Trends in prescribing behavior of

systemic agents used in the treatment

of acne among dermatologists and
nondermatologists: A retrospective
analysis, 2004-2013
John S. Barbieri, MD, MBA,a William D. James, MD,a and David J. Margolis, MD, PhDa,b
Philadelphia, Pennsylvania

Background: Despite recommendations to limit the use of oral antibiotics and increasing support for
hormonal agents in the treatment of acne, it is unclear whether there have been any significant changes in
practice patterns.

Objective: To characterize changes in prescribing behavior for systemic agents in the treatment of acne in
the United States between 2004 and 2013.

Methods: We conducted a retrospective analysis using the OptumInsight Clinformatics DataMart (Optum,
Eden Prairie, MN).

Results: The number of courses of spironolactone prescribed per 100 female patients being managed for
acne by dermatologists and nondermatologists increased from 2.08 to 8.13 and from 1.43 to 4.09,
respectively. The median duration of therapy with oral antibiotics was 126 and 129 days among patients
managed by dermatologists and nondermatologists, respectively, and did not change significantly over the
study period.

Limitations: The OptumInsight Clinformatics DataMart lacks information on acne severity and clinical
outcomes.

Conclusions: Additional work to identify patients who would benefit most from alternative therapies such
as spironolactone, oral contraceptives, or isotretinoin represents a potential opportunity to improve the
care of patients with acne. ( J Am Acad Dermatol 2017;77:456-63.)

Key words: acne vulgaris; antibiotic resistance; evidence-based medicine; guideline nonadherence;
isotretinoin; oral antibiotics; spironolactone; tetracyclines; topical retinoids; treatment guidelines.

A cne is one of the most common diseases
worldwide.1,2 Although mild acne can
typically be managed with topical therapies,
for moderate to severe acne, a variety of systemic
agents are often used, including oral antibiotics,
combined oral contraceptives, spironolactone, and
isotretinoin.3
Considering systemic therapies, oral antibiotics
are among the most frequently prescribed medica-
tions. For years, there have been concerns about the

From the Department of Dermatologya and Department of
Biostatistics and Epidemiology,b University of Pennsylvania
Perelman School of Medicine, Philadelphia.
Funding sources: None.
Conflict of interest: None declared.
Dr Barbieri had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of
the data analysis.
Accepted for publication April 14, 2017.
Reprints not available from the authors.
Correspondence to: John S. Barbieri, MD, MBA, 2 Maloney, 3400
Spruce St, Philadelphia, PA 19104. E-mail: john.barbieri@uphs.
upenn.edu.
Published online July 1, 2017.
0190-9622/$36.00
Ó 2017 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2017.04.016

456
J AM ACAD DERMATOL Barbieri, James, and Margolis 457
VOLUME 77, NUMBER 3

excessive use of antibiotics throughout medicine.4 In Study design and study population
fact, dermatologists prescribe more antibiotics per Patients who were continuously enrolled in the
capita than any other specialty.5 However, concerns OptumInsight Clinformatics DataMart with at
that these medications may be associated with least 2 claims associated with an International
adverse outcomes, including pharyngitis, inflamma- Classification of Diseases, 9th or 10th Revision,
tory bowel disease, and the development of code for acne separated by 12 months and who
antibiotic resistance, have resulted in calls to reduce were 12 to 40 years of age at the start date of their
antibiotic use in the treat- course of therapy were
ment of acne.6-12 Current included in the study popu-
guidelines, which are largely CAPSULE SUMMARY lation.2,24,25 In addition,
based on expert opinion, sensitivity analyses using
d Guidelines for acne recommend limiting
recommend limiting the inclusion criteria of 2 claims
therapy with oral antibiotics.
duration of oral antibiotic associated with a code for
treatment to 3 to 6 months, d Spironolactone use for acne is increasing, acne separated by 3 months
although the most recent although it remains relatively and 18 months were
American Academy of infrequently utilized when compared performed. Patients with
Dermatology guidelines also with oral antibiotics. any diagnosis of rosacea, for
note that there is a subset d Identifying patients who would benefit which extended courses of
of patients who are not most from alternative agents such as oral tetracyclines are also
appropriate for alternative spironolactone, oral contraceptives, or commonly used as therapy,
therapies and may require isotretinoin represents a potential were excluded.26 Patients
longer courses of oral anti- opportunity to improve care for patients who had at least 1 claim for
biotics.3,13-17 with acne. acne with a provider coded
Despite these recent rec- as a dermatologist were
ommendations regarding the considered to have been
importance of antibiotic stewardship and appro- seen by a dermatologist; otherwise, the patient
priate use of antibiotics in patients with acne, it is was considered to have been managed by
unclear whether there have been any significant nondermatologists.
changes in practice patterns. In addition, although Prescriptions for oral antibiotics, combined oral
increased utilization of hormonal agents such as contraceptives, spironolactone, and isotretinoin
spironolactone and combined oral contraceptives were identified by their National Drug Code
and earlier initiation of isotretinoin in patients with numbers. These prescriptions were consolidated
severe acne may represent opportunities to reduce into courses of therapy, for which the start date of
antibiotic exposure, how utilization of these agents therapy was defined as the date of the first
has changed over time is unknown.18-23 In this study, prescription in the series and the end date of
our aim was to characterize changes in prescribing therapy was defined as the date of the last prescrip-
behavior for each of these systemic agents in the tion in the series plus the number of days of
treatment of acne among both dermatologists and medication supplied. Because adherence to
nondermatologists in the United States between 2004 long-term medications is imperfect and may result
and 2013. in delays between prescriptions,27-30 prescriptions
separated by fewer than 30 days were considered to
be part of a single course of therapy.24-26 To avoid
METHODS including prescriptions for antibiotics prescribed for
Data source acute illnesses (eg, Lyme disease, Rocky Mountain
This study was a retrospective analysis of patients spotted fever), courses of therapy lasting fewer than
treated for acne using the OptumInsight 30 days were excluded. Finally, because we did not
Clinformatics DataMart (Optum, Eden Prairie, MN) have data after December 31, 2014, we limited our
between 2004 and 2014. The OptumInsight analysis to courses of therapy started before 2014 to
Clinformatics DataMart includes deidentified ensure at least 1 year of potential follow-up after the
commercial claims data for approximately 12 to 14 start of therapy to reduce the risk of introducing bias
million annual covered lives, for a total of roughly 56 toward a shorter duration of therapy.
million unique covered lives in the data set. These The primary outcome of interest was the number
data include both medical and pharmacy claims, as of courses of therapy with oral antibiotics, combined
well as patient demographic information such as age oral contraceptives, spironolactone, and isotretinoin
and sex. prescribed by dermatologists and nondermatologists
458 Barbieri, James, and Margolis
during the study period and changes to the
frequency of their use over time. To account for
changes in the number of patients being treated for
acne in the database over time, we divided the
number of courses of therapy prescribed each year
by the number of patients who were being managed
for acne during the same year as the start date of the
course of therapy. The number of patients being
managed for acne in each year was defined as the
number of patients who had visits with a diagnosis
code for acne that included the calendar year of
interest.
Secondary outcomes included subgroup analyses
among female and male patients, as well as among
adolescents and adults, who were defined as those
age 21 years and younger and those age 22 and older,
respectively. We also evaluated changes in the
duration of therapy with oral antibiotics over time
and the frequency of concomitant topical retinoid
use for patients receiving oral antibiotics. 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 have
been treated with a concomitant topical retinoid.
Statistical analysis
Descriptive statistics are presented with means,
medians, and percentages as appropriate for our
outcomes of interest. Poisson regression models
were used to evaluate for changes in prescribing
practices over time. Poisson regression was chosen
because our outcome of interest was a count variable.
Because the Global Alliance to Improve Outcomes in
Acne guidelines were released in 2003 and 2009, we
evaluated the time periods 2004-2009 and 2010-2013
with our regression models to assess for potential
changes associated with these guideline releases.13,14
Statistical analyses were performed with Stata 13 and
Stata 14 software (StataCorp, College Station, TX).
The institutional review board of the University of
Pennsylvania has granted a blanket exemption for all
research completed at the University of Pennsylvania
using OptumInsight data.
RESULTS
Cohort
There were 572,630 unique patients identified in
the in OptumInsight Clinformatics DataMart between
2004 and 2014 who met the inclusion and exclusion
criteria. Of these patients, 89% had seen a dermatol-
ogist at least once. The median duration of continuous
enrollment in the database was 2496 days (interquar-
tile range 1491-3652 days). The median age at the time
of the first available diagnosis of acne was 18 years
(interquartile range 15-27 years), and 65.0% of
J AM ACAD DERMATOL
SEPTEMBER 2017
patients were female. We identified 594,776 courses
of therapy among 298,439 unique patients for oral
antibiotics, 527,288 courses of therapy among 284,314
patients for combined oral contraceptives, 61,042
courses of therapy among 30,855 patients for spiro-
nolactone, and 108,664 courses of therapy among
90,870 patients for isotretinoin.
Trends in therapies prescribed
Fig 1 and Tables I and II summarize trends in
prescribing practices over the study period. Among
patients who saw a dermatologist, the number of
courses of spironolactone prescribed per 100 female
patients with acne increased from 2.08 to 8.13 during
the study period, representing a 291% increase in
use. The number of courses of combined oral
contraceptives prescribed per 100 female patients
with acne decreased from 34.31 to 30.74 over the
study period. The number of courses of oral
antibiotics prescribed per 100 patients with acne
increased from 26.24 to 27.08 during the study
period. The number of courses of isotretinoin
prescribed per 100 patients with acne decreased
from 5.43 to 5.35 over the study period. Among
patients managed by nondermatologists, the number
of courses of spironolactone prescribed per 100
female patients with acne increased from 1.43 to
4.09 during the study period, representing a 186%
increase in use. The number of courses of combined
oral contraceptives prescribed per 100 female
patients with acne increased from 31.70 to 32.13
over the study period. The number of courses of oral
antibiotics prescribed per 100 patients with acne
increased from 19.99 to 22.48 during the study
period. The number of courses of isotretinoin
prescribed per 100 patients with acne decreased
from 2.24 to 1.45 over the study period. In our
sensitivity analyses with different inclusion criteria
for the diagnosis of acne, we did not find any notable
differences in our results (Supplemental Fig 1;
available at http://www.jaad.org).
Among adult female patients seen by a dermatol-
ogist, the number of courses of spironolactone
prescribed per 100 women with acne increased
from 3.06 to 13.81 during the study period,
compared with an increase of 1.01 to 4.38 among
adolescent female patients seen by a dermatologist.
Among adult female patients managed by nonder-
matologists, the number of courses of
spironolactone prescribed per 100 women with
acne increased from 3.18 to 10.66 during the
study period, compared with an increase of
0.73 to 2.18 among adolescent female patients
managed by nondermatologists (Supplemental Figs
2 and 3; available at http://www.jaad.org).
J AM ACAD DERMATOL Barbieri, James, and Margolis 459
VOLUME 77, NUMBER 3

Fig 1. Change in the number of courses of therapy per 100 patients seen by a dermatologist
(A) and managed by nondermatologists (B) between 2004 and 2013. Tetracyclines include
doxycycline and minocycline. Other antibiotics includes trimethoprim-sulfamethoxazole,
amoxicillin, cephalexin, and azithromycin. COC, Combined oral contraceptive. *Combined
oral contraceptives, drospirenone, and spironolactone were evaluated among only female
patients with acne.

Table I. Summary of changes in prescribing behavior between 2004 and 2013 for systemic agents among
patients seen by a dermatologist
Courses per 100 acne patients Incidence rate ratio (95% CI)
Systemic agent 2004 2010 2013 2004-2009 2010-2013
Isotretinoin 5.43 4.12 5.35 0.990 (0.948-1.036) 1.105 (1.010-1.209)
Spironolactone* 2.08 4.10 8.13 1.121 (1.115-1.126) 1.259 (1.233-1.285)
All COCs* 34.31 29.65 30.74 1.016 (0.982-1.050) 1.012 (0.984-1.040)
Drospirenone COCs* 6.00 6.84 4.22 1.136 (1.070-1.206) 0.842 (0.815-0.870)
Other COCsy 28.31 22.81 26.52 0.978 (0.949-1.009) 1.053 (1.028-1.079)
All antibiotics 26.24 22.90 27.08 0.982 (0.972-0.992) 1.056 (1.051-1.061)
Tetracyclines 20.92 18.79 21.92 0.989 (0.980-0.999) 1.051 (1.042-1.059)
Nontetracyclines 5.32 4.11 5.16 0.951 (0.934-0.967) 1.080 (1.068-1.092)
TMP-SMX 2.98 2.32 2.96
Amoxicillin 1.43 1.01 1.22
Cephalexin 0.75 0.56 0.76
Azithromycin 0.16 0.21 0.22

CI, Confidence interval; COC, combined oral contraceptive; TMX-SMX, trimethoprim-sulfamethoxazole.

*Combined oral contraceptives, drospirenone, and spironolactone were evaluated only among female patients with acne.
y
Other COCs are those not containing drospirenone.

Trends in oral antibiotic use and duration of
therapy
Among patients seen by a dermatologist, the mean
and median durations of therapy were 192 and
126 days, respectively. Among patients managed by
nondermatologists, the mean and median durations
of therapy were 213 and 129 days, respectively. There
was no significant change in the mean duration of
therapy among dermatologists and nondermatolo-
gists (Fig 2). Thirty-four percent of dermatologist-
prescribed courses of oral antibiotic therapy and 36%
of nondermatologist-prescribed courses of oral anti-
biotic therapy exceeded 6 months in duration.
Concomitant topical retinoids were prescribed for
82% of patients seen by a dermatologist and 60% of
patients managed by nondermatologists. The 3 oral
antibiotics most frequently prescribed by dermatol-
ogists were minocycline, doxycycline, and extended-
release minocycline. The 3 oral antibiotics most
frequently prescribed by nondermatologists were
minocycline, doxycycline, and trimethoprim-
sulfamethoxazole (Supplemental Fig 4; available at
http://www.jaad.org).
DISCUSSION
In this large, retrospective analysis of patients
being managed by dermatologists and nondermato-
logists for acne, we observed a significant increase in
460 Barbieri, James, and Margolis J AM ACAD DERMATOL
SEPTEMBER 2017

Table II. Summary of changes in prescribing behavior between 2004 and 2013 for systemic agents among
patients managed by nondermatologists
Courses per 100 patients with acne Incidence rate ratio (95% CI)
Systemic agent 2004 2010 2013 2004-2009 2010-2013
Isotretinoin 2.24 1.23 1.45 0.908 (0.849-0.970) 1.058 (0.937-1.195)
Spironolactone* 1.43 2.25 4.09 1.141 (1.063-1.225) 1.207 (1.167-1.248)
All COCs* 31.70 31.76 32.13 1.045 (1.013-1.077) 0.998 (0.979-1.018)
Drospirenone COCs* 4.14 6.11 4.20 1.206 (1.127-1.292) 0.860 (0.809-0.915)
Other COCsy 27.56 25.65 27.93 1.007 (0.983-1.032) 1.026 (1.014-1.038)
All antibiotics 19.99 18.40 22.48 0.987 (0.983-0.991) 1.071 (1.062-1.081)
Tetracyclines 16.59 14.90 18.45 0.982 (0.978-0.987) 1.077 (1.067-1.087)
Nontetracyclines 3.39 3.51 4.03 1.008 (1.001-1.016) 1.047 (1.035-1.059)
TMP-SMX 1.38 1.71 1.93
Amoxicillin 1.29 1.26 1.23
Cephalexin 0.65 0.39 0.72
Azithromycin 0.08 0.14 0.16

CI, Confidence interval; COC, combined oral contraceptive; TMX-SMX, trimethoprim-sulfamethoxazole.

*Combined oral contraceptives, drospirenone, and spironolactone were evaluated only among female patients with acne.
y
Other COCs are those not containing drospirenone.

the frequency of use of spironolactone between 2004
and 2013. This growth was most notable among
adults. Whereas we initially observed a slight
decrease in oral antibiotic use, this trend has
reversed in recent years.
Given concerns about antibiotic resistance and
other complications associated with oral antibiotic
use, it is encouraging to observe an increase in the
use of alternative agents such as spironolactone for
the treatment of acne in female patients. In addition,
given that recent work published after our study
period has supported reduced laboratory monitoring
for female patients being treated with spironolactone
for acne, it is likely that spironolactone use will
continue to grow in the coming years as clinicians
and patients become more comfortable with this
medication.31 Although we did not observe a
decrease in the absolute use of oral antibiotics in
2013 compared with that in 2004, oral antibiotic use
had been gradually declining until around 2010,
at which time utilization began to increase.
Interestingly, this shift follows the dramatic decrease
in use of drospirenone-containing combined oral
contraceptive pills starting in 2009, which may be
related to concerns about increased risk for
development of venous thromboembolism.32 It is
possible that because of concerns about the safety of
drospirenone-containing combined oral contracep-
tive pills, clinicians shifted their prescribing behavior
toward the use of more oral antibiotics. Although
drospirenone-containing combined oral contracep-
tive pills are effective for the treatment of acne, it is
important to note that any combined oral contracep-
tive pill can be helpful in the treatment of acne, and a
recent meta-analysis has suggested that combined
oral contraceptives have similar effectiveness when
compared with oral antibiotics in the treatment of
female patients with acne.20
Although spironolactone use has increased
substantially over the study period, its use remains
relatively uncommon when compared with use of
oral antibiotics. In 2013, there were 2.8 and 4.6
courses of oral antibiotics prescribed for every
course of spironolactone among female patients
seen by dermatologists and nondermatologists,
respectively. In addition, spironolactone use is
substantially more frequent among adults than
among adolescents. As a result, spironolactone and
other hormonal agents may still be relatively
underutilized in the treatment of female patients
with moderate to severe acne, especially among
adolescents. Finally, spironolactone use should not
be limited only to female patients with acne that
flares with their menstrual period or that is more
prominent on the lower face, as spironolactone is
effective in all types of acne.21,33,34
We found that concomitant topical retinoid
therapy for patients taking oral antibiotics was not
implemented in 40% of patients managed by
nondermatologists alone and 18% of patients seen
by a dermatologist. Because topical retinoids have
been shown to result in improved outcomes in the
setting of treatment with oral antibiotics, increasing
the use of these agents among patients being
prescribed oral antibiotics is a potential practice
gap.35-38 However, it is also important to consider
that some patients may not be eligible for a topical
retinoid or may have previously failed a retinoid
J AM ACAD DERMATOL Barbieri, James, and Margolis 461
VOLUME 77, NUMBER 3

Fig 2. Mean and median durations of therapy with oral antibiotics among patients seen by a
dermatologist (A) and patients managed by nondermatologists alone (B) between 2004 and
2013.

before entering the OptumInsight Clinformatics
DataMart, so it should not be expected that 100%
of patients would receive concomitant topical reti-
noids, even if all clinicians were attempting to follow
the guideline recommendations.
As in prior studies, we observed that the duration
of therapy with oral antibiotics was not aligned
with the optimal recommendations of recent
guidelines.24-26 Nonadherence to clinical guidelines
is frequently observed across a variety of clinical
settings.39 Guideline complexity, unsupportive
clinical settings, and clinician disagreement with
recommendations are some factors that have been
suggested to be associated with nonadherence
462 Barbieri, James, and Margolis
to clinical guidelines.39,40 Given that guideline
recommendations regarding the optimal duration
of therapy with oral antibiotics are largely derived
from expert opinion, nonadherence to these
guidelines may result from clinician disagreement.
In addition, patient preferences, medication side
effects and contraindications, and insurance
coverage and cost are other potential factors that
could result in nonadherence to guidelines.
Additional research to clarify the optimal duration
of treatment with oral antibiotics and to identify the
most appropriate patients for alternative agents to
oral antibiotics may help with the development of
future clinical guidelines and potentially lead to
improved adherence to recommended prescribing
behavior among clinicians.
The results of our study should be interpreted in
the context of the study design. Because patient
adherence may not be complete, our results may
overestimate actual exposure to the systemic agents
evaluated in this study.27 However, given that the
objective of this study was to evaluate clinician
practices, whether the patient was adherent to the
course of therapy is less relevant than the intent of
the prescribing clinician. In addition, we were
unable to assess rates of combination therapy with
both oral antibiotics and spironolactone. Because
OptumInsight Clinformatics DataMart does not
contain information on severity of illness or
outcomes, we are unable to evaluate the impact of
these factors in this study. Although the nature of our
data source does not allow us to validate that patients
in our cohort received antibiotics for acne, we have
taken multiple steps to reduce the risk for potential
bias as described in the Methods section. Finally,
comparisons between patients who saw a
dermatologist and those who were managed by
nondermatologists should be made with caution,
because it is likely that patients who saw a
dermatologist have more severe disease.
In summary, our study highlights that
spironolactone is becoming an increasingly popular
systemic therapy in the treatment of acne among
dermatologists as well as among nondermatologists,
although it remains relatively infrequently utilized
when compared with oral antibiotics. Like the
authors of prior studies, we observe that prescribing
behavior for oral antibiotics and the use of
concomitant topical retinoids are not well aligned
with current guidelines, although additional research
is needed to understand the optimal duration of
therapy with oral antibiotics. Given the importance
of judicious use of oral antibiotics to prevent
potential complications, increasing the use of
concomitant topical retinoids and additional work
J AM ACAD DERMATOL
SEPTEMBER 2017
to identify those patients who would benefit most
from alternative agents such as spironolactone,
combined oral contraceptive pills, or isotretinoin
represent potential opportunities to improve the care
of patients with acne.
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463.e1 Barbieri, James, and Margolis J AM ACAD DERMATOL
SEPTEMBER 2017

Supplemental Fig 1. Sensitivity analysis for the change in the number of courses of therapy per
100 patients using inclusion criteria of 2 claims associated with a code for acne separated
by 3 months and seen by a dermatologist (A) or managed by nondermatologists (B), separated
by 12 months and seen by a dermatologist (C) or managed by nondermatologists (D), and
separated by 18 months and seen by a dermatologist (E) or managed by nondermatologists (F).
Tetracyclines includes doxycycline and minocycline. Other antibiotics includes trimethoprim-
sulfamethoxazole, amoxicillin, cephalexin, and azithromycin. COC, Combined oral contraceptive.
*Combined oral contraceptives, drospirenone, and spironolactone were evaluated among only
female patients with acne.
J AM ACAD DERMATOL Barbieri, James, and Margolis 463.e2
VOLUME 77, NUMBER 3

Supplemental Fig 2. Change in the number of courses of therapy per 100 patients seen by a
dermatologist between 2004 and 2013 among adolescents (A), adults (B), female patients (C),
and male patients (D). Tetracyclines includes doxycycline and minocycline. Other antibiotics
includes trimethoprim-sulfamethoxazole, amoxicillin, cephalexin, and azithromycin. COC,
Combined oral contraceptive. *Combined oral contraceptives, drospirenone, and spironolac-
tone were evaluated among only women with acne.
463.e3 Barbieri, James, and Margolis J AM ACAD DERMATOL
SEPTEMBER 2017

Supplemental Fig 3. Change in the number of courses of therapy per 100 patients managed for
acne by nondermatologists between 2004 and 2013 among adolescents (A), adults (B), female
patients (C), and male patients (D). Tetracyclines includes doxycycline and minocycline. Other
antibiotics includes trimethoprim-sulfamethoxazole, amoxicillin, cephalexin, and azithromycin.
COC, Combined oral contraceptive. *Combined oral contraceptives, drosperinone, and
spironolactone were evaluated among only women with acne.
J AM ACAD DERMATOL Barbieri, James, and Margolis 463.e4
VOLUME 77, NUMBER 3

Supplemental Fig 4. Proportion of courses prescribed with different classes of oral antibiotics
among patients seen by a dermatologist (A) and patients managed by nondermatologists alone (B)
between 2004 and 2013. ER, Extended-release; TMP-SMX, trimethoprim-sulfamethoxazole.