Background: The optimal polymyxin B dosage needed to achieve an efficacy target of 50-100 mg·h/L when treating multi-drug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. Methods: This was a prospective, observational pharmacokinetic (PK) study of nine CF adults receiving intravenous polymyxin B as part of usual clinical care. Doses preceding PK sampling ranged from 50-100 mg every 12 hours. Five PK samples were collected following the fourth or fifth dose and concentrations of polymyxin subcomponents, B1 and B2, were quantified using Liquid Chromatography Mass Spectrometry (LC-MS). Population PK (NONMEM® software) analysis was performed using pooled polymyxin B1+B2 concentrations. Results: Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21-57 years) and 58.0kg (range 38.3-70.4kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution, 2.09 L/hr and 12.7 L, respectively, corresponding to a 4.1 hour mean half-life (t 1/2 ). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 hours was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients; acute kidney injury events in two patients. These events resolved within 2-4 days after discontinuing polymyxin B. Conclusions: Fixed maintenance dosing of polymyxin B without loading is predicted to achieve the targeted therapeutic exposure in CF adults. Treatment-limiting neurotoxicities are very common in this population.

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Background Mounting evidence shows association between COVID-19 and new diagnoses of diabetes. It is unclear, however, if COVID-19 increases detection of pre-existing diabetes or if it can induce new-onset of the disease. Methods We established a global online registry of COVID-19-related diabetes (CoviDIAB) using a web-enabled data capture system (Dendrite Clinical Systems). In this study we aimed to investigate whether COVID-19 can induce new-onset diabetes, its subtypes and clinical manifestations. To this end, we analyzed clinical and laboratory data from cases of newly-diagnosed diabetes occurring during or within four weeks from an episode of COVID-19. To exclude pre-existing hyperglycaemia, new-onset diabetes was defined as: blood sugar levels above diabetes thresholds (fasting glycaemia ≥ 126 mg/dL or non-fasting glycemia > 200 mg/dL), no prior history of the disease or use of glucose-lowering medications, and HbA1c < 6·5% at presentation. Results Between October 2020 and April 2022, 67 contributors from 61 hospitals in 25 countries entered data on 537 eligible cases of newly-diagnosed diabetes. New-onset diabetes was identified in 102 of 473 newly-diagnosed cases with recorded HbA1c (22%). Among adults, diabetes subtypes were type 2 (59%) and “not-yet known” (41%). There were two cases of new-onset type 1 diabetes among children. Hyperglycaemia persisted beyond resolution of the infection in 39 of 89 (45%) patients with new-onset diabetes who survived the episode of COVID-19. Further follow-up data beyond 3-months was available for 28 such cases, showing remission of diabetes in five and persistent diabetes in 23 cases (82%). Conclusions This study shows clinical plausibility for a diabetogenic effect of COVID-19, supporting screening for diabetes in people who contract the infection. Further investigation is warranted to confirm mechanisms of viral interference with glucose metabolism. The CoviDIAB registry is accessible online at http://covidiab.e-dendrite.com.