Clinical Infectious Diseases

Major Article

Doxycycline Versus Azithromycin for the Treatment of

Rectal Chlamydia in Men Who Have Sex With Men:
A Randomized Controlled Trial
Julia C. Dombrowski,1,2 Michael R. Wierzbicki,3 Lori M. Newman,4 Jonathan A. Powell,3 Ashley Miller,5 Dwyn Dithmer,2 Olusegun O. Soge,6 and
Kenneth H. Mayer7,8
1
Department of Medicine, University of Washington, Seattle, Washington, USA; 2HIV/STD Program, Public Health—Seattle & King County, Seattle, Washington, USA; 3The Emmes Company, LLC,
Rockville, Maryland, USA; 4Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA; 5FHI 360,
Durham, North Carolina, USA; 6Departments of Medicine and Global Health, University of Washington, Seattle, Washington, USA; 7Fenway Health, Boston, Massachusetts, USA; and 8Department
of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

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Background. Azithromycin and doxycycline are both recommended treatments for rectal Chlamydia trachomatis (CT) infec-
tion, but observational studies suggest that doxycycline may be more effective.
Methods. This randomized, double-blind, placebo-controlled trial compared azithromycin (single 1-g dose) versus doxycy-
cline (100 mg twice daily for 7 days) for the treatment of rectal CT in men who have sex with men (MSM) in Seattle and Boston.
Participants were enrolled after a diagnosis of rectal CT in clinical care and underwent repeated collection of rectal swabs for nucleic
acid amplification testing (NAAT) at study enrollment and 2 weeks and 4 weeks postenrollment. The primary outcome was microbi-
ologic cure (CT-negative NAAT) at 4 weeks. The complete case (CC) population included participants with a CT-positive NAAT at
enrollment and a follow-up NAAT result; the intention-to-treat (ITT) population included all randomized participants.
Results. Among 177 participants enrolled, 135 (76%) met CC population criteria for the 4-week follow-up visit. Thirty-three partici-
pants (19%) were excluded because the CT NAAT repeated at enrollment was negative. Microbiologic cure was higher with doxycycline
than azithromycin in both the CC population (100% [70 of 70] vs 74% [48 of 65]; absolute difference, 26%; 95% confidence interval [CI],
16–36%; P < .001) and the ITT population (91% [80 of 88] vs 71% [63 of 89]; absolute difference, 20%; 95% CI, 9–31%; P < .001).
Conclusions. A 1-week course of doxycycline was significantly more effective than a single dose of azithromycin for the treat-
ment of rectal CT in MSM.
Clinical Trials Registration. NCT03608774.
Keywords. Chlamydia trachomatis; sexually transmitted diseases; rectal infection; sexual and gender minorities; therapeutics.

Incidence rates of sexually transmitted infections (STIs) among
men who have sex with men (MSM) in the United States have
risen substantially over the last decade [1]. Rectal Chlamydia
trachomatis (CT) is the most common bacterial STI among
MSM [1, 2], but because it rarely causes symptoms, the infec-
tion often remains undetected in the absence of extragenital
screening. National surveillance data demonstrated 10–21% test
positivity for rectal CT among MSM in STI clinics in 2018 and
18% among MSM in human immunodeficiency virus (HIV)
care in 2013–2014 [1, 3]. Among a nonclinical population of
asymptomatic MSM recruited in 5 cities, 7% had rectal CT [2].
Received 23 October 2020; editorial decision 7 February 2021; published online 19 February
2021.
Correspondence: J. C. Dombrowski, 325 Ninth Ave, Box 359777, Seattle, WA 98104
(jdombrow@uw.edu).
Clinical Infectious Diseases®  2021;73(5):824–31
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/ciab153
Rectal CT can lead to urethral CT infections in male partners
[4] and increases the risk of HIV acquisition by approximately
2-fold [5, 6]. Thus, effective detection and treatment of rectal
CT is central to chlamydia control among MSM and may con-
tribute to HIV prevention.
Although the 2015 STI treatment guidelines from the Centers
for Disease Control and Prevention (CDC) recommend both
doxycycline and azithromycin as first-line treatments for rectal
CT [7], retrospective studies suggest that doxycycline is more ef-
fective. A meta-analysis of 8 observational studies estimated the
efficacy of a 7-day course of doxycycline to be 99.6% (95% con-
fidence interval [CI], 98.6–100%) compared with 82.9% (76.0–
89.8%) for single-dose azithromycin [8]. However, the relative
effectiveness of these regimens remains uncertain without a
prospective study. Definitive data are needed to inform clin-
ical practice, particularly because many clinicians prefer to use
azithromycin due to the simplicity of a single-dose regimen [9].
We conducted a randomized controlled trial (RCT) of single-
dose azithromycin versus a 7-day course of doxycycline for the
treatment of rectal CT in MSM.

824 • cid 2021:73 (1 September) • Dombrowski et al

METHODS
Study Design
The study was a randomized, double-blind, placebo-controlled
clinical trial among MSM with rectal CT detected by a nucleic
acid amplification test (NAAT) in clinical care. We randomized
study participants to azithromycin (single 1-g oral dose) or dox-
ycycline (100 mg orally twice daily for 7 days) plus matching
placebo. Participants repeated rectal swabs for CT NAAT at the
time of study enrollment and 2 weeks and 4 weeks after enroll-
ment. The study was conducted at the Public Health—Seattle &
King County Sexual Health Clinic in Seattle, Washington, and
Fenway Health in Boston, Massachusetts.
The primary outcome was the proportion of participants with
microbiologic cure (CT-negative NAAT) in each study arm at 4
weeks (visit 3). Secondary outcomes included the proportion
of participants with microbiologic cure at 2 weeks and the pro-
portion with microbiologic cure at 2 and 4 weeks stratified by
infection with lymphogranuloma venereum (LGV) biovar CT.
Exploratory outcomes included the proportion of participants
with microbiologic cure in subgroups defined by HIV status,
medication adherence, and rectal symptoms. We explored the
impact of antacid and rectal lubricant or douche use on treat-
ment effectiveness based on the hypothesis that these might
alter the concentration of azithromycin in the rectum [10].
Population
Eligible individuals were male sex at birth (inclusive of any
gender identity), 18 years or older, had at least 1 male sex partner
in the past 12 months, and agreed to abstain from condomless
receptive anal sex during the study. Participants were excluded
if they had a clinical diagnosis of acute proctitis [7], concom-
itant untreated gonorrhea or primary or secondary syphilis,
known allergy to tetracyclines or macrolide antibiotics, or had
received antimicrobial therapy active against CT within 21 days
of the positive rectal CT NAAT result or between the date of the
test and study enrollment.
Randomization and Blinding
Participants were randomized to a treatment arm in a 1-to-1
ratio using site-stratified, permuted, blocked randomization.
Participants, clinical study staff, data entry personnel, and lab-
oratory personnel were blinded to treatment assignment. The
study drug was provided in identical kits with overencapsulated
pills and identical placebos containing lactose monohydrate.
Study Visit Procedures
During the enrollment visit, clinicians assessed whether parti-
cipants had rectal symptoms, such as discomfort, irritation, or
itching; examined inguinal lymph nodes; collected information
on HIV status and antiretroviral therapy or pre-exposure pro-
phylaxis (PrEP); and collected information on sexual behavior
in the past 60 days, including partner number, anal and other
sex acts, condom use, lubricant use, and douching. Research
staff observed participants taking the dose of azithromycin (or
placebo) plus 1 dose of doxycycline (or placebo) but did not
otherwise provide adherence support. At follow-up visits, ad-
herence to the study medications was assessed by self-report
and, if available, pill count from returned study drug. We col-
lected limited data on adverse events since the safety profile of
both study medications is well documented.
Rectal swabs were collected by the study clinician or
self-collected by participants in the clinic per clinic standard
practice. In addition, after February 2019, participants could
mail in self-collected rectal swabs at the 2- and 4-week time
points. Prior studies and CDC guidelines support the use of
patient-collected swabs as comparable to clinician-collected
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swabs for rectal CT diagnosis [7, 11–13]. Participants with a
positive or indeterminate rectal CT NAAT result at the final
study visit were notified by an unblinded clinician who ensured
appropriate re-treatment. The NAAT results from the 2-week
visit were not released during the study or used for clinical care.
Laboratory Methods
All laboratory testing was performed in the University of
Washington (UW) Global Health STI Laboratory. CT NAAT
was conducted using the Aptima Combo 2 Assay (Hologic, Inc,
San Diego, CA, USA). All specimens positive for CT at the time
of study enrollment were tested using a validated LGV poly-
merase chain reaction (PCR) [14].
Sample Size
The trial utilized a 2-staged group sequential design using
O’Brien-Fleming boundaries with 1 semi-blinded interim anal-
ysis of the primary outcome once half the target evaluable pop-
ulation had been enrolled with primary endpoint data and a
stopping rule based on efficacy. An overall type I error rate of
5% was set for the analyses. To determine the sample size, we
assumed a range of cure rates of doxycycline and azithromycin
consistent with published studies. A sample size of 246 parti-
cipants would have more than 80% power to detect a 10% or
greater difference across a range of cure rates. Anticipating 10%
ineligibility for the primary analysis, the enrollment target was
274 participants. We calculated the probability of stopping the
trial at the interim analysis to be less than 1% if the cure pro-
portions were equal and 23% if cure proportions of doxycycline
and azithromycin were 97% and 87%, respectively.
Statistical Analysis
The primary, secondary, and exploratory study outcomes were
analyzed in the complete case (CC) population, which included
participants with a CT-positive NAAT at enrollment and at the
corresponding follow-up time point. Additionally, we evaluated
the primary and secondary outcomes in the intention-to-treat
(ITT) population, which included all enrolled participants,
Rectal Chlamydia Treatment Study • cid 2021:73 (1 September) • 825
and the per-protocol (PP) population, which included parti-
cipants who met the CC population criteria and reported no
condomless anal intercourse or receipt of antibiotics effective
against CT during the study, sufficiently adhered to the study
medication, and completed a 4-week study visit in the specified
time frame. In the absence of a defined minimally effective reg-
imen of doxycycline for the treatment of rectal CT, we defined
“sufficient adherence” a priori as completing the first doses of
study medication under observation and reporting at least 9 ad-
ditional doses of doxycycline/placebo within 10 days.
For the primary analysis comparing 4-week microbiologic
cure outcomes in the 2 treatment groups in the CC population,
a 2-sided Pearson chi-square test was used with significance
levels defined by the O’Brien-Fleming boundaries. To derive
the P value, the point estimate, and CI for the difference in cure
proportions, stage-wise ordering of the sample space was used
[15]. The resulting P value, median unbiased estimate, and CI
are reported here. For the analyses of the 4-week and 2-week
outcomes in the ITT and PP populations, a significance level of
5% was used. For ITT analyses, subjects with missing cure out-
comes were classified as treatment failures and outcomes were
imputed as microbiologic failures.
For exploratory analyses, we conducted subgroup analyses of
the 4-week cure outcomes stratified by HIV status, LGV biovar
status, rectal symptoms (symptomatic or asymptomatic), adher-
ence, and antacid medication use. Based on the high level of ef-
fectiveness in the doxycycline treatment group, we decided post
hoc to report the comparisons only within the azithromycin
arm and excluded the adherence comparison.
Human Research Protections
The study protocol was approved by Institutional Review
Boards at the UW and Fenway Health. The study is regis-
tered at ClinicalTrials.gov (NCT03608774). A Data and Safety
Monitoring Board (DSMB) provided oversight, including re-
view of data at specified times during the study for participant
and overall study progress, semi-blinded interim analysis re-
sults, serious adverse events, and, at the conclusion of the trial,
safety data.
RESULTS
Study Population
Between July 2018 and February 2020, 177 participants were en-
rolled and randomized to doxycycline or azithromycin (Figure
1). Enrollment ended after the DSMB recommended stopping
based on efficacy in accordance with the prespecified stopping
rule for the interim analysis. Enrolled subjects who were on-
going follow-up at the time of the interim analysis were not in-
cluded in the analysis provided to the DSMB. The data from
these subjects were incorporated in the analyses reported in this
study [16, 17].
826 • cid 2021:73 (1 September) • Dombrowski et al
Seventy six percent of enrolled participants (n = 135) met CC
population criteria at 4 weeks, and the most common exclusion
reason (n = 33; 19% of all enrolled) was a negative result on
the CT NAAT repeated at enrollment. This proportion did not
differ substantially between the 2 study sites (17% and 21%).
Ninety-four participants were included in the PP population,
with condomless receptive anal sex during the study being the
most common reason for exclusion from the PP population
among participants included in the CC population (n = 25; 19%
of the CC population).
The median age of participants was 34 years, and 95% iden-
tified as cisgender men (Table 1). Sixty-three percent were
White, 21% were Hispanic/Latino, 5% were Black, and 4% were
Asian or Pacific Islander. Over half of participants (54%) were
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HIV-seronegative and taking HIV PrEP and 15% were HIV-
seropositive. A minority had rectal symptoms (18%) or inguinal
lymphadenopathy (4%).
Microbiologic Cure
Microbiologic cure at 4 weeks was higher with doxycycline than
azithromycin in all analysis populations (Table 2). In the CC
population, the cure proportion was 100% (95% CI, 90–100%)
in the doxycycline arm versus 74% (95% CI, 56–86%) in the
azithromycin arm, with an absolute difference of 26% (95%
CI, 16–36%; P < .001). In the ITT population, the cure rate for
doxycycline was 91% (95% CI, 83–95%) versus 71% (95% CI,
61–79%) for azithromycin (P < .001). Cases imputed as treat-
ment failures in the doxycycline group were driven by loss to
follow-up (n = 7); only 1 participant had a positive NAAT at
4 weeks.
At the 2-week follow-up visit, doxycycline was more effective
than azithromycin in all analysis populations. The absolute dif-
ference between doxycycline and azithromycin was 11% (95%
CI, 0–22%) in the CC population, 7% (95% CI, −4 to 17%) in
the ITT population, and 15% (95% CI, 4–27%) in the PP popu-
lation. Among participants who received doxycycline, the pro-
portion with microbiologic cure was lower at 2 weeks than at
4 weeks, but the opposite pattern was observed in participants
who received azithromycin (Figure 2). Among participants in
the CC population who received azithromycin, 8 of 56 (14%)
who had a negative NAAT at 2 weeks had a positive NAAT
again at 4 weeks.
The LGV PCR was positive in CT specimens from 8 parti-
cipants (6% of the 4-week CC population). These were equally
distributed between the study arms (n = 4 in each). Among par-
ticipants in Seattle, 6 (6% of 104) had LGV-biovar infections
versus 2 (3% of 73) in Boston. All participants with LGV-biovar
CT who received doxycycline had microbiologic cure at both
2 and 4 weeks, as did 3 of 4 (75%) who received azithromycin
(25% absolute difference; 95% CI, −.28 to .70). Among parti-
cipants with non-LGV CT biovars, the absolute difference be-
tween study arms was 26% (95% CI, .15–.38).
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Figure 1. Study flow chart. Abbreviations: CC, complete case; CT, Chlamydia trachomatis; ITT, intention-to-treat; NAAT, nucleic acid amplification testing; PP, per
protocol.

Medication Adherence and Sexual Behavior
In the CC population at 4 weeks, 131 of 135 participants (97%)
met the definition of sufficient adherence to the 7-day course
of doxycycline/placebo. Among 4 who reported insufficient ad-
herence, 2 were randomized to each treatment, and all had mi-
crobiologic cure at 4 weeks.
Sexual behavior between enrollment and follow-up did not
differ between treatment assignment groups (Table 3). Overall,
75 participants (45% of those with follow-up data) reported
having receptive anal sex and 25 (14%) reported condomless
anal sex.

Rectal Chlamydia Treatment Study • cid 2021:73 (1 September) • 827

Table 1.   Demographic and Baseline Clinical Characteristics of Participants

Doxycycline Azithromycin All Subjects

(n = 88)a (n = 89) (n = 177)

Gender, n (%)
Cisgender male 83 (94) 85 (96) 168 (95)
Transgender, nonbinary, other 4 (5) 4 (4) 8 (5)
Age, mean (SD), years 34 (12) 34 (11) 34 (11)
Race/ethnicity, n (%)
White 58 (66) 54 (61) 112 (63)
Black 5 (6) 3 (3) 8 (5)
Asian or Pacific Islander 13 (15) 12 (14) 25 (14)
American Indian or Alaska Native 1 (1) 1(1) 2 (1)
Multiracial 6 (7) 16 (18) 22 (12)
Missing 5 (6) 3 (3) 8 (5)
Ethnicity, n (%)

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Hispanic or Latino 21 (24) 16 (18) 37 (21)
Not Hispanic or Latino 67 (76) 71 (80) 138 (78)
Unknown 0 2 (2) 2 (2)
HIV statusb; ART and PrEP status, n (%)
Positive, on ART 14 (16) 12 (14) 26 (15)
Positive, not on ART 0 0 0
Negative, on PrEP 44 (50) 52 (58) 96 (54)
Negative, not on PrEPc 29 (33) 22 (25) 51 (29)
Missing 1 (1) 3 (3) 4 (2)
Rectal symptoms,d n (%)
Yes 13 (15) 18 (20) 31 (18)
No 74 (84) 71 (80) 145 (82)
Inguinal lymphadenopathy,d n (%)
Yes 4 (5) 3 (3) 7 (4)
No 83 (94) 86 (97) 169 (95)
Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; PrEP, pre-exposure prophylaxis.
a
One participant in the doxycycline group did not have baseline data available.
b
Based on participant self-report.
c
At baseline; 6 subjects started PrEP between study entry and follow-up visits.
d
Symptoms that met the clinical definition of proctitis were excluded.

HIV Status, Rectal Symptoms, and Antacid Medication Use
Among 8 HIV-seropositive participants randomized to
azithromycin, all were cured at 4 weeks (100%; 95% CI,
68–100%) compared with 70% (38 of 54; 95% CI, 57–81%) of
HIV-seronegative participants. Among 14 participants with
rectal symptoms at baseline, 79% (95% CI, 52–92%) had cure
with azithromycin compared with 73% (37 of 51; 95% CI,
59–83%) in those without symptoms. One participant in the
azithromycin group who reported using antacid medication
had a positive NAAT at 4 weeks.

Table 2.   Microbiologic Cure at 4 Weeks, by Treatment Group, in Each Analysis Population

Complete Case Populationa Intent-to-Treat Populationb Per Protocol Populationc

Doxycycline Azithromycin Doxycycline Azithromycin Doxycycline Azithromycin

(n = 70) (n = 65) (n = 88) (n = 89) (n = 46) (n = 48)

Participants with microbiologic cure, n 70 48 80 63 46 37

Participants with microbiologic cure, % (95% CI) 100 (90–100) 74 (56–86) 91 (83–95) 71 (61–79) 100 (92- 100) 77 (63–87)
Difference in proportion, % 26 (16–36) 20 (9 – 31) 23 (11 – 37)
P value <.001 <.001 <.001
Abbreviations: CI, confidence interval; CT, Chlamydia trachomatis; NAAT, nucleic acid amplification testing.
a
Participants who had positive rectal CT NAAT at baseline and follow-up microbiologic data.
b
All enrolled participants.
c
Participants who had a positive rectal CT NAAT at baseline, follow-up microbiologic data, reported no condomless anal intercourse or receipt of antibiotics effective against CT during the
study, adhered sufficiently to study medication, and completed visit 3 within the time frame specified in the protocol.

828 • cid 2021:73 (1 September) • Dombrowski et al

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Figure 2. Comparison of 2-week and 4-week cure percentage by treatment group and analysis population.

Safety and Tolerance DISCUSSION

One serious adverse event occurred, which was unrelated to the
In this randomized placebo-controlled trial, we found that a
study. Additionally, 1 participant assigned doxycycline and 2 as-
7-day course of doxycycline was significantly more effective
signed azithromycin reported vomiting the study medication, 1
than a single dose of azithromycin for the treatment of rectal
of whom (assigned azithromycin) terminated study participa-
CT in MSM, with point estimate cure proportions of 100% for
tion early.

Table 3.   Follow-up Sexually Transmitted Infection and Sexual History by Treatment Group

All Subjects
Doxycycline Azithromycin (n = 177),
(n = 88), n (% of total) (n = 89), n (% of total) n (% of total)

Any STI since enrollment

No 84 (97) 85 (96) 169 (96)
Yes 3 (3) 4 (4) 7 (4)
Sexual behaviors during the study
Any receptive anal sex 37 (45) 38 (45) 75 (45)
Condomless receptive anal sex 15 (17) 10 (11) 25 (14)
Rimming 18 (22) 30 (35) 48 (29)
Fisting 2 (2) 4 (5) 6 (4)
Lubricant use during receptive anal sex
No 47 (57) 48 (56) 95 (57)
Yes 35 (43) 37 (44) 72 (43)
  Silicone-based 20 (67)a 25 (76) 45 (71)
  Water-based 17 (57) 12 (36) 29 (46)
  Saliva 17 (57) 19 (58) 36 (57)
  Ejaculate 4 (13) 4 (12) 8 (13)
  Oil 3 (10) 3 (9) 6 (10)
  Other/unknown 5 (17) 7 (21) 12 (19)
Rectal douches
No 52 (63) 52 (61) 104 (62)
Yes 30 (37) 33 (39) 63 (38)
  Water 29 (97)a 32 (97) 61 (97)
  Fleet enema 6 (20) 4 (12) 10 (16)
The denominator for percentages is the number of subjects with follow-up sexual history data. Abbreviation: STI, sexually transmitted infection.
a
The denominators for lubricant and douche types are the number of persons who reported using lubricants or douches, respectively.

Rectal Chlamydia Treatment Study • cid 2021:73 (1 September) • 829

doxycycline and 74% for azithromycin in the CC population and
91% for doxycycline and 71% for azithromycin in the ITT popu-
lation. Only 1 of 88 participants randomized to doxycycline had
a positive NAAT at 4 weeks, with the remainder of noncures in
the ITT population reflecting loss to follow-up. Although the
proportion of participants with microbiologic cure in the dox-
ycycline arm increased from 2 to 4 weeks postenrollment, the
proportion with cure in the azithromycin arm decreased from
2 to 4 weeks. Infection with LGV-biovar CT was uncommon.
Both treatments were safe and well tolerated.
Our main study finding confirms the results of previous
observational studies [8, 9]. However, the effectiveness of
azithromycin in our study (74%; 95% CI, 56–86%) was even
lower than estimated in pooled results of retrospective studies
(83%; 95% CI, 76–90%) and well below the 95% threshold gen-
erally considered acceptable for STI treatment. Our findings
were comparable to those of a prospective study of women with
CT, most of whom had concomitant rectal and urogenital in-
fections, which found approximately 96% microbiologic cure
with doxycycline and 79% with azithromycin at the rectum
[18]. Forthcoming results from an Australian study of rectal CT
in MSM will add to the body of evidence on this topic [19].
Taken together, the existing studies conclusively demonstrate
that doxycycline is superior to azithromycin for the treatment
of rectal CT.
Approximately 20% of the study participants had a nega-
tive NAAT repeated at the enrollment visit after a recent pos-
itive NAAT in clinical care. This could be due to participants
receiving antibiotics outside of the study, false-positive tests in
the clinic or false-negative tests at study entry, or spontaneous
clearance. In the absence of treatment, rectal CT infection can
last for weeks to months, but the duration of infection varies
widely between individuals [20]. The natural history of CT in-
fection is not well understood and is an important topic for fu-
ture research.
The mechanism of azithromycin treatment failure in rectal
CT is not known but is not likely due to antibiotic resistance,
inadequate tissue penetration of the drug, or the prevalence
of LGV biovars. Azithromycin resistance among CT has never
been conclusively demonstrated, and 1 prior report of re-
sistance was refuted with additional laboratory testing [21].
A pharmacokinetic study demonstrated that drug concentra-
tions of azithromycin in rectal tissue after a single azithromycin
dose remain above the minimum inhibitory concentration for
CT for at least 14 days [10]. Animal studies have also shown
that azithromycin is ineffective in treating gastrointestinal CT
infections, even though it is effective for genital infections, de-
spite comparable drug levels in both anatomic tracts [22]. Our
finding that LGV-biovar CT was uncommon in the study pop-
ulation and that azithromycin was substantially less effective
than doxycycline for the treatment of non–LGV-biovar CT
830 • cid 2021:73 (1 September) • Dombrowski et al
infections refutes the idea that LGV-biovar infections account
for the inadequacy of azithromycin.
Different host–microbe interactions in the rectal environ-
ment than in the genital tract may alter the effect of azithromycin
on CT. The pattern of NAAT clearance we observed with
azithromycin was the opposite of that expected with progres-
sive bacterial clearance. This is consistent with, but not proof of,
recrudescent infection following a period of transient bacterial
latency [23]. The positive-negative-positive pattern could also
indicate reinfection, but this would not be expected to differ be-
tween arms in a placebo-blinded RCT nor do our behavioral
data suggest differential reinfection.
One reason that many clinicians prefer to use azithromycin
for CT treatment is concern about inadequate patient adher-
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ence to a week-long doxycycline regimen. Our study did not
yield sufficient data to examine the impact of adherence, in
part because we used generous parameters to define sufficient
adherence, but this concern should not be a barrier to using
doxycycline in practice. It is unlikely that imperfect adherence
in a typical clinic population would negate the difference in ef-
fectiveness between the 2 treatments. Moreover, some evidence
suggests that doxycycline is effective even with imperfect adher-
ence and at lower doses than typically used in the treatment of
genitourinary CT infections [24, 25].
The limitations of our study include the number of parti-
cipants with LGV-biovar infections, which was too small to
draw conclusions about the effectiveness of either regimen for
the treatment of LGV-biovar CT. Our study population was
almost entirely cisgender male, and the relevance of our find-
ings for transgender people and women with rectal CT is un-
certain. We studied only 2 regimens and were thus unable to
judge the impact of alternate dosing of azithromycin, such as
the weekly 3-dose regimen recommended by the World Health
Organization for the treatment of LGV [26].
In summary, this study demonstrated that a 7-day course
of doxycycline is substantially more effective than single-dose
azithromycin for the treatment of rectal CT. Azithromycin per-
formed so poorly that, even in the context of expected imperfect
adherence in real-world use, doxycycline should be the recom-
mended treatment for rectal CT in MSM.
Notes
Acknowledgments. The authors thank the individuals who participated in
this study and the study staff who contributed to it. The authors specifically
acknowledge Melinda Tibbals at the National Institutes of Health; Angela
LeClair, Rushlenne Pascual, Tamara Bass, Laura Rishel, and Jennifer Morgan
at the University of Washington; Mo Drucker and Valerie Rugulo at Fenway
Health; Martine Policard, Aditi Sharma, Keven Huang, Logan Richlak, and
Bruno Dos Santos at Emmes; Ginger Pittman and Linda McNeil at FHI
360; Drs Jeanne Marrazzo and Edward Hook at the University of Alabama,
Birmingham (UAB); the scientific review committee members of the UAB
Sexually Transmitted Infections Clinical Trials Group; Dr Timothy Menza,
currently with the Oregon State Department of Health; and the San Francisco
Department of Public Health Laboratory for technical assistance.
 Financial support. This work was supported by the National Institutes
of Health (National Institute of Allergy and Infectious Diseases contract
HHSN272201300014I, protocol 17–0092).
Potential conflicts of interest. O. O. S. has participated in research sup-
ported by grants to the University of Washington from Hologic, Inc, and
SpeeDx, Inc. J. C. D. has participated in research funded by grants to the
University of Washington from Hologic, Inc. All other authors report no po-
tential conflicts. All authors have submitted the ICMJE Form for Disclosure
of Potential Conflicts of Interest. Conflicts that the editors consider relevant
to the content of the manuscript have been disclosed.
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