The exceptions that prove the rule-a historical view of bedaquiline susceptibility.

In the accompanying study, Nimmo and colleagues estimated the dates of emergence of mutations in mmpR5 (Rv0678), the most important resistance gene to the anti-tuberculosis drug bedaquiline, in over 3500 geographically diverse Mycobacterium tuberculosis genomes. This provided important insights to improve the design and analysis of clinical trials, as well as the World Health Organization catalogue of resistance mutations, the global reference for interpreting genotypic antimicrobial susceptibility testing results.

Estimated glomerular filtration rate as a tool for early identification of patients with insufficient exposure to beta-lactam antibiotics in intensive care units.

BACKGROUND: Only about 50% of intensive care unit (ICU) patients reach a free trough concentration above MIC (100% fT > MIC) of beta-lactam antibiotics. Although dose adjustments based on therapeutic drug monitoring (TDM) could be beneficial, TDM is not widely available. We investigated serum creatinine-based estimated GFR (eGFR) as a rapid screening tool to identify ICU patients at risk of insufficient exposure. METHOD: Ninety-three adult patients admitted to four ICUs in southeast Sweden treated with piperacillin/tazobactam, meropenem, or cefotaxime were included. Beta-lactam trough concentrations were measured. The concentration target was set to 100% fT > MICECOFF (2, 4, and 16 mg/L based on calculated free levels for meropenem, cefotaxime, and piperacillin, respectively). eGFR was primarily determined via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and compared to three other eGFR equations. Data was analysed using logistic regression and receiver operative characteristic (ROC) curves. RESULTS: With intermittent standard dosing, insufficient exposure was common in patients with a relative eGFR ≥48mL/min/1.73m2 [85%, (45/53)], particularly when treated with cefotaxime [96%, (24/25)]. This eGFR cut-off had a sensitivity of 92% and specificity of 82% (AUC 0.871, p < 0.001) in identifying insufficient exposure. In contrast, patients with eGFR <48mL/min/1.73m2 had high target attainment [90%, (36/40)] with a wide variability in drug exposure. There was no difference between the four eGFR equations (AUC 0.866-0.872, cut-offs 44-51 ml/min/1.73m2). CONCLUSION: Serum creatinine-based eGFR is a simple and widely available surrogate marker with potential for early identification of ICU patients at risk of insufficient exposure to piperacillin, meropenem, and cefotaxime.

Evaluating regression and probabilistic methods for ECG-based electrolyte prediction.

Imbalances in electrolyte concentrations can have severe consequences, but accurate and accessible measurements could improve patient outcomes. The current measurement method based on blood tests is accurate but invasive and time-consuming and is often unavailable for example in remote locations or an ambulance setting. In this paper, we explore the use of deep neural networks (DNNs) for regression tasks to accurately predict continuous electrolyte concentrations from electrocardiograms (ECGs), a quick and widely adopted tool. We analyze our DNN models on a novel dataset of over 290,000 ECGs across four major electrolytes and compare their performance with traditional machine learning models. For improved understanding, we also study the full spectrum from continuous predictions to a binary classification of extreme concentration levels. Finally, we investigate probabilistic regression approaches and explore uncertainty estimates for enhanced clinical usefulness. Our results show that DNNs outperform traditional models but model performance varies significantly across different electrolytes. While discretization leads to good classification performance, it does not address the original problem of continuous concentration level prediction. Probabilistic regression has practical potential, but our uncertainty estimates are not perfectly calibrated. Our study is therefore a first step towards developing an accurate and reliable ECG-based method for electrolyte concentration level prediction-a method with high potential impact within multiple clinical scenarios.

Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis.

Linezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB). We conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992-2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0). Of all participants (n=132), 43.2% were female and the median age 28 years. The median linezolid treatment was 6.5 months (IQR 3.0-12.7) with a median daily dose of 9.6 mg/kg/day. Any ADR was seen in 58.3% (n=77) of participants, with 35.6% having peripheral neuropathy (n=47), 27.3% anaemia (n=36), 22.0% leukopenia (n=36) while 6.1% (n=8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1-5.9) and 8.3 months (6.2-10.7) for optic neuritis. A >2.0 mg/L trough concentration (n=40) was associated with anaemia (p=0.0038) and thrombocytopenia (p=0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/day was associated with time to peripheral neuropathy (HR 2.89, 95%CI 1.08-7.74, p=0.035), anaemia (HR 6.62, 95%CI 2.22-19.8, p=0.001) and leukopenia (HR 5.23, 95% CI 1.48-18.5, p=0.010). Linezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.

Integrated Surveillance of Disparities in Vaccination Coverage and Morbidity during the COVID-19 Pandemic: A Cohort Study in Southeast Sweden.

We aimed to use the digital platform maintained by the local health service providers in Southeast Sweden for integrated monitoring of disparities in vaccination and morbidity during the COVID-19 pandemic. The monitoring was performed in the adult population of two counties (n = 657,926) between 1 February 2020 and 15 February 2022. The disparities monitored were relocated (internationally displaced), substance users, and suffering from a psychotic disorder. The outcomes monitored were COVID-19 vaccination, SARS-CoV-2 test results, and hospitalization with COVID-19. Relocated residents displayed an increased likelihood of remaining unvaccinated and a decreased likelihood of testing as well as increased risks of primary SARS-CoV-2 infection and hospitalization compared with the general population. Suffering from a major psychiatric disease was associated with an increased risk of remaining unvaccinated and an increased risk of hospitalization but a decreased risk of SARS-CoV-2 infection. From the digital monitoring, we concluded that the relocated minority received insufficient protection during the pandemic, suggesting the necessity for comprehensive promotion of overall social integration. Persons with major psychiatric diseases underused vaccination, while they benefitted from proactively provided testing, implying a need for active encouragement of vaccination. Further research is warranted on legal and ethical frameworks for digital monitoring in vaccination programs.

Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Chest Radiograhic Patterns of Smear Positive Tuberculosis in Relation to HIV: A Cross-Sectional Study in a Population with a High Burden of HIV and Tuberculosis.

Aim: The purpose of this study was to investigate the chest radiographic patterns of smear positive pulmonary tuberculosis patients in relation to HIV co-infection. Study Deign: Cross-sectional descriptive study Place and Duration of the Study: The study was conducted at Gondar University hospital between May 2004–December 2007. Methodology: We studied chest radiographs of 207 (128 HIV negative and 79 HIV positive) consecutive sputum smear positive pulmonary tuberculosis patients according to the standard classification. Mean and percentages/ proportions were used for descriptive analysis. Chi square test was used to measure association. Results: The prevalence of HIV in patients with smear positive pulmonary tuberculosis was 38.2%. The most common chest radiographic patterns were fibronodular (83.1%), cavity (60.4%), lobar consolidation (49.8%), and brochopnemonic consolidation (9.2%). Lymphadenopthy and pleural effusion were more common in HIV co infected patients (p<0.01). Cavities, upper lobe disease and increased mean number of lung lobes involved were more prominent in HIV negative patients (P<0.05). Despite a higher rate of patients with far advanced CXR patterns in HIV negative TBC patients compared to HIV positive (p<0.026), there was no significant difference in the radiographic, sputum smear conversion or clinical response in terms of increased body mass index after 8 weeks of anti TBC treatment between HIV negative and HIV positive patients. Conclusion: Post primary pulmonary tuberculosis was the commonest chest radiographic pattern at presentation in both HIV positive and HIV negative patients, but atypical chest radiographic presentations were associated with co-infection. It was more common for HIV negative tuberculosis patients to have a radiologically far advanced pattern which did not correspond to the clinical and radiological response. This may prompt a need for revision of the current radiological classification.