https://orcid.org/0000-0002-3299-894X
Abstract
The ongoing spread of antimicrobial resistance has made the treatment of uncomplicated urinary tract infections (UTIs) and urogenital gonorrhoea increasingly difficult. New oral treatment options are urgently needed. Gepotidacin (previously GSK2140944) is a novel, bactericidal, oral, ‘first-in-class’ triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes. Mutations in both enzymes would likely be necessary for resistance to occur, thus raising hopes that the drug will be able to maintain long-term effectiveness. Data from Phase II clinical trials of gepotidacin in UTIs and urogenital gonorrhoea appear promising, and Phase III trials are underway. In this review we summarize the development of gepotidacin and discuss its potential role in clinical practice. If approved, gepotidacin will be the first new oral antibiotic for UTIs in more than 20 years.
Introduction
The continuing spread of antimicrobial resistance (AMR) in Gram-negative bacteria is a serious threat to global public health. Two of the most common Gram-negative infections worldwide are urinary tract infections (UTIs) and urogenital gonorrhoea. The uropathogen Escherichia coli was the second most common cause of mortality worldwide due to bacteria in 2019.1 UTIs are among the most frequently encountered conditions in clinical practice, with an estimated 50%–60% of adult women developing at least one during their lifetime.2 Given this high prevalence and the associated healthcare costs, optimizing antibiotic therapy for UTIs is paramount. The current IDSA guidelines recommend nitrofurantoin, fosfomycin and trimethoprim/sulfamethoxazole (as long as local resistance rates do not exceed 20% or if the infecting strain is known to be susceptible) as first-line agents for uncomplicated UTIs.3 Experts have been ardent about discouraging the use of quinolones due to their propensity to cause ‘collateral damage’, such as disruption of the gut microbiome, Clostridiodes difficile, tendonitis and abdominal aneurysm rupture, and to reduce the dissemination of quinolone-resistant strains. Whereas older studies demonstrated a high rate of quinolone prescribing for UTIs,4,5 more recent data suggest quinolone use has been curtailed.6
Treating UTIs is increasingly difficult due to the continuing spread of AMR. This is especially true because MDR strains of Gram-negative uropathogens are becoming increasingly prevalent in ambulatory settings.7 These include E. coli, Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae and Klebsiella oxytoca. Uropathogenic E. coli (UPEC) cause more than 75% of all uncomplicated and catheter-associated UTIs.8 One of the most concerning trends in the development of AMR in UTIs, especially in UPEC, is the production of ESBLs. These lead to resistance against penicillins, cephalosporins and aztreonam.9 Notably, UTIs due to ESBL-producing organisms have been associated with recurrent infections and worse outcomes.10,11 Treatment of MDR pathogens usually involves parenteral antibiotics, which is less convenient and generally more costly than oral agents. Thus, a clinical need for novel antibiotics that are safe and effective against MDR uropathogens needs to be addressed. This need has been recognized by the US FDA, which has been advocating for the development of new antibiotics to combat bacterial resistance.12
Untreated urogenital gonorrhoea can lead to serious complications, such as pelvic inflammatory disease and infertility. The recent emergence of MDR Neisseria gonorrhoeae has led the CDC to classify it as an urgent threat, on a par with carbapenem-resistant Acinetobacter, Candida auris, C. difficile and carbapenem-resistant Enterobacteriaceae.13 Whereas this condition was previously amenable to oral therapy, first-line treatment has now become a single intramuscular (IM) dose of ceftriaxone. Treatment options are limited for patients unable or unwilling to receive IM ceftriaxone. Second-line therapy is a single IM dose of gentamicin plus a single oral dose of azithromycin, which has an elevated risk of gastrointestinal side effects.14 Although a single oral dose of cefixime is another alternative regimen, it does not provide as high or sustained bactericidal drug levels as ceftriaxone. There are also reports of N. gonorrhoeae strains resistant to ceftriaxone.15,16 Thus, new oral antibiotics for gonorrhoea are an important unmet clinical need.
The urgency for additional oral agents to treat MDR UTIs and gonorrhoea has been a driving factor in the development of the novel antibiotic gepotidacin (Figure 1). In this review, we discuss the main characteristics of gepotidacin, including its mechanism of action, antibacterial spectrum of activity, pharmacodynamic (PD) and pharmacokinetic (PK) properties, clinical trials results and where we see its role in clinical practice. We used PubMed to identify relevant English-language articles on gepotidacin published between 2016 and 2023.
Chemical structure of gepotidacin.
Development of gepotidacin
The evolution of resistance to quinolones has driven research into different agents that target bacterial topoisomerases. The main mechanisms of resistance to quinolones are efflux pumps, changes in cell wall permeability, and point mutations in genes encoding DNA gyrase and DNA topoisomerase IV.17 Bax et al.18 reported the first agent in a new class of type IIA topoisomerase inhibitors, which has broad-spectrum antibacterial activity and a new mode of inhibition that circumvents quinolone resistance. This agent, designated GSK2140944, has since progressed through Phase I, II and III clinical trials, along with a multitude of PK/PD and in vitro activity studies. Gepotidacin formulations used in the PK evaluations included mesylate salt for an IV solution, tablets, capsules and the free base for capsules and tablets.19 As clinical development progressed, the mesylate salt oral tablet formulation was selected for potential commercialization. Oral formulations are potentially useful for treating MDR UTIs and gonorrhoea because most current therapies are parenteral. Oral antibiotics have several advantages compared with many parenteral formulations, for patients and healthcare organizations alike, including lower overall costs, reduced hospital length of stay, fewer complications and more convenience.20 Moreover, changing parenteral antibiotics to an effective oral therapy in hospitalized patients is an important goal in antibiotic stewardship to limit the spread of AMR.
Mechanism of action and PK/PD characteristics
Topoisomerases are important and ubiquitous enzymes that regulate DNA topology by causing temporary single- (type I) or double-strand (type II) DNA breaks.21 Type II DNA topoisomerases are divided into subtypes IIA and IIB. Most bacteria have two type IIA topoisomerases, DNA gyrase and topoisomerase IV. Described as a novel (or non-fluoroquinolone) bacterial topoisomerase inhibitor, gepotidacin selectively inhibits topoisomerase IV and the B subunit of DNA gyrase.22,23 Gepotidacin induces high levels of gyrase-mediated single-stranded breaks.24 This mechanism is bactericidal and results in a low rate of spontaneous single-step resistance. Structural data with type II topoisomerase and DNA gyrase show gepotidacin has a novel binding mode that distinguishes it from fluoroquinolones.18 Moreover, gepotidacin has in vitro activity against target bacteria carrying resistance determinants to fluoroquinolones.25 Szili et al.26 selected gepotidacin single-step mutations in E. coli and K. pneumoniae resulting in gepotidacin MICs of 256 mg/L and >256 mg/L, respectively. They concluded that prolonged exposure to ciprofloxacin co-selected for reduced susceptibility against gepotidacin. Also, further antibiotic use might select for mutations that serve as stepping stones toward resistance against antimicrobials still under development.
The PK characteristics of gepotidacin were well defined in healthy adult participants during Phase I and II clinical trials.19 The PK/PD index associated with gepotidacin efficacy was shown to be similar to that of fluoroquinolone agents.27 The MIC of gepotidacin for E. coli isolates in Mueller–Hinton broth ranged from 1 to 4 mg/L. VanScoy et al.28 demonstrated that the median gepotidacin free-drug AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 cfu reductions were 33.9, 43.7 and 60.7. Also, free-drug AUC/MIC ratios of 275 and greater were sufficient to suppress microbial resistance.28
Plasma concentrations of gepotidacin peak at 3.00 h with a single dose.19 However, two plasma concentration peaks were observed at 1.5 h and 2.25 h after administration of two doses of gepotidacin in an interval of 12 or 6 h.19 For a single dose of 1500 mg mesylate salt capsule of gepotidacin while fasting, the mean AUC0–∞ value was 15.8, and the mean Cmax was 4.37 μg h/mL, with a mean terminal elimination t½ of 11.8 h.19 Similar values were observed with a free-base roller-compacted tablet (AUC0–∞17.5 μg h/mL; Cmax 4.49; t1/2 10.2 h) and a free-base high-shear wet granulation tablet (AUC0–∞ 18.6 μg h/mL; Cmax 5.35; t½ 10.2 h), both while fasting.19
In a Phase IIa PK trial in female participants with an uncomplicated UTI, a free-base 750 mg tablet formulation demonstrated adequate plasma concentration and an acceptable risk-safety profile.29 One study demonstrated gepotidacin urine concentrations of >4 mg/L after administration of 1500 mg gepotidacin that was maintained for 24 h.30 Another found that approximately 50% of the oral dose is absorbed and eliminated mainly as unchanged drug in the urine (∼20% of dose).31
Earlier clinical trials provided evidence for the dose selection and interval for Phase III clinical trials of gepotidacin to be 1500 mg twice daily for 5 days to treat uncomplicated UTI, and two doses of gepotidacin 3000 mg 10–12 h apart to treat urogenital gonorrhoea.19,32 The increased time interval is felt to be helpful in gastrointestinal tolerance and minimizing Cmax-related adverse effects such as QT prolongation, while reducing the risk of N. gonorrhoeae becoming resistant to gepotidacin.32 Spacing the two doses 10–12 h apart also increased systemic exposure two-fold compared with a single 3000 mg dose, with MICs of 1 mg/L.32
The gastrointestinal side effects (e.g. nausea, emesis, diarrhoea, abdominal pain and flatulence) of gepotidacin are recognized, with a dose-related increase in prevalence and severity. In one study, both adult and adolescent participants experienced emesis shortly after administration of gepotidacin; however, Cmax and AUC values across participants with or without emesis were similar, suggesting little impact in plasma concentration due to emesis.19 Although side effects related to acetylcholinesterase inhibition including cardiovascular side effects are reported, they were rare in the study.19
Microbiological spectrum of activity and antimicrobial susceptibility
Gepotidacin demonstrates potent in vitro activity against a number of common bacterial pathogens. Using isolates from a global collection established between 2010 and 2012, Biedenbach et al.33 tested it against Streptococcus pneumoniae (n = 549), Haemophilus influenzae (n = 981), Moraxella catarrhalis (n = 158), Streptococcus pyogenes (n = 199), Staphylococcus aureus (n = 1008), E. coli (n = 1010), Shigella spp. (n = 21) and Clostridium perfringens (n = 101) (Table 1). For E. coli, the MIC90 was 2 mg/L (range: ≤0.03 to >32), whereas among levofloxacin-non-susceptible isolates the MIC90 increased to 4 mg/L (range: 0.06 to >32). MIC90 values increased from 2 to 4 mg/L against nitrofurantoin-non-susceptible, fosfomycin-non-susceptible and ESBL screen-positive isolates. Approximately 75% of the ESBL screen-positive E. coli isolates were resistant to levofloxacin, and the MIC90 was 4 mg/L against this subset. These findings coincide with a report of the activity of gepotidacin against urine isolates of E. coli from German outpatient departments.34
MIC data for gepotidacina
| Organism | MIC50 (mg/L) | MIC90 (mg/L) | Range |
|---|---|---|---|
| MRSA | 0.25 | 0.5 | ≤0.06 to 1 |
| MSSA | 0.5 | 0.5 | 0.12 to 2 |
| S. pneumoniae | 0.12 | 0.25 | 0.03 to 1 |
| S. pyogenes | 0.25 | 0.25 | 0.03 to 0.5 |
| H. influenzae | 0.5 | 1 | ≤0.015 to 8 |
| M. catarrhalis | ≤0.06 | ≤0.06 | ≤0.06 to 0.12 |
| E. coli | 2 | 2 | ≤0.03 to >32 |
| Shigella spp. | 0.5 | 1 | not provided |
| C. perfringens | 0.12 | 0.5 | not provided |
| N. gonorrhoeae | 0.25 | 0.5 | ≤0.015 to 1 |
| Organism | MIC50 (mg/L) | MIC90 (mg/L) | Range |
|---|---|---|---|
| MRSA | 0.25 | 0.5 | ≤0.06 to 1 |
| MSSA | 0.5 | 0.5 | 0.12 to 2 |
| S. pneumoniae | 0.12 | 0.25 | 0.03 to 1 |
| S. pyogenes | 0.25 | 0.25 | 0.03 to 0.5 |
| H. influenzae | 0.5 | 1 | ≤0.015 to 8 |
| M. catarrhalis | ≤0.06 | ≤0.06 | ≤0.06 to 0.12 |
| E. coli | 2 | 2 | ≤0.03 to >32 |
| Shigella spp. | 0.5 | 1 | not provided |
| C. perfringens | 0.12 | 0.5 | not provided |
| N. gonorrhoeae | 0.25 | 0.5 | ≤0.015 to 1 |
From references 34 and 35.
MIC data for gepotidacina
| Organism | MIC50 (mg/L) | MIC90 (mg/L) | Range |
|---|---|---|---|
| MRSA | 0.25 | 0.5 | ≤0.06 to 1 |
| MSSA | 0.5 | 0.5 | 0.12 to 2 |
| S. pneumoniae | 0.12 | 0.25 | 0.03 to 1 |
| S. pyogenes | 0.25 | 0.25 | 0.03 to 0.5 |
| H. influenzae | 0.5 | 1 | ≤0.015 to 8 |
| M. catarrhalis | ≤0.06 | ≤0.06 | ≤0.06 to 0.12 |
| E. coli | 2 | 2 | ≤0.03 to >32 |
| Shigella spp. | 0.5 | 1 | not provided |
| C. perfringens | 0.12 | 0.5 | not provided |
| N. gonorrhoeae | 0.25 | 0.5 | ≤0.015 to 1 |
| Organism | MIC50 (mg/L) | MIC90 (mg/L) | Range |
|---|---|---|---|
| MRSA | 0.25 | 0.5 | ≤0.06 to 1 |
| MSSA | 0.5 | 0.5 | 0.12 to 2 |
| S. pneumoniae | 0.12 | 0.25 | 0.03 to 1 |
| S. pyogenes | 0.25 | 0.25 | 0.03 to 0.5 |
| H. influenzae | 0.5 | 1 | ≤0.015 to 8 |
| M. catarrhalis | ≤0.06 | ≤0.06 | ≤0.06 to 0.12 |
| E. coli | 2 | 2 | ≤0.03 to >32 |
| Shigella spp. | 0.5 | 1 | not provided |
| C. perfringens | 0.12 | 0.5 | not provided |
| N. gonorrhoeae | 0.25 | 0.5 | ≤0.015 to 1 |
From references 34 and 35.
Another study reported the activity of gepotidacin against 145 N. gonorrhoeae isolates as well as the effect of in vitro test conditions on susceptibility testing for gepotidacin and two other antibacterials (ciprofloxacin and ceftriaxone) against a separate set of nine N. gonorrhoeae isolates and a quality control strain (Table 1).35 Several factors were found that potentially influence gepotidacin MIC determinations including media type, inoculum concentration, media pH and incubation in 10% CO2.35 The ciprofloxacin and ceftriaxone MICs also tended to be slightly lower when agar plates were incubated in 10% CO2 compared with the reference MICs.36 Gepotidacin has also been tested against Gram-negative (n = 333) and Gram-positive (n = 225) anaerobes by agar dilution.37 It inhibited 90% of isolates at concentrations of 4 and 2 mg/L, respectively. A 5 day course of gepotidacin does not appear to have long-lasting effects on the human microbiome, with rebound to pre-dosing states evident within the first month post-treatment.38
Clinical trials
In a Phase I study with healthy volunteers, doses of 1000 and 1800 mg of IV gepotidacin caused a mild increase (7–10 beats/min) in resting heart rate and slight QT prolongation.39 The IV formulation was chosen in order to achieve supratherapeutic plasma levels. A second Phase I non-randomized, open-label, multicentre clinical trial evaluated 1500 mg of oral gepotidacin in three different hepatic settings (normal, moderate impairment and severe impairment).40 Gepotidacin was determined to be safe and generally well tolerated in all subjects. Based on these results, dosing adjustments will not likely be necessary for patients with mild to moderate hepatic impairment. However, severe hepatic impairment may require an increase in dosing interval or a dose reduction.
A Phase II clinical trial evaluated the efficacy and safety of gepotidacin in adult patients with suspected or confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs).41 The mean exposures to IV and oral gepotidacin were 3.4 days and 7.5 days, respectively. There were 122 patients included in the modified ITT and safety populations using three gepotidacin doses. Most had a wound infection (44%), followed by a cutaneous abscess (32%) or cellulitis (24%). The study met the protocol-defined primary objective, which was a composite of efficacy (cure rate) and safety (withdrawal rate). The most common adverse events were gastrointestinal, mainly nausea (20%) and diarrhoea (13%). Four patients (3%) experienced an adverse event that led to study withdrawal (one patient) or permanent discontinuation of study treatment (three patients). This study further determined microbiological efficacy as a secondary endpoint; 76% of isolates were S. aureus (69% MRSA, 31% MSSA), the remaining isolates were other Gram-positive aerobes (11%), Gram-negative aerobes (12%) and anaerobes (1%). Post-therapy microbiological success (by culture-confirmed eradication of pretreatment pathogen or presumed eradication based on clinical success) for S. aureus was 90% in the 750 mg q12h dosing, 89% in the 1000 mg q12h dosing, and 73% in the 1000 mg q8h dosing groups.42 A similar pattern was observed for other Gram-positive pathogens.
A second Phase II clinical trial enrolled 69 adult patients with urogenital gonorrhoea and randomized them 1:1 to receive either a 1500 mg or 3000 mg single oral dose of gepotidacin.28 Microbiological eradication of N. gonorrhoeae was achieved by 97% and 95% of participants for the 1500 and 3000 mg dose groups, respectively. Of the three participants who were microbiological failures, all had N. gonorrhoeae isolates with a gepotidacin MIC of 1 µg/mL. Adverse events occurred in 27 of 52 (52%) participants in the 1500 mg group, and in 34 of 53 (64%) participants in the 3000 mg treatment group. The most frequently reported adverse events were diarrhoea (27%), flatulence (23%), abdominal pain (15%) and nausea (13%). Treatment-limiting adverse events did not occur for either dose. A third Phase II clinical trial enrolled 22 women with a UTI who were given 1500 mg of oral gepotidacin twice daily for 5 days and returned to the clinic for test-of-cure (TOC) (days 10 to 13) and follow-up (day 28 ± 3) visits.29 At TOC, clinical success was observed for 19 of 22 participants (86%). Nearly all (21/22) had gastrointestinal adverse events, mainly diarrhoea (n = 18, 82%), nausea (n = 17, 77%) and vomiting (n = 5, 23%). Clinically significant ECG findings or changes from baseline were not observed. Moreover, none of the participants had a QT interval corrected for heart rate according to Fridericia of ≥480 ms or an increase of >30 ms.
Multiple Phase III clinical trials are underway. EAGLE-1 (NCT04010539, www.clinicaltrials.gov) is comparing oral gepotidacin with IM ceftriaxone plus oral azithromycin in approximately 600 adolescents and adults with uncomplicated urogenital gonorrhoea. Participants will receive gepotidacin 3000 mg orally at the study site during the baseline (day 1) visit followed by self-administration of a second 3000 mg oral dose 10–12 h after the first dose as an outpatient. The primary outcome will be the number of subjects with culture-confirmed bacterial eradication of N. gonorrhoeae from the urogenital site at the TOC, with a time frame up to day 8. The study is expected to finish in October 2023. EAGLE-2 (NCT04020341, www.clinicaltrials.gov) and EAGLE-3 (NCT04187144, www.clinicaltrials.gov) were designed to evaluate the therapeutic response of oral gepotidacin compared with oral nitrofurantoin for treatment of uncomplicated UTI in adolescent and adult female participants.43 The primary therapeutic endpoint was a combination of clinical and microbiological efficacy, with non-inferiority comparisons made in individuals with a qualifying (≥105 cfu/mL urine) nitrofurantoin-susceptible urinary pathogen. Participants were randomized 1:1 to receive gepotidacin 1500 mg orally twice a day for 5 days plus placebo or nitrofurantoin 100 mg orally every 12 h plus placebo for 5 days. In November 2022 the manufacturer (GSK) announced a halt to the trial due to strong efficacy data. The decision came after a recommendation from an independent data monitoring committee on a prespecified interim analysis of safety and efficacy data in more than 3000 patients already enrolled in the trial.44 A similar Phase III trial (EAGLE-J, NCT05630833, www.clinicaltrials.gov) is underway in Japan. This study aims to enroll 300 female subjects aged 12 years and older with an uncomplicated UTI and compare the therapeutic response of gepotidacin with nitrofurantoin at the TOC visit (days 10 to 13). The trial is expected to be completed in September 2023.
Potential roles in clinical practice for gepotidacin
UTIs
Given the frequency of UTIs and the emergence of AMR, gepotidacin could fulfil an unmet need for an additional oral agent against E. coli and an option for treatment of MDR strains. A Phase II clinical trial for uncomplicated UTI showed a high rate of clinical success of 86%, but with almost all patients having gastrointestinal adverse events.45 Gastrointestinal tolerability of gepotidacin has been noted to be significantly improved with food intake in a recent Phase I trial.41 The forthcoming data from the recently completed Phase III EAGLE-2 and EAGLE-3 trials comparing oral gepotidacin with nitrofurantoin are anticipated to be among the largest trials of uncomplicated UTI ever performed (>3000 patients) and will give additional support to the therapeutic efficacy and data regarding adverse events of gepotidacin.39 Further data are needed regarding the clinical use of gepotidacin for complicated UTI and pyelonephritis, although gepotidacin was found to be effective in a rat animal model of MDR E. coli pyelonephritis using recreated human drug exposure.46 Moreover, investigation of gepotidacin against other common uropathogens besides E. coli is warranted.
Urogenital gonorrhoea
The emergence of MDR N. gonorrhoeae worldwide has severely limited treatment options for urogenital gonorrhoea in recent years. A Phase II clinical trial of single-dose oral gepotidacin for urogenital gonorrhoea demonstrated >95% microbiological eradication.37 Over 50% of subjects had adverse events, which were primarily gastrointestinal side effects. The higher gepotidacin MIC in the three patients who failed microbiological eradication in this trial determined dosing selection of two 3000 mg oral doses given 10–12 h apart in the Phase III trial to improve efficacy and decrease emergence of resistance.47 This ongoing Phase III EAGLE-1 clinical trial comparing oral gepotidacin with IM ceftriaxone and oral azithromycin will provide more information regarding efficacy and tolerability for this indication. It is important to note that currently there is no evidence that gepotidacin is effective for gonorrhoea at other sites, e.g. rectal or pharyngeal.
Others
Because of its broad in vitro activity against Gram-positive, Gram-negative and anaerobic pathogens, a number of other clinical applications for gepotidacin are possible. As previously noted in Phase II trials, treatment of ABSSSIs appears clinically and microbiologically effective, but Phase III studies are needed to compare with current standard therapies.41 Gepotidacin has shown efficacy against Yersinia pestis in a primate animal model.48In vitro studies show promise against mycoplasma and ureaplasma infections, including drug-resistant Mycoplasma genitalium.49,50In vitro and in vivo animal models have shown activity of gepotidacin against mycobacterial pathogens, including Mycobacterium tuberculosis and drug-resistant non-tuberculous mycobacteria.51,52 The antibacterial spectrum of gepotidacin also could give it a role in the treatment of pneumonia (especially against MDR nosocomial pathogens), but additional investigation, including clinical trials, is needed for this indication.22 A recent report demonstrated good activity against Stenotrophomonas maltophilia, an increasingly recognized nosocomial pathogen that is often resistant to multiple antibiotics.53
Conclusions
There is an urgent demand for new antibiotics to treat MDR infections, particularly agents with an oral formulation. Early trial data for gepotidacin appear promising in terms of safety and efficacy, although the high rate of gastrointestinal side effects is concerning. Hopefully the development of gepotidacin continues to progress as it would fulfil an important unmet need in the clinic. If approved, gepotidacin would be the first new antibiotic for UTIs in more than 20 years.
Funding
This paper was written as part of our routine work.
Transparency declarations
R.R.W. has received research grant support from Allergan and serves as a consultant for bioMérieux. R.A.B. has received grants from Entasis, Merck, Wockhardt, Shionogi and Venatorx outside the submitted work. T.L.L and D.T. have nothing to declare.
