Doxycycline in the management of sexually transmitted infections

Abstract

Doxycycline is a second-generation tetracycline, available worldwide for half a century. It is an inexpensive broad-spectrum antimicrobial agent largely used in the management of several bacterial infections, particularly involving intracellular pathogens, as well as in the treatment of acne or for the prophylaxis of malaria. Physicochemical characteristics of doxycycline (liposolubility) allow a high diffusion in the tissues and organs. It has high bioavailability and a long elimination half-life allowing oral administration of one or two daily doses. Over the last decade, the prevalence of bacterial sexually transmitted infections (STIs) (syphilis, chlamydiosis, gonorrhoea and Mycoplasma genitalium infections) has increased in most countries, mainly in MSM, many of whom are infected with HIV. In light of increasing prevalence of resistance towards first-line regimens of some STI agents and recently updated recommendations for STI management, doxycycline appears to be an attractive option compared with other available antibiotics for the treatment of some STIs due to its efficacy, good tolerability and oral administration. More recently, indications for doxycycline in STI prophylaxis have been evaluated. Considering the renewed interest of doxycycline in STI management, this review aims to update the pharmacology of, efficacy of, safety of and resistance to doxycycline in this context of use.

Introduction

Doxycycline is a second-generation tetracycline, available worldwide since 1967. Its liposolubility confers excellent bioavailability and high tissue and fluid penetration. Doxycycline is a bacteriostatic antibiotic that acts on the ribosomal protein synthesis unit. It has a broad antibacterial spectrum, including intracellular pathogens and bacteria responsible for sexually transmitted infections (STIs) (Chlamydia trachomatis, Treponema pallidum, Neisseria gonorrhoeae and Mycoplasma genitalium).¹

According to recently updated recommendations for STI management, doxycycline can be used as the first-line treatment in C. trachomatis infections and as the third-line option in the management of M. genitalium infections whereas it is not recommended any more in N. gonorrhoeae infections because of a high percentage of strains resistant to tetracycline (45% in 2015, in France).² In syphilis, few studies are available on the use of doxycycline but suggest that doxycycline may be an alternative for patients with penicillin hypersensitivity.³

Over the last decade, the incidence of STIs has highly increased in most countries, mainly in MSM, many of whom are infected with HIV.^4,5 Otherwise, in France, in 2015, an increase of chlamydiosis was also observed in heterosexual women.² This increase in the STI incidence raises the question of prophylaxis strategies, which may include doxycycline.

In this context, we aimed to review available data on the efficacy of doxycycline in the main STIs, including pharmacokinetics, safety and resistance data.

Doxycycline pharmacokinetics

After oral administration, doxycycline is readily and almost completely absorbed (mean value close to 95%) from the gastrointestinal tract and absorption is not significantly affected by the presence of milk or food in the stomach or duodenum.⁶ Mean plasma concentrations of 2.6 mg/L have been measured 2 h after a 200 mg oral dose, falling to 1.45 mg/L at 24 h.

About 80% to 95% of doxycycline in the circulation is reported to be bound to plasma proteins.

The half-life of doxycycline is  20 h allowing once or twice daily dosing. Doxycycline is more liposoluble than tetracycline and is widely distributed in body tissues and fluids.^7,8 The highest concentrations are found in the excretory organs such as the liver, kidneys and digestive tract.

Particularly, doxycycline diffuses in the CNS and 4 h after administration of 200 mg of doxycycline an average CSF concentration of 0.6 mg/L is reached, which is higher than the MICs reported for T. pallidum (0.2 mg/L).^9,10 After the seventh dose of doxycycline (200 mg twice daily for 21 days), the mean level of doxycycline in serum was 5.8 mg/L, with a mean drug level in the CSF of 1.3 mg/L (mean penetration of blood to CSF ratio of 26%).¹¹

Doxycycline concentration was also measured in seminal fluids showing concentrations of 0.89 ± 0.07 mg/L and 0.45 ± 0.26 mg/L 6 h and 12 h after administration of a single dose of 100 mg, respectively.¹² To date, there are no other data on doxycycline diffusion in the genito-urinary tract.

There are limited available data on the pharmacokinetics of doxycycline in rectal tissue. However, a double-blind randomized clinical trial of a single 200 mg dose of doxycycline for prophylaxis in colonic surgery conducted in 1975 found that concentrations of doxycycline in colon and rectal tissue were above the MIC for Chlamydia within 4–6 h post-dose. This trial also found that doxycycline accumulated in the mucosal layer of the bowel, where it would be close to the site of infection for rectal C. trachomatis infection.¹³

Unlike conventional tetracyclines, doxycycline is largely eliminated by non-renal mechanisms, with only 30% to 40% eliminated by the kidneys.¹³ Furthermore, a decrease in the fraction of doxycycline bound to plasma proteins and erythrocytes has been noted in renal failure. This causes a compensatory increase in non-renal clearance (hepatic, intestinal, or both) of the drug.¹⁴ Therefore, the serum levels and half-life of doxycycline are not altered even in the presence of severe renal insufficiency. No accumulation occurs after repeated doses, even in patients with anuria.¹⁵ In contrast to other tetracyclines, doxycycline does not induce a catabolic state in patients with chronic renal failure. Consequently, acidosis and worsening of uraemia are not seen. Therefore, doxycycline can be safely administered to patients with renal failure.

Variability of doxycycline pharmacokinetics

There are no data on the impact of gender, pregnancy, lactation or liver impairment on doxycycline pharmacokinetics.⁶

The pharmacokinetics of doxycycline has been studied in the elderly, undernourished patients and patients with hyperlipidaemia, infected patients and patients with renal impairment.

In older patients (>65 years old), serum concentrations were higher than those reported for other age groups with a C_max of 8–30 mg/L and concentrations at 10 h in the range 5–10 mg/L.¹⁶

In undernourished patients, a decrease in the AUC is observed and, in patients with hyperlipidaemia, a significant increase in the AUC is observed.⁶

Drug interactions

Absorption is impaired by ferrous sulfate, bismuth and other antacids containing aluminium, calcium and magnesium salts.^17–22 Doxycycline should be given 2 h prior to or 3 h after iron supplementation.¹⁷ It is not reduced by concomitant ranitidine.²³

Although doxycycline has been reported to undergo partial inactivation in the liver, some sources consider this doubtful. However, the pharmacokinetics of doxycycline has been reported to be altered in patients receiving drugs that induce hepatic metabolism (rifampicin, carbamazepine …).²⁴ In addition, there are a few risks of drug interaction between doxycycline and antiretroviral agents.

Tetracyclines may lower plasma prothrombin activity, so patients on anticoagulant therapy may require reduction of their anticoagulant dose.^25,26

The half-life of doxycycline was shown to be significantly reduced in long-term alcohol consuming subjects compared with controls and in some patients, the serum concentration of doxycycline decreased below the generally accepted minimum therapeutic concentration when dosed once daily.²⁷

There are no published data on a possible interaction between doxycycline and recreational drugs: however, taking into account the pharmacokinetics of doxycycline, the risk of such interaction is not expected.

Use in pregnancy and breastfeeding

Doxycycline is labelled as Pregnancy Category D in the FDA classification. So, doxycycline should be avoided during pregnancy because of severe adverse effects including teratogenicity, permanent yellowish-brown teeth discoloration after in utero exposure and rare fatal hepatotoxicity,²⁸ and is therefore contraindicated past the fifth week of pregnancy. However, despite this categorization as a class D agent, doxycycline was FDA approved for use in pregnant women following exposure to biothreat agents, including Bacillus anthracis, Yersinia pestis and Francisella tularensis.²⁸

Recently, a systematic review of doxycycline in pregnant women revealed a safety profile significantly different from that of tetracycline with no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children.²⁹

Although doxycycline produces measurable milk levels, it is not contraindicated during the nursing period.

Doxycycline safety in adults

Doxycycline is generally well tolerated.

In a review on doxycycline safety, oesophageal erosion (55%) and photosensitivity (36%) were the main adverse events reported.³⁰ In clinical trials, the most common reported adverse events were gastrointestinal effects (0.54% of adverse effects in a study of 1653 patients treated with doxycycline 100–200 mg/day for 4–20 days for respiratory tract infection to 51.7% in 120 patients given doxycycline 100 mg twice daily for 10–20 days for the treatment of early Lyme disease) and skin reactions: 0.42% (in a study of 1653 patients) to 30.5% (among 36 patients with asymptomatic abdominal aortic aneurysms who were given doxycycline 100 mg twice daily for 6 months).³⁰

Gastrointestinal disorders

Gastrointestinal disturbances are reported to be less frequent with doxycycline than with tetracycline, and include nausea, epigastralgia, diarrhoea, anorexia, glossitis, enterocolitis and anal or genital candidiasis.³¹

Tetracyclines are deposited in teeth, causing permanent discoloration and enamel hypoplasia. However, doxycycline binds less with calcium than other tetracyclines and these changes are less frequently observed.³¹

Oesophageal ulceration may be a particular problem if capsules or tablets are taken with insufficient fluid or in a recumbent posture. In order to reduce this risk, doxycycline is now formulated only as tablets.³¹

Skin disorders

Doxycycline may be associated with photosensitivity, rash and erythrodermia.³² Photosensitivity is the main dermatological side effect of doxycycline. A systematic review was recently available concerning phototoxicity related to doxycycline.³³ By analysing the publications, the rates of phototoxic reaction related to doxycycline were found to vary from 6% to 42%.³³ The clinical manifestations of phototoxic reaction to doxycycline include sunburn-like sensation in sun-exposed areas, slightly palpable erythematous plaques, small papules, moderate to intense pain or itching as well as blisters.³³ Another possible symptom of a phototoxic reaction to doxycycline is photo-onycholysis.³⁴

Immune system disorders

Doxycycline may be associated with allergic reactions: urticaria, rash, pruritus, angioedema, anaphylactic reaction, rheumatoid purpura, pericarditis and exacerbation of preexisting lupus erythematosus.

CNS disorders

Doxycycline has been rarely associated with benign intracranial hypertension.^35,36 Presenting symptoms are headaches, tinnitus, visual loss, diplopia, nausea and vomiting. If raised intracranial pressure occurs, doxycycline treatment should be stopped. However, tetracycline is the most commonly implicated medication.

Recommended dosage of doxycycline

The usual dose of doxycycline in adults is 200 mg once or twice daily. The maximum recommended dose is 300 mg daily.³⁷

In STIs, the recommended dosages according to the diseases and the recommendations are reported in Table 1.

Resistance to doxycycline

STI bacterial agents are innately susceptible to doxycycline; however, the action of tetracyclines on the ribosome and protein synthesis may be affected by 4 mechanisms leading to acquired bacterial resistance: efflux, which is the most common mechanism; drug enzymatic inactivation; target mutation corresponding to mutations in the 16S rRNA gene; and ribosomal protection proteins.³⁸ Resistance is acquired through horizontal gene transfer of plasmids, transposons or insertion elements, or via mutations. Over 40 different acquired tetracycline resistance determinants are currently recognized, i.e. 38 tet genes (tetracycline resistance), 3 otr genes (oxytetracycline resistance) and 1 tcr gene.³⁹ Among them, tet genes mediating efflux or ribosomal protection have been identified in Chlamydia [tet(C)/efflux], Mycoplasma [tet(M)/ribosomal protection], Neisseria [tet(B)/efflux, tet(M), tet(O), tet(Q) and tet(W)/ribosomal protection] and Treponema [tet(B)/efflux].³⁹

Studies investigating antimicrobial resistance of STI pathogens remain generally rare. Indeed, N. gonorrhoeae is the only STI pathogen for which antimicrobial susceptibility testing can be routinely performed when culture is used for diagnosis, other STI pathogens being either non-cultivable (T. pallidum), displaying highly fastidious growth (M. genitalium) or requiring specific conditions like cell lines for both culture and antimicrobial susceptibility testing (C. trachomatis),⁴⁰ resulting in a limited number of antimicrobial susceptibility studies available in the literature. Such studies were mainly conducted on β-lactams (for N. gonorrhoeae), macrolides and fluoroquinolones; those on the prevalence and characteristics of doxycycline resistance remaining even more scarce. They will be presented later for each pathogen but it is noteworthy that study comparisons are limited by the absence of standard procedures to assess in vitro susceptibility to antibiotics of intracellular pathogens and pathogens with fastidious growth and the absence of specific clinical breakpoints for strain clinical categorization as susceptible, intermediate or resistant to doxycycline.

Doxycycline in syphilis

In syphilis, according to the CDC guidelines, whatever the stage, doxycycline is proposed as an alternative in patients who are allergic to penicillin with contraindication to desensitization.^5,41 The 2014 European guidelines on the management of syphilis recommend the use of doxycycline in syphilis in cases of penicillin allergy or parenteral treatment refusal.⁴² However, on the basis of antibacterial activity, pharmacokinetics and safety, few studies have evaluated the use of doxycycline in combination or as a substitute for penicillin in syphilis. These are non-randomized studies. These studies are summarized in Table 2. These studies with different designs or methodologies showed that doxycycline may be a suitable choice for the treatment of syphilis comparatively to penicillin.^43–46 In all these studies, safety of the treatment regimen, especially for doxycycline, was not reported.

Recently, a meta-analysis of the treatment of syphilis has been published.⁴⁷ The efficacy of ceftriaxone appeared to be equivalent to that of penicillin in treating early syphilis in terms of serological response rate and treatment failure rate. The authors considered that compared with doxycycline/tetracycline, ceftriaxone is more suitable for use, as a substitute for penicillin, in the treatment of early syphilis.⁴⁷

In addition, several case reports documented the use of doxycycline in specific clinical settings of syphilis infection. Successful treatment of neurosyphilis with doxycycline 200 mg twice daily for 28 days was reported in two HIV-infected patients.⁴⁸ At this dosage, doxycycline was well tolerated except for gastric distress and dizziness and abdominal pain (one patient each) that resolved spontaneously. Asymptomatic neurosyphilis is frequent in HIV-infected patents, a population at high risk of syphilis.^49,50 While the CDC recommends oral doxycycline as alternative therapy to treat primary and secondary syphilis only, the United Kingdom National Guideline recommends doxycycline as an alternative agent to treat neurosyphilis.⁵¹

Few data are available concerning the use of doxycycline in syphilitic uveitis. In this localization, the recommended treatment is benzyl penicillin. In the most recent case studies, among 85 cases of syphilitic uveitis, doxycycline was used in 5 cases and was effective in all cases.⁵²

In secondary syphilis, osteitis and hepatitis were successfully treated with doxycycline 100 mg twice daily for 6 weeks and 21 days, respectively, in HIV-infected patients with penicillin allergy.^53,54

The recommended treatment of otosyphilis is intravenous penicillin therapy, with a response rate varying between 23% and 31%. Doxycycline treatment (200 mg twice daily for 21 days) in otosyphilis was evaluated in 19 patients. The treatment was well tolerated, with one patient developing minor allergy to doxycycline and two patients reporting mild nausea. This study demonstrated that doxycycline in otosyphilis provided a similar result with a 47.4% improvement of hearing by patient report and a 36.8% improvement by audiogram and suggested that doxycycline may be an effective alternative treatment for otosyphilis.⁵⁵

The standard dosage of 200 mg daily results in a concentration in the CSF greater than the T. pallidum MIC.¹⁰ However, in case series or case reports, a dose of 200 mg twice daily has been used in the case of neurosyphilis or otosyphilis with favourable safety and efficacy.^48,55 This dose also results in a concentration in the CSF that is 2-fold higher.¹¹

Doxycycline resistance and T. pallidum

Although serological failure, defined as a lack of 4-fold decline in rapid plasma reagin (RPR) titres following therapy, was observed in patients treated with doxycycline (for example 15% of the patients in the recent study by Salado-Rasmussen et al.⁴⁶), no resistance study that could explain treatment failure was conducted and currently a unique study concerns doxycycline resistance of T. pallidum. In this study, Xiao et al.⁵⁶ investigated the presence of the G1058C point mutation in the 16S rRNA gene associated with decreased susceptibility to doxycycline and found no mutation among 2253 whole blood specimens sampled from Chinese patients with secondary or latent syphilis between 2013 and 2015.

Doxycycline in C. trachomatis infections

C. trachomatis is the most common STI bacterial agent worldwide with  100 million adults infected at any point in time.⁵⁷ The recommended regimen for Chlamydia infections is reported in Table 1.³ A meta-analysis of 12 randomized clinical trials of azithromycin versus doxycycline for the treatment of urogenital chlamydial infection demonstrated that the treatments were equally efficacious, with microbial cure rates of 97% and 98%, respectively.⁵⁸ In one recent study, the rate of efficacy of the doxycycline regimen reached 100%.⁵⁹

However, in MSM, in which the prevalence of C. trachomatis infection is high, available data suggest that the prevalence of rectal C. trachomatis infection is higher than that of urethral infection, and in rectal C. trachomatis infection, treatment failures of up to 22% have been reported with the single dose azithromycin regimen versus 8% with doxycycline.⁶⁰

Summarized data on doxycycline in rectal C. trachomatis infection provided in Table 3 suggest that doxycycline (100 mg twice daily for 7 days) may be more effective than azithromycin (single-dose 1 g).^60–62 Recently, a meta-analysis and systematic review analysed the data regarding the efficacy of doxycycline for rectal lymphogranuloma venereum (LGV) in MSM.⁶³ This meta-analysis found a pooled treatment efficacy of 98.5% (96.3%–100%; I² = 0%) for 100 mg doxycycline twice daily for 21 days. These data as well as a recent review of clinical cases support doxycycline at this dosage and duration (21 days) as the first-line therapy for rectal LGV.^63,64

Pharmacokinetic data may explain the higher efficacy of doxycycline in rectal chlamydial infection in comparison with azithromycin. Indeed, unlike azithromycin, doxycycline is highly lipid-soluble, a property facilitating its rapid absorption into the tissues.

Doxycycline resistance and C. trachomatis

Despite the absence of recent MIC data for C. trachomatis, low values of MICs of doxycycline were reported in the literature with MIC₉₀ usually ≤0.125 mg/L.^40,65,66 Interestingly, doxycycline minimum chlamydiacidal concentrations (MCCs) varied according to the clinical presentation and the bacterial serovar, with lower MCCs in cases of asymptomatic infection than in mucopurulent cervicitis and pelvic inflammatory disease, and the highest MCCs observed for serovar Ia and J in mucopurulent cervicitis and pelvic inflammatory disease.⁶⁶ In contrast, no MIC or MCC difference was observed between isolates recovered in the case of treatment failure or persistence compared with single-episode isolates.⁴⁰ From these data and treatment success rates, pathogen resistance is expected to be low. However, tetracycline- and doxycycline-resistant isolates and isolates resistant to multiple antibiotics have been reported, some of them—but not all—being involved in relapsing or persistent infection.^67–69

These isolates displayed MICs of doxycycline >4 mg/L, sometimes >64 mg/L, with the particularity to contain both a dominant susceptible and a minor (<1%) resistant subpopulation defining heterotypic resistance.^67,68,70 Two additional studies suggested a role for heterotypic resistance in persistent infection.^70,71 More recently, controversy has emerged regarding heterotypic resistant C. trachomatis with two strains initially described as tetracycline-resistant subsequently found to be susceptible to tetracycline by tetracycline resistance assays and WGS.⁷² Other authors suggested that persistence, rather than antibiotic resistance, might explain therapeutic failure, the pathogen being able to persist in a quiescent, viable but non-cultivable state, more insensitive to antibiotics in the host cells.⁷³

N. gonorrhoeae infections

In the USA, an estimated 820 000 new N. gonorrhoeae infections occur each year,⁷⁴ with MSM being at high risk for gonorrhoea. The recommendations for the treatment of N. gonorrhoeae infections are reported in Table 1. The recommendations differ on the use of azithromycin, in association with ceftriaxone or cefixime, and the use of doxycycline in salvage therapy. In its recommendation in 2016, the French Society of Dermatology stated that azithromycin can only be active in gonorrhoea at high doses (2 g), which then causes significant digestive problems. Consequently, this antibiotic has no place at present in this indication, especially since resistances appeared rapidly.⁷⁵ The prevalence of resistance of azithromycin to N. gonorrhoeae in the US Gonococcal Isolate Surveillance Project (GISP) was 2.5% in 2014.⁷⁶

Because of the prevalence of tetracycline resistance among the GISP isolates, the use of azithromycin as the second antimicrobial agent is preferred. However, in the case of azithromycin allergy, doxycycline (100 mg orally twice daily for 7 days) can be used in place of azithromycin as an alternative second antimicrobial agent when used in combination with ceftriaxone or cefixime.³ However, the French Society of Dermatology in 2016 avoided the use of tetracyclines in gonococcal infection.⁷⁵

Doxycycline resistance and N. gonorrhoeae

Emergence of gonococcal resistance to tetracycline became widespread during the early 1980s.⁷⁷ At present, N. gonorrhoeae has developed significant rates of resistance to various antibiotics and MDR/XDR N. gonorrhoeae is now considered a superbug of high concern for public health.^78–81

Resistance to tetracyclines is associated with the presence of the tet(M) gene on conjugal plasmids, among which Dutch and American type conjugative plasmids were the most prevalent, resulting in high-level cross-resistance to tetracycline, doxycycline and minocycline, and to chromosomal mutations associated with less elevated MIC.^80–83 Of note, coexistence of chromosomally and plasmid-mediated resistance to tetracycline has been observed in resistant isolates.⁸⁴

The prevalence of tetracycline resistance in N. gonorrhoeae depends on the time period and the country of strain isolation, being described in 12% to 100% of the isolates studied (for a recent review, see Młynarczyk-Bonikowska et al.,⁸¹ 2016). Most studies only refer to tetracycline for which the resistance breakpoint is ≥2 mg/L. If we consider studies that specifically tested doxycycline and, in the absence of a specific resistance breakpoint for doxycycline, retained the tetracycline breakpoint for evaluating doxycycline resistance, doxycycline resistance rates over 50% were reported in most studies (8.6% to 99%).^81,85–89

Resistance rates may also vary according to the N. gonorrhoeae strains circulating at the time of the study, such as ST 611 characterized by MDR, including tetracycline resistance, in Italy and ST 1405 in Poland,^81,90,91 and to the population studied because the percentage of tetracycline-resistant isolates was greater in isolates from MSM than in those from men who have sex with women.^92,93

Resistance to doxycycline is usually associated with resistance to other antibiotic classes; for example, of the 2009–10 isolates with decreased susceptibility to cefixime reported by the CDC, all of them exhibited tetracycline resistance.⁷⁹

M. genitalium infection

Doxycycline is the third-line recommended treatment for persistent M. genitalium infection after azithromycin and moxifloxacin (see Table 1). In these cases, doxycycline (100 mg twice daily for 14 days) eradicated M. genitalium in approximately 30% of the patients.⁹⁴ Three randomized controlled trials have compared azithromycin and doxycycline therapy in men with urethritis. Two trials showed the superiority of azithromycin compared with doxycycline for microbiological cure of M. genitalium (P = 0.002), with cure rates for azithromycin and doxycycline ranging from 67% to 87% and from 31% to 45%, respectively.^95,96 The third and most recent trial found no significant difference in the efficacy of azithromycin (1 g) and doxycycline (100 mg twice daily for 7 days) and high levels of treatment failure with both regimens (40% versus 30%, P = 0.41),⁹⁷ suggesting that the efficacy of single-dose azithromycin therapy is declining.

Doxycycline resistance and M. genitalium

Information on antimicrobial susceptibility of M. genitalium is scarce because of the limited number of strains isolated from clinical samples. Studies reporting MICs of doxycycline usually found low MIC values, i.e. 5 strains with MICs ranging from ≤0.008 to 0.031 mg/L⁹⁸ and 14 strains with MICs ranging from 0.06 to 0.12 mg/L (MIC₅₀=0.12 mg/L).⁶⁵ However, an in vitro antimicrobial susceptibility testing study conducted using both broth dilution (23 isolates) and quantitative PCR (17 isolates) showed an MIC range of 0.063–1 mg/L indicating that the strains displayed reduced susceptibility to doxycycline (1 mg/L) but that these isolates remained rare.⁹⁹ Finally, a recent larger study showed that 2 isolates out of 103 displayed MIC >8 mg/L while for other isolates, MICs ranged from <0.125 to 2 mg/L.¹⁰⁰ However, doxycycline MICs did not correlate with treatment outcomes in this study. As far as molecular detection of mutations mediating resistance is concerned, macrolides and fluoroquinolones were mainly studied and to our knowledge, tetracycline resistance-associated mutations have not so far been identified in M. genitalium. Altogether, MICs mostly indicated susceptibility of M. genitalium to doxycycline and the rare isolates with reduced susceptibility cannot explain the poor efficacy of doxycycline (<50%) in the treatment of M. genitalium infections.^94,101 Considering the emergence of MDR (macrolide-resistant and fluoroquinolone-resistant) M. genitalium strains, it thus appears important to elucidate reasons— other than poor patient compliance—for the poor efficacy of doxycycline.¹⁰²

Perspectives of doxycycline use in STIs

Recently, oral pre-exposure prophylaxis (PrEP) using a combination of the antiretroviral drugs tenofovir and emtricitabine has been recommended for preventing HIV infection among individuals at high risk, including MSM.¹⁰³ In September 2015, the WHO recommended offering PrEP for all persons at substantial risk of HIV infection including MSM.¹⁰⁴ A recent meta-analysis reported that MSM using PrEP were significantly more likely to acquire a N. gonorrhoeae, C. trachomatis or syphilis compared with MSM not using PrEP.¹⁰⁵ Recreational drug use in MSM and the association with sexual risk behaviour have been documented on an international level and in Western Europe, where transmission of HIV and other STIs remains high. This partly explains why MSM are a high-risk STI group.¹⁰⁶ These practices, called ‘ChemSex’ are defined by the use of certain sexually-disinhibiting recreational drugs (amphetamines, synthetic cathinones) before or during sex with the specific purpose of facilitating or enhancing sex.¹⁰⁶

In this context, doxycycline is currently being assessed in prophylaxis to reduce the incidence of syphilis and other STIs. Doxycycline prophylaxis was assessed to reduce incident syphilis among HIV-infected MSM who have high-risk sex.¹⁰⁷ Thirty MSM with syphilis were randomized to receive either daily doxycycline prophylaxis or contingency management with incentive payments for remaining free of STI. Subjects receiving doxycycline were significantly less likely to test positive for any selected STIs (gonorrhoea, Chlamydia, syphilis or any combination thereof; OR = 0.27; CI = 0.09–0.83) compared with contingency management. One patient stopped doxycycline because of gastroesophageal reflux related to the drug. Another recent study, presented at the 2017 Conference on Retroviruses and Opportunistic Infections, investigated post-exposure prophylaxis (PEP) with doxycycline in MSM enrolled in a pre-exposure prophylaxis open trial (ANRS Ipergay trial).¹⁰⁸ Participants (n = 232) were randomized to receive either doxycycline (2 pills of 100 mg) within 72 h after condomless sexual intercourse or no PEP. The incidence of STIs (C. trachomatis infection and syphilis) during the study period was significantly lower in the PEP arm versus no PEP: 24% versus 38.8% for an HR of 0.53 (95% CI = 0.47–1.47, P = 0.008). HRs for gonorrhoea, chlamydiosis and syphilis separately were 0.83 (95% CI = 0.47–1.47, P = 0.52), 0.30 (95% CI = 0.13–0.70, P = 0.006) and 0.27 (95% CI = 0.07–0.98, P < 0.05), respectively. In this study, the safety of doxycycline was favourable with only 8 patients (3.45%) discontinuing PEP because of gastrointestinal adverse events.

The questions about doxycycline in prophylaxis of bacterial STIs concern the safety and the risk for acquired resistance. Use of doxycycline in clinical practice to prevent STI, particularly C. trachomatis and syphilis, is still not validated, pending further analysis.

Conclusions

Doxycycline has advantages (available worldwide, inexpensive, oral route, well tolerated) in the treatment of STIs. In the treatment of syphilis, the available results are in favour of effectiveness comparable with antibiotics recommended with simpler modalities of use and suggest that oral doxycycline might be considered in this indication including neurosyphilis. In C. trachomatis infection, doxycycline remains one of the first-line recommended antibiotics based on pharmacokinetics, safety and high rates of clinical cure although it is not recommended any more in N. gonorrhoeae infections, based on high resistance levels, or recommended as third-line treatment of M. genitalium infections, based on poor clinical efficacy as yet not related to antimicrobial resistance. Despite some cases of therapeutic failure having been reported, doxycycline resistance appeared rare in STI pathogens other than N. gonorrhoeae and was not systematically related to treatment failure; however, it has globally received far less attention than resistance to either macrolides or fluoroquinolones. In the global context of widespread increase in antimicrobial resistance, the current impossibility of testing doxycycline susceptibility in routine practice for STI pathogens other than N. gonorrhoeae impairs studies relating susceptibility to pathogen genotype or serovar to treatment outcome, and therefore requires further development to improve STI management.

Finally, preliminary data are available on the use of doxycycline in STI prophylaxis and show significant efficacy in reducing the number of newly acquired STIs in treated subjects. However, indications and conditions of use should be more specified.

Transparency declarations

None to declare.

References