Persistent colonization and the spread of antibiotic resistance in nosocomial pathogens: resistance is a regional problem

Infections with antibiotic-resistant bacteria (ARB) in hospitalized patients are becoming increasingly frequent despite extensive infection-control efforts. Infections with ARB are most common in the intensive care units of tertiary-care hospitals, but the underlying cause of the increases may be a steady increase in the number of asymptomatic carriers entering hospitals. Carriers may shed ARB for years but remain undetected, transmitting ARB to others as they move among hospitals, long-term care facilities, and the community. We apply structured population models to explore the dynamics of ARB, addressing the following questions: (i) What is the relationship between the proportion of carriers admitted to a hospital, transmission, and the risk of infection with ARB? (ii) How do frequently hospitalized patients contribute to epidemics of ARB? (iii) How do transmission in the community, long-term care facilities, and hospitals interact to determine the proportion of the population that is carrying ARB? We offer an explanation for why ARB epidemics have fast and slow phases and why resistance may continue to increase despite infection-control efforts. To successfully manage ARB at tertiary-care hospitals, regional coordination of infection control may be necessary, including tracking asymptomatic carriers through health-care systems.Nosocomial infections with antibiotic-resistant bacteria (ARB) occur with alarming frequency (1), and new multidrug-resistant bacteria continue to emerge, including vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), two recent but isolated cases of vancomycin-resistant S. aureus (2, 3), and multiple-drug resistance in Gram-negative bacteria. In response, hospitals have used a variety of infection-control measures, some of which are costly and difficult to implement (4). Despite efforts to reduce transmission of ARB within hospitals, the incidence of VRE, MRSA, and other antibiotic-resistant infections continues to increase (1).An important distinction in the epidemiology of ARB is made between infection and colonization. Infection is characterized by serious illness when ARB contaminate wounds, the bloodstream, or other tissues. In contrast, colonization with ARB may occur in the gut, nasal cavities, or other body surfaces. Colonizing bacteria may persist for years without causing disease or harming their hosts (5, 6); we call such individuals carriers. These carriers increase colonization pressure; the number of patients who are shedding increases the risk that another patient becomes a carrier for ARB or acquires a resistant infection (7). Hospitals that reduce the incidence of resistance (the number of new cases) may see no reduction in overall prevalence (the fraction of patients with ARB), because these hospitals admit an increasing number of ARB carriers (8, 9). Patients infected with ARB generally remain hospitalized until the symptoms are cured, but they may continue to carry and shed ARB for months or years.We show that the prevalence of ARB in hospitals approaches equilibrium rapidly because of the rapid turnover of patients; the average length of stay (LOS) is ≈5 days (10, 11). Moreover, prevalence changes rapidly in response to changes in hospital infection control (11-17), so slow and steady increases in resistance must be due to something else, such as increases in the proportion of carriers admitted from the catchment population of a hospital, defined as the population from which patients are drawn, including long-term care facilities (LTCFs), other hospitals, and the community (5, 18). The health-care institutions that serve a common catchment population vary substantially in their relative size, transmission rates, and average LOS. How do increases in the number of ARB carriers in the catchment population contribute to increases in infections by ARB in the hospital, and what can be done about it?Mathematical models play an important role in understanding the spread of ARB (19). We have built on existing theory for the transmission dynamics of ARB developed for simple, well-mixed populations (12, 20), but we are focused on phenomena that occur at a large spatial scale, ignoring competition between sensitive and resistant bacteria and the biological cost of resistance (21) and the relationship between antibiotic use and the prevalence of ARB (11, 22, 23). We have developed mathematical models with multiple institutions connected by patient movement; such models are called “structured” populations or “metapopulations.” Thus, we are developing epidemiological models (20, 21, 24) focused specifically on the consequences of persistent colonization and population structure, applying existing theory for structured populations (20, 24-27).