006 (Source: EARSS data. Available at: http://www.earss.rivm.nl)
Escherichia coli infections are often assumed to be food poisoning. E. coli is, however, a member of the normal human gut flora most frequently responsible for the urinary tract infections. It is also associated with peritonitis and may cause wound infections particularly in abdominal surgery. E. coli has shown resistance to broad spectrum penicillins and more recently to third generation cephalosporins worldwide.
E. coli aminopenicillin resistance varied from between 29% to 84% (median 55%) in Europe during 2006. Fourteen countries reported increasing trends over the period from 1998 to 2005. The prevalence of aminopenicillin-resistant E. coli in the BSR does not exceed the EU median but is higher in the Baltic States (particularly in Lithuania with 55%) and lower in Nordic countries (lowest in Sweden with 29%) (Fig. 7).
Fig. 7. Resistance of invasive (blood and CSF) Escherichia coli in BSR countries, 2006 (Source: EARSS data. Available at: http://www.earss.rivm.nl)
E. coli resistance to third generation cephalosporins, quinolones and aminoglycosides shows a similar tendency with a higher level of resistance in the Baltic States as compared to the Nordic countries. The exception is Estonia where resistance rates are low. It is noteworthy that resistance to quinolones is lower than the EU median in all BSR countries. Lithuania (15%) exceeds EU median of E. coli resistance to aminoglycosides (7%, range: 2-40%) more than twice.
Accessibility to the well-functioning European network, the ESAC and the EARSS, led to the development of antimicrobial use and resistance surveillance systems in the countries of the Baltic Sea Region. Consequently, preliminary data on antimicrobial use and resistance are available for all Baltic countries. Antibiotic use in the Baltic countries is low and similar in the different countries, and does not exceed the European mean values. The situation concerning antimicrobial resistance in the region is not so homogenous. Higher resistance rates of some bacteria e.g. P. aeruginosa, E. coli, K. pneumoniae, warrant further vigilance or conceivably immediate intervention.
- WHO Global Strategy for Containment of Antimicrobial Resistance. WHO, 2001
- Council Recommendation of 15 November 2001 on the prudent use of antimicrobial agents in human medicine (2002/77/EC)
- Council Conclusions on Antimicrobial Resistance (AMR) addopted at 2876th Employment, Social Policy, Health and Consumer Affairs Council meeting in
Luxembourg, 10 June 2008Council recommendation 2008 (available at http://www.consilium.europa.eu/uedocs/cms_Data/docs/pressdata/en/lsa/101035.pdf)
- Bad Bugs: No drugs, IDSA, July 2004 (Available on http://www.fda.gov/ohrms/dockets/dockets/04s0233/04s-0233-c000005-03-IDSA-vol1.pdf)