Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (Tmax) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (Tmax, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [Cmax]) similar to that of the ascending dose study and a median Tmax of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.)

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Patients with a high comorbidity burden (high-risk) can achieve similar improvements in quality of life compared to low-risk patients, but greater morbidity may deter surgeons from operating on these patients. Whether surgeon volume influences THA outcomes in high-risk patients has not been investigated. This study aimed to compare complication rates and implant survivorship in high-risk patients operated on by high volume (HV) and non-HV THA surgeons.Patients with Charlson Comorbidity Index ≥ 5 and American Society of Anesthesiologist Classification of 3 or 4 undergoing primary, elective THA between 2013 and 2021 were retrospectively reviewed. Patients were separated into groups based on whether they were operated on by a HV surgeon (defined as the top 25% of surgeons at our institution by number of primary THAs per year) or a non-HV surgeon. Groups were propensity matched 1:1 to control for demographic variables. A total of 1,134 patients were included in the matched analysis. Ninety day readmissions and revisions were compared between groups, and Kaplan-Meier analysis was used to evaluate implant survivorship within the follow-up period.Years of experience were comparable between Non-HV and HV surgeons (p=0.733). The HV group had significantly shorter surgical times (p<0.001), and shorter length of stay (p=0.009) compared to the Non-HV group. The HV group also had significantly fewer 90-day readmissions (p=0.030), all-cause revisions (p=0.023) and septic revisions (p=0.020) compared to the non-HV group at latest follow-up. The HV group had significantly greater freedom from all-cause (p=0.023) and septic revision (p=0.020) compared to the non-HV group.High-risk THA patients have fewer 90-day readmissions, all-cause revisions, septic revisions, as well as shorter length of stay when treated by HV surgeons. THA candidates with a high comorbidity burden may benefit from referral to high-volume surgeons to reduce procedural risk and improve postoperative outcomes.