Gonorrhea is the second most common notifiable infection in the United States, with more than 460,000 cases reported to the Centers for Disease Control and Prevention (CDC) in 2016. Including undiagnosed and unreported infections, more than 800,000 cases of gonorrhea occur annually.1,2 Moreover, infection rates are now rising rapidly, with an almost 50% increase in reported gonorrhea cases between 2009 and 2016.
The threat posed by rising gonorrhea rates is compounded by the emergence of Neisseria gonorrhoeae that are increasingly difficult to treat owing to antimicrobial resistance.3 Since the inception of antimicrobial therapy, the gonococcus has serially developed resistance to sulfonamides, penicillins, tetracyclines, and quinolones.4 Fluoroquinolones were widely used to treat gonorrhea in the 1980s and 1990s; emergence of resistance first limited, and then eliminated, use of fluoroquinolones for gonococcal infection in the United States by 2007.5,6 In 2012, in response to several reported cases of multidrug-resistant gonorrhea and increasing infections with elevated minimum inhibitory concentration (MIC) values to the extended-spectrum oral cephalosporin cefixime, the CDC ceased recommending cefixime as first-line treatment and narrowed its primary gonorrhea treatment recommendation to a single therapeutic regimen: a 250-mg intramuscular (IM) dose of ceftriaxone plus a single 1-g oral dose of azithromycin.7,8 However, even this regimen now may be in jeopardy, with almost 4% of gonorrhea in 2016 caused by organisms that have reduced susceptibility to azithromycin using US criteria (MIC ≥2 μg/mL) and 11% with resistance using European criteria (MIC ≥1 μg/mL).9 New treatment options are urgently needed.4
Delafloxacin is a novel broad-spectrum fluoroquinolone, with increased potency and target affinity relative to older fluoroquinolones; delafloxacin also demonstrates more balanced activity against both DNA gyrase and topoisomerase IV, creating a greater threshold for resistance development.10 Previous studies showed potent activity for delafloxacin against drug-resistant isolates of N. gonorrhoeae.11,12 In one study, delafloxacin was tested against a panel of 110 clinical isolates and 7 CDC Gonococcal Isolate Surveillance Project reference strains with diverse antimicrobial resistance profiles, and a ciprofloxacin resistance rate of 67.5%. The delafloxacin MIC50/MIC90 (0.06/0.125 μg/mL; defined as the lowest concentration of antibiotic at which 50% and 90% of isolates were inhibited) was 64- to 128-fold lower than the MIC50/MIC90 of ciprofloxacin and was similar to the MIC50/MIC90 of ceftriaxone and cefixime.12 These in vitro data suggested that delafloxacin would be effective against N. gonorrhoeae infections caused by organisms that are resistant to other quinolones currently marketed in the United States. A phase 1 pharmacokinetic study provided support that a single 900-mg dose of oral delafloxacin should achieve drug plasma levels that would provide sufficient antimicrobial coverage across the range of reported N. gonorrhoeae MICs (mean total exposure [AUC0–inf] and mean peak plasma concentration [Cmax] were 44.1 μg·h/mL and 10.4 μg/mL, respectively)13; however, it should be noted that there are no animal models or genitourinary tissue penetration data relevant to gonorrhea infection to inform dose selection. Results of phase 2 and phase 3 studies demonstrated that delafloxacin was well tolerated and exhibited clinical and microbiological efficacy in the treatment of acute bacterial skin and skin structure infections.14–16 This trial investigated the efficacy and safety of a single oral 900-mg dose of delafloxacin compared with a single 250-mg IM injection of ceftriaxone in participants with uncomplicated urogenital gonorrhea.
MATERIALS AND METHODS
This was a randomized, open-label, single-dose, multicenter study. Participants with uncomplicated urogenital gonorrhea were treated with single-dose delafloxacin or ceftriaxone at 25 US study sites between January and December 2014. Delafloxacin is currently Food and Drug Administration approved for acute bacterial skin and skin structure infection; its use in the treatment of gonorrhea is investigational. Ceftriaxone was chosen as the comparator based on Food and Drug Administration guidance and the CDC's 2010 STD treatment guidelines recommending ceftriaxone plus azithromycin as first-line therapy17–19; azithromycin (or other recommended therapy) was administered at the test-of-cure (TOC) visit for participants found to have Chlamydia trachomatis at the enrollment visit.
At enrollment (day 1), clinical assessments and specimens for N. gonorrhoeae and C. trachomatis testing were obtained. Participants returned for TOC visit on 7 ± 3 days to assess clinical and microbiological cure. Participants with baseline chlamydia infection were treated at the TOC visit and provided with follow-up according to the standard of care for the site.
All sites received approval from their institutional review boards, and the trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice (ClinicalTrials.gov registration number NCT02015637).
Participants were eligible if they were at least 15 years of age with no use of antibiotics with activity against N. gonorrhoeae in the previous 4 weeks, and met one or more of the following criteria: (a) a urogenital specimen culture or nucleic acid amplification test (NAAT) positive for N. gonorrhoeae within 14 days before study drug administration; (b) unprotected genital contact within 14 days before enrollment with a person reported to be infected with N. gonorrhoeae; (c) a urogenital specimen demonstrating the presence of gram-negative diplococci on Gram stain; or (d) a male participant with purulent urethral discharge supporting a diagnosis of urethritis, or a female participant with mucopurulent cervical discharge supporting a diagnosis of cervicitis.
The study excluded women if they were pregnant or breastfeeding. Women of childbearing potential had to have a negative pregnancy test result at enrollment. Participants had to be in good health based on medical history, as determined by study clinicians. Additional exclusion criteria included the following: confirmed or suspected complicated gonococcal infection; ingestion of magnesium/aluminum antacids, sucralfate, didanosine chewable/buffered tablets, other highly buffered drugs, or other products containing calcium, iron, or zinc within 6 hours of enrollment and dosing; use of systemic or intravaginal antibiotics potentially effective against N. gonorrhoeae within 4 weeks before study drug administration; history of seizures; or current treatment with drugs that reduce or have the potential to reduce the threshold for seizure activity. Participants were also ineligible if they had used systemic corticosteroid or immunosuppressive drugs; were known to have significant immunosuppression (e.g., CD4 cell count <200/mm3 or absolute neutrophil count <500/mL); had cytotoxic chemotherapy or radiation therapy within 3 months before study drug administration; were known to be coinfected with an additional STD for which treatment could not be safely deferred until the TOC visit, unless the treatment was not potentially effective against N. gonorrhoeae; had used an investigational drug or product within 30 days before study drug dosing; or had a medical history of type 1 hypersensitivity to quinolone or cephalosporin antibiotic classes. Women who were posthysterectomy without a cervix were also ineligible.
Before enrollment, all prospective participants received a full explanation of the study and provided institutional review board–approved written informed consent. Study staff asked participants to avoid condomless sex in the period between enrollment and the final study visit to minimize the risk of N. gonorrhoeae reinfection. Sexual partnerships as reported by the participants were used in determining demographic characteristics.
An interactive Web response system was used to randomize participants to receive a single dose of delafloxacin 900-mg (two 450-mg tablets) or single IM injection of 250-mg of ceftriaxone in a 2:1 ratio. The randomization schedule was generated by statistical personnel at the contract research organization.
This was an open-label study. Given that the primary end point was based on a laboratory assessment (N. gonorrhoeae culture result), the potential for information bias was considered limited. The laboratory performing culture testing and the sponsor were blinded. The participant, treating physician, pharmacy, and contract research organization were not blinded.
At enrollment, specimens from the cervix (female participants), urethra (male participants), rectum (excluding those who denied receptive anal intercourse), and pharynx (all participants) were collected for N. gonorrhoeae culture and NAAT (Aptima Combo 2) before study drug administration. A specimen for C. trachomatis NAAT testing was also collected, but no follow-up assessments of C. trachomatis were done. At the TOC visit, culture specimens were collected at each anatomical site that had a positive N. gonorrhoeae culture at enrollment, and NAAT specimens were collected at each anatomical site that had a positive N. gonorrhoeae NAAT result at enrollment. If pretreatment N. gonorrhoeae test results were not available at the time of the TOC visit, culture/NAAT swabs were collected from each anatomical site tested at the enrollment visit.
Cultures were analyzed by local laboratories for N. gonorrhoeae, and identified isolates were sent to a central laboratory (The University of Alabama Birmingham Infectious Disease STD Program Laboratory) for agar dilution susceptibility testing using standard methods.12,20 Clinical sites and local laboratory procedures were assessed by the central laboratory and clinical research associates to ensure proper specimen handling of N. gonorrhoeae culture and NAAT samples.
At the enrollment visit, clinicians assessed signs and symptoms of N. gonorrhoeae infection at all anatomical sites assessed microbiologically. At the TOC visit, signs and symptoms at all anatomical sites that had a positive culture or NAAT result at the enrollment visit were assessed.
Safety and Tolerability Assessments
Safety assessments included adverse event (AE) reporting, physical examination findings, vital sign measurements, and clinical laboratory test results. Participants were contacted by telephone 30 ± 3 days after the enrollment visit for assessment of AEs and posttreatment concomitant medications.
All participants who received study drug comprised the safety population. The intention-to-treat (ITT) population included all randomized participants. Participants with a positive N. gonorrhoeae culture from 1 or more anatomical sites who did not receive other antimicrobial therapy potentially effective against N. gonorrhoeae before the day 7 ± 3 TOC visit comprised the microbiological ITT (MITT) population, whereas those with a positive culture for N. gonorrhoeae from a urogenital site comprised the urogenital MITT (UMITT) population. Participants in the MITT group who received study drug and had no important protocol deviations that could have affected the assessment of efficacy formed the microbiologically evaluable (ME) population. All participants in the UMITT analysis set who received study drug and had no important protocol deviations that would affect the assessment of efficacy formed the urogenital ME (UME) population. The modified UME (mUME) population contained all randomized participants who had a positive NAAT result for N. gonorrhoeae at a urogenital site at enrollment, received study drug, and had no important protocol deviations that would affect the assessment of efficacy. The modified extragenital ME (mEME) population consisted of all randomized participants who had a positive NAAT result for N. gonorrhoeae from an extragenital site at enrollment, received study drug, and had no important protocol deviations that would affect the assessment of efficacy.
The primary efficacy end point was the urogenital microbiological outcome (cure or failure) in the UMITT population. Cure was defined as eradication of N. gonorrhoeae at the TOC visit, as determined by a negative culture, with no additional administration of antibiotics with activity against N. gonorrhoeae between the enrollment and TOC visits. Positive urogenital N. gonorrhoeae culture at the TOC visit, missing microbiologic data (including participants lost to follow-up), or additional administration of antimicrobials with activity against N. gonorrhoeae from the enrollment visit through the TOC visit were considered failures.
The planned sample size of 604 participants (402 delafloxacin and 202 ceftriaxone) was calculated using a normal approximation approach (Wald test) to provide at least 90% power at the 0.025 significance level (1-sided) to demonstrate the noninferiority (NI) of delafloxacin versus ceftriaxone, using an NI margin of 10%, and assuming a response rate of at least 85% for ceftriaxone. An interim efficacy analysis by an independent Data Monitoring Committee (DMC) was planned when 290 UMITT participants had primary efficacy end point data available to determine the advisability of stopping the trial on the basis of futility. Based on the interim analysis results, the study was discontinued by the sponsor per the recommendation of the DMC.
A statistical analysis plan was developed before database lock. For all efficacy outcomes, participants who had missing TOC microbiology data or who received additional antimicrobials with activity against N. gonorrhoeae from the enrollment visit until the TOC visit were considered failures in all analysis sets. To test for NI, 2-sided 95% confidence intervals (CIs) were constructed using the Wald test for comparisons between delafloxacin and ceftriaxone. A hierarchical approach was used for the primary and secondary analyses to control for the overall type 1 error rate of 0.05 due to multiple comparisons. Noninferiority was concluded if the lower limit of the 95% CI was greater than the NI margin of −10%.
Participant Demographics and Baseline Characteristics
Of 462 participants screened, 460 were randomized (ITT population): 306 and 154 to delafloxacin and ceftriaxone, respectively (Fig. 1). Among enrolled participants, 447 (97.2%) completed the study: 298 (97.4%) in the delafloxacin group and 149 (96.8%) in the ceftriaxone group. Reasons for discontinuation were lost to follow-up (3 in the delafloxacin group and 5 in the ceftriaxone group) and AEs (3 participants in the delafloxacin group discontinued the study because of AEs of vomiting immediately after dosing). In all, 458 randomized participants received a single dose of study drug (safety population). A total of 328 (71.3%) participants comprised the primary analysis, or UMITT, population.
In general, participant demographics were similar between treatment groups (Table 1) and across the ITT, safety, and UMITT populations. Most participants were men (79.3%) and black or African American (60.9%). The median age was 27 years (range, 16–63 years); 3 adolescents (<18 years old) were enrolled. Among male participants, 45.5% (112 of 246) in the delafloxacin group and 50.4% (60 of 119) in the ceftriaxone group were bisexual or men who have sex with men (MSM) based on their self-report of sexual partners. Overall, 72.6% (334/460) of ITT participants had positive urogenital N. gonorrhoeae cultures, 10.7% (49) had positive pharyngeal cultures, and 7.8% (36) had positive rectal cultures (note, of the 155 participants who had rectal culture results obtained, 23.2% [36/155] tested positive for N. gonorrhoeae; Table 2). Similar results were observed by treatment group, with a slightly higher urogenital culture positivity rate on the delafloxacin arm compared with ceftriaxone.
Of 451 participants in the ITT population with both culture and NAAT testing performed on urogenital specimens, similar proportions of participants had positive urogenital cultures for N. gonorrhoeae (74.1% [334 participants]) compared with positive NAATs for N. gonorrhoeae (77.2% [348 participants]) at enrollment. In contrast, NAATs detected more than twice as many pharyngeal and rectal gonorrhea infections than culture (pharyngeal: 25.8% [116/450 participants in the ITT population who had both culture and NAAT testing performed on a pharyngeal specimen] by NAAT versus 10.9% [49/450] by culture; rectal: 52.9% [82/155 participants in the ITT population who had both culture and NAAT testing performed on a rectal specimen] by NAAT versus 23.2% [36/155] by culture). For C. trachomatis, 22.4% (n = 103), 2.4% (n = 11), and 7.0% (n = 32) of participants in the ITT population had a positive NAAT result at urogenital, pharyngeal, and rectal sites, respectively. The proportion of participants with signs and symptoms at each anatomical site were similar across the delafloxacin and ceftriaxone treatment groups (Table 2).
In the prespecified primary analysis population, UMITT, the urogenital cure rate was 85.1% (194/228 participants) in the delafloxacin group and 91.0% (91/100 participants) in the ceftriaxone group, with a difference of −5.9% (95% CI, −13.18% to 1.36%; Table 3). The lower bound of the CI exceeded the prespecified −10% NI margin, and NI of delafloxacin versus ceftriaxone for treatment of uncomplicated urogenital gonorrhea could not be concluded. Similar differences between treatment groups were observed for the assessment of microbiological response in the urogenital microbiologically evaluable (UME) population, as well as across all anatomical sites (Fig. 2; ”All anatomical sites, all participants” in Table 3); culture confirmed extragenital treatment failures were limited to the delafloxacin arm.
Consistent with the microbiologic results, the investigator's assessment of urogenital clinical cure (based on resolution of signs and symptoms) at the TOC visit in the UME population was significantly higher in the ceftriaxone group (91.9% [79/95] of participants) compared with the delafloxacin group (82.4% [169/226] of participants; Table 4). Of participants in the UME population with positive extragenital cultures for N. gonorrhoeae at baseline, most were asymptomatic at the enrollment visit and at the TOC visit at both extragenital sites (pharynx and rectum); therefore, limited analyses were possible given the low numbers of symptomatic participants.
An exploratory objective of the trial was to evaluate clearance of N. gonorrhoeae as determined by NAAT in ME populations (mUME and mEME, in which participants had baseline positive N. gonorrhoeae NAAT results at urogenital and extragenital sites, respectively, and were evaluable by NAAT at TOC). In the mUME population, N. gonorrhoeae clearance, as determined by a negative NAAT, for urogenital sites at TOC was 77.4% (178/230 participants) in the delafloxacin group and 93.4% (99/106 participants) in the ceftriaxone group. The difference in nucleic acid clearance between treatment groups was −16.0% (95% CI, −23.19% to −8.82%), which was statistically significant, favoring ceftriaxone. Similarly, for the mEME population, the clearance rate for extragenital sites at the TOC visit was higher for the ceftriaxone group (79.2% [38/48] of participants) compared with the delafloxacin group (66.7% [74/111] of participants). There was no correlation between C. trachomatis NAAT positivity at baseline and urogenital microbiological outcome at TOC for N. gonorrhoeae.
In Vitro Antimicrobial Susceptibility
The delafloxacin MIC50, MIC90, and MIC range were 0.0005, 0.03, and 0.0005 to 0.06 μg/mL, respectively, for all baseline N. gonorrhoeae isolates (including isolates from all anatomical sites and from participants in both treatment groups). The same MIC50/MIC90 was observed for the subset of isolates from each anatomical site (urogenital, pharyngeal, rectal) as well as for the subset of isolates from participants in the delafloxacin treatment group only. Subgroup analyses of women, heterosexual men, and MSM/bisexual men showed a delafloxacin MIC50 of 0.0005 μg/mL for each participant subgroup; however, the delafloxacin MIC90 varied by subgroup, ranging from 0.0005 μg/mL in women or heterosexual men at pharyngeal sites to 0.03 μg/mL in MSM/bisexual men at any anatomical site.
Most baseline isolates from both treatment groups had a delafloxacin MIC of 0.0005 μg/mL; most of these isolates had a ciprofloxacin MIC of ≤0.015 μg/mL. Elevated delafloxacin MICs were seen among gonococci with higher ciprofloxacin MICs. The delafloxacin MIC distribution by subgroup shows that elevated delafloxacin MIC values were more often associated with MSM/bisexual men than with other subgroups (Fig. 3). Isolates from MSM/bisexual men also tended to have higher ciprofloxacin MIC values compared with isolates from other subgroups.
MIC Versus Microbiological Response
Delafloxacin microbiologic cure rates were consistently lower for isolates with delafloxacin MICs at or greater than 0.008 μg/mL, regardless of anatomic location, analysis population, or subgroup (Table 5). At urogenital sites in the ME population, 99.4% (176/177) of participants who received delafloxacin and had a pretreatment delafloxacin MIC <0.008 μg/mL were cured, whereas only 35.4% (17/48) of participants with pretreatment MICs ≥0.008 μg/mL were cured. Similar patterns were observed for extragenital infections in the ME population. On the ceftriaxone arm, treatment failures were associated with urogenital infection only and baseline isolate ceftriaxone MICs of ≤0.015 μg/mL (range of ceftriaxone MICs for all N. gonorrhoeae isolates in the trial, ≤0.008–0.125 μg/mL).
Because elevated delafloxacin MICs were more often observed in the MSM/bisexual male subgroup than in the female and heterosexual male participants, decreased cure rates related to higher delafloxacin MICs were correspondingly reflected in subgroup microbiological cure rates. Subgroup analyses of the UMITT population (Table 3) showed that, for women and heterosexual men, the cure rates were similar between treatment groups (women: −1.6% [95% CI, −15.46% to 12.23%]; heterosexual men: 1.1% [95% CI, −8.14% to 10.26%]), whereas for MSM/bisexual men, there was a large difference in the cure rate between the delafloxacin and ceftriaxone groups, favoring ceftriaxone (−18.4%; 95% CI, −33.13% to −3.76%).
One participant with a microbiologic failure (on the delafloxacin arm, MSM/bisexual male subgroup) had a TOC N. gonorrhoeae isolate that showed a 4-fold change in delafloxacin MIC from the baseline isolate (0.008 μg/mL at baseline to 0.03 μg/mL at TOC). Sequence analysis of the quinolone resistance–determining region of this isolate pair showed that no new quinolone resistance–determining region mutations had been acquired from the baseline to the TOC isolate; this decrease in delafloxacin susceptibility may be related to a change in efflux pump expression.21,22
In the safety population, a total of 151 (49.7%) of 304 participants in the delafloxacin group and 50 (32.5%) of 154 participants in the ceftriaxone group experienced 1 or more AE; 47.7% (145/304) and 22.1% (34/154) of participants in the delafloxacin and ceftriaxone groups, respectively, experienced AEs that were assessed as related or possibly related to study drug. The most common AEs were gastrointestinal disorders (Table 6). In both treatment groups, most AEs (>80%) were assessed as mild in severity. One participant (in the ceftriaxone group) experienced a serious AE of ankle fracture, which was assessed as unrelated to study drug. Three participants (all in the delafloxacin group) discontinued the study because of AEs of vomiting within 30 minutes after receiving study drug; all 3 of the AEs were considered treatment related.
There were minimal mean changes from baseline in hematology and chemistry parameters or vital sign measurements (diastolic and systolic blood pressure, heart rate, and respiratory rate). There were no notable physical examination findings.
Over the past decade, global gonorrhea control efforts have been challenged by shifting epidemiology, increasing rates, and continued progression of antimicrobial resistance. Rates in higher income nations have increased in part due to epidemic increases in gonorrhea among MSM. In addition, fueled by the increased sensitivity of NAATs for gonorrhea diagnosis, there has been an appreciation that extragenital infections are relatively common and present particular challenges to treatment. Although delafloxacin did not prove to be noninferior to ceftriaxone, the currently recommended treatment, we believe that reporting of negative evaluations of potential new drugs for gonorrhea therapy provides important insights into the prospects for addressing the challenge of managing gonorrhea in this current era. Despite relatively high overall clinical and microbiological efficacy, the present study was discontinued after interim-independent DMC analysis of data from approximately 290 participants that determined that a single 900-mg dose of delafloxacin would not be found noninferior to ceftriaxone therapy for urogenital microbiological cure in our study population. Treatment failures based on culture were observed at all anatomical sites of infection; lower microbiological cure rates on the delafloxacin arm were also reflected in lower rates of clinical cure, as well as lower rates of nucleic acid clearance based on NAAT testing. Of note, we observed a larger difference between treatment groups in NAAT TOC results than in culture results. We suspect that this difference primarily reflects more rapid clearance of gonococcal RNA after ceftriaxone treatment compared with delafloxacin treatment. In so far as culture is used as the gold standard for defining treatment efficacy, this difference between laboratory end points suggests that nucleic acid clearance at 4 to 10 days is not a reliable method for determining comparative antimicrobial efficacy in future gonorrhea treatment trials.
Delafloxacin exhibited potent in vitro activity against the baseline N. gonorrhoeae isolates obtained in this trial, with an MIC50/MIC90 of 0.0005/0.03 μg/mL (n = 411). Seventy-nine percent of urogenital infections among study participants in the UME population were caused by gonococci with delafoxacin MICs <0.008 μg/mL, and in this group, delafloxacin cured 99.4% of infections. However, delafloxacin cured only 35% of urogenital infections caused by organisms with MICs ≥ 0.008 μg/mL. Thus, the overall outcomes were driven by higher treatment failure rates among persons infected with N. gonorrhoeae with elevated delafloxacin MICs, a group disproportionately composed of MSM/bisexual men. Of note, MSM/bisexual male enrollment was higher at sites along the US West Coast, where ciprofloxacin resistance also tends to be higher.3
Although the relationship between diminished in vitro antimicrobial susceptibility and increased risk of treatment failure has been documented for multiple antimicrobials since initially noted for penicillin in the 1950s,23 many questions remain regarding antimicrobial pharmacokinetics, antibiotic penetration at different anatomic sites of infection, and other potential determinants of treatment success. The required drug exposure for target attainment in gonorrhea is challenging to assess, animal model data are limited, and N. gonorrhoeae may be present in a variety of human mucosal tissues where antibiotic levels may vary. Delafloxacin exhibits relatively short systemic pharmacokinetics after single dosing (half-life of 5–18 hours for single doses ≥800-mg13,24), and tissue distribution into genitourinary, pharyngeal, and rectal sites of infection has not been studied.
Given delafloxacin's in vitro potency, the current patterns of antimicrobial resistance in the United States, and the results of this study, we conclude that the single 900-mg oral dose was not sufficient to provide sustained infection site exposure high enough for microbial eradication of N. gonorrhoeae with higher MIC values. Additional studies with alternative dosing regimens could be considered. It may be relevant for future studies of delafloxacin for gonorrhea to assess drug levels at different anatomic sites of infection using alternate dosing regimens to evaluate sufficiency of drug exposure. In addition, targeting patient populations with higher rates of fluoroquinolone resistance may help to determine whether alternative dosing regimens are able to cover N. gonorrhoeae isolates with elevated MIC values.
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