High intrapulmonary rifampicin and isoniazid concentrations are associated with rapid sputum bacillary clearance in patients with pulmonary tuberculosis

This work was supported by a Wellcome Trust Clinical PhD Fellowship [grant number 105392/B/14/Z to A.D.M. and L69AGB to JM]. ELC was supported by Wellcome [200901/Z/16/Z]. The Malawi-Liverpool-Wellcome Clinical Research Programme is supported by a strategic award from the Wellcome Trust [206545/Z/17/Z]. We also acknowledge infrastructural support for bioanalysis from the Liverpool Biomedical Research Centre funded by Liverpool Health Partners.Background Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modelling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. Methods Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0 to 8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (AUC and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. Results Among 157 participants (58% HIV co-infected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavourable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. Conclusions Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.Publisher PDFPeer reviewe

Ultrasound Guided Cryoablation of Morton’s Neuroma: Case Series Including Post-Ablation MRI Appearances

Category: Midfoot/Forefoot; Other Introduction/Purpose: Morton’s neuroma (MN) is a very common compressive neuropathy of the interdigital nerve. Non- operative management is recommended initially and many therapies have been described. Cryoablation has shown promising results, however there are limited published studies in the literature. The purpose of this study was to assess the safety and efficacy of Cryoablation in patients with MN. A secondary aim was to evaluate post-procedure MRI appearances. Methods: A retrospective analysis was completed for 24 MN treated between June 2021 and September 2022. All patients had refractory MN symptoms after previous US guided steroid and LA injection within the previous year. Three patients also had refractory symptoms after prior alcohol ablation. Cryoablation was performed as a single outpatient procedure under continuous US monitoring and local anesthesia with 1 cycle for average of 2 minutes. Telephone follow up by radiology department with a 0–10 visual analogue scale (VAS) score was performed at 6 weeks and 3 months post-ablation. The patients were also encouraged to submit patient reported outcomes to a British Foot and Ankle Society (BOFAS) online scoring database as facilitated by the surgical team. Post-ablation MRI was performed to evaluate for post-procedure appearances at various intervals between 3 to 14 months. Results: 24 MN were treated. The mean size of MN treated was 12.3mm. Technical success was 100% and all patients tolerated the procedure well under local anesthesia. Mean pre-procedure VAS pain score was 8, which reduced to 1 at 6 weeks, and 2 at 3 months follow up in the treated MN. There is high patient satisfaction with 20 cases (83%) very satisfied. Four cases had various persistent symptoms and would want to have it done again (17%). Post-ablation MRI showed various bone and soft tissue changes in the ablation zone. There were two cases of fibrosis in the intermetatarsal space and one residual neuroma observed on MRI, although the patients were asymptomatic in the ablation site. No complications occurred e.g. infection, fracture or thermal injury. Conclusion: In this small series, ultrasound guided Cryoablation was deemed safe and effective treatment for MN. Clinical advantages of the procedure are good patient tolerance, single outpatient procedure, high patient satisfaction and reduced risk of scarring or residual neuroma. Further controlled prospective studies would be beneficial