Antibiotic resistance in Norway
Both the number of healthy people colonised with resistant bacteria, and the number of patients who have infections caused by these bacteria have increased.
- The development of antibiotic resistance by bacteria is an increasing problem both in Norway and worldwide.
- The most important interventions to combat the development of resistance are to prevent infections and limit antibiotic consumption.
- A common type of antibiotic resistant bacteria is Staphylococcus aureus that has developed resistance to methicillin and other antibiotics (MRSA; methicillin resistant Staphylococcus aureus).
- MRSA infections are a particular threat to hospital patients. If the incidence of MRSA in health institutions increases, treatment of staphylococcal infections can be less effective and much more expensive.
- Globally, the incidence of blood poisoning (septicaemia) and other infections with ESBL-resistant bacteria has increased dramatically and are also increasing in Norway.
- There are only a few treatment alternatives for gonorrhoea.
Resistance to treatment is seen in all types of microbes; bacteria, viruses, fungi and parasites. In this chapter, we will mainly discuss antibiotic resistance, i.e. resistance among bacteria to antibiotics.
Antibiotic resistance allows bacteria to survive and multiply despite exposure to antibiotics.
Some bacteria are naturally resistant to certain antibiotics; both these and others may also develop resistance after exposure to antibiotics themselves. This second method is called acquired resistance. Bacteria can develop resistance to more than one antibiotic. Those that are resistant to two or more antibiotics are called multidrug-resistant (MDR).
Resistant bacteria are usually no more pathogenic than normal bacteria but when they cause disease, these infections are more difficult to treat than other infections. The patient may have a longer disease course with greater risk of complications and higher mortality. In addition, the antibiotics that are used for these infections may increase the risk of even more resistant bacteria arising. In the worst case scenario, a patient could be infected with a bacteria that is resistant to all available antibiotics.
Bacteria can become resistant to antibiotics in several ways, including changes (mutations) in their own genetic material (DNA) or transfer of resistance genes from other bacteria, known as horizontal gene transfer.
How does antibiotic resistance spread?
Antibiotic resistance increases when resistant bacteria are spread among humans, animals and the environment, or when the resistance genes transfer between bacteria.
Antibiotic-resistant bacteria will often become established among normal bacterial flora, for example in the gut. People then become carriers of resistant bacteria. Carriers may not become sick but can contribute to the further spread of antibiotic resistance.
Surveillance of antibiotic resistance in Norway
Surveillance is necessary if the health service is to deliver medical treatment safely in the future. In Norway, resistance to antibiotics is monitored in several ways:
- Norwegian Surveillance System for Communicable Diseases (MSIS)
- Norwegian Surveillance System for antimicrobial drug resistance (NORM)
- Norwegian Surveillance System for antimicrobial drug resistance - Veterinary Medicine (NORM-VET)
Below are figures and graphs about various antibiotic-resistant bacteria, with descriptions of the current situation and developments over time.
Methicillin-resistant Staphylococcus aureus (MRSA)
S. aureus bacteria are commonly found on the skin and mucous membranes in humans. Between 20 and 40 per cent of the population are colonised without symptoms. Most people will encounter these bacteria during their lifetime. In healthy individuals, these bacteria rarely cause disease but S. aureus is one of the most common causes of infection in healthcare institutions.
MRSA bacteria do not differ from "sensitive" S. aureus in terms of infection risk or ability to cause disease but they are resistant to all penicillin-derived antibiotics. This resistance makes it harder to treat infections caused by MRSA.
Resistance to linezolid, a so-called “last resort” antibiotic, has been detected in S. aureus and enterococci (Doern, 2016; Gu, 2013).
Notified cases of MRSA per year
There has been a sustained and significant increase in reported colonised individuals. There has also been a slight increase in the number of infections over recent years. In 2015, there were 2235 notified cases of MRSA, of which 785 were for MRSA infection and 1450 were colonised (NIPH, 2016a).
Figure 1: Trends in the number of notified cases of MRSA-infection and carrier status 2010-2016. *As per 23rd November 2016. Source: MSIS.no
Where does MRSA infection occur?
The Norwegian Institute of Public Health registers whether MRSA infections are healthcare-associated (HA), community-associated (CA), or are acquired abroad, based on the following criteria:
- HA-MRSA: healthcare personnel or cases diagnosed relating to a stay in hospital or nursing home without reported infection abroad.
- CA-MRSA cases diagnosed in the primary health service, without having been hospitalised, worked in a healthcare institution or reported infection abroad.
- Imported infection: cases where infection acquired abroad are reported, or from an unknown site of infection if born abroad.
From 2010 to 2016 there was a steep increase in community-associated MRSA and imported MRSA infection (figure 2 below) (NIPH, 2016a).
Figure 2. Number of reported cases of MRSA per year, split by health service associated (HA), community-associated (CA) and MRSA acquired abroad (import). * As per 23rd Nov.2016. Source: Norwegian Surveillance System for Communicable Diseases (MSIS). (NIPH, 2016b).
Norway has lower prevalence of MRSA than most other countries
Norway has one of the lowest levels of MRSA notifications in the world. For septicaemia caused by S.aureus, the proportion caused by MRSA is over 20 per cent in most European countries and is often over 50 per cent in other parts of the world. In Norway, the proportion is still below one per cent; however, the incidence is increasing (NORM / NORM-VET, 2016).
The challenge to control MRSA in hospitals and nursing homes
MRSA infections are a particular threat to hospital patients, people with impaired immune systems and the elderly. These groups are more susceptible to serious infections and depend on the correct antibiotic treatment early in the course of their infection. If the prevalence of MRSA in health care increases, the treatment of staphylococcal infections will become less effective and considerably more expensive.
If the increase in MRSA in the community continues and eventually leads to a high incidence of MRSA in the population, the current infection control measures will no longer be appropriate and new strategies must be developed to prevent MRSA from becoming established in hospitals and nursing homes.
MRSA in Norwegian pig farming
Another threat is the occurrence of livestock-associated MRSA (LA-MRSA). In Denmark and other European countries this is a major problem in pig farming. There have also been outbreaks of LA-MRSA in Norwegian pig farming. Significant resources and a new monitoring programme have been introduced to prevent further spread and establishment of LA-MRSA. Norway is the only country we are aware of that has a national strategy to prevent and combat MRSA in livestock (Norwegian Food Safety Authority, 2016).
Vancomycin-resistant enterococci (VRE)
Enterococci are bacteria that usually live in the bowel. They are usually not aggressive bacteria but can cause serious infections in people with an impaired immune system. Enterococci are naturally resistant to many antibiotics. If there is an infection with vancomycin-resistant enterococci (VRE), treatment is difficult because there are few alternative drugs available.
Several outbreaks of VRE in hospitals in Norway
Figure 3 shows the number of notified cases of VRE from 2008 to November 2016. There were less than 10 cases reported annually until 2010. Since then, Norway has had several major outbreaks of VRE in hospitals and consequently the total number of VRE cases has increased significantly. In 2011, there were 289 reported cases and in 2013 there were 117 (NIPH, 2016 a).
If hospitals with outbreaks are excluded from the statistics, there is still a small increase in the number of reported cases of VRE infection in Norway. In 2015, excluding hospital outbreaks, there were 77 cases of VRE reported to MSIS, three cases with Linezolid Resistant Enterococci and one case with Vancomycin and Linezolid Resistant Enterococci.
Figure 3. Number of reported infections with vancomycin-resistant enterococci (VRE) per year, Source: Norwegian Surveillance System for Communicable Diseases (MSIS)
Comprehensive measures including contact tracing, screening and isolation are intended to keep VRE outbreaks in hospitals under control.
Resistance in gram-negative bacteria
There are many different types of resistance among gram-negative bacteria. ESBL is short for extended-spectrum beta-lactamase and is a resistance mechanism that inactivates some of the main types of antibiotics we have to treat infections, particularly those caused by intestinal bacteria such as E.coli. There are many variants of the ESBL-resistance mechanism.
Increase in infections caused by ESBL
The incidence of bacterial infections caused by bacteria that produce ESBL has increased dramatically internationally and is also increasing in Norway. For example, the proportion of E. coli with ESBL as the cause of septicaemia has increased ten-fold in the last 10 years and in 2016 had increased to 6.5 per cent of all septicaemia cases caused by E.coli in Norway (NORM/NORM-VET 2016). This is serious.
Travel is probably a major cause of the global spread of these bacteria. There is a high risk of becoming a carrier when travelling in Southeast Asia and Africa, and even in southern Europe (Lubbert. 2015).
It is feared that bacteria with the resistance mechanism ESBLCARBA will spread to the Norwegian health care system. This form of ESBL-resistance is the most concerning and there are few treatment options for these patients. Therefore, only bacteria with this variant are included in the national surveillance system.
Surveillance began in 2012, and the number of reported cases of infection is very low. In 2015, there were 45 cases reported with these bacteria. In 2012, there were 10 cases. Nearly all were related to patients who had received treatment abroad. There are reports of increasing numbers of outbreaks of such infections internationally and mortality is high (Souli, 2010).
Figure 4. Proportion of ESBL-positive E. coli and Klebsiella spp in blood and urine (NORM/NORM-VET, 2016). Source: NORM/NORM-VET.
Figure 5. Number of people registered per year with one or more gram-negative bacteria with ESBLCARBA. Source: MSIS (5).
So far we have discussed microbes with resistance mechanisms with particular significance for healthcare institutions. For society in general, microbes with other resistance mechanisms may have significance, particularly resistance in tuberculosis and gonorrhoea.
Multidrug-resistant tuberculosis (MDR-TB)
In Norway in recent years, between 3 and 12 cases of MDR-TB have been treated annually. In 2015 there were 5 cases, which was a reduction compared to recent years (NIPH, 2016c).
Internationally, MDR-TB is a large and growing problem, particularly in the countries that were part of the former Soviet Union.
To prevent tuberculosis bacteria from developing resistance, it is important to treat the patient with at least three drugs simultaneously. In addition, the drugs must be taken for a sufficiently long period, i.e. 6-12 months.
WHO recommends that tuberculosis medication is taken as directly observed therapy (DOT), which means that healthcare professionals follow the patient throughout the treatment course and check that the patient takes medicine every day. Norway supports this recommendation, with some adaptations for individual patients.
Resistance in gonorrhoea
The incidence of gonorrhoea is increasing in Norway. In 2015, there were 851 diagnosed cases (NIPH, 2016b).
The bacterium that causes gonorrhoea, Neisseria gonorrhoeae, has shown a high ability to develop resistance. There are only a few treatment options available that the bacteria are not resistant to or have not reduced sensitivity to. In Norway, gonorrhoea must now be treated with an intramuscular injection of antibiotics.
Only drugs that act against bacteria are known as antibiotics. However, there are similar problems with resistance to drugs against other microbes, such as viruses. Strains are appearing that are resistant to anti-viral medicine.
Examples of viral resistance include resistance to the influenza drug oseltamivir, HIV medicines and drugs used against viral hepatitis. See the report for viral resistance in Norway (RAVN).
International increase in antibiotic resistance
There has been an increase in reports worldwide of patients being infected with bacteria that are resistant to all available antibiotics, including in Europe. It is feared that these bacteria could gain a foothold and establish themselves in the Norwegian health service. Although there has been an increase in infections with antibiotic-resistant bacteria in Norway in recent years, the problem is significantly lower than in most other countries, see statistics above under sections MRSA, VRE and ESBL.
However, increased antibiotic use, travel, import of food and spread of resistant bacteria in food production can change the situation. Norway has been able to control the prevalence of antibiotic resistance with sustained and comprehensive measures in health institutions but the infection pressure can eventually become so large that the measures are no longer effective.
The development of new antibiotics has stopped
The combination of increasing incidence of resistance and the lack of new antibiotics is why the WHO and other international agencies (ECDC) believe that antibiotic resistance is a serious threat to future medical treatment (O’Neill, 2016). The development of new classes of antibiotics has come to a halt in the last 30 years and only a few new antibiotics have become available.
However, there are new international initiatives to improve this situation, for example DriveAB. This project aims to develop new economic models. The current model, where industry seeks the highest possible sales to cover the cost of research and development while trying to make a profit is not compatible with the international community’s efforts to reduce antibiotic consumption.
Interventions to prevent antibiotic resistance
Awareness around the growing problem of antibiotic resistance has been increasing, and in 2015, the government published the National Strategy for Antibiotic Resistance 2015 – 2020 (Ministry of Health and Care Services, 2015). The main goals of the strategy include:
- Reducing total antibiotic use
- Correct use of antibiotics – «only when needed»
- increase knowledge about what is causing the development and spread of antibiotic resistance
- Be a driving force in international, normative work to strengthen access, responsible use and development of new antibiotics, vaccines and better diagnostic tools.
The health-specific goals for the period 2015 – 2020 are:
- Antibiotic consumption in the population will be reduced by 30 per cent, measured in defined daily doses (DDD) compared with 2012.
- Norway will be among the three countries in Europe who use least antibiotics for humans, measured in DDD/ 1000 inhabitants per day.
- The average prescription of antibiotics will be reduced from the current 450 prescriptions to 250 prescriptions per 1000 inhabitants per year.
- There will be studies of burden of disease relating to antibiotic resistance, the consequences of insufficient antibiotic consumption and the effect of infectious disease control.
There are also sector-specific goals for livestock, pets and fish as well as climate and environments.
In 2016, the Ministry of Health and Care Services (HOD) published an action plan for antibiotic resistance in the health service, which included the interventions that HOD will implement to achieve the goals of the strategy (HOD, 2016). The interventions are organised under six areas of action; national organisation of the work, interventions aimed at the general population, interventions directed at general practitioners and doctors at out-of-hours health services, towards specialist health services, municipal health institutions and dental services.
Some of these points are explained in more detail below.
Reducing antibiotic use
The most important preventative interventions are to limit antibiotic use and choose narrow-spectrum instead of broad-spectrum antibiotics. In 2015 in Norway, 37 metric tons of antibiotics were used for humans, 5.9 metric tons for livestock and 0.3 metric tons for fish farming (NORM/NORM-VET, 2016).
Today, nearly 90 per cent of all antibiotic use in humans occurs outside hospitals and nursing homes (NORM / MORM-VET 2016).
Figure 6. Use of antibacterial agents in Norway, 1999-2015 in terms of defined daily doses (DDD) per 1000 inhabitants per day Source: Wholesale Dug Statistics, NIPH.
The use of antibiotics in agriculture is an important contributor to the total global consumption. Norwegian agriculture has a low consumption compared with other countries. The decline in antibiotic use in fish-farming from 48 metric tons in 1987 to 0.3 metric tons in 2015 is an example of a positive trend.
Use narrow-spectrum instead of broad-spectrum antibiotics
Narrow-spectrum antibiotics affect fewer types of bacteria and thus cause more limited development of resistance.
In Norway, there is a high consumption of narrow-spectrum penicillin-derived antibiotics. The increase in antibiotic use from 2000 to 2015 is mainly due to increased use of this group, see Figure 6.
Limit environmental pollution and the spread of resistant bacteria
Antibiotic use in food production is of concern because the spread of resistant microbes to the environment is undesirable and may spread to humans. In particular, LA-MRSA in livestock is a problem. It has already been detected in animal herds in Norway but is a much bigger problem in other European countries. E. coli bacteria with ESBL and resistance to quinolone antibiotics have been detected in Norwegian chicken (NORM / NORM-VET, 2012).
Travel: The spread of antibiotic resistance from countries and regions with a high incidence of resistance to areas with low incidence may be related to travel (Lubbert, 2015; Tängdén, 2010). In areas with high prevalence, the environment is contaminated with resistant bacteria. It can be very difficult to avoid ingesting these through food (Tängdén, 2010).
There is also a risk of being infected with antibiotic-resistant bacteria when entering a health care institution in areas with high rates of resistance. This applies to ESBL-expressing bacteria, MRSA and VRE.
Infectious disease control in the health service is essential
Considerable efforts are being made within infection control in the Norwegian health service to limit antibiotic resistance, because it stops the spread of infection and keeps the need for antibiotic treatment to the lowest possible level. It is essential that this work is prioritised, especially in the face of an ever-increasing infection pressure (Tangden, 2015).
If the strict infectious disease control measures in the health service are maintained together with a restrictive antibiotic consumption practice, there is hope that the prevalence of antibiotic resistance can be kept at the current low level.