Health services research
Original Article
The antibiotic management of gonorrhoea in
Ontario, Canada following multiple changes in
guidelines: an interrupted time-series analysis
1 2
Catherine Dickson, Monica Taljaard, Dara Spatz Friedman, Gila
4 5 6
Metz, Tom Wong, Jeremy M Grimshaw
Abstract
Objective This study assessed adherence with
first-line gonorrhoea treatment recommendations
in Ontario, Canada, following recent guideline
changes due to antibiotic resistance.
Methods We used interrupted times-series analyses to
analyse treatment data for cases of uncomplicated
gonorrhoea reported in Ontario, Canada, between January
2006 and May 2014. We assessed adherence with first-
line treatment according to the guidelines in place at the
time and the use of specific antibiotics over time. We used
the introduction of new recommendations in the Canadian
Guidelines for Sexually Transmitted Infections in 2008 and
2011 and the release of the province of Ontario’s
Guidelines for the Treatment and Management of
Gonococcal Infections in Ontario in 2013 as interruptions
in the time-series analysis. Results Overall, 34 287
gonorrhoea cases were reported between 1 January 2006
and 31 May 2014. Treatment data were available for 32  summarises each new guideline’s treatment recom-
312 (94.2%). Our analysis included 32 272 (94.1%) cases
without either a conjunctival or disseminated infection.
Following the release of the 2011 recommendations,
adherence with first-line recommendations immediately
decreased to below 30%. Adherence slowly increased but
did not reach baseline levels before the 2013 guidelines
were released. Following release of the 2013 guidelines,
adherence again decreased; adherence is slowly
recovering but by May 2014, was only approximately 60%.
Conclusions Due to concerns about antibiotic
resistance, gonorrhoea treatment guidelines need to be
updated regularly and rapidly adopted in practice. Our
study showed poor adherence following dissemination of
updated guidelines. Over a year after the latest Ontario
guidelines were released, 40% of patients did not receive
first-line treatment, putting them at risk
of treatment failure and potentially promoting further drug
resistance. Greater attention should be devoted to
dissemination and implementation of new guidelines.
Introduction
With current trends in gonorrhoea antimicrobial resis-
tance, we may soon face untreatable multidrug-re-
sistant infections.1 The WHO highlights ‘effective
prevention and control of gonococcal infections’
including ‘appropriate treatment regimens’ as key in
slowing the progression of antimicrobial resistance. 2
3
Clinical guidelines assist clinicians to select appro-
priate treatment regimens. Due to rapidly evolving
resistance patterns, gonorrhoea treatment recommen-
dations have changed frequently. For example, the
Canadian Guidelines on Sexually Transmitted Infec-
tions’ first-line gonorrhoea treatment changed twice
within 4 years: first with the removal of fluoroquino-
lones in 2008,3 then in 2011 with the doubling of
recommended doses of cefixime and ceftriaxone, the
first-line recommendation that ceftriaxone be used to
treat men who have sex with men as well as pharyn-
geal infections, and the addition of combination
gonorrhoea therapy with azithromycin for all cases. 4
In Ontario, Canada’s most populated province, the
2013 Guidelines for the Treatment and Management
of Gonococcal Infections in Ontario introduced a third
change, making intramuscular ceftriaxone plus
azithromycin the only first-line treatment. 5Table 1
mendations.
In Ontario, patients with gonorrhoea are seen and
managed in a variety of settings including sexual
health and STI clinics and community primary care
settings that infrequently manage STIs. While anti-
biotic treatment for gonorrhoea is provided free by
public health in Ontario, patients may need to pay for
the antibiotic treatment out of pocket if seen in
primary care. With frequently changing recommen-
dations, rapid uptake of new guidelines is a concern,
especially among clinicians who rarely treat gonor-
rhoea. Past research has shown that best practice
uptake in gonorrhoea management is limited. 6–13
Few studies have looked at STI guideline adherence in
Canada and none are recent.14 15
The interrupted time-series (ITS) design is a
powerful quasi-experimental approach that can
be used to evaluate the impact of an
intervention such as a policy change in real-
world settings. In this design, outcomes are
measured repeatedly over time, both before and after
the intervention is introduced. A major strength of the
ITS design is that it can account for underlying
secular trends in order to measure the incremental
effect of an intervention. 16 Segmented regression
analysis is typically used to analyse ITS data. The
regression model is specified to compare change
between pre-intervention and postinter-vention, and
can be used to assess both immediate changes (a
sudden change in level following the inter-vention)
and gradual changes (a change in slope).16 17
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Health services research

Table 1  A summary of changes in recommendations on the treatment of gonorrhoea in Canada and Ontario from 2004 to the present
Year Jurisdiction First-line treatment Second-line treatment
2004 (a new version of the guidelines Canada Cefixime 400 mg PO, once Azithromycin 2 g PO, once
was released in 2006 but the treatment OR OR
recommendations remained the
same)26 Ciprofloxacin 500 mg PO, once* Spectinomycin 2 g intramuscular, once
OR
Ofloxacin 400 mg PO, once*
OR
Ceftriaxone 125 mg intramuscular, once
January 2008—chapter was updated in Canada Cefixime 400 mg PO, once Ceftriaxone 125 mg intramuscular, once
January 2010 but recommendations in OR
summary table remained the same3 Azithromycin 2 g PO, once
OR
Spectinomycin 2 g intramuscular, once
OR
Ciprofloxacin 500 mg PO, once
OR
Ofloxacin 400 mg PO, once
December 2011—notice on change Canada— Ceftriaxone 250 mg intramuscular, Cefixime 800 mg PO, once‡+azithromycin 1 g PO, once
published, updated guideline document update once†+azithromycin 1 g PO, once OR
released in 2013.4 OR Azithromycin 2 g PO, once
Cefixime 800 mg PO, once+azithromycin 1 g OR
PO, once Spectinomycin 2 g intramuscular, once+azithromycin 1 g PO,
Once
April 20135 Ontario Ceftriaxone 250 mg intramuscular, one Cefixime 400 mg PO, once+azithromycin 1 g PO, once
dose+azithromycin 1 g PO, one dose OR
Spectinomycin 2 g intramuscular, once+azithromycin 1 g PO,
Once
OR
Azithromycin 2 g PO, once
*If quinolones not contraindicated due to resistance.
†If patient is a man who has sex with men (MSM), or the infection is pharyngeal, this is the only first-line option.
‡iIf patient is an MSM, or the infection is pharyngeal.
recommendations for these infections differ from those for
uncomplicated infections in other sites.4
The purpose of this study was to use interrupted time-
series analysis to evaluate changes in adherence to first-line
gonorrhoea treatment recommendations in Ontario. Our
main hypotheses were that practice would lag behind guideline
changes and that changes in adherence would vary with guideline
releases, based on the scope of the guideline changes. For example,
in 2008, only clinicians prescribing fluoroquinolones would need to
change their behaviour; however, in 2011, all clinicians would need
to double prescribed doses of cephalosporins and prescribe
azithromycin combination therapy, and in 2013, clinicians who have
not already done so would need to begin prescribing ceftri-axone for
all gonorrhoea cases.

Methods
Dataset
We analysed data from Ontario’s Integrated Public Health
Information System (iPHIS). Local Ontario public health units use
iPHIS to submit information on reportable diseases to the Ontario
Ministry of Health and Long Term Care. In Ontario, all physicians
and laboratories are mandated by law to report all diagnosed cases
of gonorrhoea to local public health. Our dataset consisted of all
reported gonorrhoea cases in Ontario between 1 January
2006 and 31 May 2014 and included sex, infection site(s),
treatment, the date the public health was noti-fied, and
whether the patient self-identified as having sex with
members of the same sex.

We excluded cases without treatment data and those with either a

disseminated or conjunctival infection as treatment
 Interrupted time-series analyses
We classified the prescribed antibiotics into drug families
We conducted an interrupted time-series analysis using a segmented
(summarised in online supplementary file S1).
autoregressive linear regression model to analyse changes in the
For each patient, we defined a dichotomous indicator for whether
percentage of cases receiving first-line treatment over time. 17 We
or not the patient had received first-line treatment according to the
segmented the model following the 2008, 2011 and 2013 guide-line
clinical guidelines of the time. Following the release of the Ontario
updates by including a fixed term representing a change in intercept
guidelines in 2013, we considered the provincial guidelines, as the
and a fixed term representing a change in slope to corre-spond with
guidelines of the time. Online supple-mentary file S2 summarises
the timing of each guideline update. This allowed us to evaluate
the criteria used to define adherence to first-line treatment
both sudden and gradual changes in level of guideline adherence or
recommendations.
rate of uptake of current recommendations, after new
Reporting dates were grouped into biweekly time intervals. For
recommendations were introduced. We tested each model for
each interval, we calculated the aggregate percentage of cases
stationarity using the Engle-Granger co-integration test. We tested
receiving first-line treatment and specific antibiotics. We considered for autocorrelation using the Durbin-Watson test. Where autocor-
a guideline to be in effect as of the first biweekly interval in the relation was detected, we included the autoregressive parameters in
month following the guideline’s release. the model. We conducted the analyses using SAS V. 9.4.
2 Dickson C, et al. Sex Transm Infect 2017;0:1–6. doi:10.1136/sextrans-2017-053224
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Health services research

6.6 to 18.4, p<0.0001) and then increased over time, although

Figure 1  Percentage of patients with gonorrhoea in Ontario

receiving first-line treatment according to the treatment guideline
of the time over time from 1 January 2006 to 31 May 2014.

As secondary analyses, using the same modelling strategy, we

conducted separate interrupted times-series analyses for cefixime,
ceftriaxone and each drug family that had been a first-line
gonorrhoea treatment in the past 10 years.
For simplicity and interpretability, all analyses were conducted on
the percentage scale with changes expressed as absolute differences
in percentage. We examined the fit of the models using log-
likelihood ratio tests, histograms of residuals, normal probability
plots and partial autocorrelation function plots. To account for
potential non-linear trends over time and/or devi-ations from the
normal assumption, we repeated the analyses on the log-odds (logit)
scale, with changes expressed as relative differences.

Ethics approval for this study was obtained from the Ottawa
Health Science Network Research Ethics Boards (approval number
OHSN-REB 20140074–01H).

Results
Overall, 34 287 gonorrhoea cases were reported between 1 January
2006 and 31 May 2014. Treatment data were available for 32 312
(94.2%) cases. Our analysis included 32 272 (94.1%) cases without
either a conjunctival or disseminated infection. The monthly number
of cases increased gradually over time (135 cases in the first
biweekly period; 224 in the final biweekly period). Online
Supplementary file 3 shows the monthly distri-bution of cases.

Adherence to first-line treatment recommendations

Figure 1 shows the observed and model-based adherence
rates. The results of the segmented regression analysis are
presented in table 2. Initially, approximately 90% of cases
received guide-line-recommended first-line treatment; this
remained relatively stable until a small reduction in use of
first-line treatment, which did not improve with time, prior
to the 2011 guideline change. After the 2011 update to the
Canadian recommendations, there was a sudden absolute
decline in first-line treatment to 21.9% (a 61.4% absolute
decrease over that expected, 95% CI: 56.3 to 66.5, p<0.0001)
followed by a gradual increase in uptake over time
(p<0.0001), reaching 58.3% just prior to the 2013 release of
the Ontario guidelines. Following the introduction of the
2013 Ontario guidelines, use of first-line treatment
decreased to 42.2% (a 12.5% absolute decrease over that
expected, 95% CI:
 segmented regression analyses are presented in online
Table 2  Segmented regression analysis of percent adherence supplementary file 4
to guidelines of the time for gonorrhoea treatment, showing . Until 2011, the relative frequencies of cefixime and ceftriaxone
regression coefficient estimates, standard errors and p values use remained around 85% and below 5%, respectively. After the
2011 guideline change, cefixime use dropped from 85.3% to
Regression
coefficient SE p Value 79.0% (a 5.8% absolute decrease over that expected, 95% CI: 1.4 to
10.3, p=0.002) while ceftriaxone use increased from 8.9% to 14.5%
2004 Canadian Guidelines on Sexually
Transmitted Infections update (measured as of
(a 4.9% absolute increase over that expected, 95% CI: 1.4 to 8.4,
1 January 2006) p=0.007). Following these recommendations, the relative frequency
Intercept 91.5 2.02 <0.0001 of cefixime use decreased (p<0.0001) and the relative frequency of
Baseline trend 0.02 0.06 0.703
ceftriaxone use increased over time (p<0.0001). With the
introduction of the 2013 Ontario recom-mendations, an immediate
2008 Canadian Guidelines on Sexually
Transmitted Infections update (January 2008) drop in cefixime use from 61.1% to
Level change after 2008 guideline change −3.92 2.26 0.085
39.1% (a 21.5% absolute decrease over that expected, 95% CI:
17.0 to 26.0, p<0.0001) and a corresponding increase in ceftri-
Trend change after 2008 guideline change −0.09 0.07 0.199
axone use from 36.3% to 58.9% (a 22.1% absolute increase over
2011 Canadian Guidelines on Sexually
Transmitted Infections update (December 2011)
that expected, 95% CI: 17.8 to 26.4, p<0.0001) were observed.
Following the new recommendations, ceftriaxone use continued to
Level change after 2011 guideline change −61.4 2.59 <0.0001
increase and cefixime use continued to decrease at levels not
Trend change after 2011 guideline change 1.13 0.12 <0.0001
different than those following the introduction of the 2011 Canadian
2013 Guidelines for Testing and Treatment of
recommendations. By May 2014, 71.6% of cases were treated with
Gonorrhoea in Ontario (April 2013)
ceftriaxone and 26.3% of cases were treated with cefixime,
Level change after 2013 guideline change −12.5 3.03 <0.0001
suggesting that most patients receiving non-first-line treatment were
Trend change after 2013 guideline change −0.59 0.20 0.004
treated with cefixime.
In early 2011, when a decrease in adherence to first-line
treatment recommendations not related to a new guideline was
at a slower rate than before (p=0.0042). By the end of the study,
noted, a small decline in cefixime use and corresponding rise in
adherence to first-line recommended treatment had reached 59.1%,
ceftriaxone use were observed.
substantially lower than at the beginning of the obser-vation period.
Use of main antibiotic families
Online supplementary file S5 shows the observed and model-based
Specific antibiotic use
use of antibiotic families over time, while
Figure 2 presents the observed and model-based cefixime
and ceftriaxone prescription patterns. The results of the
Dickson C, et al. Sex Transm Infect 2017;0:1–6. doi:10.1136/sextrans-2017-053224 3
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Health services research
Figure 2  Percentage of patients with gonorrhoea in
Ontario receiving cefixime and ceftriaxone over time from 1
January 2006 to 31 May 2014.
online supplementary file S6 shows the results of the segmented
regression analyses. Initial cephalosporin (including cefixime and
ceftriaxone) use was 87.5% and increased gradually with no
changes in trend corresponding to any guideline change. The rate of
macrolide use (mainly azithromycin) increased with both the
introduction of the 2011 Canadian guideline change and the 2013
Ontario guideline. The rate of fluoroquinolone use (not a first-line
option since 2008) started at 12.4% and gradually decreased with a
small number of cases (2.4%) still receiving fluoroquinolones in
2014.
Initial rate of macrolide use (including azithromycin) was 74.6%,
likely because treatment for chlamydia was recom-mended for
people with gonorrhoea unless a negative test result is available.
Following the release of the 2011 update that recommended
combination therapy for all cases with azithro-mycin, a sudden
increase in macrolide use from 69.7% to 76.2% (a 6.2% absolute
increase over that expected, 95% CI: 3.4 to 9.0, p<0.0001) was
observed followed by increased uptake over time. Following the
introduction of the 2013 Ontario guide-lines, another sudden
increase in uptake from 86.2% to 90.5% (a 4.3% absolute increase
over that expected, 95% CI: 0.7 to 8.0, p=0.022) was noted followed
by a continued rise.
Discussion
This study showed that adherence to first-line treatment recom-
mendations for gonorrhoea in Ontario, Canada, decreased following
guideline changes; these effects were greater following major
changes in recommendations.
Our study was unique in its longitudinal analysis of clinician
behaviour across multiple changes in gonorrhoea treatment
guidelines. Other studies have undertaken cross-sectional anal-ysis
of adherence to guideline first-line treatment recommen-dations, 8 9
11 examined changes in guideline adherence over time 7 or
compared behaviour before and after a single guideline change. 6 10
12 Two studies used interrupted time-series analyses to assess
fluoroquinolone use before and after the US guidelines stopped
recommending its use.6 10 Studies that compared adher-ence
patterns between practitioner groups found that guideline adherence
varied by geographical location,6 7 11 type of practice
(eg, specialised STI or genitourinary medicine clinics are more
likely to adhere to guidelines) 7 9 11–13 and number of gonor-
rhoea cases treated at a location or by a provider. 8 12 US studies
4 Dickson C, et al. Sex Transm Infect 2017;0:1–6. doi:10.1136/sextrans-2017-053224
group.bmj.com
on ceftriaxone use found higher guideline adherence than our
study.7 8 11 12
Our study has several limitations. The iPHIS database was
designed for administrative purposes and only includes infor-mation
reported to public health. Treatment information may be incomplete
if a patient is re-treated without notifying public health. Data are
collected and entered locally, and methods may differ between
health units. A second limitation is that we did not consider
treatment dates when determining whether a patient had received
first-line treatment. Some cases received multiple courses of
treatment and were considered as having received the first-line
treatment if they received the appropriate dose(s) of antibiotics at
any point. The proportions of cases receiving first-line treatment
would have been lower if we had only considered those who
initially received the recommended treatment or who received both
combination therapy drugs at the same time as having received
first-line treatment. Third, we assumed that cases not treated
according to first-line treat-ment recommendations were treated by
clinicians not following guidelines; it is possible that in some cases,
the treating clini-cian was selecting an alternative treatment
informed by a culture and sensitivity analysis. Finally, for
simplicity of interpretation, we conducted analyses using an
additive model and assuming a linear trend over time. Inspection of
histograms of residuals and normal probability plots revealed no
major departures from the modelling assumptions, and sensitivity
analyses conducted on the log-odds scale (not presented) did not
change the substantive conclusions of our analyses.
To examine other factors coinciding with guideline changes that
might influence physician behaviour, we searched Pubmed and
Canadian Newstand, looking for articles in major medical journals
and news stories on gonorrhoea in the 3 months before and after
each recommendation was released. Publications found in both
medical journals and national or Ontario-based news-papers
highlighted antimicrobial resistance trends and likely would have, if
anything, promoted guideline use (the publica-tions are summarised
in supplementary file S7). We similarly investigated the decline in
guideline adherence and increase in ceftriaxone use in early 2011
that was not related to a guide-line change. We searched the same
databases for publications between 1 November 2010 and 30 June
2011. Case reports of treatment failure with cephalosporins in
Europe and Japan18–21 were published during this time. In
addition, cases of cefixime treatment failure in Toronto were
reported in early 2011. 22 Some clinicians may have been aware of
these cases and preemp-tively changed their prescribing behaviour.
To date, Canadian and Ontario STI guidelines have largely been
disseminated through passive strategies, such as journal
publications, webinars, conference presentations, web mate-rials
and mobile applications. The relatively slow uptake of new
Canadian and Ontario treatment recommendations seen in this study
suggests the need for more effective dissemination and
implementation strategies. Active dissemination strategies, such as
educational outreach, working with opinion leaders, elec-tronic
reminders, and audit and feedback, tailored to address the barriers
faced by the targeted clinicians have been shown to be effective in
promoting changes in practice.23 24 Such inter-ventions should
ideally be designed to allow for rigorous evalu-ation of their
impact, for example, by using parallel arm cluster randomised
controlled designs, or stepped wedge designs with staggered
implementation of the intervention across an entire health
system.24 25
Ineffective gonorrhoea treatment has broad public health
implications, through permitting transmission of infection,
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promoting drug resistance and putting individuals at risk of
complications of infection. As gonorrhoea treatment recom-
mendations will continue to change in response to antimicro-bial
resistance patterns, guideline developers and public health systems
should consider ways to enhance uptake. This could also be relevant
to developers of guidelines for other infections with similarly
rapidly evolving resistance patterns. As STIs are managed in a
variety of settings, future research could explore the determinants of
recommendation adherence following the introduction of new
guidelines in order to identify targets for enhanced dissemination
efforts.
Key messages
►► Appropriate treatment of gonorrhoea infections is
important to keep up with changes in antibiotic
resistance patterns and to avoid treatment failure.
►► After major guideline changes, the proportion of
patients receiving first-line treatment for
gonorrhoea infections decreased dramatically
followed by a gradual uptake over time.
►► After a guideline change, there is the risk that older
potentially less effective regimens will be used.
►► Active guidelines dissemination and implementation strategies
may accelerate the uptake of new recommendations.
Author affiliations
1
Medical Resident,School of Epidemiology, Public Health and Preventive
Medicine, University of Ottawa, Alta Vista Campus Room, Ottawa, Canada
2 6 Dowell D, Tian LH, Stover JA, et al. Changes in fluoroquinolone
Department of Clinical Epidemiology Program, Ottawa Hospital Research
Institute, The Ottawa Hospital, Civic Campus, Ottawa, Canada
3
Department of Epidemiologist, Ottawa Public Health, Ontario, Canada
4
Medical Director for Sexual Health, Ottawa Public Health, Ottawa, Canada
5
Office of Population and Public Health, First Nations and Inuit Health
Branch, Health Canada, Ottawa, Canada
6 8
Department of Clinical Epidemiology Program, Ottawa Hospital
Research Institute, Center for Practice Changing Research
Building, The Ottawa Hospital, General Campus, Ottawa, Canada
Contributors  CD developed the research protocol, worked with Public
Health Ontario to obtain the data sets, conducted the data analysis and
conducted the majority of the writing of the manuscript. MT provided guidance
on the statistical analyses and the interpretation of the results, and revised the
manuscript critically for important intellectual content. GM provided guidance
on the planning of the manuscript, and revised the manuscript critically for
important intellectual content. DSF provided guidance on the planning of the
manuscript, assisted with data access, and revised the manuscript critically
for important intellectual content. TW provided guidance on the planning of
the manuscript, and revised the manuscript critically for important intellectual
content. JG provided guidance on the planning of the manuscript, and revised
the manuscript critically for important intellectual content.
Funding  No funding was received for this study. JMG holds a Canada
Research Chair for Health Knowledge Transfer and Uptake. The corresponding
author has the right to grant on behalf of all authors and does grant on behalf of
all authors, an exclusive licence (or non-exclusive for government employees)
on a worldwide basis to the BMJ Publishing Group to permit this article (if
accepted) to be published in STI and any other BMJ PGL products and
sublicences such use and exploit all subsidiary rights, as set out in our licence
http://group.bmj.com/products/journals/instructions- for-authors/licence-forms.
Competing interests  All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and declare no support from
any organisation for the submitted work; no financial relationships with any
organisations that might have an interest in the submitted work in the previous three
years; no other relationships or activities that could appear to have influenced the
submitted work. In accordance with the authorship criteria of the ICMJE,
all authors provided final approval prior to the submission of the
manuscript, and all authors agree to be accountable for all aspects of the
work in ensuring that questions related to the accuracy or integrity of any
part of the work are appropriately investigated and resolved.
Health services research
Patient consent  Detail has been removed from this case
description/these case descriptions to ensure anonymity. The editors
and reviewers have seen the detailed information available and are
satisfied that the information backs up the case the authors are making.
Ethics approval  Ottawa Health Science Network Research Ethics
Board (OHSN-REB) – IRB00002616, protocol #: 20140074-01H.
Provenance and peer review  Not commissioned; externally peer reviewed.
Data sharing statement  No additional data is available. Anyone interested in
obtaining the data would need to contact Public Health Ontario.
© Article author(s) (or their employer(s) unless otherwise stated in
the text of the article) 2017. All rights reserved. No commercial use
is permitted unless otherwise expressly granted.
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