Efficacy of rifapentine and other rifamycins against Coxiella burnetii in vitro.

Since 1999, doxycycline and hydroxychloroquine have been the recommended treatment for chronic Q fever, a life-threatening disease caused by the bacterial pathogen, Coxiella burnetii. Despite the duration of its use, the treatment is not ideal due to the lengthy treatment time, high mortality rate, resistant strains, and the potential for contraindicated usage. A literature search was conducted to identify studies that screened large panels of drugs against C. burnetii to identify novel targets with potential efficacy against C. burnetii. Twelve candidate antimicrobials approved for use in humans by the US Food and Drug Administration were selected and minimum inhibitory concentrations (MICs) were determined against the low virulence strain Nine Mile phase II. Rifabutin and rifaximin were the best performing antibiotics tested with MICs of ≤0.01 µg mL-1. Further screening of these top candidates was conducted alongside two drugs from the same class, rifampin, well-characterized, and rifapentine, not previously reported against C. burnetii. These were screened against virulent strains of C. burnetii representing three clinically relevant genotypes. Rifapentine was the most effective in the human monocytic leukemia cell line, THP-1, with a MIC ≤0.01 µg mL-1. In the human kidney epithelial cell line, A-498, efficacy of rifapentine, rifampin, and rifabutin varied across C. burnetii strains with MICs between ≤0.001 and 0.01 µg mL-1. Rifampin, rifabutin, and rifapentine were all bactericidal against C. burnetii; however, rifabutin and rifapentine demonstrated impressive bactericidal activity as low as 0.1 µg mL-1 and should be further explored as alternative Q fever treatments given their efficacy in vitro. IMPORTANCE: This work will help inform investigators and physicians about potential alternative antimicrobial therapies targeting the causative agent of Q fever, Coxiella burnetii. Chronic Q fever is difficult to treat, and alternative antimicrobials are needed. This manuscript explores the efficacy of rifamycin antibiotics against virulent strains of C. burnetii representing three clinically relevant genotypes in vitro. Importantly, this study determines the susceptibility of C. burnetii to rifapentine, which has not been previously reported. Evaluation of the bactericidal activity of the rifamycins reveals that rifabutin and rifapentine are bactericidal at low concentrations, which is unusual for antibiotics against C. burnetii.

Effectiveness of rifaximin and probiotics for the correction of intestinal permeability in patients with metabolic-associated fatty liver disease in combination with type 2 diabetes mellitus.

OBJECTIVE: Aim: To investigate the effectiveness of rifaximin and probiotics for the correction of intestinal permeability in patients with metabolic-associated fatty liver disease (MAFLD) in combination with type 2 diabetes mellitus. PATIENTS AND METHODS: Materials and Methods: The prospective interventional randomized investigation included 68 patients with MAFLD in combination with type 2 diabetes, who were examined and divided into the 2 groups of treatment. RESULTS: Results: The serum levels of interleukin (IL) - 6, IL-10 and zonulin, indicators of liver functional activity, liver attenuation coefficient between treatment group vs. control group after 2 weeks, 1 month, 3 and 6 months of therapy were significant differed. The serum levels of IL-6 and zonulin significantly decreasing and increasing of IL-10 in the treatment group after 2 weeks, 1, 3 and 6 months of combined therapy. When comparing of stool short-chain fatty acids concentration between treatment group vs. control group after 2 weeks, 1 month, 3 and 6 months of therapy the levels of acetic, butyric and propionic acids significantly differences and increase in their levels were established. CONCLUSION: Conclusions: The results of the study in dynamics during 6 months show that the additional appointment of rifaximin, multispecies probiotic and prebiotic to metformin in patients with MAFLD and type 2 diabetes led to the elimination of subclinical inflammation, modulation of the permeability of the intestinal barrier and lowering increased intestinal permeability, as well as to the lower serum activity of liver aminotransferases and decrease the stage of steatosis.

High rifaximin out-of-pocket costs are associated with decreased treatment retention among patients with hepatic encephalopathy.

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) is associated with significant morbidity and mortality for those with cirrhosis. Despite the known benefits of rifaximin use for HE, treatment retention remains low. This study aimed to evaluate the impact of out-of-pocket (OOP) rifaximin cost on treatment retention among commercially insured patients in the United States. METHODS: Adult patients with cirrhosis and HE were identified from the IBM MarketScan claims database. Those who began rifaximin treatment between January 1, 2011, and December 1, 2021 were included. Regression models were used to analyze the relationship between patients' 30-day OOP rifaximin cost and rifaximin retention (≥80% eligible days with rifaximin supply) at 180, 360, and 540 days. Models were controlled for patient demographic and clinical characteristics including age, sex, comorbid conditions, Charlson comorbidity index (CCI), and lactulose use. RESULTS: A total of 6839 adult patients were included. Most patients were between 55 and 64 years (57.1%), male (60.4%), and living in urban settings (84.6%). Treatment retention was low for all time periods; retention rates for rifaximin were 42%, 25%, and 16% at 180, 360, and 540 days, respectively. In multivariable analysis, 30-day OOP costs of ≥ $150 were associated with a decreased likelihood of rifaximin retention at 180, 360, and 540 days [relative risk (RR) = 0.67, RR = 0.62, and R = 0.60, respectively]. Younger age was associated with reduced treatment retention for all time periods. Metastatic cancer and depression were associated with reduced treatment retention at 180 days (RR = 0.70 and RR = 0.87, respectively). CONCLUSIONS: Rates of rifaximin treatment retention are low despite the known benefits of rifaximin use for breakthrough HE. High 30-day OOP cost is associated with reduced rifaximin treatment retention.

Nanoscaled Discovery of a Shunt Rifamycin from Salinispora arenicola Using a Three-Color GFP-Tagged Staphylococcus aureus Macrophage Infection Assay.

Antimicrobial resistance has emerged as a global public health threat, and development of novel therapeutics for treating infections caused by multi-drug resistant bacteria is urgent. Staphylococcus aureus is a major human and animal pathogen, responsible for high levels of morbidity and mortality worldwide. The intracellular survival of S. aureus in macrophages contributes to immune evasion, dissemination, and resilience to antibiotic treatment. Here, we present a confocal fluorescence imaging assay for monitoring macrophage infection by green fluorescent protein (GFP)-tagged S. aureus as a front-line tool to identify antibiotic leads. The assay was employed in combination with nanoscaled chemical analyses to facilitate the discovery of a new, active rifamycin analogue. Our findings indicate a promising new approach for the identification of antimicrobial compounds with macrophage intracellular activity. The antibiotic identified here may represent a useful addition to our armory in tackling the silent pandemic of antimicrobial resistance.

Defining the minimum inhibitory concentration of 22 rifamycins in iron limited, physiologic medium against Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates.

Recently, we reported rifabutin hyper-activity against Acinetobacter baumannii. We sought to characterize if any additional rifamycins (n = 22) would also display hyper-activity when tested in iron-limited media against A. baumannii, K. pneumoniae, and E. coli. MICs were determined against representative clinical isolates using the iron-limited media RPMI-1640. Only rifabutin was hyperactive against A. baumannii.

Asymmetric Total Synthesis of Cytotrienin A: Late-Stage Installation of C11 Side Chain onto the Macrolactam Scaffold.

Cytotrienin A, an ansamycin-class antibiotic, exhibits potent apoptosis-inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late-stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxy group by the traceless Staudinger reaction. This study also demonstrated that the boron-Wittig/iterative Suzuki-Miyaura cross-coupling sequence was effective for the concise and selective construction of the (E,E,E)-conjugated triene moiety. The developed route opens new opportunities for the structure-activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies.

Avances en tuberculosis en el 54° Congreso Chileno de enfermedades respiratorias. 3a parte: Prevención de la tuberculosis activa mediante el tratamiento de la tuberculosis latente / Advances in tuberculosis at the 54th Chilean Congress of Respiratory Diseases. Part 3: prevention of active tuberculosis by treating latent tuberculosis

La infección tuberculosa latente (ITL) es un estado asintomático de la infección por Mycobacterium tuberculosis incapaz de transmitir la infección a otros, pero con el potencial de originar una tuberculosis (TBC) activa en el infectado, especialmente ante la presencia de factores de riesgo inmunológico. Es importante en personas de riesgo de desarrollar TBC reconocer la ITL utilizando test como la reacción a la tuberculina (PPD o TST) y los ensayos de liberación de Interferón-γ (IGRAs). Sin embargo, estos tests tienen limitaciones en su capacidad de predicción de riesgo de evolución de infección a enfermedad lo que conlleva a tener que tratar muchas personas para evitar algún caso de enfermedad. Nuevos tests se encuentran en desarrollo para mejorar la sensibilidad de reconocimiento de la ITL, distinguir infecciones recientes (que tienen el mayor riesgo de progresión a enfermedad) e incluso con la capacidad de detectar enfermedad subclínica o inicial. Para reducir la probabilidad de enfermar por TBC se utilizan tratamientos preventivos con fármacos, pero la cobertura mundial de esta terapia es reducida y la adherencia a terapias auto-administradas, como en el caso del uso de isoniazida diaria oral, es también baja. Otro problema de esta terapia son los riesgos de reacciones adversas (hepatitis, erupciones cutáneas) aunque no frecuentes. La recomendación de terapia actual de la ITL incluye el uso de rifamicinas y sus derivados. La asociación de isoniazida con rifapentina en una dosis semanal durante tres meses, administrada bajo supervisión, es la terapia de primera línea para mayores de 2 años, mostrando menos riesgo de hepatotoxicidad y mayor adherencia.

Latent Tuberculosis infection (LTBI) is the asymptomatic state of infection caused by Mycobacterium tuberculosis. Although untransmissible, LTBI can progress to active tuberculosis (TB), especially in people with immune risk factors. It is important to recognize LTBI in people at risk of developing TB; tuberculin skin test (PPD or TST) or interferon-γ release assays (IGRAs) are current diagnostic tests. However, these tests have limitations in their ability to predict subjects who will evolve from infection to disease; consequently, a large number of people with LTBI need treatment to avoid a reduced number of future TB disease cases. Newer tests are under development to improve the sensitivity in recognizing LTBI, distinguish recent infections with highest risk of progression to disease, and even be able to detect initial subclinical disease. Antimicrobial preventive treatment effectively reduces the probability of getting sick with TB, but worldwide availability of TB preventive therapy is limited, and adherence to self-administered therapies, as in the case of the use of daily oral isoniazid, is low. Adverse reactions risk (hepatitis, skin rash) although infrequent, is another problem with these therapies. Currently, LTBI management guidelines include regimens with use of rifamycins and their derivatives. The combination of isoniazid and rifapentine in a weekly dose for three months administered under supervision is the first line choice for LTBI therapy in those over 2 years of age, showing less hepatoxicity risk and greater adherence.

Evaluación del efecto antibacteriano sinérgico de rifamicina en propóleo sobre bacterias grampositivas / Evaluation of the synergistic antibacterial effect of rifamycin in propolis on gram-positive bacteria

Introducción: En la medicina militar, la aplicación de las sustancias antibacterianas en las infecciones tópicas, es importante en el tratamiento de las tropas. Objetivos: Evaluar el efecto antibacteriano sinérgico de rifamicina en propóleo sobre bacterias grampositivas. Métodos: Estudio experimental in vitro y comparativo. Se efectuó el análisis fitoquímico preliminar del propóleo de Apis mellífera. Se utilizaron 96 placas de agar Muller Hinton (Britania®) (48 placas para cada especie bacteriana) repartidas en 6 grupos (n = 8). grupo I (agua destilada), grupo II (alcohol etílico al 96 por ciento), grupo III (rifamicina al 0,5 por ciento), grupo IV (rifamicina al 1 por ciento), grupo V (propóleo al 20 por ciento) y grupo VI (rifamicina al 1 por ciento en propóleo al 40 por ciento); se empleó la metodología de Kirby - Bauer; las cepas usadas fueron Staphylococcus aureus ATCC 25923, Streptococcus pyogenes ATCC 19615 y las mediciones de las zonas de inhibición se efectuaron a las 24 horas. Resultados: Se detectaron compuestos fenólicos, taninos, flavonoides, alcaloides y triterpenoides en propóleo. Se comprobó el efecto antibacteriano del grupo V con 18,627 ± 0,1008 mm (92,59 por ciento) y 19,247 ± 0,0762 mm (96,74 por ciento), y el efecto antibacteriano sinérgico del grupo VI con 19,316 ± 0,1202 mm (96,02 por ciento) y 19,613 ± 0,0820 mm (98,58 por ciento), comparados con rifamicina al 1 por ciento (100 por ciento) sobre S. aureus ATCC 25923 y S. pyogenes ATCC 19615. Conclusiones: La combinación de rifamicina al 1 por ciento unida al propóleo al 40 por ciento presenta una mayor actividad antibacteriana in vitro sobre bacterias grampositivas debido a su efecto sinérgico(AU)

Introduction: In military medicine, the application of antibacterial substances in topical infections are important in the treatment of troops. Objectives: To evaluate the synergistic antibacterial effect of rifamycin in propolis on gram-positive bacteria. Methods: In vitro and comparative experimental study. Preliminary phytochemical analysis of Apis mellifera propolis was carried out. 96 Muller Hinton agar plates (Britania®) (48 plates for each bacterial species) divided into 6 groups (n = 8) were used group I (distilled water), group II (96 percent ethyl alcohol), group III (rifamycin 0,5 percent), group IV (rifamycin 1 percent), group V (propolis 20 percent) and group VI (rifamycin 1 percent in 40 percent propolis); Kirby-Bauer methodology was used; the strains used were Staphylococcus aureus ATCC 25923, Streptococcus pyogenes ATCC 19615 and the measurements of the zones of inhibition were carried out at 24 hours. Results: Phenolic compounds, tannins, flavonoids, alkaloids and triterpenoids were detected in propolis. The antibacterial effect of group V was verified with 18,627 ± 0,1008 mm (92,59 percent) and 19,247 ± 0,0762 mm (96,74 percent), and the synergistic antibacterial effect of group VI with 19,316 ± 0,1202 mm (96,02 percent) and 19,613 ± 0,0820 mm (98,58 percent), compared with rifamycin 1 percent (100 percent) on S. aureus ATCC 25923 y S. pyogenes ATCC 19615. Conclusions: The combination of rifamycin 1 percent together with propolis 40 percent has a greater antibacterial activity in vitro on gram-positive bacteria due to its synergistic effect(AU)

Xpert MTB/RIF Ultra enhanced tuberculous pleurisy diagnosis for patients with unexplained exudative pleural effusion who underwent a pleural biopsy via thoracoscopy: A prospective cohort study.

INTRODUCTION: To evaluate the performance of Xpert MTB/RIF Ultra (Xpert-Ultra) in testing pleural tissue and fluid collected by medical thoracoscopy among patients with unexplained exudative pleural effusion. METHODS: Patients with an undiagnosed exudative pleural effusion were prospectively and consecutively recruited. Pleural tissue and fluid were collected by medical thoracoscopy and subjected to culture, Xpert MTB/RIF (Xpert) and Xpert-Ultra assays. Histopathological examination was also performed with the tissue and used as the major reference. RESULTS: Sixty-one patients were enrolled, including: 27 tuberculosis (TB) pleurisy, 15 malignancy and 19 other chronic infection cases. The sensitivity, specificity, positive predictive value, and negative predictive value of Xpert-Ultra for TB diagnosis were 85.19% (23/27), 97.06% (33/34), 95.83% (23/24), and 89.19% (33/37), respectively. Xpert-Ultra testing with the biopsy tissue alone had an equivalent diagnostic capacity to that of pathological examination for the diagnosis of confirmed TB cases. By combining the pathological examination with Xpert-Ultra for biopsy, the percentage of confirmed TB cases greatly increased (i.e. 92.59% (25/27)). The "trace" positive outcome of Xpert-Ultra was highly supportive of TB diagnosis for both biopsy tissue and pleural fluid examinations. CONCLUSION: With the specimens collected by medical thoracoscopy, the Xpert-Ultra assay presented high value in identifying TB among pleurisy patients who had difficulties in etiological diagnosis.

8-Deoxy-Rifamycin Derivatives from Amycolatopsis mediterranei S699 ΔrifT Strain.

Proansamycin X, a hypothetical earliest macrocyclic precursor in the biosynthesis of rifamycin, had never been isolated and identified. According to bioinformatics analysis, it was proposed that RifT (a putative NADH-dependent dehydrogenase) may be a candidate target responsible for the dehydrogenation of proansamycin X. In this study, the mutant strain Amycolatopsis mediterranei S699 ΔrifT was constructed by deleting the rifT gene. From this strain, eleven 8-deoxy-rifamycin derivatives (1-11) and seven known analogues (12-18) were isolated. Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data and high-resolution ESI mass spectra. Compound 1 is a novel amide N-glycoside of seco-rifamycin. Compounds 2 and 3 feature conserved 11,12-seco-rifamycin W skeleton. The diverse post-modifications in the polyketide chain led to the production of 4-11. Compounds 2, 3, 5, 6, 13 and 15 exhibited antibacterial activity against Staphylococcus aureus (MIC (minimal inhibitory concentration) values of 10, 20, 20, 20, 40 and 20 µg/mL, respectively). Compounds 14, 15, 16, 17 and 18 showed potent antiproliferative activity against KG1 cells with IC50 (half maximal inhibitory concentration) values of 14.91, 44.78, 2.16, 18.67 and 8.07 µM, respectively.

Capsular contracture around silicone miniimplants following bacterial contamination: an in vivo comparative experimental study between textured and polyurethane implants.

BACKGROUND: Capsular contracture remains a problem following breast implant surgery. Although impact of biofilm and implant surface on capsule formation has been demonstrated, interaction of microorganisms with different surface types has not been clarified yet. We aimed to compare the ability of biofilm formation of implants with different surfaces, under standard conditions and to demonstrate its impact on capsular contracture. METHODS: Twenty-four rats were divided into four groups. Mini-implants with three different surfaces (fine-textured, rough-textured and polyurethane) were placed on the dorsum of each rat. In Group-1, sterile implants were placed in submuscular pockets. In Group-2, implants were incubated in Staphylococcus epidermidis medium before implantation. In Group-3, before implantation, implants were immersed in Rifamycin solution following bacterial contamination. In Group-4, sterile implants were immersed in Rifamycin solution before implantation, and served as the control group. Rats were sacrificed at three months. Clinical, microbiological, histological and immunohistochemical evaluations were performed. RESULTS: Capsule contracture developed only on infected rough-textured implants. Rough-textured and polyurethane implants showed more biofilm formation than fine-textured implants. Capsule thickness and inflammatory cell density were higher on rough-textured implants compared to fine-textured implants (p = 0.004). Actin sequence was parallel and concentric on fine-textured and rough-textured implants; but was in irregular array on polyurethane implants. CONCLUSION: In presence of bacterial contamination, rough-textured implants have the most propensity of developing capsular contracture comparing to fine-textured and polyurethane implants at three months after implantation. Despite high bacterial load and biofilm formation, polyurethane implants are resistant to capsule contracture due to surface characteristics.

Nicotinic acid transport into human liver involves organic anion transporter 2 (SLC22A7).

Nicotinic acid (NA) and nicotinamide (NAM) are biosynthetic precursors of nicotinamide adenine dinucleotide (NAD+) - a physiologically important coenzyme that maintains the redox state of cells. Mechanisms driving their entry into cells are not well understood. Here we evaluated the hepatic uptake mechanism(s) of NA and NAM using transporter-transfected cell systems and primary human hepatocytes. NA showed robust organic anion transporter (OAT)2-mediated transport with an uptake ratio (i.e., ratio of accumulation in transfect cells to wild-type cells) of 9.7 ± 0.3, and a Michaelis-Menten constant (Km) of 13.5 ± 3.3 µM. However, no transport was apparent via other major hepatic uptake and renal secretory transporters, including OAT1/3/4, organic anion transporting polypeptide (OATP)1B1/1B3/2B1, sodium-taurocholate co-transporting polypeptide, organ cation transporter 1/2/3. OAT2-specific transport of NA was inhibited by ketoprofen and indomethacin (known OAT2 inhibitors) in a concentration-dependent manner. Similarly, NA uptake into primary human hepatocytes showed pH- and concentration-dependence and was subject to inhibition by specific OAT2 inhibitors. Unlike NA, NAM was not transported by the hepatic and renal solute carriers upon assessment in transfected cells, although its uptake into human hepatocytes was significantly inhibited by excess unlabelled NAM and a pan-SLC inhibitor (rifamycin SV 1 mM). In conclusion, these studies demonstrate, for the first time, a specific transport mechanism for NA uptake in the human liver and suggest that OAT2 (SLC22A7) has a critical role in its physiological and pharmacological functions.

Rifamycin SV exhibits strong anti-inflammatory in vitro activity through pregnane X receptor stimulation and NFκB inhibition.

Rifamycin SV (rifamycin), is a member of the ansamycin family of antimicrobial compounds which kills bacteria commonly associated with infectious diarrhea and other enteric infections. Rifamycin has been found to be effective in experimental animal models of gut inflammation and its efficacy in these settings has been attributed partially to immunomodulatory non-bactericidal activities. This study aimed to further evaluate the anti-inflammatory activities of rifamycin by analyzing its effect on two key regulators of inflammation: PXR and NFκB. Rifamycin stimulated PXR transcriptional activity in two PXR reporter cell lines and induced expression of two genes known to be regulated by PXR and are directly involved in cellular detoxification: CYP3A4 and PgP. Moreover, CYP3A4 metabolic activity was induced by rifamycin in HepG2 cells. Rifamycin also antagonized TNFα and LPS-induced NFκB activities and inhibited IL1ß-induced synthesis of inflammatory chemokine, IL8. Although reciprocal regulation of PXR and NFkB by rifamycin was not directly addressed, the data suggest that in the absence of PXR, inhibition of NFκB by rifamycin is not dependent on PXR stimulation. Thus, rifamycin exhibits potent anti-inflammatory activities, characterized by in vitro PXR activation and concomitant CYP3A4 and PgP induction, in parallel with potent NFκB inhibition and concomitant IL8 inhibition.

Discovery of 16-Demethylrifamycins by Removing the Predominant Polyketide Biosynthesis Pathway in Micromonospora sp. Strain TP-A0468.

A number of strategies have been developed to mine novel natural products based on biosynthetic gene clusters and there have been dozens of successful cases facilitated by the development of genomic sequencing. During our study on biosynthesis of the antitumor polyketide kosinostatin (KST), we found that the genome of Micromonospora sp. strain TP-A0468, the producer of KST, contains other potential polyketide gene clusters, with no encoded products detected. Deletion of kst cluster led to abolishment of KST and the enrichment of several new compounds, which were isolated and characterized as 16-demethylrifamycins (referred to here as compounds 3 to 6). Transcriptional analysis demonstrated that the expression of the essential genes related to the biosynthesis of compounds 3 to 6 was comparable to the level in the wild-type and in the kst cluster deletion strain. This indicates that the accumulation of these compounds was due to the redirection of metabolic flux rather than transcriptional activation. Genetic disruption, chemical complementation, and bioinformatic analysis revealed that the production of compounds 3 to 6 was accomplished by cross talk between the two distantly placed polyketide gene clusters pks3 and M-rif This finding not only enriches the analogue pool and the biosynthetic diversity of rifamycins but also provides an auxiliary strategy for natural product discovery through genome mining in polyketide-producing microorganisms.IMPORTANCE Natural products are essential in the development of novel clinically used drugs. Discovering new natural products and modifying known compounds are still the two main ways to generate new candidates. Here, we have discovered several rifamycins with varied skeleton structures by redirecting the metabolic flux from the predominant polyketide biosynthetic pathway to the rifamycin pathway in the marine actinomycetes species Micromonospora sp. strain TP-A0468. Rifamycins are indispensable chemotherapeutics in the treatment of various diseases such as tuberculosis, leprosy, and AIDS-related mycobacterial infections. This study exemplifies a useful method for the discovery of cryptic natural products in genome-sequenced microbes. Moreover, the 16-demethylrifamycins and their genetically manipulable producer provide a new opportunity in the construction of novel rifamycin derivates to aid in the defense against the ever-growing drug resistance of Mycobacterium tuberculosis.

Long-Term Effect of Rifaximin with and without Lactulose on the Active Bacterial Assemblages in the Proximal Small Bowel and Faeces in Patients with Minimal Hepatic Encephalopathy.

BACKGROUND: Gut microbiota play an essential role in the pathogenesis of hepatic encephalopathy (HE). Treatment strategies are directed to modulate intestinal microbiota profiles and their function by the administration of the non-absorbable disaccharide lactulose and the non-absorbable antibiotic rifaximin, which are required for long terms, but little is known on their long-term effect on gut microbiota composition and function. AIM: To characterize the active bacterial assemblages in duodenum and faeces in patients with minimal HE (MHE) before, during and after long-term therapy with rifaximin. METHODS: We analysed the microbiota composition in 5 patients with liver cirrhosis and MHE treated either with rifaximin 550 mg bid alone continuously for a period of 3 months or combined with lactulose 30-60 mL daily for 3 months. In addition to clinical assessments of HE, biopsies from duodenum and stool samples were analysed for their specific bacterial community applying NGS after RNA isolation before treatment, after 3 months of treatment and 3 months after the end of treatment. RESULTS: All 5 patients had a significant improvement of their MHE. Bacterial communities were different and distinct in duodenal samples and faeces. No statistically significant changes were found in the bacterial community profile at the different time points. CONCLUSION: Rifaximin therapy with and without lactulose over a period of 3 months does not affect the bacterial community composition. The improvement of HE with rifaximin is lasting also after the end of treatment and therefore a prolonged effect on microbiota metabolic function is suggested.

Locally Used Antibiotics for Spinal Infection Prophylaxis and Their Effects on Epidural Fibrosis: an Experimental Laminectomy Study in Rats Using Rifamycin and Gentamycin.

The study aims to assess the effects of antibiotics (ABs), which are typically used in spinal infection prophylaxis, on the formation of epidural fibrosis (EF). Specifically, we investigated the effect of rifamycin and gentamycin on EF formation in laminectomized rats. Thirty-two rats were randomly and equally divided into four groups as follows: laminectomy and physiological saline (0.9% NaCl) solution (control); laminectomy and rifamycin; laminectomy and gentamicin; and laminectomy and a mixture of rifamycin and gentamicin. Laminectomy was performed on L1 and L2 vertebrae in all rats. One month after spinal surgery, spinal tissue samples surrounding the laminectomy were cut with a microtome and stained with hematoxylin-eosin and Masson's trichrome. The histopathological analysis included examining the extent of EF, fibroblast cell density, and cartilage and bone regeneration. Statistical analysis was performed using the IBM SPSS Statistics 22 program (SPSS IBM, Turkey). A value of p < 0.05 was considered statistically significant. EF value differences between the AB treatment groups and the control group were statistically significant (p = 0.030). Specifically, binary comparisons indicated that the EF value was significantly higher in the rifamycin group than that in the control group (p = 0.003; p < 0.05). Our study suggests that locally applied ABs, especially rifamycin, should be diluted before administration to the epidural space.

Tuberculosis-HIV treatment with rifampicin or rifabutin: are the outcomes different?

BACKGROUND Rifamycins are a group of antibiotics mainly used in the treatment of tuberculosis (TB), however they interact with antiretroviral therapy (ART). Rifabutin allows more regimens options for concomitant imunodeficiency virus (HIV) treatment compared to rifampicin. OBJECTIVE Compare the outcomes of TB-HIV co-infected patients who used rifampicin or rifabutin. METHODS We analysed data from a prospective cohort study at National Institute of Infectious Diseases Evandro Chagas, Rio de Janeiro (RJ), Brazil. Patients who were treated for TB and HIV with rifampicin or rifabutin, from February 2011 to September 2016 were included. FINDINGS There were 130 TB-HIV patients, of whom 102 were treated with rifampicin and 28 with rifabutin. All patients in the rifabutin-treated group and 55% of the rifampicin-treated group patients were ART-experienced. Patients treated with rifampicin had similar abandon and cure rates, interruptions in treatment due to adverse reactions, immune reconstitution inflammatory syndrome and a similar mortality rate as those treated with rifabutin. However, rifampicin-treated patients had higher CD4 counts and more frequently undetectable HIV viral load by the end of treatment (67% versus 18%, p < 0.001) compared to rifabutin-treated patients, even when only ART-experienced patients were evaluated (66,6% versus 36,3%, p = 0.039). CONCLUSIONS Patients who used rifabutin had worst immune and virological control. This group had more ART-experienced patients. New and simpler regimens are needed for patients who do not respond to previous antiretroviral therapies.

The intriguing role of Rifaximin in gut barrier chronic inflammation and in the treatment of Crohn's disease.

INTRODUCTION: The gastrointestinal tract acts as a functional unit organized as a semipermeable multilayer system, in which commensal gut microbiota represents the anatomical barrier. Recently, several studies have highlighted the involvement of gut microbiota in inflammatory bowel diseases (IBD) pathogenesis, in sustaining gut barrier chronic inflammation, and in conditioning disease course and therapeutical response. This evidence provides a rationale for treating patients with gut microbiota modifiers. Among these, Rifaximin represents a non-traditional antibiotic able to act as a 'eubiotic' on intestinal barrier. AREAS COVERED: The purpose of this narrative review is to explore the impact of Rifaximin on gut barrier and gut microbiota in IBD, in particular in Crohn's disease (CD), and to analyze its potential therapeutic applications. EXPERT OPINION: The possibility of a beneficial activity of Rifaximin in chronic intestinal inflammation and CD has been debated and evaluated with different studies having obtained promising but still preliminary data. Larger trials are therefore needed. This gut-specific antibiotic could represent an alternative to systemic antibiotics thanks to its favorable safety profile and promising efficacy data. Rifaximin could exert, when appropriate, a synergic effect with immunomodulators in IBD, acting on both the microbial and the immunological sides of gut barrier impairment.

The use of rifaximin in pre-operative period of patients with tumors of the gastrointestinal tract - a retrospective study (2013-2016).

ntroduction: One of the most important goals of preparing a patient for elective gastrointestinal cancer surgery is prevention of postoperative complications. The literature gives many ways to prepare for surgery, but only a few suggests that pre-operative use of rifaximin provides benefits in the form of fewer perioperative complications and reduces the severity of pain during this period. O bjective: The presented project is a retrospective analysis of the effectiveness of rifaximin in the prevention of perioperative complications in patients treated in the Unit of General Surgery with the Orthopedic and Urology in the Hospital of the Ministry of the Interior and Administration in Lublin, and a review of international literature in this subject. MATERIALS AND METHODS: A retrospective analysis of the results of pre-operative use of rifaximin was performed in 181 patients scheduled for rectal and colorectal cancer between 2013 and 2016 in the General Surgery Unit with the Orthopedic and Urology in the Hospital of the Ministry of Interior and Administration in Lublin. Patients undergoing urgent surgery were excluded from the study. Patients were divided into 2 groups. The first group of 139 patients - patients operated on for rectal and colorectal cancer in 2013 until 2015, in whom rifaximine was not used in the preoperative period. The second group is 42 patients, operated on in 2016, in which the rifaximin was used in the pre-operative period at a dose of 2x2 tablets (400 mg) per day, 12-hour interval, for 7 days before the planned operation. Additionally, a probiotic was administered for 7 days. Drugs were ordained at the Oncological Outpatient Clinic as part of the pre-hospitalization check. R esults: The use of rifaximin in the preoperative period in patients with colorectal cancer had an effect on shortening the time of post-operative hospitalization and reduced post-surgical pain in comparison with the control group. The analysis of the cynumber and intensity of surgical complications in both groups did not differ. C onclusions: Large studies on the influence of rifaximin on the development of colorectal cancer have not been published so far. Only single reports suggest that its use has a positive effect on the perioperative period of patients treated for colorectal cancer including rectum and our retrospective analysis confirms these observations.

Ribosome engineering and fermentation optimization leads to overproduction of tiancimycin A, a new enediyne natural product from Streptomyces sp. CB03234.

Tiancimycin (TNM) A, a recently discovered enediyne natural product from Streptomyces sp. CB03234, showed rapid and complete killing of cancer cells and could be used as a payload in antibody drug conjugates. The low yield of TNM A in the wild-type strain promoted us to use ribosome engineering and fermentation optimization for its yield improvement. The Streptomyces sp. CB03234-R-16 mutant strain with a L422P mutation in RpoB, the RNA polymerase ß-subunit, was obtained from the rifamycin-resistant screening. After fermentation optimization, the titers of TNM A in Streptomyces sp. CB03234-R-16 reached to 22.5 ± 3.1 mg L-1 in shaking flasks, and 13 ± 1 mg L-1 in 15 L fermentors, which were at least 40-fold higher than that in the wild-type strain (~ 0.3 mg L-1). Quantitative real-time RT-PCR revealed markedly enhanced expression of key genes encoding TNM A biosynthetic enzymes and regulators in Streptomyces sp. CB03234-R-16. Our study should greatly facilitate the future efforts to develop TNM A into a clinical anticancer drug.