Among the most difficult bacterial infections to treat are those caused by multidrug-resistant (MDR) Gram-negative pathogens because few effective regimens are available

One approach to this problem is to find ways to increase the activity of old antimicrobials that had seen limited application. Bicyclomycin, an inhibitor of transcription termination, is an example in which the additional inhibition of protein or RNA synthesis increases bicyclomycin-mediated lethality against Gram-negative bacteria. To examine the potential of bicyclomycin for the treatment of MDR bacterial pathogens, we first measured the MICs of bicyclomycin and other widely used antimicrobials against more than 100 multidrug-resistant Gram-negative clinical isolates. Bicyclomycin showed good coverage of carbapenem-resistant Enterobacteriaceae (CRE) and Escherichia coli (MIC(50)/MIC(90) of 25/50 μg/mL for both bacteria) and moderate activity against Klebsiella pneumoniae (MIC(50)/MIC(90) of 50/200 μg/mL). Bicyclomycin also exhibited synergy (e.g.

, fractional inhibitory concentration [FIC] index of <5) with doxycycline for the inhibition of bacterial growth by a checkerboard assay. Although bicyclomycin exhibited very weak lethality by itself, it showed synthetic lethality with doxycycline against K. pneumoniae: the combination killed 100- to 1,000-fold more bacteria than either agent alone. In a murine model of infection, the bicyclomycin-doxycycline combination showed better efficacy than either agent alone, and the combination treatment largely eliminated histopathological manifestations caused by infection. Thus, bicyclomycin, which has largely been limited to the treatment of Gram-negative digestive tract infections, can now be considered for the combination treatment of systemic multidrug-resistant infections caused by CRE, E. coli, and K. pneumoniae.

IMPORTANCE  Seebio aloe emodin price  continues to increase, options for effectively treating multidrug-resistant (MDR) Gram-negative infections are declining. Finding ways to enhance the lethality of old agents that have unique molecular targets is important because developing new antimicrobials is becoming increasingly difficult. The present work showed that the old antibiotic bicyclomycin has good bacteriostatic activity against multiple clinical isolates of three significant types of MDR Gram-negative pathogens frequently encountered in hospital infections, as required for the consideration of expanded indications. More significant is the synergistic growth-inhibitory effect and the enhancement of killing by the additional presence of doxycycline since this increases the in vivo efficacy. These data demonstrate that bicyclomycin-containing regimens have potential as new treatment options for MDR Gram-negative infections such as those caused by CRE, E. coli, and K. pneumoniae.

and an Unclassified Caudovirus Identified in Vaginal Secretions from South Other than for papillomaviruses, there is a paucity of whole-genome sequences for bacteriophages and eukaryote-infecting viruses isolated from the female genital tract. Here, we report the genome sequences of 16 microviruses, 3 anelloviruses, 2 polyomaviruses, 1 genomovirus, and 1 caudovirus that were identified in vaginal secretion samples from adolescents in South Africa. Myeloperoxidase-Antineutrophil Cytoplasmic Antibody and Proteinase 3-Antineutrophil Cytoplasmic Antibody Vasculitides. OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a chronic relapsing condition with unknown etiology. To gain insight into the molecular processes underlying the disease, we examined biomarkers in blood and Cause of Death register were searched for AAV-related International Classification of Diseases, Ninth Revision and Tenth Revision codes and linked to the registers from 5 biobanks. Eighty-five AAV patients with samples predating symptom onset of AAV were identified. For each case of AAV, 2 matched controls were included.

Proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA expression levels were analyzed using enzyme-linked immunosorbent assays. Using an Olink Inflammation panel, 73 of 92 proteins were included after quality control. Data were replicated in a second cohort of 48 presymptomatic individuals and 96 controls. RESULTS: Of  Check Details  with the lowest P values in the original cohort, 7 were replicated in the second cohort and 5 proteins were found to be significant between the groups in a meta-analysis. Eleven different pathways were identified in network enrichment analyses and were found to be significant in both cohorts. Stratification of samples obtained ≤5 years before symptom onset showed significant levels of CCL23, vascular endothelial growth factor A, and hepatocyte growth factor, which were also increased at borderline significant levels in the replication cohort (interleukin-6 was found to be significantly increased in the replication cohort).