Duration of oral tetracycline-class

antibiotic therapy and use of topical

retinoids for the treatment of acne
among general practitioners (GP):
A retrospective cohort study
John S. Barbieri, MD, MBA,a Ole Hoffstad, MA,b and David J. Margolis, MD, PhDa,b
Philadelphia, Pennsylvania

Background: Guidelines recommend limiting the duration of oral antibiotic therapy in acne to 3 to
6 months and prescribing concomitant topical retinoids for all patients.

Objective: We sought to evaluate the duration of therapy with oral tetracyclines and the use of topical
retinoids among patients with acne treated primarily by general practitioners in the United Kingdom.

Methods: We conducted a retrospective cohort study using the Health Improvement Network database.

Results: The mean duration of therapy was 175.1 days. Of antibiotic courses, 62% were not associated with
a topical retinoid; 29% exceeded 6 months in duration. If all regions were to achieve uses similar to the
region with the shortest mean duration of therapy, approximately 3.3 million antibiotic days per year could
be avoided in the United Kingdom.

Limitations: The Health Improvement Network does not include information on acne severity and clinical
outcomes.

Conclusions: Prescribing behavior for oral antibiotics in the treatment of acne among general practitioners
is not aligned with current guideline recommendations. Increasing the use of topical retinoids and
considering alternative agents to oral antibiotics when appropriate represent opportunities to reduce
antibiotic exposure and associated complications such as antibiotic resistance and to improve outcomes in
patients treated for acne. ( J Am Acad Dermatol 2016;75:1142-50.)

Key words: acne vulgaris; antibiotic resistance; costs; evidence-based medicine; geographic variation; oral
antibiotics; topical retinoids; treatment guidelines.

A cne is one of the most common diseases

worldwide.1,2 In the treatment of acne, both
topical and oral antibiotics are frequently used
and antibiotic use is becoming more prevalent among
Abbreviations used:
GP:
THIN:
UK:
general practitioner
the Health Improvement Network
United Kingdom
both dermatologists and nondermatologist pro-
viders.3-5 Despite the popularity of antibiotics in the
treatment of acne, there are concerns that these Antibiotic therapy is associated with disruption of the
medications may be associated with adverse outcomes. normal oropharyngeal flora and the development of

From the Departments of Dermatologya and Biostatistics and
Epidemiology,b University of Pennsylvania Perelman School of
Medicine.
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication June 28, 2016.
Reprints not available from the authors.
Correspondence to: John S. Barbieri, MD, MBA, Department of
Dermatology, University of Pennsylvania Perelman School of
Medicine, 2 Maloney, 3400 Spruce St, Philadelphia, PA 19104.
E-mail: john.barbieri@uphs.upenn.edu.
Published online August 5, 2016.
0190-9622/$36.00
Ó 2016 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2016.06.057

1142

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J AM ACAD DERMATOL Barbieri, Hoffstad, and Margolis 1143
VOLUME 75, NUMBER 6

pharyngitis,6-10 and tetracycline-class antibiotic use
may be associated with the development of inflamma-
tory bowel disease.11 In addition, antibiotic overuse
and resistance is a growing global concern, both for the
effectiveness of acne therapies and for the treatment of
infectious diseases.12-17 Recent reports have again
raised concerns about the development of bacteria
resistant to all available antibi-
otic therapies.18
Given the complications of CAPSULE SUMMARY
antibiotic therapy in the treat-
ment of acne, there have been Guidelines for acne recommend limiting
d
examine duration of therapy.27 In this study, our goal
was to examine the duration of therapy with oral
tetracyclines and the use of concomitant topical
retinoids for the treatment of acne among GPs
participating in the Health Improvement Network
(THIN) database of the United Kingdom (UK).
METHODS
Data source
This study was a retrospec-
tive cohort study of patients

treated for acne included in

calls to limit the duration of therapy with oral antibiotics and
THIN. THIN is a medical re-
antibiotic use in this setting.15 prescribing topical retinoids for all
cord database used by GPs in
Current guidelines recom- patients.
the UK to track patient clinical
mended limiting the duration In all, 29% of courses of oral tetracyclines
d
information, including patient
of oral antibiotic treatment to prescribed by general practitioners in demographics, medical en-
3 to 6 months.19-26 Guidelines the United Kingdom exceeded 6 months counters, diagnoses, and pre-
released by the Global Allia- and 62% did not include topical scriptions, and it is considered
nce to Improve Outcomes in retinoids. to be representative of the
Acne in 2003 and 2009 rec- Prolonged use of oral antibiotics and lack
d patient population in England
ommended attempting to of concomitant topical retinoids are and Wales with respect to age,
limit the duration of therapy practice gaps. sex, and geographic distribu-
with oral antibiotics to 3 to tion. THIN captures data from
4 months and 3 months, re- software used by GPs to elec-
sepectively.19,20 Further, 2004 tronically prescribe medica-
guidelines released by the European expert group on tions and to receive government reimbursement for
oral antibiotics in acne recommended limiting the these prescriptions. THIN was chosen for this study
duration of therapy with oral antibiotics to 6 months.21 because it is one of the world’s largest sources of high-
In addition, concomitant topical retinoid therapy is quality anonymized longitudinal data from primary
recommended as maintenance in all patients receiving care practices. Previous work has shown that THIN is
oral or topical antibiotics.15,19-21,25 reliable for pharmacoepidemiologic research and it has
Prior studies focused on the duration of antibiotic been used to study multiple common and chronic
therapy among patients who were seen by a derma- conditions, including acne.8,11,28,29
tologist using the MarketScan Commercial Claims For our analysis of medication costs, we used data
and Encounters database found that in the United from the 2014 Prescription Cost Analysis published
States 18% and 16% of courses of oral antibiotics by the National Health Service, which includes all
exceeded 6 months in adolescents and adults, prescriptions written by GPs.30 We used the cost per
respectively. In addition, concomitant topical reti- pill for the most commonly prescribed formulations.
noid therapy was not prescribed in 58% and 69% of Costs were weighted based on the frequency of use
adolescents and adults, respectively.3,4 Although of each type of tetracycline antibiotic identified in
these studies represent some of the most thorough our analysis of acne prescribing practices.
investigation of this topic to date, the MarketScan
database is limited to patients who are continuously Study design and study population
enrolled with the same set of insurers and may Our outcome of interest was the duration of
therefore have incomplete longitudinal data and therapy with tetracycline-class antibiotics among
these studies were limited to 3 years of follow-up. patients with acne and whether these patients were
In addition, these studies only included patients who prescribed a concomitant topical retinoid. All study
were seen by a dermatologist, likely excluding many subjects had a diagnosis of acne as defined by their
patients treated by their general practitioner (GP) diagnostic Read codes and were between the ages of
alone. Because acne is commonly managed by GPs, 12 and 22 years. This age range was chosen because
examining prescribing behaviors in this population patients of this age are likely to have acne and
is also important. Previous work has shown that unlikely to have other chronic conditions for which
preadolescents are more likely to receive antibiotics tetracycline-class antibiotics might be used as treat-
from GPs than from dermatologists, but did not ment, such as rosacea. For our primary outcome, we

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1144 Barbieri, Hoffstad, and Margolis J AM ACAD DERMATOL
DECEMBER 2016

Fig 1. Frequency of oral tetracycline antibiotic therapy by antibiotic type (A) and topical
retinoid therapy by retinoid type (B). Change in frequency of use for types of oral tetracycline
antibiotics (C) and topical retinoids (D) between 2003 and 2013. BPO, Benzoyl peroxide.

then identified patients who received a course of
therapy with a tetracycline-class antibiotic starting
between January 1, 2003, and December 31, 2013.
Oral tetracycline use and topical retinoid use were
defined using the appropriate formulary codes. We
defined a course of therapy as being at least 30 days
in duration to exclude patients who might receive an
antibiotic for an acute illness (eg, Lyme disease,
Rocky Mountain spotted fever). To capture multiple
prescriptions as part of the same course of therapy,
we considered prescriptions with less than a 180-day
gap between the start of the prescriptions as being
part of 1 course of therapy. We defined the start date
of therapy as the date of the first prescription in the
series and the end date of therapy as the date of the
last prescription in the series plus the number of days
of medication supplied. Finally, we excluded
courses of therapy lasting longer than 5 years
(\0.5% of antibiotic courses) to reduce the risk of
overestimating the duration of therapy, because
many of these prescriptions were noted to have
errors in data coding. With respect to topical retinoid
use, we considered any patient who received a
topical retinoid, either before or after starting the
course of antibiotics, to be treated with a concom-
itant topical retinoid. In addition, we conducted
subgroup analysis among the 13 Health Service
Authorities included in THIN to evaluate for
geographic variation in our outcome of interest.
Confounding and bias
We explored for potential confounding by age,
sex, Health Service Authority, and medical practice
in our analyses. Use of prospective data collected by
GPs unaware of the hypotheses in this study mini-
mizes information bias. In addition, selection bias is
minimized, as this is a broadly representative
population-based study.
Statistical analysis
Descriptive statistics are presented using means,
medians, and percentages as appropriate for our

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J AM ACAD DERMATOL
VOLUME 75, NUMBER 6
Fig 2. Frequency of oral tetracycline antibiotic therapy by duration of treatment.
primary outcome of interest. Multivariate linear
regression models were used to evaluate for changes
in prescribing practices over time. Moran’s I, with
weights based on Euclidian distance, was used to
assess for spatial autocorrelation (nonrandom asso-
ciation by geographic location) when conducting
our subgroup analysis stratified by Health Service
Authority. Moran’s I ranges from 1.0, which repre-
sents perfect dispersion (checkerboard pattern), to
11.0, which represents perfect correlation (clustered
pattern).31 Statistical analyses were performed in
Stata 13 (StataCorp, College Station, TX) and
GeoDa (GeoDa Center for Geospatial Analysis and
Computation, Tempe, AZ). This study was approved
the Institutional Review Board of the University of
Pennsylvania and the THIN Scientific Review
Committee.
RESULTS
Cohort
There were 105,914 antibiotic prescriptions
among 79,565 patients identified that met the
inclusion and exclusion criteria for our primary
outcome of interest. The median age of patients
was 16.9 years (interquartile range 15.4-18.9 years)
and 55.2% of patients were male. Fig 1 summarizes
the most commonly prescribed oral antibiotics,
which were lymecycline (39.4%), followed
by oxytetracycline (30.0%), minocycline (18.9%),
doxycycline (10.3%), and tetracycline (1.4%). The
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Barbieri, Hoffstad, and Margolis 1145
most commonly prescribed topical retinoids and
changes in prescribing practices over time are also
summarized in Fig 1.
Main results
The mean duration of therapy was 175.1 days
(95% confidence interval [CI] 174.0-176.2 days). The
median duration of therapy was 112 days (interquar-
tile range 56-224 days). The mean number of pre-
scription as part of course of therapy was 3.93
prescriptions (95% CI 3.90-3.95). In all, 56%, 29%,
and 12% of courses of antibiotics exceeded 3 months,
6 months, and 1 year, respectively (Fig 2). In
addition, 62% of antibiotic courses were not associ-
ated with a concomitant prescription for a topical
retinoid.
Subgroup analyses
With respect to geographic variation, the mean
duration of therapy was 156.5 days and 191.0 days in
the regions with the shortest and longest mean
duration of therapy, respectively. The frequency of
concomitant topical retinoid use ranged from 33% in
the region with the lowest use to 48% in the region
with the highest use (Fig 3). With respect to mean
duration of therapy, Moran’s I was 0.18 (P = .18).
With respect to retinoid use, Moran’s I was 0.075
(P = .46). If all regions were to achieve an average
duration of therapy equal to that of the region using
the shortest mean duration of therapy, 179,202
1146 Barbieri, Hoffstad, and Margolis J AM ACAD DERMATOL
DECEMBER 2016

Fig 3. Quintile maps of geographic variation in mean duration of therapy (A) and use of
concomitant topical retinoids (B).

antibiotic days per year could be avoided in the study
population. If this result is scaled to the population
size of the UK, approximately 3.3 million antibiotic
days per year could be avoided. At an average cost of
$0.27 per pill, we estimate these potentially avoid-
able antibiotic prescriptions are associated with costs
of approximately $1.8 million per year.
Secondary analyses
The mean duration in therapy was 195.3 days
(95% CI 193.4-197.1) in patients who received a
topical retinoid and 162.7 days (95% CI 161.39-
163.98) in patients who did not receive a topical
retinoid. The mean duration of therapy was
162.7 days (95% CI 161.2-164.1) in female patients
and 185.2 days (95% CI 183.7-186.7) in male patients.
In all, 41% of female patients and 35% of male
patients received a concomitant prescription for a
topical retinoid. The addition of medical practice or
Health Service Authority to the model did not have a
significant impact on the outcomes of interest.
Fig 4 summarizes the changes in mean and me-
dian duration of therapy with tetracyclines and
concomitant topical retinoid use over time. After
controlling for age and sex, mean duration of therapy
decreased by 1.43 days per year (95% CI 1.09-1.77)
over the study period. Concomitant use of topical
retinoids increased by an absolute percent increase
of 0.78% per year (95% CI 0.68-0.87%).
DISCUSSION
In this large, retrospective cohort study of patients
with acne treated by GPs in THIN, we found many
courses of oral tetracyclines were not aligned with
current guideline recommendations to limit the
duration of therapy to 3 to 6 months and to use
concomitant topical retinoids in all patients receiving
oral antibiotics.19-26 Only 38% of patients had a
topical retinoid prescribed in this cohort. In addition,
56% of antibiotic courses exceeded 3 months in
duration and 29% exceeded 6 months in duration.
Prior work focused on patients who were seen by
a dermatologist has also shown that prescribing
practices for oral antibiotics and topical retinoids
were not completely aligned with guideline recom-
mendations.3,4,6 In addition, a recent retrospective

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J AM ACAD DERMATOL Barbieri, Hoffstad, and Margolis 1147
VOLUME 75, NUMBER 6

Fig 4. Change in duration of therapy with oral tetracycline antibiotics (A) and concomitant
topical retinoid use (B) between 2003 and 2013.

cohort study found that patients who eventually
received isotretinoin were exposed to a mean
duration of antibiotic use of 331.3 days with 64.2%
receiving antibiotics for 6 months or more.32 In this
population of patients treated primarily by GPs in
THIN, we have found similar results to prior studies
examining patients who had seen a dermatologist,
with infrequent use of concomitant topical retinoids
and with an even greater percentage of courses of
therapy with oral tetracycline antibiotics exceeding
the duration recommended by current guidelines.
Increasing the frequency with which topical
retinoids are prescribed represents an important
opportunity to improve the quality of care for

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1148 Barbieri, Hoffstad, and Margolis
patients with acne, because these are first-line agents
and monotherapy with oral or topical antibiotics is
strongly discouraged in the current guidelines.25 In
addition, multiple studies have shown that concom-
itant and maintenance treatment with topical reti-
noids results in improved outcomes in the setting of
treatment with oral antibiotics.33-36 Given that almost
two thirds of the patients in our study did not receive
a concomitant topical retinoid, ensuring access to
these medications and designing educational or
other interventions that target GPs may be important
steps to address this practice gap. Of note, multiple
consensus guidelines were released during the study
period recommending limiting antibiotic use and
encouraging topical retinoid therapy in all patients,
yet we do not observe any clinically meaningful
changes in prescribing practices in relation to the
release of these guidelines. This finding suggests that
guidelines alone may not be an effective method for
changing prescribing behaviors among GPs. Finally,
because we defined topical retinoid use as any
prescription before or after the start of the antibiotic
course, it is likely that true concomitant topical
retinoid therapy is even less common in clinical
practice than what we have reported in our results.
We have also identified that there is an opportu-
nity to decrease the duration of therapy with oral
tetracyclines, which could reduce the incidence of
complications associated with antibiotics, prevent
the development of antibiotic resistance, and poten-
tially reduce costs to the health system. Although we
did not observe evidence of spatial autocorrelation,
there is substantial geographic variation in prescrib-
ing patterns among our study population, suggesting
that it is possible to treat this population using
shorter courses of antibiotic therapy. Future studies
will be needed to better understand the cause of this
variation, but there may be local factors that are
influencing nearby regions, such as physicians
practicing nearby to where they trained. Based on
this variation, we estimate that approximately 3.3
million antibiotic days per year could be avoided in
the UK. Although it is possible that regions with
lower rates of antibiotic use have poorer outcomes
or patients with less severe acne, we are not aware of
any evidence to support this assertion. In addition, it
is likely that there are opportunities for increased use
of hormonal agents such as oral contraceptive pills
and spironolactone, and for increased use of isotret-
inoin to improve outcomes and reduce duration of
antibiotic exposure in patients with acne. For
instance, a recent meta-analysis found that after
6 months of use, oral contraceptive pills were equally
effective to oral antibiotics in the treatment of acne in
women.37 Given that the most commonly prescribed
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J AM ACAD DERMATOL
DECEMBER 2016
formulations of spironolactone and co-cyprindiol
each cost $0.13 per pill and the least expensive
topical retinoid costs approximately $0.13 per gram
compared with $0.27 per pill for the most commonly
prescribed tetracyclines used for acne, there may be
potential for cost-savings as well.30 Because the
patients in our study are primarily treated by GPs,
there may also be a role for increased use of
dermatology consultations to help treat patients
requiring oral agents and future research is war-
ranted to explore these topics.
Although there are likely opportunities to reduce
the duration of therapy with oral tetracycline antibi-
otics to better align practice patterns with current
guidelines, it is important to note that current
guidelines with respect to duration of therapy with
antibiotics are largely derived from expert opinion.
For some patients who cannot achieve adequate
improvement with topical agents alone and for
whom an alternative oral agent such as isotretinoin
or spironolactone is not feasible or contraindicated,
longer courses of oral antibiotics may be the most
appropriate treatment approach.25 As a result,
although increasing the frequency of treatment
with topical retinoid therapy and attempting to
achieve rates of antibiotic use similar to that of the
regions with the lowest use are clear opportunities to
align prescribing behavior with current guidelines
and to improve quality of care, further research is
needed on the optimal duration of therapy with oral
antibiotics and to identify which patients are most
likely to benefit from alternative agents.
The results of our study should be interpreted in
the context of the study design. Because patients
may not be adherent to prescriptions from their GPs,
our results may overestimate patients’ actual expo-
sure to antibiotics.38 However, the objective of this
study was to evaluate provider prescribing behavior
and adherence to guidelines; therefore, whether or
not the patient took the medication is less relevant
than the intent of the treatment plan prescribed by
the GP. In some prior studies, more conservative
approaches have been used to define a course of
therapy.3,4 Although these more conservative ap-
proaches may fail to capture clinically meaningful
prescriptions as part of the same course of therapy,
we have conducted a more conservative sensitivity
analysis using this alternative approach, which is
available in Supplemental Table I (available at http://
www.jaad.org), with similar results for many of our
key findings including the use of topical retinoids
and potentially avoidable prescribing based on
geographic variation. In addition, because THIN
does not contain information on severity of illness
or clinical outcomes, we are not able to evaluate
J AM ACAD DERMATOL
VOLUME 75, NUMBER 6
these factors in the current study. This study popu-
lation consists of patients treated by GPs in the UK
National Health Service. We do not have data on
dermatology practices and therefore cannot assess
the impact of dermatology consultations on our
outcomes of interest.
In summary, our study highlights that, in this
population of patients treated primarily by GPs in the
UK, concomitant topical retinoids were not pre-
scribed in 62% of antibiotic courses and that 29% of
these courses were longer than the guideline rec-
ommendations of limiting treatment to 3 to 6 months.
Antibiotic overuse and resistance continues to be a
global problem. We all need to practice judicious use
of antibiotics. Increasing the use of topical retinoids
and considering alternative agents to oral antibiotics
when appropriate, such as hormonal agents and
isotretinoin, represent opportunities to reduce anti-
biotic exposure and associated complications such
as antibiotic resistance and to improve outcomes in
patients being treated for acne.
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J AM ACAD DERMATOL Barbieri, Hoffstad, and Margolis 1150.e1
VOLUME 75, NUMBER 6

Supplemental Table I. In this supplement, we describe a very conservative sensitivity analysis with respect to
our definition of whether 2 prescriptions are part of the same course of therapy. In our primary analysis for the
article, we defined prescriptions with a gap of fewer than 180 days from the start of the prescription to the start
of the next prescription to be part of the same course of therapy. We choose 180 days because, to our
knowledge, 180 days is the longest single prescription that can be written by general practitioners in the United
Kingdom. As a very conservative sensitivity analysis, we also examined the impact of using a very short gap of
28 days from the end of the prescription to the start of the next prescription as an alternative definition to
determine whether 2 prescriptions were part of the same course of therapy. The results of this very conservative
sensitivity analysis are displayed in the table below. Although we do observe a decrease in the mean duration
of therapy with this approach, we continue to observe infrequent prescription of concomitant topical retinoids,
and in our analysis of geographic variation, we again identify a substantial opportunity to reduce the duration
and use of antibiotics in the treatment of acne.
180 d, start to start gap 28 d, end to start gap
Mean duration of therapy, d (95% confidence interval) 175.1 (174.0-176.2) 118.2 (117.7-118.7)
Median duration of therapy, d (interquartile range) 112 (56-224) 84 (56-120)
Courses exceeding:
3 mo 59% 45%
6 mo 29% 14%
1y 12% 4%
Courses associated with a topical retinoid 62% 60%
Avoidable antibiotic days per year (United Kingdom) 3.28 million 3.31 million

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