Friday, November 30, 2007

Emergence of Methicillin-Resistant Staphylococcus aureus of Animal Origin in Humans

Volume 13, Number 12–December 2007Research

Emergence of Methicillin-Resistant Staphylococcus aureus of Animal Origin in Humans

Inge van Loo,*1 Xander Huijsdens,†1 Edine Tiemersma,† Albert de Neeling,† Nienke van de Sande-Bruinsma,† Desiree Beaujean,† Andreas Voss,‡ and Jan Kluytmans§¶ *Elisabeth Hospital, Tilburg, the Netherlands; †National Institute for Public Health and the Environment, Bilthoven, the Netherlands; ‡Wilhelmina Hospital, Nijmegen, the Netherlands; §Amphia Hospital, Breda, the Netherlands; and ¶VUmc Medical Center, Amsterdam, the Netherlands


In 2003 in the Netherlands, a new methicillin-resistant Staphylococcus aureus (MRSA) strain emerged that could not be typed with Sma1 pulsed-field gel electrophoresis (NT-MRSA). The association of NT-MRSA in humans with a reservoir in animals was investigated. The frequency of NT-MRSA increased from 0% in 2002 to >21% after intensified surveillance was implemented in July 2006. Geographically, NT-MRSA clustered with pig farming. A case–control study showed that carriers of NT-MRSA were more often pig or cattle farmers (pig farmers odds ratio [OR] 12.2, 95% confidence interval [CI] 3.1–48.6; cattle farmers OR 19.7, 95% CI 2.3–169.5). Molecular typing showed that the NT-MRSA strains belonged to a new clonal complex, ST 398. This study shows that MRSA from an animal reservoir has recently entered the human population and is now responsible for >20% of all MRSA in the Netherlands.


On the basis of the above-mentioned findings, we conclude that this new MRSA strain is of animal origin (pigs and probably cows). Transmission of MRSA between animals and humans has previously been described, e.g., associated with colonized companion animals, horses, and persons who take care of them (16–19). However, the MRSA clones in these reports were known human clones, suggesting human-to-animal transmission in origin. Baptiste et al. found specific PFGE clones in horses that were never observed before (20). Until now, transmission of these clones to humans has not been reported.

We assume that this problem is not limited to the Netherlands. First, widespread dissemination in pigs in the Netherlands has been found. When one considers the intensive international transport of pigs, it is unlikely that this situation is limited to the Netherlands. Second, 3 of the case-patients came from abroad, 1 tourist and 2 adopted children from Asia. Also, MLST 398 was recently found in animals (pig, dog, and foal) and in humans in Germany (21). Finally, in Hong Kong Special Administrative Region, People's Republic of China, MRSA with MLST 398 has been found in 2 patients with bacteremia (22).

The origin of the current NT-MRSA situation is difficult to elucidate. One earlier study can be found on carriage of S. aureus in pig farmers and pigs in France (23). It reported an increased carriage rate in pig farmers caused by transmission of S. aureus from pigs that also carried MLST ST 9 and 398. Further typing of the French ST 398 isolates at RIVM showed homology with the Dutch isolates. However, in the French study most of the MLST 398 strains were susceptible to β-lactam antimicrobial agents. The most likely explanation for the current findings is that MLST 398 is a commensal strain in pigs, which originally was methicillin susceptible. As most NT-MRSA isolates were resistant to doxycycline, the spread is facilitated by the abundant use of tetracyclines in pig and cattle farming (15).

What are the implications of these findings? Persons working or living in close contact with pigs or cows are at increased risk of becoming colonized and infected with MRSA. Infections can be severe, as is indicated by the hospital admission rate. Also, a case of endocarditis has been reported recently (24). At present, whether this strain is spreading further in the community is not clear. Before final recommendations for control can be made, the current size of the reservoir in farm animals and in humans has to be determined at an international level.


Volume 13, Number 12–December 2007Research

Hospitalizations and Deaths Caused by Methicillin-Resistant Staphylococcus aureus, United States, 1999–2005

Eili Klein,* David L. Smith,† and Ramanan Laxminarayan* *Resources for the Future, Washington DC, USA; and †National Institutes of Health, Bethesda, Maryland, USA

Suggested citation for this article


Hospital-acquired infections with Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA) infections, are a major cause of illness and death and impose serious economic costs on patients and hospitals. However, the recent magnitude and trend of these infections have not been reported. We used national hospitalization and resistance data to estimate the annual number of hospitalizations and deaths associated with S. aureus and MRSA from 1999 through 2005. During this period, the estimated number of S. aureus–related hospitalizations increased 62%, from 294,570 to 477,927, and the estimated number of MRSA-related hospitalizations more than doubled, from 127,036 to 278,203. Our findings suggest that S. aureus and MRSA should be considered a national priority for disease control.


DiscussionMRSA, a common cause of nosocomial infections, has emerged as an increasingly common cause of community-associated infections (20). Our analysis extends the work of Kuehnert et al. (13) and quantifies recent trends and the effect of S. aureus and MRSA on the US healthcare system.

This study focused on the effect and trends in the incidence of S. aureus–related infections generally and MRSA-related infections specifically. Although the number of hospitalizations associated with an S. aureus infection increased 62% or ≈8.4% per year, the number of S. aureus infections resistant to methicillin increased 119% or ≈14% per year. In addition, although steady growth was observed in the incidence of S. aureus– and MRSA-related septicemia, pneumonia, and device-associated infections that are typically nosocomial, dramatic increases were observed in the incidence of skin and soft tissue infections that are typically community associated. We also found no trend in the number of deaths caused by MRSA, and a decreasing trend in the percentage of S. aureus– and MRSA-related hospitalizations that resulted in death. These results suggest a change in the ecology of the disease; community-associated MRSA is spreading more rapidly and possibly making its way into hospitals.

The indication that community-associated MRSA is spreading rapidly into hospitals has implications for hospital and community infection control as well as empirical treatment. In hospitals, handwashing practices, which have been shown to be the leading intervention for limiting the spread of nosocomial infections, should be improved to meet recommended guidelines (21). Because of the increase in skin and soft tissue infections, standard precautions, including use of gloves, are likely warranted when dealing with all skin and soft tissue infections in outpatient clinics and acute-care facilities. Contact precautions, including use of gowns and gloves, should be implemented for all wound care in acute-care facilities, and institutional programs to enhance antimicrobial drug stewardship should be implemented. Programs to increase community awareness to control spread of infections and initiatives to reduce inappropriate use of antimicrobial drugs should also be implemented, especially in institutions that are focal institutions such as daycare centers, schools, and prisons, as well as in high-risk groups such as immunodeficient persons, children, and elderly persons. Clinicians should be aware of the magnitude of the issue and consider MRSA a highly likely cause of skin and soft skin tissue infections, even in areas where the prevalence of MRSA is believed to be low.

Previous hospitalization has been associated with community MRSA carriage (22), and some recent studies have suggested that MRSA infection rates in the community are positively correlated with S. aureus infection rates in the hospital (23,24). Although a recent study suggests that community-associated MRSA is causing hospital-acquired MRSA (25), it is unclear from our study whether community-associated MRSA is responsible for increasing rates of nosocomial MRSA or the other way around. In all likelihood, MRSA is spreading in hospitals and communities and complicating efforts to prevent infections in hospitalized patients. Regardless, our findings demonstrate that recent reports of localized increases in community-acquired MRSA (7,26–28) are part of a larger trend of MRSA becoming rapidly endemic in communities all over the United states, emulating the wave-like pattern of emerging resistance to penicillin in the middle of the 20th century (5).

Hospital-acquired infections from all causes are estimated to cause >90,000 deaths per year in the United States and are the sixth leading cause of death nationally. Nosocomial infections increase patient illness and the length of hospital stays. The direct cost has been estimated to be >$6 billion (inflation adjusted) (29); costs of longer inpatient visits are shared by hospitals. The increasing trend in hospitalizations associated with S. aureus infections has considerable cost implications for the healthcare system, including costs when community-associated infections require hospitalization and the additional expenses from associated nosocomial infections.

Antimicrobial drug–resistant infections impose even greater costs than susceptible infections. Several studies have estimated that antimicrobial drug–resistant infections increase death, illness, and direct costs by 30%–100% (30). Estimates of the excess cost of an infection with MRSA compared with an infection with methicillin-sensitive S. aureus range from ≈$3,000 to $35,000 (31–33). This suggests that MRSA cost the healthcare system (patients and hospitals) an extra $830 million–$9.7 billion in 2005, even without taking into account indirect costs related to patient pain, illness, and time spent in the hospital.

Another important implication of our analysis is that the increasing incidence of MRSA in hospitalized patients, whether the infection was acquired in the hospital or the community, is likely to increase the demand for vancomycin. Despite several new (daptomycin, linezolid, tigecycline) and old (trimethoprim-sulfamethoxazole, clindamycin) antimicrobial drugs available for treatment of MRSA infections, vancomycin has remained the first-line drug for treating MRSA (12,34). This pattern has broad implications for the future control of MRSA as well as other pathogens. S. aureus infections resistant to vancomycin are already emerging (35), and vancomycin-resistant enterococci are already a major problem in hospitals. Vancomycin use should be restricted to methicillin-resistant S. aureus infections and used only for MRSA infections in situations where other drugs are not appropriate.

Our analysis has some limitations. First, it was restricted to the incidence of disease associated with acute-care management within the hospital setting. Recent reports suggest that MRSA has been increasing in outpatients (36,37). Thus, our results represent only a part of the problem, although hospitalizations outweigh outpatient visits by ≈4 to 1.

Second, NHDS data enables the coding of only 7 diagnosis codes; hospital information systems typically include 15–20 diagnosis codes for each admission (38). Thus, additional diagnoses in which S. aureus played a role may have been excluded. Errors in ICD coding when transcribing from doctors' discharge summaries are another potential source of bias, as is the possibility that multiorgan failure, an end stage of sepsis, was coded as septicemia. One study concluded that the positive predictive value of the 038 code on NHDS records to predict sepsis was 88.9%–97.7%, depending on the criteria, and the negative predictive value was 80.0% (39). The authors of another study that examined whether sepsis was coded correctly on hospital bills concluded that strict reliance on administrative data may be prone to bias because only 75.4% of sepsis cases were accurately coded (38). Thus, our results may be an underestimate of the true effect, although trends are likely robust to coding errors.

Third, TSN data provide information concerning only the site of isolate collection and not the infection. Thus, some isolates from blood or the lung area may not be associated with septicemia or pneumonia, respectively. In addition, the code for S. aureus septicemia was given priority over the other more site-specific codes; this could have affected the estimates of MRSA infections. However only a limited number of records had overlapping codes.

Fourth, although the 2 data sources from TSN and NHDS used in this article are nationally representative, they may not represent a stratified random sample of hospitals by type and region. However, the trends are likely robust enough to avoid bias. In addition, the percentage of S. aureus isolates resistant to methicillin reported in the TSN database has increased similar to that reported by other national studies (Figure 4). Finally, our estimates of the number of hospitalizations and deaths are associated with, but cannot be directly attributed to, S. aureus and MRSA because NHDS does not report the immediate cause of death, and older, sicker patients are more likely to contract a nosocomial infection (40).

Our findings suggest that S. aureus and MRSA should become a national priority for disease control. Possible responses include expanding national surveillance or reporting requirements for S. aureus and MRSA infections, more research to quantify the relative importance and interaction between community- and healthcare-associated colonization and infection, improved investments in hospital-infection control, and greater public investment to support research and development of an S. aureus vaccine.