Solithromycin versus ceftriaxone plus azithromycin for the treatment of uncomplicated genital gonorrhoea (SOLITAIRE-U): a randomised phase 3 non-inferiority trial

doi:10.1016/S1473-3099(19)30116-1

The Lancet Infectious Diseases

Volume 19, Issue 8, August 2019, Pages 833-842

https://doi.org/10.1016/S1473-3099(19)30116-1 Get rights and content

Summary

Background

Antibiotic-resistant gonorrhoea represents a global public health threat, and new therapies are needed. We aimed to compare the efficacy and safety of solithromycin, a fourth generation macrolide, with ceftriaxone plus azithromycin for the treatment of gonorrhoea.

Methods

We did an open-label, multicentre, non-inferiority trial of patients aged 15 years or older with uncomplicated untreated genital gonorrhoea at two sites in Australia and one site in the USA. Patients were randomly assigned (1:1) to receive single dose oral solithromycin 1000 mg or intramuscular ceftriaxone 500 mg plus oral azithromycin 1000 mg. Neisseria gonorrhoeae cultures were obtained at baseline and test of cure (day 7 ± 2). The primary outcome was the proportion of patients with eradication of genital N gonorrhoeae based on culture at test of cure, assessed in the microbiological intention-to-treat (mITT) population, which included all randomly assigned patients who received any dose of study drug and had a positive genital culture for N gonorrhoeae at baseline. 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%. Safety was analysed in all patients who received any dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02210325.

Findings

Between Sept 3, 2014, and Aug 27, 2015, 262 patients were randomly assigned and 261 received treatment (130 in the solithromycin group and 131 in the ceftriaxone plus azithromycin group). In the mITT population, 99 (80%) of 123 patients in the solithromycin group and 109 (84%) of 129 patients in the ceftriaxone plus azithromycin group had N gonorrhoeae eradication at test of cure (difference −4·0%, 95% CI −13·6 to 5·5), thus solithromycin did not meet the criterion for non-inferiority at the prespecified −10% margin. The frequency of adverse events was higher in the solithromycin group than the ceftriaxone plus azithromycin group (69 [53%] of 130 patients vs 45 [34%] of 131 patients), the most common of which were diarrhoea (31 [24%] of 130 patients vs 20 [15%] of 131 patients), and nausea (27 [21%] of 130 patients vs 15 [11%] of 131 patients).

Interpretation

Solithromycin as a single 1000 mg dose is not a suitable alternative to ceftriaxone plus azithromycin as first-line treatment for gonorrhoea. If insufficient duration of solithromycin exposure at the infection site in a subset of individuals was the reason for treatment failures, this might be adequately addressed with dose adjustment. However, any further trials with longer dosing need to consider the potential risk of gastrointestinal effects and liver enzyme elevations.

Funding

Cempra Pharmaceuticals.

Introduction

Gonorrhoea is one of the most prevalent bacterial sexually transmitted infections worldwide with an estimated 78 million new cases of gonorrhoea occurring globally in 2012.¹ Genital infection with Neisseria gonorrhoeae causes urethral discharge in men and vaginal discharge in women. In women, gonococcal infections can cause pelvic inflammatory disease and resultant sequelae, and can be transmitted from mother to child resulting in neonatal infection. Extragenital N gonorrhoeae infections of the pharynx and rectum are usually asymptomatic, act as reservoirs for further transmission, and are prevalent among men who have sex with men.2, 3 Gonorrhoea is believed to increase the risk for HIV transmission.⁴

N gonorrhoeae has a propensity to acquire mutations conferring antimicrobial resistance, and has acquired resistance to all antibiotics used to treat gonorrhoea.⁵ Several national and regional guidelines6, 7, 8, 9 recommend combination therapy with single dose ceftriaxone (250 or 500 mg) plus azithromycin (1 or 2 g) as first-line therapy. However, evidence of high-level azithromycin resistance in N gonorrhoeae isolates is increasing worldwide,10, 11 and reports of high-level resistance to ceftriaxone and sporadic ceftriaxone treatment failures are of concern.12, 13, 14 Cases of N gonorrhoeae resistant to both ceftriaxone and azithromycin have been reported in the UK and Australia.¹⁵ These reports indicate that untreatable gonorrhoea is a global public health threat; however, a limited number of new drugs are in development for the treatment of gonorrhoea.¹⁶

Research in context

Evidence before this study

Antimicrobial resistance in Neisseria gonorrhoeae is increasing worldwide and poses a global threat to public health. This has been highlighted by gonorrhoea cases resistant to both ceftriaxone and azithromycin. There have not been any new antibiotics approved to treat gonorrhoea for many years. We searched PubMed between Jan 1, 2000, and Aug 8, 2018, using the terms “uncomplicated gonorrhoea” or “uncomplicated gonorrhea” and “clinical trial”, and ClinicalTrials.gov using the term “gonorrhea” for randomised clinical trials (phase 2–4). Our search identified seven trials of drugs other than solithromycin for the treatment of uncomplicated gonorrhoea. Of these, only gemifloxacin and gentamicin are options in WHO and US Centers for Disease and Control Prevention treatment guidelines for uncomplicated gonorrhea, and these drugs are only recommended in combination with azithromycin, either as an alternative therapy for patients with cephalosporin allergies or as a retreatment option after treatment failure using a first-line option. In a phase 2 trial of uncomplicated gonorrhoeae, 100% of patients treated with solithrymoycin had N gonorrhoeae eradication based on culture.

Added value of this study

In this randomised, multicentre trial, we compared the efficacy of single dose solithromycin with ceftriaxone plus azithromycin for the treatment of genital gonorrhoea. We found that solithromycin did not demonstrate non-inferiority to ceftriaxone plus azithromycin, with a higher rate of persistently positive genital N gonorrhoeae culture at test of cure. To our knowledge, this is the first randomised trial of gonorrhoea treatment that includes a rigorous algorithm for assessing repeat infection as a potential cause of persistent infection using whole genome sequencing.

Implications of all the available evidence

Solithromycin as a single 1000 mg dose is not a suitable first-line treatment for gonorrhoea. We found no in-vitro evidence that solithromycin treatment failure was due to solithromycin resistance. Insufficient duration of drug exposure at the infection site might account for treatment failure. Efficacy could potentially be improved through adjustment of solithromycin dose; however, any future trials aimed at determining the efficacy of longer dosing must consider the potential for adverse events.

Solithromycin, a fourth generation macrolide, has potent in-vitro activity against N gonorrhoeae and against other genital pathogens including Chlamydia trachomatis.17, 18 Solithromycin has additional binding sites to the 23S RNA of the 50S ribosomal subunit relative to older macrolides, resulting in the in-vitro activity observed against macrolide-resistant strains.¹⁹ In a phase 2 study²⁰ 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. Although the efficacy of solithromycin was comparable across both doses, 1000 mg was better tolerated than 1200 mg with fewer gastrointestinal adverse events (eg, diarrhoea, vomiting), supporting further evaluation of the 1000 mg dose in a phase 3 study.

We therefore did this phase 3 study to compare the efficacy of solithromycin with combination ceftriaxone plus azithromycin for the treatment of uncomplicated genital gonorrhoea.

Section snippets

Study design and patients

This open-label, randomised, controlled, phase 3, non-inferiority trial was done at two sites in Australia (Melbourne Sexual Health Centre [Melbourne, VIC] and Sydney Sexual Health Centre [Sydney, NSW]) and one recruitment site in the USA (Thomas F McCafferty Health Center [Cleveland, OH] and J Glen Smith Health Center [Cleveland, OH]).

Eligible patients were aged 15 years or older with untreated uncomplicated genital gonorrhoea who had tested positive for N gonorrhoeae by genital culture or

Results

Between Sept 3, 2014, and Aug 27, 2015, 263 patients were assessed for eligibility. 262 patients were randomly allocated to receive solithromycin (n=131) or ceftriaxone plus azithromycin (n=131; figure), of whom 261 received treatment (130 in the solithromycin group and 131 in the ceftriaxone plus azithromycin group). The most common reason for study discontinuation was loss to follow-up (ie, patients did not return for an indicated visit [day 7 or day 21]). Five men and four women who had a

Discussion

In this randomised trial of uncomplicated genital gonorrhoea, solithromycin was not shown to be non-inferior to ceftriaxone plus azithromycin. Among the mITT population, 80% of patients in the solithromycin group versus 84% of patients in the ceftriaxone plus azithromycin group had eradication of genital gonorrhoeae at day 7. Persistence of genital N gonorrhoeae by culture at day 7 was higher in the solithromycin group than ceftriaxone plus azithromycin group, in which no patients had

References (33)

DM Whiley et al.
Evidence that the gonococcal porA pseudogene is present in a broad range of Neisseria gonorrhoeae strains; suitability as a diagnostic target
Pathology
(2006)
JC Kwong et al.
Whole genome sequencing in clinical and public health microbiology
Pathology
(2015)
CM Barrera et al.
Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-ORAL)
Lancet Infect Dis
(2016)
L Newman et al.
Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting
PLoS One
(2015)
ME Patton et al.
Extragenital gonorrhea and chlamydia testing and infection among men who have sex with men—STD Surveillance Network, United States, 2010–2012
Clin Infect Dis
(2014)
CK Fairley et al.
Frequent transmission of gonorrhea in men who have sex with men
Emerg Infect Dis
(2017)
LA Barbee et al.
New human immunodeficiency virus diagnosis independently associated with rectal gonorrhea and chlamydia in men who have sex with men
Sex Transm Dis
(2017)
N Goire et al.
Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance
Nat Rev Microbiol
(2014)
C Bignell et al.
UK national guideline for the management of gonorrhoea in adults, 2011
Int J STD AIDS
(2011)
KA Workowski et al.
Sexually transmitted diseases treatment guidelines, 2015
MMWR Recomm Rep
(2015)

WHO guidelines for the treatment of Neisseria gonorrhoeae. Geneva: World Health Organization

Australian STI management guidelines for use in primary care. Gonorrhoea

K Stevens et al.

Neisseria gonorrhoeae isolates with high-level resistance to azithromycin in Australia

J Antimicrob Chemother

(2015)

SA Chisholm et al.

An outbreak of high-level azithromycin resistant Neisseria gonorrhoeae in England

Sex Transm Infect

(2016)

M Unemo et al.

High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure

Antimicrob Agents Chemother

(2012)

MM Lahra et al.

A new multidrug-resistant strain of Neisseria gonorrhoeae in Australia

N Engl J Med

(2014)

Cited by (43)

Challenges in Managing Gonorrhea and New Advances in Prevention
2023, Infectious Disease Clinics of North America
Efficacy of ertapenem, gentamicin, fosfomycin, and ceftriaxone for the treatment of anogenital gonorrhoea (NABOGO): a randomised, non-inferiority trial
2022, The Lancet Infectious Diseases
Citation Excerpt :
Coupled with the lower rates of treatment success for infections at this site, it is thus justifiable to first establish promising treatment options for infections at sites other than the pharynx. Most other recent gonorrhoea trials have mainly focused on patients with anogenital gonorrhoea.13,32 The optimal follow-up period to do a NAAT TOC for anogenital gonorrhoea has been clarified, yet not for pharyngeal infections.18
Neisseria gonorrhoeae causes gonorrhoea, a common sexually transmitted infection. Emerging strains resistant to first-line ceftriaxone threaten N gonorrhoeae management. Hence, alternative treatments are needed. We aimed to evaluate the efficacy of ertapenem, gentamicin, and fosfomycin as alternative treatments for anogenital N gonorrhoeae.
In a randomised, controlled, double-blind, non-inferiority trial (three experimental groups and one control group) at the Centre for Sexual Health in Amsterdam, Netherlands, we included adults aged 18 years or older, with anorectal or urogenital gonorrhoea. With random permuted blocks, participants were randomly assigned (1:1:1:1) to receive intramuscular 500 mg ceftriaxone (control group), intramuscular 1000 mg ertapenem, intramuscular 5 mg/kg gentamicin (maximum 400 mg), or oral 6 g fosfomycin. The primary outcome was the proportion of participants with a negative nucleic acid amplification test of the predefined primary infected site, 7−14 days after treatment. The primary analysis was per protocol (ie, excluding those lost to follow-up). The modified intention-to-treat analysis included all randomly assigned patients with anogenital gonorrhoea considering those lost-to-follow-up as treatment failure. Non-inferiority was established if the lower Hochberg-corrected 95% CI for difference between the experimental and control groups was greater than −10%. For the analysis of adverse events, we included all participants who received medication. The trial was registered at ClinicalTrials.gov (NCT03294395) and is complete.
Between Sept 18, 2017, and June 5, 2020, from 2160 patients invited to participate, we assigned 346 (16%) participants to receive either ceftriaxone (n=103), ertapenem (n=103), gentamicin (n=102), or fosfomycin (n=38). The fosfomycin group was terminated early after interim analysis revealed less than 60% efficacy. In the primary per-protocol analysis, 93 (100%) of 93 patients in the ceftriaxone group, 86 (99%) of 87 patients in the ertapenem group, 79 (93%) of 85 patients in the gentamicin group, and four (12%) of 33 patients in the fosfomycin group cleared N gonorrhoeae (risk difference vs ceftriaxone −0·01 [95% CI −0·08 to 0·05] for ertapenem and −0·07 [−0·16 to −0·01] for gentamicin). Thus, ertapenem proved non-inferior to ceftriaxone. In mITT analysis, risk differences versus ceftriaxone were −0·08 (−0·17 to 0·003) for ertapenem and −0·11 (−0·21 to −0·04) for gentamicin. We observed a higher proportion of patients with at least one adverse event in the ertapenem group (58 [56%] of 103) and fosfomycin group (36 [95%] of 38) versus the ceftriaxone group (24 [23%] of 103).
Single-dose 1000 mg ertapenem is non-inferior to single-dose 500 mg ceftriaxone in gonorrhoea treatment. Yet, 5 mg/kg gentamicin (maximum 400 mg) is not non-inferior to ceftriaxone. Ertapenem is a potential effective alternative for anogenital N gonorrhoeae infections and merits evaluation for ceftriaxone-resistant infections.
ZonMw and GGD-Amsterdam.
For the Dutch translation of the abstract see Supplementary Materials section.
Macrolide Antibiotics
2022, Comprehensive Pharmacology
Macrolide are inhibitors of protein synthesis. Three members of this class are widely used in clinical medicine. These are erythromycin, clarithromycin and azithromycin. Although their spectrum overlaps, each of these is a unique compound in the context of application. They also have differing pharmacological properties. Target site mutation, efflux, and inactivation can lead to macrolide resistance. Macrolides have important drug interactions. The main areas of macrolide therapeutics are respiratory tract infections, certain gastrointestinal infections, skin & skin structure infections, sexually transmitted infections, non-tubercular mycobacterial infections and, of late, azithromycin has been used in coronavirus disease although the evidence base for this is lacking. One compound in this class called spiramycin can prevent transmission of Toxoplasma infection from mother to baby. Macrolides can lead to serious adverse effects which include gastrointestinal side effects, thrombophlebitis, ototoxicity, toxic effects on liver and heart, and neurotoxicity. A related group of compounds are ketolides such as telithromycin. Telithromycin has been associated with a constellation of adverse effects which are together known as ketek effects.
Pharmacokinetic/pharmacodynamic considerations for new and current therapeutic drugs for uncomplicated gonorrhoea—challenges and opportunities
2020, Clinical Microbiology and Infection
Citation Excerpt :
Oral solithromycin was compared with the currently recommended single-dose combination of intramuscular ceftriaxone plus azithromycin and oral delafloxacin with intramuscular ceftriaxone administered as single-dose therapies. These failed Phase 3 RCTs and limited experience in developing new drugs for uncomplicated urogenital gonorrhoea raised concern in the scientific and drug development communities [11–13]. A combination of ceftriaxone plus azithromycin, which has been the standard of care in the USA for three decades, has been required by the US Food and Drug Administration (FDA) as the comparator regimen for ongoing trials, raising further the bar for new drugs that are evaluated as monotherapy [14–18].
Increasing multidrug resistance rates in Neisseria gonorrhoeae have raised concerns and an urgent call for new antibiotics for treatment of gonorrhoea. Several decades of subdued drug development in this field and the recent failures of two new antibiotics to show non-inferiority compared with the current first-line antibiotics ceftriaxone plus azithromycin highlight the need for improved preclinical tools to predict clinical outcome of new drugs in the development process.
To summarize current pharmacokinetic/pharmacodynamic (PK/PD) knowledge and dose-finding strategies for antibiotics against gonorrhoea.
Literature review of published papers and discussions by global experts at a special workshop on this topic.
We review current knowledge of gonococcal specific PK/PD principles and provide an update on new in vitro and in vivo models to correlate drug exposure with clinical outcome, and identify challenges and gaps in gonococcal therapeutic research.
Identifying the ideal antimicrobial agent and dose for treating uncomplicated urogenital and pharyngeal gonococcal disease requires appropriate validated non-clinical PK/PD models. Recent advances in adapting in vitro and in vivo models for use in gonorrhoea are an important step for enabling the development of new drugs with reduced risk of failure in Phase 3 clinical development and diminish the risk of emergence of resistance.
Optimising treatments for sexually transmitted infections: surveillance, pharmacokinetics and pharmacodynamics, therapeutic strategies, and molecular resistance prediction
2020, The Lancet Infectious Diseases
Citation Excerpt :
A phase 3 randomised controlled clinical trial (RCT) with the first fluoroketolide, solithromycin, for gonorrhoea was published in 2019.71 In the microbiological intention-to-treat (mITT) population, solithromycin 1·0 g monotherapy showed microbiological cure in only 80·5% of urogenital gonorrhoea infections.71 Gepotidacin, a triazaacenaphthylene topoisomerase II inhibitor, was more than 95% effective as monotherapy for uncomplicated urogenital gonorrhoea in a phase 2 RCT.69
Progressive antimicrobial resistance in Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis has created a pressing need for treatment optimisations for sexually transmitted infections (STIs). In this Review, we aim to highlight urgent needs in global STI management, including: (1) improved surveillance to monitor antimicrobial resistance and clinical outcomes; (2) systematic pharmacokinetic and pharmacodynamic evaluations to ensure resistance suppression and bacterial eradication at all sites of infection; (3) development of novel, affordable antimicrobials; and (4) advancements in new molecular and point-of-care tests to detect antimicrobial resistance determinants. Antimicrobial resistance among STIs is a global public health crisis. Continuous efforts to develop novel antimicrobials will be essential, in addition to other public health interventions to reduce the global STI burden. Apart from prevention through safer sexual practices, the development of STI vaccines to prevent transmission is a crucial research priority.
Neisseria gonorrhoeae vaccines: a contemporary overview
2024, Clinical Microbiology Reviews

View all citing articles on Scopus

View full text

ArticlesSolithromycin versus ceftriaxone plus azithromycin for the treatment of uncomplicated genital gonorrhoea (SOLITAIRE-U): a randomised phase 3 non-inferiority trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Pathology

Pathology

Lancet Infect Dis

Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting

PLoS One

Extragenital gonorrhea and chlamydia testing and infection among men who have sex with men—STD Surveillance Network, United States, 2010–2012

Clin Infect Dis

Frequent transmission of gonorrhea in men who have sex with men

Emerg Infect Dis

New human immunodeficiency virus diagnosis independently associated with rectal gonorrhea and chlamydia in men who have sex with men

Sex Transm Dis

Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance

Nat Rev Microbiol

UK national guideline for the management of gonorrhoea in adults, 2011

Int J STD AIDS

Sexually transmitted diseases treatment guidelines, 2015

MMWR Recomm Rep