International Journal of Antimicrobial Agents 34, S3 (2009) S6 S10

The tide of antimicrobial resistance and selection

Mark H. Wilcox*
Department of Microbiology, Leeds Teaching Hospitals NHS Trust, The General Inrmary, Old Medical School, Leeds LS1 3EX, UK

ARTICLE

INFO

Keywords:
Antibiotic resistance
Selection pressure
Tigecycline
Carbapenems
Meticillin-resistant Staphylococcus
aureus
Clostridium difcile

ABSTRACT
The cumulative ecological damage, both to the individual patient and to patient populations,
secondary to antibiotic prescribing is increasingly recognised. The impact of antibiotics on
pathogens and normal ora should be a criterion for antimicrobial selection. Measures to
reduce the use of third-generation cephalosporins and uoroquinolones should be considered.
Increased reliance on carbapenems may accelerate the emergence of extremely resistant
isolates, and these antimicrobials should be restricted to key scenarios. There is a clear
need for new agents with novel modes of action and low ecological damage potential
to treat nosocomial infections. Tigecycline has a spectrum of activity that theoretically
may reduce the selection pressure for key nosocomial pathogens, and represents an
alternative to carbapenems. Further studies are needed to conrm this potentially low
selection pressure.
2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Antibiotic-induced ecological damage

There is clear evidence that antibiotic choice is increasingly
limited by the relentless emergence of antimicrobial resistance. The largest recent increases in resistance prevalence
have been seen in cephalosporin- and uoroquinolone-resistant
Enterobacteriaceae, and in Acinetobacter baumannii that are
resistant to almost all available antibiotics. However, this is
part of a wider phenomenon of antibiotic-induced detrimental
ecological effects. Such collateral damage includes one
or more of the following adverse effects of antibiotic
therapy: the disturbance of normal ora, potentially with
unintended consequences; the selection of drug-resistant
organisms; and colonisation or infection with multidrugresistant organisms. 1
The analogy of squeezing a balloon is sometimes used to
describe collateral damage; thus, receipt of an antibiotic
(an event on one side of the balloon) triggers a reaction
among exposed bacteria (a resultant change elsewhere).
Repeated exposure to antibiotics, either in an individual
or in a patient population, leads to an accumulation of
these trigger reactions. Cumulative antibiotic resistance
and selection pressure are analogous to the algal blooms
that occur in aquatic systems because of nutrient excess;
i.e. a tide of resistance genes and/or altered ora. This
* Tel.: +44 (0)113 392 6818; fax: +44 (0)113 343 5649.
E-mail address: Mark.Wilcox@Leedsth.nhs.uk (M.H. Wilcox).
0924-8579/ $

comparison is useful, as it emphasises the increasing ecological

cost of antibiotic prescribing resulting from selection and
resistance pressure.
It is now not uncommon to see patients colonised with
meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and multiply resistant,
extended-spectrum b-lactamase- (ESBL) producing Enterobacteriaceae, and who are at risk of Clostridium difcile
infection. A related phenomenon is the co-selection pressure
of one antimicrobial class on another (e.g. the use of
uoroquinolones being a risk factor for the selection of ESBLproducing pathogens). The most common explanation for this
phenomenon is the co-location of resistance genes on a
transposable DNA element; thus, multiple resistance genes are
acquired, despite there being only one antimicrobial resistance
selection pressure. Such effects mean that key pathogens can
typically display resistance to multiple antimicrobial classes,
as demonstrated by Table 1. 2 These European surveillance
data demonstrate that resistance to three antibiotic classes
in Klebsiella spp. is more common than to only one or two
antibiotic classes. 2 Of major concern is the accumulating
evidence for the emergence and spread of carbapenem
resistance, threatening the conventional last line of antibiotic
defence. 3 This review considers the tide of antibiotic
resistance and selection pressures that are now severely
compromising our treatment choices.

see front matter 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

M.H. Wilcox / International Journal of Antimicrobial Agents 34 (2009) S6 S10

Table 1. Resistance and co-resistance in 10 046 invasive Klebsiella

pneumoniae isolates submitted to the European Antimicrobial Resistance
Surveillance System (EARSS) in 2007 a
Resistance phenotype
Fully susceptible
Resistant to one antibiotic class

% isolates
68.4
7.9

Fluoroquinolones

3.9

Third-generation cephalosporins

2.7

Aminoglycosides

1.3

Resistant to two antibiotic classes

9.3

Fluoroquinolones + third-gen. cephalosporins

1.6

Fluoroquinolones + aminoglycosides

3.4

Third-gen. cephalosporins + aminoglycosides

Resistant to three antibiotic classes
Fluoroquinolones + third-gen. cephalosporins + aminoglycosides

4.3
14.4
14.4
100

Resistance results shown only for three antibiotic classes, as reporting of

carbapenem susceptibility was not obligatory in EARSS in 2007. 2

2. ESBL risk and antimicrobial prescribing

There has been a several-fold increase in the frequency
of cephalosporin resistance during the last decade, to
levels that now threaten the safe empirical use of these
antibiotics for severe infection. 4 In 2007 in the UK (except
Scotland), 14% and 12% of bacteraemic Klebsiella spp.
and Escherichia coli, respectively, were resistant to thirdgeneration cephalosporins, compared with 6% and 2%,
respectively, in 2000. 5 These data hide some large interhospital and inter-regional variations in resistance prevalence
resulting from clonal spread. Even higher proportions
(approximately one-third) of Enterobacter spp. and related
species are cephalosporin resistant because of the production
of derepressed b-lactamases. 5 Fluoroquinolone resistance
in E. coli over the same time period increased from
5% to 23%, 5 which has effectively curtailed the use of these
antibiotics for severe infection unless prior susceptibility
has been documented. Many studies have described the
risk factors for infection by ESBL-producing bacteria. Length
of hospital stay, severity of illness, time in the intensive
care unit, intubation and mechanical ventilation, urinary or
arterial catheterisation, and exposure to antibiotics, especially
the oxyimino b-lactams, were signicantly associated with
infection by ESBL-producing bacteria. 6,7 Similarly, Colodner
et al. 8 found that hospitalisation in the past 3 months, receipt
of antibiotics in the past 3 months, age 60 years or older,
male gender, diabetes, infection with Klebsiella spp., and
treatment with second- or third-generation cephalosporins,
uoroquinolones or penicillins were signicantly associated
with ESBL-producing isolates. Crucially, however, of all these
risk factors only the choice of antimicrobial therapy is
prospectively amenable to manipulation for a given patient,
and thus can be exploited to reduce the chance of infection
with ESBL-producing bacteria.

S7

hitherto been the role of these antibiotics. Ironically, the

threat of resistance per se increases the potential that
carbapenems are prescribed, notably in complex patients
at risk of poor outcome. For example, the Surviving Sepsis
Campaign has rightly emphasised the early prescribing of an
antibiotic as crucial for increasing the chance of survival. 9
Carbapenems have been cited as ideal antibiotics to be
used in the patient who is displaying signs of sepsis,
although these would not provide cover against MRSA, a
common nosocomial pathogen. Unfortunately, to the less
experienced prescriber, the use of a carbapenem in this
setting may erroneously be translated into a perceived need
to use these agents in any patient with potentially resistant
pathogens and/or complicated infection. Such broader-scale
prescribing, in the context of hitherto rare carbapenemresistant potential pathogens, notably Enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter strains, will
exacerbate the selection pressure for these bacteria.
Of particular concern is the potential for rapid dissemination of carbapenem resistance. Notably, the spread
of K. pneumoniae and E. coli carrying plasmid-encoded
K. pneumoniae carbapenemase (KPC) has been reported. 10 12
In an early outbreak in New York, USA, of more than
600 K. pneumoniae that were characterised, almost half of
the isolates produced an ESBL and, of these, 3.3% were
carbapenem resistant (because of KPC-2 production). Two
hospitals experienced the rapid spread of these carbapenemresistant isolates among 58 patients. The crude 14-day
mortality in bacteraemic patients was 47%. 10 Subsequent
reports have highlighted the international occurrence of
carbapenem resistance. 3 Alerts have recently been issued in
the UK and the USA concerning the increased detection of
carbapenemase-producing bacteria. 13,14
In the UK, until the end of 2007, the Centre for Antibiotic
Resistance Monitoring and Reference Laboratory (ARMRL) in
London had only ever had eight UK isolates referred that
produced carbapenemases. This total more than doubled to
17 during 2008. 13 While these remain low numbers, there
is no place for complacency, not least because it is likely
that such isolates are far more common than this, as there
are no active surveillance schemes for carbapenemases.
Furthermore, the laboratory detection of carbapenemases
is not straightforward, and positive isolates may thus be
missed. 13,14 Of the 17 UK isolates, 16 were K. pneumoniae
(in particular two clones: ST258 and OXA-48). Most worrying,
no overseas link was identied in 12 of these 13 ; thus it would
appear that the majority of carbapenemase-producing isolates
seen in the UK are acquired and/or have their origin here.
The OXA-48 K. pneumoniae strains are only susceptible to
gentamicin, polymyxin and tigecycline.
By contrast with the relatively low numbers of carbapenemase-producing (fully carbapenem-resistant) isolates
referred to ARMRL to date, ertapenem-resistant Enterobacteriaceae are much more common (150 isolates). 13 This reects
the fact that it is biologically easier for resistance to develop
to ertapenem than to other carbapenems; production of an
ESBL coupled with impermeability secondary to porin changes
is sufcient to mediate resistance to the former.

3. Carbapenemase risk and antimicrobial prescribing

The importance of the threat of carbapenem resistance
and the selection of carbapenemase-producing bacteria is
underlined by the status of last line of defence that has

4. MRSA risk and antimicrobial prescribing

Prescribing uoroquinolones and third-generation cephalosporins provides a selection pressure for MRSA, and so, as

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M.H. Wilcox / International Journal of Antimicrobial Agents 34 (2009) S6 S10

these antibiotics are used more frequently, the prevalence

of MRSA in hospitalised patients increases. 15,16 Retrospective,
observational and modelling studies have described the association between MRSA and prior exposure to uoroquinolones
and cephalosporins, 15,16 but there is a lack of controlled
intervention studies to determine the effect that altering
antimicrobial prescribing has on the prevalence of MRSA. The
rate of MRSA isolation in one hospital in France decreased
signicantly, by comparison with three control hospitals, when
uoroquinolones were restricted for 1 year (32% vs. 37%
of S. aureus isolates were MRSA; odds ratio 0.82; 95% CI
0.69 0.99; P = 0.036). 17
A recent report from Switzerland examined the relationship
between MRSA incidence and both the consumption of
antibiotics and a hand-hygiene promotion campaign. 18 By using
a mathematical model to determine the effect of alcohol
hand-rub and antibiotic use on preventing and promoting,
respectively, MRSA incidence, it was estimated that these two
factors explained 57% of the variance in MRSA rates. This
nding emphasises the signicance of antimicrobial prescribing
(and conventional infection-control measures) in reducing the
risk of selecting for and disseminating nosocomial MRSA.
5. Clostridium difcile infection risk and antimicrobial
prescribing
Clostridium difcile infection (CDI) has become endemic
in many hospitals in Europe, the USA and Canada, and is
associated with excess length of stay, cost and mortality. 19
Altering antimicrobial prescribing has clearly been recognised
as a proven way to reduce the risk of CDI. Most studies
of the effectiveness of interventions to change antibiotic
prescribing are methodologically poor. 20,21 However, there is
clear evidence that restricting the use of broad-spectrum
antibiotics, specically cephalosporins or clindamycin, can
reduce CDI. 21 Crossover and long-term surveillance studies
on acute elderly medicine wards have shown that effective
restriction of third-generation cephalosporins is associated
with a reduction in incidence of CDI. 22 24
Both uoroquinolones and cephalosporins induce CDI in
a human gut model. 25,26 Conversely, neither piperacillin
tazobactam nor tigecycline cause proliferation of C. difcile
or toxin production in this model, despite clear perturbation
of gut ora secondary to their broad-spectrum activity. 27,28
The activity of piperacillin tazobactam and tigecycline (but
not uoroquinolones and cephalosporins) against common
C. difcile clones may at least partly explain this lack
of CDI induction. If an antibiotic has poor activity against
C. difcile and/or when its concentration in the gut lumen
decreases below that which will inhibit the bacteria, then
germination of C. difcile spores, if present, can occur.
Vegetative cells may then produce toxin before they enter the
next sporulation phase. It is possible that some antibiotics may
directly stimulate toxin production by C. difcile. It is also
evident that the relative resistance of a C. difcile strain to
an antibiotic may affect the population risk of selecting for
C. difcile.
The propensity of new antimicrobial agents to induce CDI
is often unclear given the limitations of prelicensing studies,
especially as these are not normally carried out in settings
endemic for C. difcile, and uncommonly include patients at
high risk of CDI. Nevertheless, clinical trial database searches

for evidence of CDI were performed on four phase 2 and

nine phase 3 studies of tigecycline. 29 CDI was very uncommon
following tigecycline administration, was associated with prior
exposure to other antibiotics, and was of a similar frequency
to that seen with comparator antibiotics (~0.2% of study
recipients). Further clinical data are desirable to conrm that
the extended broad-spectrum activity of tigecycline does not
result in increased risk of CDI.
6. Ecological damage potential affects antibiotic choice
As the consequences of the ecological damage caused by
antimicrobial therapy have become better understood, the
realisation has grown that these issues may be important
differentiators when choosing between antibiotics. Thus, the
traditional main factors that affect antibiotic choice (drug
activity, pharmacokinetics, adverse-effect prole) should be
augmented by consideration of the potential for ecological
damage. Unfortunately, this creates a complex matrix of
risk issues that should be considered. The reality is that
such complexity requires specialist advice (e.g. from medical
microbiologists or infectious disease physicians). Specialist
advice is particularly needed when choosing therapy for
the treatment of infection in patients at increased risk of
multiply antibiotic-resistant pathogens, typically because of
prior multiple antibiotic exposure, or known presence of
and/or contact with such bacteria.
However, the ecological damage caused by an antibiotic
prescription may extend far beyond the patient receiving the
drug. The potential for pathogen transmission means that
collateral damage may affect other individuals beyond the
index case, most evidently in the hospital setting. Thus,
highly transmissible bacteria and suboptimal infection control,
sometimes including insufcient capacity to isolate patients,
conspire to exacerbate the ecological damage associated with
antibiotic prescribing.
7. The (missing) antibiotic care-bundle
The recognition of the powerful effect of altering or restricting
antimicrobial prescribing in the control of CDI has not
been fully exploited to control other healthcare-associated
pathogens. Thus, conventional infection-control measures to
reduce the prevalence of healthcare-associated pathogens
have generally not included altering antimicrobial prescribing.
To their credit, Cooke and Holmes 30 coined the term missing
care-bundle when recognising this omission, in recognition
of the vogue for using healthcare bundles. These are key
elements that, when implemented together, improve the
delivery of clinical care. In the present context, optimisation
of antimicrobial prescribing can be considered to represent
the missing care-bundle to reduce the risk of healthcareassociated infection. The antibiotic care-bundle aims to
optimise treatment of the infection, and at the same time to
reduce the selective pressure for key pathogens in the index
patient and others. The antibiotic care-bundle comprises the
use of monotherapy, whenever possible, for initial (empirical)
treatment, optimising the dose and duration of antimicrobial
therapy (which requires daily review of the patient), and
performing a regular risk assessment to monitor the impact
of the antimicrobial prescribing policy (to identify special
problems that may need intervention).

M.H. Wilcox / International Journal of Antimicrobial Agents 34 (2009) S6 S10

MRSA

VRE

ESBL

MDR PA

S9

C.
difficile

Carbapenems
Piperacillintazobactam
3rd generation
cephalosporins
Fluoroquinolones

Clear evidence of
selection risk

No clinical activity;
potential to select

Borderline clinical activity

and/or selection risk

Fig. 1. Potential selection risks associated with the prescribing of major antimicrobial classes. 1,21,22,24,31 35 ESBL, extended-spectrum b-lactamase; MDR-PA,
multidrug-resistant Pseudomonas aeruginosa; MRSA, meticillin-resistant Staphylococcus aeruginosa; VRE, vancomycin-resistant enterococci.

Figure 1 illustrates the complexity of issues that need to

be taken into account when considering the potential for
resistance selection. These have been considered for the major
broad-spectrum antibiotic classes, with the exception of the
glycylcycline, tigecycline. The capacity of an antibiotic to
select for resistance is determined by multiple factors. Is
the antibiotic active against the main potential pathogens?
Does it reach the site where potential pathogens either
colonise or infect the patient? What is the risk of spontaneous
(mutational) resistance, acquisition of resistance genes
(plasmids, transposons, insertion sequences) or derepression
of resistance? What are the deleterious effects of the
antibiotic on commensal bacteria that may provide resistance
to colonisation and/or expansion of potential pathogens?
Figure 1 summarises the evidence for resistance selection pressure that exists for the common antimicrobial
classes. 1,21,22,24,31 35 Using MRSA as an example, cephalosporins
(excluding the anti-MRSA cephalosporins) and uoroquinolones
lack activity against (all or most, respectively) of the common
strains. Coupled with their broad-spectrum activity against
commensal bacterial ora, this creates a selection pressure
for MRSA that is already present, or soon acquired, to
proliferate. Such theoretical potential to select for MRSA
exists for piperacillin tazobactam and carbapenems, as these
agents are inherently inactive against these bacteria. However,
there is no robust evidence to substantiate this risk, possibly
reecting the differences in the effects on key commensal
ora of piperacillin tazobactam and carbapenems compared
with cephalosporins and uoroquinolones. Resistance selection
risks are not well dened for tigecycline, given that it has not
been available as long as the other classes. Also, tigecycline
has a unique spectrum of activity that includes Grampositive resistant pathogens (including MRSA and VRE), Gramnegative resistant pathogens (including most ESBL-producing
bacteria, but excluding Pseudomonas spp., Proteus spp.,
Providencia spp. and Morganella spp.), atypical bacteria and
anaerobes. This means that the theoretical risk of selection
of resistant pathogens should be lower with tigecycline than
with other broad-spectrum antibiotic classes, possibly helped
by the option of monotherapy with tigecycline, avoiding the

use of two- or three-drug combinations that incorporate the

other major broad-spectrum antibiotic classes. Clearly, further
experience with tigecycline will be required to conrm this
theoretical potential for low resistance selection pressure.
There is a clear need for new agents with novel modes of
action and low potential to cause ecological damage for the
treatment nosocomial infections.
Funding: MHW received an honorarium for writing this
article from Wyeth Pharmaceuticals.
Competing interests: MHW has received honoraria for
consultancy work, nancial support to attend meetings
and research funding from Bayer, Genzyme, Nabriva,
Novacta, Pzer, Targanta Therapeutics, ViroPharma and
Wyeth.
Ethics approval: Not required.
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