Long-Term Treatment with Bulevirtide in Patients with Chronic Hepatitis D and Advanced Chronic Liver Disease.

Bulevirtide (BLV) is approved for the treatment of chronic hepatitis D (CHD). Because only limited long-term experience has been reported, we aimed to evaluate the efficacy and safety of BLV treatment in patients with advanced chronic liver disease (ACLD). We performed a retrospective analysis of patients with CHD who received BLV 2 mg/day for >12 months at a tertiary center. Virological response (VR) was defined as a reduction in hepatitis delta virus-ribonucleic acid (HDV-RNA) ≥2 log10 from baseline or HDV-RNA negativity and biochemical response (BR) as gender-specific normalization of transaminases. We identified 14 patients (9 men, 5 women; median age of 48 years; interquartile range (IQR) of 37-55), of whom 12 (86%) had suggested or assumed ACLD according to Baveno VI criteria. The median duration of BLV treatment was 26 months (IQR 17-27). During treatment, the mean HDV-RNA level decreased from log10 5.58 IU/ml to levels between log10 2.19 IU/ml and log10 3.19 IU/ml. HDV-RNA negativity was achieved in up to 63% after 24 months. VR and BR were 86% and 43% after 12 months, 90% and 60% after 18 months, 75% and 75% after 24 months, and 100% and 50% after 30 months, respectively. Two nonpersisting viral breakthroughs were observed after 24 months of treatment. The Child Pugh score and model of end-stage liver disease (MELD) scores remained stable or improved in 12 patients (86%). Only one patient developed hepatic decompensation after 24 months of treatment with ascites requiring large-volume paracentesis which was not associated with viral breakthrough, portal vein thrombosis, or hepatocellular carcinoma. Treatment with BLV beyond one year is effective and safe for patients with CHD and ACLD. Liver function remained stable or improved during treatment in the vast majority of patients, and only one case of hepatic decompensation occurred during a median follow-up of 26 months.

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus.

Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

Performance of a loop-mediated isothermal amplification assay (Isoplex CRE-ART) to detect common carbapenemase-encoding genes in Gram-negative bacteria.

Carbapenem-resistant Gram-negative bacteria (CR-GNB) are a major source of nosocomial infections worldwide. In this study, the ability of a loop-mediated isothermal amplification (LAMP)-based method (Isoplex CRE-ART) to rapidly detect carbapenemase-encoding genes bla OXA-48-like, bla OXA-23-like, bla OXA-24-like, bla KPC, bla VIM, bla NDM and bla IMP in 231 carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii isolates was investigated. The accuracy of the LAMP test was compared to results of molecular isolate characterization using a Laboratory Developed Test multiplex carbapenemase PCR assay. The LAMP test correctly identified the presence of on-panel carbapenemases with a sensitivity of 99.16 % [95 % confidence interval (CI): 95.39-99.96 %] and a specificity of 98.21 % (95 % CI: 93.72-99.68 %) in 60 min. Our findings suggest that the Isoplex CRE-ART assay is able to rapidly identify carbapenemase genes in CR-GNB and improves options for pathogen characterization in the context of clinical microbiological and infection control diagnostics.

Influence of local epidemiology on the performance of common colistin drug susceptibility testing methods.

OBJECTIVES: To determine the influence of local spread of clonal strains and testing of follow-up isolates on categorical (CA) and essential agreement rates (EA) of common colistin (COL) drug susceptibility testing methods with the broth microdilution (BMD) reference method. METHODS: COL MICs were determined for 178 bacterial isolates (Enterobacteriaceae, n = 97; Pseudomonas aeruginosa, n = 81) collected within one year from 64 patients by BMD according to ISO standard 20776-1 (reference method), the SensiTest BMD panel (ST), agar dilution (AD), the VITEK 2 instrument, and gradient diffusion (GD) using antibiotic strips of two and Muller-Hinton agar plates of three manufacturers. CA and EA with BMD were calculated for all isolates and compared to the subset of 68 unique isolates. RESULTS: CA ranges were 79.4% to 94.1% for the unique isolateq panel and 89.9% to 96.1% for all tested isolates. EA ranges were 64.7% to 86.8% and 67.4% to 91.0%, respectively. In both panels, EA for all GD assays was lower than 90%. Both lower and higher EA values ranging from-18.3% (MTS on BD agar) to + 6.3% (AD, Vitek 2) were observed in the full one-year sample. Acquisition of colistin resistance under therapy was observed for 3 patients. CONCLUSIONS: i) Repeat testing and local spread of clonal strains can positively or negatively affect CA and EA, ii) CA is more robust towards local influences than EA, iii) EA of GD and AD methods for COL with the reference BMD method is insufficient.

Carbapenem-resistant Gram-negative pathogens in a German university medical center: Prevalence, clinical implications and the role of novel ß-lactam/ß-lactamase inhibitor combinations.

OBJECTIVES: To determine the spectrum of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and the clinical impact of the newly available betalactam/betalactamase inhibitor combinations ceftolozane/tazobactam and ceftazidime/avibactam in a German academic tertiary care center. METHODS: Retrospective analysis. RESULTS: Between September 1, 2015 and August 31, 2016, 119 individual patients (0.22% of all hospital admissions) were colonized or infected with carbapenem-resistant MDR-GNB. The species distribution was Pseudomonas aeruginosa, n = 66; Enterobacteriaceae spp., n = 44; and Acinetobacter baumannii, n = 18. In 9 patients, carbapenem-resistant isolates belonging to more than one species were detected. Infection was diagnosed in 50 patients (total: 42.0%; nosocomial pneumonia: n = 23, 19.3%; bloodstream infection: n = 11, 9.2%). Antimicrobial treatment with broad-spectrum antibiotics prior to detection of a carbapenem-resistant isolate was documented in 105 patients (88.2%, prior administration of carbapenems: 62.2%). Nosocomial transmission was documented in 29 patients (24.4%). In 26 patients (21.8%), at least one carbapenem-susceptible, third-generation cephalosporin non-susceptible isolate was documented prior to detection of a carbapenem-resistant isolate belonging to the same species (median 38 days, IQR 23-78). 12 patients (10.1%) had documented previous contact to the healthcare system in a country with high burden of carbapenemase-producing strains. Genes encoding carbapenemases were detected in 60/102 patient isolates (58.8%; VIM-2, n = 25; OXA-48, n = 21; OXA-23-like, n = 10). Susceptibility to colistin was 94.3%. Ceftolozane/tazobactam and ceftazidime/avibactam were administered to 3 and 5 patients, respectively (in-hospital mortality: 66% and 100%). Development of drug-resistance under therapy was observed for both antimicrobials. CONCLUSIONS: i) The major predisposing factors for acquisition of carbapenem-resistant MDR-GNB were selective pressure due to preceding antimicrobial therapy and nosocomial transmission. ii) Colistin remains the backbone of antimicrobial chemotherapy for infections caused by carbapenem-resistant MDR-GNB. iii) Novel ß-lactam/ß-lactamase inhibitor combinations are of limited usefulness in our setting because of the high prevalence of Ambler class B carbapenemases and the emergence of nonsusceptibility under therapy.