Association Between Increased Linezolid Plasma Concentrations and the Development of Severe Toxicity in Multidrug-Resistant Tuberculosis Treatment.

BACKGROUND: Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity. METHODS: We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates. RESULTS: SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30-.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26-4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55-4.47; P < .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk. CONCLUSIONS: Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L.

Spiroplasma ixodetis Infections in Immunocompetent and Immunosuppressed Patients after Tick Exposure, Sweden.

We report 2 cases of Spiroplasma ixodetis infection in an immunocompetent patient and an immunocompromised patient who had frequent tick exposure. Fever, thrombocytopenia, and increased liver aminotransferase levels raised the suspicion of anaplasmosis, but 16S rRNA PCR and Sanger sequencing yielded a diagnosis of spiroplasmosis. Both patients recovered after doxycycline treatment.

Multidrug-resistant tuberculosis imported into low-incidence countries-a GeoSentinel analysis, 2008-2020.

BACKGROUND: Early detection of imported multidrug-resistant tuberculosis (MDR-TB) is crucial, but knowledge gaps remain about migration- and travel-associated MDR-TB epidemiology. The aim was to describe epidemiologic characteristics among international travellers and migrants with MDR-TB. METHODS: Clinician-determined and microbiologically confirmed MDR-TB diagnoses deemed to be related to travel or migration were extracted from GeoSentinel, a global surveillance network of travel and tropical medicine clinics, from January 2008 through December 2020. MDR-TB was defined as resistance to both isoniazid and rifampicin. Additional resistance to either a fluoroquinolone or a second-line injectable drug was categorized as pre-extensively drug-resistant (pre-XDR) TB, and as extensively drug-resistant (XDR) TB when resistance was detected for both. Sub-analyses were performed based on degree of resistance and country of origin. RESULTS: Of 201 patients, 136 had MDR-TB (67.7%), 25 had XDR-TB (12.4%), 23 had pre-XDR TB (11.4%) and 17 had unspecified MDR- or XDR-TB (8.5%); 196 (97.5%) were immigrants, of which 92 (45.8%) originated from the former Soviet Union. The median interval from arrival to presentation was 154 days (interquartile range [IQR]: 10-751 days); 34.3% of patients presented within 1 month after immigration, 30.9% between 1 and 12 months and 34.9% after ≥1 year. Pre-XDR- and XDR-TB patients from the former Soviet Union other than Georgia presented earlier than those with MDR-TB (26 days [IQR: 8-522] vs. 369 days [IQR: 84-827]), while patients from Georgia presented very early, irrespective of the level of resistance (8 days [IQR: 2-18] vs. 2 days [IQR: 1-17]). CONCLUSIONS: MDR-TB is uncommon in traditional travellers. Purposeful medical migration may partly explain differences in time to presentation among different groups. Public health resources are needed to better understand factors contributing to cross-border MDR-TB spread and to develop strategies to optimize care of TB-infected patients in their home countries before migration.

Bedaquiline and delamanid for drug-resistant tuberculosis: a clinician's perspective.

Drug-resistant tuberculosis (TB) represents a substantial threat to the global efforts to control this disease. After decades of stagnation, the treatment of drug-resistant TB is undergoing major changes: two drugs with a new mechanism of action, bedaquiline and delamanid, have been approved by stringent regulatory authorities and are recommended by the WHO. This narrative review summarizes the evidence, originating from both observational studies and clinical trials, which is available to support the use of these drugs, with a focus on special populations. Areas of uncertainty, including the use of the two drugs together or for prolonged duration, are discussed. Ongoing clinical trials are aiming to optimize the use of bedaquiline and delamanid to shorten the treatment of drug-resistant TB.

Nonopportunistic infection leading to rapidly progressive dementia in a patient with HIV/AIDS: A case report.

RATIONALE: Cognitive dysfunction is a common presenting symptom in patients with HIV/AIDS. It is usually directly associated with HIV infection or due to opportunistic infection. Rapidly progressive dementia, however, is rarely observed in acute HIV infection or during immune reconstitution. Recently, a case of Creutzfeld-Jakob disease (CJD) has been reported in a patient with chronic HIV infection. The incidence of CJD is not known to be increased among immunocompromised patients. PATIENT CONCERNS: We here report the case of a 59-year-old male patient with a recent diagnosis of HIV/AIDS and Pneumocystis jiroveci pneumonia presenting with secondary behavioral changes and disorientation. Over the course of several weeks, progressive dementia developed characterized by apraxia, gait ataxia, and mutism. DIAGNOSES: After the exclusion of common HIV-associated neurologic conditions, the clinical course as well as findings on electroencephalogram (EEG), magnetic resonance imaging (MRI), and a positive 14-3-3 assay converged into a probable diagnosis of CJD. The diagnosis was later confirmed histopathologically. OUTCOMES: Palliative care was provided, and the patient passed away within 2 months of symptom onset. LESSONS: HIV/AIDS is an important stratifying condition during the work-up of many clinical syndromes including encephalopathy but may prematurely exclude important differential diagnoses. Non-opportunistic etiologies have to be considered as part of a secondary workup as this case of concomitant AIDS and CJD demonstrates. Rapidly progressive dementia should be distinguished from delirium as early as possible in order to be able to choose the correct diagnostic pathway. Despite the common occurrence of neurologic syndromes in the setting of immunodeficiency, an analytical diagnostic approach is advisable to minimize diagnostic bias.

3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer related death. It is lethal in nearly all patients, due to an almost complete chemoresistance. Most if not all drugs that pass preclinical tests successfully, fail miserably in the patient. This raises the question whether traditional 2D cell culture is the correct tool for drug screening. The objective of this study is to develop a simple, high-throughput 3D model of human PDAC cell lines, and to explore mechanisms underlying the transition from 2D to 3D that might be responsible for chemoresistance. METHODS: Several established human PDAC and a KPC mouse cell lines were tested, whereby Panc-1 was studied in more detail. 3D spheroid formation was facilitated with methylcellulose. Spheroids were studied morphologically, electron microscopically and by qRT-PCR for selected matrix genes, related factors and miRNA. Metabolic studies were performed, and a panel of novel drugs was tested against gemcitabine. RESULTS: Comparing 3D to 2D cell culture, matrix proteins were significantly increased as were lumican, SNED1, DARP32, and miR-146a. Cell metabolism in 3D was shifted towards glycolysis. All drugs tested were less effective in 3D, except for allicin, MT100 and AX, which demonstrated effect. CONCLUSIONS: We developed a high-throughput 3D cell culture drug screening system for pancreatic cancer, which displays a strongly increased chemoresistance. Features associated to the 3D cell model are increased expression of matrix proteins and miRNA as well as stromal markers such as PPP1R1B and SNED1. This is supporting the concept of cell adhesion mediated drug resistance.