Antibiotics: A Selective Pressure at the Hospital
It is now accepted that excessive and improper antibiotic
use in hospitals has played a major role in the emergence
and rapid spread of antibiotic-resistant bacteria in humans.
Overuse/misuse of antibiotics was the major factor responsible for the development of nosocomial infections (hospitalacquired infections). Penicillin-resistant bacteria and
methicillin-resistant Staphylococcus aureus (MRSA) arose
within a few years of penicillin and methicillin introduction
in the 1940s and 1959, respectively (Taubes 2008). MRSA
are now common in clinical care settings but also appeared
a decade ago as community-acquired infections. Similarly,
in the 1980s the physicians responded to enterococci resistance by using vancomycin to treat enterococci infections.
Vancomycin-resistant Enterococcus was first reported in
1986, and the vanA gene soon spread throughout bacterial
species including the MRSA.
Within Gram-negative bacteria, Enterobacteriaceae
highly contribute to nosocomial and community-acquired
infections. Penicillin and its derivates were effective
treatments against these bacterial infections until the emergence of β-lactamase-producing strains. To counteract the
effect of these β-lactamases, novel classes of β-lactams were
then developed such as cephalosporins, carbapenems, or
monobactams. But new β-lactamases emerged rapidly, and
more than 300 enzymes are presently described (Kong et al.
2010). Moreover, the worldwide spread of extendedspectrum β-lactamases, such as SHV, TEM, and OXA
types, which conferred resistance to most β-lactams, as
well as carbapenemases, such as VIM and IMP types,
currently poses a major public health problem. These genes
are not only present among Enterobacteriaceae but are
also widespread among Pseudomonas aeruginosa or
Acinetobacter baumannii.
Opportunistic pathogens (i.e., ubiquitous bacteria infecting immuno-debilitated patients such as young children or
elderly people, cystic fibrosis individuals, severely burn, or
under chemotherapy patients) are becoming important new
emergent infectious agents. Among the most frequently
observed, Pseudomonas aeruginosa is characterized by a
high intrinsic resistance to antibiotics, thanks to a low permeability of its outer membrane, constitutive expression of
numerous efflux pumps, and production of various enzymes
enabling antibiotic inactivation (i.e., cephalosporinases).
It was estimated that 1.8 % of the genome of this species
contributes to its intrinsic resistance (Fajardo and Martı ´nez
2008). This species is also characterized by its important
ability to acquire new resistance determinants through
horizontal gene transfer (Mesaros et al. 2007). P. aeruginosa
as well as other opportunistic species (i.e., Acinetobacter
baumannii and Stenotrophomonas maltophilia) is developing resistance toward all available antibiotics (Taubes 2008).
Antibiotic Use Outside the Hospital
Similarly the use of antibiotics to treat animal diseases
and/or promote animal growth in livestock production
also contributed to the development of drug-resistant
infections among animals. Resistant bacteria from animal
food may be passed through the food chain to humans
resulting in resistant infections. A recent French survey of
antibiotic resistance among Escherichia coli, the most common pathogen isolated from cattle, pigs, goats, or horses,
evidenced a high level of resistance toward the oldest and
most frequently used antibiotics, amoxicillin and tetracyclines. It also showed numerous resistances toward betalactams including the third generation of cephalosporins
(cefotaxime, ceftazidime) and the presence of blaCTX-M
genes similar to those initially detected among E. coli strains
isolated from human. Furthermore, the presence of these
genes on plasmids that also carry resistance genes for other
antibiotics (florfenicol) suggests that the selective pressure
associated to one antibiotic can select for diverse unrelated
resistance mechanisms. In Europe, the use of the glycopeptide antibiotic avoparcin as a growth promoter for pig, and
thus its use at subtherapeutic levels, also led to an increase of
vancomycin-resistant enterococcus prevalence in animal but
also in human populations. Despite the ban of avoparcin as a
feed additive in some countries more than 10 years ago, a
recent study proved that acquired vancomycin-resistant gene
vanA can still be detected in food-producing animals raising
the question of gene persistence in the absence of the selective agent and its potential reemergence and risk for human
health.
Outside hospital and animal farms, the selective
pressure of antibiotics can also occur in various natural or
human-made environmental compartments and then
impact and modify the evolution rate of antibiotic resistance within indigenous microbial communities. High
concentrations of antibiotics are likely to occur in hospital
effluents, sewage treatment facilities, streams with large
amounts of agricultural runoff from livestock areas, or
aquaculture units. Most of them are not eliminated during
wastewater treatments due to some limits of present sewage
treatment plants. Manure and other animal farm effluents
also stand for an important source of veterinary products,
including antibiotics, in the environment. As many
antibiotics are poorly adsorbed in the guts, about 20–90 %
of the administered antibiotics are excreted rapidly after the
treatment (Kummerer 2003). Antibiotics such as tetracycline and tylosin have been detected in various animal
wastes, i.e., cattle or poultry manure and pig slurry. Values
as high as 0.50 mg.kg
À1 and 35.5 mg.kg
À1 for oxytetracycline and sulfachloropyridazine, respectively, in poultry
manures were reported. In chicken manure maximum
concentrations of enrofloxacin up to 2.8 mg.kg
À1 were
636
P. Lebaron et al.
It is now accepted that excessive and improper antibiotic
use in hospitals has played a major role in the emergence
and rapid spread of antibiotic-resistant bacteria in humans.
Overuse/misuse of antibiotics was the major factor responsible for the development of nosocomial infections (hospitalacquired infections). Penicillin-resistant bacteria and
methicillin-resistant Staphylococcus aureus (MRSA) arose
within a few years of penicillin and methicillin introduction
in the 1940s and 1959, respectively (Taubes 2008). MRSA
are now common in clinical care settings but also appeared
a decade ago as community-acquired infections. Similarly,
in the 1980s the physicians responded to enterococci resistance by using vancomycin to treat enterococci infections.
Vancomycin-resistant Enterococcus was first reported in
1986, and the vanA gene soon spread throughout bacterial
species including the MRSA.
Within Gram-negative bacteria, Enterobacteriaceae
highly contribute to nosocomial and community-acquired
infections. Penicillin and its derivates were effective
treatments against these bacterial infections until the emergence of β-lactamase-producing strains. To counteract the
effect of these β-lactamases, novel classes of β-lactams were
then developed such as cephalosporins, carbapenems, or
monobactams. But new β-lactamases emerged rapidly, and
more than 300 enzymes are presently described (Kong et al.
2010). Moreover, the worldwide spread of extendedspectrum β-lactamases, such as SHV, TEM, and OXA
types, which conferred resistance to most β-lactams, as
well as carbapenemases, such as VIM and IMP types,
currently poses a major public health problem. These genes
are not only present among Enterobacteriaceae but are
also widespread among Pseudomonas aeruginosa or
Acinetobacter baumannii.
Opportunistic pathogens (i.e., ubiquitous bacteria infecting immuno-debilitated patients such as young children or
elderly people, cystic fibrosis individuals, severely burn, or
under chemotherapy patients) are becoming important new
emergent infectious agents. Among the most frequently
observed, Pseudomonas aeruginosa is characterized by a
high intrinsic resistance to antibiotics, thanks to a low permeability of its outer membrane, constitutive expression of
numerous efflux pumps, and production of various enzymes
enabling antibiotic inactivation (i.e., cephalosporinases).
It was estimated that 1.8 % of the genome of this species
contributes to its intrinsic resistance (Fajardo and Martı ´nez
2008). This species is also characterized by its important
ability to acquire new resistance determinants through
horizontal gene transfer (Mesaros et al. 2007). P. aeruginosa
as well as other opportunistic species (i.e., Acinetobacter
baumannii and Stenotrophomonas maltophilia) is developing resistance toward all available antibiotics (Taubes 2008).
Antibiotic Use Outside the Hospital
Similarly the use of antibiotics to treat animal diseases
and/or promote animal growth in livestock production
also contributed to the development of drug-resistant
infections among animals. Resistant bacteria from animal
food may be passed through the food chain to humans
resulting in resistant infections. A recent French survey of
antibiotic resistance among Escherichia coli, the most common pathogen isolated from cattle, pigs, goats, or horses,
evidenced a high level of resistance toward the oldest and
most frequently used antibiotics, amoxicillin and tetracyclines. It also showed numerous resistances toward betalactams including the third generation of cephalosporins
(cefotaxime, ceftazidime) and the presence of blaCTX-M
genes similar to those initially detected among E. coli strains
isolated from human. Furthermore, the presence of these
genes on plasmids that also carry resistance genes for other
antibiotics (florfenicol) suggests that the selective pressure
associated to one antibiotic can select for diverse unrelated
resistance mechanisms. In Europe, the use of the glycopeptide antibiotic avoparcin as a growth promoter for pig, and
thus its use at subtherapeutic levels, also led to an increase of
vancomycin-resistant enterococcus prevalence in animal but
also in human populations. Despite the ban of avoparcin as a
feed additive in some countries more than 10 years ago, a
recent study proved that acquired vancomycin-resistant gene
vanA can still be detected in food-producing animals raising
the question of gene persistence in the absence of the selective agent and its potential reemergence and risk for human
health.
Outside hospital and animal farms, the selective
pressure of antibiotics can also occur in various natural or
human-made environmental compartments and then
impact and modify the evolution rate of antibiotic resistance within indigenous microbial communities. High
concentrations of antibiotics are likely to occur in hospital
effluents, sewage treatment facilities, streams with large
amounts of agricultural runoff from livestock areas, or
aquaculture units. Most of them are not eliminated during
wastewater treatments due to some limits of present sewage
treatment plants. Manure and other animal farm effluents
also stand for an important source of veterinary products,
including antibiotics, in the environment. As many
antibiotics are poorly adsorbed in the guts, about 20–90 %
of the administered antibiotics are excreted rapidly after the
treatment (Kummerer 2003). Antibiotics such as tetracycline and tylosin have been detected in various animal
wastes, i.e., cattle or poultry manure and pig slurry. Values
as high as 0.50 mg.kg
À1 and 35.5 mg.kg
À1 for oxytetracycline and sulfachloropyridazine, respectively, in poultry
manures were reported. In chicken manure maximum
concentrations of enrofloxacin up to 2.8 mg.kg
À1 were
636
P. Lebaron et al.