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Important considerations regarding the widespread use of doxycycline
chemoprophylaxis against sexually transmitted infections
Fabian Yuh Shiong Kong
1
*, Chris Kenyon
2,3
and Magnus Unemo
4,5
1
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne,
Australia;
2
HIV/STI Unit, Institute of Tropical Medicine, Antwerp, Belgium;
3
Division of Infectious Diseases and HIV Medicine, University of
Cape Town, Cape Town, South Africa;
4
WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs,
Department of Laboratory Medicine, Örebro University, Örebro, Sweden;
5
Faculty of Population Health Sciences, Institute for Global
Health, University College London, London, UK
*Corresponding author. E-mail: kongf@unimelb.edu.au
@fabian_kong
Rates of sexually transmitted infections (STIs) continue to rise across the world and interventions are essential
to reduce their incidence. Past and recent studies have indicated this may be achieved using doxycycline post-
exposure prophylaxis (PEP) and this has sparked considerable interest in its use. However, many unanswered
questions remain as to its long-term effects and particularly potentially negative impact on human micro-
biomes and antimicrobial resistance among STIs, other pathogens, and commensals. In this review, we discuss
seven areas of concern pertaining to the widespread use of doxycycline PEP.
Introduction
As rates of sexually transmitted infections (STIs) increase around
the world, interventions are urgently needed to reduce their inci-
dence and associated morbidity.
1
Successful implementation of
preventative interventions such as HIV pre-exposure prophylaxis
(PrEP) has resulted in dramatic reductions in the incidence of HIV
globally.
2
This has led to studies that have assessed if doxycyc-
line, taken prophylactically, pre- and/or post-sexual exposure,
can reduce the incidence of bacterial STIs such as syphilis (aetio-
logical agent: Treponema pallidum subspecies pallidum), chla-
mydia (Chlamydia trachomatis) and gonorrhoea (Neisseria
gonorrhoeae).
3,4
In 2015, the French IPERGAY trial by Molina et al.
3
randomly
assigned 232 men or transgender women who have sex with
men (MSM or TGW) at high risk of acquiring HIV (condomless
anal sex with >2 different partners during past 6 months) using
HIV PrEP to take 200 mg of doxycycline (a broad-spectrum tetra-
cycline antibiotic) within 24 h, but no later than 72 h after having
sex (doxycycline post-exposure prophylaxis; PEP). This resulted in
a 70%–73% lower incidence of chlamydia and syphilis infections
but had no effect on N. gonorrhoeae. A recent DoxyPEP trial in the
USA by Luetkemeyer et al.,
4
reported similar reductions in STI in-
cidence (66%) including a 55% lower incidence of gonorrhoea
among 501 MSM or TGW who were counselled to take doxycyc-
line after condomless sex with at least one male in the past
2 months and taking HIV PrEP. The difference in effect on
gonorrhoea incidence between these two studies may be
partly explained by the lower prevalence of gonococcal
resistance to doxycycline in the USA (20%–30% resistance;
https://www.cdc.gov/std/statistics/gisp-profiles/default.htm)
5
com-
pared with France (56% resistance)
6
at the time of the trial,
and that in DoxyPEP,
4
participants were permitted to have
more doses than in IPERGAY
3
(seven versus three doses a
week). Similar reductions in incident STIs (overall 65% and 55%
for N. gonorrhoeae) were seen in the recent French DOXYVAC trial
comparing 200 mg of doxycycline with Meningococcal B vaccine
(4CMenB, Bexsero
®
) in 332 MSM on HIV PrEP
7
and among MSM
taking doxycycline daily (doxycycline PrEP) from a small pilot trial
in 2011 from the USA (OR 0.3; 95% CI 0.08–1.09).
8
However, due
to the low sample size (n = 30) in the latter, doxycycline PrEP has
not yet been recommended by public health organizations and,
accordingly, this discussion will focus on doxycycline PEP.
The findings of these PEP studies and similar studies have led
the San Francisco Public Health Unit to recommend doxycycline
PEP to cis men and trans women who: (1) have had a bacterial
STI in the past year; (2) report condomless anal or oral sexual
contact with ≥1 cis male or trans female partner in the past
year; and (3) those with a history of syphilis.
9
Although the interim CDC statement in 2023 after the CROI
conference does not advocate for or against doxycycline PEP, it
has previously included a box in its HIV PrEP guidelines describing
how this doxycycline PEP could be given if required.
10
The USA
International Antiviral Society in 2022,
11
in contrast, states that
pending further data on doxycycline’s effect on antimicrobial re-
sistance (AMR) and the microbiome, the use of DoxyPEP should
be considered on a case-by-case basis. In 2022, the British
Association for Sexual Health and HIV and the UK Health
Security Agency updated their guidance that they do not endorse
the use of doxycycline taken as PEP or PrEP to prevent STIs.
12
The
© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For
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WHO has not yet provided any strong statement advocating for
or against its use.
In this targeted review, we reviewed the published literature
regarding the effects of using doxycycline on AMR, specifically
in the four most common bacterial STIs, other bacterial patho-
gens, and on the human microbiome as a proxy for what could
occur in practice during widespread doxycycline PEP use. Where
no direct evidence was available for doxycycline, we provide evi-
dence from other antimicrobials or current AMR concerns. Using
this evidence, we generated seven hypotheses pertaining to im-
portant concerns about the widespread use of doxycycline PEP.
AMR
AMR in STIs
AMR in N. gonorrhoeae
The doxycycline PEP randomized controlled clinical trials (RCTs)
3,4
have only published results on the effects of doxycycline PEP on
tetracycline resistance in N. gonorrhoeae and C. trachomatis. No
statistically significant increase in doxycycline resistance was seen
in either of the two RCTs that reported this outcome.
3,4
The import-
ant caveats to this finding include the short time of follow-up
and the very small number of C. trachomatis [n = 5 (IPERGAY)
3
]
and N. gonorrhoeae isolates assessed [n = 9 (IPERGAY);
3
n = 47
(DoxyPEP)].
4
Notably, a substantial proportion of the N. gonorrhoeae
isolates detected in the doxycycline arm of the DoxyPEP study were
cultured from the oropharynx—a site where infection is mostly
asymptomatic and where the risk is high for the acquisition of
AMR through horizontal gene transfer of resistance determinants
from commensal Neisseria species.
13
Interim results presented at
CROI 2023
14
found that in each arm of the trial, two high-level
tetracycline-resistant N. gonorrhoeae isolates were found, but in
the DoxyPEP arm, there were an additional four low-level-resistant
N. gonorrhoeae isolates (none in the control arm). The anatomical
site from which these isolates were cultured from was not specified.
Additional data from CROI 2023
14
reported that the N. gonorrhoeae
in the DoxyPEP arm had acquired resistance to a greater number of
other antibiotics compared with those in the control arm. Among 20
N. gonorrhoeae isolates from DoxyPEP users, three were resistant to
azithromycin, two to ciprofloxacin, and one to benzylpenicillin. In 19
non-PEP users, the only additional resistance found was to benzyl-
penicillin in two isolates. No isolate was resistant to ceftriaxone or
cefixime, the drugs currently used to treat gonorrhoea. However
low sample size limits inference of statistical significance.
While there was no significant increase in doxycycline-
resistant commensal Neisseria in the DoxyPEP arm between
baseline and Month 12 (63%–70%), at Month 12, however, there
was significantly higher doxycycline resistance compared with
control (70% versus 45%, P = 0.0017).
13
Co-selection of resistance to other classes of antimicrobials is
another possible concern for N. gonorrhoeae and other bacterial
species.
15
Many concerns are hypothetical, i.e. because we lack
evidence that we hope will be gathered in many ongoing and fu-
ture studies. Both the tet(M) gene and the rpsJ V57M mutation
are strongly associated with gonococcal resistance and de-
creased susceptibility to doxycycline and selection by doxycycline
use. However, also increased MtrCDE efflux is associated with
doxycycline decreased susceptibility to doxycycline as well as
to many other antimicrobials.
16
Furthermore, both the tet(M)
gene and the rpsJ V57M mutation may decrease susceptibility
to other current but also future tetracycline derivates. Recent
genomic studies of N. gonorrhoeae isolates have highlighted
the potential for selecting cross-resistance to other antimicro-
bials with doxycycline use, especially when all tetracycline
lineages are selected.
17,18
Among MSM populations, the majority
of N. gonorrhoeae isolates were found to have intermediate
tetracycline MICs, which the authors warned could represent a
reservoir for rapid evolution of resistance.
17
AMR in C. trachomatis
No evidence of elevated doxycycline MICs was found in the five C.
trachomatis isolates assessed in the IPERGAY study.
3
The suc-
cessful use of doxycycline for STIs for over five decades with little
evidence of the emergence of resistance
19
suggests it is a limited
risk that doxycycline PEP selects C. trachomatis resistance to
doxycycline. Nonetheless, the transfer of tetracycline resistance
genes between Chlamydia species has been reported in vitro in
pigs, and likely resulted from pigs being fed fish meal treated
with tetracyclines.
20
Similarly treatment failures with reduced
susceptibility to tetracycline has been reported.
21–24
In the
DoxyPEP study,
4
C. trachomatis incidence was reduced by 74%–
88%. The emergence of doxycycline resistance in C. trachomatis
would be serious as it is the most efficacious treatment for uro-
genital
25
and rectal chlamydial infections,
26
especially for lym-
phogranuloma venereum (LGV) infections.
AMR in Mycoplasma genitalium
Doxycycline is very important for empirical treatment of non-
gonococcal urethritis and cervicitis and has emerged as an im-
portant component of sequential therapy for M. genitalium. In
the sequential therapy, doxycycline is given for 7 days to cure
30%–40% of M. genitalium infections
27
and reduce the M. genita-
lium bacterial load in many of the uncured M. genitalium infec-
tions and thereby facilitate the clearance by subsequent
macrolide or fluoroquinolone therapy. Resistance to doxycycline
in M. genitalium would reduce the effectiveness of doxycycline in
this successful empiric as well as sequential treatment. In an
IPERGAY sub-study, the authors reported mutations that have
been previously associated with tetracycline resistance in other
bacterial species in-vivo in participants who had taken doxycyc-
line for treatment or prophylaxis, suggesting that the acquisition
of these mutations may have been enhanced by the use of doxy-
cycline.
28
Another recent study has found that tetracycline resist-
ance in M. genitalium can be caused by alterations in intrinsic
efflux pumps resulting in increased MICs of doxycycline, tetracyc-
line and minocycline.
29
Intensive intermittent use of doxycycline,
particularly in a high-prevalent MSM population on HIV PrEP, may
thus reduce the efficacy of not only doxycycline but also one of
the last resort M. genitalium treatments—minocycline.
30,31
AMR in T. pallidum
Difficulties with culturing T. pallidum have made it difficult to
evaluate tetracycline resistance in T. pallidum.
32
There are, how-
ever, rare published reports of treatment failure following doxy-
cycline therapy (n = 1),
33
and resistance-conferring tet(B) genes
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were detected in a small proportion of T. pallidum-positive sam-
ples in a single study.
34
However, contamination of these samples
with tet(B) from another source cannot be excluded.
32
Resistance
to doxycycline could hypothetically emerge via acquisition of
tet(B), but also mutations in ribosomal proteins or point mutations
in the 16S rRNA gene. Whilst these 16S rRNA mutations have not
been detected thus far, they are rarely screened for and they
might emerge explosively, as was the case for the analogous
23S rRNA macrolide-resistance mutations whose prevalence in-
creased from 0% to 90% in T. pallidum in some settings during
only 10 years following intensive use of macrolides.
35,36
In summary, for the treatment of STIs, while doxycycline is not
recommended for treatment of N. gonorrhoeae due to the high
rates of resistance, the potential risks for C. trachomatis where
doxycycline remains the optimal treatment, M. genitalium where
doxycycline is important for empirical treatment as well as in
sequential treatment, and effects in regard to selection of
cross-resistance to other tetracyclines and other classes of anti-
microbials, enhanced phenotypic and molecular doxycycline re-
sistance surveillance are urgently warranted, including tests of
cure and genomic sequencing of STI pathogens from doxycycline
treatment failures and individuals taking doxycycline PEP.
AMR in other pathogenic bacterial species
The WHO has declared AMR as one of the greatest threats to
global health that will cost an estimated US$3.4 trillion a year
by 2030.
37
It has been estimated that AMR infections resulted
in 1.3–5.0 million deaths in 2019.
38
The majority were caused
by six pathogens, most of which can also be human commen-
sals in different anatomical sites—namely Escherichia coli,
Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus
pneumoniae, Acinetobacter baumannii and Pseudomonas aeru-
ginosa. A number of studies have found that much of the AMR in
these pathogens is caused by bystander selection, i.e. due to
antimicrobials used for other indications.
39
An example of this
effect is the strong positive association between country-level
penicillin consumption and reduced susceptibility to penicillin
in S. pneumoniae.
40
Further studies have suggested the need
to keep population-level antimicrobial consumption below cer-
tain thresholds to prevent the emergence of AMR.
31
To the best
of our knowledge, no such threshold has been established for
tetracyclines. Tetracyclines such as doxycycline do, however,
also exert an evident bystander effect.
15
A recent systematic
review of the AMR selection by the use of oral tetracyclines
on human flora
41
reported increases in tetracycline-resistant
Streptococcus strains in subgingival flora, E. coli in the gastro-
intestinal tract and a 5.8-fold increase in tetracycline-resistant
respiratory tract pathogens. An RCT also found that the use of
tetracycline for acne was associated with increased prevalence
of tetracycline resistance in E. coli in the guts of patients and
their relatives.
42
Another RCT found that the receipt of 14 days
of oral tetracycline resulted in an elevated prevalence of
tetracycline resistance in subgingival bacteria and that this
effect persisted for over 12 months.
43
Interim data from
CROI 2023
14
reported an 8% absolute increase in doxycycline-
resistant S. aureus in the DoxyPEP study
4
arm (from 4% to
12%, P = 0.0008) (but not in the control arm) between baseline
and Month 12. No change was seen for MRSA. Larger sample
sizes will be required to evaluate if these increases are
significant.
AMR in commensal bacterial species
By virtue of their frequent ubiquitous presence and high bacterial
loads, commensal bacterial are at the highest risk for bystander se-
lection of AMR.
39
This is of significant concern as selected chromo-
somal and plasmid-harboured AMR determinants can be
subsequently transferred to pathogens via horizontal gene transfer
mechanisms such as conjugation and transformation.
44
Plasmids
frequently contain genes that confer resistance to tetracyclines as
well as other classes of antimicrobials. Intense doxycycline selec-
tion pressure could thus also increase the prevalence of resistance
to other classes of antimicrobials.
15,45,46
While tetracyclines are not
recommended for the primary treatment of anaerobic infections,
previous reports have shown that increased use of tetracyclines re-
sults in commensal anaerobic bacteria no longer responding to
first- and second-generation tetracyclines.
47
Persistence, tolerance and AMR
AMR involves the inherited ability of a bacterial species to grow at
high concentrations of an antimicrobial. As such it involves an in-
crease in the MIC of the antimicrobial for the microbe.
48
Tolerance, in contrast, refers to the ability to survive transient ex-
posure to high concentrations of antimicrobials without an in-
crease in antimicrobial MIC. Tolerance is typically acquired by
slowing down several bacterial metabolic processes.
48
Transient
exposures to high in vitro concentrations of antimicrobials, includ-
ing tetracyclines, has been shown to induce tolerance in all bacter-
ial species studied thus far, including N. gonorrhoeae.
49
Bacterial
tolerance has also been linked to persistent and recurrent infec-
tions with E. coli and P. aeruginosa.
50
Tolerance has also been
shown to play a key role in the pathway toward the genesis of
AMR in a number of bacteria.
48,50
Off-target effects of tetracyclines
In many bacterial species, tetracyclines at therapeutic and sub-
therapeutic doses can induce or select resistance to other classes
of antimicrobials through co-localization of AMR genes on chro-
mosomes or plasmids, enhanced activity of efflux pumps
51
and
other mechanisms.
52
In addition, tetracyclines can have antime-
talloprotease and possibly anti-inflammatory activity in hu-
mans.
52
Several studies have found an increased risk of various
infections following long-term antibiotic (mainly tetracycline)
use for acne [upper respiratory tract infection (OR 2.8, 95% CI
2.4–3.2), urinary tract infection in women (OR 1.9, 95% CI 1.4–
2.5) and pharyngitis (OR 4.3, 95% CI 1.5–12.5)].
53
This effect
may be mediated by reduced colonization resistance for the
pathogens. Accordingly, tetracyclines may reduce the abun-
dance of commensal bacteria, which normally protect their
host from initial colonization and subsequent infection by the
pathogen.
54
Doxycycline can cause photosensitivity in response
to UV radiation, an effect that is mediated by doxycycline-
induced oxidative stress and mitochondrial toxicity.
55
Finally, a
range of rare adverse events experienced by patients taking
doxycycline have been noted to improve or resolve following
doxycycline discontinuation, such as benign intracranial
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hypertension and oesophagitis.
55
These uncommon adverse
events were reflected in the low discontinuation rates in the re-
cent doxycycline trials—0.9% and 2.0% in the DOXYVAC
7
and
DoxyPEP
4
trials, respectively. In the DoxyPEP trial, five partici-
pants had an adverse event possibly related to doxycycline, while
in the DOXYVAC trial, drug-related adverse events occurred in
5.7% taking doxycycline and 34.6% with 4CMenB.
Altered microbiome
The effects of antimicrobials on the microbiome, which frequently
protects us from infections and diseases, are extremely complex.
In particular, much remains to be learnt about the clinical signifi-
cance of antimicrobial-induced changes in the microbiome.
Recent studies have, for example, shown that a number of classes
of antimicrobials have a dose-dependent effect on increasing the
risk for a range of conditions such as obesity, allergy, asthma, in-
flammatory bowel disease, coeliac disease and attention-deficit
hyperactivity disorder (ADHD).
56
This effect may persist for decades
after the cessation of the antimicrobial and may even be trans-
ferred transgenerationally—presumably both the effect and trans-
fer are associated with the microbiome.
56
Whilst tetracyclines
appear to be one of the safer classes of antimicrobials for the gut
microbiome,
57
a number of studies have found that they can in-
duce large perturbations in the microbiome. For example, one
RCT found that doxycycline taken for 10 days resulted in reduced
gut bacterial diversity including a 100-fold reduction in bifidobac-
teria, as well as increased prevalence of tetracycline resistance in
gut commensals.
58
The effects on the microbiome may be even more complex in
those living with HIV, who show an altered microbiome com-
pared with those who are HIV negative.
59
Lastly, tetracyclines
have been reported to have an effect on the gut microbiomes
of both humans and food animals such as pigs, chickens and
cows.
60–62
Further evidence of clinically relevant effects on the micro-
biome come from studies that reveal that tetracycline intensifies
the blood-thinning effect of anticoagulant medication (via redu-
cing the abundance/activity of bacteria that produce vitamin
K).
55
Studies have found that the concomitant consumption of
doxycycline with acenocoumarol or phenprocoumon increases
the risk of bleeding by approximately 2.5-fold.
63
Arrested immunity and loss of colonization
resistance
Human studies have theorized that if STIs are treated before im-
munity is developed to the infection, then the risk of reinfection
can be higher due to the loss of any temporary and/or partial im-
munity. A study following up women with genital C. trachomatis
infection found that those treated with antimicrobials had a
4-fold higher probability of reinfection than women in whom
the infection was cleared by their immune system.
64
The authors
concluded that treatment for chlamydia may attenuate protect-
ive immunity in some patients. Similar findings have been found
for syphilis.
65
In the case of chlamydia, this arrested immunity is
a plausible explanation for the paradoxical increase in chlamydia
incidence in populations that have experienced intensive
screening and treatment.
66,67
It is possible that intermittent
doxycycline use will reduce individual and population partial im-
munity to C. trachomatis as well several other STI agents and
pathogens and thus paradoxically increase the risk of reinfection.
It is, however, important to note that the major doxycycline PEP
studies have not found any evidence of arrested immunity but
only reduced incidence (including reinfections) of various STIs.
Difficulties in syphilis diagnosis and treatment
Doxycycline is active against T. pallidum; however, because 14–
28 day treatments are needed to effectively cure many syphilis
cases, doxycycline PEP may fail to cure a proportion of incident
syphilis cases. This problem will be aggravated by the fact that
in the contemporary syphilis epidemics, a substantial proportion
of all the cases of syphilis can be repeat episodes.
68
Syphilis rein-
fections are typically asymptomatic and detected only by detect-
ing a two-titre increase in non-treponemal tests.
69,70
Hypothetically, this detection could prove difficult for healthcare
practitioners in a number of settings
68
such as where only trepo-
nemal tests (rapid point-of-care tests) are used. It remains un-
known how the intermittent use of doxycycline will affect the
clinical and serological progression of syphilis. We theorize that
if someone uses doxycycline PEP a week after reinfection with
T. pallidum, this may limit the increase in non-treponemal titre
to a maximum of one titre instead of two titres if no doxycycline
has been taken. This would mean that this repeat episode of
syphilis would not be diagnosed at this visit. In this circumstance
the growth and dissemination of T. pallidum could be delayed
and missed. Because T. pallidum is known to disseminate and in-
vade the CNS early after infection, it is also possible that neuro-
syphilis infections will be masked and their detection delayed.
Historical examples of chemoprophylaxis were
halted due to AMR
Chemoprophylaxis pre- and post-sex have been used since World
War I in attempts to reduce the incidence of STIs.
71–76
Although
many of these studies used historical control groups, the initial
studies reported impressive reductions in the incidence of STIs
such as gonorrhoea, syphilis and chancroid.
72
As with the recent
results of the doxycycline PEP trials, these positive findings gener-
ated considerable enthusiasm for chemoprophylaxis.
73
However,
the widespread use of antimicrobials was followed by the emer-
gence of AMR. In one such study, the use of minocycline PEP to
prevent N. gonorrhoeae infection was noted to be efficacious
against susceptible N. gonorrhoeae isolates but had no effect
against resistant isolates.
73
It was concluded that extensive
use of minocycline would ‘have limited effectiveness as a
public-health measure because of the tendency to select resist-
ant gonococci.’ These insights curbed the enthusiasm for these
interventions.
73
Doxycycline PEP results in high doxycycline
exposure in a subset of users
In the DoxyPEP study,
4
while participants were permitted to take
one dose per day, the median number of doses taken per month
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was 4 based on self-reporting, which is similar to that used in the
IPERGAY trial where participants took a median of 6.8 pills
(680 mg) per month (about three 200 mg doses).
3
However, in
the DoxyPEP trial, 25% took 10 or more doses (≥2 g per month).
4
These doses are higher than the 1.4 g (100 mg twice a day for
7 days) used to treat chlamydia. Therefore for those where chla-
mydia is the sole infection, the preventative doxycycline PEP con-
sumption was higher than if these participants were treated
monthly for chlamydia.
The only organization that currently recommends the use of
PEP (the San Francisco Public Health Unit) follows the DoxyPEP
study
4
protocol that allows the very high level consumption of
200 mg of doxycycline per day.
9
Of note, the San Francisco guide-
lines continuing recommending 3 monthly STI screening in those
using doxycycline, which may question the efficacious utility of
doxycycline use between screens.
Rollout of doxycycline PEP and the
precautionary principle
If public health agencies advocate for the use of doxycycline PEP
beyond controlled research settings this implies that they have
concluded that sufficient evidence is available and the benefits
outweigh the risks and potential future harms. Understandably,
the lay public will consider this means that doxycycline PEP is evi-
dently safe and its use will likely increase dramatically among
MSM but also additional populations. It will be very hard to reverse
this trend and we cannot exclude that additional therapeutic anti-
microbials will also be in the pipeline for PEP (or PrEP), i.e. pre-
scribed by clinicians or purchased online without a prescription
(see below). This would significantly challenge a lot of the work
performed to improve antimicrobial stewardship globally.
Limitations
We did not use a systematic review methodology. In addition, in-
terpretation of published evidence is often limited by small sam-
ple sizes and few isolates tested for AMR, both in the doxycycline
PEP studies
3,4
and in the published literature. This makes drawing
robust conclusions difficult. Ongoing surveillance of doxycycline
PEP studies will hopefully provide more definitive evidence.
Given these issues, we cannot exclude any biases arising from
the limited evidence currently available and cognitive biases in
our interpretation of this evidence.
Important counter arguments
In addition to the proven efficacy of doxycycline PEP, we acknow-
ledge a number of other counter arguments and where doxycyc-
line PEP use could provide benefits.
Firstly, it has been estimated that approximately 8%–10% of
people using HIV PrEP have used doxycycline prophylaxis from sur-
veys of clients at London, Melbourne and Amsterdam sexual health
clinics.
74–76
A reasonable argument could be made that it would be
preferable for these individuals to take their doxycycline under
supervision. This is of particular concern given the small number
of individuals who reported using antibiotics other than doxycycline
such as amoxicillin,
75
azithromycin
77
or ciprofloxacin
76
as PEP in
studies undertaken prior to the recent doxycycline PEP trials,
3,4
i.e.
previous studies in the UK (n = 107 from 2018),
73
Belgium (n = 187
from 2022)
75
and the Netherlands (n = 321 from 2018),
74
respect-
ively. Many of these antibiotics were purchased online or were left-
overs.
77
Online purchase of doxycycline without a prescription is
also possible. A popular international website, for example, has
since 2018 offered online links to pharmacies that provide access
to HIV PreP and doxycycline with or without a prescription (https://
www.purchase-prep.com/). Secondly, if doxycycline could be tar-
geted to the individuals most central in the sexual network, this
could have a dramatic effect on the incidence of C. trachomatis, T.
pallidum and possibly N. gonorrhoeae infections, at least in some
countries. In Australia, for example, it has been estimated that 22
730 individuals have been prescribed HIV PrEP, with a small core
group of 6% of these individuals accounting for 36% of all STIs.
78
Targeting this group of 6% may have a large effect on STI incidence.
Similarly, in the IPERGAY study, analysis among 429 MSM reported
39% of participants accounted for 86% of STIs.
79
Analysis of 10
500 electronic health records by Traeger et al.
80
explored 10 hypo-
thetical doxycycline PEP-prescribing strategies and suggested that
prescribing doxycycline PEP for a period of 12 months to people
with an STI diagnosis, regardless of HIV PrEP status, could avert
42% of all subsequent STIs (while reducing the number of prescrip-
tions by 59%). Similarly, targeting those with a syphilis diagnosis
would avert 14% of all STIs and reduce prescriptions by 91%.
Thirdly, by reducing the incidence of these STIs, targeted doxycyc-
line PEP could also reduce the consumption of ceftriaxone and pos-
sibly macrolides in this population.
14
Fourthly, proponents of
doxycycline chemoprophylaxis argue that doxycycline is already
used widely for the management of acne, malaria prophylaxis,
skin and soft tissue and other infections. Whilst this is true, as re-
viewed above, this use has resulted in the emergence of AMR in a
range of bacterial species as well as other problems. Lastly, some
users and prescribers have reported that doxycycline PEP can em-
power users to take control of their sexual health. They report
that a lower STI incidence may reduce their distress, thereby mak-
ing sex more enjoyable for them.
In summary, doxycycline PEP is a novel intervention that may
reduce the incidence of STIs, particularly of some STIs among
high-risk MSM or TGW on HIV PrEP and MSM/TGW who are HIV
positive. These findings are exceedingly exciting. However, as de-
tailed above, many unknowns remain regarding: the long-term
effects of intermittent, frequently high-consumption, doxycycline
use (in PEP and PrEP), and likely future use of additional antimicro-
bials, and especially potentially negative impact on human micro-
biomes; selection of AMR and/or antimicrobial tolerance in STI
agents, other pathogens and commensals; doxycycline off-target
effects; effects on arrested immunity and colonization resistance;
and effective messages concerning STI prevention and antimicro-
bial stewardship. Based on the need for continued collection of
evidence regarding broader and long-term consequences, we
consider it would be more prudent to follow the precautionary
principle and provide doxycycline PEP in controlled settings,
such as prioritizing prescriptions targeted at those with a recent
STI combined with ongoing AMR surveillance for STIs, other
pathogens and commensals. More attention should be placed
also on the development of STI vaccines,
81,82
and increased ac-
cess to testing of symptomatic STI cases, including increased im-
plementation of websites providing access to self-sampling
Review
5 of 8
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testing kits
83
or to pathology centres
84
and the development of
rapid, accurate point-of-care tests (detecting STIs plus AMR deter-
minants).
85
Finally, it is clear that people are already taking doxy-
cycline for STI prophylaxis, some purchasing this online, and it is
important that clinicians are fully informed of the potential risks
to users and the possible population effects from AMR.
Funding
This work was undertaken as part of routine work. F.Y.S.K is supported by a
University of Melbourne Faculty C.R. Roper Fellowship and by the
Australian Research Council Industrial Transformation Research Hub to
Combat Antimicrobial Resistance (IH190100021) .
Transparency declarations
None to declare.
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