We examined how differences in age-structured patterns of antibiotic use and hospitalization rates can promote coexistence of CA- and HA-MRSA. Overall, our results show that hospital and community-associated strains of MRSA can coexist if the broader resistance spectrum of the hospital-associated strains is balanced by intermediate fitness-disadvantages in the absence of treatment. For such intermediate fitness costs, the hospital-associated strains have higher fitness in the hospital, where treatment rates are high, whereas community-associated strains have a higher fitness in the community were treatment rates are low. Despite opposite directions of selection, both strains are present in both environments if there is coexistence at all (see Figure S3
for example runs). This occurs because of the high rates of discharge and hospitalization, which cycle individuals between the hospital and the community. Moreover, our results also indicate that opposite directions of selection are not sufficient for maintaining coexistence. This is especially true for our basic model describing well-mixed populations in the hospital and community, in which we found coexistence only for a very narrow range of HA-MRSA fitness-costs.
Including heterogeneity in the form of realistic age- and treatment-structures into the model significantly increases the range of parameters over which coexistence can occur, making it a likely outcome. Furthermore, the fitness cost of HA-MRSA in the absence of treatment is presumably weaker in the hospital than in the community because of factors such as easier invasion due to open wounds, catheters, etc., as well as increased use of antiseptics to which the hospital strain might be better adapted. Taking this possibility into account leads to an additional, substantial increase in the range over which coexistence is likely. Thus, coexistence between HA-MRSA and CA-MRSA is a likely outcome due to the combined effect of hospital-community interactions, age-structure, treatment-structure, and possibly setting dependent fitness costs in the absence of treatment.
Coexistence is mainly dependent upon the cost of HA-MRSA being neither too high nor too low. It should be noted, however, that the upper bound for resistance costs is, in this context, more informative than the lower bound. For costs of HA-MRSA below the lower bound, we would expect that CA-MRSA could not invade the HA-MRSA equilibrium. However, such an invasion is exactly what occurred during the 1990s. Thus, we know that fitness-costs of HA-MRSA are high enough to allow the invasion of CA-MRSA. The crucial question is whether they are low enough for this invasion to stop before CA-MRSA has completely replaced HA-MRSA.
The width of the coexistence range depends strongly on how effectively MRSA can transmit in the hospital. In our simulations we quantified this transmissibility as the average number of secondary cases caused by the admission of one patient to the hospital containing only susceptible patients (RA
). If this value is considerably smaller than one (i.e. hospitals cannot maintain the spread of MRSA on their own), then the coexistence range becomes very narrow. This is because coexistence relies on opposite directions of selection in the hospital and community environment. If however, one of these environments does contribute only very weakly to transmission, this balancing effect cannot take place. The only published estimate for RA
we are aware of found values of 0.68 (0.47–0.95) and 0.93 (0.71–1.21) for two Dutch hospitals; one implies a broad and one a narrow coexistence range (The same study also reported an RA
value of 0.16, which however corresponded to an animal derived strain) 
. Because the Netherlands has been exceptionally successful in reducing nosocomial spread of MRSA 
values are likely to be higher (and hence coexistence ranges broader) in most other settings. The sensitivity on RA
also implies that in regions with better infection control in hospitals (and hence lower RA
) one would expect CA-MRSA to completely replace HA-MRSA and hence also to cause most MRSA infections in hospitals.
Even though our model realistically includes several levels of population structure, our analysis might still underestimate the range over which CA-MRSA and HA-MRSA can coexist. First, other types of heterogeneity might promote coexistence in a similar way as the ones discussed here. Examples include spatial heterogeneities like rural vs. urban areas, small vs. large hospitals (which would impose different levels of stochastic effects and thereby affect strain abundances 
), the cycling of older patients into long-term care facilities 
, or the highly variable length of time individuals remain colonized 
. We also neglected (due to the absence of data) age- or department-structured antibiotic usage rates in hospitals, though this could further promote coexistence. Temporal heterogeneity, such as the seasonal use of antibiotics might be an additional factor contributing to coexistence in MRSA 
. We have also broadly categorized the multitude of different MRSA strains as either CA- or HA-MRSA. This diversity could also contribute to coexistence, as different strains may have different resistance phenotypes (It should be noted however that explaining the coexistence of such individual strains is an additional challenge). In addition to such heterogeneities, coexistence might be facilitated by co-infection with different strains 
, either through co-colonization of the nares 
or specialization of different strains to different anatomical sites. For instance, CA-MRSA primarily causes infections of the skin, whereas HA-MRSA infections are generally more invasive 
. However, it is not clear to what extent different MRSA strains can co-infect a host, and it has also been shown in a different context that co-infection leads only under very specific conditions to coexistence 
. Moreover, other studies have shown that colonization with MSSA can be protective from MRSA 
, suggesting that competition may limit the extent of co-colonization with different strains.
Even though our model can explain the coexistence between HA-MRSA and CA-MRSA, we did not find any parameter combination that supports coexistence at equilibrium between more than two strains (HA-MRSA, CA-MRSA and MSSA). This suggests that the system as described by our model corresponds to only two ecological niches. This implies that the maintenance of the diversity within HA-MRSA and CA-MRSA has to be explained by mechanisms not included in our model (such as the geographical and temporal variation mentioned above). Moreover, , , and S3
also indicate that the system approaches equilibrium only very slowly, such that a long transient maintenance of this diversity is conceivable even if it would not persist in an equilibrium state.
Our model also describes a static situation in which the properties of the strains and the age structure do not change over time. However, both demographic change in the human population and evolutionary change of the MRSA strains are likely to occur and their impact on coexistence between competing strains is an interesting question for future studies. Demographic change will most likely increase the proportion of old people in the US and most western countries. In the context of our model this means that selection will tend to favor hospital adapted strains, as the hospitalization rates are considerably higher for the old age classes. However, the direction of evolutionary change depends very strongly on the physiological constraints underlying antibiotic resistance. For instance, if CA-MRSA can increase its resistance spectrum while maintaining a high transmissibility, it could eventually out-compete HA-MRSA. If on the other hand a higher fitness cost is the inevitable consequence of a broad resistance spectrum, then such a replacement is unlikely to occur. Such evolutionary changes may be particularly important given the very long transient phases during which CA- and HA-MRSA can coexist. These long transient phases provide the opportunity for evolutionary adaptation of the inferior strain (by way of compensatory mutations or extension of the resistance spectrum), which could allow it to persist, even though coexistence is not expected on the basis of the current pathogen fitness.
The classical ecological paradigm of niche overlap states that two species can coexist if their resource usage differs sufficiently 
. The present study represents an application of those concepts to the important public health question of whether hospital- and community-associated strains of MRSA are expected to coexist in the long-term. An eventual replacement of HA-MRSA by CA-MRSA could cause important changes in the epidemiology of S. aureus
. CA-MRSA can more readily cause infections in healthy individuals than HA-MRSA 
and hence symptomatic MRSA infections could extend to a broader class of patients. CA-MRSA strains have also been associated with a higher virulence and invasiveness than HA-MRSA strains 
, as well as worse clinical outcomes 
. This higher virulence and invasiveness has been associated with an increased expression of several cytolytic toxins (such as PVL). However, the exact mechanisms underlying the higher virulence of CA-MRSA are still uncertain 
. An increase in virulence is also not universal, as other studies have described better clinical outcomes associated with CA-MRSA infections 
. This may be because CA-MRSA infections are largely associated with skin and soft-tissue infections, which generally have favorable outcomes 
. In addition, CA-MRSA strains have a narrower resistance spectrum which makes it easier to provide effective treatment. Overall, while the empirical evidence is mixed, there does seem to be some indication that CA-MRSA differs from HA-MRSA with regards to virulence, the range of resistance, and transmissibility (see in 
, and 
). Accordingly, a replacement of HA-MRSA with CA-MRSA in hospitals would entail a change in these important properties of nosocomial MRSA infections.
More fundamentally, the transmission route of MRSA in hospitals might change. The current view is that MRSA in hospitals is mainly transmitted indirectly through short-term contaminated health-care workers 
. This dynamic could change should the more invasive and more transmissible CA-MRSA replace HA-MRSA in hospitals. Accordingly, prevention efforts that focus currently on hand-hygiene among health-care workers could lose their effectiveness in reducing the spread of MRSA. Interestingly, our results suggest that a replacement of HA-MRSA by CA-MRSA is especially likely in those locations in which infection control in hospital is currently successful and hence transmission rates in the hospital are low. However, our results also indicate that due to the large heterogeneities characterizing human populations, coexistence between hospital- and community-associated strains of MRSA is overall a likely outcome.