Gunar Günther

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking. TBNET consensus statement on the management of patients with MDR/XDR-TB has been released in the Eur Respir J http://ow.ly/uizRD

Multidrug-resistant and extensively drug-resistant tuberculosis: a review of current concepts and future challenges

Multidrug-resistant and extensively drug-resistant tuberculosis are recent global health issues, which makes tuberculosis - after the success of short course treatment during the second half of the last century - a major health challenge. Globalisation, health inequalities, competing economic interests and political instability contribute substantially to the spread of drug-resistant strains, which are associated with high rates of morbidity and mortality. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and a lengthy, toxic treatment need to be overcome by innovative approaches to tuberculosis control, prevention, diagnostics and treatment. This review addresses recent developments and future concepts.

Multidrug-resistant tuberculosis in Europe, 2010-2011.

Ongoing transmission, high levels of drug resistance, and poor diagnostic

Increased expression of beta-defensin 1 (DEFB1) in chronic obstructive pulmonary disease.

On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear. Genome-wide linkage analyses provide evidence for significant linkage to airway obstruction susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Moreover, a genetic variation in the defensin beta 1 (DEFB1) gene was found to be associated with COPD. Therefore, we hypothesized that DEFB1 is differently regulated and expressed in human lungs during COPD progression. Gene expression of DEFB1 was assessed in bronchial epithelium and BAL fluid cells of healthy controls and patients with COPD and using bisulfite sequencing and ChIP analysis, the epigenetic control of DEFB1 mRNA expression was investigated. We can demonstrate that DEFB1 mRNA expression was significantly increased in bronchopulmonary specimen of patients with COPD (n = 34) vs. healthy controls (n = 10) (p<0.0001). Furthermore, a significant correlation could be detected between DEFB1 and functional parameters such as FEV1 (p = 0.0024) and the FEV1/VC ratio (p = 0.0005). Upregulation of DEFB1 mRNA was paralleled by changes in HDAC1-3, HDAC5 and HDAC8 mRNA expression. Whereas bisulfite sequencing revealed no differences in the methylation state of DEFB1 promoter between patients with COPD and controls, ChIP analysis showed that enhanced DEFB1 mRNA expression was associated with the establishment of an active histone code. Thus, expression of human DEFB1 is upregulated and related to the decrease in pulmonary function in patients with COPD.

Treatment Outcomes in Multidrug-Resistant Tuberculosis

Multidrug-resistant tuberculosis is a major global challenge. This report examines the definition of treatment success and its effect on determining cure.

Availability, price and affordability of anti-tuberculosis drugs in Europe: a TBNET survey

Data on availability and cost of anti-tuberculosis (TB) drugs in relation to affordability at national level are scarce. We performed a cross-sectional study on availability and cost of anti-TB drugs at major TB-reference centres in 37 European countries. Costs of standardised treatment regimens used for pan-sensitive TB, multidrug-resistant (MDR) TB, pre-extensively drug-resistant (XDR) TB, and XDR-TB were compared using a purchasing power analysis. Affordability was evaluated in relation to monthly national gross domestic products per capita (GDP). At least one second-line injectable and either moxifloxacin or levofloxacin were available in all countries. Linezolid and clofazimine were available in 79% and 46% of the countries, respectively. Drug cost for XDR-TB was three-times more expensive than those for MDR-TB. The average price of treatment for pan-sensitive TB represented a maximum of 8.5% of the monthly GDP across countries, while for standard MDR-TB treatment this was <30% in only six countries and more than 100% in four countries. Treatment of XDR-TB represented more than 100% of a months GDP in all countries where the regimen was available. High cost and limited availability of drugs for treatment of drug-resistant TB, particularly beyond resistance to first-line drugs, are a major impediment to successful TB control in Europe. Limited availability and high cost of drugs hamper the treatment of drug-resistant tuberculosis in Europe http://ow.ly/CrhbM

Personalized Medicine for Chronic Respiratory Infectious Diseases: Tuberculosis, Nontuberculous Mycobacterial Pulmonary Diseases, and Chronic Pulmonary Aspergillosis.

Chronic respiratory infectious diseases are causing high rates of morbidity and mortality worldwide. Tuberculosis, a major cause of chronic pulmonary infection, is currently responsible for approximately 1.5 million deaths per year. Although important advances in the fight against tuberculosis have been made, the progress towards eradication of this disease is being challenged by the dramatic increase in multidrug-resistant bacilli. Nontuberculous mycobacteria causing pulmonary disease and chronic pulmonary aspergillosis are emerging infectious diseases. In contrast to other infectious diseases, chronic respiratory infections share the trait of having highly variable treatment outcomes despite longstanding antimicrobial therapy. Recent scientific progress indicates that medicine is presently at a transition stage from programmatic to personalized management. We explain current state-of-the-art management concepts of chronic pulmonary infectious diseases as well as the underlying methods for therapeutic decisions and their implications for personalized medicine. Furthermore, we describe promising biomarkers and techniques with the potential to serve future individual treatment concepts in this field of difficult-to-treat patients. These include candidate markers to improve individual risk assessment for disease development, the design of tailor-made drug therapy regimens, and individualized biomarker-guided therapy duration to achieve relapse-free cure. In addition, the use of therapeutic drug monitoring to reach optimal drug dosing with the smallest rate of adverse events as well as candidate agents for future host-directed therapies are described. Taken together, personalized medicine will provide opportunities to substantially improve the management and treatment outcome of difficult-to-treat patients with chronic respiratory infections.

Nosocomial transmission of multidrug-resistant tuberculosis.

Nosocomial transmission of multidrug-resistant tuberculosis (MDR-TB) was ascertained by 24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) and spoligotyping at four hospitals in the Republic of Moldova, a high MDR-TB burden country. Overall, 5.1% of patients with pan-susceptible TB at baseline were identified with MDR-TB during in-patient treatment. In 75% of cases, the MDR-TB strain was genetically distinct from the non-MDR-TB strain at baseline, suggesting a high rate of nosocomial transmission of MDR-TB. The highest proportion (40.3%) of follow-up MDR-TB isolates was associated with the M. tuberculosis URAL 163-15 strain.

Relapse-free cure from multidrug-resistant tuberculosis in Germany

Multidrug-resistant (MDR) tuberculosis (TB), defined by bacillary resistance against rifampicin and isoniazid, has been identified as a global threat to mankind [1]. According to the latest report by the European Centres for Disease Prevention and Control, and World Health Organization (WHO) regional office for Europe, only approximately 50% of MDR-TB patients in Europe reach favourable treatment outcomes [2]. Successful treatment outcomes are achieved for less than 25% of patients with extensively drug-resistant (XDR)-TB (MDR plus resistance against a least one fluoroquinolone and one second-line injectable drug) in the European Union/European Economic Area Countries [2]. Under optimal conditions we observed similar rates of relapse-free cure in patients with M/XDR-TB and non-M/XDR-TB http://ow.ly/SRvd30hPu73

Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia

The substantial decline in the Pneumocystis jirovecii pneumonia (PCP) incidence in HIV-infected patients after the introduction of antiretroviral therapy (ART) in resource-rich settings and the growing number of non-HIV-infected immunocompromised patients at risk leads to considerable epidemiologic changes with clinical, diagnostic, and treatment consequences for physicians. HIV-infected patients usually develop a subacute course of disease, while non-HIV-infected immunocompromised patients are characterized by a rapid disease progression with higher risk of respiratory failure and higher mortality. The main symptoms usually include exertional dyspnea, dry cough, and subfebrile temperature or fever. Lactate dehydrogenase may be elevated. Typical findings on computed tomography scans of the chest are bilateral ground-glass opacities with or without cystic lesions, which are usually associated with the presence of AIDS. Empiric treatment should be initiated as soon as PCP is suspected. Bronchoalveolar lavage has a higher diagnostic yield compared to induced sputum. Immunofluorescence is superior to conventional staining. A combination of different diagnostic tests such as microscopy, polymerase chain reaction, and (1,3)-β-D-glucan is recommended. Trimethoprim/sulfamethoxazole for 21 days is the treatment of choice in adults and children. Alternative treatment regimens include dapsone with trimethoprim, clindamycin with primaquine, atovaquone, or pentamidine. Patients with moderate to severe disease should receive adjunctive corticosteroids. In newly diagnosed HIV-infected patients with PCP, ART should be initiated as soon as possible. In non-HIV-infected immunocompromised patients, improvement of the immune status should be discussed (e.g., temporary reduction of immunosuppressive agents). PCP prophylaxis is effective and depends on the immune status of the patient and the underlying immunocompromising disease.