OBJECTIVES:This multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain.METHODS:Adults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24 μg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (≥1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (≥3 SBMs per week) for at least 9 of the 12 treatment weeks.RESULTS:In total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3% placebo, 2.8%) were related to lubiprostone.CONCLUSIONS:Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.

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Genetic diversity among Borrelia burgdorferi isolates recovered from the skin of Lyme disease patients was assessed by ribosomal DNA (rDNA) spacer restriction fragment length polymorphism analysis, genomic restriction site polymorphism analysis, and plasmid content analysis. There was a significant association between the three rDNA spacer types, the six pulsed-field gel types, and plasmid content (P < 0.001). The association between distinct chromosomal and plasmid markers implies a clonal origin for each genotype.Lyme disease, a disorder which may affect multiple organ systems, results from infection with the spirochete Borrelia burgdorferi. Between 1989 and 1997, 114,314 cases of Lyme disease were reported to the Centers for Disease Control and Prevention, making Lyme disease the most common vectorborne disease in the United States (16,21). Early Lyme disease is manifested by a characteristic skin rash, erythema migrans (EM), and is frequently accompanied by systemic symptoms (14, 15). Molecular analysis of B. burgdorferi isolates has resulted in the differentiation of B. burgdorferi sensu lato into 10 distinct species (23). B. burgdorferi sensu stricto is the only known Lyme disease borrelia infecting patients in North America. Significant genetic heterogeneity among B. burgdorferi sensu stricto isolates in North America has been reported (1,6,8,13). The type strain of B. burgdorferi sensu stricto, B31 has a large linear genome of 910,725 bp and 21 linear and circular plasmids with a total size of 610,694 bp (3, 7).It has long been recognized that the clinical expression of B. burgdorferi infection is diverse (15). Possible explanations for this variability are differences in the genotypes of the infecting strain of B. burgdorferi. We developed a typing method based on restriction fragment length polymorphism (RFLP) in the 16S-23S ribosomal DNA (rDNA) spacer of B. burgdorferi and used it to analyze clinical isolates obtained from early Lyme disease patients (9). A highly significant association was found between the infecting RFLP type in the skin and the presence of spirochetemia or multiple EM lesions (25), suggesting that differences in the clinical presentations of Lyme disease patients may, indeed, be related to B. burgdorferi genotype. rDNA spacer analysis provides genetic typing information for a single genomic locus and interrogates a chromosomal region which is unlikely to have a direct role in pathogenesis. In order to obtain additional, broader typing information, 48 cutaneous isolates from early Lyme disease patients were analyzed by pulsed-field gel electrophoresis (PFGE).Subjects, skin biopsy, and cultivation. All subjects were adults with EM enrolled in a prospective study at the Lyme Disease Diagnostic Center of the Westchester Medical Center, Valhalla, N.Y. Skin biopsy specimens (2 mm) were obtained from the leading edge of primary EM lesions and cultured in BSK-II medium as described previously (19).PFGE. Spirochetes were harvested by centrifugation and washed twice with sterile phosphate-b...

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ImportanceA safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.ObjectivesTo evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.Design, Setting, and ParticipantsThis phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.InterventionsSER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.Main Outcomes and MeasuresThe main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.ResultsOf 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).Conclusions and RelevanceIn this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.Trial RegistrationClinicalTrials.gov identifier: NCT03183141