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      Distance to pig farms as risk factor for community-onset livestock-associated MRSA CC398 infection in persons without known contact to pig farms-A nationwide study

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          Abstract

          <p id="P1">MRSA CC398 is an emerging MRSA strain found in livestock, mainly in pigs. Direct occupational livestock contact is the principal risk factor for human MRSA CC398 infection. Nonetheless, in recent years, an increasing number of MRSA CC398 cases has been observed in persons without known pig contact. Such cases, referred to as MRSA CC398 of unknown origin (MUO CC398), have, like livestock-onset (LO) MRSA CC398 cases, been found concentrated in rural, livestock-producing areas. The presence of MUO CC398 cases indicates alternative and unknown MRSA CC398 transmission pathways into the community. We performed a nationwide study in Denmark of the geographic distributions of MRSA cases in general and persons with MUO CC398 or LO MRSA CC398 infections (1 January 2006–11 February 2015), with the Danish population as background population. Place of living of study persons was mapped using the ArcGIS software, and information on pig farms was retrieved from the Central Husbandry Register. The incidence of MUO CC398 infections was clearly higher in rural than in urban areas, and such cases lived on average closer to pig farms than the general population. However, within three pig-farming-dense municipalities, patients with MUO CC398 infections did not live closer to pig farms than population controls. This shows that direct environmental spread from neighbouring pig farms of MRSA CC398 is unlikely. Instead, community spread through other means of transmission than direct spread from farms may more likely explain the clustering of MUO CC398 in livestock-dense areas. </p>

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          Livestock-associated Methicillin-Resistant Staphylococcus aureus in Humans, Europe

          To estimate the proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolates from humans that were sequence type (ST) 398, we surveyed 24 laboratories in 17 countries in Europe in 2007. Livestock-associated MRSA ST398 accounted for only a small proportion of MRSA isolates from humans; most were from the Netherlands, Belgium, Denmark, and Austria.
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            Pigs as Source of Methicillin-Resistant Staphylococcus aureus CC398 Infections in Humans, Denmark

            Methicillin-resistant Stapylococcus aureus (MRSA) is becoming increasingly recognized among persons in the community without established risk factors ( 1 , 2 ). MRSA primarily causes human disease and animals have not, until now, been considered a source of infection. It has recently become apparent that animals, particularly pigs, can constitute a separate MRSA reservoir and be a source of a novel and rapidly emerging type of MRSA in humans; namely MRSA clonal complex (CC)398 by multilocus sequence typing (MLST) ( 3 ). MRSA CC398 consists of 8 MLST types (www.saureus.mlst.net), the predominant type being sequence type (ST)398, and a range of closely related protein A (spa) gene types (i.e., t011, t034, t108, and t1793) ( 4 , 5 ). Although transmission appears to be primarily between animals, indistinguishable isolates have been found in their human contacts, particularly those with occupational exposure ( 3 – 7 ). MRSA CC398 (ST398) was first detected in 4 pigs and 1 healthy pig farmer in France ( 3 , 8 ). Clinical infection was described in the daughter of a pig farmer in the Netherlands in 2004 ( 7 ). That study showed that 23% of pig farmers in a small survey in the same region were seropositive for MRSA CC398. Denmark has a low incidence of MRSA. In 2006, only 706 new MRSA patients (colonization only or infection) were reported, which corresponds to 13/100,000 population ( 9 ). To maintain this status, Denmark has adopted a strict “Search and Destroy” policy, which includes active screening of at-risk persons at admission to a hospital ( 10 ). Prompted by reports from the Netherlands, we identified a small ( 2 non-CC398 MRSA case-patients were identified within ± 4 months of diagnosis of the case-patient, 2 were randomly selected from the list generated. Data Collection After written informed consent was obtained, case-patients, controls, and non-CC398 case-patients were interviewed by using a structured telephone-administered questionnaire. Questions captured demographic and clinical data as well as information on known/identified risk factors for MRSA (including hospitalization and other medical exposures, contact sports, and travel) and hypothesized farm and animal exposures for MRSA CC398 (including living or working on a farm, exposure to farm animals, contact with farm workers, preference for eating, and contact with pets) in the year before case-patient diagnosis. Data were double-entered into Epidata version 3.1 (Statens Serum Institut, Copenhagen, Denmark) and collected and handled according to the requirements of the Danish Data Protection Agency. The study did not require ethical approval. Statistical Analysis Univariable and multivariable conditional logistic regression analyses were conducted to estimate matched odds ratios (MORs). Unmatched logistic regression was used for variables for which MORs could not be calculated because not enough controls were exposed to MRSA. Multivariable conditional logistic regression analysis included significant variables (based on a p value of 0.05) from univariable analysis. Stepwise exclusion was used, and variables were tested for significance by using the likelihood ratio test. Stata version 9.2 software (StataCorp, College Station, TX, USA) was used for all analyses. Farm Investigations For case-patients, controls, and non-CC398 case-patients reporting contact with production animals, the farm owner was contacted. If the owner consented, nasal swabs were taken from 10 randomly selected animals (from 10 different pens where possible) and tested for MRSA. Microbiologic Analysis Human isolates were tested by using PCR to identify the mecA gene ( 13 ), pulsed-field gel electrophoresis (PFGE) with the Harmony protocol ( 14 ), spa typing ( 15 ), and staphylococcal cassette chromosome mec (SCCmec) typing ( 16 ). Isolates were also tested for lukF/lukS genes encoding Panton-Valentine leukocidin (PVL) ( 17 ). Results of PFGE and spa typing were interpreted by using BioNumerics version 4.6 software (Applied Maths, Sint-Martens-Latem, Belgium). Because spa typing is acknowledged as being a proxy for MLST, the MLST clonal complex annotation was inferred on the basis of spa types. One of the human isolates was typed by MLST for confirmation. Furthermore, a random selection of 7 isolates were tested by PCR for the exotoxin genes tst, eta, and etb encoding staphylococcal toxic shock syndrome toxin 1, exfoliative toxin A, and exfoliative toxin B, respectively ( 18 ). Animal swabs were plated directly on CHROM-MRSA agar (Becton Dickinson, Heidelberg, Germany) and blood agar (containing 5% bovine blood) and subsequently placed in selective broth (tryptic soy broth, 2.5% salt, aztreonam [20 mg/L], and cefoxitin [3.5 mg/L]; SSI Diagnostika, Hillerød, Denmark). After incubation for 24 hours, the CHROM-MRSA agar was inspected for putative MRSA. Subcultivation on CHROM-MRSA was conducted with samples from the enrichment broth. Possible MRSA colonies were subcultivated on blood agar plates, identified by PCR for the mecA gene ( 13 ), and subjected to spa typing and SCCmec typing. Human and animal isolates underwent antimicrobial drug susceptibility testing by using disc diffusion (D) with Neosensitabs (Rosco, Taastrup, Denmark) on Danish blood agar (SSI Diagnostika) or microbroth dilution (M) ( 19 ). Susceptibility tests were performed for tetracycline (D and M), erythromycin (D and M), streptomycin (D and M), kanamycin (D), norfloxacin (D), pencillin (D), clindamycin (D), fusidic acid (D), rifampicin (D), cefoxitin (D), ceftiofur (M), chloramphenicol (M), ciprofloxacin (M), florfenicol (M), spectinomycin (M), sulfamethoxazole (M), tiamulin (M), and trimethoprim (M). Results Descriptive Epidemiology Thirty-one case-patients with MRSA with spa types related to MRSA CC398 were detected from October 29, 2003, through February 16, 2007. Of these, 6 were excluded from the study because they were secondary case-patients (3 family clusters). Of the remaining eligible case-patients, we were unable to interview 4 because of a death (n = 1) and refusal to participate (n = 3). The questionnaire was therefore administered to 21 of 25 primary case-patients. Median age of the case-patients was 29 years (age range 8 months to 80 years), and 13 (62%) were female. Three case-patients reported having Dutch relatives, and 2 case-patients had a connection to the People’s Republic of China; 1 case-patient was an adopted child from China and another case-patient had adopted a child from China. Ten case-patients (48%) reported having had an infection, of which all were skin and soft tissue infections. Moreover, sinusitis developed in 1 case-patient, and a severe invasive infection with multiorgan failure after knee surgery developed in another case-patient. Univariable Analysis Several exposure variables related to farms and animals were associated with CC398 in the case–control and case–case studies (Table 1). Case–control analysis also identified 4 medical-related risk factors (Table 1). No association was found in the case–control and case–case studies for the following exposures: travel 12 months before diagnosis, working in the healthcare sector, contact with primary healthcare sector (doctor, specialist), visiting an emergency department, presence of a person in the household with a skin condition, presence of a person in the household with staphylococcal infection, smoking daily, contact sports, owning or having contact with dog(s) or horse(s), preference for eating pork, and being born outside Denmark. Table 1 Statistically significant associations by univariable analysis for infection with MRSA CC398, Denmark* Exposure variable No. (%) case-patients exposed (n = 21) Odds ratio (95% confidence interval) for MRSA infection Case–control study, population controls (n = 42) Case–case study, non-CC398 case-patients (n = 39) Animal and farm-related exposures Lived or worked on farm with animals 14 (67) 22.1 (2.9–170.3) 11.6 (2.6–51.7) Worked with animals or meat 11 (50) 16.2 (2.0–127.8) ∞† Worked on farm with animals 10 (48) ∞† ∞† Lived on farm with animals 9 (43) 6.9 (1.5–32.8) 7.9 (1.7–36.7) Exposure to pigs 13 (62) ∞† ∞† Exposure to cattle 6 (29) ∞† ∞† Exposure to other farm animals (hens, goats, 
 sh eep) 7 (33) 11.1 (1.4–92.4) 5.9 (1.2–28.8) Provided antimicrobial drugs to animals 10 (48) ∞† ∞† Contact with farm workers 16 (76) 5.2 (1.4–19.3) ∞† Contact with farmer 14 (67) 3.2 (1.0–10.6) ∞† Contact with veterinarian 7 (33) 6.3 (1.3–30.7) 6.6 (1.4–31.8) Lived in countryside 13 (62) 7.2 (1.5–33.8) 5.2 (1.4–18.9) Had cat in home 11 (50) 3.2 (1.0–10.6) 3.4 (1.1–9.9) Used manure in garden 7 (33) 3.2 (0.9–11.0) 6.6 (1.4–31.8) Visited farm, zoo, or stables 12 (57) 0.8 (0.3–2.4) 4.7 (1.3–17.4) Medical-related exposures Admission to hospital in 12 mo before
 diagnosis 13 (62) 6.8 (1.9–24.4) 1.5 (0.4–5.2) Someone in household with chronic condition 12 (57) 3.8 (1.2–12.5) 2.0 (0.8–9.3) Antimicrobial drug use in 12 mo before 
 diagnosis 9 (43) 3.4 (1.0–11.5) 2.6 (0.8–9.2) Contact with person with skin sore or other 
 skin infection 5 (26) 8.6 (1–74.9) 0.6 (0.2–1.9) *MRSA, methicillin-resistant Staphylococcus aureus; CC, clonal complex.
†p<0.01, by unmatched analysis. Multivariable Analysis Logistic regression models were applied separately to the case–control and case–case studies. In both studies, the first model only included farm and animal-related exposures: lived or worked on a farm with animals, worked with animals or meat, exposed to pigs, exposed to cattle, exposed to other farm animals, provided antimicrobial drugs to animals, owned cat(s), and had contact with any farm workers. Other farm and animal exposures were excluded because of colinearity. In both case–control and case–case studies, living or working on a farm with animals remained the independent association in this first model. A second model combined living or working on a farm with animals with medical-related exposures: contact with a person having a skin sore or other skin infection, history of hospital admission in the 12 months before diagnosis, antimicrobial drug use in the 12 months before diagnosis, and someone in the household with a chronic condition. Living or working on a farm with animals was an independent risk factor for CC398 in the case–control study (MOR 35.4, 95% confidence interval [CI] 2.7–469.8) and the case–case study (MOR 14.5, 95% CI 2.7–76.7). A history of hospital admission in the 12 months before diagnosis was associated with an increased risk in the case–control study (MOR 11.4, 95% CI 1.4–94.8) but not in the case–case study. Farm Investigations Nine pig farms and 2 cattle herds, with which 10 case-patients had contact, were identified. One case-patient had contact with 2 pig farms, and 2 case-patients had contact with the same pig farm. No controls or non-CC398 case-patients had direct contact with a pig or cattle farm. The owners of 5 pig farms and of the 2 cattle herds agreed to participate in the study. The length of time between date of patient diagnosis and farm sampling was 2–24 months. Microbiologic Analysis All but 1 of 31 human isolates were nontypeable by PFGE after digestion with SmaI. Twenty-nine isolates had spa type t034, including the isolate typeable by PFGE, and the other 2 were related variants of t034 (t108 and t1793). Because of the strong correlation between spa typing and MLST, all isolates could be assigned to CC398. One isolate (PFGE nontypeable, spa type t034) was typed by MLST and confirmed to be ST398. SCCmec typing showed that 24 isolates harbored SCCmec type V. SCCmec type IV was also found in 2 isolates (PFGE nontypeable, spa type t034). Three isolates were ccrAB2 positive, which indicated either a type II or type IV variant, but the mec class could not be determined. Two isolates were nontypeable. Isolates from the 21 case-patients were spa types t034 (SSCmec IV, n = 2, SSCmec V, n = 16, and a type II or type IV variant, n = 1, typeable by PFGE), t108 (SSCmec V, n = 1), and t1793 (SSCmec V, n = 1). These isolates showed considerable variation in antimicrobial drug resistance patterns; most isolates were resistant to tetracycline and erythromycin. All isolates from case-patients who reported exposure to pigs were tetracycline resistant and PVL negative. Two isolates were PVL positive; these were from case-patients who reported a connection to China. All isolates tested for exotoxin showed negative results for all toxins examined. Twenty-three (46%) of 50 pigs on 4 of 5 sampled farms carried CC398 spa type t034. All isolates were resistant to tetracycline and trimethoprim. Pig isolates were indistinguishable or only differed by 1 additional antimicrobial drug class when compared with isolates from case-patients who had contact with them (Table 2). MRSA was not detected in the 2 cattle herds. Table 2 Isolate characteristics for human case-patients and contact pig herds sampled, Denmark, March 2007* Case-patient no. Date of diagnosis Resistance pattern spa type Contact herd No. isolates Resistance pattern spa type 1 2005 Mar tet, ery, cli, str, tmp t034 A 9 tet, ery, cli, str, spe, tmp t034 2 2005 Oct tet, tmp t034 B 5 tet, tmp t034 4 tet, str, tmp t034 1 tet, str, tmp t038 3 2006 Oct tet, ery, cli, str, spe, tmp t034 C 1 tet, ery, cli,str, spe, tmp t034 2 tet, str, spe, tmp t034 4 2006 Nov tet, kan, str, spe, tmp t034 D 1 tet, ery, cli, kan, str, spe, tmp t034 *spa, staphylococcal protein A; tet, tetracycline; ery, erythromycin; cli, clindamycin; str, streptomycin; tmp, trimethoprim; spe, spectinomycin; kan, kananmycin. Discussion This study provides compelling epidemiologic and microbiologic evidence that persons living or working on farms in Denmark, particularly pig farms, are at increased risk of being colonized or infected with MRSA CC398. We provide evidence for pigs being a substantial reservoir of human MRSA CC398 in Denmark, as appears to be the case in other European countries such as the Netherlands and France ( 3 , 4 , 7 , 12 ), and in Canada ( 6 ). In the case–case analysis, only animal and farm-related exposures were associated with being a case-patient, which indicates that these exposures are the major factors associated with CC398 acquisition. Furthermore, comparison of results from the case–control study (where farm/animal and medical-related variables remained associated) indicates that medical-related exposures are risk determinants for community-detected MRSA in general but not specifically for subtype CC398. This finding can be deduced because the design of the case–case analysis controls for exposures common to both groups, which means that these exposures will not be identified as a risk or might be underestimated ( 20 ). Because of evidence of prolonged MRSA carriage ( 21 ), questions related to exposures referred to a period of 1 year before patient diagnosis. This lengthy recall period is a limitation of this study. However, all questions related to memorable activities and lifestyle choices; any bias introduced is therefore thought to be minimal. Our finding that living or working on a farm with animals is associated with CC398 acquisition reinforces results of studies in France, the Netherlands, and Canada that indicated that CC398 is transmissible from animals to humans ( 3 , 4 , 6 , 7 ). Also in the Netherlands, a CC398 prevalence of 3.9% in 179 veterinarians has been described; all positive persons had recent or regular contact with pigs and cows ( 22 ). Screening participants from 38 countries at a veterinary conference in Denmark in 2006 found a CC398 prevalence of 9.6% (26/272); the highest prevalence was in German and Dutch delegates ( 23 ). In comparison, the prevalence of CC398 among delegates attending several national animal conferences in Denmark was 0.7% (4/576) ( 24 ). Pig isolates from contact herds were indistinguishable, or only differed by 1 additional antimicrobial drug class, from the isolates from human case-patients who worked or lived on farms where these pigs were located. These samples were obtained months, in some cases years, after the human case-patient’s infection was diagnosed, findings that lend weight to the hypotheses that CC398 carriage in animals is unlikely to be transient and that animals are a reservoir of CC398. Although we isolated CC398 from 23 pigs on 4 of 5 pig farms, but not from cattle farms, this type may not be exclusive to pigs. CC398 has been shown to have a prevalence of 39% in pigs in the Netherlands ( 25 ). However, it has also been found in horses and dogs in Germany and Austria (5) and in cattle and poultry in the Netherlands ( 26 , 27 ). These findings are particularly interesting because S. aureus is usually host specific ( 28 ). Our study has highlighted other important human epidemiologic aspects of CC398. The clinical picture for CC398, with ≈50% of case-patients having had an infection and all reporting skin and soft tissue infections, is similar to that seen in community-acquired MRSA isolates in general ( 29 , 30 ). There was a serious invasive infection with MRSA reported in a man in Denmark after surgery on his knee; arthritis and multiorgan failure also developed ( 31 ). Serious complications from CC398 have also been described in other reports including ventilator-associated pneumonia ( 5 ) and endocarditis ( 32 ). Because no statistical association was found with travel abroad, this finding indicates that CC398 is endemic among pigs in Denmark. Nevertheless, there was an overrepresentation of case-patients or their family members who have had contact with another country, 2 with adopted children from China and 3 case-patients with relatives from the Netherlands. Likewise, in the Netherlands, a child adopted from China was found to be an MRSA CC398 carrier in 2004 ( 12 ). Three family clusters were identified in the present study, which indicates that CC398 can be transmitted from person to person. This finding is not surprising because of the adaptability of MRSA. Its potential for transmission between humans has also been observed in the Netherlands ( 4 , 7 ). MRSA has been isolated from dairy products, beef, chicken and pork ( 33 – 37 ) and although foodborne transmission is plausible ( 34 ), the risk is thought to be low. Preference for eating pork was not associated with being a CC398 case-patient in our study. A high degree of variability in the types of CC398 (resistance patterns, spa types, and SCCmec types) suggests that this type is either rapidly evolving or emerging from a hitherto unrecognized reservoir. In the latter case, CC398 must have been introduced into Denmark on more than 1 occasion or by various routes to explain the high degree of variance. When one considers the rapid adaptability of MRSA, it may only be a matter of time before we see an increased prevalence of CC398 in humans, including those in hospitals as has been recently reported in the Netherlands ( 12 ). A high prevalence of tetracycline resistance in CC398 patients in contact with pigs has also been observed in the Netherlands; this finding suggests that use of tetracyclines and possibly other antimicrobial drugs in food animals is selecting these multidrug-resistant bacteria ( 25 ). Two case-patients who were positive for PVL had direct connections to China. To our knowledge, there are no published reports of CC398 patients in China but isolates from pigs have recently been reported from Singapore, with Indonesian origin ( 38 ). In conclusion, transmission of CC398 from a zoonotic reservoir to humans could undermine existing MRSA control programs. We therefore recommend increased awareness among healthcare professionals that animals are a possible source of MRSA infection and that the potential for person-to-person spread exists. To limit further spread, pig farmers may warrant screening and isolation on admission to hospitals as has been implemented in the Netherlands ( 39 ). However, further studies are required to better understand the human and veterinary epidemiology of this emerging zoonosis. Areas of study should include size of the reservoir in pigs, whether other animals constitute a reservoir of CC398, and how frequently CC398 is transmitted from animals to humans and from humans to humans. The European Union baseline survey on the prevalence of MRSA in breeding pigs, initiated in January 2008, is an important step in addressing the first of these points ( 40 ).
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              High-density livestock operations, crop field application of manure, and risk of community-associated methicillin-resistant Staphylococcus aureus infection in Pennsylvania.

              Nearly 80% of antibiotics in the United States are sold for use in livestock feeds. The manure produced by these animals contains antibiotic-resistant bacteria, resistance genes, and antibiotics and is subsequently applied to crop fields, where it may put community members at risk for antibiotic-resistant infections. To assess the association between individual exposure to swine and dairy/veal industrial agriculture and risk of methicillin-resistant Staphylococcus aureus (MRSA) infection. A population-based, nested case-control study of primary care patients from a single health care system in Pennsylvania from 2005 to 2010. Incident MRSA cases were identified using electronic health records, classified as community-associated MRSA or health care-associated MRSA, and frequency matched to randomly selected controls and patients with skin and soft-tissue infection. Nutrient management plans were used to create 2 exposure variables: seasonal crop field manure application and number of livestock animals at the operation. In a substudy, we collected 200 isolates from patients stratified by location of diagnosis and proximity to livestock operations. Community-associated MRSA, health care-associated MRSA, and skin and soft-tissue infection status (with no history of MRSA) compared with controls. From a total population of 446,480 patients, 1539 community-associated MRSA, 1335 health care-associated MRSA, 2895 skin and soft-tissue infection cases, and 2914 controls were included. After adjustment for MRSA risk factors, the highest quartile of swine crop field exposure was significantly associated with community-associated MRSA, health care-associated MRSA, and skin and soft-tissue infection case status (adjusted odds ratios, 1.38 [95% CI, 1.13-1.69], 1.30 [95% CI, 1.05-1.61], and 1.37 [95% CI, 1.18-1.60], respectively); and there was a trend of increasing odds across quartiles for each outcome (P ≤ .01 for trend in all comparisons). There were similar but weaker associations of swine operations with community-associated MRSA and skin and soft-tissue infection. Molecular testing of 200 isolates identified 31 unique spa types, none of which corresponded to CC398 (clonal complex 398), but some have been previously found in swine. Proximity to swine manure application to crop fields and livestock operations each was associated with MRSA and skin and soft-tissue infection. These findings contribute to the growing concern about the potential public health impacts of high-density livestock production.
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                Author and article information

                Journal
                Zoonoses and Public Health
                Zoonoses Public Health
                Wiley
                18631959
                May 2018
                May 2018
                January 03 2018
                : 65
                : 3
                : 352-360
                Affiliations
                [1 ]Statens Serum Institut; Copenhagen Denmark
                [2 ]University of Copenhagen; Copenhagen Denmark
                Article
                10.1111/zph.12441
                6115690
                29314752
                82795e76-d9d2-4a83-b2e0-515619233d7a
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

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