Efficacy of Temocillin Compared to Standard of Care in the Treatment of Neisseria Gonorrhoeae Infections

Official title

Efficacy of Temocillin Compared to Standard of Care in the Treatment of Neisseria Gonorrhoeae Infections : A Multicenter Randomized Controlled Non-Inferiority Trial

Overview

Neisseria gonorrhoeae (Ng) infections are common and increasing in incidence. Treatment with a third generation cephalosporin, i.e ceftriaxone 1g, single dose, intramuscular (IM), is recommended as a first line treatment. Ceftriaxone is a broad-spectrum antibiotic with high impact on the intestinal microbiota associated with the acquisition of multidrug-resistant bacteria, particularly extended spectrum beta lactamase producing Enterobacteracerales (ESBL-E). Among populations at high risk for sexually transmitted infections (STI), the colonization rate of ESBL-E is particularly high, up to 30%, implying (i) a risk of transmission within the community and (ii) a risk of infections caused by multidrug-resistant organisms, which are difficult to treat. Temocillin, a narrow-spectrum antibiotic is known for its low ecological impact, appears to be a highly promising option. Ng strains currently circulating in France appear to be sensitive to it. Thus, temocillin could be as effective as ceftriaxone to treat Ng infections while avoiding the deleterious impact of broad-spectrum β-lactams on the acquisition of multidrug-resistant bacteria by patients

Detailed description

Sexually transmitted infections (STIs) are a major global public health issue. Ng infections are highly prevalent, with 100,000 cases reported in Europe in 2023, over 50% in men who have sex with men (MSM). Globally, WHO (World Health Organization) estimated 82.4 million new cases in 2020 among individuals aged 15-49, with incidence rates of 19 per 1000 women and 23 per 1000 men.

In France, Ng infections have been rising since the 2000s, particularly in MSM, with positivity rates 5-6 times higher than in heterosexual men and 7 times higher than in heterosexual women. Infections are mostly asymptomatic (\~95%), though urethritis, cervicitis, proctitis, arthritis, and disseminated infections can occur.

Ng rapidly develops antimicrobial resistance due to genetic plasticity. Multidrug-resistant strains have emerged globally, but in France nearly all strains remain ceftriaxone-sensitive, with only 0.2% resistant in 2022. Standard treatment is ceftriaxone 1 g IM, a critical antibiotic impacting microbiota, and the only effective current option. Vaccine development is ongoing: the Bexsero vaccine showed 22% efficacy in reducing infections, and Phase 1/2 trials of Ng-specific vaccines are underway. Vaccine hesitancy and heterogeneous coverage, even in high-risk populations such as HIV (Human Immunodeficiency Virus) positive MSM, may limit rapid impact.

Alternative therapies include antibiotic combinations and new agents such as zoliflodacin, though pharyngeal efficacy is lower and broad-spectrum use is limited due to resistance concerns. Repositioning antibiotics has been explored: gentamicin shows low microbiota impact but lower pharyngeal efficacy; fosfomycin is ineffective for Ng; carbapenems (ertapenem) are effective but reserved for multidrug-resistant cases; temocillin, a narrow-spectrum β-lactam, preserves microbiota and colonization resistance and may improve pharyngeal clearance when given IV (Intravenous) or IM. Patient-centered outcomes, including perceived care quality, speed, and pain, will be assessed using short satisfaction questionnaires.

The main objective of this study is to demonstrate the non-inferiority of 2g IV or IM temocillin treatment compared to the reference treatment with 1g IM ceftriaxone (Standard of Care (SOC)) for Neisseria gonorrhoeae infections at day 21 (negative PCR (Polymerase Chain Reaction) in urine/vagina, throat and/or anus).

The primary endpoint is the proportion of participants with therapeutic success at day 21.

The participants will be adults' patients consulting in the inclusion centers, having positive PCR for Ng (urine/vagina, throat or anus). We will focus on asymptomatic patients.

This trial will then have 3 arms: - Arm 1, patients will receive a single 1 g dose of IM ceftriaxone (SOC). -Arm 2, patients will receive a single 2 g dose of IM temocillin - Arm 3, patients will receive a single 2 g dose of IV temocillin.

The total duration of the study is planned to be 27 months, Follow-up visits will be scheduled at Day 21 and Day 90.

Interventions

• Drug Temocillin (NEGABAN®) 2 g intravenous with lidocaine (3ml)
  patients will receive a single 2 g dose of IV temocillin diluted in 20 mL of water for injection. In this trial, we chose to test the IV route, as the classical intramuscular (IM) injection is often described as painful. We hypothesize that the IV route may be more comfortable for patients. Moreover, after administration of a 2 g IV a slow intravenous injection (over 3 to 4 minutes), the peak plasma concentration reaches approximately 220-250 mg/L, and temocillin concentrations remain detectable
• Other Rectal swab for ESBL-E and microbiota (Eswab)
  consists of collecting a rectal specimen using a sterile eSwab system. The swab is gently inserted into the rectum and rotated to obtain a sample of rectal flora. The collected specimen is then placed in the transport medium and sent to the laboratory for microbiological analysis. The sample is used to detect ESBL-producing Enterobacterales (ESBL-E) and to analyze the intestinal microbiota composition.
• Drug Temocillin (NEGABAN®) 2 g intramuscular single dose with lidocaine (3ml)
  patients will receive a single 2 g dose of IM temocillin after reconstitution with 3 mL of lidocaine at 10 mg/mL to prevent pain at the injection site. A single 1 g dose of temocillin has been used for the treatment of N. gonorrhoeae infection (Reimer et al., 1985). We chose to use a single 2 g dose because penicillin MICs are increasing. For bacterial STIs, treatment is currently administered via the intramuscular route, which is the fastest and most practical method of antibiotic administratio
• Drug Ceftriaxone 1 g intramuscular single dose with lidocaine (3,5ml)
  patients will receive a single 1 g dose of IM ceftriaxone (SOC) after reconstitution with 3,5 mL of lidocaine at 10 mg/mL to prevent pain at the injection site
• Other Rectal, throat, urine/vagina swab (Cobas/Panther and eswab)
  consists of collecting biological specimens from rectal, throat, urine, and vaginal sites using appropriate sterile collection devices, including eSwab systems and sample kits compatible with Cobas or Panther platforms. Samples are collected according to standard clinical procedures and transported to the laboratory for microbiological and molecular analyses. These specimens are analyzed using automated diagnostic platforms (Cobas or Panther) and conventional microbiological methods to detect a
• Other Blood samples: 1 EDTA (Ethylenediaminetetraacetic acid) (7 ml) and 1dry tube (7 ml)
  The blood sample will be performed 15 min after IV administration and 60 min after IM administration.

Primary outcome measures

• Proportion of participants with a negative PCR for NG at urine/vagina site [Time frame: Day 21]

Secondary outcome measures (12)

• Proportion of participants with a negative PCR for NG at throat site [Time frame: Day 21]
• Proportion of participants with a negative PCR for NG at anus site [Time frame: Day 21]
• Proportion of participants with therapeutic success at day 21 for urine/vagina infection. [Time frame: Day 21]
• Proportion of participants with therapeutic success at day 21 for throat infection. [Time frame: Day 21]
• Proportion of participants with therapeutic success at day 21 for anus infection. [Time frame: at Day 21]
• Number of clinical AE (adverse effects) [Time frame: Day 1 to Day 90]
• Number of biological adverse effects [Time frame: Day 1 to Day 90]
• Number of grade 3 or 4 AE [Time frame: Day 1 to Day 90]
• Number of all grade AEs [Time frame: Day 1 to Day 90]
• Number of treatment-related adverse events (all grade) [Time frame: Day 1 to Day 90]
• Number of study discontinuations due to AEs [Time frame: Day 1 to Day 90]
• Number of serious adverse events [Time frame: Day 1 to Day 90]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• Positive PCR for Ng (urine/vagina and/or throat and/or anus)
• Asymptomatic Neisseria gonorrhoeae infection
• Patient who has understood the entirety of the study and accepts its constraints
• Women of child-bearing potential (i.e. fertile, following menarche and until becoming post-menopaused unless permanently sterile) who are sexually active have to apply a effective method of birth control\*, throughout the study period and for 90 days following the last dose of study treatment.
• Signature of the consent form for participation in the trial.
• Affiliation with a Social Security scheme or State Medical Aid (AME) (waiver to exempt the necessity for patients to be affiliated with a such scheme)
• French, English or Spanish speaker

Exclusion criteria

1 - Known allergy to penicillin, temocillin, ceftriaxone or other beta-lactam antibiotics (grade 3 or 4) 2-Known complete heart block 3- Known hypersensitivity to lidocaine or other amide-type anaesthetics 4- Clinical suspicion of hypovolemia 5 - Concomitant antibiotic treatment to be started or in progress for another bacterial infection except for doxycycline as post exposure prophylaxis 6 - BMI (Body Mass Index)> 35 kg/m2 7 - Another ongoing antibiotic therapy < 1 month except for doxycycline as post exposure prophylaxis) 8 - Complicated upper genital infection 9 - Pregnant or breastfeeding woman (urinary βHCG (Beta Human Chorionic Gonadotropin) at baseline for patients with childbearing potential\*) 10 - Known renal or hepatic dysfunction 11 - Patient on curative anticoagulation or known haemostasis disorder (contraindication for the IM route) 12- Prior participation in this study 13 - Patient under legal guardianship 14 - Participation in another randomized trial or trial concerning a medicinal product or clinical investigation protocol concerning a medical device (<3 months) 15- patients deprived of liberty by judicial or administrative decision 16- Patients who are the investigator or any other member of the study team, or close relatives of the investigator or persons involved in the study (e.g., assistant physicians, pharmacists, nurses…)\*A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 1 center

• Service des maladies infectieuses et tropicales, Hôpital Saint-Antoine, GHU AP-HP Sorbonne — Paris

Identifiers

NCT: NCT07631364 · APHP251262 · 2025-524475-23-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗