Andersson and Hughes 2011
Andersson and Hughes 2011
Andersson and Hughes 2011
Persistence Loss of
of resistance resistance
quantify the influence of resistance on bacterial fitness and and changes in population structure unrelated to antibiotic
to determine the relationships between fitness costs and selection) affecting the expected relationships and making
changes in the frequency of resistant pathogens. It is predictions less certain (Andersson & Levin, 1999; Austin &
noteworthy that acquired antibiotic-resistance traits are Anderson, 1999; Austin et al., 1999; Levin et al., 2000; Levin,
frequently found in bacteria isolated from humans and 2001; Andersson, 2003). Finally, we will describe the out-
animals that are not known to have been subjected to comes of laboratory studies and clinical interventions to
significant antibiotic exposure and that live in remote parts reduce the frequency of resistant bacteria at the community
of the world (Pallecchi et al., 2008). In this context, one of level and explain why reversibility, if it occurs at all, will
the most important issues is to understand how resistance is occur so slowly that it in most cases, it is unlikely to be of
stabilized in bacterial populations, in particular under practical importance.
environmental conditions where antibiotic selective pres-
sure may be very low or absent for significant periods of
time. In theory, resistance might be stabilized by (1)
Driving forces for reversibility
compensatory mutations that restore fitness without loss of When a resistance problem has been generated and the
resistance, (2) by the occurrence of rare cost-free resistance frequency of resistance has reached a level that prohibits the
mutations or (3) by genetic linkage and coselection between successful use of empirical therapy, any potential for rever-
resistance mutations and other selected genetic markers (e.g. sibility of the problem will be determined by essentially
virulence factors or resistances) as well as by other factors two factors – dilution and the fitness cost – depending on
(Fig. 1). There is experimental evidence that supports the whether one considers open or closed systems. Examples of
relevance of each of these stabilization mechanisms and we an open system would be a hospital or an animal farm where
will discuss some examples in later sections. There are also a there is a continuous in- and out-flow of humans or animals
number of theoretical studies modeling the relationship and where the incoming population has a lower frequency of
between the biological cost of resistance, the rate by which resistance than the resident population (which is generally
resistance develops and the steady-state frequency of resis- exposed to a higher antibiotic pressure). If antibiotic use is
tance at a given antibiotic pressure as well as the rate by reduced in the hospital/animal farm, the driving force for
which resistance is predicted to disappear if antibiotic use is reversibility is essentially a dilution effect where the incom-
reduced (Levin et al., 1997; Andersson & Levin, 1999; Austin ing population reduces the frequency of resistance in the
& Anderson, 1999; Austin et al., 1999; Levin et al., 2000; hospital/farm. This notion is supported by mathematical
Levin, 2001, 2002; Andersson, 2003). In addition, there are modeling (Austin & Anderson, 1999; Lipsitch et al., 2000;
factors that will confound these models (e.g. clonal shifts Bonten et al., 2001) as well as by clinical interventions where
c 2011 Federation of European Microbiological Societies FEMS Microbiol Rev 35 (2011) 901–911
Published by Blackwell Publishing Ltd. All rights reserved
Persistence of antibiotic resistance 903
quite rapid (weeks to months) reductions in resistance can Sub-MIC selective window
be observed after the use of specific antibiotic has been MSC
decreased (McGowan, 1986; Mahamat et al., 2007; Aldeyab Selective window
et al., 2008). In a closed system, for example in a community
Growth
where migration is limited, the main factor determining Resistant
whether antibiotic-resistant populations can be displaced MICsusc MICres
with antibiotic-susceptible ones is the biological fitness cost Susceptible
of resistance, i.e. any effect the resistance mechanism has on
reducing the ability of the pathogen to reproduce and spread
Antibiotic concentration
in the host population. Both theoretical arguments (Levin
et al., 1997, 2000; Levin, 2001; De Gelder et al., 2004) and Fig. 2. Schematic representation of growth rates as a function of
of genetic linkage, the frequency of resistance to a particular mycin-resistant Streptococcus pyogenes while in Iceland a
antibiotic could in theory remain stable or even increase in decrease in Streptococcus pneumoniae resistant to penicillin
environments where the antibiotic might not currently be in followed a decrease in the use of antibiotics in children a
use. The causes governing the dynamics of an unselected couple of years earlier. However, later reanalysis of the data
resistance marker in a bacterial population could be many. suggested that for both studies, the reduction might have
Selection might be for another resistance determinant or for been caused by clonal replacements unrelated to the reduc-
a determinant of clonal fitness not directly related to tion in antibiotic use (Kataja et al., 1999; Arason et al.,
antibiotic resistance. Regardless of the particular cause, the 2002). The actual driving force for this clonal replacement is
implication of coselection is that those strains that increase not known, but logic suggests that it is likely to be a
in the population do so because they are more fit in the consequence of the different fitness profiles of the different
presence of the antibiotics that are in use. There are clones involved; however, this has not been tested.
c 2011 Federation of European Microbiological Societies FEMS Microbiol Rev 35 (2011) 901–911
Published by Blackwell Publishing Ltd. All rights reserved
Persistence of antibiotic resistance 905
recently been demonstrated with regard to resistance to are serially passaged, compensatory mutations are easily
fluoroquinolones in E. coli (Marcusson et al., 2009). Resis- selected, although the degree of restoration varies and is
tance to fluoroquinolones develops in E. coli in a multistep usually below that of the original susceptible strain. How-
process, typically including the acquisition of efflux muta- ever, in principle, by the reiteration of cycles of selective
tions and several different mutations altering drug-target compensation, resistant clones could become as fit as
proteins (Heisig, 1996; Komp Lindgren et al., 2003, 2005). In susceptible clones. Accordingly, genetic compensation could
addition, there is increasing evidence that a large variety of act to stabilize and maintain resistant populations even in
fluoroquinolone-resistance genes and mechanisms can be the absence of antibiotic selection. The details of which
acquired by HGT events (Martinez-Martinez et al., 1998; mutations will be associated with genetic compensation for
Robicsek et al., 2006; Perichon et al., 2007; Jacoby et al., any particular drug–bacteria combination should depend
2008). Each individual resistance mutation, gene or me- on the interplay of mutation rates, fitness of different
many bacteria from duplicate tufA and tufB genes (Hughes, Bouma & Lenski, 1988; Smith & Bidochka, 1998; Johnsen
1990). Depending on the type of selection pressure that is et al., 2002; Dahlberg & Chao, 2003). The nature of these
imposed, either for increased drug resistance, or for in- costs may vary and, in most cases, has not been determined,
creased fitness, the process of tuf gene conversion can either but it is likely that the costs are strongly associated with the
copy a resistance mutation to the second tuf gene or it can disruptive physiological effects of introducing multiple new
restore a wild-type sequence to both tuf genes (Abdulkarim biochemical pathways into the host bacteria. Compensatory
& Hughes, 1996; Hughes, 2000). This makes the develop- evolution following plasmid acquisition by naı̈ve E. coli has
ment of resistance to drugs that target the products of been shown experimentally to occur both on the plasmid
repetitive genes (such as rRNAs and EF-Tu) highly unstable. and on the chromosome and to create genetic combinations
On the one hand, resistance is very unlikely to arise in one for which fitness would be reduced if the plasmid were
step because it is recessive and would require multiple subsequently lost (Dahlberg & Chao, 2003). In such situa-
c 2011 Federation of European Microbiological Societies FEMS Microbiol Rev 35 (2011) 901–911
Published by Blackwell Publishing Ltd. All rights reserved
Persistence of antibiotic resistance 907
setting as initially feared and the number of MRSA strains or the presence of other mechanisms that ensure persistence.
that are also resistant to vancomycin remains very small Apart from the previously mentioned processes (1–6),
(Perichon & Courvalin, 2009). Pairwise comparisons of which can confer persistence to both chromosome- and
isogenic MRSA strains with and without three different plasmid-encoded resistance mechanisms, there exist several
clinical isolates of the VanA resistance operon showed that plasmid-specific mechanisms that ensure plasmid mainte-
when induced, the fitness cost was large and reduced the nance even in the absence of direct selection. For example,
growth rates by 20–38% (Foucault et al., 2009). In contrast, several interesting cases have been described where plasmids
in the absence of induction, the fitness cost of carrying the confer increased fitness in the form of faster growth rates in
VanA operon was only 0.04–0.3%. Thus, VanA-type resis- the absence of any selective pressures. Thus, both conjuga-
tance can persist because it has a low cost in the absence of tive and nonconjugative plasmids (carrying various antibio-
the drug and although it is costly in absolute terms when tic resistance genes) can substantially increase bacterial
mechanisms would be associated with a high fitness cost and Austin DJ & Anderson RM (1999) Studies of antibiotic resistance
where the expected rate and/or the extent of genetic within the patient, hospitals and the community using simple
compensation would be low. A second possibility is to apply mathematical models. Philos T Roy Soc B 354: 721–738.
our growing understanding of the physiological basis for Austin DJ, Kristinsson KG & Anderson RM (1999) The
fitness costs associated with resistance, to design novel relationship between the volume of antimicrobial
therapies, possibly involving drug combinations, to target consumption in human communities and the frequency of
any Achilles heel associated with a particular resistance resistance. P Natl Acad Sci USA 96: 1152–1156.
mechanism. Finally, the knowledge we are accumulating of Bahl MI, Hansen LH & Sorensen SJ (2009) Persistence
the dynamics and mechanisms of antibiotic resistance mechanisms of conjugative plasmids. Methods Mol Biol 532:
development should be integrated into mathematical mod- 73–102.
Baquero F, Negri MC, Morosini MI & Blazquez J (1997) The
els that can predict the effects of different drug-dosing
c 2011 Federation of European Microbiological Societies FEMS Microbiol Rev 35 (2011) 901–911
Published by Blackwell Publishing Ltd. All rights reserved
Persistence of antibiotic resistance 909
Cohen T, Sommers B & Murray M (2003) The effect of drug Heisig P (1996) Genetic evidence for a role of parC mutations in
resistance on the fitness of Mycobacterium tuberculosis. Lancet development of high-level fluoroquinolone resistance in
Infect Dis 3: 13–21. Escherichia coli. Antimicrob Agents Ch 40: 879–885.
Cosgrove SE (2006) The relationship between antimicrobial Helms M, Vastrup P, Gerner-Smidt P & Molbak K (2002) Excess
resistance and patient outcomes: mortality, length of hospital mortality associated with antimicrobial drug-resistant
stay, and health care costs. Clin Infect Dis 42 (suppl 2): Salmonella typhimurium. Emerg Infect Dis 8: 490–495.
S82–S89. Hossain A, Reisbig MD & Hanson ND (2004) Plasmid-encoded
Criswell D, Tobiason VL, Lodmell JS & Samuels DS (2006) functions compensate for the biological cost of AmpC
Mutations conferring aminoglycoside and spectinomycin overexpression in a clinical isolate of Salmonella typhimurium.
resistance in Borrelia burgdorferi. Antimicrob Agents Ch 50: J Antimicrob Chemoth 53: 964–970.
445–452. Hughes D (1990) Both genes for EF-Tu in Salmonella
Levin BR (2001) Minimizing potential resistance: a population Meka VG, Pillai SK, Sakoulas G, Wennersten C, Venkataraman L,
dynamics view. Clin Infect Dis 33 (suppl 3): S161–S169. DeGirolami PC, Eliopoulos GM, Moellering RC Jr & Gold HS
Levin BR (2002) Models for the spread of resistant pathogens. (2004b) Linezolid resistance in sequential Staphylococcus
Neth J Med 60 (suppl): 58–64; discussion 64–66. aureus isolates associated with a T2500A mutation in the 23S
Levin BR, Lipsitch M, Perrot V, Schrag S, Antia R, Simonsen L, rRNA gene and loss of a single copy of rRNA. J Infect Dis 190:
Walker NM & Stewart FM (1997) The population genetics of 311–317.
antibiotic resistance. Clin Infect Dis 24 (suppl 1): S9–S16. Morosini MI, Ayala JA, Baquero F, Martinez JL & Blazquez J
Levin BR, Perrot V & Walker N (2000) Compensatory mutations, (2000) Biological cost of AmpC production for Salmonella
antibiotic resistance and the population genetics of adaptive enterica serotype Typhimurium. Antimicrob Agents Ch 44:
evolution in bacteria. Genetics 154: 985–997. 3137–3143.
Lew W, Pai M, Oxlade O, Martin D & Menzies D (2008) Initial Nagaev I, Bjorkman J, Andersson DI & Hughes D (2001)
c 2011 Federation of European Microbiological Societies FEMS Microbiol Rev 35 (2011) 901–911
Published by Blackwell Publishing Ltd. All rights reserved
Persistence of antibiotic resistance 911
Sandegren L & Andersson DI (2009) Bacterial gene amplification: resistance after a drastic reduction in trimethoprim use.
implications for the evolution of antibiotic resistance. Nat Rev J Antimicrob Chemoth 65: 350–360.
Microbiol 7: 578–588. Thiele-Bruhn S (2003) Pharmaceutical antibiotic compounds in
Sander P, Springer B, Prammananan T, Sturmfels A, Kappler M, soils – a review. J Plant Nutr Soil Sc 166: 145–167.
Pletschette M & Bottger EC (2002) Fitness cost of Tubulekas I & Hughes D (1993) Suppression of rpsL phenotypes
chromosomal drug resistance-conferring mutations. by tuf mutations reveals a unique relationship between
Antimicrob Agents Ch 46: 1204–1211. translation elongation and growth rate. Mol Microbiol 7:
Seppälä H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, 275–284.
Lager K & Huovinen P (1997) The effect of changes in the Willems RJ, Top J, van Santen M, Robinson DA, Coque TM,
Baquero F, Grundmann H & Bonten MJ (2005) Global
consumption of macrolide antibiotics on erythromycin
spread of vancomycin-resistant Enterococcus faecium from
resistance in group A streptococci in Finland. Finnish Study
distinct nosocomial genetic complex. Emerg Infect Dis 11:
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