THE LANCET Infectious Diseases 2019

Published Online: June 10, 2019 doi: 10.1016/S1473-3099(19)30116-1

Journal Club, 24. Juni 2019 Mihaela Sava 1 . local resistance data should determine the choice of therapy (both for dual therapy and single therapy)

. Dual therapy . ceftriaxone 250 mg intramuscular (IM) as a single dose PLUS azithromycin 1 g orally as a single dose . cefixime 400 mg orally as a single dose PLUS azithromycin 1 g orally as a single dose

. Single therapy (one of the following, based on data confirming susceptibility to the antimicrobial) . ceftriaxone 250 mg IM as a single dose . cefixime 400 mg orally as a single dose . spectinomycin 2 g IM as a single dose.

http://www.who.int/reproductivehealth/publications/rtis/gonorrhoea-treatment-guidelines/en/ 2 . Treatment for uncomplicated genital, anorectal and phayngeal gonococcal infection . Ceftriaxon 500mg i.m. as single Dose

. Cave! Azithromycin 1g to 2g orally as single dose should be added . Potential co-infection with Chlamydia trachomatis and . to reduce the potential of aquiring antimicrobial resistance for Ceftriaxon- Monotherapy

https://webedition.sanfordguide.com/en/weissbuch/hiv-infektion/sexuell-ubertragbare-infektionen 3 4 https://ecdc.europa.eu/sites/portal/files/documents/RRA- Gonorrhoea%2C%20Antimicrobial%20resistance-United%20Kingdom%2C%20Australia.pdf 5 . Nine trials for the treatment of uncomplicated gonorrhoea

. Antibiotics tested: Solithromycin, Zoliflodacin, Delafloxacin, Ertapenem, Fosfomycin Oral Suspension, Ciprofloxacin, Gentamicin and Gemifloxacin

. Of these, only gemifloxacin and gentamicin are options in WHO and US CDC treatment guidelines for uncomplicated gonorrhoea . only recommended in combination with azithromycin

https://clinicaltrials.gov/ct2/results?term=uncomplicated&cond=Gonorrhea 6 THE LANCET Infect Dis 2019

Published Online: June 10, 2019 doi: 10.1016/S1473-3099(19)30116-1

7 . fourth generation macrolide . potent in-vitro activity against N gonorrhoeae and other genital pathogens including Chlamydia trachomatis. . additional binding sites to the 23S RNA of the 50S ribosomal subunit relative to older macrolides, resulting in observed the in-vitro activity against macrolide-resistant strains. . In a phase 2 study of gonorrhoea in men and women, solithromycin eradicated all N gonorrhoeae infections (genital, pharyngeal, and rectal) as determined by culture at both 1200 mg and 1000 mg doses.

8 . open-label, randomised, controlled, phase 3, noninferiority trial . Multicentre: two sites in Australia and one in USA . Inclusion criteria: . aged 15 years or older . untreated uncomplicated genital gonorrhoea . positive test for N gonorrhoeae by genital culture or nucleic acid amplification test (NAAT) within the previous 2 weeks . or urethral or cervical Gram stain demonstrating Gram-negative intracellular diplococci and leucocytes. . Exclusion Criteria: . Complicated or systemic gonococcal infection . Antibacterial Treatment within previous 7 days

9 . Study drugs: • a single dose of oral solithromycin 1000 mg or • combination intramuscular ceftriaxone 500 mg plus oral azithromycin 1000 mg

. Day 1: • Microbiological testing prior to drug administration: • N gonorrhoeae culture from genital sites, pharyngeal, and rectal sites • NAATs for N gonorrhoeae and C trachomatis from genital, pharyngeal, and rectal sites

. Day 7 (± 2 days): • Resampled anatomical sites which initially tested positive for N gonorrhoeae • Questionnaire about sexual activity within last 7 days

. Day 21: • Repeat C. trachomatis NAAT from anatomical sites tested positive initially • Adverse events were recorded throughout the study.

10 . N. gonorrhoeae susceptibility testing for solithromycin, azithromycin, ceftriaxone, cefixime, ciprofloxacin, penicillin, spectinomycin, and tetracycline

. Multilocus sequence typing (MLST) and antimicrobial resistance genotyping on all N. gonorrhoeaea

. Genomic sequencing for N. gonorrhoeae isolates cultured from same site at baseline and test of cure (Day 7) were performed for cases with suspected treatment failure

. Safety assessments at baseline and test of cure

11 . The primary outcome: . the proportion of patients with eradication of genital N gonorrhoeae based on culture at Day 7 . in mITT population (microbiological intention-to-treat) . Secondary outcomes, proportion of patients with: . N. gonorrhoeae eradication at each anatomical site at Day 7 (culture) . N. gonorrhoeae eradication at all anatomical sites by patient at Day 7 (culture) . N. gonorrhoeae clearance at Day 7 (NAAT) . C. trachomatis clearance at Day 21 (NAAT) . in microbiologically evaluable population . Non-inferiority of solithromycin was to be concluded if the lower limit of the 95% CI for the between group differences was greater than –10%.

12 Definitions: . Eradication = N. gonorrhoeae culture negative at Day 7 . Persistence = N. gonorrhoeae culture positive at Day 7 . Indeterminate = N. gonorrhoeae culture results not available

. Clearance = NAAT negative at Day 7 for N. gonorrhoeae or at Day 21 for C. trachomatis . Persistence = NAAT positive at Day 7 for N. gonorrhoeae or at Day 21 for C. trachomatis

. mITT population = patients who received any study drug and had a positive genital gonorrhoea culture at baseline . microbiologically evaluable population = all patients with baseline positive culture or NAAT for N. gonorrhoea or C. trachomatis at any anatomical site and repeat test at day 7 and 21

* NAAT= nucleic acid amplification test

13 . September 2014 – August 2015

. LTFU most common reason for study discontinuation

14 15 . 313 N. gonorrhoeae isolates at baseline : . 24.9% ciprofloxacin – resistance . 18.5% penicillin – resistance . 28.1 % tetracycline – resistance

. 100% Cefriaxone - susceptibility . 99.4% Cefixime – susceptibility . 100% Solithromycin – susceptibility (MIC range 0.004 – 0.25 μg/ml)

. 11 N. gonorrhoeaea isolates considered Azithromycin- resistant (MIC >0,5 μg/ml) . 1/313 N. gonorrhoeae isolates Azithromycin-MIC 2μg/ml . 10/313 N. gonorrhoeae isolates Azithromycin-MIC 1μg/ml

16 . Solithromycin did not meet the criteria for non-inferiority

. No differences in Solithromycin-MIC values among groups were observed

. Clearance – rates of N. gonorrhoeae from any anatomical site based on NAAT (212 patients) were similar to culture eradication at Day 7

. Clearance of C. trachomatis based on NAAT (38 patients) was 70-80% in Solithomycin group and 100% in Ceftriaxon/Azithromycin group at Day 21

17 . Gatrointestinal adverse events were the most common

. AE mild-moderate severity in Solithromycin group

. 1 patient in Ceftriaxon/Azithromycin group with severe Diarrhoea

. Mild-moredate ALAT/ASAT elevations were observed in 4% and 2 % of the Solithromycin recepients

18 . Solithromycin did not show non-inferiority to standard of care . Persistance of genital gonorrhea was higher in the solithomycin group

. More gastrointestinal adverse events in solithomycin group . Mild-moderate elavations of the liver enzymes . Severe elevation of the liver enzymes in 5-9% of Solithromycin recipients under prolonged antibiotic treatment (5-7 days) for treatment of CAP (Barrera et al., File et al.) . No evidence of reinfection in most patients . Solithromycin shows no in-vitro resistance . Plasma concentration of Solithromycin was not measured in this trial . Need for Solithromycin Dose-adjustment ? . Solithromycin maintained in- vitro activity against azithromycin-resistant strains

19 . Patients LTFU were included in “treatment failure” group for the analysis . -7,6% (95%CI -14.3 to – 3.9) difference in primary outcome after exclusion of patients LTFU from the analysis . Solithromycin was used as monotherapy only . Possible suboptimal sampling . Reduced number of extravaginal gonorrhoea and chlamydia infections among participants . MSM predominant study population . Small proportion of women enrolled . Pharmacokinetik data on solithromycin was not collected

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