Neisseria Gonorrhoeae
Conditions
Brief summary
In this Randomized Controlled Trial, the investigators will recruit 42 men attending the STI and HIV clinic at the Institute of Tropical Medicine, with a diagnosis of N. gonorrhoeae and randomize them 1:1 to receive either ceftriaxone or ceftriaxone/azithromycin. They will be followed-up for a test of cure visit at day 14 post-treatment where urine, oropharyngeal and anorectal samples will be taken to test for cure and monitor treatment effects on the microbiome and resistome. The primary outcome will be evaluating the difference in the abundance of resistance conferring genes in the rectal microbiome in the two arms, 14 days after the receipt of therapy.
Interventions
DRUGRocephin
Single dose of Rocephine® (= ceftriaxone 1g + lidocaine 35mg) intramuscular injection
DRUGAzithromycin
Single dose of Rocephine® (= ceftriaxone 1g + lidocaine 35mg) intramuscular injection + single dose of azithromycin 2g orally
Sponsors
Institute of Tropical Medicine, Belgium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able and willing to provide written informed consent 2. Male sex at birth 3. At least 18 years old 4. Confirmed diagnosis of urethritis, proctitis or pharyngitis N. gonnorrhea - symptomatic or asymptomatic (Diagnosis of N. gonnorrhea will be by a positive NAAT performed according to the ITMs current laboratory protocols or for patients with urethritis a positive gram/methylene blue stain)
Exclusion criteria
1. Use of any macrolide antibiotics (azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin) in previous 6 months 2. Known contra-indications or allergy to ceftriaxone, azithromycin or lidocaine 3. Presence of any other condition, including other Sexually Transmitted Infections that will (likely) require the administration of another antibiotic at the time of enrollment, as assessed by the treating physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Macrolide Resistance Determinants | Day 14 | During the bioinformatic analyses, each identified antibiotic-resistance determinant will be categorized at the class level using a read-based classification tool. The primary outcome will be the ratio of mean macrolide resistance determinants in the day 14 anorectal samples between the two treatment groups. This ratio will be calculated by dividing the mean normalized read count of macrolide- resistance determinants categorized at the class level in the Ceftriaxone/Azithromycin group by the corresponding mean quantity in the Ceftriaxone group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Day 14 | The ratio of mean normalized read count of resistance determinants for each non-macrolide antibiotic class in the day 14 anorectal samples between the two treatment groups |
| Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Day 0 and Day 14 | The difference in time until acquisition of phenotypic resistance to Azithromycin by N. gonnorrhea in the morbidostat upon exposure to commensal Neisseria DNA extracts from each treatment group |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rocephine® ceftriaxone 1g + lidocaine 35mg; intramuscular injection
Rocephin: Single dose of Rocephine® (= ceftriaxone 1g + lidocaine 35mg) intramuscular injection | 22 |
| Rocephine® + Azithromycin ceftriaxone 1g + lidocaine 35mg intramuscular injection + azithromycin 2g orally
Rocephin: Single dose of Rocephine® (= ceftriaxone 1g + lidocaine 35mg) intramuscular injection
Azithromycin: Single dose of Rocephine® (= ceftriaxone 1g + lidocaine 35mg) intramuscular injection + single dose of azithromycin 2g orally | 20 |
| Total | 42 |
Baseline characteristics
| Characteristic | Rocephine® | Rocephine® + Azithromycin | Total |
|---|---|---|---|
| Age, Continuous | 40 years | 41.5 years | 40 years |
| Amoxicillin/Clavulanic acid | 0 Participants | 2 Participants | 2 Participants |
| Ceftriaxone | 0 Participants | 0 Participants | 0 Participants |
| Dental caries | 0 Participants | 0 Participants | 0 Participants |
| Doxycycline | 0 Participants | 0 Participants | 0 Participants |
| HIV status: Negative | 17 Participants | 16 Participants | 33 Participants |
| HIV status: Positive | 5 Participants | 4 Participants | 9 Participants |
| Infection site: Anorectal | 2 Participants | 1 Participants | 3 Participants |
| Infection site: Pooled | 16 Participants | 14 Participants | 30 Participants |
| Infection site: Urethral | 4 Participants | 5 Participants | 9 Participants |
| Number of partners (last 3 months) | 5 partners | 5 partners | 5 partners |
| Penicillin | 0 Participants | 0 Participants | 0 Participants |
| PrEP use | 14 Participants | 13 Participants | 27 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex/Gender, Customized Male sex at birth | 22 participants | 20 participants | 0 participants |
| Symptomatic NG | 7 Participants | 6 Participants | 13 Participants |
| Teeth discoloration | 0 Participants | 0 Participants | 0 Participants |
| Use of antibiotics in the last 12 months | 8 Participants | 10 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 20 |
| other Total, other adverse events | 2 / 22 | 4 / 20 |
| serious Total, serious adverse events | 0 / 22 | 0 / 20 |
Outcome results
Primary
Macrolide Resistance Determinants
During the bioinformatic analyses, each identified antibiotic-resistance determinant will be categorized at the class level using a read-based classification tool. The primary outcome will be the ratio of mean macrolide resistance determinants in the day 14 anorectal samples between the two treatment groups. This ratio will be calculated by dividing the mean normalized read count of macrolide- resistance determinants categorized at the class level in the Ceftriaxone/Azithromycin group by the corresponding mean quantity in the Ceftriaxone group.
Time frame: Day 14
Population: The primary analysis of assessing the ratio between the mean normalized read count of macrolide resistance determinants in anorectal microbiome between the two groups was done using permutation test with 10 000 permutations.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rocephine | Macrolide Resistance Determinants | 110.3 normalized determinants/million reads |
| Azithromycin / Rocephine® | Macrolide Resistance Determinants | 167.53 normalized determinants/million reads |
p-value: 0.102695% CI: [0.55, 1.83]Permutation testing
Secondary
Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea
The difference in time until acquisition of phenotypic resistance to Azithromycin by N. gonnorrhea in the morbidostat upon exposure to commensal Neisseria DNA extracts from each treatment group
Time frame: Day 0 and Day 14
Population: change of proportion of isolates resistant to azithromycin between day 0 and day 14
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rocephine | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Streptococci day 0 | 0.649 Proportion of isolates resistant to AZM |
| Rocephine | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Streptococci day 14 | 0.572 Proportion of isolates resistant to AZM |
| Rocephine | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Commensal Neisseria day 0 | 0.534 Proportion of isolates resistant to AZM |
| Rocephine | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Commensal Neisseria day 14 | 0.542 Proportion of isolates resistant to AZM |
| Azithromycin / Rocephine® | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Commensal Neisseria day 14 | 0.638 Proportion of isolates resistant to AZM |
| Azithromycin / Rocephine® | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Streptococci day 0 | 0.669 Proportion of isolates resistant to AZM |
| Azithromycin / Rocephine® | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Commensal Neisseria day 0 | 0.471 Proportion of isolates resistant to AZM |
| Azithromycin / Rocephine® | Acquisition of Phenotypic Resistance to Azythromycin by N. Gonnorrhea | Streptococci day 14 | 0.739 Proportion of isolates resistant to AZM |
Comparison: For streptococcip-value: 0.196Wilcoxon (Mann-Whitney)
Comparison: For streptococcip-value: 0.568Wilcoxon (Mann-Whitney)
Comparison: For Neisseriap-value: 0.978Wilcoxon (Mann-Whitney)
Comparison: For Neisseriap-value: 0.184Wilcoxon (Mann-Whitney)
Secondary
Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class
The ratio of mean normalized read count of resistance determinants for each non-macrolide antibiotic class in the day 14 anorectal samples between the two treatment groups
Time frame: Day 14
Population: The normalized macrolide resistance determinants were calculated by dividing the number of macrolide resistance reads by the total number of bacterial reads. The resulting proportion was then multiplied by 106 to present results in normalized determinants per million reads. No sample had a total number of reads below 95 thousand.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Tetracyclines | 348.12 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Trimethoprim | 2.73 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Cationic antimicrobial peptides | 16.52 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Aminoglycosides | 34.41 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Bacitracin | 4.63 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Glycopeptides | 0.26 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Mupirocin | 0.84 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Metronidazole | 0.2 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Fluoroquinolones | 9.44 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Sulfonamides | 5.47 normalized determinants/million reads |
| Rocephine | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Betalactams | 110.46 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Sulfonamides | 0.62 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Betalactams | 89.82 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Glycopeptides | 0.14 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Trimethoprim | 1.55 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Cationic antimicrobial peptides | 5.52 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Fluoroquinolones | 23.9 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Tetracyclines | 423.8 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Metronidazole | 0.06 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Aminoglycosides | 22.22 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Mupirocin | 0 normalized determinants/million reads |
| Azithromycin / Rocephine® | Read Count of Resistance Determinants for Each Non-macrolide Antibiotic Class | Bacitracin | 1.11 normalized determinants/million reads |
Comparison: For mupirocinp-value: 195% CI: [0, 5.34]Permutation testing
Comparison: For metronidazolep-value: 195% CI: [0, 3.22]Permutation testing
Comparison: For aminoglycosidesp-value: 195% CI: [0.47, 2.19]Permutation testing
Comparison: For betalactamsp-value: 195% CI: [0.69, 1.44]Permutation testing
Comparison: For bacitracinp-value: 195% CI: [0.05, 20.15]Permutation testing
Comparison: For glycopeptidesp-value: 195% CI: [0, 1.91]Permutation testing
Comparison: For trimethoprimp-value: 195% CI: [0.32, 3.15]Permutation testing
Comparison: For cationic antimicrobial peptidesp-value: 195% CI: [0.07, 14.64]Permutation testing
Comparison: For fluoroquinolonesp-value: 195% CI: [0.02, 46.02]Permutation testing
Comparison: For sulfonamidesp-value: 195% CI: [0.01, 148.86]Permutation testing
Comparison: For tetracyclinesp-value: 0.562195% CI: [0.79, 1.27]Permutation testing