Abstract
Recent data suggest that azithromycin may not be as effective as doxycycline in eradication of genital chlamydial infection. The aim of this study was to compare the eradication rate of pharyngeal Chlamydia trachomatis infection after treatment with azithromycin 1 g stat with that of doxycycline 100 mg twice a day for seven days. A prospective open-label observational study was conducted on patients with pharyngeal Chlamydia trachomatis diagnosed at Whittall Street Clinic, University Hospitals Birmingham, Birmingham, UK, between July 2012 and July 2013. We confirmed eradication of pharyngeal Chlamydia trachomatis with a negative test of cure. We treated all our patients with azithromycin 1 g stat until February 2013. At that stage, we offered doxycycline to patients with pharyngeal Chlamydia trachomatis. A total of 398 patients (52 men, 346 women) were diagnosed with pharyngeal Chlamydia trachomatis during the study period. Of the 172 patients included in the final analysis, 78 were treated with azithromycin and 64 with doxycycline. Treatment failure was identified among 8/78 (10%) patients treated with azithromycin and 1/64 (2%) treated with doxycycline (absolute difference: 8 percentage points, 95% CI: 0–17%, p = 0.041). In our study, doxycycline 100 mg twice a day for seven days was associated with less treatment failure of oropharyngeal chlamydia compared with azithromycin 1 g stat. Future randomised studies should investigate whether patients with pharyngeal Chlamydia trachomatis should be followed up with a test of cure when treated with azithromycin, or be treated with doxycycline.
Introduction
Chlamydia trachomatis is the most common sexually transmitted infection (STI) in the UK; comprising 47% of all infections diagnosed in 2013. 1 The prevalence of pharyngeal chlamydia infection has been reported as between 1.1% and 2.3% among men who have sex with men (MSM)2,3 and between 1.9% and 2.6% among women attending STI services.2,4
The majority of individuals with pharyngeal chlamydia infection are asymptomatic, which makes its diagnosis challenging.2,4–7
Few data are currently available on the natural history of pharyngeal chlamydial infection. A study on neonates reported persistence of infection in 35% at the age of one year with one child remaining infected for 866 days after birth. 8 In a study on adults, 37.2% of MSM and 36.4% of women spontaneously cleared pharyngeal chlamydia infection after a median of 13.0 (inter-quartile range [IQR] 9,19) and 8.5 (IQR 8,13.5) days, respectively. 2
Oral sex is commonly practised in the UK. Among the participants in the recent National Survey of Sexual Attitudes and Lifestyles (NATSAL 3), 60% of 8869 women and 67% of 6293 men reported engaging in oral sex in the previous year. 9
It is unclear if oral sex can lead to transmission of C. trachomatis. Some data support this hypothesis. In cross-sectional analyses of clinic visits of men with urethral chlamydia infection, fellatio was the only form of urethral exposure in 2% of 10,817 clinic visits in men who have sex with women and in 4.8% of 397 clinic visits of MSM.10,11
The current guidelines recommend azithromycin 1 g stat or doxycycline 100 mg twice daily for seven days for treatment of chlamydia infection.12,13 There are some reports on the possible shortcoming of the stat dose of azithromycin in treatment of rectal C. trachomatis.14–16 It has been hypothesised that azithromycin, the most widely used antibiotic for chlamydial infection, may not establish anti-chlamydial concentration long enough to eradicate chlamydia infection in non-genital tissues. 17 Few data on the potency of azithromycin 1 g stat for eradication of pharyngeal chlamydia currently exist. In the present study, we compared the eradication rate of pharyngeal C. trachomatis infection after treatment with azithromycin 1 g stat with that of doxycycline 100 mg twice a day for seven days.
Methods
Study design
This was a prospective open-label observational study on patients with oropharyngeal C. trachomatis infection diagnosed at Whittall Street Clinic, University Hospitals Birmingham, Birmingham, UK, between July 2012 and July 2013. We confirmed eradication of oropharyngeal chlamydia infection with a negative test of cure (TOC). We offered azithromycin to patients with oropharyngeal chlamydia between July 2012 and February 2013. At that stage (February 2013), we offered doxycycline 100 mg twice a day for seven days to the infected patients. Those who declined treatment with doxycycline were offered azithromycin. We stopped the study in July 2013. The TOC results of patients treated with azithromycin after February 2013 were also included in the study. We reviewed the results of TOC of all patients after closure of study recruitment.
Clinical intervention and laboratory investigation
Patients with a history of giving oral sex were screened for chlamydial and gonococcal infections with Gen-Probe Aptima Combo 2 assay (Hologic, San Diego, CA, USA). The manufacturer’s cotton wool swab was introduced in the individual’s mouth and gently contacted with the tonsils and the back of their throat. The swab was then inserted in the manufacturer’s special transport medium. The specimens were transported to the medical microbiology laboratory at Queen Elizabeth Hospital Birmingham within four hours. The specimens were processed in the laboratory within 24 hours.
Infected patients were informed by the department’s automated text messaging system immediately after authorisation of the results by the laboratory. They were invited to attend the department as soon as possible.
Patients treated with azithromycin took their tablets in the clinic. They were advised to attend the clinic for more treatment if they developed diarrhoea or vomiting within six hours of taking azithromycin. Patients treated with doxycycline received packs of a seven-day treatment course with clear instructions on the need for 12-hourly intake of the tablets.
In our clinic drug history and information on drug allergy is routinely obtained from patients. Azithromycin and doxycycline are prescribed for patients without history of allergy. The antibiotics are prescribed when there is no serious interaction with other medicines patients may be taking.
All patients infected with oropharyngeal infection were invited to attend the clinic for TOC between four and six weeks after completion of their treatment. They were advised not to give oral sex before their TOC.
At their TOC appointment a sexual history was obtained to establish possible re-exposure to infection. History of vomiting or diarrhoea within six hours after taking azithromycin and time of completion of treatment course (intake of last tablet of doxycycline) were obtained where applicable.
Where required by sexual history, a repeat screening for STIs (chlamydia, gonorrhoea, syphilis and HIV) was offered. Otherwise, an oropharyngeal swab for chlamydia infection TOC was obtained.
Treatment failure was defined as having a positive TOC when non-adherence to treatment and repeat exposure were excluded.
Patients with pharyngeal chlamydia who received treatments other than azithromycin or doxycycline (for treatment of pelvic inflammatory disease, gonorrhoea or epididymo-orchitis), those with history of oral sex after treatment and before TOC, those with vomiting and diarrhoea after taking azithromycin, those not completing the treatment course with doxycycline within the anticipated seven-day period and those who did not have a TOC result were excluded from the final analysis.
Based on the published data on 85% eradication rate of oropharyngeal chlamydia infection with azithromycin and the desired eradication rate of equal to or over 95% with any antibiotic, we required at least 49 patients in each study group to show a difference of 10% with 95% confidence interval and a beta error level of 50%. 18
The following data for each patient were collected; gender, age, concurrent sexually transmitted infection(s), treatment regimen received for pharyngeal chlamydia and the TOC result.
We calculated the difference between the proportion of patients failing with azithromycin and doxycycline with their 95% confidence intervals (95% CI).
Results
Baseline characteristics of patients with oro-pharyngeal chlamydia (n = 398).
GC: N. gonorrhoea infection; HIV: human immunodeficiency virus infection; PID: pelvic inflammatory disease; TV: T. vaginalis infection; HSV: herpes simplex virus infection; 95% CI: 95% confidence interval.
Of all patients with oropharyngeal chlamydial infection, 372 (93%) attended the department for treatment. We excluded 230 (68%) of patients from the final analysis according to the study’s exclusion criteria. Failure to attend for TOC was the most common reason followed by having had oral sex between treatment and TOC (Figure 1).
Study flow summary for oropharyngeal chlamydia infection. PID: pelvic inflammatory disease.
Of the 172 patients included in the final analysis, 78 were treated with azithromycin and 64 with doxycycline. Treatment failure was identified among nine (5%) patients; 8/78 (10%) treated with azithromycin and 1/64 (2%) treated with doxycycline (absolute difference: 8 percentage points, 95% CI: 0–17%, p = 0.041). All eight patients who failed treatment with azithromycin were heterosexual women. The one patient who failed treatment with doxycycline was an MSM.
Discussion
In our study, azithromycin treated 90% cases of oropharyngeal chlamydia compared to 98% with doxycycline; a difference that was statistically significant. Our data are consistent with a previous report of oropharyngeal chlamydia treatment rate of 85% with azithromycin. 18
Azithromycin is an effective antibiotic against genital chlamydial infection. A widely quoted meta-analysis of 12 studies reported a cure rate of 97% with azithromycin and comparable to that of 98% for doxycycline. 19 Only one of the studies in that analysis used DNA amplification assays for detection of chlamydia. This raises some concerns about the validity of the analysis’ conclusions in current clinical practice.
Recent studies suggest azithromycin may not be as effective as doxycycline in treatment of urogenital chlamydia. A randomised study reported a significantly higher cure rate of urethral chlamydial infection in men treated with doxycycline (95%) compared with those treated with azithromycin (77%), p = 0.01. 20 A meta-analysis comparing the efficacy of azithromycin and doxycycline in treating symptomatic men with urogenital chlamydial infections reported a statistically significant pooled efficacy difference of 7% in favour of doxycycline. 21 Other reports on lower cure rate of genital chlamydia with azithromycin compared with doxycycline have also been published. 22
There are a number of hypotheses to explain the difference in cure rate of oropharyngeal chlamydia infection between azithromycin and doxycycline. Different efficacy rate against the two stages of chlamydia life-cycle may be a cause. Data from in vitro experiments suggest that doxycycline may be more effective against the chlamydial reticulate bodies (acute infection) whereas azithromycin has an excellent effect against chlamydial elementary bodies (persistent infection). 23
Another possibility may be the presence of sub-populations of chlamydia infection with different susceptibility to azithromycin that consequently result in selection of ‘persister cells’ that can lead to treatment failure. 24
Recent data suggest that slow release of azithromycin from acidic compartments inside the cells to free form could be responsible for its prolonged half-life. This model predicts concentrations of free azithromycin in the interstitial space fluid to be sub-inhibitory to some bacteria that can lead to treatment failure. 25 Reports of series of in vitro experiments stated that a 10-day exposure to macrolides was required to eradicate infectious chlamydia strains including L2. A single dose of azithromycin has a half-life of 68 hours that does not cover such a duration. 26 Based on these data and the evidence of clinical eradication of Chlamydophila pneumoniae, it has been proposed that a four-day course of azithromycin prescribed as 1 g stat followed by 500 mg daily for three days should provide anti-chlamydial effect for all chlamydia strains for at least 10 days in vivo. 17
Sub-optimal azithromycin levels in oropharyngeal tissues may be another reason for its lower efficacy in eradication of chlamydia infection. A recent study on 12 healthy volunteers reported that azithromycin concentration was substantially lower in soft tissues compared with white blood cells and plasma. 27
Presence of serovars L1–L3 of C. trachomatis in the oropharynx may yet pose another cause of lower eradication rate with azithromycin. These serovars are the cause of lymphogranuloma venereum (LGV). LGV has been reported mostly among MSM with history of receptive anal sex. 28 The current clinical guidelines recommend screening for L1–L3 serovars of MSM with symptoms of proctitis and rectal chlamydia infection.29,30
Little is known on the prevalence of C. trachomatis serovars L1–3 in oropharyngeal tissue. LGV has previously been described in the oropharyngeal tissues anecdotally.31,32 Genotyping of oropharyngeal chlamydia in 23 MSM who had a sexual partner with LGV reported two (8.7%) positive cases. 2 In a study carried out in Germany, LGV was detected in two (15%) out of 28 MSM with oropharyngeal chlamydia. 33 In a Finnish study, one (2%) of 56 oropharyngeal chlamydia specimens obtained from MSM was positive for LGV. 34
Presence of multi-drug resistant C. trachomatis strains may be another reason for failure of azithromycin in some cases. In vitro experiments have shown that point mutations in ribosomal protein of C. trachomatis serovar L result in the development of azithromycin resistance.35,36 In another in vitro experiment pre-exposure to penicillin resulted in resistance to azithromycin. 37 There are currently few data on detection of azithromycin-resistant genital chlamydial infection in the literature. An earlier case series report on three patients, including a husband and wife, suggested treatment failure secondary to azithromycin resistance. 38 An earlier study reported identification of resistance to doxycycline and erythromycin in four patients suspected of failing treatment. 39 These data suggest a benefit for investigation of azithromycin resistance in future cases of failure of treatment.
Our study suffered from a number of short falls. This was not a randomised study and the possibility of unaccounted bias should therefore be considered. In addition, a large number of participants in our study defaulted from follow-up appointments for TOC. Despite this, we managed to recruit nearly twice the number of patients planned for the study. The possible study overpowering could account for the statistical difference between treatment rates of doxycycline and azithromycin. The possibility of false positive results of TOC in the azithromycin group in our study should also be considered. In a study on eradication of chlamydia infection in women treated with azithromycin, 79% of women had a negative TOC after 14 days, and mathematical modelling predicted 100% eradication rate with Aptima Combo assay after 17 (95% CI 16–18) days. 40 It is therefore likely that positive TOC after four weeks of treatment in our study were true cases of chlamydial infection, a concern already raised by other authors. 41 We did not perform typing of C. trachomatis outer membrane protein A (OmpA) to confirm the persistence infections for those with positive TOC.
A quarter of patients in our study had evidence of chlamydia infection only in their throat. This is an argument for obtaining throat swabs routinely for individuals with history of receptive oral sex.
In conclusion, in our study, doxycycline 100 mg twice a day for seven days was associated with less treatment failure of oropharyngeal chlamydia compared with azithromycin 1 g stat.
Future randomised studies should investigate whether patients with pharyngeal Chlamydia trachomatis should be followed up with a TOC when treated with azithromycin, or be treated with doxycycline.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.