The 14th DANMAP report, DANMAP 2009, describes the annual consumption of antimicrobial agents and the occurrence of resistance in different reservoirs. The continuous monitoring of antimicrobial resistance and consumption makes it possible to analyse the trends in antimicrobial consumption and resistance over time.

Focus Area: Extended Spectrum Beta-Lactamase (ESBL)-producing bacteria in Danish pigs, Danish and Imported Retail Meat and Human Patients

Bacteria that produce extended spectrum beta-lactamase (ESBL) are resistant to the wide-spectrum penicillins normally used for treatment and their occurrence – even at low levels – is therefore a matter of concern. In 2009, the prevalence of these bacteria in meat and pigs as well as among human patients was examined.

Pigs and meat

Eleven per cent of pigs carried ESBL-producing Escherichia coli at slaughter. In samples from meat, the prevalence was low, 0.7 to 3.4 per cent; however, in 36 per cent of the imported broiler meat, ESBL-producing E. coli were detected. The most commonly detected gene among ESBL-positive isolates from pigs was CTX-M-1 (66 per cent) and among isolates from imported broiler meat CMY-2 (48 per cent) was most commonly found. CTX-M-15 a gene often found among human isolates was found among two per cent of the isolates from pigs.

Humans

The prevalence of ESBL-producing E. coli and Klebsiella pneumonia from blood and urine infections increased significantly (except for E. coli from blood) from 2007 to 2009. ESBL resistance in K. pneumoniae from bloodstream infections reached 14.6 per cent.

The parallel increase in prevalence of ESBL-producing bacteria in both humans and animals indicate that antimicrobial selection takes place in both reservoirs, and food derived spread of ESBL-producing E. coli may be the origin in at least part of the human cases.

Antimicrobial Consumption

DANMAP presents the use of antimicrobial agents in humans and animals. In humans, the use of prescription medicines has been monitored by the Danish Medicines Agency at the level of the individual patient since the early 1990s. In animals, data on all medicines prescribed by veterinarians for use in animals have been registered at farm and species level by the VetStat programme at the Veterinary Institute (Technical University of Denmark) since 2001.

Antimicrobial Consumption in Animals

* "In 2009, the total consumption of antimicrobial agents in animals amounted to 129.7 tonnes. This was a 10.4 per cent increase compared with 2008."

In 2009, the total consumption of antimicrobial agents in animals amounted to 129.7 tonnes. This was a 10.4 per cent increase compared with 2008. The increase could mainly be attributed to consumption in pigs. Subsequently, the term 'ADD' is used for the defined animal daily dose.

An increasing number of pigs were exported at 30kg live weight. When the statistics are adjust accordingly, antimicrobial consumption in pigs increased by 12.7 per cent from 2008 to 2009. The consumption in pigs reached 4.9ADD_kg per kilo of pork produced.

The increase could largely be attributed to tetracyclines (12 per cent), macrolides (16 per cent) and pleuromutilins; these antimicrobial agents are commonly used for mass medication in feed or drinking water in pig herds with disease problems. The use of wide-spectrum cephalosporins in pigs decreased by 25 per cent compared to 2008.

The consumption of antimicrobial agents in cattle, increased to 15 tonnes, but has been relatively stable at around 14 to 15 tonnes since 2005. Narrow spectrum penicillins comprised 57 per cent of the systemic treatment in cows. Penicillins were also the most frequently used agents for intramammary use. In 2009, the use of wide-spectrum cephalosporins for intramammary use decreased by 32 per cent, and comprised 13 per cent of the intramammary consumption in 2009. Also, the consumtpion of cephalosporins for systemic use in cattle decreased by 14.7 per cent.

The consumption of antimicrobial agents in poultry increased from 556kg in 2008 to 1070kg in 2009. However, even with a doubling of the consumption of antimicrobial agents in Danish broilers, the consumption remains at a very low level, equivalent to 0.15ADD_kg per kilo of meat produced.

In turkeys, the consumption increased by 165 per cent, reaching 1.8ADD_kg per kilo of meat produced, the highest level since 2002.

In aquaculture, the antimicrobial consumption decreased by four per cent to 3.3 tonnes in 2009 compared with 2008, due to a reduction in consumption in salt-water fish.

Antimicrobial Consumption in Humans

Primary health care and hospitals

The total consumption of antibacterial agents for systemic use in humans amounted to 17.9 DDDs per 1,000 inhabitants per day (DID) compared with 17.8 DID in 2008. Since 2000, consumption has increased by 4.2 DID (31.1 per cent). Consumption in primary health care comprises approximately 90 per cent of the total consumption.

Primary health care

In 2009, the total antibacterial consumption (J01) amounted to 15.95DID compared with 15.91DID in 2008. It seems that the continuing increase in consumption in primary healthcare has levelled off. However, the levelling in total consumption was mainly due to a reduction in beta-lactamase sensitive penicillins (0.18 DID) and macrolides (0.08 DID) counterbalanced by an increase in combinations of penicillins/beta-lactamase inhibitors (0.18 DID) and tetracyclines (0.07 DID). Beta-lactamase sensitive penicillins (narrow spectrum) still represented the largest group of antibacterial agents consumed (32 per cent of the total consumption) followed by penicillins with extended spectrum (21 per cent) and macrolides (14 per cent). Total consumption expressed in DID increased by 31 per cent during 2000–2009.

Hospitals

The total consumption (J01) expressed in DDDs per 100 occupied bed-days (DBD) increased by 4.8 per cent (from 74.56 in 2008 to 78.13 in 2009). When expressed as the number of DDDs per 100 discharged patients it increased by 1.6 per cent during 2007–2009 (from 288.7 in 2007 to 293.3 in 2009). The difference reflects shorter duration of hospitalisation per patient, but more admissions to hospitals. The consumption of all the major antibacterial groups (>1.0 DBD) increased with the exception of beta-lactamase sensitive penicillins, aminoglycosides and imidazole derivates. Cephalosporins, mainly 2nd generation, accounted for 21 per cent of the total consumption in the hospital sector. Penicillins with extended spectrum (18 per cent), fluoroquinolones (13 per cent) and beta-lactamase sensitive penicillins (12 per cent) were other major contributing antibacterial groups. Over the last decade (2000–2009), total consumption has increased by 31.2 DBD (66.4 per cent).

Overall, the antimicrobial consumption in humans has been at a steady level the past two years but the use of broad-spectrum antimicrobial agents, e.g. cephalosporins and fluoroquinolones, has increased.

The opposite situation is seen in the veterinary sector, where the consumption of the most critically important antimicrobial agents is decreasing (cephalosporins) or the use is very low (fluoroquinolones). Concurrently, a steep increase in overall antimicrobial consumption – particularly in pigs – occurred in 2009, including increasing consumption of macrolides (critically important).

Resistance in Zoonotic Bacteria

* "Thirteen per cent of the pigs at slaughter were positive for MRSA and 93 per cent of these were CC398."

Among Salmonella Typhimurium isolates from Danish pigs, no significant change in occurrence of antimicrobial resistance was observed from 2008 to 2009, although significant increasing trends throughout the decade continued for sulfonamide, ampicillin and streptomycin. In S. Typhimurium from pork, the occurrence of resistance to four antimicrobial agents was significantly higher in imported pork (22 per cent for ciprofloxacin) compared to domestic products (0 per cent for ciprofloxacin). Several human S. Typhimurium outbreaks occurred in 2009; the two largest consisted of 212 and 83 cases, respectively. The occurrence of resistance in human domestically acquired S. Typhimurium cases was in general lower than the occurrence in both Danish and imported pork and might at least in part be explain by the outbreaks. A significantly higher occurrence of nalidixic acid and ciprofloxacin resistance was observed in travel associated cases when compared with domestically acquired cases.

Salmonella Enteritidis is relatively rare in the Danish poultry production; in 2009, it was isolated only from imported broiler meat. Among the isolates tested, notably the occurrence of resistance to ciprofloxacin and nalidixic acid increased, with 49 per cent of the isolates resistant to nalidixic acid and ciprofloxacin. Resistance to ampicillin, ciprofloxacin and nalidixic acid was significantly more frequent in travel associated cases compared to those acquired in Denmark.

From 2008 to 2009, no significant changes in occurrence of resistance were observed among Campylobacter jejuni from Danish broilers and cattle or Campylobacter coli from pigs. In Danish chicken meat, ciprofloxacin- and nalidixic acid-resistance in C. jejuni decreased significantly, with no resistant isolates in 2009. Imported chicken meat contained C. jejuni with significantly higher levels of resistance to ciprofloxacin (56 per cent), nalidixic acid (56 per cent) and tetracycline (52 per cent) compared to Danish broiler meat. In human campylobacter cases, resistance to ciprofloxacin, nalidixic acid and tetracycline was significantly higher in cases associated with travel than in cases acquired in Denmark.

Overall, the monitoring programme for the foodborne zoonoses shows that even though there is reason to keep an eye on the development within the country, the Danish status with regard to antimicrobial resistance is better than in many other countries within and outside Europe.

Pigs at slaughter and retail meat (pork, beef and broiler meat) was investigated for the prevalence of MRSA. Thirteen per cent of the pigs at slaughter were positive for MRSA and 93 per cent of these were CC398. In Danish meat, MRSA was found in 4.6 per cent, 1.4 per cent and 0 per cent of pork, beef and broiler meat, respectively. In imported meat, the occurrence was 7.5 per cent, 0 per cent and 18 per cent in pork, beef and broiler meat, respectively. Based on human data, meat are not suspected as a source of infection.

Resistance in Indicator Bacteria

* "The occurrence of resistance in Danish pork has been increasing in past years and is not significantly lower than in imported pork."

Indicator bacteria were included in the programme to provide information about the general levels of resistance in healthy food animals.

From 2008 to 2009, a significant increase in occurrence of ampicillin resistance was detected in both Enterococcus faecium and Enterococcus faecalis from pigs, presumably as a result of increased usage of penicillins. For some antimicriobials, the occurrence of resistance in pork was lower than that found in the live pigs.

In Enterococci from broilers, the occurrence of resistance to four antimicrobials increased significantly from 2008 to 2009. Compared to isolates from broilers, significantly lower occurrence of resistance was found in the broiler meat regarding salinomycin, ampicillin and avilamycin resistance among E. faecium, and tetracycline resistance among E. faecalis. Compared to imported broiler meat, resistance was significantly lower in Danish produced broiler meat for erythromycin, kanamycin, tetracycline and others.

In Escherichia coli from pigs, there was an increasing occurrence of resistance to a number of antimicrobial agents, with some of the trends in resistance temporally related to trends in consumption of antimicrobial agents. Similar increases were seen for some antimicrobial agents in E. coli from pork. In contrast to what we found for Salmonella, there were no significant differences in resistance in E. coli between Danish and imported pork.

In E. coli from broilers, for the first time one case of resistance to ceftiofur (a cephalosporin), possibly ESBL-producing, was detected. The occurrence of resistance to at least 14 antimicrobial agents was significantly higher in imported chicken meat that in chicken meat produced in Denmark.

Among E. coli isolates from cattle and from Danish and imported beef, occurrence of resistance was low.

Overall, the occurrence of resistance was significantly lower within the indicator bacteria found in Danish broiler meat compared with imported broiler meat. The occurrence of resistance in Danish pork has been increasing in past years and is not significantly lower than in imported pork. However, resistance to ciprofloxacin was very low in E. coli from Danish pork (one per cent), in contrast to imported pork (six per cent).

Resistance in Human Clinical Bacteria

Data on antimicrobial resistance in bacteria from diagnostic submissions are gathered by voluntary reporting from the DANRES group which covers the departments of clinical microbiology (DCM) in Denmark. The only exceptions are methicillin resistant Staphylococcus aureus and invasive Streptococcus pneumoniae that are notifiable. Data on these bacteria are obtained from the reference laboratories at SSI.

Among E. coli blood isolates, the occurrence of resistance to fluoroquinolones (ciprofloxacin) and cephalosporins (3rd generation cephalosporins) increased significantly from 2008 to 2009, reaching levels seen in several other European countries. The increase in resistance corresponds to the increase in the consumption of these antimicrobial agents seen over the years. No E. coli isolates from blood were carbapenem resistant.

In E. coli urine isolates obtained from hospitals and primary health care, resistance to ampicillin, ciprofloxacin, nalidixic acid and cefuroxime increased significantly in 2009. In E. coli urine isolates obtained from hospitalized patients, resistance to mecillinam and sulfonamide also increased significantly. Resistance to 3rd generation cephalosporins reached six per cent in isolates from both hospitals and primary health care.

In Klebsiella pneumoniae blood isolates, 3rd generation cephalosporin (12 per cent) (reported as ceftazidime, ceftriaxone, cefpodoxime or cefotaxime) and gentamicin resistance (nine per cent) was above the 2008 level in the other Nordic countries. Resistance to ciprofloxacin was 18 per cent; however, a significantly larger occurrence was seen in Eastern Denmark (23 per cent) than in Western Denmark (nine per cent). No K. pneumoniae isolates from blood were carbapenem-resistant. The occurrence of multi-resistant isolates (3rd generation cephalosporins, quinolones and gentamicin) increased from one per cent in 2006 to eight per cent in 2009. Also, a 24 per cent increase in the number of K. pneumoniae blood isolates since 2006 was observed.

In this DANMAP report, resistance in K. pneumoniae urine isolates obtained from hospitals and primary health care was reported for the first time. Ciprofloxacin resistance was 17 per cent in isolates from hospitals and 13 per cent in isolates from primary health care, 3rd generation cephalosporin resistance (reported as ceftazidime, cefpodoxime or cefotaxime) was13 per cent in isolates from hospitals and 8 per cent in isolates from PHC. Carbapenem (meropenem) resistance was present in these isolates; however, the occurrence of antimicrobial resistance in this species in not mandatory reportable and no calculation of the frequency of carbepenem resistance could be made.

The occurrence of resistance in Pseudomonas aeruginosa isolates obtained from blood was low for all the tested antimicrobial agents.

Resistance to penicillins and erythromycin in Streptococcus pneumoniae, Group A, B, C and G streptococci remained low in 2009. In S. pneumoniae isolates, macrolide resistance (four per cent) decreased significantly in 2009.

Resistance to ampicillin was high (87 per cent) in Enterococcus faecium isolates from blood. The occurrence of vancomycin resistance was 1.6 per cent in the E. faecium and less than one per cent in the E. faecalis blood isolates. Only one of the DCMs tested all enterococci from bloodstream infections for high level gentamicin resistance (HLGR). Here, 34 per cent of the tested E. faecalis isolates were HLGR, as were 56 per cent of the tested E. faecium isolates. Treatment with fluoroquinolones, cephalosporins or carbapenems has been described as risk factors for development of an E. faecium infection. An increasing consumption of these antimicrobial agents has also been observed in hospitals in Denmark during the past years and this might explain the increasing numbers of E. faecium bloodstream infections.

In 2009, 1,466 cases of Staphylococcus aureus bacteraemia were reported, corresponding to 26.6 cases per 100,000 inhabitants. The number of methicillin-resistant S. aureus (MRSA) was 23 (1.6 per cent). This frequency is very low compared to the incidence in most other European countries. Resistance frequencies to other antimicrobials were at the same level as in previous years.

In 2009, the number of new cases of MRSA was comparable to the number in 2008. Nineteen percent of the cases were acquired abroad, seven per cent in hospitals and 10 per cent of the cases were persons with recent contact to hospitals or nursing homes while 61 per cent of the cases were community acquired. Sixty per cent of all cases presented with infections at the time of diagnosis. The trend observed since 2006 that most cases are acquired in the community thus continues while the number of hospital-acquired cases remains the same. The clonal complex CC398 which is associated with swine and other livestock animals constitutes a minor proportion of all MRSA cases (39 cases) and so far, no signs of transmission to the general population are seen. The control of MRSA in hospitals was effective while the prevalence of community acquired MRSA represents an increasing challenge.

Regarding blood and urine infections in human patients, the occurrence of multi-resistance is increasing, particularly occurrence of ESBL-producing E. coli and Klebsiella pneumoniae. This may in part be driven by increasing consumption of fluoroquinolones and cephalosporins. The increased consumption of fluoroquinolones and cephalosporins may also drive the increasing occurrence of the ampicillin-resistant Enterococcus bloodstream infections. However, the occurrence of resistance in Pseudomonas and streptococci is still generally low. Also, the hospital-acquired infections with MRSA remain the same, but an overall increase in MRSA infections is driven by spread in the community.

Further Reading

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October 2010