EVOLUTION

INTERNATIONAL JOURNAL OF ORGANIC EVOLUTION

PUBLISHED BY
THE SOCIETY FOR THE STUDY OF EVOLUTION

Vol. 59 March 2005 No. 3

Evolution, 59(3), 2005, pp. 477491

EVOLUTION OF ANTIBIOTIC RESISTANCE BY HUMAN AND

BACTERIAL NICHE CONSTRUCTION
MACIEJ F. BONI1,2 AND MARCUS W. FELDMAN1,3
1 Department of Biological Sciences, 371 Serra Mall, Stanford University, Stanford, CA 94305
2 E-mail: maciek@charles.stanford.edu
3 E-mail: marc@charles.stanford.edu

Abstract. Antibiotic treatment by humans generates strong viability selection for antibiotic-resistant bacterial strains.
The frequency of host antibiotic use often determines the strength of this selection, and changing patterns of antibiotic
use can generate many types of behaviors in the population dynamics of resistant and sensitive bacterial populations.
In this paper, we present a simple model of hosts dimorphic for their tendency to use/avoid antibiotics and bacterial
pathogens dimorphic in their resistance/sensitivity to antibiotic treatment. When a constant fraction of hosts uses
antibiotics, the two bacterial strain populations can coexist unless host use-frequency is above a critical value; this
critical value is derived as the ratio of the fitness cost of resistance to the fitness cost of undergoing treatment. When
strain frequencies can affect host behavior, the dynamics may be analyzed in the light of niche construction. We
consider three models underlying changing host behavior: conformism, the avoidance of long infections, and adherence
to the advice of public health officials. In the latter two, we find that the pathogen can have quite a strong effect on
host behavior. In particular, if antibiotic use is discouraged when resistance levels are high, we observe a classic
niche-construction phenomenon of maintaining strain polymorphism even in parameter regions where it would not be
expected.

Key words. Antibiotic resistance, evolutionary epidemiology, microbial population genetics, niche construction, pop-
ulation dynamics, reduced prescribing.

Received July 8, 2004. Accepted November 5, 2004.

The increasing frequency of antibiotic resistance in human
bacterial pathogens has been a problem since the introduction
of penicillin in 1943 (Neu 1992; Palumbi 2001a). Scientists
and public health officials have been considering the benefits
and detriments of many methods of slowing the evolution of
antibiotic or drug resistance; these include reducing prescrib-
ing rates (Lipsitch 2001; Livermore 2004), varying patterns
of antibiotic use (Bonhoeffer et al. 1997), restricting the use
of new antibiotics (Palumbi 2001b; Hall 2004), accelerated
drug discovery (Neu 1992; Livermore 2003), and multidrug
treatment (Bonhoeffer et al. 1997; Palumbi 2001b; Bon-
hoeffer 2002). While some of these strategies have met with
limited success, none has been shown to consistently reduce
levels of antibiotic resistance. Multidrug treatment, for ex-
ample, can be effective, but it is highly dependent on com-
pliance to the drug regimen (Blower et al. 1996; Castillo-
Chavez and Feng 1997; Levin and Anderson 1999). The dis-
covery of newer and better drugs seems too hopeful, as there
have been very few discoveries of novel antibiotic types over
the past 40 years (Walsh 2003). At present, antibiotic-resis-
tant microbes are spreading faster than we can stop them;
they are becoming the dominant strains in the bacterial spe-
477
q 2005 The Society for the Study of Evolution. All rights reserved.
cies that colonize humans (Neu 1992; Iseman 1994; Swartz
1994; Levin and Anderson 1999; Palumbi 2001b; McGeer
and Low 2003).
Resistant mutant strains of bacterial (and other) pathogens
often exist at low frequencies in a host before treatment be-
gins (Neu 1992; Iseman 1994; Lipsitch 2001), but they can
also arise during treatment as a result of antibiotic-induced
hypermutation (Baquero et al. 1998; Martnez and Baquero
2000; Blazquez 2003) or plasmid-mediated transfer of resis-
tance genes (Austin et al. 1997; Lipsitch 2001). Once a re-
sistant type exists, its frequency often remains low but rises
during the course of antibiotic treatment. The two key phe-
notypic properties that allow this dynamic to occur are that
(1) the resistant strains are usually less fit than the antibiotic-
sensitive wild-type strains in the absence of antibiotic treat-
ment; and (2) the resistant strains are more fit than the wild-
type strains in the presence of antibiotic treatment (Swartz
1994; Levin et al. 1997; Andersson and Levin 1999; Martnez
and Baquero 2002). During treatment, the more fit resistant
strains flourish, overtaking the sensitive strains in frequency.
When treatment ceases or is slowed, the population can revert
back to sensitivity, though this reversion is usually slow
478 M. F. BONI AND M. W. FELDMAN
(Frost and McLean 1994; Levin et al. 1997; Nowak et al.
1997; Austin et al. 1999). Reversion to sensitivity can be
further hampered by a resistant strains acquisition of com-
pensatory mutations that increase its fitness, bringing it closer
to the wild types pre-antibiotic fitness level (Levin et al.
2000; Martnez and Baquero 2002; Livermore 2004).
Mathematical models of the evolution of antibiotic resis-
tance usually use a treatment parameter to describe the effects
of antibiotic treatment on the host populations mean recov-
ery rate (Bonhoeffer et al. 1997; Castillo-Chavez and Feng
1997; Lipsitch et al. 2000). In some models, this treatment
parameter describes the fraction of the population (sick or
healthy) currently undergoing treatment (Austin et al. 1997,
1999; Stewart et al. 1998). Sometimes, treatment is assumed
to occur for every host, and models use a treatment failure
rate to describe what fraction of treated individuals will
evolve resistance (Blower et al. 1996).
In our study, we propose a simple model that incorporates
all of these features. The most important new feature of our
model is that we make antibiotic use an individual host trait.
Each human host will either possess or lack a tendency to
self-medicate. One could interpret this as a tendency to seek
or avoid antibiotic treatment, but only if we assume that all
hosts who seek treatment receive it. We define different re-
covery rates for treated hosts and untreated hosts; we always
have a well-defined fraction of the population undergoing
treatment; and we have the equivalent of a treatment failure
rate, a parameter that determines the fraction of treated in-
fections that evolve resistance. Thus, our model includes all
the critical features of previous models of the evolution of
antibiotic resistance. Finally, like most previous models, we
are careful to recognize the importance of epidemic dynam-
ics. Cohen (1992), Levin et al. (2000), Lipsitch and Samore
(2002), and recently Smith et al. (2004) have all noted the
importance of between-host transmission to the spread of
resistant microbes.
Making antibiotic use a host trait allows us to explore
several scenarios in which host behavior is dynamic, chang-
ing in response to cultural pressures or medical recommen-
dations. In making treatment level a dynamic variable, we
go further than previous analyses and suggest ways in which
the relative frequencies of the endemic strains can affect the
population-wide level of antibiotic treatment. In short, we
propose a population dynamic model of bacterial evolution
where host antibiotic use affects bacterial strain frequencies
and strain frequencies can feed back into effects on host
antibiotic use. This sort of population dynamic model lends
itself readily to a niche-construction interpretation (Laland
et al. 1996, 1999; Odling-Smee et al. 1996, 2003).
Niche Construction
Niche construction is the phenomenon of constructing, de-
stroying, or altering ones environment and thus changing
the selection pressures exerted by that environment. Beavers
build dams and thus pass down an altered environment to
their progeny. Earthworms alter the chemical composition of
their soil and in so doing change the selection pressures on
future generations. Numerous examples of niche construction
are suggested in Odling-Smee et al. (2003).
In host-parasite systems, we can view either the evolution
of the parasite or the evolution of the host in a niche-con-
struction framework, as long as we are careful to define the
components of the environment and the processes by which
they change. Because bacterial generation times are much
shorter than human generation times, we analyze our system
on the time scale of bacterial reproduction, ignoring host vital
dynamics. Then, with an evolutionarily static host population
and an evolutionarily dynamic bacterial population, we con-
duct a niche-construction analysis of our system, defining the
bacteria as the evolving organisms and everything else as
their environment. Our bacteria evolve in an environment
whose main characteristic is the background amount of an-
tibiotic usage. The pathogens strain structure may alter the
frequency of host antibiotic use; the bacteria would therefore
be altering their niche and its selection pressures.
It is natural to view the human hosts as the active agents
in this model, so we will sometimes speak of human hosts
constructing a niche for bacteria by their choices to seek or
not seek antibiotic treatment.
Alternate Model Formulations
The dynamic we describe can be interpreted in different
niche-construction frameworks from the one mentioned
above. For example, we could have chosen the hosts to evolve
behavior in a background environment defined by the relative
frequencies of resistance and sensitivity. Our model can also
be described in the light of cultural niche construction, which
has been employed to posit mechanisms for the evolution of
small family size (Ihara and Feldman 2004; Kendal et al.
2005). A tendency to seek treatment is a cultural rather than
a genetic trait, and we can view factors that alter individuals
behaviors as factors that change the cultural background of
our host population.
Alternatively, we can formulate our problem as one of trait-
trait coevolution. The infection and the behavior can both be
viewed as properties that are transferred horizontally in the
population. The theory behind these kinds of dynamics was
worked out by Tanaka et al. (2002), who analyzed a popu-
lation dynamic model in which a disease and a cultural trait
(careful or risky) were both transmissible between hosts. In
their coevolutionary framework, they found that more careful
behaviors could always enter the population (by conferring
a viability advantage on hosts); here, the infection charac-
teristics affected the cultural background. Tanaka et al. also
showed that significant behavioral differentiation decreased
the spread of the disease, thus demonstrating that the cultural
state of the population can affect disease dynamics.
If the behavior is transmitted vertically, the system would
more aptly be described as a model of gene-culture coevo-
lution (Feldman and Cavalli-Sforza 1984; Feldman and Zhi-
votovsky 1992). Any one of the previously mentioned for-
mulations may turn out to be appropriate for a particular host-
parasite dynamic.
BASIC MODEL
In this and subsequent sections, we deal with a bacterial
pathogen that colonizes humans; is communicable from hu-
man to human; and has strains (or serotypes), some of which
 ANTIBIOTIC RESISTANCE AND NICHE CONSTRUCTION
are treatable by and others resistant to a particular antibiotic.
With care, the models may be reformulated to apply to other
host-pathogen-drug interactions. In interpreting the results of
the model, it is often necessary to consider whether the bac-
terial infection is acute or chronic. Some results may hold
for acute infections only, while others hold for acute as well
as chronic infections.
We begin by dividing the host population into subclasses,
as in standard susceptible-infective-susceptible (SIS) epi-
demic models (Diekmann and Heesterbeek 2000). We have
six population classes and two strains (or two types of strains)
of a bacterial pathogen. Hosts may be uncolonized (u) by a
bacterial pathogen; these are the susceptible hosts in standard
epidemic models. The infected or diseased hosts can be col-
onized either by an antibiotic-sensitive wild-type strain (w)
or by an antibiotic-resistant mutant strain (m). The subscript
A describes those hosts that possess the behavior of self-
medicating; in short, A describes those hosts who take an-
tibiotics. In the following dynamic equations, each of the six
state variables represents the population density of a partic-
ular type of host:
u 5 2bu(w 1 m 1 w A 1 m A ) 1 vw 1 v m m, (1)
5 bu(w 1 w A ) 2 vw,
w (2)
5 bu(m 1 m A ) 2 v m m,
m (3)
u A 5 2bu A (w 1 m 1 w A 1 m A )
1 (1 2 s)v a w A 1 v m m A , (4)
A 5 bu A (w 1 w A ) 2 v a w a ,
w and (5)
A 5 bu A (m 1 m A ) 2 v m m A 1 sv a w A .
m (6)
The dots represent time derivatives. Hosts have no immunity
and upon clearing an infection re-enter the uncolonized or
susceptible class. The time for the immune system to clear
an infectious pathogen is different for the two strains (this
is referred to as a recovery rate in standard epidemic models).
An infection with the wild-type strain is cleared at the rate
v, while a wild-type infection treated with antibiotics is
cleared at a rate va. Mutant infections are resistant to and
hence unaffected by antibiotic treatment; they are cleared at
a rate vm. We assume that va . v and vm . v since recovery
rates should be faster for hosts taking antibiotics or for hosts
infected with the mutant strain. The parameter b describes
the transmissibility of the pathogen and the host contact rate.
See Figure 1 for a class diagram of the model.
Viability selection occurs in the wA class. Individuals in
this class recover at a rate va; however, only 1 2 s of these
individuals actually recover, while s of them will develop
an infection with the resistant strain that was selected for
during the course of antibiotic treatment. This is the classical
mechanism of a bacterial pathogen evolving resistance to
antibiotics (Neu 1992; Iseman 1994; Levin et al. 1997; Mar-
tnez and Baquero 2002).
The infection dynamics in equations (16) are a simplified
version of the model presented by Castillo-Chavez and Feng
(1997); alternatively, they are a version of a model by Austin
et al. (1997) with the addition of the class wA. While these
kinds of simple models provide an appropriate framework in
479
FIG. 1. Basic model described by equations (1013). The u classes
represent uncolonized or susceptible individuals and the arrows
represent infection to or recovery from the w classes (infected by
the antibiotic-sensitive wild-type strain) and m classes (infected by
the antibiotic-resistant mutant strain). The subscript A describes
individuals who are antibiotic users. Hosts infected with the wild-
type strain who are taking antibiotics have a probability s of evolv-
ing a resistant infection and moving to the mA class; with probability
1 2 s treatment is successful and these hosts recover.
which to study the dynamics of bacterial spread and evolu-
tion, it is important to remember that in general the dynamics
of bacterial infections can be quite complicated (Cvjetanovic
1982).
In equations (16) we see that not only does total popu-
lation size remain constant, but we also have
d
(u 1 w 1 m) 5 0 and (7a)
dt
d
(u 1 w A 1 m A ) 5 0. (7b)
dt A
In this first formulation of our model, the fractions of hosts
who self-medicate and do not self-medicate are constant. Nor-
malizing our population size, we can define
p5u1m1w and (8)
q 5 uA 1 mA 1 wA , (9)
with p 1 q 5 1. Hence, p and q are constants that describe
the frequency of a behavioral trait in our host population.
Simplifying further, we can rescale the equations to mea-
sure time in units of v21, the infectious period for a host
infected with the wild-type strain and not undergoing treat-
ment. We define s 5 vm/v and a 5 va/v. Then, s 2 1 can be
viewed as the selective advantage that the wild type has over
the mutant in the absence of treatment, and a 2 1 as the
selective advantage the wild type experiences in an untreated
versus a treated environment.
Our system reduces from a six-dimensional system to a
four-dimensional system. In the new time-scale, it is
5 r( p 2 w 2 m)(w 1 w A ) 2 w,
w (10)
5 r( p 2 w 2 m)(m 1 m A ) 2 sm,
m (11)
A 5 r(q 2 w A 2 m A )(w 1 w A ) 2 aw A ,
w and (12)
A 5 r(q 2 w A 2 m A )(m 1 m A ) 2 sm A 1 saw A ,
m (13)
480 M. F. BONI AND M. W. FELDMAN
where r 5 b/v is the basic reproduction ratio (Anderson and
May 1991; Diekmann and Heesterbeek 2000) of the wild type
in the absence of antibiotics. We assume r . 1, which allows
the wild type to spread in a population of uncolonized hosts.
The assumption that the wild type is more fit than the
mutant in the absence of antibiotics translates to s . 1. The
assumption that antibiotics reduce the infectious period in
wild-type-infected hosts translates to a . 1.
To calculate the basic reproduction ratio of a given path-
ogen in a given environment, we employ methods described
by Diekmann and Heesterbeek (2000, pp. 7375) and de-
veloped by Diekmann et al. (1990) and van den Driessche
and Watmough (2002). For the wild-type infection, the next-
generation matrix is
r r
q p
a a
, (14)
qr pr
yielding a basic reproduction ratio
r wild types when the host is treated with antibiotics. Hence,
R 0,w 5 pr 1 q , (15)
a s2 1 . a2 1 .
which depends on the behavior frequencies, p and q, in the
host population. The basic reproduction ratio is calculated as
the dominant eigenvalue of matrix (14). For the resistant
infection, the next generation matrix is
r r
s
q p
s
, (16)
q rs p
r faster reproduction rates yield longer infections, we need to
s look more closely at the within-host dynamics of pathogens
yielding a basic reproduction ratio
r and May (2000). It may be worth considering a21 . s21, as
R 0,m 5 , (17)
s this case may yield useful results for weak antibiotic treat-
which does not depend on the behavior frequencies in the
host population. Recall that the basic reproduction ratio is a
measure of disease spread due to between-host transmission.
Because the resistant strain is not affected by antibiotics,
R 0,m does not dependent on p and q.
One can also calculate the stability condition for the dis-
ease-free equilibrium (w 5 m 5 wA 5 mA 5 0) of equations
(1013). This equilibrium is unstable (i.e., invasion is pos-
sible, there is some eigenvalue with positive real part) if and
only if at least one of R 0,w and R 0,m is larger than unity.
Fitness Assumptions and Parameter Values
Potentially epidemic bacterial pathogens have two major
fitness components, the within-host growth rate and the be-
tween-host transmission rate. We model the epidemic dy-
namics explicitly, and we will confer fitness differences on
our pathogens by varying the length of infection. The wild
type generates infections of length one unit in untreated hosts
and infections of length a21 in treated hosts, while the re-
sistant infections are always s21 units long; infections lengths
are summarized in Table 1. The fitness of an epidemic path-
ogen is measured as R 0. Longer infections yield higher fit-
nesses.
TABLE 1. Lengths of the different types of infections. Hosts who
develop resistant infections as a result of antibiotic treatment spend
a mean a21 amount of time in the wA class and then a mean s21
amount of time in the mA class.
Infecting strain Treatment Duration
Wild type (sensitive) no treatment 1
successful treatment, host re- a21
covers
unsuccessful treatment, host a21 1 s21
develops a resistant infec-
tion
Mutant (resistant) treatment/no treatment s2 1
In our model, the simple implicit connection between du-
rations of pathogen infection and within-host reproduction
rates is that pathogens with faster in-host reproduction cause
longer infections. Under the assumption that viability selec-
tion occurs during antibiotic treatment, the resistants must
reproduce faster than the wild types during treatment, which
implies that the resistants cause longer infections than the
The implicit cost of resistance in our model means that
resistants have a slower growth rate than wild types when
the environment is antibiotic-free. In this environment, the
wild types infection length will be longer than the resistants:
1 . s21. Thus, we will work under the constraint
1 . s21 . a21
(18)
(equivalently, a . s . 1). To verify our key assumption that
and immune system cells as done by Frost and McLean
(1994), Levin et al. (1997), Nowak et al. (1997), and Nowak
ment that does not drive the evolution of antibiotic resistance.
One consequence of assuming a . s is that we cannot have
s . r because this would imply that the resistant strains
reproduction ratio is less than one and in the presence of
treatment we would have R 0,m , 1 and R 0,w , 1, which
would lead to eradication of both pathogens. This situation
is of course ideal, but somewhat less interesting to study.
Hereinafter, we will assume
a, r . s . 1. (19)
Dynamics
In equations (1013), when q 5 0, no hosts take antibiotics
and all dynamics occur in a subspace of the model which we
call the NA subspace (for no antibiotics; see Table 2). In the
NA-subspace, R 0,w . R 0,m because s . 1; resistance cannot
evolve from wild-type infections because hosts do not use
antibiotics. Equations (1013) have a globally attracting sta-
ble equilibrium with u 5 1/r and w 5 1 2 (1/r), and the
resistant strains cannot invade.
In this scenario, if resistant types do exist they will go
extinct and the microbial population will revert back to sen-
sitivity, a much desired but often elusive consequence of
ceasing antibiotic use. A linearization (see Appendix A avail-
 ANTIBIOTIC RESISTANCE AND NICHE CONSTRUCTION 481

TABLE 2. Model subspaces. Note that definitions and dimensions will be different in the experience-dependent learning (EDL) model,
where mA is broken up into two classes: mAS and mAI . The RM-subspace in the EDL-model is defined by w 5 wA 5 mAS 5 0. In the
RM-subspace of the EDL-model, we have u 1 uA 1 m 1 mAI 5 1 which makes the RM-subspace three dimensional.

Definition via Host

Subspace Subspace description state variables behaviors Dimension
RM The population only experiences resistant infec- w 5 wA 5 0 0 # p, q # 1 3; 2 if p, q are fixed
tions. All wild-type strains are extinct.
AA All hosts take antibiotics. u5m5w50 p 5 0, q 5 1 2
NA No hosts take antibiotics. u A 5 mA 5 wA 5 0 p 5 1, q 5 0 2

able online only at http://dx.doi.org/10.1554/04-425.1.s1) of ps 2 1 0 ps 0

the system reveals that reversion to sensitivity occurs at the s2r ps 2 r 0 ps
rate s 2 1, and that the time required to halve the frequency , (22)
qs 2 a
of the resistant strains is qs 0 0

0 qs s 2 r 1 sa qs 2 r
log 2
T1/ 2 5 , (20) which has eigenvalues
s21
l1 5 2r, (23a)
which grows faster than linearly with decreasing s.
When q 5 1, all hosts are antibiotic users, and dynamics l2 5 2(r 2 s), and (23b)
occur in a subspace we call the AA subspace. Here, our 1
constraint (19) gives R 0,m . R 0,w and strain persistence can l3,4 5 [2(a 1 1 2 s)
be analyzed in light of the competitive exclusion principle 2
(Bremermann and Thieme 1989). The mutant strain wins, 6 (a 1 1 2 s) 2 2 4(a 2 s 1 ps 2 pas)]. (23c)
fixing in the microbial population while driving the wild type
to extinction. The equilibrium uA 5 s/r and m A 5 1 2 (s/r) Three are obviously negative, and the fourth (l3) is negative
is globally attracting. Dynamical behaviors in the different exactly when
subspaces of equations (1013) are described in Table 3. a 2 s 1 ps 2 pas . 0, (24a)
When 0 , q , 1, both types of behaviors, use and nonuse
of antibiotics, are present in the population. Equations (10 a . sq 1 pas, (24b)
13) appear always to have an internal equilibrium, that is, an rs21
. qra21
1 pr, (24c)
equilibrium where all six population classes are present (see
Appendix B available online at http://dx.doi.org/10.1554/ R 0,m . R 0,w . (24d)
04-425.1.s1). In addition, the system has a disease-free equi- Thus, the equilibrium Em is stable exactly when the resistants
librium (w 5 m 5 wA 5 mA 5 0) that is unstable, and a have a larger basic reproduction ratio than the wild types.
boundary equilibrium Em where w 5 wA 5 0 and only re- Numerical experiments suggest that there is only one in-
sistants are present in the population. Described in the co- ternal equilibrium, and that this internal equilibrium is stable
ordinates of equations (1013), this boundary equilibrium is whenever Em is unstable. It appears that equations (1013)
always have one stable, globally attracting equilibrium that
dominates dynamics. When R 0,m . R 0,w, Em is stable and
[ 1
E m 5 0, p 1 2
s
r2 1
, 0, q 1 2
s
r ]
2
. (21) the mutant fixes; when R 0,w . R 0,m, the internal equilibrium
is stable, and the two strains coexist. Figure 2 shows the
dynamics in a two-dimensional space defined by the relative
Recall that the number of uncolonized hosts can always be
calculated from the numbers of colonized hosts. At the equi- frequency of the resistant strain
librium Em, we have u 5 ps/r and uA 5 qs/r. The total number m 1 mA
of colonized individuals at Em is m 1m A 5 1 2 s/r. fm 5 , (25)
w 1 wA 1 m 1 mA
Keeping the order of equations (1013), the Jacobian of
the linearized system at Em is: and the frequency q of antibiotic users.

TABLE 3. Qualitative behaviors (e.g. polymorphism, fixation) in the subspaces of the different models. When a subspace is not invariant,
dynamics need to be analyzed in the full five- or six-dimensional space.

Subspace Basic (eqs. 10 13) Conformism (eqs. 32 37) EDL (eqs. 38 44) FDL (eqs. 48 53)
RM Resistant strains endemic. Behav- Use-behavior fixes cA . cN. Hosts settle to polymor- Nonuse behavior
ioral polymorphism in hosts. Nonuse fixes cN . cA. phism at p 5 q 5 1/2. fixes in hosts.
AA Resistant strains fix. Resistant strains fix. Not invariant. Not invariant.
NA Wild-type strains fix. Wild-type strains fix. Not invariant. Not invariant.
482 M. F. BONI AND M. W. FELDMAN
FIG. 2. Dynamics with static host behavior. The space shown is
(q, fm) 5 [0,1] 3 [0,1]. The bottom left corner represents q 5 fm
5 0, while the top right corner represents q 5 fm 5 1. Dynamics
always occur on a vertical line where q is constant because host
behavior is static. When the wild type has an advantage (R 0,w .
R 0,m), the mutant still survives as long as some hosts are using
antibiotics and generating a small amount of resistant infections;
the two types coexist. When the resistant has an advantage (R 0,m
. R 0,w), the wild type goes extinct. Beyond the critical antibiotic
use frequency q* 5 (1 2 s21)/(1 2 a21), resistant strains have higher
basic reproduction ratio. Numerical simulations suggest that inter-
nal equilibria (curved line to the left of the cusp at q*) are always
stable, unique, and globally attracting.
Antibiotic Use as Niche Construction
We now see how hosts can act as niche constructors for
the bacteria that colonize them. Hosts can choose to self-
medicate, creating an environment favorable to resistant bac-
teria, or they can choose not to self-medicate, creating an
environment favorable to the wild-type antibiotic-sensitive
bacteria. Creating an environment favorable to one strain of
bacteria is a result of the within-host dynamics of immune
cells, bacterial colonies, and antibiotics. Between-host dy-
namics create another advantage for a particular strain, as it
will not only flourish in a particular host but will be more
transmissible to other hosts. Together, the within-host dy-
namics and the epidemiological dynamics determine whether
the environment favors the sensitive strains or the resistant
strains.
From inequalities (24ad), we see that the resistant strains
will be favored if R 0,m . R 0,w, that is, if antibiotic use sur-
passes the critical value
1 2 s21
q* 5 . (26)
1 2 a2 1
Interpreting the numerator and denominator in terms of fit-
ness, we see that
R 0,w (q 5 0) 2 R 0,m
q* 5
R 0,w (q 5 0) 2 R 0,w (q 5 1)
fitness cost of resistance
5 , (27)
fitness cost of undergoing AB-treatment
where the fitness cost is the cost to the wild type in an an-
tibiotic-free environment (i.e., when q 5 0). Essentially, q*
describes the reductions in the wild types basic reproduction
ratio. The numerator shows the difference in R 0-values be-
tween wild-type and resistant populations in an antibiotic-
free environment. The denominator shows the difference in
R 0-values for the wild type in the presence and absence of
antibiotic treatment. Because we consider R 0 the fitness pa-
rameter for a communicable pathogen, we see that q* is a
ratio of fitness differences or fitness costs.
Most niche construction models are presented as discrete
maps in a standard population genetics framework. In such
a framework, we might declare fitnesses
W w 5 1, (28a)
Wm 5 1 2 cR , and (28b)
W wA 5 1 2 c A , (28c)
where cR 5 1 2 s21 and cA 5 1 2 a21 represent the fitness
costs of resistance and antibiotic treatment, respectively. In-
equalities (24ad) then give us a condition
cR
q . q* 5 , (29)
cA
which tells us that for large enough values of q we expect
resistants to fix in the population; q* is precisely the treatment
threshold beyond which resistant strains will fix and wild-
type strains will go extinct. This q* is a simpler version of
a threshold value derived by Austin et al. (1997).
Note that if the cost of resistance (cR) is greater to the wild
type than the cost of undergoing antibiotic treatment (cA), the
hosts will never be able to construct an environment where
the resistant strains fix in the population. In our model, how-
ever, the assumption a . s implies cA . cR. Thus, it will
always be possible to set an antibiotic use frequency q which
is high enough such that the resistant strains completely re-
place the sensitive strains.
CHANGING PATTERNS OF HOST ANTIBIOTIC USE
Host behavior can change as a cultural or as an evolu-
tionary process (Cavalli-Sforza and Feldman 1981). In the
subsequent sections, we ignore host demographics because
the time scale we work with is the duration of a bacterial
colonization, and we focus on ways that hosts can change
behaviors during a single lifetime. Three different mecha-
nisms of changing host behavior are considered: conformism,
the avoidance of long infections, and adherence to the advice
of public health officials; some results are summarized in
Table 3. When host behavior changes because of the char-
acteristics of the bacterial population, the bacteria will be
altering a part of their environmentthey will be acting as
niche constructors.
Host Conformism
In this model, hosts change behavior according to the prev-
alent behavior in the population; if a majority of hosts uses
antibiotics, it is assumed to be easier for a host to change
behaviors from nonuse to use than vice versa. Hosts switch
from use to nonuse at a rate cN and from nonuse to use at a
 ANTIBIOTIC RESISTANCE AND NICHE CONSTRUCTION 483

FIG. 3. Dynamics under host conformism. The space shown is (q, fm) 5 [0, 1] 3 [0, 1]; axes are indicated in bottom left panel. Open
circles are unstable equilibria, closed circles are stable equilibria, and shaded circles are equilibria which are stable in a two- or three-
dimensional subspace, but not in the full five-dimensional space. Note that the horizontal edges represent three-dimensional spaces (only
one strain exists), and the vertical edges represent two-dimensional spaces (only one behavior exists). Hosts taking antibiotics and infected
with the wild-type strain have an infection of expected duration a21 1 ss21. The top row represents the cases when a21 1 ss21 . 1,
while the bottom row shows the cases when a21 1 ss21 , 1. Stable equilibria appear to be globally stable, except in case (e). Stability
of internal equilibrium in case (b) is known only numerically. Qualitative dynamics of (a) and (d) are identical. Qualitative dynamics
of (c) and (f) are identical.

rate cA. Only healthy individuals are capable of changing
behaviors, and infected individuals stay the course of use or
nonuse once they have become infected. One reason for
avoiding partial antibiotic use is that it may complicate our
simple selection mechanism according to which we assume
that a fraction s of individuals develop a resistant infection.
Allowing individuals to stop or start use in the middle of an
infection would affect their chances of developing a resistant
infection.
Another subtle point involves the difference between the
population-wide frequency of antibiotic-users (q) and the fre-
quency among infecteds of hosts currently taking antibiotics.
The frequencies of antibiotic use and nonuse among colo-
nized individuals are
wA 1 mA
fA 5 and (30)
w 1 wA 1 m 1 mA
w1m
fN 5 , (31)
w 1 wA 1 m 1 mA
respectively, and we postulate that hosts conform to these
levels of use among hosts that are currently sick. Under this
assumption, host behavior is not highly sensitive to the rel-
ative strain frequencies of sensitive/resistant bacteria.
The dynamic equations for our six populations classes are
u 5 2ru(w 1 w A 1 m 1 m A ) 1 w 1 sm
1 c N f N u A 2 c A f A u, (32)
5 ru(w 1 w A ) 2 w,
w (33)
5 ru(m 1 m A ) 2 sm,
m (34)
u A 5 2ru A (w 1 w A 1 m 1 m A ) 1 (1 2 s)aw A
1 sm A 2 c N f N u A 1 c A f A u, (35)
A 5 ru A (w 1 w A ) 2 aw A ,
w and (36)
A 5 ru A (m 1 m A ) 2 sm A 1 saw A .
m (37)
By assuming that the total population size is unity, we can
perform analysis on a five-dimensional system with ordered
coordinates (u, m, mA, w, wA) and uA 5 1 2 u 2 w 2 m 2
w A 2 m A.
Equations (3237) have three boundary equilibria, which
we label EwN: u 5 1/r, w 5 1 2 (1/r); EmN: u 5 s/r, m 5
1 2 (s/r); and EmA: uA 5 s/r, m A 5 1 2 (s/r), where the
omitted coordinates are zero at equilibrium. There may also
be a stable interior equilibrium; Figure 3 shows the different
484 M. F. BONI AND M. W. FELDMAN
kinds of behaviors we can expect under the scenario of host
conformism. One of the keys to determining the qualitative
dynamics of the system is the relative strength of one type
of conformity to the other. If the tendency to conform to
antibiotic use is strong (cA . cN), we expect use behavior
to spread; if the tendency to conform to nonuse is strong (cN
. cA), we expect the avoidance of antibiotics to spread.
The quantity a21 1 ss21 is also a determining factor as it
is the expected duration of a wild-type infection in an in-
dividual taking antibiotics. We see from Table 1 that if a
proportion s of wA hosts develop a resistant infection, the
expected duration of an antibiotic-treated wild-type infection
is a21 1 ss21.
When a21 1 ss21 . 1, the average colonization period for
antibiotic users is longer than that for nonusers. Treated
hosts longer colonization periods can help maintain behav-
ioral polymorphism even when conformity to nonuse is
strong (see Fig. 3b). This happens because among the col-
onized hosts, there will be more taking antibiotics than those
not taking antibiotics at any given point in time, and con-
formist behavior will move the population toward more an-
tibiotic use. The length of the infectious period can be thought
of as a demonstrator effect (Galef 1988), where the individ-
uals demonstrating for a longer period of time have more
success recruiting others to their behavior.
When a21 1 ss21 , 1, wild-type infections in treated hosts
will have expected colonization period shorter than in un-
treated hosts; in this case, use behavior may not be able to
invade even if conformity to use is stronger than that to
nonuse (cA . cN). Figure 3e shows a case with two stable
boundary equilibria where neither behavior is able to invade
when the other is fixed. Use behavior will be able to invade
if (a21 1 ss21)cA . cN (see Fig. 3 and Appendix C available
online only at http://dx.doi.org/10.1554/04-425.1.s1).
Under conformism, host behavior depends on whether con-
formity to one trait is stronger than the other and whether
the infectious period for treated hosts is longer than that of
untreated hosts. These two factors determine whether we have
fixation, polymorphism, or multiple stable equilibria. In all,
Figure 3 reveals at least four different dynamical behaviors
our system can exhibit if hosts simply copy each others
behaviors. If the power of conformity to use (nonuse) is
strong enough, the resistants (wild types) will fix in the pop-
ulation.
Empirical evidence and descriptions of experiments on hu-
man conformist behavior can be found in Boyd and Richerson
(1985) and Kameda and Nakanishi (2002). However, mea-
suring the extent to which conformity affects human behavior
in a natural setting is much more difficult. The current be-
havioral literature focuses on social acquisition of behaviors
in (nonhuman) animals. Galef (1988) presents a summary of
concepts, experiments, and challenges in the field of social
transmission and acquired behavior. For a recent review of
the current state of this field, see Galef (2004).
Human conformity studies have been thus far largely re-
stricted to theoretical models. These models can be useful as
they show the wealth of behaviors possible in a given setting.
Conformism models usually exhibit behavioral homogeneity,
group formation, and behavioral cycling (Tassier 2004); more
complicated conformism models show that the sequence of
events and spatial arrangement of individuals can determine
the behavioral steady state of a population (Miller and Page
2004). This last point is crucial, as it points to some of the
simplifications and shortcomings of analytical models.
In bridging the gap between models and observation of
human conformism, the first necessary step must be deter-
mining the significance of the conformism component in re-
lation to other possible factors that affect human decision-
making. In fact, subdivision of the population according to
some measure of status may be important (Rogers 1995, pp.
3135), and pressure from sources outside the population
might also be relevant, for example, as in Li et al. (2000).
Experience-Dependent Learning
If hosts respond to the characteristics of the infection rather
than to the behavior of other hosts, we expect more regulated
dynamics than those observed under host conformism. One
of the counter-intuitive mechanisms at work in the host con-
formity scenario is that hosts who spend a long time colonized
by a pathogen (and thus demonstrating a particular behavior
of use or nonuse) spend relatively less time in the uncolonized
class and therefore have a relatively smaller chance of switch-
ing behaviors. For this second mechanism of host behavior,
we suppose the opposite: that a host who has just experienced
a long infection is more likely to switch behaviors. We pos-
tulate that length of infection is an appropriate surrogate for
severity of infection, and we claim that hosts undergoing
longer infections will be more likely to switch behaviors in
an attempt to ameliorate their recovery upon their subsequent
infections. Currently, in our model, we have four different
infection durations (Table 1).
We define a new parameter d, where d21 is the critical
infection length beyond which a host is more likely to switch
behaviors than not. Upon recovery, all hosts return to one of
the two susceptible classes, u or uA, and we assume that a
fraction change behaviors as a result of their long infections.
As an example of how these dynamics will work, individuals
leaving the m class are assumed to behave as follows:
d 21
keep the same behavior
s21 1 d21
s21
change behaviors.
s21
1 d 21
We notice that hosts in the mA class may have arrived there
as a result of infection with the mutant strain or as a result
of selection for the mutant strain during a wild-type infection.
These hosts will have experienced different infection dura-
tions s21 and a21 1 s21, respectively. Hence, we break the
mA class into two classes: mAI, hosts who were infected by
the mutant; and mAS, hosts who were infected by the wild
type and evolved a resistant infection as a result of antibiotic
use (I, infection; S, selection). Table 4 gives the proportions
of behavioral changes for all the infected classes.
The dynamical equations are:
 ANTIBIOTIC RESISTANCE AND NICHE CONSTRUCTION 485

TABLE 4. Behavioral switching in the experience-dependent learn-

ing model. The table shows what fraction of hosts change and do
not change behaviors upon recovery from the different infectious
classes. Note that only 1 2 s of the hosts in the wA class actually
recover; the remainder develop a resistant infection and pass into
the mAS class.

Fraction keeping Fraction changing

Infected class same behavior behavior
d 21 1
w
1 1 d 21 1 1 d 21

(1 2 s) d 21 (1 2 s) a 21
wA
a 21 1 d 21 a 21 1 d 21

d 21 s 21
m or mAI
s 21
1 d 21 s 21
1 d 21
FIG. 4. Infection/recovery diagram for the experience-dependent
d 21
a 1s
21 21 learning model. All the recovery arrows begin with either a square
mAS or a triangle. The remaining horizontal arrows are infection; the
a 21 1 s 21 1 d 21 a 21 1 s 21 1 d 21 lone vertical arrow from wA to mAS represents selection. A recovery
arrow beginning with a square indicates that the previous behavior
of use or nonuse is retained upon recovery. A recovery arrow be-
ginning with a triangle indicates that upon recovery an individuals
u 5 2ru(w 1 w A 1 m 1 m AI 1 m AS ) behavior is changed. For example, individuals in class mAS expe-
rience an infection of length a21 1 s21. If a21 1 s21 is long compared
to the critical infection length d21, then we say that most individuals,
1 2 1 2
d21 a21
1 w 1 (1 2 s)aw A a fraction (a21 1 s21)/(a21 1 s21 1 d21), will change behaviors and
1 1 d 21 a21 1 d21 will avoid antibiotics during their next infection.

11 2 1 2
d21 s21
sm 1 21 sm AI
s 21
1d 21
s 1 d 21
Em will always be stable inside the RM subspace, and it will
11 2 sm
a21 1 s21 be stable inside the full space if and only if
AS , (38)
a 21
1 s21 1 d21 a21 1 1
s21 . (47)
5 ru(w 1 w A ) 2 w,
w (39) 2
5 ru(m 1 m AI 1 m AS ) 2 sm,
m (40) (see Appendix D available online only at http://dx.doi.org/
10.1554/04-425.1.s1). In other words, the resistants will fix
u A 5 2ru A (w 1 w A 1 m 1 m AI 1 m AS ) if their average infectious period is longer than the wild
types. Since at Em use and nonuse behavior are each at
11 1 d 2 w 1 1a 1 d 2 (1 2 s)aw
1 d21
1 21 21 21 A frequency 1/2 (eqs. 45, 46), using (15) and (17), condition
(47) translates to R 0,m . R 0,w, when p 5 q 5 1/2.
11
s 1d 2
sm 1 1
s 1d 2
s 21
d 21
Numerical simulations reveal that dynamics (see Fig. 5)
21 21
sm 21 21 AI are dominated by a globally attracting stable equilibrium:
either Em or an internal equilibrium. Roughly 5100 parameter
11
a 1s 1d 2
d 21
sets were tested, with eight different initial conditions in
21
sm ,
21 21 AS (41)
each: seven initial conditions close to the seven corners of
the simplex that makes up state space and one initial con-
A 5 ru A (w 1 w A ) 2 aw A ,
w (42)
dition close to Em. A fourth-order Runge-Kutta method was
AI 5 ru A (m 1 m AI 1 m AS ) 2 sm AI ,
m and (43) employed. Ninety-nine percent of the parameter sets were
dominated by a globally attracting stable equilibrium, while
AS 5 saw A 2 sm AS .
m (44) the remaining 1% of simulations exited with step-size errors.
The tested parameter ranges were 2 # r # 30, 3 # a # 40,
Figure 4 shows a class diagram and explains the derivation
2 # s # 12, 0.0001 # s # 0.9999, 1023 # d # 104.
of equations (3844). The AA subspace and the NA subspace
When R 0,m . R 0,w, the resistant strains fix with p 5 q 5
are no longer invariant in this model. The RM subspace is
1/2 at Em. Otherwise, there is polymorphism in the bacterial
invariant and is defined by w 5 wA 5 mAS 5 0. When only
strains and in host behaviors. Note that when selection against
the resistants are present, our system has a boundary equi-
the mutant is strong enough (s $ 2), there is always strain
librium Em at
polymorphism. In general, the polymorphic equilibrium fre-
s quency of the resistant strain ( fm) will depend heavily on a,
u 5 u A 5 , and (45) the efficacy of antibiotic treatment. As antibiotics cure an
2r
infection more and more quickly (i.e., as a gets larger), the
r2s antibiotic-sensitive strains will be at more of a disadvantage
5m
m AI 5 . (46)
2r and the resistants will be more frequent in the population.
486 M. F. BONI AND M. W. FELDMAN

FIG. 5. Dynamics in the experience-dependent learning model. Both boxes represent the space (q, fm) 5 [0,1] 3 [0,1]. The bottom left
corners represent q 5 fm 5 0, while the top right corners represent q 5 fm 5 1. Closed circles are stable equilibria. The shaded circle
in the left panel is an equilibrium that is stable in the RM-subspace but unstable in the full six-dimensional space. When the resistants
have a higher basic reproduction ratio at p 5 q 5 1/2, they fix; otherwise the two strains coexist.

Moreover, as antibiotics get stronger, hosts will prefer-
entially switch behaviors to take antibiotics, which will then
create further selective pressure against the wild type. Thus,
increasing the strength of an antibiotic puts twofold pressure
on the wild-type strains: (1) it reduces an individual hosts
ability to transmit the wild-type strain to another host; and
(2) increases the proportion of hosts taking antibiotics, which
reduces the population-wide incidence of wild-type infec-
tions. Hence, a weaker antibiotic may be able to play an
important role in reverting the endemic infections to sensi-
tivity. As can be seen in Figure 6, the complete equilibrial
behavior is slightly more complicated.
In this example, where a hosts individual experience with
a bacterial infection potentially leads the host to modify his
behavior, we see how hosts can act as niche constructors for
their bacterial pathogens. We can start our population with
a predominance of wild-type strains and very few antibiotic
users; in this environment the wild-type strains have higher
fitness (measured as R 0). As time progresses and hosts begin
seeking treatment, the environment changes to benefit the
resistant strains, the frequency of resistance increases, and
the resistants may even fix replacing the wild types com-
pletely. One can argue from the perspective of the bacteria
and describe the bacteria as constructing their own niche:

FIG. 6. Equilibrial frequencies of resistance and infection in the experience-dependent learning model. Here, r 5 3, s 5 1.9, s 5 0.9,
d 5 10, and a ranges from 1.9 to 7.9. In the left panel, we see the position of the equilibrium change with increasing a. The right panel
shows the relative frequency of resistant strains at equilibrium and the proportion of infected individuals at equilibrium, as a function
of the antibiotic strength a. We see that as we increase a, the relative frequency of resistant strains increases; this happens for two
reasons: the reduction of wild-type infections due to antibiotic use and the increased tendency to use antibiotics, which helps select for
resistant strains. In the left panel, as we increase a, the population-wide frequency of use behavior (q) actually decreases initially; this
happens because increasing a decreases the amount of time hosts spend in the wA class. Eventually this effect is balanced by the fact
that hosts maintain their use behavior due to the benefit of short infection durations when taking antibiotics. In the right panel, we see
that even as the relative frequency of resistants increases, the total incidence of infections in the population decreases (Bonhoeffer et
al. 1997; Bonhoeffer 2002).
 ANTIBIOTIC RESISTANCE AND NICHE CONSTRUCTION 487

when wild-type infections are predominant, the difference in

infection durations forces many hosts to switch behaviors
and take antibiotics, which in turn creates an environment
favorable to resistant strains.

Frequency-Dependent Learning
As a third model of changing host behavior, we can con-
sider a type of oblique transmission (Cavalli-Sforza and Feld-
man 1981) where hosts receive information from an outside
source as to what course of treatment they should pursue.
We consider the situation where physicians and public health
authorities determine the population-wide level of antibiotic
use depending on the prevalence of resistance in the popu-
lation. With a high frequency of resistants in the microbial
population, hosts will be discouraged from using antibiotics;
with a low amount of resistance, hosts will be encouraged
to take antibiotics. Austin et al. (1999) briefly discuss this
scenario, and their results are qualitatively similar to ours.
The following model may serve as a starting point in the
analysis of current trends to reduce antibiotic use in hospitals
or in the community at large. Livermore (2004) discusses the
effects of larger than 20% reductions in antibiotic prescribing
in the United Kingdom (between 1997 and 2002) and for
ambulatory-care patients in the United States (between 1992
and 2000). Two of the success stories in the United Kingdom
are penicillin-resistant Streptococcus pneumoniae, which de-
creased in frequency from 6.9% to 2.8%, and vancomycin-
resistant Enterococcus faecium, which decreased in frequency
from 19.9% to 17.1%. Resistance levels for other drug-bac-
teria combinations remained relatively constant or increased
slightly; for a complete review of some of the mixed results
of reduced prescribing, see Livermore (2003, 2004).
In our model (and we hope in reality) antibiotic usage
advice will depend on the frequency of resistance in the mi-
crobial population: fm as defined in (25). The relative fre-
quency of the wild type is fw 5 1 2 fm. We postulate that
individuals will be discouraged from taking antibiotics as fm
gets large. Again, cA and cN denote the rates at which in-
dividuals switch behavior from nonuse to use and from use
to nonuse, respectively. Only healthy uncolonized individuals
will be capable of switching behaviors so as not to complicate
the within-host dynamics of individual infections.
The dynamic equations for our six populations classes are
u 5 2ru(w 1 w A 1 m 1 m A ) 1 w 1 sm
1 c N f m u A 2 c A f w u, (48)
5 ru(w 1 w A ) 2 w,
w (49)
5 ru(m 1 m A ) 2 sm,
m (50)
u A 5 2ru A (w 1 w A 1 m 1 m A ) 1 (1 2 s)aw
1 sm A 2 c N f m u A 1 c A f w u, (51)
A 5 ru A (w 1 w A ) 2 aw A ,
w and (52)
A 5 ru A (m 1 m A ) 2 sm A 1 saw A .
m (53)
Note that as the relative frequency of the resistant mutant
( fm) increases, individuals have an increased tendency to
switch to nonuse behavior.
FIG. 7. Dynamics in the frequency-dependent learning model. The
black circle is a globally attracting stable equilibrium, while the
gray circle is an unstable equilibrium that is stable in the three-
dimensional subspace where only the mutant is extant (RM-sub-
space). Hosts learn to reduce antibiotic use when the frequency of
resistant infections ( fm) is high and to increase antibiotic use when
there is little antibiotic resistance. Trajectories can enter a region
of state space where the resistants have a fitness advantage (R 0,m
. R 0,w inside the gray region), but the resistants do not fix because
niche construction causes the environment to revert to a region that
favors the wild types.
Under this scenario, the RM subspace (w 5 wA 5 0) will
be invariant while the NA and AA subspaces will not. The
only boundary equilibrium that exists is EmN, where only the
mutant is extant and nonuse behavior is fixed in the popu-
lation; it is defined by
s
u 5 and (54)
r
s
512
m (55)
r
and is stable inside the RM subspace, but not inside the full
five-dimensional state space (see Fig. 7; Appendix E avail-
able online only at http://dx.doi.org/10.1554/04-425.1.sl).
The system appears to have a unique internal equilibrium
which is stable and globally attracting under a wide range
(if not all) of parameter values. More than 20,000 different
parameter sets were tested, with seven different initial con-
ditions for each. A fourth-order Runge-Kutta method was
employed. Ninety percent of the parameter sets were domi-
nated by a globally attracting stable equilibrium; 2% of sim-
ulations exited with step-size errors; and 8% had undeter-
mined outcomes which, upon inspection, seemed to be step-
size issues with the dynamics moving particularly slowly near
the boundaries of state space. The tested parameter ranges
were 2 # r # 30, 2 # a # 40, 2 # s # 8, 0.0001 # s #
0.9999, 0.001 # cA, cN # 20.
The unique internal equilibrium in our system represents
coexistence of wild-type and resistant strains; this is a direct
result of the host populations altering the microbial envi-
488 M. F. BONI AND M. W. FELDMAN
ronment to always favor the rare type. Changing the models
parameter values has the expected effect on the location of
the internal equilibrium. Lowering s increases the frequency
of resistance as well as the total number of infections; this
may give us a picture of what would happen were the resistant
strains to acquire compensatory mutations. As in the expe-
rience-dependent learning model, resistance increases with
increasing a; again, a stronger antibiotic effect lowers R 0,w
and increases the relative prevalence of resistant infections.
Likewise, increasing s increases the prevalence of resistance.
In general, s and a will be positively correlated; thus,
strengthening the antibiotic can have a two-fold effect on
helping the resistants spread. Increasing cN lowers resistance
and treatment frequencies, the desired effect. Some of these
effects can be seen in Figure 8.
Niche construction can most easily be identified in the case
of frequency-dependent behavior since bacterial strain fre-
quencies have a direct impact on host antibiotic usage. A
higher level of antibiotic use favors the resistant strain, which
then flourishes under these conditions and causes the popu-
lation to use antibiotics more sparingly; low antibiotic usage
then favors the wild-type strain, and thus the bacterial pop-
ulation reverts to sensitivity and again prompts more hosts
to use antibiotics. This process seems as though it could
produce a cycle, though numerical experiments suggest that
it does not. This sort of frequency-dependent regulation of
behavior has the effect of moving the population away from
fixation of the resistant mutant, exactly when one would ex-
pect resistance to fix in the population because of the resistant
strains higher R 0. This effect has been described in the
niche-construction literature as maintaining polymorphism
where none is expected (Laland et al. 1996, 1999).
DISCUSSION
We proposed a mathematical model of the evolution of
antibiotic resistance that is related to many previous for-
mulations (Blower et al. 1996; Austin et al. 1997; Bonhoeffer
et al. 1997; Castillo-Chavez and Feng 1997; Levin et al. 1997;
Stewart et al. 1998; Lipsitch et al. 2000). The key new el-
ement in our model is an a priori division of hosts into those
who take antibiotics and those who do not. With this pop-
ulation subdivision, we have separate recovery rates for treat-
ed and untreated hosts, rather than a mean rate that depends
on the level of treatment, as in Bonhoeffer et al. (1997) and
Castillo-Chavez and Feng (1997). We have a precise way of
expressing which hosts are treated and which ones are not,
without depending on a treatment rate parameter that de-
scribes the constant flow of hosts from treated to untreated,
as in Austin et al. (1997) and Stewart et al. (1998). In ad-
dition, our model includes a parameter s, which describes
the fraction of treated wild-type infections that evolve resis-
tance, similar to r in Blower et al. (1996), as well as the
potential to change the fraction of treated individuals, as
suggested in Austin et al. (1999).
Our model relies on several key assumptions, each of
which would need to be verified when applying the model
to a specific pathogen, drug, and population. We assume a
positive correlation between within-host bacterial reproduc-
tion and length of infection that would need to be verified
for each pathogen-drug combination under consideration.
Certainly, faster within-host reproduction can also be cor-
related with increased transmissibility; this case is taken into
account in our model since in equations (16), increasing
transmissibility (b) has the same effect on R 0 as increasing
the infection duration (v21). An additional simplification we
make involves the infection duration for hosts who become
infected with the wild type and evolve resistance. These hosts
are infected for a period a21 1 s21, which is simply the sum
of infection lengths for the wild type (under treatment) and
the resistant. Within-host models or data on the microbial
population structure during the course of an infection would
give a better estimate of infection length for hosts evolving
resistance.
Host population dynamics and host population structure
are crucial components in constructing a model for a given
pathogen. For the bacterial pathogens considered in this pa-
per, it will be necessary to determine whether the infection
is spread more commonly in hospitals or in the community
at large (for a discussion, see Swartz 1994; Levin and An-
dreasen 1999; Lipsitch et al. 2000; Lipsitch 2001; Bergstrom
et al. 2004; Smith et al. 2004). Our model formulation as-
sumes a closed, well-mixed population and is thus more ap-
propriate for community-acquired infections (tuberculosis,
cholera) than nosocomial infections (S. aureus, E. faecium),
though it is certainly not the case that any infection is spread
exclusively in hospitals or exclusively in the community. In
addition, Smith et al. (2004) note that community transmis-
sion can be quite important in the dynamics of hospital-ac-
quired infections because hosts entering and leaving hospitals
spend much less time in the hospital than in the community.
Lastly, realistic models of behavioral change would require
more than a simple quantification of our parameters cA, cN,
and d, especially because any number of processes could be
at work in addition to the three we suggest. Investigating the
influences on adopting use behavior or nonuse behavior
would necessitate carefully designed studies that measure
such key variables as health status, morbidity, time to adop-
tion, stated reason for adoption, and the behaviors observed
in an individuals social network. Many of these variables
would have to be measured in public health officials and
doctors as well as in regular hosts. Rogers (1995) outlines
some of the key experimental components and results from
the Columbia Drug Study, which investigated the pattern of
adoption for the antibiotic tetracycline, and from a hypoder-
mic needle study that parsed out the relevant communication
channels in aiding the adoption of hypodermic needle use.
The results of our model analysis indicate that if the pro-
portion of antibiotic-takers in the population is fixed, the
pathogen dynamics can be easily classified as a function of
the level of antibiotic use in the population. Without anti-
biotics, resistant strains have no advantage and cannot invade.
When antibiotics are used, the resistant strains will be able
to survive, and if the level of use is high enough they may
flourish and even force the wildtype to go extinct. The critical
value q* defined by (29) reveals a basic population genetic
principle about our two competing pathogens, namely, that
if the cost of resistance is greater than the cost of undergoing
treatment, the resistants will never be fit enough to overtake
the wild types. This result highlights two important points.
 ANTIBIOTIC RESISTANCE AND NICHE CONSTRUCTION 489

FIG. 8. Equilibrial frequencies of resistance and infection in the frequency-dependent learning model. In all the graphs, r 5 3, a 5 2.9,
cA 5 1, and s decreases from 2.9 to 1.1 in increments of 0.1. The gray circles represent the positions of the globally attracting stable
equilibrium in (q, fm) space, while the empty diamonds represent the total frequency of infections (w 1 m 1 wA 1 mA) in the population
corresponding to the gray circles below/above. A decreasing value of s gives us a picture of how the equilibrium strain and behavioral
frequencies change as the resistant microbes acquire compensatory mutations. In all cases, the frequency of resistants and the total
frequency of infections both increase as resistant strains acquire compensatory mutations. As reductions in prescribing levels are more
effective (i.e., as cN increases from the left panels to the right panels) the equilibrium frequency of resistants will be lower. Reducing
the probability of evolving resistance during treatment helps keep resistant frequencies low, unless the resistants evolve a fitness close
to the wild types fitness. This can be seen by comparing the top panels (s 5 0.90) to the bottom panels (s 5 0.01).

First, we must be acutely aware of the rates and fitness effects
of compensatory mutations that may lower the cost of resis-
tance (cR) sufficiently to allow resistant strains to fix in the
population. Second, as a public health measure we may want
to consider using drugs that are just powerful enough to stop
infections, but not so strong that they allow resistant strains
to thrive in dangerous numbers. This type of drug that is
just right would (1) lower cA and prevent resistance from
fixing in the population, (2) keep resistant population sizes
low and thus reduce the likelihood of their acquiring com-
pensatory mutations, and (3) reduce the probability that an
individual evolves resistance as a result of treatment (if s
and a are correlated).
Allowing host behavior to be a dynamic property of our
system, we see that host conformism yields at least four qual-
itatively different system behaviors. However, if hosts are
able to learn or unlearn a particular behavior based on avoid-
ing long infections or listening to public health officials, sys-
tem behavior is much more restricted. In the experience-
dependent learning model, we have polymorphism or fixation
of resistance depending on the strains basic reproduction
ratios. Changing behavior to ensure shorter infections is a
myopic strategy in the presence of strong antibiotics or a
relatively fit mutant. In this case, many hosts learn to take
antibiotics and create an environment where the resistant
strains fix, thus nullifying the effect of adopting antibiotic-
use behavior. In the frequency-dependent learning model, we
always have strain and behavioral polymorphism. Here, the
intentional reduction of treatment when resistance is high
promotes a degree of reversion to sensitive pathogens which
allows antibiotics to remain somewhat effective.
In the experience-dependent learning and frequency-de-
pendent learning models, the pathogens strain frequencies
drive host behavior, which then feeds back into the patho-
490 M. F. BONI AND M. W. FELDMAN
gens strain structure as a new selective environment. Each
time the endemic bacteria affect host patterns of antibiotic
use, the bacteria alter their environment setting in motion the
already well-studied dynamics of niche construction. Though
formal niche-construction models have not yet been applied
to hosts and their pathogens, Cohen (1992) recognized the
importance of niches and reservoirs to the study of antimi-
crobial resistance, and Baquero et al. (1998) have emphasized
the need to focus on the selective environments of microbial
populations. More recently, Bergstrom et al. (2004) have
mapped out how different resistant strains evolve and respond
to antibiotic fluctuations in their environment. Future host-
parasite investigations will surely uncover many instances of
parasites altering their selective environments.
Finally, we note that our investigation incorporated parts
of three well-known population dynamic frameworks: the
within-host dynamics of pathogens and drugs, the between-
host epidemiological dynamics of infectious diseases, and
niche construction. For a given investigation of a host-path-
ogen-drug relationship, it may not be necessary to work with-
in all three frameworks; one or two may suffice. We hope
that the basic models presented in this paper encourage the
investigation of more specific models of niche construction
and pathogen evolution.
ACKNOWLEDGMENTS
This work was supported in part by National Institutes of
Health grant GM28016 to MWF. MFB is supported by the
National Science Foundation and by the Stanford University
Office of Technology Licensing. Thanks to C. Bergstrom, J.
Kendal, S. Tuljapurkar, and an anonymous reviewer for valu-
able comments and suggestions on this manuscript.
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Corresponding Editor: S. Elena