Available via license: CC BY 2.0
Content may be subject to copyright.
R E S E A R C H A R T I C L E Open Access
A systematic review and meta-analysis of the
effects of antibiotic consumption on antibiotic
resistance
Brian G Bell
1*
, Francois Schellevis
2,3
, Ellen Stobberingh
4
, Herman Goossens
5
and Mike Pringle
1
Abstract
Background: Greater use of antibiotics during the past 50 years has exerted selective pressure on susceptible
bacteria and may have favoured the survival of resistant strains. Existing information on antibiotic resistance
patterns from pathogens circulating among community-based patients is substantially less than from hospitalized
patients on whom guidelines are often based. We therefore chose to assess the relationship between the antibiotic
resistance pattern of bacteria circulating in the community and the consumption of antibiotics in the community.
Methods: Both gray literature and published scientific literature in English and other European languages was
examined. Multiple regression analysis was used to analyse whether studies found a positive relationship between
antibiotic consumption and resistance. A subsequent meta-analysis and meta-regression was conducted for studies
for which a common effect size measure (odds ratio) could be calculated.
Results: Electronic searches identified 974 studies but only 243 studies were considered eligible for inclusion by the
two independent reviewers who extracted the data. A binomial test revealed a positive relationship between
antibiotic consumption and resistance (p < .001) but multiple regression modelling did not produce any significant
predictors of study outcome. The meta-analysis generated a significant pooled odds ratio of 2.3 (95% confidence
interval 2.2 to 2.5) with a meta-regression producing several significant predictors (F(10,77) = 5.82, p < .01). Countries
in southern Europe produced a stronger link between consumption and resistance than other regions.
Conclusions: Using a large set of studies we found that antibiotic consumption is associated with the
development of antibiotic resistance. A subsequent meta-analysis, with a subsample of the studies, generated
several significant predictors. Countries in southern Europe produced a stronger link between consumption and
resistance than other regions so efforts at reducing antibiotic consumption may need to be strengthened in this
area. Increased consumption of antibiotics may not only produce greater resistance at the individual patient level
but may also produce greater resistance at the community, country, and regional levels, which can harm individual
patients.
Keywords: Antibiotic resistance, Antibiotic usage, Community-acquired infections, Meta-analysis
* Correspondence: brian.bell@nottingham.ac.uk
1
Division of Primary Care, University of Nottingham, University Park,
Nottingham NG7 2RD, UK
Full list of author information is available at the end of the article
© 2014 Bell et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Bell et al. BMC Infectious Diseases 2014, 14:13
http://www.biomedcentral.com/1471-2334/14/13
Background
In the absence of the development of new generations of
antibiotic drugs, appropriate use of existing antibiotics is
needed to ensure the long term availability of effective
treatment for bacterial infections [1]. If antibiotics be-
come ineffective, then established and newly emerging
infectious diseases, which are becoming an increasing
threat, may lead to increased morbidity, health care util-
isation and premature mortality [2-4].
Unfortunately, greater use of antibiotics during the
past 50 years has exerted selective pressure on suscep-
tible bacteria and may have favoured the survival of re-
sistant strains [5], some of which are resistant to more
than one antibiotic. If excessive antibiotic use can be re-
duced, the expectation is that resistant bacteria may be
replaced by susceptible bacteria because resistant bac-
teria may be less ‘fit’than susceptible bacteria [6].
More than 90% of antibiotics for medical use in
Europe are prescribed to non-hospitalized patients [7].
However, existing information on antibiotic resistance
patterns from pathogens circulating among community-
based patients is substantially less than from hospitalized
patients on whom guidelines are often based. We there-
fore chose to assess the relationship between the anti-
biotic resistance pattern of bacteria circulating in the
community and the consumption of antibiotics in the
community. Although Costelloe [8] et al. studied the re-
lationship between consumption and resistance in pri-
mary care, they examined studies at the individual
patient level only, omitting ecological studies (those con-
ducted at the supra-individual level) which are included
in this review. In this paper, we present a systematic re-
view and meta-analysis of the literature on the relation-
ship between antibiotic consumption in outpatient
settings and antibiotic resistance of pathogens circulat-
ing in the community.
Methods
Search strategy
We searched both the English and non-English language
literature for studies that looked at the relationship be-
tween antibiotic resistance and human antibiotic con-
sumption in the community. An attempt was made to
find the grey literature and published scientific literature
in English, Spanish, French, German, Hungarian, Dutch,
Swedish, and Croatian. These languages were chosen be-
cause the corresponding European countries were in-
volved in the current project (Appropriateness of
Prescribing Antibiotics in Primary Health Care with re-
spect to Antibiotic Resistance). Search engines, such as
Google Scholar, Embase, and Medline, were used to find
published literature with reference lists of relevant arti-
cles searched by hand. Medline was searched from 1950
to late 2010 while Embase was searched from 1980 to
late 2010. A list of search terms and connectors, which
were used for both the English and non-English
searches, can be found in Appendix 1.
Study selection
We selected studies where a) the bacteria were acquired,
and antibiotic consumption was measured, in the com-
munity b) the majority of the participants did not have a
serious illness such as HIV or cancer c) the interval be-
tween consumption and resistance was one month or
greater because we wanted to examine whether there
was an enduring association between consumption and
resistance and d) a statistical link between consumption
and resistance was tested. Studies that presented de-
scriptive information and made no attempt to establish a
statistical connection between consumption and resist-
ance were not included in the analysis. No limits were
placed on when the study was published and few restric-
tions were placed on the type of study methodology, so
both observational and experimental studies were
included.
The level of analysis for any given study ranged from
the individual patient (or individual bacterial isolate)
level to the country (or groups of countries) level. Stud-
ies examined either children or adults or both, there
were no restrictions on which body sites were sampled
for establishing bacterial resistance or how antibiotic
consumption was measured, and all bacteria and all anti-
biotics were considered relevant. Studies undertaken
anywhere in the world were included with both English
and non-English articles retrieved for our review. The
list of the criteria we used to exclude studies is provided
in Appendix 2.
To minimise the tendency to include studies that only
reported significant results, we systematically searched
the grey literature and included studies in which the pri-
mary focus of the article was not on the relationship be-
tween antibiotic consumption and antibiotic resistance.
Abstracts were examined with full articles obtained and
translated if the study looked relevant. When questions
arose in applying the exclusion criteria, the authors re-
solved any disagreements through discussion.
Data extraction
Full articles were examined for quality and data were in-
dependently extracted by the authors using purpose-
built forms that listed the relevant variables. Any dis-
agreements were resolved by discussing the articles and
reaching consensus. Explanatory variables that were ex-
tracted from the studies are listed in Table 1.
The main dependent variable was a dichotomous cod-
ing of study outcome based on whether or not the art-
icle supported a positive relationship between antibiotic
consumption and antibiotic resistance. A positive
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 2 of 25
http://www.biomedcentral.com/1471-2334/14/13
Table 1 Explanatory variables
Variable Number (percentages in parenthesis) total sample = 243
Outcome Positive 164 (67%)
Negative or equivocal 79 (33%)
Level of sampling Individual 72 (30%)
Region/Country 124 (51%)
Other 47 (19%)
Level of analysis Individual 178 (73%)
Region/Country 53 (22%)
Other 12 (5%)
Children/Adults Children 88 (36%)
Adults 62 (26%)
Both 93 (38%)
Bacteria* Streptococcus 132 (54%)
Staphylococcus 50 (21%)
Enteric Bacteria 69 (28%)
Haemophilus 24 (10%)
Other 17 (7%)
Most common bacteria/Drug combinations** B-lactam resistant S pneumonia 104 (43%)
Macrolide resistant S pneumonia 56 (23%)
Quinolone resistant E coli 41 (17%)
B-lactam resistant E coli 35 (14%)
Sulphonamide resistant E coli 31 (13%)
Methicillin-resistant S aureus 38 (16%)
Most common antibiotics consumed*** B-lactams 132 (54%)
Macrolides 93 (38%)
Sulphonamides 59 (24%)
Quinolones 52 (21%)
Antibiotic not specified 65 (27%)
Time between consumption and resistance^ Six months or less 129 (53%)
More than 6 months 57 (23%)
Same time 43 (18%)
Not specified 14 (6%)
How antibiotic consumption was assessed# Self report 99 (41%)
Medical records 92 (38%)
Sales/Prescriptions 65 (27%)
Direct application of antibiotic 14 (6%)
Region where study was conducted## Northern Europe 66 (27%)
Southern Europe 45 (18%)
US 67 (28%)
Other 61 (25%)
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 3 of 25
http://www.biomedcentral.com/1471-2334/14/13
relationship could be represented by either increased
consumption associated with increased resistance or de-
creased consumption associated with decreased resist-
ance. A negative relationship could be represented by
either the absence of a significant relationship between
consumption and resistance or, in rare instances, a truly
negative relationship, such as increased consumption as-
sociated with decreased resistance. Studies that did not
clearly provide either positive or negative evidence were
combined with studies that produced a negative relation-
ship to form a not-positive category which was com-
pared with the positive studies in the data analysis.
Studies were classified as positive or negative based on a
preponderance of the evidence with a positive outcome
recorded when an increase in antibiotic consumption
was associated with either an increase in resistant bac-
teria or a decrease in susceptible bacteria. For the meta-
analysis the dependent variable was the odds ratio for
the study based on the standardized effect size.
Data analysis
We wanted to use all of the studies in our analysis in
order to improve power and examine whether a relation-
ship between antibiotic consumption and antibiotic re-
sistance existed for the complete set of data, so we first
ran simple correlations and a logistic regression because
the data did not generally lend themselves to a meta-
analytic approach. The studies were heterogeneous with
study design and effect size measures varying greatly be-
tween studies. Furthermore, a single effect size could
not be calculated for many studies because numerous
associations between consumption and resistance were
reported and simple averaging of effect sizes for any
given study was not appropriate. For those studies (N =
88) for which a single effect size measure could be ob-
tained a meta-analysis and meta-regression analysis were
conducted.
We ran a series of correlations between each of the ex-
planatory variables and the dichotomous outcome
variable in order to reduce the number of predictors in
the subsequent regression and ensure that the number
of cases (studies) relative to the number of predictors
was adequate. Variables that were significantly correlated
at this level were used in a logistic regression and en-
tered in a single step to predict whether a positive or
negative relationship was found between consumption
and resistance. A binomial test was also run to see
whether a significantly greater number of positive associ-
ations between consumption and resistance were found
in the studies. The binomial test examined whether the
proportion of studies with a positive association between
consumption and resistance significantly differed from
the proportion of studies with a positive association that
would be expected under the null hypothesis. The pro-
portion under the null hypothesis (no association be-
tween resistance and consumption) was 50% (i.e., the
probability of a positive association was equal to the
probability of a non-positive association). For a subset of
the studies, a meta-analysis and subsequent meta-
regression analysis were run. Analyses were conducted
in SPSS version 16 and Stata version 11.2.
Results
Application of exclusion criteria
To arrive at the studies that formed the basis of our ana-
lysis (see Figure 1), we searched the English language lit-
erature and identified 745 studies that appeared relevant.
However, 503 studies (68%) did not meet our inclusion
criteria. Most of the excluded studies (over 95%) were
eliminated for one of the following five reasons: meth-
odological weaknesses (N = 213) such as no attempt to
statistically analyse the data, review article or editorial
(N = 82), study did not measure either resistance or con-
sumption (N = 62), hospital study or the patients were
too ill (N = 80), and short interval (less than a month)
between the measurement of consumption and resist-
ance (N = 54). Altogether 242 English-language studies
or 32% (239 published studies and 3 grey literature
Table 1 Explanatory variables (Continued)
Type of study Cross-sectional 101 (42%)
Ecological 56 (23%)
Case–control 35 (14%)
Quasi-experiment 21 (9%)
Other 30 (12%)
*Percentages do not equal 100% as any given study may have examined more than one type of bacteria.
**Percentage do not equal 100% as any given study may have examined more than one combination; resistant and non-susceptible strains of S pneumonia are
combined under the resistant label for this bacterium.
***Percentages do not equal 100% as any given study may have examined more than one antibiotic.
^This variable represents the maximum time interval in any given study between when consumption occurred and resistance was measured. Studies classified as
‘same time’tended to be ecological studies where the precise interval separating consumption and resistance could not be determined, these studies often
simply reported consumption and resistance occurring together over some multi-year interval.
#Percentages do not equal 100% as any given study may have used more than one method.
##The total equals 239 as three studies were conducted in both southern Europe and northern Europe and one study was coded as not applicable.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 4 of 25
http://www.biomedcentral.com/1471-2334/14/13
documents) of the 745 originally identified studies were
considered relevant. A list of excluded studies is avail-
able from the authors upon request.
Searches conducted by colleagues in other countries
revealed 229 studies that appeared relevant, but only
one of these studies was included in our analysis. Non-
English articles were excluded, with three exceptions, be-
cause either a version of the study had already been ob-
tained in English or the study did not provide statistical
analysis of a link between antibiotic consumption and
resistance in the community. The relevant non-English
language article (Appendix 3: Dellamonica et al 2002)
along with the 242 English language articles provided us
with a total of 243 studies that formed the basis of our
analysis.
Study characteristics
Table 1 shows the number of studies that fell into vari-
ous categories for the 243 studies included in the final
analysis. More than two-thirds of the studies found a
positive relationship between antibiotic resistance and
antibiotic consumption. Most of the studies (51%) sam-
pled data at the regional or country level but analysed
data at the individual level (73%) which means that data
from individual participants were often sampled from
some larger unit, such as an entire country.
With few exceptions, the bacteria that were studied fell
into one of three classes (Streptococcus,Staphylococcus,
or Enteric bacteria, such as E coli). The most common
classes of antibiotics for which consumption was mea-
sured included B-lactams, macrolides, sulphonamides,
and quinolones although more than a quarter of the
studies did not specify which antibiotics had been
consumed.
The studies in our sample were usually conducted in
either Europe or the US. More studies took place in
northern Europe than in southern Europe although both
regions were well represented. Almost 80% of the studies
used one of three study designs: cross-sectional, eco-
logical, or case–control.
Predicting study outcome
We used the binomial test to examine whether there
were more studies that produced a positive outcome in
which either increased consumption was associated with
increased resistance or decreased consumption associ-
ated with decreased resistance. The binomial test re-
vealed that the probability of a positive outcome was
significantly greater than the probability of an outcome
that was not positive (p < .001).
We next examined the correlations between the pre-
dictor variables listed in Table 1 and our dichotomous
outcome measure. Each of the categorical variables listed
in Table 1 was turned into a set of dichotomous vari-
ables for this purpose. For example, the adult/child vari-
able was recoded into three dichotomous variables, one
Figure 1 How studies were selected.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 5 of 25
http://www.biomedcentral.com/1471-2334/14/13
representing children, another representing adults, and a
third representing both children and adults.
Three positive correlations were found: studies that
included both adults and children were more likely to
find a positive association between antibiotic consump-
tion and resistance (r = 0.17, p < .01) as were studies that
examined tetracycline-resistant Spneumonia(r = 0.14,
p < .05) and those that looked at quinolone consump-
tion (r = 0.15, P < .05). Three negative correlations were
also produced: for studies that only contained children
(r = −0.13, p < .05), those conducted in the US (r = −0.16,
p < .05) and cross-sectional studies (r = −0.15, p < .05).
Studies which contained children, those conducted in
the US, and cross-sectional studies were more likely to
find a small, either negative or not positive, associ-
ation between antibiotic consumption and antibiotic
resistance.
All of the variables for which significant correlations
were found were simultaneously entered into a logistic
regression equation to predict study outcome. None of
the variables that produced significant bivariate correla-
tions were significant predictors in the logistic regression
equation, although as a set, they did significantly predict
the outcome variable (chi-square = 22.81, df = 6, p < .01)
thereby distinguishing between studies with a positive
association and other studies. However, only a little
more than 10% of the variance in the outcome variable
was explained by these predictors (Nagelkerke R
2
=0.12).
We noticed that the relationship between consump-
tion and resistance often varied within a study depend-
ing on which bacteria were being considered. So, a study
that looked at multiple types of bacteria may have found
a positive relationship between consumption and resist-
ance for one but a negative relationship for another. Our
global outcome measure did not allow us to investigate
these differences because it was based on the preponder-
ance of evidence across bacterial classes for any given
study. Therefore, we decided to conduct a separate
analysis for each bacterial category (Streptococcus,
Staphylococcus, Enteric Bacteria, and Haemophilus/
Other). We recoded the outcome measure for those
studies that contained more than one type of bacteria so
that the outcome measure in any given analysis was
based on the relationship between consumption and re-
sistance for a single type of bacteria.
First, looking at the results from the binomial tests,
we found that only enteric bacteria and streptococcus
produced significantly morepositiveoutcomesthan
negative outcomes (p < .01 for enteric bacteria and
p < .001 for streptococcus). For Staphylococcus and
Haemophilus/Other, the results from the binomial
tests were not significant. Therefore, we decided
to focus on enteric bacteria and streptococcus in
subsequent analyses.
When correlations were run for the streptococcus bac-
teria, only two variables out of 48 were significantly
correlated with outcome. Tetracycline resistant S
pneumonia was significantly correlated with the out-
come variable (r = 0.19, p < .05) and so was trimethoprim
consumption (r = −0.23, p < .01). However, this is prob-
ably due to chance as the number of significant correla-
tions was less than 5% of the total number of
correlations that were run, so a logistic regression was
not conducted. In a similar vein, only two correlations
were significant for enteric bacteria. Patients who were
children (r = −0.28, p < .05) and quinolone consumption
(r = 0.33, p < .01) were significantly correlated with out-
come. Again, with only two significant correlations, we
can conclude that the results are probably due to
chance, so a logistic regression was not run.
Meta-analysis
We conducted a fixed-effects meta-analysis of a subset
of studies for which a common effect size could be ob-
tained. A fixed effects meta-analysis was more appropri-
ate than a random effects meta-analysis because we
wanted to determine whether heterogeneity between
the studies could be explained by our predictors [9].
Our meta-analysis focused on the most common
study designs and included articles that used cross-
sectional, case–control, cohort, non-randomised quasi-
experimental and randomized controlled trial designs.
We ran a separate meta-analysis for each of the most
common study designs (53 cross-sectional studies, 21
case–control studies, and 8 cohort studies) to see
whether the results varied by study design. Ecological
studies, which were conducted at the regional or country
level, were excluded due to much larger sample sizes
that would not allow comparisons with the much
smaller studies that were used in this analysis. We de-
cided against conducting a separate meta-analysis of the
ecological studies because there were only 17 such stud-
ies for which a common effect size measure could be
calculated. More studies than this would have been
needed to explore relationships between predictors and
effect size in any subsequent meta-regression. For the 88
studies that were included we were able to either use the
odds ratio that was reported in the study or calculate
one from the available data.
Our meta-analysis revealed that there was a significant
positive relationship between antibiotic consumption
and resistance with a pooled effect size (odds ratio) of
2.33 (z = 25.71, p < .01, 95% confidence interval 2.19 to
2.49). The results were similar for each of the most com-
mon study designs including cross-sectional (OR = 2.46,
z = 17.06, p < .01, 95% CI = 2.22 to 2.73), cohort (OR =
2.93, z = 7.02, p < .01, 95% CI = 2.17 to 3.96) and case–
control studies (OR = 2.26, z = 17.41, p < .01, 95% CI =
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 6 of 25
http://www.biomedcentral.com/1471-2334/14/13
2.07 to 2.48) so further analyses were conducted with
all 88 studies. The forest plot in Figure 2 displays the
odds ratio and weight for each study. One of the
studies (Appendix 3: Schneider-Lindner et al 2007) was
weighted more heavily than the other studies due to a very
small standard error for the odds ratio but removing this
study did not change our findings (OR = 2.74, z = 25.86,
p < .01).
Figure 2 Forest plot showing odds ratio and 95% confidence interval for each study along with study weight.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 7 of 25
http://www.biomedcentral.com/1471-2334/14/13
We should also mention, as can be seen from the fun-
nel plot in Figure 3, that there was some evidence of po-
tential publication bias in our sample of studies. The
absence of small studies in the lower left hand side of
the plot suggests that small studies that did not find a
strong association between antibiotic consumption and
resistance may not have been published, although as
Moller and Jennions [10] note, publication bias is not
the only explanation for a skewed funnel plot.
Significant heterogeneity was observed with a hetero-
geneity chi-squared value of 329.75 (p < .01). The percent-
age of variation between studies due to heterogeneity was
high (73.6%) so we decided to examine whether our in-
dependent variables could explain differences between
studies in the odds ratios. Using weighted correlations,
in which the correlation between the independent
variable and the odds ratio was weighted by the corre-
sponding standard error, we found 11 significant
correlations (see Table 2) and then conducted a meta-
regression to determine the independent effect of each
variable on the odds ratio. We excluded the variable
staphylococcus because it was highly correlated with
Methicillin-Resistant Saureus(MRSA (r = 0.97)).
The meta-regression showed that our set of independ-
ent variables significantly predicted the odds ratios
(F (10, 77) = 5.82 p < .01) although significant residual
variability remained (residual sum of squares = 187.78,
df = 77, p< .01). Five variables were significant independ-
ent predictors: ‘both children and adults’z = 3.90 < .01,
‘southern Europe’z = 2.25 p < .05, ‘B-lactam consump-
tion’z=−3.15 p < .01, ‘MRSA’z=−4.58 p < .01, and
‘quinolone-resistant E coli’(QREC) z = 2.57 p < .05. We
can conclude that studies which contained both adults
and children, those conducted in southern Europe, and
studiesthatlookedatQRECweremorelikelytofind
a strong positive relationship between antibiotic
consumption and resistance. Studies that examined B-
lactam consumption or MRSA tended to find a weaker
relationship between consumption and resistance. The
finding that southern European countries produced a
much stronger link between resistance and consumption
confirms previous observations that antibiotic resistance
due to the consumption of antibiotics may be a greater
problem in southern Europe than in northern Europe
(Appendix 3: Goossens et al 2005).
Publication bias
As noted earlier, there was some evidence of publication
bias in the subsample of studies that formed our meta-
analysis. Turning to the issue of publication bias for the
full set of 243 studies, a large number of these studies (a
third of our sample) did not find a positive association
between antibiotic consumption and antibiotic resist-
ance, which reduces the likelihood of publication bias
and lessens concerns that we chose studies for inclusion
simply because they supported our hypothesis. Concerns
with publication bias are also reduced by our contention
that studies which reported negative evidence probably
would be published since studies that found no relation-
ship between consumption and resistance would still
generate a great deal of interest. To examine potential
publication bias further, we looked at 92 studies that
were primarily concerned with something other than the
relationship between consumption and resistance. These
studies, which should be less prone to the publication
bias that we are concerned with, found a roughly similar
split in the ratio of positive to not positive outcomes that
we found with the larger sample, 60% of the studies
found a positive relationship and 40% did not find a
positive association.
Discussion
Our initial analysis with the entire sample of 243 studies
revealed that there was a positive association between
bacterial resistance and antibiotic consumption in the
community, which means that either increased con-
sumption was associated with increased resistance or de-
creased consumption was associated with decreased
resistance. Using a much larger sample of studies we
found support for Costelloe’s [8] conclusion that anti-
biotic prescribing is associated with the development of
antibiotic resistance. We also extended Costelloe’s work
by including studies that were conducted at both the
ecological level and the individual level and finding that
level of analysis did not affect the relationship between
consumption and resistance.
Although several study variables were significantly cor-
related with study outcome (whether or not a positive
association was obtained between resistance and con-
sumption), all of the correlation coefficients were small
Figure 3 Funnel plot showing effect size (odds ratio) as a
function of sample size (natural log of standard error).
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 8 of 25
http://www.biomedcentral.com/1471-2334/14/13
(0.20 or less), and none of these variables were signifi-
cant predictors of study outcome when they were en-
tered into a logistic regression equation. A lack of
significant predictors means that the association between
antibiotic consumption and bacterial resistance does not
depend on any of the demographic variables that we in-
vestigated or on other variables of interest, such as the
level at which the data were sampled or analysed. Al-
though no significant predictors were found when indi-
vidual classes of bacteria were examined either, the
binomial test showed that the positive relationship be-
tween consumption and resistance was only obtained for
enteric bacteria and streptococcus so efforts at control-
ling resistance needs to focus on these bacteria.
When the 88 studies in our meta-analysis were exam-
ined, we found that there was a significant positive rela-
tionship between consumption and resistance and
several variables that were significant predictors. Studies
that contained both adults and children, those con-
ducted in southern Europe, and studies that looked at
QREC were more likely to find a strong positive rela-
tionship between antibiotic consumption and resistance
whereas studies that examined B-lactam consumption or
MRSA tended to find a weaker relationship between
consumption and resistance. The finding that southern
European countries produced a much stronger link be-
tween resistance and consumption confirms previous
observations that antibiotic resistance due to the con-
sumption of antibiotics may be a greater problem in
southern Europe than in northern Europe (Appendix 3:
Goossens et al 2005). Also, the results from the meta-
analysis indicate that the use of quinolones may need to
be reduced when treating E Coli infections.
One of the major strengths of our review is the large
number of studies that contributed to our analysis,
which means that we had plenty of power to detect an
effect. We placed few restrictions on the types of studies
that we considered relevant, which make our findings
applicable to a wide range of settings thereby increasing
ecological validity and also reducing publication bias in
which non-published studies that do not produce signifi-
cant findings are overlooked. Our review included
English-language studies and studies published in other
languages, observational and experimental studies, grey
literature as well as published scientific literature, with
no geographical restrictions placed on where the study
was conducted. For any given study the level of analysis
ranged from the individual patient (or individual isolate)
level to the country (or groups of countries) level and
both children and adults were well represented. There
were no restrictions on which body sites were sampled
for establishing bacterial resistance, how antibiotic con-
sumption was measured, which bacteria were isolated,
or which antibiotics were consumed. In spite of the
comprehensive nature of our review, a final strength is
our targeted approach to answering the primary ques-
tion, is there a relationship between antibiotic consump-
tion and antibiotic resistance in the community, by the
use of a clear set of exclusion criteria.
Potential limitations should also be noted with our re-
view. First, our primary outcome measure was based on
a dichotomous coding of whether or not a study sup-
ported a positive relationship between antibiotic con-
sumption and antibiotic resistance so it ignored possible
differences within studies because it was based on the
preponderance of evidence for any given study. However,
we believe that using a global measure of outcome to
represent the relationship between antibiotic consump-
tion and resistance was justified as a common effect size
measure could not be calculated for most of the studies
that were used in our review. Another limitation con-
cerns poor reporting of important information and the
use of weak measures in many studies. More than a
quarter of the included studies did not specify which
Table 2 Weighted correlations between odds ratios and independent variables
Variable Correlation Significance Sample size*
Both children and adults 0.32 p < .01 20
Enteric bacteria 0.45 p < .01 20
Staphylococcus −0.44 p < .01 30
MRSA −0.48 p < .01 29
QREC 0.37 p < .01 10
B-lactam consumption −0.31 p < .01 41
Sulphonamides consumption −0.28 p < .01 20
Macrolide consumption −0.24 p < .05 16
Quinolones consumption −0.22 p < .05 12
Northern Europe −0.22 p < .05 14
Southern Europe 0.24 p < .05 15
*Number of cases in each category out of 88 cases total.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 9 of 25
http://www.biomedcentral.com/1471-2334/14/13
antibiotic had been consumed and almost half (41%) of
the studies used self-reports, which may be unreliable, to
assess antibiotic consumption. The most serious limitation
in this regard concerned inadequate reporting of how
much time had elapsed between antibiotic consumption
and the measurement of bacterial resistance. Most studies
did not provide the precise interval between when antibi-
otics were consumed and when resistance was measured,
which hindered our attempts to determine whether resist-
ance endured over time as Costelloe [8] had done. A final
limitation concerns some evidence of potential publication
bias in our meta-analysis in which smaller studies that did
not find a strong positive association between antibiotic
consumption and resistance may not have been published.
Conclusions
To conclude, our literature review reveals the following.
First, there is an association between antibiotic con-
sumption and the subsequent development of bacterial
resistance at both the individual and community level.
For clinicians this is important because our findings do
not just apply at the individual patient level but also at
the community, country and regional levels. As Bergman
(Appendix 3: Bergman et al 2006) noted, antibiotic pres-
sure at the population level may be more important than
the individual’s use of antibiotics in determining that in-
dividual’s risk of harbouring resistant bacteria. Both re-
sponsible prescribing at the individual level as well as
public policy that addresses the problem at the national
or regional level are critical components of any strategy
to reduce bacterial resistance, which supports the
current efforts of many countries, including the UK, to
ensure that antibiotics are only used when indicated and
that the most appropriate antibiotic (often an older
established antibiotic) is used. We also found that the
link between antibiotic consumption and resistance does
not depend on any of the demographic variables that we
investigated which means that antibiotic consumption
may lead to resistance for diverse groups of people in
various settings, although we would hasten to add that
several important predictors were identified in the meta-
analysis including a stronger link between resistance and
consumption in southern Europe than in other regions.
This discrepancy may have been due to the outcome
measure that was used or the particular mix of studies
that was examined in the meta-analysis. More work
needs to be done because significant residual variability
remained that could not be accounted for by the vari-
ables that were used in our meta-analysis.
Future work should also address the issue of co-
selection in which the use of one antibiotic produces
resistance to another antibiotic. If co-selection is wide-
spread, then resistance to one antibiotic could be due
to the use of another antibiotic that was not measured
in the study under investigation, in which case the conclu-
sion that there was no association between consumption
and resistance would be misleading. Unfortunately, the
studies that we examined rarely looked at this issue. More
thought also needs to be given to improving measures of
antibiotic consumption. Proxy measures, such as patient
self-report of antibiotic use, do not directly assess con-
sumption and therefore may be of limited utility.
Appendix 1 Search terms and connectors (AND/
OR) for literature search
‘Drug Resistance, Microbial’
OR
‘Drug Resistance, Bacterial’
OR
‘Bacterial Resistan*’(which captures terms such as
‘Resistant’and ‘Resistance’)
OR
‘Antimicrobial Resistan*’
OR
‘Antibiotic Resistan*’
AND
‘Consumption’
OR
‘Antibiotic Consumption’
OR
‘Antibiotic Prescri*’which includes terms such as
‘Prescribing’and ‘Prescription’
OR
‘Antibiotic Utilization’
OR
Antibiotic Use’
OR
‘Antibiotic Sales’
AND
‘Community’
OR
‘Primary Care’
OR
‘Primary Health Care’
OR
‘General Practice’
OR
‘Family Practice’
OR
‘Ambulatory Care’
Appendix 2 Exclusion criteria
A). Some studies were excluded because the infection
was not community acquired or the setting was
not appropriate:
1) Studies where more than half of the resistant
bacteria were acquired in a hospital setting or
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 10 of 25
http://www.biomedcentral.com/1471-2334/14/13
in another institutional setting such as a nursing
home.
2) Studies where antibiotic consumption was only
measured in a hospital or nursing home, not in
the community
3) In vitro studies unless in vivo resistance was also
examined
4) Studies that examined the topical use of
antibiotics for skin infections, dental use of
antibiotics, veterinary studies, and those that
looked at the use of antibiotics in agriculture or
as antiseptics
5) Studies that looked at the effects of bacteria
from waste or industry on soil, air and water
6) Studies that looked at viruses, parasites or fungi
7) Studies that only looked at treatment failure or
eradication of bacteria unless resistance was also
measured
8) Studies where most of the patients were
seriously ill (such as, when over half the patients
were on immunosuppressive therapy, were HIV
positive, had meningitis or end-stage cancer,
were using catheters, or were recruited in tertiary
centres). Those studies that looked at urinary
tract infection were only included when at least
2/3 of the sample contained women (not girls)
with an uncomplicated urinary tract infection.
B) Some studies conducted at the level of the
individual patient (as opposed to country or region)
were excluded because the temporal relationship
between consumption and resistance was not clear
or the interval between consumption and resistance
was too short (we wanted evidence of an enduring
effect):
9) Studies in which consumption was measured
after resistance or where the time between
consumption and resistance was exclusively less
than one month. Patients could be currently
taking antibiotics at the time that resistance was
measured if the long term use of antibiotics was
investigated (such as the effect of antibiotics
received in the past 6 months on resistance to
current treatment with antibiotics)
C) Some studies were given less weight than others:
10) We focused on newer studies (those conducted
since 1990) although some older studies from
the 1970s and 1980s were also included.
[Older studies tended to be methodologically
inferior (in reporting of statistics) and resistance
tends to be greater in newer studies, which
is an important consideration as the current
relationship between resistance and consumption
is more important than the relationship from 40
or 50 years ago].
11) Review articles were not included (except as a
source of references) unless the study combined
previous work in a meta-analysis or systematic
review.
12) Studies that simply looked at the biological
mechanisms which produced resistance were
excluded (However, some studies examined
bacteria that produced resistance in a particular
way, such as b-lactamase-producing bacteria.
These studies were included because they looked
at the effects of antibiotic consumption on the
production of a particular type of resistant
bacteria).
13) Studies that looked at treatment failure or bacterial
eradication were excluded unless resistance was also
measured. For example, some studies examined C
Difficile, which is difficult to eradicate, but these
articles were excluded unless resistance was also
measured.
D) Studies were generally classified as weak, and
therefore excluded, when:
14) The authors acknowledged that there was
insufficient power to detect an effect
15) No statistical analysis was conducted. In some
cases, conclusions were based on graphs and
figures with no statistical results provided, for
other studies a single participant or a handful of
participants was studied so no statistical tests
were conducted.
16) Poor measures were used, usually poor
consumption measures (such as relying on
participant self-report when recall was poor).
Appendix 3 Included studies
1. Albrich, W.C., Monnett, D.L., & Harbarth, S.,
Antibiotic selection pressure and resistance in
Streptococcus pneumoniae and Streptococcus pyogenes.
Emerging Infectious Diseases, 2004. 10(3): p. 514–517.
2. Alos, J.I., Serrano, M.G., Gomez-Garces, J.L., &
Perianes, J., Antibiotic resistance of Escherichia
coli from community-acquired urinary tract infections
in relation to demographic and clinical data.
Clinical Microbiology and Infection, 2005. 11(3):
p. 199–203.
3. Arason, V.A., Kristinsson, K.G., Sigurdsson, J.A.,
Gudmundsson, S., Molstad, S., & Dottir, G.S.,
The effect of antimicrobial (AM) use on carriage
of pencillin resistant pneumococci (PRP),in
34th Interscience Conference on Antimicrobi-
al Agents and Chemotherapy. 1994, American
Society for Microbiology: Orlando, FL USA. p. 85
Abstract C.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 11 of 25
http://www.biomedcentral.com/1471-2334/14/13
4. Arason, V.A., Kristinsson, K., Sigurdsson, J.,
Stefansdottir, G., Molstad, J., & Gudmundsson, S.,
Do antimicrobials increase the carriage rate of
penicillin resistant pneumococci in children? Cross
sectional prevalence study. British Medial Journal,
1996. 313: p. 387–391.
5. Arason, V.A., Gunnlaugsson, A., Sigurdsson, J.A.,
Erlendsdottir, H., Gudmundsson, S., & Kristinsson,
K.G., Clonal spread of resistant pneumococci
despite diminished antimicrobial use. Microbial
Drug Resistance, 2002. 8(3): p. 187–192.
6. Arason, V.A., Sigurdsson, J.A., Erlendsdottir, H.,
Gudmundsson, S., & Kristinsson, K.G., The role of
antimicrobial use in the epidemiology of resistant
penumococci: A 10-year follow up. Microbial Drug
Resistance, 2006. 12(3): p. 169–176.
7. Arnold, K.E., Leggiadro, R.J., Breiman, R.F., Lipman,
H.B., Schwartz, B., Appleton, M.A., Cleveland,
K.O., Szeto, H.C., Hill, B.C., Tenover, F.C., Elliott,
J.A., & Facklam, R.R., Risk factors for carriage of
drug-resistant Streptococcus pneumoniae among
children in Memphis, Tennessee. The Journal of
Pediatrics, 1996. 128(6): p. 757–764.
8. Arslan, H., Azap, O.K., Ergonul, O., & Timurkaynak,
F. on behalf of the Urinary Tract Study Group, Risk
factors for ciprofloxacin resistance among Escherichia
coli strains isolated from community-acquired urinary
tract infections in Turkey Journal of Antimicrobial
Chemotherapy, 2005. 56(5): p. 914–918.
9. Azap, O.K., Arslan, H., Serefhanoglu, K., Colakoglu,
S., Erdogan, H., Timurkaynak, F., & Senger, S.S.,
Risk factors for extended-spectrum B-lactamase
positivity in uropathogenic Escherichia coli isolated
from community-acquired urinary tract infections.
Clinical Microbiology and Infection, 2009. 16(2):
p. 147–151.
10. Baggett, H.C., Hennessy, T.W., Leman, R., Hamlin,
C., Bruden, D., Reasonover, A., Martinez, P., &
Butler, J.C., An outbreak of community-onset
methicillin-resistant Staphylococcus aureus skin
infections in southwestern Alaska. Infection
Control and Hospital Epidemiology, 2003. 24(6):
p. 397–402.
11. Baggett, H.C., Hennessy, T.W., Rudolph, K.,
Bruden, D., Reasonover, A., Parkinson, A., Sparks,
R., Donlan, R.M., Martinez, P., Mongkolrattanothai,
K., & Butler, J.C., Community-onset methicillin-
resistant Staphylococcus aureus associated with
antibiotic use and the cytotoxin Panton-Valentine
leukocidin during a furunculosis outbreak in rural
Alaska. Journal of Infectious Diseases, 2004. 189(9):
p. 1565–1573.
12. Bartoloni, A., Cutts, F., Leoni, S., Austin, C.C.,
Mantella, A., Guglielmetti, P., Roselli, M., Salazar,
E., & Paradisi, F., Patterns of antimicrobial use and
antimicrobial resistance among healthy children in
Bolivia. Tropical Medicine and International
Health, 1998. 3(2): p. 116–123.
13. Bassetti, M., Mantero, E., Gatti, G., Di Biagio, A., &
Bassetti, D., Streptococcus pyogenes erythromycin
resistance in Italy. Emerging Infectious Diseases,
1999. 5(2): p. 302–303.
14. Beekman, S.E., Diekema, D.J., Heilmann, K.P.,
Richter, S.S., & Doern, G.V., Macrolide use
identified as risk factor for macrolide-resistant
Streptococcus pneumoniae in a 17-center case–control
study. European Journal of Clinical Microbiology
and Infectious Diseases, 2006. 25(5): p. 335–339.
15. Belongia, E.A., Sullivan, B.J., Chyou, P., Madagame,
E., Reed, K.D., & Schwartz, B., A community
intervention trial to promote judicious antibiotic
use and reduce pencillin-resistant Streptococcus
pneumoniae carriage in children Pediatrics, 2001.
108(3): p. 575–583.
16. Ben-Ami, R., Rodriguez- Bano, J., Arslan, H., Pitout,
J.D.D.,Quentin,C.,Calbo,E.S.,Azap,O.K.,
Aroin, C., Pascual, A., Livermore, D.M., Garau, J.,
& Carmeli, Y., Amultinationalsurveyofrisk
factors for infection with extended-spectrum B-
lactamase-producing enterobacteriaceae in non-
hospitalized patients. Clinical Infectious Diseases,
2009. 49(5): p. 682–690.
17. Bergman, M., Huikko, S., Pihlajamaki, M., Laippala,
P., Palva, E., Huovinen, P., Seppala, H. & the
Finnish Study Group for Antimicrobial Resistance,
Effect of macrolide consumption on erythromycin
resistance in Streptococcus pyogenes in Finland
in 1997–2001. Clinical Infectious Diseases, 2004.
38(9): p. 1251–1256.
18. Bergman, M., Huikko, S., Huovinen, P., Paakkari,
P., Seppala, H. & the Finnish Study Group for
Antimicrobial Resistance (FiRe Network), Macrolide
and azithromycin use are linked to increased
macrolide resistance in Streptococcus pneumoniae.
Antimicrobial Agents and Chemotherapy, 2006.
50(11): p. 3646–3650.
19. Bergman, M., Nyberg, S.T., Huovinen, P., Paakkari,
P., Hakanen, A.J., & the Finnish Study Group for
Antimicrobial Resistance, Association between antimi-
crobial consumption and resistance in Escherichia coli.
Antimicrobial Agents and Chemotherapy, 2009.
53(3): p. 912–917.
20. Bischoff, W.E., Wallis, M.L., Tucker, K.B.,
Reboussin, B.A., & Sherertz, R.J., Staphylococcus
aureus nasal carriage in a student community:
Prevalence, clonal relationships, and risk factors.
Infection Control and Hospital Epidemiology, 2004.
25(6): p. 485–491.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 12 of 25
http://www.biomedcentral.com/1471-2334/14/13
21. Blaettler, L., Mertz, D., Frei, R., Elzi, L., Widmer,
A.F., Battegay, M., & Fluckiger, U., Secular trend
and risk factors for antimicrobial resistance in
Escherichia coli isolates in Switzerland 1997–2007.
Infection, 2009. 37(6): p. 534–539.
22. Block, S.L., Harrison, C.J., Hedrick, J.A., Tyler, R.
D., Smith, R.A., Keegan, E., & Chartrand, S.A.,
Pencillin-resistant Streptococcus pneumoniae in
acute otitis media: risk factors, susceptibility patterns
and antimicrobial management. The Pediatric
Infectious Disease Journal, 1995. 14(3): p. 751–759.
23. Boccia, D., Alegiani, S.S., Pantosti, A., Moro, M.L.,
& Traversa, G., The geographic relationship
between the use of antimicrobial drugs and the
pattern of resistance for Streptococcus pneumoniae
in Italy. European Journal of Clinical Pharmacology,
2004. 60(2): p. 115–120.
24. Boken, D.J., Chartrand, S.A., Goering, R.R.V.,
Kruger, R., & Harrison, C.J., Colonization with
pencillin-resistant Streptococcus pneumoniae in a
child-care center. Pediatric Infectious Disease
Journal, 1995. 14(10): p. 879–884.
25. Boken, D.J., Chartrand, S.A., Moland, E.S., & Goering,
R.V., Colonization with pencillin-nonsusceptible
Streptococcus-pneumoniae in urban and rural
child-care centers. The Pediatric Infectious Disease
Journal, 1996. 15(8): p. 667–672.
26. Borgmann, S., Jakobiak, T., Gruber, H., Schroder,
H., & Sagel, U., Prescriptions of broad-spectrum
antibiotics to outpatients do not match increased
prevalence and antibiotic resistance of respiratory
pathogens in Bavaria. Polish Journal of Microbiology,
2009. 58(2): p. 105–110.
27. Borgmann, S., Jakobiak, T., Gruber, H., Schroder,
H., & Sagel, U., Ciprofloxacin treatment of urinary
infections results in increased resistance of urinary
E coli to Ciprofloxacin and Co-trimoxazole. Polish
Journal of Microbiology, 2009. 58(4): p. 371–373.
28. Bronzwaer, S.L.A.M., Cars, O., Buchholz, U.,
Molstad, S., Goettsch, W., Veldhuijzen, I.K.,
Kool, J.L., Sprenger, M.J.W., Degener, J.W. &
participants in the European Antimicrobial
Resistance Surveillance System, A European study
on the relationship between antimicrobial use and
antimicrobial resistance. Emerging Infectious
Diseases, 2002. 8(3): p. 278–282.
29. Brook, I., Emergence and persistence of B-lactamase-
producing bacteria in the oropharynx following
penicillin treatment. Archives of otolaryngology–
head & neck surgery 1988. 114(6): p. 667–670.
30. Brook, I., & Gober, A.E., Monthly changes in the
rate of recovery of pencillin-resistant organisms
from children. The Pediatric Infectious Disease
Journal, 1997. 16(2): p. 255–257.
31. Brook, I., & Gober, A.E., Resistance to
antimicrobials used for therapy of otitis media and
sinusitis: Effect of previous antimicrobial therapy
and smoking. Annals of Otology, Rhinology and
Laryngology, 1999. 108(7): p. 645–647.
32. Butler, C.C., Dunstan, F., Heginbothom, M.,
Mason, B., Roberts, Z., Hillier, S., Howe, R., Palmer,
S., & Howard, A., Containing antibiotic resistance:
decreased antibiotic-resistant coliform urinary tract
infections with reduction in antibiotic prescribing
by general practices. British Journal of General
Practice, 2007. 57(543): p. 785–792.
33. Calbo, E., Romani, V., Xercavins, M., Gomez, L.,
Vidal, C.G., Quintana, S., Vila, J., & Garau, J., Risk
factors for community-onset urinary tract infections
due to Escherichia coli harbouring extended-
spectrum B-lactamases. Journal of Antimicrobial
Chemotherapy, 2006. 57(4): p. 780–783.
34. Campbell, K.M., Vaughn, A.F., Russell, K.L., Smith,
B., Jimenez, D.L., Barrozo, C.P., Minarcik,
J.R., Crum, N.F., Ryan, M.A.K., Risk factors for
community-associated methicillin-resistant Staphyl
ococcus aureus infections in an outbreak of disease
among military trainees in San Diego, California
in 2002. Journal of Clinical Microbiology, 2004.
42(9): p. 4050–4053.
35. Chaniotaki, S., Giakouppi, P., Tzouvelekis, L.S.,
Panagiotakos, D., Kozanitou, M., Petrikkos, G.,
Avlami, A., the WHONET study group and A.C.
Vatopoulos, Quinolone resistance among Escherichia
coli strains from community-acquired urinary tract
infections in Greece. Clinical Microbiology and
Infection, 2004. 10(1): p. 75–78.
36. Charlebois, E.D., Bangsberg, D.R., Moss, N.J., Moore,
M.R., Moss, A.R., Chambers, H.F., & Perdreau-
Remington, F., Population-based community preva-
lence of methicillin-resistant Staphylococcus aureus
in the urban poor of San Francisco. Clinical Infec-
tious Diseases, 2002. 34(4): p. 425–433.
37. Chiu, S., Ho, P.L., Chow, F.K.H., Yuen, K.L., & Lau,
Y.L., Nasopharyngeal carriage of antimicrobial-
resistant Streptococcus pneumoniae among young
children attending 79 kindergartens and day care
centers in Hong Kong. Antimicrobial Agents and
Chemotherapy, 2001. 45(10): p. 2765–2770.
38. Chung,A.,Perera,R.,Brueggemann,A.B.,Elamin,
A.E.,Harnden,A.,Mayon-White,R.,Smith,S.,Crook,
D.W., & Mant, D., Effect of antibiotic prescribing on
antibiotic resistance in individual children in primary
care: prospective cohort study. British Medical Journal,
2007. 335(7617): p. 429–433.
39. Ciftci, E., Dogru, U., Aysev, D., Ince, E., &
Guriz, H., Investigation of risk factors for penicillin-
resistant Streptococcus pneumoniae carriage in
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 13 of 25
http://www.biomedcentral.com/1471-2334/14/13
Turkish children. Pediatrics International, 2001.
43(4): p. 385–390.
40. Ciftci,E.,Dogru,U.,Guriz,H.,Aysev,D.,&Ince,E.,
Investigation of risk factors for tonsillopharyngitis
with macrolide resistant Streptococcus pyogenes in
Turkish children. Pediatrics International, 2002. 44
(6): p. 647–651.
41. Cizman, M., Pokorn, M., Seme, K., Orazem, A., &
Paragi, M., The relationship between trends in
macrolideuseandresistancetomacrolidesofcommon
respiratory pathogens. Journal of Antimicrobial
Chemotherapy, 2001. 47(4): p. 475–477.
42. Cizman, M., Theuseandresistancetoantibioticsin
the community. International Journal of Antimicrobial
Agents, 2003. 21(4): p. 297–307.
43. Clancy, M.J., Graepler, A., Breese, P.E., Price, C.S., &
Burman, W.J., Widespread emergence of methicillin
resistance in community-acquired Staphylococcus
aureus infections in Denver. Southern Medical
Journal, 2005. 98(11): p. 1069–1075.
44. Cohen, R., Levy, C., de la Rocque, F., Gelbert,
N.,Wollner,A.,Fritzell,B.,Bonnet,E.,Tetelboum,R.,&
Var on, E. , Impact of pneumococcal conjugate vaccine
and of reduction of antibiotic use on nasopharyngeal
carriage of nonsusceptible pneumococci in children with
acute otitis media. The Pediatric Infectious Disease
Journal, 2006. 25(11):p.1001–1007.
45. Colgan, R., Johnson, J.J., Kuskowski, M., & Gupta,
K., Risk factors for trimethoprim -sulfamethoxazole
resistance in patients with acute uncomplicated
cystitis. Antimicrobial Agents and Chemotherapy,
2008. 52(3): p. 846–851.
46. Colodner, R., Kometiani, I., Chazan, B., & Raz,
R., Risk factors for community-acquired urinary
tract infection due to quinolone-resistance E. Coli.
Infection, 2008. 36(1): p. 41–45.
47. Como-Sabetti,K.,Harriman,K.,Fridkin,S.,&
Lynfield, R., Community-associated Methicillin-
resistant Staphylococcus aureus infection risk factor
study. International Conference on Emerging
Infectious Diseases 2008, 2008.
48. Corea,E.,deSilva,T.,&Perera,J.,Methicillin-
resistant Staphylococcus aureus: prevalence, incidence
and risk factors associated with colonization in Sri
Lanka. Journal of Hospital Infection, 2003. 55(2):
p. 145–148.
49. Costelloe, C., Metcalfe, C., Lovering, A., Mant, D.
&Hay,A.D.,Effect of antibiotic prescribing in
primary care on antimicrobial resistance in
individual patients: systematic review and meta-
analysis. British Medial Journal, 2010. 340(7756):
c2096.
50. Costelloe, C., Lovering, A., Montgomery, A., Lewis,
D., McNulty, C., & Hay, A.D., Effect of antibiotic
prescribing in primary care on methicillin resistant
Staphylococcus aureus carriage in community
resident adults: a controlled observational study,in
GRIN. 2010: Lodz.
51. Craig, A.S., Erwin, P.C., Schaffner, W., Elliot, J.A.,
Moore, W.L., Ussery, X.T., Patterson, L., Dake,
A.D., Hannah, S.G., & Butler, J.C., Carriage of
multidrug-resistant Streptococcus pneumoniae and
impact of chemoprophylaxis during an outbreak of
meningitis at a day care center. Clinical Infectious
Diseases, 1999. 29(5): p. 1257–1264.
52. Creech, C.B., Kernodle, D.S., Alsentzer, A., Wilson,
C., & Edwards, K.M., Increasing rates of nasal
carriage of methicillin-resistant Staphylococcus
aureus in healthy children. The Pediatric Infectious
Disease Journal, 2005. 24(7): p. 617–621.
53. Dabernat, H., Geslin, P., Megraud, F., Begue, P.,
Boulesteix, J., Dubreuil, C., de La Roque, F., Trinh,
A., & Scheimberg, A., Effects of cefixime or co-
amoxiclav treatment on nasopharyngeal carriage
of Streptococcus pneumoniae and Haemophilus
influenzae in children with acute otitis media.
Journal of Antimicrobial Chemotherapy, 1998. 41(2):
p. 253–258.
54. Dagan, R., Melamed, R., Muallem, M., Piglansky, L.,
& Yagupsky, P., Nasopharyngeal colonization in
southern Israel with antibiotic-resistant pneumococci
during the first 2 years of life: Relation to serotypes
likely to be included in pneumococcal conjugate
vaccines. The Journal of Infectious Diseases, 1996.
174(6): p. 1352–1355.
55. Dagan, R., Hoberman, A., Johnson, C., Leibovitz,
E.,Arguedas,A.,Rose,F.V.,Wynne,B.R.,&
Jacobs, M.R., Bacteriological and clinical efficacy
of high dose amoxicillin/clavulanate in children
with acute otitis media. The Pediatric Infectious
Disease Journal, 2001. 20(9): p. 829–837.
56. Dagan, R., Barkai, G., Givon-Lavi, N., Sharf, A.Z.,
Vardy, D., Cohen, T., Lipsitch, M., & Greenberg,
D., Seasonality of antibiotic-resistant Streptococcus
pneumoniae that causes acute otitis media: A clue
for an antibiotic-restriction policy? Journal of
Infectious Diseases, 2008. 197(8): p. 1094–1102.
57. Datta, N.F., Reeves, M.C., Brumfitt, W., Orskov,
F., & Orskov, I., R factors in Escherichia coli in
faeces after oral chemotherapy in general practice.
The Lancet, 1971. 1(7694): p. 312–315.
58. Davis, S.L., Perri, M.B., Donabedian, S.M., Manierski,
C.,Singh,A.,Vager,D.,Haque,N.Z.,Speirs,K.,Muder,
R.R.,Robinson-Dunn,B.,Hayden,M.K.&Zervos,
M.J., Epidemiology and outcomes of community-
associated methicillin-resistant Staphylococcus aureus
infection. Journal of Clinical Microbiology, 2007.
45(6): p. 1705–1711.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 14 of 25
http://www.biomedcentral.com/1471-2334/14/13
59. Deeks, S.L., Palacio, R., Ruvinsky, R., Kertesz,
D.A.,Hortal,M.,Rossi,A.,Spika,J.S.,DiFabio,
J.L., & The Streptococcus pneumoniae working
group, Risk factors and course of illness among
children with invasive penicillin-resistant Strepto-
coccus pneumoniae. Pediatrics, 1999.
103(2): p. 409–413.
60. Dejthevaporn, C., Vibhagool, A., Thakkinstian, A.,
Sirinavin, S., & Vorachit, M., Risk factors for
penicillin-resistant Streptococcus pneumoniae ac-
quisition in patients in Bangkok. Southeast Asian
Journal Of Tropical Medicine And Public Health,
2000. 31(4): p. 679–683.
61. DeLencastre, H., Kristinsson, K. G., Brito-Avo, A.,
Sanches, I.S., Sa-Leao, R., Saldanha, J., Sigvaldadottir, E.,
Karlsson, S., Oliviera, D., Mato, R., De Sousa, M.A., &
Tomasz, A., Carriage of respiratory tract pathogens and
molecular epidemiology of Streptococcus pneumoniae
colonization in healthychildren attending daycare centers
in Lisbon, Portugal. Microbial Drug Resistance, 1999. 5(1):
p.19–29.
62. Dellamonica, P., Pradier, C., Leroy, J., Carsenti-
Etesse, H., Dupont, M.J., Roussel-Delvallez, M.,
Dabernat,H.,Dunais,B.,Martinot,A.,Estavoyer,J.
M.,Grandbastien,B.,Guillemot,D.,DeBels,F.,
Epidemiology and antibiotic susceptibility of naso-
pharyngeal S pneumoniae and H influenzae iso-
lated from children attending day-care centers in 3
French departments. Medecine et maladies infec-
tieuses, 2002. 32(12): p. 650–661.
63. DeNeeling, A.J., Overbeek, B.P., Horrevorts, A.M.,
Ligtvoet, E.E.J., & Goettsch, W.G., Antibiotic use
and resistance of Streptococcus pneumoniae in The
Netherlands during the period 1994–1999. Journal
of Antimicrobial Chemotherapy, 2001. 48(3):
p. 441–444.
64. Dias, R.C., M., Emergence of invasive erythromycin-
resistant Streptococcus pneumoniae strains in
Portugal: contribution and phylogenetic relatedness
of serotype 14. Journal of Antimicrobial Chemoth-
erapy, 2004. 54(6): p. 1035–1039.
65. Dias, R.C., M., Trends in resistance to penicillin
anderythromycinofinvasivepneumococciin
Portugal. Epidemiology and Infection, 2008. 136
(7): p. 928–939.
66. Diekama, D.J., Brueggemann, A.B., Doern, G.V.,
Antimicrobial drug use and changes in resistance
in Streptococcus pneumoniae. Emerging Infectious
Diseases, 2000. 6(5): p. 552–556.
67. Donnan, P.T., Wei, L., Steinke, D.T., Phillips, G.,
Clarke, R., Noone, A., Sullivan, F.M., MacDonald,
T.M., & Davey, P.G., Presence of bacteriuria caused
by trimethoprim resistant bacteria in patients
prescribed antibiotics: multilevel model with practice
and individual patient data. British Medical
Journal, 2004. 328: p. 1297–1301.
68. Doone, J., Klespies, S.L., & Sabella, C., Risk
factors for penicillin-resistant systemic pneumo-
coccal infections in children. Clinical Pediatrics,
1997. 36(4): p. 187–191.
69. Dromigny, J.A., Nabeth, P., Juergens-Behr, A., &
Perrier-Gros-Claude, J.D., Risk factors for antibiotic-
resistant Escherichia coli isolated from community-
acquired urinary tract infections in Dakar, Senegal.
Journal of Antimicrobial Chemotherapy, 2005.
56(1): p. 236–239.
70. Duchin, J.S., Breiman, R.F., Diamond, A.,
Lipman, H.B., Block, S.L., Hedrick, J.A., Finger,
R., & Elliott, J.A., High prevalence of multidrug-
resistant Streptococcus pneumoniae among children
in a rural Kentucky community. Pediatric Infectious
Disease Journal, 1995. 14(9): p. 745–750.
71. Dueger, E.L., Asturias, E.J., Matheu, J., Gordillo,
R., Torres, O., & Halsey, N., Increasing pencillin
and trimethoprim-sulfamethoxazole resistance in
nasopharyngeal Streptococcus pneumoniae iso-
lates from Guatemalan children, 2001–2006.
International Journal of Infectious Diseases, 2008.
12(3): p. 289–297.
72. Duerink, D.O., Lestari, E.S., Hadi, U.,
Nagelkerke, N.J.D., Severin, J.A., Verbrugh, H.
A., Keuter, M., Gyssens, I.C., van den Broek, P.J. on
behalf of the study group 'Antimicrobial Resistance in
Indonesia: Prevalence and Prevention (AMRIN),
Determinants of carriage of resistant Escherichia coli in
the Indonesian population inside and outside hospitals.
Journal of Antimicrobial Chemotherapy, 2007.
60(2): p. 377–384.
73. Dunais, B., Pradier, C., Carsenti, H., Sabah, M.,
Mancini, G., Fontas, E., & Dellamonica, P.,
Influence of child care on nasopharyngeal carraige
of Streptococcus pneumoniae and Haemophilus
influenzae. The Pediatric Infectious Disease Journal,
2003. 22(7): p. 589–592.
74. ECDC, Antibiotic Resistance. 2011. Used Figure 2
to calculate correlations between consumption and
resistance. http://www.farnhamdene.com/website/
H81615/files/Primary_Care_Factsheet_2011_
Antibiotics.pdf
75. European Centre for Disease Prevention and Control.
Annual epidemiological report on communicable
diseases in Europe. 2010. Stockholm: ECDC; 2010.
76. Einarsson, S., Kristjansson, M., Kristinsson, K.G.,
Kjartansson, G., & Jonsson, S., Pneumonia caused
by penicillin-non-susceptible and penicillin-
susceptible pneumococci in adults: A case–control
study. Scandinavian Journal of Infectious Diseases,
1998. 30(3): p. 253–256.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 15 of 25
http://www.biomedcentral.com/1471-2334/14/13
77. Ellis, M.W., Hospenthal, D.R., Dooley, D.P., Gray,
P.J., & Murray, C.K., Natural history of community-
acquired methicillin-resistant Staphylococcus aureus
colonization and infection in soldiers. Clinical
Infectious Diseases, 2004. 39(7): p. 971–979.
78. Ewig, S., Ruiz, M., Torres, A., Marco, F., Martinez, J.
A., Sanchez, M., & Mensa, J., Pneumonia acquired in
the community through drug-resistant Streptococcus
pneumoniae. American Journal of Respiratory and
Critical Care Medicine, 1999. 159(6): p. 1835–1842.
79. Fairchok, M.P., Ashton, W.S., & Fischer, G.W., Carriage
of pencillin-resistant pneumococci in a military
population in Washington, DC: Risk factors and
correlation with clinical isolates. Clinical Infectious
Diseases, 1996. 22(6): p. 966–972.
80. Finkelstein, J.A., Huang, S.S., Daniel, J., Rifas-
Shiman, S.L., Kleinman, K., Goldmann, D., Pelton,
S.I., Demaria, A., & Platt, R., Antibiotic-resistant
Streptococcus pneumoniae in the Heptavalent
pneumococcal conjugate vaccine era: Predictors of
carriage in a multicommunity sample. Pediatrics,
2003. 112(4): p. 862–869.
81. Frazee, B.W., Lynn, J., Charlebois, E.D., Lambert,
L., Lowery, D., & Perdreau-Remington, F., High
prevalence of methicillin-resistant Staphylococcus
aureus in emergency department skin and soft issue
infections. Annals of Emergency Medicine, 2005.
45(3): p. 311–320.
82. Fritz, S.A., Garbutt, J., Elward, A., Shannon, W., &
Storch, G.A., Prevalence of and risk factors
for community-acquired methicillin-resistant
and methicillin-sensitive Staphylococcus aur-
eus colonization in children seen in a practice-
based research network. Pediatrics, 2008. 121
(6): p. 1090–1098.
83. Fry,A.M.,Jha,H.C.,Lietman,T.M.,Chaudhary,
J.S.P., Bhatta, R.C., Elliott, J., Hyde, T., Schuchat,
A.,Gaynor,B.,Dowell,S.F.,Adverse and beneficial
secondary effects of mass treatment with azithromycin
to eliminate blindness due to trachoma in Nepal.
Clinical Infectious Diseases, 2002. 35(4): p. 395–402.
84. Furuno, J.P., McGregor, J.C., Harris, A.D., Johnson,
J.A., Johnson, J.K., Langenberg, P., Venezia, R.A.,
Finkelstein, J., Smith, D.L., Strauss, S.M., &
Perencevich, E.N., Identifying groups at high risk
for carriage of antibiotic-resistant bacteria. Archives
of Internal Medicine, 2006. 166(5): p. 580–585.
85. Gagliotti, C., Nobilio, L., Milandri, M., Moro, M.L.,
for the Emilia-Romagna Antibiotic Resistance Study
Group, Macrolide prescriptions and erythromycin re-
sistance of Streptococcus pyogenes. Clinical Infectious
Diseases, 2006. 42(8): p. 1153–1156.
86. Gagliotti, G., Nobilio, L., & Moro, M.L., Emergence
of ciprofloxacin resistance in Escherichia coli isolates
from outpatient urine samples. Clinical Microbiology
and Infection, 2007. 13(3): p. 328–331.
87. Garau, J., Xercavins, M., Rodriguez-Carballeira, M.,
Gomez-Vera, J.R., Coll, I., Vidal, D., Llovet, T., &
Ruiz-Bremon, A., Emergence and dissemination of
quinolone-resistant Escherichia coli in the commu-
nity. Antimicrobial Agents and Chemotherapy,
1999. 43(11): p. 2736–2741.
88. Garcia-Rey, C., Aguilar, L., Bacquero, F., Casal, J.,
& Martin, J.E., Pharmacoepidemiological analysis
of provincial differences between consumption of
macrolides and rates of erythromycin resistance
among Streptococcus pyogenes isolates in Spain.
Journal of Clinical Microbiology, 2002. 40(8):
p. 2959–2963.
89. Garcia-Rey, C., Aguilar, L., Baquero, F., Casal, J., &
Dal-Re, R., Importance of local variations in anti-
biotic consumption and geographical differences of
erythromycin and pencillin resistance in Streptococ-
cus pneumoniae. Journal of Clinical Microbiology,
2002. 40(1): p. 159–164.
90. Garcia-Rey, C., Fenoll, A., Aguilar, L., & Casal, J.,
Effect of social and climatological factors on
antimicrobial use and Streptococcus pneumoniae
resistance in different provinces in Spain.
Journal of Antimicrobial Chemotherapy, 2004. 54
(2): p. 465–471.
91. Gaynor, B.D., Chidambaram, J.D., Cevallos, V., Miao,
Y.,Miller,K.,Jha,H.C.,Bhatta,R.C.,Chaudhary,J.S.
P., Holm, S.O., Whitcher, J.P., Holbrook, K.A., Fry,
A.M., & Lietman, T.M. , Topical ocular antibiotics
induce bacterial resistance at extraocular sites. British
Journal of Ophthalmology, 2005. 89(9): p. 1097–1099.
92. Gehanno, P., N'guyen, L., Derriennic, M., Pichon, F.,
Goehrs, J., & Berche, P., Pathogens isolated during
treatment failures in otitis. The Pediatric Infectious
Disease Journal, 1998. 17(10): p. 885–890.
93. Ghaffar, F., Muniz, L.S., Katz, K., Reynolds, J., Smith,
J.L., Davis, P., Friedland, I.R., & McCracken, G.H.,
Effects of amoxicillin/clavulanate or azithromycin on
nasopharyngeal carriage of Streptococcus pneumoniae
and Haemophilus influenzae in children with acute
otitis media. Clinical Infectious Diseases, 2000. 31(4):
p. 875–880.
94. Gobernardo, M., Valdes, L., Alos, J.I., Garcia-Rey,
C., Dal-Re, R., Garcia-de-Lomas, J., and the
Spanish Surveillance Group for Urinary Pathogens,
Antimicrobial susceptibility of clinical Escherichia
coli isolates from uncomplicated cystitis in women
over a 1-year period in Spain. Rev Esp Quimioterap,
2007. 20(1): p. 68–76.
95. Goettsch, W., van Pelt, W., Nagelkerke, N., Hendrix,
M.G.R., Buiting, A.G.M., Petit, P.L., Sabbe, L.J.M., van
Griethuysen, A.J.A., & de Neeling, A.J., Increasing
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 16 of 25
http://www.biomedcentral.com/1471-2334/14/13
resistance to fluoroquinolones in Escherichia coli from
urinary tract infections in The Netherlands. Journal of
Antimicrobial Chemotherapy, 2000. 46(2): p. 223–
228.
96. Gomez-Barreto, D., Calderon-Jaimes, E., Rodriguez,
R.S., Espinosa, L.E., Vina-Flores, L., & Jimenez-
Rojas, V., Carriage of antibiotic-resistant pneumo-
cocci in a cohort of a daycare center. Salud Publica
de Mexico, 2002. 44(1): p. 26–32.
97. Goossens, H., Lammens, C., Lontie, M., Stalpaert,
M., Andre, M., Van Pelt, H., Dellanoy, P., Drion, S.,
& Hendrickx, E., Streptococcus pyogenes (S Py)
resistance to erythromycin (ERY) in relation to
mechanism of resistance, genotype, and comsumption
of macrolides (M) Abstracts of the 41st Interscience
Conference on Antimicrobial Agents and Chemotherapy,
2001: p. 134–135 Abstract C2-1314.
98. Goossens, H., Ferech, M., Vander Stichele, R. &
Elseviers, M., Outpatient antibiotic use in Europe
and association with resistance: a cross-national
database study. The Lancet, 2005. 365(9459):
p. 579–587.
99. Gottesman, B.S., Carmeli, Y., Shitrit, P., &
Chowers, M., Impact of quinolone restriction on
resistance patterns of Escherichia coli isolated from
urine by culture in a community setting. Clinical
Infectious Diseases, 2009. 49(6): p. 869–875.
100. Granizo, J.J., Aguilar, L., Casal, J., Garcia-Rey, C.,
Dal-Re, R. & Baquero, F., Streptococcus pneumo-
niae resistance to erythromycin and penicillin in
relation to macrolide and B-lactam consumption
in Spain (1979–1997) Journal of Antimicrobial
Chemotherapy, 2000. 46(5): p. 767–773.
101. Granizo, J.J., Aguilar, L., Casal, J., Dal-Re, R. &
Baquero, F., Streptococcus pyogenes resistance to
erythromycin in relation to macrolide consump-
tion in Spain (1986–1997). Journal of Antimicro-
bial Chemotherapy, 2000. 46(6): p. 959–964.
102. Greenberg, D., Givon-Lavi, N., Sharf, A. Z., Vardy,
D., & Dagan, R., The association between anti-
biotic use in the community and nasopharyngeal
carriage of antibiotic-resistant Streptococcus pneu-
moniae in Bedouin children. The Pediatric Infec-
tious Disease Journal, 2008. 27(9): p. 776–782.
103. Grivea, I.N., Tsantouli, A. G., Chryssanthopoulou,
D.C., & Syrogiannopoulos, G.A., Interaction of the
heptavalent pneumococcal conjugate vaccine and
the use of individial antiibotics among children on
nasopharyngeal colonization with erythromycin-
resistant Streptococcus pneumoniae. European
Journal of Clinical Microbiology and Infectious
Diseases, 2010. 29(1): p. 97–105.
104. Groom, A.V., Wolsey, D.H., Naimi, T.S., Smith,
K., Johnson, S., Boxrud, D., Moore, K.A., &
Cheek, J.A., Community-acquired methicillin-
resistant Staphylococcus aureus in a rural American
Indian community. Journal of the American
Medical Association, 2001. 286(10): p. 1201–1205.
105. Guillemot, D., Carbon, C., Balkau, B., Geslin, P.,
LeCoeur, H., Vauzelle-Kervroedan, F., Bouvenot, G.,
& Eschwege, E., Low dosage and long treatment
duration of B-lactam Risk factors for carriage of
pencillin-resistant Streptococcus pneumoniae.
Journal of the American Medical Association, 1998.
279(5): p. 365–370.
106. Guillemot, D., Boutou, O., Carbon, C., Balkau, B.,
Geslin, P., Lecoeur, H., Weber, P., & Eschwege,
E., Pencillin-resistant Streptococcus pneumoniae
(PRSp) carriage is strongly related to B-lactam
use,inThirty-Eighth Interscience Conference on
Antimicrobial Agents and Chemotherapy 1998,
American Society for Microbiology: San Diego,
CA USA. p. 75.
107. Guillemot, D., Varon, E., Bernede, C., Weber, P.,
Henriet, L., Simon, S., Laurent, C., Lecoeur, H., &
Carbon, C., Reduction in antibiotic use in the
community reduces the rate of colonization
with pencillin G-nonsusceptible Streptococcus
pneumoniae. Clinical Infectious Diseases, 2005.
41(7): p. 930–938.
108. Gunnarsson, O., & Ekdahl, K., Previous respiratory
tract infections and antibiotic consumption in
children with long- and short-term carriage of
penicillin-resistant Streptococcus pneumoniae.
Epidemiology and Infection, 1998. 121(3): p. 523–528.
109. Gupta, K., Hooton, T.M., & Stamm, W.E., Isolation
of fluoroquinolone-resistant rectal Escherichia coli
after treatment of acute uncomplicated cystitis.
Journal of Antimicrobial Chemotherapy, 2005.
56(1): p. 243–246.
110. Hannah, E.L., Angulo, F.J., Johnson, J.R., Haddadin,
B., Williamson, J., & Samore, M.H. , Drug-resistant
Escherichia coli, rural Idaho. Emerging Infectious
Diseases, 2005. 11(10): p. 1614–1617.
111. Harbarth, S., Sax, H., Fankhauser-Rodriguez, C.,
Schrenzel, J., Agostinho, A., & Pittet, D., Evaluating
the probability of previously unknown carriage of
MRSA at hospital admission. The American Journal
of Medicine, 2006. 119(3): p. e15-e23.
112. Hay, A.D., Thomas, M., Montgomery, A.,
Wetherell, M., Lovering, A., McNulty, C., Lewis,
D., Carron, B., Henderson, E., & MacGowan, A.,
The relationship between primary care antibiotic
prescribing and bacterial resistance in adults
in the community: a controlled observational
study using individual patient data. Journal
of Antimicrobial Chemotherapy, 2005. 56(1):
p. 146–153.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 17 of 25
http://www.biomedcentral.com/1471-2334/14/13
113. Hennessy, T.W., Petersen, K.M., Bruden, D.,
Parkinson, A.J., Hurlburt, D., Getty, M., Schwartz,
B., & Butler, J.C., Changes in antibiotic-prescribing
practices and carriage of penicillin-resistant
Streptococcus pneumoniae: A controlled interven-
tion trial in rural Alaska. Clinical Infectious
Diseases, 2002. 34(12): p. 1543–1550.
114. Hennessy, T.W., Bruden, D., Petersen, K.M.,
Parkinson, A.J., Hurlburt, D., Getty, M., Butler, J.
C., & Schwartz, B, Effect of high-dose amoxicillin
on the prevalence of penicillin-resistant Strepto-
coccus pneumoniae in rural Alaska. The Journal
of the American Medical Association, 2002.
287(16): p. 2078–2079.
115. Hidron, A.I., Kourbatova, E.V., Halvosa, J.S., Terrell,
B.J., McDougal, L.K., Tenover, F.C., Blumberg, H.M.,
&King,M.D.,Risk factors for colonization with
methicillin-resistant Staphylococcus aureus (MRSA)
in patients admitted to an urban hospital: Emer-
gence of community-associated MRSA nasal
carriage. Clinical Infectious Diseases, 2005. 41(2):
p. 159–166.
116. Hillier, S., Roberts, Z., Dunstan, F., Butler, C.,
Howard, A., & Palmer, S., Prior antibiotics and
risk of antibiotic-resistant community-acquired
urinary tract infection: a case–control study.
Journal of Antimicrobial Chemotherapy, 2007.
60(1): p. 92–99.
117. Hjaltested, E.K.R., Bernatoniene, J., Erlendsdottir,
H., Kaltenis, P., Bernatoniene, G., Gudnason, T.,
Haraldsson, A., & Kristinsson, K.G., Resistance in
respiratory tract pathogens and antimicrobial use
in Icelandic and Lithuanian children. Scandinavian
Journal of Infectious Diseases, 2003. 35(1): p. 21–26.
118. Ho,P.,Yip,K.,Chow,K.,Lo,J.Y.C.,Que,T.,&
Yuen, K., Antimicrobial resistance among
uropathogens that cause acute uncomplicated
cystitis in women in Hong Kong: a prospective
multicenter study in 2006 to 2008. Diagnostic
microbiology and infectious disease, 2010. 66(1):
p. 87–93.
119. Hoberman, A., Paradise, J.L., Block, S., Burch,
D.J., Jacobs, M.R., Balanescu, M.I., Efficacy of
amoxicillin/clavulanate for acute otitis media:
Relation to Streptococcus pneumoniae susceptiblity.
The Pediatric Infectious Disease Journal, 1996.
15(10):p.955–962.
120. Howard, A.J., Magee, J.T., Fitzgerald, K.A., &
Dunstan, F.D.J., Factors associated with antibiotic
resistance in coliform organisms from community
urinary tract infections in Wales. Journal of
Antimicrobial Chemotherapy, 2001. 47(3): p. 305–313.
121. Hsueh, P., Shyr, J., & Wu, J., Decreased erythromycin
use after antimicrobial reimbursement restriction
for undocumented bacterial upper respiratory
tract infections significantly reduced erythromycin
resistance in Streptococcus pyogenes in Taiwan.
Clinical Infectious Diseases, 2005. 40(6): p. 903–905.
122. Hsueh, P.R., Decreasing rates of resistance to
pencillin, but not erythromycin, in Streptococcus
pneumoniae after introduction of a policy to restrict
antibiotic use in Taiwan. Clinical Microbiology and
Infection, 2005. 11(11): p. 925–927.
123. Hsueh, P.R., Shyr, J.M., & Wu, J.J., Changes in
macrolide resistance among respiratory pathogens
after decreased erythromycin consumption in
Taiwa n . Clinical Microbiology and Infection, 2006.
12(3): p. 296–298.
124. Huang, W.H., P., Methicillin-resistant Staphylococcus
aureus infections in acute rhinosinusitis. The
Laryngoscope, 2006. 116(2): p. 288–291.
125. Hyatt,J.M.,Bhavnani,S.M.,Forrest,A.,Faden,H.,&
Schentag, J.J., Factors associated with changes in
nasopharyngeal strains of Streptococcus pneumoniae
in children from birth through two years of age,
in Thirty-Eight Interscience Conference on
Antimicrobial Agents and Chemotherapy. 1998,
American Society for Microbiology: San Diego,
CA USA. p. 74.
126. Jackson,M.A.,Shelton,S.,Nelson,J.D.,&
McCracken, G.H., Relatively penicillin-resistant
pneumococcal infections in pediatric patients.
Pediatric Infectious Disease, 1984. 3(2): p. 129–132.
127. Jakobsson, H., Wreiber, K., Fall, K., Fjelstad, B.,
Nyren, O., & Engstrand, L., Macrolide resistance
in the normal microbiota after Helicobacter pylori
treatment. Scandinavian Journal of Infectious
Diseases, 2007. 39(9): p. 757–763.
128. Jensen, U.S., Muller, A., Brandt, C.T., Frimodt-
Moller, N., Hammerum, A.M., & Monnet, D. L.
on behalf of the DANRES study group, Effect of
generics on price and consumption of ciprofloxacin
in primary healthcare: the relationship to increas-
ing resistance. Journal of Antimicrobial Chemo-
therapy, 2010. 65(6): p. 1286–1291.
129. Jernigan, J.A., Pullen, A.L., Partin, C., & Jarvis, W.R.,
Prevalence of and risk factors for colonization with
methicillin-resistant Staphylococcus aureus in an
outpatient clinic population. Infection Control and
Hospital Epidemiology, 2003. 24(6): p. 445–450.
130. Jindrak, V., Marek, J., Vanis, V., Urbaskova, P., Vlcek,
J., Janiga, L., & Maresova, V., Improvements in
antibiotic prescribing by community paediatricians
in the Czech Republic. Euro Surveillance, 2008.
13(46): p. pii = 19040.
131. Johnson, S.R., Thompson, R.C.F., Humphreys, H., &
Macfarlane, J.T., Clinical features of patients with
B-lactamase producing Haemophilus influenzae
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 18 of 25
http://www.biomedcentral.com/1471-2334/14/13
isolated from sputum. Journal of Antimicrobial
Chemotherapy, 1996. 38(5): p. 881–884.
132. Kahlmeter, G., Menday, P., & Cars, O., Non-hospital
antimicrobial use and resistance in community-
acquired Escherichia coli urinary tract infection.
Journal of Antimicrobial Chemotherapy, 2003. 52(6):
p. 1005–1010.
133. Kahlmeter, G., Prevalence and antimicrobial
susceptbility of pathogens in uncomplicated cystitis
in Europe. The ECO-SENS study. International
Journal of Antimicrobial Agents, 2003. 22
(Supplement 2): p. S49-S52.
134. Kalter,H.D.,Gilman,R.H.,Moulton,L.H.,Cullotta,
A.R., Cabrera, L., & Velapatino, B., Risk factors for
antibiotic-resistant Escherichia coli in young children
in Peru: community-based cross-sectional prevalence
study. The American Journal of Tropical Medicine
and Hygiene, 2010. 82(5): p. 879–888.
135. Kandemir, O., Akbay, E., Sahin, E., Milcan, A., &
Gen, R., Risk factors for infection of the diabetic foot
with multi-antibiotic resistant microorganisms.
Journal of Infection, 2007. 54(5): p. 439–445.
136. Karpanoja, P., Nyberg, S.T., Bergman, M., Voipio, T.,
Paakkari, P., Huovinen, P., Sarkkinen, H., & the
Finnish Study Group for Antimicrobial Resistance
(FiRe Network), Connection between trimethoprim-
sulfamethoxazole use and resistance in Streptococcus
pneumoniae Haemophilus influenzae, and Mor-
axella catarrhalis. Antimicrobial Agents and
Chemotherapy, 2008. 52(7): p. 2480–2485.
137. Katsarolis, I., Poulakou, G., Analitis, A.,
Matthaiopoulou, I., Roilides, E., Antachopoulos, C.,
Kafetzis, D.A., Daikos, G.I., Vorou, R., Koubaniou,
C., Pneumatikos, I., Samonis, G., Syriopoulou,
V., Giamarellou, H., & Kanellakopoulou, K., Risk
factors for nasopharyngeal carriage of drug-
resistant Streptococcus pneumoniae: data from a
nation-wide surveillance study in Greece. BMC
Infectious Diseases, 2009. 9(1): p. 120–129 ?
138. Kellner, J.D., Ford-Jones, E.L., & Members of the
Toronto Child Care Centre Study Group, Strepto-
coccus pneumoniae carriage in children attending
59 Canadian child care centers. Archives of
Pediatrics and Adolescent Medicine, 1999. 153(5):
p. 495–502.
139. Kristiansson, C., Grape, M., Gotuzzo, E.,
Samalvides, F., Chauca, J., Larsson, M., Bartoloni,
A., Pallecchi, L., Kronvall, G., & Petzold, M.,
Socioeconomic factors and antibiotic use in relation
to antimicrobial resistance in the Amazonian
area of Peru. Scandinavian Journal of Infectious
Diseases, 2009. 41(4): p. 303–312.
140. Kronenberger,C.B.,Hoffman,R.E.,Lezotte,D.
C.,&Marine,W.M.,Invasive penicillin-resistant
pneumococcal infections: A prevalence and histor-
ical cohort study. Emerging Infectious Diseases,
1996. 2(2): p. 121–124.
141. Kwan, G., T.S., Davis, R.L., Shay, D.K., Black, S.,
Shinefield, H., & Koepsell, T., Is household anti-
biotic use a risk factor for antibiotic-resistant
pneumococcal infection? Epidemiology and Infec-
tion, 2002. 129(3): p. 499–506.
142. Leach, A.J., Shelby-James, T.M., Mayo, M., Gratten,
M.,Laming,A.C.,Currie,B.J.,&Mathews,J.D.,A
prospective study of the impact of community-based
azithromycin treatment of trachoma on carriage and
resistance of Streptococcus pneumoniae. Clinical
Infectious Diseases, 1997. 24(3): p. 356–362.
143. Lee, D.S., Lee. C.B., & Lee. S., Prevalence and risk
factors for extended spectrum beta-lactamase-
producing uropathogens in patients with urinary
tract infection. Korean Journal of Urology, 2010.
51(7): p. 492–497.
144. Leflon-Guibout, V., Ternat, G., Heym, B., & Nicolas-
Chanoine, M., Exposure to co-amoxiclav as a risk
factor for co-amoxiclav-resistant Escherichia coli
urinary tract infection. Journal of Antimicrobial
Chemotherapy, 2002. 49(2): p. 367–371.
145. Leman, R., Alvarado-Ramy, F., Pocock, S., Barg,
N., Kellum, M., McAllister, S., Cheek, J., &
Kuehnert, M., Nasal carriage of methicillin-
resistant Staphylococcus aureus in an American
Indian population. Infection Control and Hospital
Epidemiology, 2004. 25(2): p. 121–125.
146. Lescure, F., Locher, G., Eveillard, M., Biendo, M., Van
Agt,S.,LeLoup,G.,Douadi,Y.,Ganry,O.,
Vandenesch, F., Eb, F., Schmit, J., & Etienne,
J., Community-acquired infection with healthcare-
associated methicillin-resistant Staphylococcus aureus:
Theroleofhomenursingcare.Infection Control and
Hospital Epidemiology, 2006. 27(11): p. 1213–1218.
147. Lietzau, S., Sturmer, T., Erb, A., von Baum, H., Marre,
R., & Brenner, H., Prevalence and determinants of
nasal colonization with antibiotic-resistant Staphylo-
coccus aureus among unselected patients attending
general practitioners in Germany. Epidemiology and
Infection, 2004. 132(4): p. 655–662.
148. Lietzau, S., Hoewner, M., von Baum, H., Marre, R.,
&Brenner,H.,Antibiotic resistant fecal isolates of
Enterococci among unselected patients outside the
clinical sector: an epidemiological study from
Southern Germany. Pharmacoepidemiology and
Drug Safety, 2006. 15(4): p. 275–277.
149. Lietzau, S., Raum, E., von Baum, H., Marre, R., &
Brenner, H., Clustering of antibiotic resistance of E
coli in couples: suggestion for a major role of
conjugal transmission. BMC Infectious Diseases,
2006. 6(1): p. 119–123.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 19 of 25
http://www.biomedcentral.com/1471-2334/14/13
150. Lietzau,S.,Raum,E.,vonBaum,H.,Marre,R.,&
Brenner, H., Household contacts were key factor for
children's colonization with resistant Escherichia
coli in community setting. Journal of Clinical
Epidemiology, 2007. 60(11): p. 1149–1155.
151. Livermore,D.M.,Stephens,P.,Weinberg,J.,Johnson,
A.P.,Gifford,T.,Northcutt,D.,James,D.,George,R.C.
&Speller,D.C.E.,Regional variation in ampicillin
and trimethoprim resistance in Escherichia coli in
England from 1990 to 1997, in relation to bacterial
prescribing. Journal of Antimicrobial Chemotherapy,
2000. 46(3): p. 411–422.
152. Livermore, D.M., Reynolds, R., Stephens, P.,
Duckworth, G., Felmingham, D., Johnson, A.P.,
Murchan, S., Murphy, O., Gungabissoon, U.,
Waight, P., Pebody, R., Shackcloth, J., Warner, M.,
Williams, L., & George, R.C., Trends in penicillin
and macrolide resistance among pneumococci in
the UK and the Republic of Ireland in relation to
antibiotic sales to pharmacies and dispensing
doctors. International Journal of Antimicrobial
Agents, 2006. 28(4): p. 273–279.
153. Lucet, J., Chevret, S., Durand-Zaleski, I., Chastang,
C., & Regnier, B., Prevalence and risk factors for
carriage of methicillin-resistant Staphlococcus aur-
eus at admission to the intensive care unit. Archives
of Internal Medicine, 2003. 163(2): p. 181–188.
154. Magee, J.T., Pritchard, E.L., Fitzgerald, K.A.,
Dunstan, D.J. & Howard, A.J., Antibiotic prescribing
and antibiotic resistance in community practice:
retrospective study, 1996–8. British Medial Journal,
1999. 319(7219): p. 1239–1240.
155. Malhotra-Kumar, S., Lammens, C., Coenen, C., Van
Herck, K., & Goossens, H, Effect of azithromycin
and clarithromycin therapy on pharyngeal carriage
of macrolide-resistant streptococci in healthy
volunteers: a randomised, double-blind, placebo-
controlled study. The Lancet, 2007. 369(9560):
p. 482–490.
156. Marton, A.M., Z., Epidemiological studies on
drug resistance in Streptococcus pneumoniae in
Hungary: An update for the 1990s. Microbial
Drug Resistance, 1999. 5(3): p. 201–205.
157. McMahon, B.J., Hennessey, T.W., Bensler, M.,
Bruden, D.L., Parkinson, A.J., Morris, J.M.,
Reasonover, A.L., Hurlburt, D.A., Bruce, M.G.,
Sacco, F., & Butler, J.C., The relationship between
previous antimicrobial use, antimicrobial resistance,
and treatment outcomes for Helicobacter pylori
infections. Annals of Internal Medicine, 2003.
139(6): p. 463–469.
158. Melander, E., Molstad, S., Persson, K., Hansson,
H.B., Soderstrom, M., & Ekdahl, K., Previous
antibiotic consumption and other risk factors for
carriage of penicillin-resistant Streptococcus
pneumoniae in children. European Journal of
Clinical Microbiology and Infectious Diseases,
1998. 17(12): p. 834–838.
159. Melander, E., Ekdahl, K., Jonsson, G., & Molstad,
S., Frequency of penicillin-resistant pneumococci
in children is correlated to community utilization
of antibiotics. Pediatric Infectious Disease Journal,
2000. 19(12): p. 1172–1177.
160. Mera, R.M., Miller, L.A., & White, A.,
Antibacterial use and Streptococcus pneumoniae
pencillin resistance: A temporal relationship
model. Microbial Drug Resistance, 2006. 12(3):
p. 158–163.
161. Metlay,J.P.,Strom,B.L.&Asch,D.A.,Prior
antimicrobial drug exposure: a risk factor for
trimethoprim-sulfamethoxazole-resistant urin-
ary tract infections. Journal of Antimicrobial
Chemotherapy, 2003. 51(4): p. 963–970.
162. Miller, L.G., Perdreau-Remington, F., Bayer, A.S.,
Diep, B., Tan, N., Bharadwa, K., Tsui, J., Perlroth, J.,
Shay, A., Tagudar, G., Ibebuogu, U., & Spellberg, B.,
Clinical and epidemiologic characteristics cannot
distinguish community-associated methicillin-
resistant Staphylococcus aureus infection from
methicillin-susceptible S aureus infection: A pro-
spective investigation. Clinical Infectious Diseases,
2007. 44(4): p. 471–482.
163. Molstad, S., Eliasson, I., Hovelius, B., Kamme, C., &
Schalen, C., Beta-lactamase production in the
upper respiratory tract flora in relation to anti-
biotic consumption: A study in children attending
day nurseries. Scandinavian Journal of Infectious
Diseases, 1988. 20(3): p. 329–334.
164. Moore, M.R., Hyde, T.B., Hennessy, T.W., Parks,
D.J., Reasonver, A.L., Harker-Jones, M., Gove, J.,
Bruden, D.L., Rudolph, K., Parkinson, A., Butler,
J.C., & Schuchat, A., Impact of a conjugate vac-
cine on community-wide carriage of nonsuscepti-
ble Streptococcus pneumoniae in Alaska. The
Journal of Infectious Diseases, 2004. 190(11):
p. 2031–2038.
165. Moran, G.J., Krishnadasan, A., Gorwitz, R.J., Fosheim,
G.E., McDougal, L.K., Carey, R.B., & Talan, D.A.,
Methicillin-resistant S aureus infections among patients
in the emergency department. The New England
Journal of Medicine, 2006. 355(7): p. 666–674.
166. Moreno,F.,Crisp,C.,Jorgensen,J.H.,Patterosn,J.E.,
Methicillin-resistant Staphylococcus aureus as a
community organism. Clinical Infectious Diseases,
1995. 21(5): p. 1308–1312.
167. Moreno, F., Garcia-Leoni, M.E., Cercenado, E., Diaz,
M.D., Bernaldo de Quiros, J.C.L., & Bouza, E., Infec-
tions caused by erythromycin-resistant Streptococcus
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 20 of 25
http://www.biomedcentral.com/1471-2334/14/13
pneumoniae: Incidence, risk factors, and response to
therapy in a prospective study. Clinical Infectious
Diseases, 1995. 20(5): p. 1195–1200.
168. Nasrin, D., Collignon, P.J., Roberts, L., Wilson, E.J.,
Pilotto, L.S., Douglas, R.M., Effect of B lactam
antibiotic use in children on pneumococcal
resistance to penicillin: prospective cohort
study. British Medical Journal, 2002. 324(7328):
p. 28–30.
169. Nava, J.M., Bella, F., Garau, J., Lite, J., Morera, M.,
Marti, C., Fontanals, D., Font, B., Pineda, V., Uriz,
S., Deulofeu, F., Calderon, A., Duran, P., Grau,
M., & Agudo, A., Predictive factors for invasive
disease due to pencillin-resistant Streptococcus
pneumoniae: A population-based study. Clinical
Infectious Diseases, 1994. 19(5): p. 884–890.
170. Neto, A.S., Lavado, P., Flores, P., Dias, R., Pessanha,
M.A., Sousa, E., Palminha, J.M., Canica, M., &
Esperanca-Pina, J. , Risk factors for the nasopharyn-
geal carriage of respiratory pathogens by Portuguese
children: Phenotype and antimicrobial susceptibility
of Haemophilus influenzae and Streptococcus
pneumoniae. Microbial Drug Resistance, 2003. 9(1):
p. 99–108.
171. Neuman, M.I., Kelley, M., Harper, M.B., File,
T.M., & Camargo, C.A., Factors associated
with antimicrobial resistance and mortality in
pneumococcal bacteremia. The Journal of
Emergency Medicine, 2007. 32(4): p. 349–357.
172. Nicoletti, J., Kuster, S.P., Sulser, T., Zbinden, R.,
Ruef, C., Ledergerber, B., & Weber, R., Risk factors
for urinary tract infections due to ciprofloxacin-
resistant Escherichia coli in a tertiary care urology
department in Switzerland. Swiss Medical Weekly,
2010. 140: p. E1-E8.
173. Nielsen, H.U.K., Monet, D.L., Sorensen, T.L.,
Kaltoft,M.,Konradsen,H.B.,&Frimodt-
Moller, N., Relationship between antimicrobial
use and rate of invasive erythromycin-resistant
Streptococcus pneumoniae at county level. Ab-
stracts of the 41st Interscience Conference on Anti-
microbial Agents and Chemotherapy, 2001: p. page
137 Abstract C2-1867.
174. Nielsen, H.U.K.H., A.M., Ekelund, K., Bang, D.,
Pallesen, L.V., & Frimodt-Moller, N., Tetracycline
and macrolide co-resistance in Streptococcus pyo-
genes: Co-selection as a reason for increase in
macrolide-resistant S pyogenes? Microbial Drug
Resistance, 2004. 10(3): p. 231–238.
175. Nilsson, P.L., M.H., Impact of socioeconomic
factors and antibiotic prescribing on pencillin-
non-susceptible Streptococcus pneumoniae in the
city of Malmo. Scandinavian Journal of Infectious
Diseases, 2005. 37(6–7): p. 436–441.
176. Nissinen, A., Gronroos, P., Huovinen, P., Herva, E.,
Katila, M., Klaukka, T., Kontiainen, S., Liimatainen,
O., Oinonen, S., & Makela, P., Development of
B-lactamase mediated resistance to pencillin in
middle-ear isolates of Moraxella catarrhalis in
Finnish children, 1978–1993. Clinical Infectious
Diseases, 1995. 21(5): p. 1193–1196.
177. NORM/NORM-VET, Usage of antimicrobial
agents and occurrence of antimicrobial resistance
in Norway. 2009. http://www.vetinst.no/eng/
Publications/Norm-Norm-Vet-Report/Norm-Norm-
Vet-report-2009
178. Ortega, M., Marco, F., Soriano, A., Almela, M.,
Martinez, J.A., Munoz, A., & Mensa, J., Analysis
of 4758 Escherichia coli bacteraemic episodes:
predictive factors for isolation of an antibiotic-
resistant strain and their impact on the outcome.
Journal of Antimicrobial Chemotherapy, 2009.
63(3): p. 568–574.
179. Panhotra, B.R., Saxena, A.K., & Al Mulhim, A.S.,
Prevalence of methicillin-resistant and methicillin-
sensitive Staphylococcus aureus nasal colonization
among patients at the time of admission to the
hospital. Annals of Saudi Medicine, 2005. 25(4):
p. 304–308.
180. Pedersen, G., Schonheyder, H.C., Steffensen, F.H., &
Sorensen, H.T., Risk of resistance related to antibiotic
use before admission in patients with community-
acquired bacteraemia. Journal of Antimicrobial
Chemotherapy, 1999. 43(1): p. 119–126.
181. Pedersen, G., Schonheyder, H.C., Kristensen, B., &
Sorensen, H.T., Community-acquired bacteraemia
and antibiotic resistance. Danish Medical Bulletin,
2000. 47(4): p. 296–300.
182. Pena,C.,Albareda,J.M.,Pallares,R.,Pujol,M.,
Tubau, F., & Ariza, J., Relationship between
quinolone use and emergence of ciprofloxacin-
resistant Escherichia coli in bloodstream infec-
tions. Antimicrobial Agents and Chemotherapy,
1995. 39(2): p. 520–524.
183. Petrosillo, N., Pantosti, A., Bordi, E., Spano, A., Del
Grosso, M., Tallarida, B., & Ippolito, G., Prevalence,
determinants, and molecular epidemiology of
Streptococcus pneumoniae isolates colonizing the
nasopharynx of healthy children in Rome.
European Journal of Clinical Microbiology and
Infectious Diseases, 2002. 21(3): p. 181–188.
184. Pihlajamaki, M., Kotilainen, P., Kaurila, T.,
Klaukka,T.,Palva,E.,Huovinen,P.&the
Finnish Study Group for Antimicrobial Resistance
(FiRe Network), Macrolide-resistant Streptococcus
pneumoniae and use of antimicrobial agents.
Clinical Infectious Diseases, 2001. 33(4):
p. 483–488.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 21 of 25
http://www.biomedcentral.com/1471-2334/14/13
185. Pradier, C., Dunais, B., Largillier, R., Carsenti-Etesse,
H., Bernard, E., Scheimberg, A., & Dellamonica, P.,
Nasopharyngeal carriage of Streptococcus pneumo-
niae in children's day-care centers: 10-month
follow-up study in Nice, France. Clinical Microbiology
and Infection, 1997. 3(6): p. 705–708.
186. Priest, P., Yudkin, P., McNulty. C. & Mant, D.,
Antibacterial prescribing and antibacterial
resistance in English general practice: cross
sectional study. British Medical Journal, 2001.
323(7320): p. 1037–1041.
187. Radetsky, M.S., Istre, G.R., Johansen, T.L., Parmelee,
S.W., Lauer, B.A., Wiesenthal, A.M., & Glode,
M.P., Multiply resistant pneumococcus causing
meningitis: its epidemiology within a day-care center.
The Lancet, 1981. 2(8250): p. 771–773.
188. Raz, R., Hefter, H. Oren, B. Kennes, Y., Antimicrobial
resistance of urinary isolates in the community
and its relation to antibiotic use. Israel Journal of
Medical Sciences, 1993. 29(4): p. 207–210.
189. Raz, R., Okev, N., Kennes, Y., Gilboa, A., Lavi, I., &
Bisharat, N., Demographic characteristics of patients
with community-acquired bacteriuria and sus-
ceptibility of urinary pathogens to antimicrobials
in Northern Israel IMAJ, 2000. 2(6): p. 426–429.
190. Ready, D., Lancaster, H., Qureshi, F., Bedi, R.,
Mullany, P., & Wilson, M., Effect of amoxicillin
use on oral microbiota in young children.
Antimicrobial Agents and Chemotherapy, 2004.
48(8): p. 2883–2887.
191. Regev-Yochay, G., Raz, M., Shainberg, B., Dagan, R.,
Varon, M., Dushenat, M., & Rubinstein, E.,
Independent risk factors for carriage of pencillin-non-
susceptible Streptococcus pneumoniae. Scandinavian
Journal of Infectious Diseases, 2003. 35(4):
p. 219–222.
192. Reichler, M.R., Allphin, A.A., Breiman, R.F.,
Schreiber, J.R., Arnold, J.E., McDougal, L.K.,
Facklam, R.R., Boxerbaum, B., May, D., Walton, R. O.,
& Jacobs, M.R., The spread of multiply resistant
Streptococcus pneumoniae at a day care center in
Ohio. The Journal of Infectious Diseases, 1992.
166(6): p. 1346–1353.
193. Reichler, M.R., Rakovsky, J., Sobotova, A.,
Slacikova, M., Hlavacova, B., Hill, B., Krajcikova, L.,
Tarina, P., Facklam, R.R., & Breiman, R.F., Multiple
antimicrobial resistance of pneumococci in children
with otitis media, bacteremia, and meningitis
in Slovakia. International Journal of Pediatric
Otorhinolaryngology, 1996. 34(3): p. 288–289.
194. Reinert, R.R., Al-Lahman < A., Lemperie, M.,
Tenholte, C., Briefs, C., Haupts, S., Hubert Gerards,
H., & Lutticken, R., Emergence of macrolide and
penicillin resistance among invasive pneumococci
isolates in Germany. Journal of Antimicrobial
Chemotherapy, 2002. 49(2): p. 61–68.
195. Renneberg, J.R., V.T., Epidemiological studies of
pencillin resistance in Danish Staphylococcus aureus
strains in the period 1977–1990. Scandinavian Journal
of Infectious Diseases, 1992. 24(4): p. 401–409.
196. Rezende, N.A., Blumberg, H.M., Metzger, B.S.,
Larsen, N.M., Ray, S.M., & McGowan, J.E., Risk
factors for methicillin-resistance among patients
with Staphylococcus aureus bacteremia at the
time of hospital admission. The American Journal
of the Medical Sciences, 2002. 323(3): p. 117–123.
197. Ridgway, E.J., Tremlett, C.H., & Allen, K.D.,
Capsular serotypes and antibiotic sensitivity of
Streptococcus pneumoniae isolated from primary-
school children. Journal of Infection, 1995. 30(3):
p. 245–251.
198. Riedel, S., Beekman, S.E., Heilmann, K.P., Richter,
S.S., Garcia-de-Lomas, J., Ferech, M., Goosens, H., &
Doern, G.V., Antimicrobial use in Europe and anti-
microbial resistance in Streptococcus pneumoniae.
European Journal of Clinical Microbiology and
Infectious Diseases, 2007. 26(7): p. 485–490.
199. Ruhe, J.J., & Hasbun, R., Streptococcus pneumoniae
bacteremia: Duration of previous antibiotic use
and association with penicillin resistance. Clinical
Infectious Diseases, 2003. 36(9): p. 1132–1138.
200. Ruhe, J.J., Myers, L., Mushatt, D., & Hasbun, R.,
High-level penicillin-nonsusceptible Streptococcus
pneumoniae bacteremia: Identification of a low-
risk subgroup. Clinical Infectious Diseases, 2004.
38(4): p. 508–514.
201. Saah, A.J., Mallonee, J.P., Tarpay, M., Thornsberry,
C.T., Roberts, M.A., & Rhoades, E.R., Relative
resistance to penicillin in the pneumococcus: A
prevalence and case–control study. Journal of the
American Medical Association, 1980. 243(18):
p. 1824–1827.
202. Samore, M.H., Magill, M.K., Alder, S.C., Severina,
E., Morrison-de Boer, L., Lynn Lyon, J., Carroll, K.,
Leary, J., Bishop Stone, M., Bradford, D., Reading,
J., Tomasz, A., & Sande, M., High rates of multiple
antibiotic resistance in Streptococcus pneumoniae
from healthy children living in isolated rural com-
munities: Association with cephalosporin use and
intrafamilial transmission. Pediatrics 2001. 108(4):
p. 856–865.
203. Samore, M.H., Lipsitch, M., Alder, S.C., Haddadin,
B., Stoddard, G., Williamson, J., Sebastian, K.,
Carroll, K., Ergonul, O., Carmeli, Y., & Sande,
M.A., Mechanisms by which antibiotics promote
dissemination of resistant pneumococci in human
populations. American Journal of Epidemiology,
2005. 163(2): p. 160–170.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 22 of 25
http://www.biomedcentral.com/1471-2334/14/13
204. Sattler, C.A., Mason, E.O., & Kaplan, S.L.,
Prospective comparison of risk factors and
demographic and clinical characterisitcs of
community-acquired, methicillin-resistant versus
methcillin-susceptible Staphylococcus aureus in-
fectioninchildren.Pediatric Infectious Disease
Journal, 2002. 21(10):p.910–916.
205. Sax, H., Harbarth, S., Gavazzi, G., Henry, N.,
Schrenzel, J., Rohner, P., Michel, J.P., & Pittet, D.,
Prevalence and prediction of previously unknown
MRSA carriage on admission to a geriatric hospital.
Age and Ageing, 2005. 34(5): p. 456–462.
206. Schneider-Lindner, V., Delaney, J.A., Dial, S., Dascal,
A., & Suissa, S., Antimicrobial drugs and
community-acquired methicillin-resistant Staphylo-
coccus aureus, United Kingdom. Emerging In-
fectious Diseases, 2007. 13(7): p. 994–1000.
207. Schrag, S.J., Pena, C., Fernandez, J., Sanchez, J.,
Gomez, V., Perez, E., Feris, J.M. & Besser, R.E.,
Effect of short-course, high-dose amoxicillin therapy
on resistant pneumococcal carriage: A randomized
trial. Journal of the American Medical Association,
2001. 286(1): p. 49–56.
208. Seaton, R.A., Steinke, D. T., Philipps, G.,
MacDonald, T., & Davey, P.G., Community
antibiotic therapy, hospitalization and subsequent
respiratory tract isolation of Haemophilus influenzae
resistant to amoxycillin: a nested case–control study.
Journal of Antimicrobial Chemotherapy, 2000.
46(2): p. 307–309.
209. Seppala, H., Klaukka, T., Lehtonen, R., Nenonen,
E., the Finnish Study Group for Antimicrobial
Resistance & Huovinen, P., Outpatient use of
erythromycin: Link to increase erythromycin
resistance in Group A streprococci. Clinical
Infectious Diseases, 1995. 21(6): p. 1378–1385.
210. Skiest, D.J., Brown, K., Cooper, T.W., Hoffman-
Roberts, H., Mussa, H.R., & Elliott, A.C., Pro-
spective comparison of methicillin-susceptible
and methicillin-resistant community-associated
Staphylococcus aureus infections in hospitalized
patients. Journal of Infection, 2007. 54(5): p. 427–434.
211. Skull, S.A., Shelby-James, T., Morris, P.S., Perez,
G., Yonovitz, A., Krause, V., Roberts, L.A., &
Leach, A.J., Streptococcus pneumoniae antibiotic
resistance in Northern Territory children in day
care. Journal of Paediatrics and Child Health,
1999. 35(5): p. 466–471.
212. Sotto, A., DeBoever, C.M., Fabbro-Peray, P., Gouby,
A., Sirot, D., & Jourdan, J., Risk factors for
antibiotic-resistant Escherichia coli isolated from
hospitalized patients with urinary tract infections: a
prospective study. Journal of Clinical Microbiology,
2001. 39(2): p. 438–444.
213. Sportel, J.H., Koeter, G.H., van Altena, R.,
Lowenberg, A., & Boersma, W.G., Relation between
beta-lactamase producing bacteria and patient
characteristics in chronic obstructive pulmonary
disease (COPD) Thorax, 1995. 50:p.249–253.
214. Steinke, D.T., Seaton, R.A., Philipps, G.,
MacDonald, T.M. & Davey, P.G., Factors associated
with trimethoprim-resistant bacteria isolated
from urine samples. Journal of Antimicrobial
Chemotherapy, 1999. 43(6): p. 841–843.
215. Steinke, D.T., Seaton, R.A., Phillips, G., MacDonald,
T.M., & Davey, P., Prior trimethoprim use and
trimethoprim-resistant urinary tract infection: a
nested case–control study with multivariate analysis
and for other risk factors. Journal of Antimicrobial
Chemotherapy, 2001. 47(6): p. 781–787.
216. Sundqvist, M., Antibiotic resistance and population
dynamics of Escherichia coli in relation to a
large scale antibiotic consumption intervention,
in Medicine. 2010, Uppsala University: Uppsala,
Sweden. p. 78.
217. Syrogiannopoulos, G.A., Grivea, I.N., Davies,
T.A., Katopodis, G.D., Appelbaum, P.C., & Beratis,
N.G., Antimicrobial use and colonization with
erythromycin-resistant Streptococcus pneumoniae
in Greece during the first 2 years of life. Clinical
Infectious Diseases, 2000. 31:p.887–893.
218. Syrogiannopoulos, G.A., Katopodis, G.D., Grivea,
I.N., & Beratis, N.G., Antimicrobial use and serotype
distribution of nasopharyngeal Streptococcus
pneumoniae isolates recovered from Greek children
younger than 2 years old. Clinical Infectious
Diseases, 2002. 35(10):p.1174–1182.
219. Tacconelli, E., De Angelis, G., Cataldo, M.A., Pozzi,
E. & Cauda, R., Does antibiotic exposure increase
the risk of methicillin-resistant Staphlococcus
aureus (MRSA) isolation? A systematic review
and meta-analysis. Journal of Antimicrobial
Chemotherapy, 2008. 61(1): p. 26–38.
220. Talan, D.A., Krishnadasan, A., Abrahamian, F.M.,
Stamm, W.E., & Moran, G.J., Prevalence and risk
factor analysis of trimethoprim-sulfamethoxazole-
and fluoroquinolone-resistant Escherichia coli in-
fection among emergency department patients
with pyelonephritis Clinical Infectious Diseases,
2008. 47(9): p. 1150–1161.
221. Tentolouris, N., Jude, E.B., Smirnof, I., Knowles, E.A.,
& Boulton, A.J.M., Methicillin-resistant Staphylococcus
aureus: an increasing problem in a diabetic foot
clinic. Diabetic Medicine, 1999. 16(9): p. 767–771.
222. Tentolouris, N., Petrikkos, G., Vallianou, N., Zachos,
C., Daikos, G.L., Tsapogas, P., Markou, G., &
Katsilambros, N., Prevalence of methicillin-resistant
Staphylococcus aureus in infected and uninfected
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 23 of 25
http://www.biomedcentral.com/1471-2334/14/13
diabetic foot ulcers. Clinical Microbiology and
Infection, 2006. 12(2): p. 186–189.
223. Toltzis, P., Dul, M., O'Riordan, M.A., Toltzis, H., &
Blumer, J.L., Impact of amoxicillin on pneumococcal
colonization compared with other therapies for
acute otitis media. The Pediatric Infectious Disease
Journal, 2005. 24(1): p. 24–28.
224. Toltzis, P., Dul, M., O'Riordan, M.A., Toltzis, H.
& Blumer, J.L., Comparitive effects of single-dose
ceftriaxone versus three oral antibiotic regimens
on stool colonization by resistant bacilli in children.
The Pediatric Infectious Disease Journal, 2007.
26(1): p. 25–30.
225. Tomasson, G., Gudnason, T., & Kristinsson, K.G.,
Dynamics of pneumococcal carriage among healthy
Icelandic children attending day-care centres.
Scandinavian Journal of Infectious Diseases, 2005.
37(6–7): p. 422–428.
226. Troillet, N., Carmeli, Y., Samore, M.H., Dakos, J.,
Eichelberger, K., DeGirolami, P.C. & Karchmer,
A.W., Carriage of methicillin-resistant Staphylococ-
cus aureus at hospital admission. Infection Control
and Hospital Epidemiology, 1998. 19(3): p. 181–185.
227. Tsolia, M., Kouppari, G., Zaphiropuulou, A.,
Gavrili, S., Tsirepa, M., Kafetzis, D., & Karpathhios,
T., Prevalence and patterns of resistance of
Streptococcus pneumoniae strains isolated from
carriers attending day care centers in the area of
Athens. Microbial Drug Resistance, 1999. 5(4):
p. 271–278.
228. Urbanek, K., Kolar, M., Strojil, J., Koukalova, D.,
Cekanova, L., & Hejnar, P., Utilization of
fluoroquinolones and Escherichia coli resistance
in urinary tract infection: inpatients and
outpatients. Pharmacoepidemiology and Drug
Safety, 2005. 14(10): p. 741–745.
229. Ussery, X.T., Gessner, B.D., Lipman, H., Elliot, J.A.,
Crain,M.J.,Tien,P.C.,Parkinson,A.J.,Davidson,M.
Facklam, R.R., & Breiman, R.F., Risk factors for
nasopharyngeal carriage of resistant Streptococcus
pneumoniae and detection of a multiply resistant
clone among children living in the Yukon-Kuskokwim
Delta region of Alaska. The Pediatric Infectious
Disease Journal, 1996. 15(11):p.986–992.
230. van de Sande-Bruinsma, N., Grundmann, H., Verloo,
D., Tiemersma, E., Monen, J., Goossens, H, Ferech, M.,
& the European Antimicrobial Resistance Surveillance
System & European Surveillance of Antimicrobial
Consumption Project Groups, Antimicrobial drug
use and resistance in Europe. Emerging Infectious
Diseases, 2008. 14(11): p. 1722–1730.
231. Van der Veen, E.L., Schilder, A.G.M., Timmers,
T.K., Rovers, M.M., Fluit, A.C., Bonten, M.J., &
Leverstein-van Hall, M.A., Effect of long-term
trimethoprim/sulfamethoxazole treatment on resist-
ance and integron prevalence in the intestinal flora:
a randomized, double-blind, placebo-controlled
trial in children. Journal of Antimicrobial Chemo-
therapy, 2009. 63(5): p. 1011–1016.
232. Van Eldere, J., Mera, R.M., Miller, L.A., Poupard,
J.A., & Amrine-Madsen, H., Risk factors for
development of multiple-class resistance to
Streptococcus pneumoniae strains in Belgium
over a 10-year period: Antimicrobial consump-
tion, population density, and geographic loca-
tion. Antimicrobial Agents and Chemotherapy,
2007. 51(10): p. 3491–3497.
233. Vanderkooi, O.G., Low, D.E., Green, K., Powis, J.E.
& McGeer, A for the Toronto Invasive Bacterial
Disease Network, Predicting antimicrobial resistance
in invasive pneumococcal infections. Clinical
Infectious Diseases, 2005. 40(9): p. 1288–1300.
234. Vasquez, G.A., Siu, H.R., Luna, E.M., Reyes, K.C., &
Zervos, M.J., Risk factors for quinolone-resistant
Escherichia coli urinary tract infection. Infectious
Diseases in Clinical Practice, 2009. 17(5): p. 309–313.
235. Vellinga, A., Murphy, A.W., Hanahoe, B., Bennett,
K., & Cormican, M., A multilevel analysis of
trimethoprim and ciprofloxacin prescribing and
resistance of uropathogenic Escherichia coli in
general practice. Journal of Antimicrobial
Chemotherapy, 2010. 65(7): p. 1514–1520.
236. Volonakis, K., Souli, M., Kapaskelis, A., Bazaika, F.,
Grammelis, V., Ziakas, P.D., & Giamarellou, H.,
Evolution of resistance patterns and identification
of risk factors for Streptococcus pneumoniae
colonization in daycare centre attendees in Athens.
Greece. International Journal of Antimicrobial
Agents, 2006. 28(4): p. 297–301.
237. Weber, P., Plaisance, J., & Mancy, C., Lack of
increase in resistance to quinolones in general
practice isolates of Escherichia coli. Journal
of Antimicrobial Chemotherapy, 1994. 34(1):
p. 187–188.
238. Welby, P.L., Keller, D.S., Cromien, J.L., Tebas, P., &
Storch, G.A., Resistance to pencillin and non-beta-
lactam antibiotics of Streptococcus pneumoniae at
a children's hospital. The Pediatric Infectious
Disease Journal, 1994. 13(4): p. 281–287.
239. Wright, S.W., Wrenn, K.D., Haynes, M.L.,
Trimethoprimn-sulfamethoxazole resistance among
urinary coliform isolates. Journal of General
Internal Medicine, 1999. 14(10): p. 606–609.
240. Wright, S.W., Wrenn, K.D., Haynes, M.L., &
Haas, D.W., Prevalence and risk factors for
multidrug resistant uropathogens in ED patients.
American Journal of Emergency Medicine, 2000.
18(2): p. 143–146.
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 24 of 25
http://www.biomedcentral.com/1471-2334/14/13
241. Yagci, D., Yoruk, F., Azap, A, & Memikoglu, O.,
Prevalence and risk factors for selection of
quinolone-resistant Escherichia coli strains in fecal
flora of patients receiving quinolone therapy.
Antimicrobial Agents and Chemotherapy, 2009.
53(3): p. 1287–1289.
242. Yagupsky, P., Porat, N., Fraser, D., Prajgrod, F.,
Merires, M., McGee, L., Klugman, K.P., & Dagan,
R., Acquisition, carriage, and transmission of
pneumococci with decreased antibiotic susceptibility
in young children attending a day care facility in
southern Israel. . The Journal of Infectious Diseases,
1998. 177(4): p. 1003–1012.
243. Zaidi, M.B., Zamora, E., Diaz, P., Tollefson, L.,
Fedorka-Cray, P.J., & Headrick, M.L., Risk factors for
fecal quinolone-resistant Escherichia coli in Mexican
children. Antimicrobial Agents and Chemotherapy,
2003. 47(6): p. 1999–2001.
Competing interests
The authors declare that they have no competing interests.
Authors’contribution
BB performed the searches, analysed the data, and drafted first sections of
the text. MP designed the study and formulated the hypotheses. FS led the
APRES team. HG and ES provided their expertise in microbiology. MP and BB
are the guarantors. All authors had full access to all of the data (including
statistical reports and tables) in the study and can take responsibility for the
integrity of the data and the accuracy of the data analysis. All authors read
and approved the final manuscript.
Acknowledgements
Carol Coupland provided statistical advice. We also wish to thank our
colleagues in other countries who helped us search the non-English lan-
guage literature: Kathryn Hoffman and Manfred Maier (Austria), Dragan Soldo
(Croatia), Didier Duhot, Gilles Hebbrecht and Andrea Poppelier (France), Joke
Korevaar (Holland), Laszlo Kolozsvari (Hungary), Albert Boada and Boni Bolibar
(Spain), and Sigvard Molstad (Sweden). We want to acknowledge comments
made on an earlier draft by Casper den Heijer (University of Maastricht), Gilles
Hebbrecht (Société Française de Médecine Générale), Samuel Coenen (ESAC)
John Paget (NIVEL), and Evelien van Bijnen (NIVEL).
Funding
This research was funded through the Seventh Framework Programme by
the European Commission as part of the APRES (The Appropriateness of
Prescribing Antibiotics in Primary Health Care with respect to Antibiotic
Resistance) project, led by NIVEL in Utrecht, Holland (project number
223083). The work reported in this paper was led by the University of
Nottingham as part of the APRES project, an EU project investigating
antibiotic resistance in Europe. The views expressed in this publication are
those of the authors and not necessarily those of the University of
Nottingham. The funder had no role in the study design, data collection,
data analysis, interpretation of the data, writing the report, or in the decision
to submit the article for publication. The researchers were independent of
the funder.
Data sharing
Limited to other researchers on personal request.
Author details
1
Division of Primary Care, University of Nottingham, University Park,
Nottingham NG7 2RD, UK.
2
NIVEL (Netherlands Institute for Health Services
Research), PO Box 1568, 3500 BN Utrecht, the Netherlands.
3
Department of
General Practice and Elderly Care Medicine/EMGO Institute for Health and
Care Research, VU University Medical Centre, Amsterdam, the Netherlands.
4
Caphri University of Maastricht/Maastricht, University Hospital, Medical
Microbiology, P.Debyelaan 25, 6229 HX Maastricht, the Netherlands.
5
University of Antwerpen, Universitair Ziekenhuis Antwerpen, Laboratory of
Medical Microbiology, Wilrijkstraat 10, B-2650 Edegem, Belgium.
Received: 10 June 2013 Accepted: 19 December 2013
Published: 9 January 2014
References
1. Kaplan W, Laing R: Priority Medicines for Europe and the World. Geneva:
World Health Organization; 2004.
2. Livermore DM: Bacterial resistance: origins, epidemiology and impact.
Clin Infect Dis 2003, 36(1):S11–S23.
3. Levy SB: Antibiotic resistance: the problem intensifies. Adv Drug Deliv Rev
2005, 57(10):1446–1450.
4. Harbarth SS, Samore MH: Antimicrobial resistance determinants and
future control. Emerg Infect Dis 2005, 11(6):794–801.
5. Summers AO: Generally overlooked fundamentals of bacterial genetics
and ecology. Clin Infect Dis 2002, 34(3):S85–S92.
6. Lipsitch M, Bergstrom CT, Levin BR: The epidemiology of antibiotic
resistance in hospitals: paradoxes and prescriptions. Proc Natl Acad Sci
USA 2000, 97(4):1938–1943.
7. Goossens H, Ferech M, Vander Stichele R, Elseviers M: Outpatient antibiotic
use in Europe and association with resistance: a cross-national database
study. The Lancet 2005, 365(9459):579–587.
8. Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD: Effect of antibiotic
prescribing in primary care on antimicrobial resistance in individual
patients: systematic review and meta-analysis. British Medial Journal 2010,
340(7756):c2096.
9. Lipsey MW, Wilson DB: Practical Meta-Analysis. Thousand Oaks: Sage
Publications; 2001.
10. Moller APJ, Jennions MD: Testing and adjusting for publication bias.
Trends Ecol Evol 2001, 16(10):580–586.
doi:10.1186/1471-2334-14-13
Cite this article as: Bell et al.:A systematic review and meta-analysis
of the effects of antibiotic consumption on antibiotic resistance.
BMC Infectious Diseases 2014 14:13.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit
Bell et al. BMC Infectious Diseases 2014, 14:13 Page 25 of 25
http://www.biomedcentral.com/1471-2334/14/13
