Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023. RESULTS: 24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries. CONCLUSION: Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe.

Use of cystic fibrosis inhaled medication before and after elexacaftor/tezacaftor/ivacaftor initiation.

Elexacator/tezacaftor/ivacaftor (ETI) has improved cystic fibrosis (CF) outcomes. A reduction in use of maintenance medication after its initiation has been reported. Seventy-one adult people with CF (PwCF) who are followed in three CF centers and completed one year of treatment with ETI were included in this study. Their use of inhaled dornase-α, colistin, tobramycin, aztreonam and levofloxacin during this period was compared with the corresponding use during one year without ETI, using the Medication Possession Ratio (MPR). MPR was significantly decreased after ETI initiation for dornase-α (67±35% vs 48±40%, p<0.001) and for all four inhaled antibiotics together (62±33% vs 41±37%, p<0.001). The findings of this multi-center, retrospective, study suggest that the initiation of ETI significantly leads to decrease in use of standard inhaled medication in PwCF. The significance of this finding in the course of the disease is yet to be investigated by larger prospective clinical trials.

Tigecycline Pharmacokinetic and Pharmacodynamic Profile in Patients with Chronic Obstructive Pulmonary Disease Exacerbation.

BACKGROUND: We aimed to evaluate the pharmacokinetic profile of tigecycline in plasma and its penetration to sputum in moderately ill patients with an infectious acute exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: Eleven patients hospitalized with acute respiratory failure due to an acute COPD exacerbation with clinical evidence of an infectious cause received tigecycline 50 mg twice daily after an initial loading dose of 100 mg. Blood and sputum samples were collected at steady state after dose seven. RESULTS: In plasma, mean Cmax pl was 975.95 ± 490.36 ng/mL and mean Cmin pl was 214.48 ±140.62 ng/mL. In sputum, mean Cmax sp was 641.91 ± 253.07 ng/mL and mean Cmin sp was 308.06 ± 61.7 ng/mL. In plasma, mean AUC 0-12 pl was 3765.89 ± 1862.23 ng*h/mL, while in sputum mean AUC 0-12 sp was 4023.27 ± 793.37 ng*h/mL. The mean penetration ratio for the 10/11 patients was 1.65 ± 1.35. The mean Free AUC0-24 pl/MIC ratio for Streptococcus pneumoniae and Haemophilus influenzae was 25.10 ± 12.42 and 6.02 ± 2.97, respectively. CONCLUSIONS: Our findings support the clinical effectiveness of tigecycline against commonly causative bacteria in COPD exacerbations and highlight its sufficient lung penetration in pulmonary infections of moderate severity.

Evaluation of Pain Scales and Outcome in Critically Ill Patients of a Greek ICU.

The purpose of the study was to evaluate painful procedures in ICU patients and to investigate their effect as well as the role of analgesia in the outcome. We measured pain level and vital signs before, during and after potentially painful procedures by using the Behavioral Pain Scale (BPS) and the Critical Care Pain Observation Tool (CPOT). We analyzed the correlation of these measurements and of analgesia with the outcome. Twenty-eight patients were subjected to 160 stimuli. There were statistically significant differences in pain scores and most vital signs between the different timepoints (before-during, during-after). Most of them were significantly correlated with each other. Physiotherapy proved to be the most painful procedure. Regarding the outcome, the administration of extra analgesia predicted less days of mechanical ventilation (p = 0.015) and of ICU stay (p = 0.016). The higher change in BPS was correlated with more days of mechanical ventilation [B (95% CI) = 3.640 (1.001-6.280), p = 0.007] and of ICU stay [B (95% CI) = 3.645 (1.035-6.254), p = 0.006]. The higher change in CPOT and the nonuse of extra analgesia were related to increased mortality [OR (95% CI) = 1.492 (1.107-2.011), p = 0.009 and OR (95% CI) = 2.626 (1.013-6.806), p = 0.047]. Increased pain in ICU patients was successfully assessed by the BPS and CPOT and correlated to worse outcomes, which the administration of extra analgesia might improve.

Pulmonary medication adherence among children and adults with cystic fibrosis: Is there an association with disease severity?

BACKGROUND: Adherence to pulmonary medication is pivotal in delaying the progression of lung disease in cystic fibrosis (CF). Further exploring the consequences of poor adherence and its impact on disease severity may be valuable to personalize CF treatment strategy. AIM: To evaluate indicators of disease severity among children and adults with CF and investigate which of them are related to pulmonary medication adherence. METHODS: This is a retrospective cohort study. Data of children and adults followed up in one pediatric and one adult CF Unit were evaluated over 4 years. Disease severity was assessed by measuring body mass index (BMI), lung function, history of pulmonary exacerbations, and medication complexity. Adherence was assessed by calculating a 12-month medication possession ratio (MPR) for each pulmonary medication and then averaged for a composite MPR (cMPR) for each patient. Regression analysis was performed to explore the association of adherence with disease severity. RESULTS: Ninety-five patients were included in our study, 52 children and 43 adults. The overall cMPR was 0.74 (SD = 0.25); 0.68 (SD = 0.24) for children and 0.81 (SD = 0.24) for adults. Adults presented higher adherence, with overall mean cMPR 0.81 (SD = 0.24) compared to children with mean cMPR 0.68 (SD = 0.24) (p < 0.05, 95% CI = -0.27 to -0.03). Adherence was inversely related to FEV1 % predicted (ß = -0.002, 95% CI = -0.004 to 0, p = 0.023) and FVC% predicted (ß = -0.003, 95% CI = -0.005 to -0.001, p = 0.006) in regression analysis. Adherence was not found to be associated with BMI, history of exacerbations and medication complexity. The analysis of each medication showed that adherence to Dornase-alpha, Tobramycin and Colomycin was significantly related to specific disease severity indicators. CONCLUSION: An overall moderate to high level of adherence was found among our study population. Adults presented higher adherence compared to children. FEV1% and FVC% predicted were related to a significant decrease in adherence. Among our group of CF patients with an overall moderate to high level of adherence, adherence to pulmonary medication was inversely related to disease severity.

Clinical, imaging and functional determinants of sarcoidosis phenotypes in a Greek population.

Background: The aim of the present study was the application of the latest phenotype recommendations in Greek patients, in order to identify specific clinical, imaging and spirometric characteristics, at initial diagnosis of sarcoidosis, related to disease phenotypes. Methods: Our cohort included 147 patients coming from Northern Greece, recruited from the Outpatient Sarcoidosis Clinic, of Aristotle University of Thessaloniki. The observation period was 5 years. The Scadding staging system and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) Clinical Outcome Status instrument were used. Phenotypes were defined by the latest DELPHI consensus recommendations. Results: The following clinical phenotypes were identified: asymptomatic 59%, acute 14.3%, chronic 12.9% and advanced 33.3%. The observed phenotypes were not related to Scadding stages. Lung function decline was in line with phenotype severity. The presence of fibrosis to any extent upon diagnosis differed among phenotypes (asymptomatic 13.8%, acute 38.1%, chronic 57.9%, advanced 61.2%, P<0.001) and was common for relapsing patients (P<0.001). In spontaneously remitting patients, fibrosis upon diagnosis was found less often than in non-remitting patients (P<0.001). Renal involvement was more frequently found in the advanced phenotype (P=0.032). Skin involvement was more common for patients with acute onset (P<0.001) and spontaneous remission (P=0.012). Ocular involvement was mainly found in relapsing patients (P<0.001). Conclusions: In our cohort, sarcoidosis clinical phenotypes have certain clinical, imaging and functional characteristics, at initial diagnosis of the disease, which could be assessed in everyday practice.

Country-specific lockdown measures in response to the COVID-19 pandemic and its impact on tuberculosis control: a global study.

The objective of this study was to describe country-specific lockdown measures and tuberculosis indicators collected during the first year of the COVID-19 pandemic. Data on lockdown/social restrictions (compulsory face masks and hand hygiene; international and local travel restrictions; restrictions to family visits, and school closures) were collected from 24 countries spanning five continents. The majority of the countries implemented multiple lockdowns with partial or full reopening. There was an overall decrease in active tuberculosis, drug-resistant tuberculosis, and latent tuberculosis cases. Although national lockdowns were effective in containing COVID-19 cases, several indicators of tuberculosis were affected during the pandemic.

BALF and BLOOD NK- cells in different stages of pulmonary sarcoidosis.

BACKGROUND AND OBJECTIVE: Data on natural killer (NK)- and natural killer T (NKT)- like cells in the immunopathogenesis of sarcoidosis remain limited. The aim was to assess NK- and NKT-like cells across different stages in bronchoalveolar lavage (BALF) versus peripheral blood (PB) in comparison to controls. METHODS: Forty four patients (32 women and 12 men, mean age 46.6±14.4 years) with biopsy-proven sarcoidosis and 10 healthy individuals (6 women, 4 men mean age 52.6±19.1 years) were submitted to BALF. Total cells and cell differentials were counted, while CD45+, CD3+, CD4+, CD8+, CD19+, CD3-CD16/56 (NK cells) and CD3+CD16/56+ (NKT-like cells) were determined by dual flow cytometry in BALF and PB. RESULTS: A significantly lower percentage of both NK and NKT-like cells was observed in BALF of controls and sarcoid patients (SP) compared to PB. Both BALF NK and NKT-cell counts were significantly higher in SP than in controls (NK: p=0.046, NKT-like: p=0.012) In addition BALF NK cell percentage differed among sarcoidosis stages (p=0.005). In PB NK-cell count was lower in sarcoidosis patients but the difference did not reach statistical significance. Also, in sarcoid patients' BALF NK-cell percentage negatively correlated with lymphocyte percentage (r=-0.962, p<0.001). CONCLUSIONS: The increased count of BALF NK and NKT-like cells in sarcoidosis compared to controls along with the increase of NK cells with stage progression are in line with a growing number of investigations suggesting the involvement of NK- and NKT-like cells in the pathogenesis of sarcoidosis.

Adherence to inhaled therapies over 4 years in people with cystic fibrosis.

BACKGROUND: This study examined the drug-specific and overall adherence of teenagers and adults with cystic fibrosis (CF) to inhaled therapies, to assess the degree of adherence, stability over a period of 4 years, and its association with health outcomes. METHODS: Fifty-five participants (30 women and 25 men) aged 14 years or older from two CF centers were enrolled in a retrospective review of inhaled medication adherence over 4 years. Adherence was assessed by the number of doses that were obtained by each participant based on the "e-prescription.gr" platform and the calculation of the medication possession ratio (MPR). RESULTS: The mean composite MPR (cMPR) for the entire research period was 0.75 ± 0.19. A total of 43.4% of participants showed a variance of adherence <25%. Participants with stable adherence had a significantly higher mean cMPR compared with those with variable adherence (0.86 ± 0.16 vs. 0.66 ± 0.17, p < 0.001). A statistically significant difference between groups of patients with different degrees of mean cMPR and mean weight was observed (p = 0.011). Patients with a mean cMPR ≥0.80 weighed significantly more than those with moderate and low adherence. In addition, mean weight correlated significantly with the mean cMPR (Β [95% confidence interval] = 14.845 [0.191-29.498], r = 0.269, p = 0.047). CONCLUSIONS: In our setting, the cMPR was easy to assess and showed that adherence was probably better than expected. The association of cMPR with weight should be further investigated. Stable adherence seemed to be related to high adherence. This observation could enhance our understanding of people with CF and their approach to treatment.

Country-specific lockdown measures in response to the COVID-19 pandemic and its impact on tuberculosis control: a global study / Medidas de confinamento específicas de cada país em resposta à pandemia de COVID-19 e seu impacto no controle da tuberculose: um estudo global

ABSTRACT The objective of this study was to describe country-specific lockdown measures and tuberculosis indicators collected during the first year of the COVID-19 pandemic. Data on lockdown/social restrictions (compulsory face masks and hand hygiene; international and local travel restrictions; restrictions to family visits, and school closures) were collected from 24 countries spanning five continents. The majority of the countries implemented multiple lockdowns with partial or full reopening. There was an overall decrease in active tuberculosis, drug-resistant tuberculosis, and latent tuberculosis cases. Although national lockdowns were effective in containing COVID-19 cases, several indicators of tuberculosis were affected during the pandemic.

RESUMO O objetivo deste estudo foi descrever as medidas de confinamento específicas de cada país e os indicadores de tuberculose coletados durante o primeiro ano da pandemia de COVID-19. Dados referentes a confinamento/restrições sociais (uso obrigatório de máscaras faciais e higiene obrigatória das mãos; restrições a viagens internacionais e locais; restrições a visitas familiares e fechamento das escolas) foram coletados de 24 países em cinco continentes. A maioria dos países implantou múltiplos confinamentos, com reabertura parcial ou total. Houve uma redução geral dos casos de tuberculose ativa, tuberculose resistente e tuberculose latente. Embora os confinamentos nacionais tenham sido eficazes na contenção dos casos de COVID-19, vários indicadores de tuberculose foram afetados durante a pandemia.

Occupational Exposure to Zoonotic Tuberculosis Caused by Mycobacterium caprae, Northern Greece, 2019.

Pulmonary tuberculosis caused by Mycobacterium caprae was diagnosed in a 65-year-old goat breeder from northern Greece. This case represents a documented occupational transmission of M. caprae and highlights the importance of enhanced laboratory screening and increased surveillance for zoonotic tuberculosis control.

Severe Pulmonary Disease Caused by Mycolicibacter kumamotonensis.

Severe Mycolicibacter kumamotonensis-pulmonary disease was diagnosed in a 68-year-old immunocompetent woman in Greece; the disease was initially treated as tuberculosis. The patient responded favorably to a new treatment regimen of azithromycin, amikacin, moxifloxacin, and linezolid. Complete symptom resolution and radiologic improvement resulted.

Longitudinal changes in exercise capacity among adult cystic fibrosis patients.

INTRODUCTION: Longitudinal data regarding changes in exercise capacity among adult cystic fibrosis (CF) patients are currently scarce. The aim of this brief report was to assess changes in exercise capacity among adult CF patients with stable and mild-to-moderate disease eight years after their initial evaluation. MATERIAL AND METHODS: Maximum cardiopulmonary exercise testing (CPET) was utilized. Other assessments included Doppler echocardiography, the 6-minute walking test, spirometry, and lung volume evaluation. RESULTS: Eleven (6 male, 5 female) patients completed both evaluations (initial and after eight years). During follow-up, indices of ventilatory impairment (such as ventilatory reserve; p=0.019, and ventilatory equivalent for carbon dioxide; p = 0.047) deterio-rated significantly following a decline in respiratory function measurements. Peak oxygen uptake (VO2), both as an absolute (26.6 ± 8.46 vs 23.89 ± 6.16 mL/kg/min; p = 0.098) and as a % of predicted value (71.21 ± 16.54 vs 70.60 ± 15.45; p = 0.872), did not deteriorate. This is also true for oxygen pulse (p = 0.743), left heart ejection fraction (p = 0.574), and pulmonary artery systolic pressure (p = 0.441). However, the anaerobic threshold, both as an absolute (p = 0.009) and as a % of predicted value (p = 0.047), was significantly lower during follow-up. CONCLUSION: In adult CF patients with stable, mild-to-moderate disease, a peak VO2 may be preserved for several years. However, even in these patients, deconditioning is present.

18F-FDG PET/CT contribution to tuberculous vertebral osteomyelitis diagnosis: a case report.

Tuberculous vertebral osteomyelitis (TVO) is an extrapulmonary tuberculosis form characterized by difficulty and delay in diagnosis. PET/CT is a valuable, well-established tool in the diagnostic workup of cancer and fever of unknown origin, which is increasingly appreciated in the management of infectious diseases. We report a TVO case where PET/CT had a valuable contribution towards diagnosis and monitoring of treatment response, highlighting its advantages and future perspectives when dealing with infectious diseases.

Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study.

INTRODUCTION: Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls. METHODS AND ANALYSIS: Patients aged 18 years or older with sputum smear and culture-positive pulmonary MDR-TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if >80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM. ETHICS AND DISSEMINATION: Ethical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03409315).

A rare pulmonary pathology complicated with an unusual condition.

Differential diagnosis should never be limited to the obvious diagnoses http://ow.ly/ybTM30obh6H.

Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients.

Therapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve the response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest, the area under the concentration-time curve. This study aimed to develop LSSs for moxifloxacin alone (MFX) and together with rifampin (MFX+RIF) in tuberculosis (TB) patients. Population pharmacokinetic (popPK) models were developed for MFX (n = 77) and MFX+RIF (n = 24). In addition, LSSs using Bayesian approach and multiple linear regression were developed. Jackknife analysis was used for internal validation of the popPK models and multiple linear regression LSSs. Clinically feasible LSSs (one to three samples, 6-h timespan postdose, and 1-h interval) were tested. Moxifloxacin exposure was slightly underestimated in the one-compartment models of MFX (mean -5.1%, standard error [SE] 0.8%) and MFX+RIF (mean -10%, SE 2.5%). The Bayesian LSSs for MFX and MFX+RIF (both 0 and 6 h) slightly underestimated drug exposure (MFX mean -4.8%, SE 1.3%; MFX+RIF mean -5.5%, SE 3.1%). The multiple linear regression LSS for MFX (0 and 4 h) and MFX+RIF (1 and 6 h), showed mean overestimations of 0.2% (SE 1.3%) and 0.9% (SE 2.1%), respectively. LSSs were successfully developed using the Bayesian approach (MFX and MFX+RIF; 0 and 6 h) and multiple linear regression (MFX, 0 and 4 h; MFX+RIF, 1 and 6 h). These LSSs can be implemented in clinical practice to facilitate TDM of moxifloxacin in TB patients.

Burden and Characteristics of the Comorbidity Tuberculosis-Diabetes in Europe: TBnet Prevalence Survey and Case-Control Study.

BACKGROUND: The growing burden of diabetes mellitus (DM) is posing a threat to global tuberculosis (TB) control. DM triples the risk of developing TB, modifies the presenting features of pulmonary TB, and worsens TB treatment outcomes. We aimed to analyze the prevalence of DM among TB patients and to describe the characteristics and clinical presentation of TB-DM patients in Europe. METHODS: We performed a cross-sectional survey on the prevalence of DM among consecutively diagnosed adult TB patients in 11 European TB referral centers located in France, Germany, Greece, Italy, Russia, Slovakia, Spain, and the United Kingdom over the period 2007-2015. We also selected DM-TB cases and TB only controls with a 1:3 ratio to perform a case-control analysis, including patients selected from the countries mentioned above plus Norway and Ukraine. RESULTS: Among 3143 TB enrolled patients, DM prevalence overall was 10.7% and ranged from 4.4% in Greece to 28.5% in the United Kingdom. Patients' median ages ranged from 36 to 49 years, and all centers had >60% males; the proportion of foreign-born patients varied widely across sites. In the case-control study, DM was independently associated with older age and, among older patients, with being foreign-born. Among patients with pulmonary involvement, cavities on chest imaging were more frequently observed among those with DM. CONCLUSIONS: Diabetes mellitus represents a challenge for TB control in Europe, especially in foreign-born and in elderly patients. Specific screening strategies should be evaluated.

Moxifloxacin in Chronic Obstructive Pulmonary Disease: Pharmacokinetics and Penetration into Bronchial Secretions in Ward and Intensive Care Unit Patients.

This study aimed to evaluate the pharmacokinetic profile of moxifloxacin (MXF) in serum and sputum/bronchial secretions of 22 patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) hospitalized in the ward and intensive care unit (ICU). The data showed that ICU patients had lower concentrations in secretions (P = 0.01). However, no other statistically significant differences were observed in pharmacokinetic parameters and penetration in secretions between ward and ICU patients. MXF showed a favorable pharmacokinetic profile, and the pharmacodynamic targets for common pathogens for AECOPD were achieved.