Participants and study design
The study protocol was reviewed and approved by the Hai Phong International Hospital Institutional Review Board. The study was conducted in accordance with the Declaration of Helsinki and International Conference on the Harmonization of the Technical Requirements for the Registration of Pharmaceuticals for Human Use—Good Clinical Practice guidelines and the guideline for Vietnamese Good Clinical Practice. Written informed consent was obtained from all participants before study initiation. This trial was registered with ClinicalTrials.gov (NCT05216744) on 31/01/22.
This study was a single-center, parallel-group, randomized controlled trial that compared treatment with 1 g of ceftriaxone IV to treatment with oral cefixime together with doxycycline in patients with NG and CT co-infection. This study was conducted in The Department of Nephrology – Urology of Hai Phong International Hospital from 1 October 2021 to 02 February 2022.
Individuals aged > 18 years were eligible for participation if they had a diagnosis of untreated gonorrhea and chlamydia. The untreated status was defined as no antibiotic taken in the previous 28 days to treat gonorrhea and chlamydia, either partially or completely. Diagnosis was based on the detection of NG and CT by NAAT from the first voided urine or urethral, endocervical, vulvovaginal, pharyngeal, or rectal swabs.
Exclusion criteria were known contraindications or hypersensitivity to cephalosporins, penicillins, or doxycycline; gonorrhea with complications, such as pelvic inflammatory disease or epididymo-orchitis; and significant renal failure or hepatic failure. Women who were pregnant or breastfeeding were excluded. Significant renal failure is defined as the presence of decreased kidney function (defined as estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2). Interventions will not be initiated if the patient exhibits active liver disease or increased transaminases (ALT > 2.5 times the upper limit of normal) at baseline.
Randomization and intervention
Within 24 h of admission, patients were randomly assigned to one of two groups using a computer-generated list of random numbers, with one group taking a regimen of 1 g of ceftriaxone IV and the other receiving one oral dose of 800 mg cefixime. All participants were administered 100 mg of doxycycline orally twice a day for 7 days. For 1 g ceftriaxone intravenous injection, ceftriaxone was dissolved in 10 mL of water for injections and then injected over 5 min, directly into the vein of participants.
Safety information was recorded daily with the assistance of a clinical pharmacist to document any adverse events. All participants were asked to abstain from sex until the end of the study.
Outcomes and follow-up
Patients were clinically evaluated at two time-points, including day 1 (before drug administration) and day 8 (end of the 7-day treatment) by nephrologist-urologists. Clinically reported symptoms included genital discharge, dysuria, sore throat, anorectal pain, rectal bleeding, rectal discharge, and constipation. In general, NAAT and culture are the tests of choice for the microbiologic diagnosis of NG and CT infection. Samples were collected from the participants for the detection of NG and CT before treatment initiation and on the day 8 of the study for NAAT and cultures. The samples were selected according to the sex and sexual orientation of the participant: urethral samples from heterosexual men; urethral, pharyngeal, and rectal samples from men who have sex with men; cervical, pharyngeal, and rectal samples from women. NAAT and cultures were performed on the samples from the cervix, pharynx, and rectum. Follow-up was performed 1 week after treatment, when NAAT and cultures for NG were repeated for sites that had been positive at the baseline. All pre- and post-treatment samples were subjected to NAAT (Aptima Combo 2, Hologic, MA, USA). The identification of NG by culture was performed according to guidelines of the CDC . The E-test method (Durham, NC, USA), was applied to determine the minimum inhibitory concentration (MIC) of ceftriaxone, and cefixime for the NG isolates. Whole blood samples were obtained to assess the renal function of patients in both the groups on the first and last day of the study.
The primary endpoint was the clearance of NG from all the initially infected sites, which was defined as a negative NAAT after 1 week of treatment . Success was defined as the eradication of NG and CT (absence of the original pathogens in adequate samples taken after the completion of therapy). Failure was defined as persistence (continued presence of the original bacterial infection upon completion of treatment).
The secondary endpoints included the resolution of the clinical symptoms, including genital discharge, dysuria, sore throat, anorectal pain, rectal bleeding, rectal discharge, and constipation as well as changes in the serum clearance levels, estimated glomerular filtration rate, and antibiotic minimum inhibitory concentration (MIC).
Sample size and statistical analyses
The sample size was estimated based on the primary outcomes of a trail by Muratani et al. , that had a 100% treatment success rate in patients treated with 1 g of ceftriaxone IV, and a trial by Allen et al. , that had a treatment success rate of 93% in patients treated with cefixime. In total, 114 patients were required in both arms of the study to compare the effects of 1 g ceftriaxone IV therapy and 800 mg PO cefixime therapy in combination with doxycycline 100 mg twice daily on day 8 with 80% statistical power at a 5% level of significance.
All analyses were performed using SAS (version 9.4, SAS Institute, Cary, NC, USA) and R software, version 3.2.4 . The Independent samples t-test was selected to compare the means between two independent groups on a continuous variables with normal distribution. The Mann–Whitney U test was used to compare differences between two group of non-normally distributed data. Fisher’s exact test was performed to analyzed the difference in proportions between the two categories . There were no missing data.