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a computerized decision support system5. Florian M. Wagenlehner1* and Kurt G. Naber2* applied in a surveillance study. PLOS ONE 14, e0214710 (2019). 1 Some approaches have been specifically Clinic for Urology, Pediatric Urology and Andrology, 7. Haldrup, S. et al. Microbiological point of care tested in UTI. For example, weighted inci- Justus-Liebig University, Giessen, Germany. testing before antibiotic prescribing in primary care: considerable variations between practices. BMC Fam. 2Department of Urology, Technical University dence syndromic combination antibiograms Pract. 18, 9 (2017). (WISCA) is a method derived from surveil- of Munich, Munich, Germany. 8. Fritzenwanker, M. et al. Modern diagnostic methods for urinary tract infections. Expert Rev. Anti. Infect. Ther. *e-mail: Florian.Wagenlehner@ lance data and is calculated by obtaining the 14, 1047–1063 (2016). cumulative sum of the relative incidence of chiru.med.uni-giessen.de; [email protected] each pathogen multiplied by the chances https://doi.org/10.1038/s41585-019-0240-0 Competing interests F.M.W. declares personal fees and other from Bionorica, 6 of susceptibility . Including Bayesian analy- 1. Yelin, I. et al. Personal clinical history predicts ­during the conduct of the study; personal fees and other sis, which treats each time point as a set of antibiotic resistance of urinary tract infections. from Achaogen, personal fees from AstraZeneca, personal Nat. Med. 25, 1143–1152 (2019). fees and other from Bionorica, other from Enteris prior information to build up towards the cur- 2. Sundqvist, M. et al. Little evidence for reversibility BioPharma, other from Helperby Therapeutics, personal fees rent information, can be used to modify this of trimethoprim resistance after a drastic reduction from Janssen, personal fees from LeoPharma, personal in trimethoprim use. J. Antimicrob. Chemother. 65, fees from MerLion, personal fees from Merck Sharp and setting and provide prospective information. 350–360 (2010). Dohme (MSD), personal fees and other from OM Pharma/ In the case of antimicrobial surveillance, the 3. Eliakim-Raz, N. et al. Risk factors for treatment Vifor Pharma, personal fees from Pfizer, personal fees failure and mortality among hospitalized patients from RosenPharma, personal fees and other from Shionogi, development of antimicrobial resistance can with complicated urinary tract infection: a multicenter personal fees from VenatoRx, personal fees from be predicted and, therefore, probable anti­ retrospective cohort study (RESCUING Study Group). GlaxoSmithKline (GSK) and other from Deutsches Zentrum Clin. Infect. Dis. 68, 29–36 (2019). für Infektions­forschung (DZIF) (Giessen-Marburg- microbial susceptibility data can be provided, 4. Tandog˘du, Z. et al. Antimicrobial resistance in Langen site), outside the submitted work. K.G.N declares improving empirical treatment. urosepsis: outcomes from the multinational, personal fees from Adamed, personal fees from Allecra, per­ multicenter global prevalence of infections in urology sonal fees from Apogepha, personal fees from Aristo, Another method to improve antibiotic (GPIU) study 2003–2013. World J. Urol. 34, personal fees from Bionorica, personal fees from Bio­ treatment is to use microbiological point- 1193–1200 (2016). merieux, personal fees from Enteris, personal fees from 5. Paul, M. et al. Improving empirical antibiotic GlaxoSmithKline, personal­ fees from Gruenenthal Mexico, of-care testing tools, which have been imple- treatment using TREAT, a computerized decision personal fees from Helperby, personal fees from Marpinion, mented to some extent in primary care support system: cluster randomized trial. personal fees from MerLion, personal fees from Medice, 7 J. Antimicrob. Chemother. 58, 1238–1245 (2006). non-­financial support from Mission Pharmacal, personal settings . Techniques to confirm the presence 6. Tandogdu, Z. et al. Appropriate empiric antibiotic fees from MSD, personal fees from OM Pharma/Vifor, or absence of bacteria, or even the type of bac- choices in health care associated urinary tract personal fees from Paratek, personal fees from Roche, per- infections in urology departments in Europe from sonal fees from Saxonia and personal fees from Zambon, teria present, have now been implemented in 2006 to 2015: a Bayesian analytical approach outside the submitted work. many areas of medicine, and modern diagnos- tic methods for UTI are increasingly focused 8 on point-of-care scenarios . However, these SEXUAL MEDICINE approaches are now of limited value, owing to the increasing levels of antibiotic resist- ance in almost all bacterial species. Thus, Oxytocin antagonists: the next evolution of these approaches is required to enable point-of-care susceptibility testing. If susceptibility results were routinely available frontier in PE treatment within 2 hours of testing, many issues associ- ated with antibiotic resistance would be omit- Murat Gul and Ege Can Serefoglu ted: antibiotic treatment would only be started in patients with a demonstrated bacterial Oxytocin antagonists seem to have potential as a treatment option for infection; the prescribed antibiotic treatment premature ejaculation (PE), but the parameters of their use are vague. would be appropriate to the specific organ- Two recently published studies highlight the need for large-scale trials to ism; and antimicrobial stewardship could be elucidate the value of these drugs in the treatment of PE. immediately included in the primary treat- ment regimen, always selecting antibiotics Refers to McMahon, C. et al. The oxytocin antagonist cligosiban prolongs intravaginal ejaculatory latency and with low rates of collateral adverse effects. improves patient-reported outcomes in men with lifelong premature ejaculation: results of a randomized, Various clinical data are associated with double-blind, placebo-controlled proof-of-concept trial (PEPIX). J. Sex. Med. 16, 1178–1187 (2019) | Althof, S. et al. The oxytocin antagonist cligosiban fails to prolong intravaginal ejaculatory latency in men with lifelong prema- antimicrobial resistance, and these should ture ejaculation: results of a randomized, double-blind, placebo-controlled phase IIb trial (PEDRIX). J. Sex. Med. 16, be routinely included in antimicrobial sur- 1188–1198 (2019). veillance systems. Resistance, once emerged, does not return to baseline levels even if the Premature ejaculation (PE) is the most com- effect of oxytocin on the ejaculatory process, selective pressure is withdrawn, leading to a mon sexual dysfunction among men world- suggesting that blocking oxytocin receptors continuously increasing antimicrobial resist- wide1. The exact pathophysiology of PE is might be a promising method for treating ance burden. The traditional reporting of unknown, and current treatment modalities PE4. Epelsiban was the first oxytocin antag- antimicrobial resistance, which only descrip- are inadequate2. Dapoxetine, a short-acting onist used for treating PE in clinical trials5. tively lists retrospective information, could selective serotonin reuptake inhibitor, is the However, this molecule has failed to signifi- be considerably improved by using math- only medication approved in Europe, but it cantly improve intravaginal ejaculatory latency ematical modelling algorithms such as the has not yet been approved in the USA owing time (IELT) compared with placebo5. Failure computerized decision support system5 or to its limited efficacy and several safety con- was assumed to be associated with the periph- the WISCA6 method. The clinical application cerns3. Thus, the search for an efficacious and erally acting nature of epelsiban. However, of such algorithms could help improve the safe treatment for PE is ongoing. interest in the inhibition of both central and appropriateness of antimicrobial treatments Oxytocinergic neurotransmission has a peripheral oxytocin receptors in the treatment and, therefore, reduce treatment failure and role in the sexual response of men and women. of PE remained, leading to research on another improve antimicrobial stewardship. Numerous studies have shown the stimulatory oxytocin antagonist, cligosiban6.

696 | DECEMBER 2019 | volume 16 www.nature.com/nrurol News & Views

Cligosiban (formerly known as IX-01) is a these contradictory results. First, in the include some patients who might not have small molecule that potently antagonizes the PEPIX trial9 there was only one cligosiban lifelong PE, suggesting that patients in PEPIX oxytocin receptor and has been shown to have group and patients were able to manipulate could have been selected more carefully (creat- good central nervous system (CNS) penetra- their dose of cligosiban to half or twice the ing selection bias). However, post-hoc analysis tion in both preclinical and clinical studies7,8. initial set dose (400 mg) of the drug, whereas of the results did not show any difference in Recently, two phase II trials of cligosiban in the PEDRIX10 trial three different fixed- terms of type of centre. (PEPIX9 and PEDRIX10 trials) were published dose cligosiban groups (400 mg, 800 mg and Owing to the aforementioned similari- simultaneously but reported contradictory 1,200 mg) were compared with the placebo ties in the characteristics of the PEPIX9 and results. In the PEPIX study9, eligible patients group. Notably, almost 90% of the patients PEDRIX10 studies, explaining the discrep- were randomized to receive cligosiban (n = 58) in the PEPIX trial9 doubled the initial 400 mg ancy in their outcomes is very difficult. or placebo (n = 30) to be taken 1–6 hours cligosiban dose, indicating the low efficacy Thus, further studies are needed to deter- before planned sexual activity over an 8-week of a 400 mg of this drug. Moreover, this mine the optimal administration form and treatment period. The starting dose was observation might also suggest that giving dose of cligosiban and answer the unresolved 400 mg and patients were allowed to increase patients some control over their medi­cation question of the potential value of CNS- (800 mg) or decrease (200 mg) the dose after 2 may have an effect on the perceived effi- penetrating oxytocin receptor antagonists for and/or 4 weeks of treatment.9 In the ­cligosiban cacy of the study drug (commitment bias). the treatment of PE. group, the geometric mean IELT value Additionally, cligosiban was administered Murat Gul 1,2 and Ege Can Serefoglu3,4,5* 9 increased 2.1-fold, which was significantly orally as capsules (200 mg) in the PEPIX trial , 1Laboratory of Reproductive Biology, higher than the fold increases observed in but caplets (400 mg) were used to deliver Copenhagen University Hospital Rigshospitalet, the placebo arm (1.1-fold, P = 0.079). The cligosiban in the PEDRIX study10. The caplet Copenhagen, Denmark. patient-reported outcome measures were was initially chosen to improve the bioavaila- 2Department of Urology, Aksaray University School also significantly improved in the cligosiban bility of cligosiban and to reduce the number of Medicine, Aksaray, Turkey. group compared with the placebo group of pills taken by patients who were receiving 3Department of Urology, Bahceci Health Group, (P < 0.05 for all). No serious treatment-related more than 400 mg of cligosiban7. Although Istanbul, Turkey. adverse events were reported and all-causality no research directly compares the pharmaco­ 4Department of Histology and Embryology, Istanbul Medipol University, Istanbul, Turkey. and treatment-related adverse events were kinetics of the capsule versus caplet forms of 5Department of Urology, Biruni University School similar for the cligosiban and placebo cligosiban, the bioavailability of the aqueous of Medicine, Istanbul, Turkey. treatment groups9. dispersions of the capsule and caplet forms *e-mail: [email protected] Taking the promising outcomes of this were found to be similar7. However, the dis- https://doi.org/10.1038/s41585-019-0238-7 proof-of-concept trial into consideration, crepancy between the results of the PEPIX9 10 1. Saitz, T. R. & Serefoglu, E. C. The epidemiology the authors conducted another phase IIb and PEDRIX trials cannot be fully eluci- of premature ejaculation. Transl Androl. Urol. 5, trial (the PEDRIX study10) that included dated until the pharmacological properties 409–415 (2016). 2. Saitz, T. R. & Serefoglu, E. C. Advances in 239 patients with PE. With a design very similar of the capsule and caplet forms of cligosiban understanding and treating premature ejaculation. 9 to the PEPIX study , patients were random­ are conducted properly. Nat. Rev. Urol. 12, 629–640 (2015). 3. Giuliano, F. & Clement, P. Pharmacology for the ized to take either one fixed dose of cligosiban The magnitude of the placebo response in treatment of premature ejaculation. Pharmacol. Rev. 10 10 (400 mg, 800 mg or 1,200 mg) or placebo . the PEDRIX study was found to be higher 64, 621–644 (2012). However, unlike the PEPIX trial9, no signifi­ than that in the PEPIX study9, which might 4. Veening, J. G. et al. The role of oxytocin in male and female reproductive behavior. Eur. J. Pharmacol. 15, cant differences in the efficacy end points and account for the lack of statistically significant 209–228 (2014). patient-reported outcomes were observed improvements in the main outcomes measures 5. Shinghal, R. et al. Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: when comparing any of cligosiban groups (Table 1). This phenomenon could be attri­ a randomized, double-blind, placebo-controlled, with the placebo group (Table 1). Similar to buted to the larger sample size and number of fixed-dose study. J. Sex. Med. 10, 2506–2517 (2013). 6. McMahon, C. et al. PD69-01 a phase IIa study to 9 the PEPIX trial , cligosiban was well-tolerated study centres used in the PEDRIX study. In the investigate the efficacy and safety of the selective and the safety profile was acceptable. PEPIX study9, men with PE were selected from oxytocin receptor antagonist, IX-01, in men with lifelong premature ejaculation. J. Urol. 197, e1344 (2017). The studies were well-designed and centres with expertise in sexual medicine, 7. Osterloh, I. H. et al. Pharmacokinetics, safety, and almost identical in methodology, but a few whereas patients from generalist centres were tolerability of single oral doses of a novel oxytocin receptor antagonist-cligosiban-in development for 10 differences are evident that might explain also included in the PEDRIX study and could premature ejaculation: three randomized clinical trials in healthy subjects. J. Sex. Med. 15, 1547–1557 (2018). 8. Wayman, C. et al. Cligosiban, a novel brain-penetrant, Table 1 | Comparison with cligosiban to placebo on the change in geometric mean IELT selective oxytocin receptor antagonist, inhibits ejaculatory physiology in rodents. J. Sex. Med. 15, Trials Groups IELT (geometric mean) Refs 1698–1706 (2018). 9. McMahon, C. et al. The oxytocin antagonist cligosiban b Baseline mean Fold P value prolongs intravaginal ejaculatory latency and improves IELT (seconds) changea patient-reported outcomes in men with lifelong premature ejaculation: results of a randomized, 9 PEPIX Cligosiban (n = 54) 400 mg 29.5 2.10 0.0079 double-blind, placebo-controlled proof-of-concept trial to 800 mg or to 200 mg (PEPIX). J. Sex. Med. 16, 1178–1187 (2019). 10. Althof, S. et al. The oxytocin antagonist cligosiban fails Placebo (n = 25) 26.0 1.10 NA to prolong intravaginal ejaculatory latency in men with lifelong premature ejaculation: results of a randomized, PEDRIX Cligosiban 400 mg (n = 46) 33.5 1.56 0.4240 10 double-blind, placebo-controlled phase IIb trial (PEDRIX). J. Sex. Med. 16, 1188–1198 (2019). Cligosiban 800 mg (n = 65) 34.2 1.76 0.9740 Acknowledgements Cligosiban 1,200 mg (n = 64) 30.8 1.54 0.3360 M.G. is supported by the European Urological Scholarship Programme (EUSP) for his post-doctoral andrology fellowship Placebo (n = 46) 36.8 1.77 NA training IELT, intravaginal ejaculatory latency time; NA, not applicable. aFold change of geometric mean IELT from Competing interests baseline to last 4 weeks of treatment. bAll P values are in reference to the placebo. The authors declare no competing interests.

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