s41579-023-00936-9-1

nature reviews microbiology https://doi.org/10.
1038/s41579-023-00936-9
Review article Check for updates
Antibiotic-induced collateral
damage to the microbiota
and associated infections
Laura de Nies , Carolin M. Kobras & Mathew Stracy
Abstract Sections
Antibiotics have transformed medicine, saving millions of lives since Introduction
they were first used to treat a bacterial infection. However, antibiotics Antibiotic-induced disruption
administered to target a specific pathogen can also cause collateral of microbiota homeostasis
damage to the patient’s resident microbial population. These drugs can Loss of colonization resistance
and increased infection risk
suppress the growth of commensal species which provide protection
against colonization by foreign pathogens, leading to an increased Overgrowth of pre-existing
pathogens within the
risk of subsequent infection. At the same time, a patient’s microbiota microbiota
can harbour potential pathogens and, hence, be a source of infection. Misidentified
Antibiotic-induced selection pressure can cause overgrowth of antibiotic-associated
infections
resistant pathogens pre-existing in the patient’s microbiota, leading to
hard-to-treat superinfections. In this Review, we explore our current Recovery of the microbiota
following antibiotics
understanding of how antibiotic therapy can facilitate subsequent
Strategies to minimize
infections due to both loss of colonization resistance and overgrowth antibiotic-associated
of resistant microorganisms, and how these processes are often infections
interlinked. We discuss both well-known and currently overlooked Conclusions and outlook
examples of antibiotic-associated infections at various body sites from
various pathogens. Finally, we describe ongoing and new strategies to
overcome the collateral damage caused by antibiotics and to limit the
risk of antibiotic-associated infections.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. e-mail: [email protected]
Nature Reviews Microbiology | Volume 21 | December 2023 | 789–804 789

Review article
Introduction treatment can perturb the microbiota. These include drug-specific fac-
Antibiotic treatment is a double-edged sword: although these drugs are tors such as the drug mechanism of action, spectrum of activity, route
crucial for the treatment of bacterial infections, they can also strongly of administration and route of elimination30–33 (Fig. 2). Host-specific
disrupt the commensal microbiota, select for resistant pathogens and factors are also important. It is becoming increasingly apparent that
facilitate subsequent infections. Although most courses of antibiotics the response to antibiotics is highly variable between individuals34 and
do not result in adverse events, these drugs are prescribed in prolific determined by factors such as the make-up of the patient’s microbiota
quantities, with more than 40 billion doses of antibiotics estimated to and the resistance of strains within it, as well as host comorbidities and
be taken annually1, and we still have much to learn about the personal immune status35–38. Furthermore, the microbiota at different body sites
risks of antibiotic exposure2. are highly distinct6,39; although most studies on the impact of antibiotics
At the individual-patient level, the unwanted consequences on normal microbiota have been carried out on the microorganisms
of antibiotic treatment fall broadly into two categories (Fig. 1). Firstly, inhabiting the intestinal tract30, antibiotics can lead to perturbation
antibiotics prescribed to treat a specific infection also act on the com- of the oral, skin and vaginal microbiota30.
mensal species living within the patient, leading to disruption of micro-
biota homeostasis and subsequent disease2–5. Humans are host to Drug-specific factors
trillions of microorganisms that form diverse microbial communities The disruption to the microbiota caused by antibiotics can vary sub-
within the gut, the skin and various epithelial surfaces at other body stantially between different drugs40. Much of our understanding of
sites6. Most of the commensal microbiota reside in the colon7, which how specific antibiotics perturb the microbiota derives from studies
forms a relatively stable ecological habitat in healthy adults8. However, in patients or healthy volunteers, particularly metagenomic analyses
exposure to antibiotics can drastically perturb the ecological equilib- of swabs or stool samples. Other reviews discuss these effects on a
rium of the microbiota. Although antibiotic-induced imbalances in the drug by drug level30,31,40,41, and here we give examples and outline some
composition and behaviour of the microbiota have been associated key trends. For example, the colon is home to ~98% of the microbiota
with various non-communicable diseases such as obesity, diabetes and and a major factor determining the disruption caused by an antibiotic
asthma9–14, in this Review we focus specifically on the risk of infectious is therefore the concentration it reaches in the large intestine. The
disease following antibiotic use. In particular, perturbation of the com- route of administration and pharmacokinetics are the main factors
mensal microbiota can cause loss of protection against colonization that determine the drug concentration reached at a specific body site.
by foreign pathogens, increasing the risk of subsequent bacterial15,16, Orally administered antibiotics are directly carried to the gastrointes-
fungal17,18 and even viral19 infections. tinal tract33, but the absorption within the intestine strongly affects the
Secondly, the use of antibiotics selects for drug resistance, thereby concentration which reaches the densest population of microorgan-
limiting their own efficacy20,21. This is often perceived as primarily a isms residing in the colon. Absorption of peroral macrolides, such as
population-level problem, but the selective pressures that antibiotics erythromycin, is incomplete and high faecal concentrations strongly
exert can have a direct negative impact on the individual patient being affect the normal intestinal microbiota30. By contrast, peroral nitro-
treated. Even a single course of antibiotics can lead to overgrowth of furantoin, which is readily absorbed in the intestine, does not reach
pre-existing resistant strains residing in the patient’s microbiota22–24. high concentrations in the colon and has not typically been associated
Ever increasing rates of antibiotic resistance have led to a high risk that with major perturbations to the gut microbiota42.
patients harbour resistant potential pathogens within their microbiota Although topical antibiotic application is likely to induce the least
prior to therapy25–27. Therefore, although the microbiota confers pro- collateral damage, it can still perturb the local microbiota43. Intra-
tection against colonization by foreign pathogens, it can also act as a venous administrations can indirectly reach the intestine, but the
potential source of infection. Indeed, antibiotic-induced proliferation level depends on the route of elimination of the drug44. Drugs which
of a typically low-abundance species to a high-abundance state can undergo biliary excretion are secreted into the gastrointestinal tract
cause disease or can facilitate translocation of potential pathogens and excreted in the faeces. In mice, intravenous administration of anti-
to other body sites, leading to hard-to-treat resistant superinfections, biotics excreted mainly by renal clearance, such as ampicillin, perturb
during or soon after treatment28. the intestinal microbiota less than drugs with higher excretion via the
Despite both perturbation of microbiota homeostasis and selec- bile, such as tetracyclines44. Other animal studies have found that oral
tion for the spread of resistance being well-known side effects of and intravenous administration of the same antibiotic both led to simi-
antibiotic therapy, these are often treated as separate issues and the lar levels of intestinal microbiota disruption, but oral administration
relationship between these phenomena remains poorly understood15. led to a slower return of species richness and diversity levels to pre-
In this Review we will outline the factors that contribute to the inter- treatment levels45, and promoted higher levels of antibiotic resistance
linked processes of antibiotic-induced disruption of microbiota home- dissemination within the gut microbiome46. However, there remain
ostasis and overgrowth of resistant pathogens. We give examples few studies directly comparing the effect of antibiotic administration
of diverse infections that are associated with antibiotic therapy and route on microbiota disruption in humans.
describe new approaches to reduce the risk of such infections. Beyond the drug pharmacokinetics, its spectrum of activity is
also very important32. Most bacteria inhabiting the intestinal tract
Antibiotic-induced disruption of microbiota are anaerobes from the Bacteroidota, Bacillota and Actinomycetota
homeostasis phyla7,47,48. The next most represented phylum is Pseudomonadota,
Antibiotics administered to target a specific pathogen have off-target which includes a wide variety of pathogenic Gram-negative genera,
effects that can kill or suppress the growth of commensal strains. such as Escherichia, Salmonella and Acinetobacter. The activity of
This can lead to altered species richness and diversity within the an antibiotic against these bacteria is therefore particularly impor-
microbiota as well as a reduced total number of bacteria29. There are tant for determining the disruption it causes49. Drugs broadly active
many factors that determine the extent and manner in which antibiotic against commensal anaerobes include β-lactams, metronidazole,

Review article
a Colonization by exogenous pathogens b Overgrowth of resistant pathogens Fig. 1 | Two mechanisms of infection following
pre-existing in the microbiota antibiotic treatment. a, A healthy microbiota
provides protection against colonization by
Low abundance Pre-existing
foreign pathogens. Antibiotic therapy can
Commensal (no disease) resistant pathogen
microbiota or pathobiont suppress commensal bacteria living within
the host and significantly increase the risk of
colonization and infection upon exposure to
foreign pathogens. b, The microbiota can also
harbour potential pathogens, often present in low
abundance without causing disease. Antibiotic
treatment can lead to overgrowth of any resistant
pathogens pre-existing within the microbiota.
Overgrowth to high abundance can cause local
disease or facilitate the translocation of these
pathogens to other body sites where they cause
disease, such as the bloodstream.
Antibiotic Antibiotic
treatment treatment
Loss of
colonization
resistance
Translocation
Exposure to leading to disease
foreign pathogen Translocation at other body sites
High abundance
causing local disease
chloramphenicol, clindamycin, macrolides and tetracyclines32,50. The microbiota disruption caused by a specific antibiotic
Some antibiotics, such as metronidazole, narrowly target obligate can also be inferred based on the risk of adverse events such as
anaerobes and can therefore lead to increased relative abundance antibiotic-associated diarrhoea (AAD)52. AAD is one of the most com-
of oxygen-tolerant bacteria, including potential pathogenic genera mon side effects of antibiotics occurring in 5–30% of patients treated
such as Enterococcus and Salmonella51. Broad-spectrum β-lactams, with antibiotics, with frequencies varying according to the type of
by contrast, are active against both obligate and facultative anaer- antibiotic administered4,5,53. Although almost all antibiotics have been
obes. It should be noted that the spectrum of activity can vary implicated in AAD, higher frequencies of AAD have been associated
strongly even between antibiotics with the same mechanism of with exposure to antibiotics active against anaerobic bacteria such
action32. For example, an in vitro screen of human gut commensals as clindamycin, cephalosporins and broad-spectrum penicillins5,53.
has shown that quinolone antibiotic activity is very dependent on Higher levels of AAD are also often seen in patients treated with com-
the drug generation, ranging from first-generation variants effec- binations of antibiotics5, such as clindamycin in combination with
tive against few species to fourth-generation variants which inhib- another antibiotic53, or combinations of three or more antibiotics54.
ited almost all tested species32. The effects of different antibiotics
on oropharyngeal, skin and vaginal microbiota are less studied, Host-specific factors
but drug-specific effects on the extra-intestinal microbiota have Although trends can be observed in how different antibiotics behave,
been reviewed30. host-specific factors play an equally important role in determining the

Review article
a Drug-specific factors b Host-specific factors
Other medication
Route of
• Antidiabetic
administration
• Proton pump
• Oral Individual
inhibitors
• Topical make-up of the
Spectrum • Non-steroidal
• Intravenous microbiota
of activity anti-inflammatory
• Narrow • Resilience to
• Broad perturbations
Comorbidities
• Immunodeficiency
Pharmacokinetics
• Drug absorption
• Route of
elimination
Resistant
pathogens
• Overgrowth
and disease
Commensal Mechanism
microbiota of action
Resistant commensals
Pre-existing
• Reservoir of resistance
resistant
• Community protection
pathogen or
pathobiont
Resistant
commensal
Fig. 2 | Factors contributing to antibiotic-induced disruption of microbiota the presence of antibiotic resistance among both commensals and potential
homeostasis. a, Drug-specific factors include the route of administration, pathogens. Patient comorbidities as well as co-administration of non-antibiotic
drug pharmacokinetics, mechanism of action and spectrum of activity. b, Host drugs also determine the level of antibiotic-induced microbiota perturbation.
factors include the individual make-up of the patient’s microbiota, including
effect of antibiotics on the microbiota34,55. Indeed, the heterogeneous subsequent infections, as covered in detail later. Resistance among
response between individuals can make it difficult to predict the effect commensals can have different effects. On the one hand, these com-
of specific antibiotics on the microbiota. For example, the proportion of mensals can act as a reservoir for resistance genes that can spread
the antibiotic ceftriaxone secreted in the bile was shown to vary by up to horizontally to pathogenic species. On the other hand, commensals
3-fold between individuals, and the perturbation to the gut microbiota which are resistant to a particular antibiotic will be less perturbed
correlated with this biliary excretion rate56. Moreover, the microbiota itself by drug treatment and, hence, lead to lower overall disruption to
is highly heterogenous between individuals. Ecological models and the microbial community. Furthermore, the bacteria present in the
experimental evidence suggest that the species present and their microbiota can also modulate the effect of drugs, providing protec-
interspecies interactions determine the stability of the microbiota and tion for their antibiotic-susceptible neighbour36. The secretion of
its response to perturbations such as antibiotics57. In studies in which antibiotic-degrading enzymes, such as β-lactamase enzymes, by the
healthy volunteers were administered the same antibiotic, the response microbiota may compromise antibiotic efficacy and, in turn, provide
of the gut microbiota was highly variable between individuals34,55,58,59. passive resistance to a microbial community37,61,62. The composition
In one study, a subset of volunteers showed particularly strong com- of an individual’s microbiota is influenced by environmental factors.
positional changes and prolonged reduction in microbiome diversity For instance, exposure to environmental reservoirs, for example live-
after antibiotics, suggesting that some individuals may be at higher stock or wastewater, likely promotes the transmission of not only
risk of adverse outcomes following antibiotics than others59. Lower environmental microorganisms but also their antimicrobial resistance
microbiota stability is also observed in infants60 and older people35 genes to the human microbiome63. As the initial state of the micro-
compared with healthy adults. Although it is clear that the response to biota impacts how it is perturbed by antibiotics55, these environmental
antibiotics depends on the individual make-up of the microbiota, we factors ultimately also affect the individual response to antibiotics.
still have much to learn about the factors that govern this behaviour. The microbiota is also highly regulated by the host immune sys-
The presence of antibiotic resistance within the microbiota also tem, with the host playing an essential role in microbiota homeostasis64.
determines the resulting effect of antibiotics. Antibiotic-resistant The microbiota, in turn, influences the function of the immune
pathogens present within the microbiota can lead to overgrowth and system38,65. As such, patient immune status and comorbidities can

Review article
impact the disruption caused by antibiotics. The gut microbiota of associated with antibiotic-induced loss of gut microbiota-mediated
individuals who are immunosuppressed, such as patients receiving colonization resistance. For example, Klebsiella oxytoca has been
chemotherapy or stem cell transplants, can be highly distinct from identified as a causative organism of antibiotic-associated haemor-
those of healthy individuals, and hence are likely to have altered rhagic enterocolitis16. Other pathogens, such as methicillin-resistant
risk of antibiotic-induced microbiota perturbation51. Furthermore, Staphylococcus aureus (MRSA), are likely also responsible for cases
some non-antibiotic drugs, such as proton pump inhibitors (PPIs), of non-C. difficile antibiotic-associated enterocolitis87,88. Numerous
anti-inflammatory drugs and antipsychotics, have been shown to studies in animals have shown that antibiotics can facilitate Salmonella
supress various gut commensal species in vitro66, and have been asso- infection79,89. In humans, epidemiological evidence suggests that
ciated with changes to the microbiota composition in humans67. The prior antibiotic use is a significant risk factor for infections from both
use of these drugs in parallel with antibiotics can change the host’s risk non-typhoidal90–92 and typhoidal93,94 Salmonella, although the causality
of antibiotic collateral damage66,68. For example, PPIs strongly inhibit of these associations remains to be established.
gastric acid production and are a known risk factor for AAD69,70.
Colonization resistance and antibiotic-associated infections
Loss of colonization resistance and increased at other body sites
infection risk Although the gut represents the largest and most diverse microbial
An intact microbiota confers protection against a wide range of invad- reservoir in the human body, colonization resistance also extends
ing pathogens, a concept termed colonization resistance. There are to other body sites and prior antibiotics have been associated with
various mechanisms by which a healthy microbiota provides coloni- increased risk of various extra-intestinal infections in both communtiy94
zation resistance (Box 1). These can be direct, through interbacterial and hospital settings95. For example, the skin microbiota has an essen-
interactions such as nutrient competition71,72 or secretion of bacte- tial function against invasion of exogenous pathogens. Similar to the
riocins and other antimicrobials73. The microbiota can also provide intestinal microbiota, these microorganisms may metabolize host
colonization resistance indirectly, for example by preparing the host proteins and lipids to produce bioactive molecules, such as antimicro-
immune system to combat infection74–76. It has long been known that bial peptides, for their competitive advantage96. For instance, various
antibiotic-induced perturbations can disrupt colonization resistance commensal Staphylococcus spp., commonly found on the skin, were
and drastically increase the risk of infection. Indeed, studies performed previously shown to produce antimicrobial peptides which inhibited
as early as the 1950s showed that antibiotic administration to mice or the growth of S. aureus39,97,98. Moreover, commensal skin microbiota, or
guinea pigs rendered these animals up to 100,000-fold more suscepti- their metabolic products, may stimulate production of host-derived
ble to subsequent infection by enteric pathogens such as Vibrio cholerae antimicrobial peptides99,100.
and Salmonella enterica than untreated animals74,77–80. The niche-specific microbial community of the upper respiratory
Clinically, Clostridioides difficile is one of the most well known tract also has an important function for inhibiting the dissemina-
and widely studied pathogens which cause infections following anti- tion of pathogens to the lungs101, and therefore for the prevention of
biotic treatment. C. difficile infections (CDIs) are responsible for respiratory infections101–104. An intact upper respiratory microbiota can
between 10% and 25% of all diagnosed cases of AAD, and can cause provide indirect protection from infection through its role in regulating
serious intestinal infections such as antibiotic-associated pseu- the host immune response. Indeed, in mouse models the commensal
domembranous colitis4. Various antibiotics have been associated microbiota regulates T cell and antibody responses following influenza
with risk of CDIs, but particularly high-risk drug classes are clinda- virus infection, and antibiotic treatment has been shown to exacerbate
mycin and various β-lactams, including monobactams, carbapenems disease severity in various viral infections19,105. Antibiotic perturba-
and cephalosporins15,81. The dosage and the duration of antibiotic tion to the microbiota of the oropharynx has been observed to cause
treatment are important factors determining the risk for CDIs, with increased colonization by various Enterobacteriaceae30 and Streptococ-
risks increasing for longer treatments and when multiple antibiotics cus pyogenes43, and prior antibiotic treatment may be associated with
are administered81. The essential role that a healthy gut microbiota upper respiratory infections in humans106. Studies have also shown
plays in protecting against CDIs has been demonstrated by numer- that prior antibiotics significantly increase the risk of urinary tract
ous studies showing that CDIs could be cured by administration of a infections (UTIs); women treated with antibiotics for other illnesses
consortium of commensal gut species82 or donor faeces83. A healthy were three to six times more likely to experience a subsequent UTI
gut microbiota provides protection against CDIs through several than untreated women107.
mechanisms. In particular, metabolism of host-produced bile acids
by certain members of the healthy microbiota makes them toxic to Overgrowth of pre-existing pathogens within the
C. difficile vegetative growth. It has been shown in mice that coloni- microbiota
zation resistance to C. difficile can be restored with the addition of a It is well established that a disrupted microbiota following anti
single species, Clostridium scindens, which generates secondary bile biotics can increase the risk of colonization and infection by foreign
acid through 7α-dehydroxylation84. Other mechanisms also impor- pathogens108. Experimental models of colonization resistance typically
tant for colonization resistance against C. difficile — for example, recapitulate this by measuring infection by an exogenous pathogen
competition by members of the microbiota for nutrients essential for introduced to the animal following antibiotic treatment. However,
C. difficile growth — can protect against CDIs independently of bile in many cases, potential pathogens are already present in the patient’s
acid effects85,86. In mice, antibiotic treatment increased the amounts microbiota prior to therapy109–113 (Box 2), sometimes at low levels or
of sugars, amino acids and other nutrients which C. difficile uses undetectable in surveillance cultures, known as occult or subclini-
for growth72. cal colonization114. Self-infection can also be caused by ‘pathobionts’:
Beyond the well-studied example of C. difficile, there is evi- commensal species typically not considered pathogens, but which
dence that infections with various other enteric pathogens are also can cause disease in certain contexts, such as individuals who are

Review article
Box 1
Colonization resistance
Commensal bacteria can protect against exogenous pathogens glycans. As such, commensal microorganisms that share similar
by various mechanisms. These fall into two categories: direct nutrition preferences or glycan restrictions, as pathogens, compete
mechanisms via bacterial–bacterial interactions, or indirect mech for the same metabolic niche, which in turn limits pathogen
anisms via microbiota-mediated modification of host factors (see the colonization181–183. Other mechanisms include direct attacks via
figure). Microbial competition and subsequent depletion of nutrition type VI secretion systems (T6SSs) used by Gram-negative species
represent one aspect of direct colonization resistance. Dietary to kill competing species via contact-dependent transport of
carbohydrates or host-derived substrates may be metabolized by toxin proteins184,185. Furthermore, many gut commensals secrete
different microbial groups, whereas metabolic end products may bacteriocins, a subgroup of antimicrobial peptides, that directly inhibit
become metabolic inputs for other syntrophic microorganisms6. other bacterial species, including pathobionts and pathogens166,186.
Additionally, whereas some bacteria can catabolize both monosac Indirect mechanisms of colonization resistance, on the other
charides and polysaccharides, others are restricted to specific hand, require host–microorganism interactions to inhibit exogenous
Direct Indirect
Dietary carbohydrates
Commensal or host-derived substrates
microbiota
Nutrient
competition Primary Secondary
bile acids bile acids
Inhibited
Metabolic pathogen T6SS-mediated
end products delivery of toxic
effectors
Mucus
Microorganism-associated
molecular patterns (MAMPs)
Bacteriocins
and other
antimicrobials
Epithelial cell
Host-derived
antimicrobial
peptides
Immune
receptor
Paneth cell
DC Macrophage
Microbiota-mediated
Commensal Pathogen immune responses
ILC3 Neutrophil

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(continued from previous page)

bacteria. Although the mucus layer forms a physical barrier limiting cytokines6,74. Besides promoting the host’s immune system75,76,
pathogen interaction with the underlying epithelium, commensal members of the microbiota may also interact with host-derived
microorganisms may further limit pathogen colonization by inducing molecules themselves. Primary bile acids are secreted into the
mucus production and maintaining the mucosal barrier. Moreover, intestinal tract187. Hydrolases produced by a wide range of bacterial
interaction of the microbiota with host receptors can elicit the taxa deconjugate the primary bile acids, which can be converted into
production of host-derived antimicrobial peptides by epithelial cells. various secondary bile acids that are known to inhibit the growth of
Simultaneously, interactions of the microbiota with innate immune pathogens such as Clostridioides difficile84. DC, dendritic cell; ILC3,
receptors lead to downstream production of pro-inflammatory type 3 innate lymphoid cell.
immunocompromised110. Antibiotic treatment can lead to overgrowth bacteria and has been shown to lead to increased Enterococcus abun-
of these opportunistic pathogens or pathobionts that were previously dance in humans51. C. difficile is intrinsically resistant to various
persisting at low levels in the patient’s microbiota23. Knowing whether broad-spectrum antibiotics used against other pathogens127,128. Despite
an antibiotic-associated pathogen is of exogenous or endogenous ori- being one of the most common nosocomial infections, studies have
gin is important for developing preventative strategies, as described shown that many CDIs are not a result of transmission events within
later in this Review. hospitals, suggesting they may instead be a result of antibiotic-induced
The main mechanism by which a potential pathogen can out- overgrowth of C. difficile already present in the microbiota129. In agree-
compete other species during antibiotic treatment is when it is more ment with this, a systematic review has shown that patients colonized
resistant to the drug than its competitors, either due to intrinsic or with C. difficile are at significantly higher risk of CDIs than patients who
acquired resistance (Fig. 3a). However, an antibiotic can affect par- are not colonized109.
ticular bacteria differently depending on the interspecies interactions
with other microorganisms within the community115–117. As such, even Overgrowth of pathogens with acquired resistance
apparently susceptible pathogens can overgrow within the microbiota Antibiotics can also lead to overgrowth of strains from typically
during antibiotic treatment as a result of preferential loss of commensal sensitive species which have evolved or acquired resistance to
species that confer colonization resistance to them49,51,77. Here, the role
of the resident microbiota might more accurately be described as ‘pro-
liferation resistance’: preventing the proliferation of a low-abundance
microorganism to a high-abundance, disease-causing state.
Box 2
Overgrowth of intrinsically resistant pathogens Infection from within

One of the most well-known examples of overgrowth of intrinsically
antibiotic-resistant pathogens is post-antibiotic fungal infection. Vari- Many bacterial pathogens are members of species that are
ous fungi are found in the microbiota of healthy humans in various body primarily commensals which do not cause disease as an obligate
sites, including the skin, oropharynx, intestine and lower reproduc- part of their life cycle112,188. Indeed, globally, more than half of
tive tract118. Although usually benign, antibiotic-induced loss of com- the deaths associated with bacterial pathogens come from five
mensal bacteria can lead to the proliferation of fungi and subsequent species that are commonly identified in the microbiota of healthy
disease. In particular, the overgrowth of the opportunistic pathogen individuals: Staphylococcus aureus, Escherichia coli, Streptococcus
Candida albicans leading to vulvovaginal and oral candidiasis119 is a pneumoniae, Klebsiella pneumoniae and Pseudomonas
very common adverse effect of antibiotic treatment17,120,121, particularly aeruginosa189. Disease from these species, as well as many other
β-lactams122. Moreover, C. albicans is a common cause of nosocomial opportunistic pathogens, can be self-infections, that is, caused
bloodstream infections and past antibiotic treatment is a strong risk by bacteria pre-existing in a patient’s microbiota rather than
factor for candidaemia18,123–125. Antibiotics, particularly with anaero- transmission events110,113,188. For example, in one prospective
bic activity or high concentrations in the intestine, caused sustained study of patients with nasal colonization by S. aureus, 86% who
increase in intestinal colonization by yeasts126. Intestinal domination by went on to experience S. aureus bacteraemia had blood isolates
Candida spp. has been observed to precede bloodstream infections125, clonally identical to the isolates identified in their nasal swabs
suggesting that overgrowth in the gut may facilitate these systemic up to 14 months prior151. Carriage of uropathogenic E. coli (UPEC)
yeast infections. in the gut microbiota is common, and these uropathogens can
Other antibiotic-associated infections may also be caused by over- act as a reservoir for urinary tract infections (UTIs)150,190. Potential
growth of intrinsically resistant pathogens persisting within the micro- pathogens may be able to persist in the microbiota over very long
biota. Gram-negative species are intrinsically resistant to antibiotics periods of time. In one study, a multidrug-resistant UPEC strain
such as clindamycin and vancomycin, and can overgrow in the intestine was found to move between the gut and the bladder of a patient
during treatment with these drugs114. In mice, treatment with a single suffering from recurrent UTI over a 5-year period143. For all of these
dose of clindamycin resulted in a marked expansion of Enterobacte- potential pathogens within the host microbiota, various drivers can
riaceae species, followed by multiple shifts in microbiota composition trigger the transition from a low-abundance, commensal state to a
over the next 4 weeks24. Metronidazole is active against commensal high-abundance, disease-causing state110.
obligate anaerobes, but generally ineffective against oxygen-tolerant

Review article
a
Intrinsic resistance Aquired resistance Overgrowth of suceptible strains
Commensal
microbiota
E. coli Enterococcus
species
C. albicans
Drug-resistant
E. coli
Enterobacteriaceae
C. difficile
Antibiotic Antibiotic Anti-anaerobic

treatment treatment antibiotic treatment
b c Clearance
of initial UTI
Urinary tract
Shedding and spreading via external route
Antibiotic
treatment Translocation
Gut
Collateral
damage
Drug-resistant E. coli
Sensitive E. coli
Translocation to bloodstream Local disease

(Enterococcus species, C. albicans) (C. difficile, K. oxytoca)
specific drugs. Antibiotic-resistant opportunistic pathogens lead to ‘blooms’: overgrowth of a strain that was previously persisting
and pathobionts can frequently persist asymptomatically within at low levels leading to transient domination of the microbiota by a
an individual’s microbiota, including hard-to-treat pathogens single strain resistant to the drug23,113. Antibiotic-induced blooms of
such as carbapenem-resistant Enterobacteriaceae (CRE) and drug-resistant Escherichia coli and Klebsiella pneumoniae have been
vancomycin-resistant enterococci (VRE)25–27,49,113. When resistant observed in humans22, with the relative abundance of these species
strains are present in the microbiota prior to therapy, antibiotics can increasing from a few per cent before treatment to account for nearly

Review article
Fig. 3 | Overgrowth and infection from pre-existing pathogens within the disease, such as colitis caused by the overgrowth of enteric pathogens C. difficile
microbiota. a, Potential pathogens are frequently present in the patient’s and Klebsiella oxytoca in the gut. Alternatively, microbiota disruption can lead to
microbiota prior to therapy. Antibiotic-induced overgrowth can occur when a weakened intestinal barrier, or reduced host defences, allowing overgrowing
these pathogens are intrinsically resistant to the administered drug, such as pathogens, such as Candida spp. and Enterococcus spp., to cross into the
Clostridioides difficile, and fungi such as Candida albicans (left). Pathogens bloodstream. Overgrowth within the intestine can lead to increased shedding
with acquired resistance, such as drug-resistant Escherichia coli and other in the faecal matter, facilitating spread to other body sites via external routes.
Enterobacteriaceae, can overgrow by outcompeting not just other species c, Antibiotic-associated infections may be easily misidentified as treatment
but also sensitive members of the same species (centre). Even susceptible failures if the treatment promotes reinfection at the same body site as the
pathogens can overgrow due to antibiotic-induced loss of species conferring original infection. For example, an antibiotic may clear a susceptible pathogen
colonization resistance. Antibiotics active against commensal anaerobes can from the urinary tract, but at the same time lead to overgrowth of resistant
promote overgrowth of potentially pathogenic oxygen-tolerant species such uropathogens in the gut microbiota, thereby facilitating resistant reinfection of
as enterococci and Enterobacteriaceae despite in vitro activity against these the urinary tract. UTI, urinary tract infection.
species (right). b, Antibiotic-induced overgrowth can directly lead to local
a quarter of the entire microbiota following treatment. Even resist- it to be sensitive to the administered drug77. This has been shown in
ant strains present at initially very low abundance can overgrow to studies focused on the common nosocomial pathogen VRE. In mice
high levels during antibiotic treatment. In a mouse model of occult colonized by VRE, treatment with piperacillin–tazobactam, a β-lactam
colonization, treatment with various antibiotics including ampi- antibiotic and β-lactamase inhibitor combination medication which
cillin and azithromycin caused overgrowth of multidrug-resistant is broadly active against commensal anaerobes, promoted persistent
K. pneumoniae from initially undetectable levels to high abundance VRE overgrowth despite moderate in vitro activity against the VRE
in the stool114. Furthermore, in antibiotic-treated mice, overgrowth strain tested113. Treatment with bacitracin, an antibiotic with potent
of a multidrug-resistant E. coli previously benignly inhabiting the gut activity against both the VRE isolate used and commensal anaerobes,
led to systemic spread and rapid sepsis-like death130. led to suppressed VRE colonization, but then to relapse and overgrowth
Antibiotic-induced overgrowth of a strain which has evolved resist- to moderate levels after discontinuation of treatment. In patients colo-
ance is subtly different to that of an intrinsically resistant species. In nized with VRE, the density of VRE in stool increased during treatment
the former case, this strain can outcompete not just other species not only with vancomycin but also with various antibiotics that target
but also its closest competitors: susceptible strains of the same spe- the commensal anaerobes49,77.
cies. As they typically compete for an identical set of resources, these In mouse models it has been shown that antibiotic treatment can
same-species competitors are often critical for providing colonization lead to downregulation of host expression of an antimicrobial protein,
resistance131,132. For example, in a recent preprint, the introduction of RegIII, which is active against VRE138, showing that antibiotic-induced
an engineered non-pathogenic Salmonella strain to a mouse micro- loss of indirect colonization resistance factors can potentially facilitate
biota was shown to provide stronger protection against pathogenic overgrowth, even of pathogens that are apparently susceptible to the
Salmonella infection compared with other species, as it occupies a near treatment. This also highlights that overgrowth of pathogens that are
identical metabolic niche133. Similarly, germ-free mice mono-associated resistant to the administered antibiotic may frequently occur due to
with a single Bacteroides sp. are resistant to colonization by the same, a combination of the direct growth advantage against other microor-
but not different, species134. Even antibiotics which cause relatively little ganisms as well as due to the loss of microbiota-mediated colonization
perturbation to overall species abundances may therefore still allow resistance and other indirect factors. For example, treatment with
resistant strains to overgrow in the microbiota by dominating their β-lactams induces release of large quantities of peptidoglycan frag-
species-specific niche135. In a study of travellers, a 14-day prophylactic ments from commensal bacteria that potently induce the invasive
course of trimethoprim–sulfamethoxazole led to no change in total fae- hyphal growth of C. albicans122.
cal Enterobacteriaceae abundance in most persons, but led to selection
for high-level resistance to the drugs in virtually all faecal Enterobac- Antibiotic-induced translocation between body sites
teriaceae strains isolated135. Furthermore, a study comparing the gut Antibiotic-induced pathogen overgrowth can cause localized disease
microbiota of children found that children who had received multiple at the initial colonization site, such as proliferation of C. difficile in the
courses of antibiotics in their first 3 years of life had significantly more intestine leading to colitis. Overgrowth can also facilitate transloca-
species dominated by a single strain compared with children with no tion of microorganisms benignly inhabiting one body site to a new
antibiotic exposure22. body site where it causes disease139 (Fig. 3b). The gut microbiota can be
host to many potential pathogens which rarely lead to enteric disease
Pathogen overgrowth and loss of colonization resistance are but can frequently cause infection at other body sites113. In particular,
interlinked antibiotic-induced overgrowth of potential pathogens in the intestine
Importantly, antibiotic-induced overgrowth of pre-existing pathogens can lead to serious bloodstream infections139. Intestinal domination,
and loss of colonization resistance are interlinked processes. Treatment with a single species accounting for >30% of the gut microorganisms,
with antibiotics that strongly suppress obligate anaerobes, which make has been shown to be a risk factor for bloodstream infection with
up the majority of the human gut microbiota, can lead to an increased various pathogens, including Candida, Enterococcus, Streptococcus
abundance of some oxygen-tolerant, potentially pathogenic bacte- and various Pseudomonadota species51,125,139,140. In mouse models,
ria, such as Enterococcus and various Enterobacteriaceae51,77,114,136,137. antibiotic-induced overgrowth has been shown to facilitate the sys-
As such, antibiotic treatment can lead to overgrowth of a potential temic spread of pathobionts and commensal gut bacteria130,141. This
pathogen within the microbiota, despite in vitro susceptibility showing antibiotic-induced translocation from the gut to the bloodstream may

Review article
be a consequence of host defences being overwhelmed by pathogen occurs during treatment with numerous studies of the gut microbiota
overgrowth or due to increased breakdown of the intestinal barrier showing profound loss of diversity, shifts in community composi-
caused by disruption of the gut microbiota142. tion and decreases in bacterial counts, occurring within a few days of
Movement of pathogens also occurs between the intestinal micro- drug initiation40,59,136. Once treatment ends, the microbiota typically
biota and other body sites, such as the urinary tract143,144 and respiratory returns rapidly towards its initial state, a quality known as resilience
tract145. Antibiotic-induced overgrowth within the gut can lead to high (Fig. 4). Most studies of the intestinal microbiota show recovery within
levels of shedding of these pathogens in the faecal matter114,146 and 2–8 weeks after the cessation of treatment40,59,136. In agreement with a
external spread to other body sites, such as the urinary tract, within the fast initial recovery from a strongly disrupted state once antibiotics are
host. Antibiotic-induced intestinal overgrowth of VRE leads to increased removed, many cases of AAD are self-limiting once antibiotic treatment
spreading to the environment in hospital settings49, suggesting that ends4,5. However, the recovery of the microbiota from acute disrup-
this mechanism of translocation is also likely to facilitate the spread to tion can be incomplete, leading to a long-term altered state34,59,136. One
other patients. Although relatively poorly studied, antibiotic-induced study of antibiotic treatment in healthy volunteers found that an acute
overgrowth of microorganisms benignly inhabiting other body sites, decrease in species richness and bacterial counts during treatment was
such as the lower reproductive tract, skin or oral cavity, may similarly followed by a return to pretreatment species richness after 2 months,
facilitate translocation to other body sites where they can cause disease. but with an altered taxonomy, resistome and metabolic output59.
Similarly, another study observed blooms of Enterobacteriaceae and
Misidentified antibiotic-associated infections other pathobionts such as Enterococcus faecalis and Fusobacterium
Determining whether antibiotic therapy is a primary cause of a subse- nucleatum during treatment, followed by recovery to near-baseline
quent infection is not straightforward, especially because these drugs composition within 1.5 months. However, multiple common species
are prescribed at very high frequencies and particularly to individuals were lost during treatment and remained undetectable in most of the
already at high risk of infection. In acute care settings, three quarters of subjects after 180 days136. The resilience of the intestinal microbiota
antimicrobial drugs are prescribed for infections of the lower respira- appears to decrease with repeated antibiotic treatments34.
tory tract, urinary tract or skin and soft tissues147. The most well-known Similar to the changes observed in the composition of the micro-
antibiotic-associated nosocomial infection, CDI, is an enteric disease biota, its resistome also experiences acute and chronic perturbations
with very different symptoms to the most common infections for which following antibiotic treatment. Treatment can lead to transient blooms
antibiotics are initially prescribed. Do antibiotics preferentially increase of resistant strains to extremely high levels within the gut microbiota22.
the risk of infections with a different pathology to the original infection? As species abundances return to baseline level, resistance levels also
It seems likely that the infections that are most commonly associated decrease; however, they frequently return to an elevated level com-
with antibiotic use are those where the link between infection risk and pared with before treatment. This can be a consequence of resistant
antibiotic use is easiest to discern, that is, a completely new infection strains becoming dominant within their species-specific niche or
occurred as a result of antibiotic treatment. However, if antibiotics pre- because of the horizontal spread of mobile resistance genes between
scribed for a particular infection also facilitate rapid reinfection at the species22. Indeed, it has been hypothesized that overgrowth or typi-
same body site with similar symptoms, these will be harder to identify. cally low-abundance species within the intestine might act as a driver
An example of this is the emergence of antibiotic resistance during of horizontal gene transfer, promoting pathogen evolution and the
treatment, which is a common occurrence for various bacterial infec- spread of antibiotic resistance23. Although the acute phase of micro-
tions. Although this can be a consequence of the original pathogen biota disruption during and immediately following treatment is clearly
evolving resistance, recent evidence has shown that for several infec- associated with the highest risk of subsequent infections, there is still
tion types, such as UTIs and wound infections, this is most frequently much we need to learn about how long-term antibiotic-associated
caused by strain replacement: clearance of the original susceptible perturbations to microbiota species abundance and resistance levels
pathogen followed by rapid reinfection with a different resistant bac- affect the future risk of infection152–154.
terium likely originating from within the patient’s microbiota148,149.
In the case of UTIs, which are predominantly caused by uropathogenic Strategies to minimize antibiotic-associated
E. coli (UPEC), these rapid reinfections were typically a new strain of infections
the same species. Without frequent culturing and strain-level reso- Antibiotic-associated infections are a consequence of the collateral
lution, such cases could easily be misidentified as simple treatment damage of administered antibiotics, through the reduction in coloni-
failures, that is, a failure of the antibiotic to clear the original pathogen zation resistance and by the overgrowth of resistant microorganisms
(Fig. 3c). Many bacterial infections originate from the patient’s own within the microbiota. Strategies to minimize antibiotic-associated
microbiota110,143,150,151. Antibiotic treatment can lead to overgrowth of infections therefore focus on preventively reducing the collateral
pre-existing pathogens, particularly when they are resistant to the damage through antibiotic stewardship, targeted antibiotics and
administered drug, and can also facilitate the translocation of strains personalized treatment, or on mitigating the infection risk associ-
between body sites. The true prevalence of antibiotic-associated ated with this collateral damage by infection control methods or
infections therefore remains unknown, but these are important to altering the microbiota to restore or improve colonization resist-
distinguish from treatment failures because there are many potential ance (Fig. 5). In the following sections, we describe these potential
strategies to reduce the unwanted collateral effect of antibiotics that strategies, highlighting their advantages and current limitations.
cause these infections, as detailed later in this Review.
Minimizing the collateral damage caused by antibiotics
Recovery of the microbiota following antibiotics Antibiotic stewardship. Antibiotic stewardship programmes to
Antibiotic-induced perturbations to the microbiota can be thought of promote the accurate use of antibiotics have been one of the major
as having both acute and chronic impacts. The strongest disruption approaches to reduce the occurrence of antibiotic-associated

Review article
Disruption of
Pretreatment microbiota Rapid initial Long-term
microbiota homeostasis recovery altered state
Commensal microbiota
Pre-existing resistant pathogen or pathobiont
Resistant commensal
Individualized response to antibiotics

Perturbation
Day 1 Week 1 Week 2 Year 1

Time
Antibiotic treatment
Fig. 4 | Recovery of the microbiota after antibiotic treatment ends. Perturbation levels, typically showing recovery within 2–8 weeks. However, recovery can be
of microbiota homeostasis is rapid upon antibiotic administration (left). incomplete, leading to long-lasting changes to species abundance, metabolic
Disruption of the intestinal microbiota occurs within a few days of treatment activity and antibiotic resistance levels. Both the initial disruption and subsequent
starting. After treatment ends, the microbiota rapidly returns towards baseline recovery can be highly distinct between different individuals (right).
infections155. These approaches include auditing, restriction of specific These resistance-gaining reinfections could be predicted based on
antibiotics, restriction of treatment duration and antibiotic cycling or antibiotic susceptibility data from the patient’s past infection history
mixing156. Although effective, such approaches have generally been and minimized by machine learning-personalized antibiotic recom-
limited to specific antibiotics associated with well-understood infec- mendations. Although these personalized medicine approaches offer
tions such as CDIs in hospital settings. For example, restrictions in the a promising means to reduce the within-host spread of resistant patho-
clinical use of drugs associated with a high risk of causing CDIs, such as gens and other unwanted adverse outcomes, they require significant
cephalosporins, clindamycin and fluoroquinolones, have been one suc- baseline knowledge of the patient’s medical history, which is often
cessful approach to limit CDIs155–157. In addition to antibiotic restriction, not available.
antibiotic cycling — in which treatment with a first preferred antibiotic
is followed by treatment with a second antibiotic of a different class but Targeted antibiotics. The collateral damage caused by antibiotics
with a similar spectrum of activity — has been proposed as an effective can be reduced by using more targeted drugs. This includes applying
strategy156. Clinical studies, however, have come to contradictory targeted drug delivery approaches to reduce the concentrations of
results regarding the true effectiveness of antibiotic cycling158. antibiotics at off-target body sites160,161. Pathogen-specific drugs162
and drug delivery approaches also offer a promising route to reduce
Personalized medicine. There is growing evidence that the response the collateral damage to other species163. An alternative strategy has
to antibiotics differs strongly between individuals, suggesting that been to use antibiotic combinations that are species specific164. Fur-
a more personalized approach to antibiotic prescribing could help thermore, antibiotics in combination with other drugs can specifically
reduce collateral damage. For example, a better understanding of antagonize the activity against abundant commensal species but not
antibiotic pharmacokinetics in individuals who fall outside typical against relevant pathogens. Using this approach, a study identified
weight and height ranges may help optimize drug dosing159. Data-driven ‘antidote’ drugs that selectively protected Bacteroides spp. from eryth-
approaches can also reduce the unwanted effects of antibiotics. In a romycin treatment in the gut microbiota of mice, while maintaining
study focusing on UTIs and wound infections, it was shown that anti- its efficacy against the opportunistic pathogen E. faecalis32. Potential
biotic treatment frequently led to rapid reinfection with a resistant therapeutics such as bacteriophages165 and bacteriocins166,167 can also
strain probably originating from the patient’s own microbiota148. have extremely narrow activity spectra. Bacteriophages are typically

Review article
a Minimizing collateral damage

Antibiotic stewardship Personalized medicine Targeted antibiotics
Targeted delivery Narrow spectrum
b Mitigating infection risk

Infection control Pathogen decolonization Restoring colonization resistance
Probiotic Feacal microbiota transplant
Fig. 5 | Strategies to minimize antibiotic-associated infections. a, The risk can also be reduced by mitigating the infection risk associated with antibiotic
of antibiotic-associated infections can be reduced by directly minimizing collateral damage via infection control strategies, decolonizing patients
the collateral damage caused by antibiotics through antibiotic stewardship, of potential pathogens, or altering the microbiota to restore or improve
personalized medicine approaches and better targeted antibiotics. b, This risk colonization resistance.
specific for a particular bacterial host; some bacteriophages can microorganisms has been demonstrated to restore colonization
infect several closely related species, but others are specific for a few resistance and clear infections82. So far, clinical trials have primarily
individual strains within a species168. Compared with small molecule focused on the use of probiotics to alleviate the risk of AAD and CDIs.
antibiotics, the vast natural reservoir of bacteriophages allows for One study, performing a meta-analysis of randomized controlled
personalized approaches by identifying bacteriophages that target clinical trials, reported that probiotics reduced the development
the exact strain causing an infection. Small-scale clinical studies have of AAD and CDIs4,5. CDIs can be cured by administration of a con-
resulted in the successful clearance of various antibiotic-resistant sortium of commensal gut species82. Unfortunately, due to limited
pathogens, including Mycobacterium abscessus169 and Acinetobacter regulation, probiotics with no evidence for their benefit in reducing
baumannii170. Likewise, antimicrobial peptides produced by bacte- antibiotic-associated infections are still used in clinical settings, and
ria, such as bacteriocins, can often have species-specific activity. For in some cases inappropriate use can do more harm than good173–175.
instance, the bacteriocin thuricin CD produced by Bacillus thuringiensis Nevertheless, various rationally designed live therapeutics show
is active against C. difficile, but has little impact on most intestinal promise for mitigating the antibiotic collateral damage in animal
commensals171. However, narrow-spectrum therapeutics may also not models. For example, a single-species probiotic has been shown
be a viable option for polymicrobial infections. Moreover, the use of to restore bile acid-mediated colonization resistance to CDIs84. An
narrow-spectrum drugs requires knowing which pathogen is present, engineered strain of Lactococcus lactis that secretes β-lactamase pro-
which can take days to discover so empirical broad-spectrum therapy vides community protection and prevented the loss of colonization
is commonly prescribed while waiting for results. As such, the wide- resistance against CDIs in ampicillin-treated mice62.
spread use of pathogen-targeted and narrow-spectrum therapeutics
also requires advancement in rapid pathogen detection technologies. Restoring colonization resistance with faecal microbiota trans-
plantation. Faecal microbiota transplantation (FMT) can result
Mitigating infection risk associated with antibiotic collateral in the establishment of a complex, donor-derived microbiota and
damage promote re-expansion of recipient bacterial species174. There have
Infection control measures. The risk of infection following antibiotic- been numerous randomized clinical trials documenting the effec-
induced loss of colonization resistance can be partially mitigated tiveness of FMT, particularly for treating chronic CDIs83,176. The
by reducing the exposure of these patients to potential pathogens. re-established microbiota can suppress C. difficile by competing for
Infection control measures, such as placing patients with CDIs in single- the same niche or enhancing innate immune defences177. FMT is also
patient rooms with a dedicated toilet, are standard guidelines in acute being explored as a prophylactic measure in patients at particularly
care settings172. Although such measures are important to reduce the high risk of antibiotic-associated infections. During stem cell trans-
spread of pathogens between patients, many antibiotic-associated plantation, antibiotic administration is essential for optimal clinical
infections occur from pathogens already present within the patient’s outcomes, but also leads to loss of many beneficial microorganisms
microbiota and, hence, require alternative mitigation strategies. and an increased risk of subsequent infections. Loss of gut micro-
biota diversity during stem cell engraftment increases mortality, but
Restoring colonization resistance with probiotics. Targeted admin- post-treatment FMT using autologously derived faecal microbiota
istration of live bacteria to compensate for loss of specific commensal has been shown to restore the intestinal microbiota composition178.

Review article
It should be noted, however, that insufficient screening of donor and are therefore important not just for improving treatment outcomes
faeces can also lead to recipient colonization and infection with at the individual-patient level but also for preventing the spread of
drug-resistant pathogens179 and that the long-term impacts of FMT resistant pathogens between individuals.
are currently poorly understood.
Published online: 4 August 2023
Decolonizing patients of potential pathogens. To mitigate the risk
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Antibiotics have transformed medicine, saving millions of lives since Introduction

Nature Reviews Microbiology | Volume 21 | December 2023 | 789–804 789

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a Drug-specific factors b Host-specific factors

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(continued from previous page)

Overgrowth of intrinsically resistant pathogens Infection from within

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Antibiotic Antibiotic Anti-anaerobic

Translocation to bloodstream Local disease

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Pre-existing resistant pathogen or pathobiont

Individualized response to antibiotics

Day 1 Week 1 Week 2 Year 1

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a Minimizing collateral damage

b Mitigating infection risk

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