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.

Targeted delivery of rifaximin using P6.2-decorated bifunctional PLGA nanoparticles for combating Staphylococcus aureus infections.

The emergence of antibiotic resistance makes the treatment of bacterial infections difficult and necessitates the development of alternative strategies. Targeted drug delivery systems are attracting great interest in overcoming the limitations of traditional antibiotics. Here, we aimed for targeted delivery of rifaximin (RFX) by decorating RFX-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) with synthetic P6.2 peptide, which was used as a targeting agent for the first time. Our results showed that encapsulation of RFX into NPs increased its antibacterial activity by improving its solubility and providing controlled release, while P6.2 modification allowed targeting of NPs to S. aureus bacterial cells. A promising therapeutic approach for bacterial infections, these P6.2-conjugated RFX-loaded PLGA NPs (TR-NP) demonstrated potent antibacterial activity against both strains of S. aureus. The antibacterial activity of RFX-loaded PLGA NPs (R-NP) showed significant results with an increase of 8 and 16-fold compared to free RFX against S. aureus and MRSA, respectively. Moreover, the activity of targeted nanoparticles was found to be increased 32 or 16-fold with an MBC value of 0.0078 µg/mL. All nanoparticles were found to be biocompatible at doses where they showed antimicrobial activity. Finally, it revealed that P6.2-conjugated targeted nanoparticles extremely accumulated in S. aureus rather than E. coli.

Clinical considerations and pharmacokinetic interactions between HIV and tuberculosis therapeutics.

INTRODUCTION: Tuberculosis (TB) is a leading infectious disease cause of mortality worldwide, especially for people living with human immunodeficiency virus (PLWH). Treating TB in PLWH can be challenging due to numerous drug interactions. AREAS COVERED: This review discusses drug interactions between antitubercular and antiretroviral drugs. Due to its clinical importance, initiation of antiretroviral therapy in patients requiring TB treatment is discussed. Special focus is placed on the rifamycin class, as it accounts for the majority of interactions. Clinically relevant guidance is provided on how to manage these interactions. An additional section on utilizing therapeutic drug monitoring (TDM) to optimize drug exposure and minimize toxicities is included. EXPERT OPINION: Antitubercular and antiretroviral coadministration can be successfully managed. TDM can be used to optimize drug exposure and minimize toxicity risk. As new TB and HIV drugs are discovered, additional research will be needed to assess for clinically relevant drug interactions.

Rifamycin use for treatment of Helicobacter pylori infection: a review of recent data.

Helicobacter pylori eradication has become increasingly challenging. We focused on recent data about rifamycin resistance and rifamycin-containing regimens. Rifampin (rifampicin) resistance rates were <1-18.8% (often ≤7%), while those to rifabutin were 0-<4%. To detect rifabutin resistance by rifampin, 4 mg/l breakpoint was suggested. Eradication success by rifaximin-based regimens was disappointing (<62%), while that of rifabutin-containing regimens was 54.5->96%, reaching >81% in four studies. Some newer rifamycin analogs like TNP-2092 need further investigation. Briefly, although rifabutin-based regimens carry a risk of adverse effects or increasing mycobacterial resistance, they may be a rational choice for some multidrug-resistant H. pylori strains and as a third-line eradication therapy. Bismuth addition to rifabutin-based therapy and combined rifabutin-containing capsules (Talicia) are promising treatment options.

Repositioning rifamycins for Mycobacterium abscessus lung disease.

Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. Areas covered: In this review, the authors discuss the rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.

High-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model of Mycobacterium ulcerans Disease.

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last 4 weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over 4 weeks of treatment in a mouse model of M. ulcerans disease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT-containing regimens were more effective on M. ulcerans All RPT-containing regimens achieved culture negativity after only 4 weeks, while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose-dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses than are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer.

Rifamycin SV-MMX® for treatment of travellers' diarrhea: equally effective as ciprofloxacin and not associated with the acquisition of multi-drug resistant bacteria.

Background: The novel oral antibiotic formulation Rifamycin SV-MMX®, with a targeted delivery to the distal small bowel and colon, was superior to placebo in treating travellers' diarrhea (TD) in a previous study. Thus, a study was designed to compare this poorly absorbed antibiotic with the systemic agent ciprofloxacin. Methods: In a randomized double-blind phase 3 study (ERASE), the efficacy and safety of Rifamycin SV-MMX® 400 mg twice daily (RIF-MMX) was compared with ciprofloxacin 500 mg twice daily in the oral treatment of TD. Overall, 835 international visitors to India, Guatemala or Ecuador with acute TD were randomized to receive a 3-day treatment with RIF-MMX (n = 420) or ciprofloxacin (n = 415). Primary endpoint was time to last unformed stool (TLUS), after which clinical cure was declared. Stools samples for microbiological evaluation were collected at the baseline visit and the end of treatment visit. Results: Median TLUS in the RIF-MMX group was 42.8 h versus 36.8 h in the ciprofloxacin group indicating non-inferiority of RIF-MMX to ciprofloxacin (P = 0.0035). Secondary efficacy endpoint results including clinical cure rate, treatment failure rate, requirement of rescue therapy as well as microbiological eradication rate confirmed those of the primary analysis indicating equal efficacy for both compounds. While patients receiving ciprofloxacin showed a significant increase of Extended Spectrum Beta Lactamase Producing-Escherichia coli (ESBL-E. Coli) colonization rates after 3-days treatment (6.9%), rates did not increase in patients receiving RIF-MMX (-0.3%). Both drugs were well-tolerated and safe. Conclusion: The novel multi-matrix formulation of the broad-spectrum, poorly absorbed antibiotic Rifamycin SV was found non-inferior to the systemic antibiotic ciprofloxacin in the oral treatment of non-dysenteric TD with the advantage of a lower risk of ESBL-E. Coli acquisition.

Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03474198, NCT01659437.

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.

Metabolic acidosis in short bowel syndrome: think D-lactic acid acidosis.

Short bowel syndrome (SBS) is a condition when a person's gastrointestinal function is insufficient to supply the body with essential nutrients and hydration. Patients with SBS suffer from diarrhoea and symptoms of malabsorption such as weight loss, electrolyte disturbances and vitamin deficiencies. Long-term management of this condition can be complicated by the underlying disease, the abnormal bowel function and issues related to treatment like administration of parenteral nutrition and the use of a central venous catheter. Here, we describe a case of D-lactic acid acidosis, a rarer complication of SBS, presenting with generalised weakness and severe metabolic acidosis.

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.

Is Lactulose Plus Rifaximin Better than Lactulose Alone in the Management of Hepatic Encephalopathy?

OBJECTIVE: To compare the efficacy of lactulose plus rifaximin with efficacy of lactulose alone in the treatment of hepatic encephalopathy. STUDY DESIGN: A randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Medicine, Jinnah Hospital, Lahore, from December 2014 to June 2015. METHODOLOGY: All patients who presented with hepatic encephalopathy due to decompensated chronic liver disease were randomly divided into two groups of 65 patients each. One group was given 30 ml thrice daily lactulose alone and the other lactulose plus rifaximin 550 mg twice daily for 10 days. Informed consents were taken from the participants' attendants. Grades II-IV hepatic encephalopathy was noted according to West-Haven Classification. All subjects were followed until 10 days after admission. RESULTS: The mean age of patients was 56.06 +11.2 years, among which 46.9% were females and 53.1% were males. After ten days of follow-up, reversal was seen in 58.46% in lactulose alone group and 67.69% in lactulose plus rifaximin group (Chi-square p=0.276). CONCLUSION: There was no difference in effectiveness of lactulose plus rifaximin and lactulose alone in treatment of hepatic encephalopathy.

Rediscover the clinical value of small intestinal bacterial overgrowth in patients with intestinal Behçet's disease.

BACKGROUND AND AIMS: Many patients with intestinal Behçet's disease (BD) still suffer from gastrointestinal symptoms despite the disease being in endoscopic or radiological remission. Previous studies report that small intestinal bacterial overgrowth (SIBO) can be associated with inflammatory bowel disease. However, there have been no reports about SIBO in patients with intestinal BD. We sought to identify the frequency of SIBO in patients with inactive intestinal BD by hydrogen breath test (HBT) and to investigate the efficacy of rifaximin as a treatment for SIBO. METHODS: Twenty-five patients with intestinal BD who had gastrointestinal symptoms even in endoscopic or radiological remission status were enrolled between January 2012 and January 2016. The patients filled out a questionnaire regarding their subjective gastrointestinal symptoms and took an HBT. Patients with positive HBT results were recommended to take 800-mg rifaximin daily for 14 days. RESULTS: Nine patients (9/25, 36%) had a positive HBT test. Eight (8/9, 88.9%) were women, and their mean age was 48.7 years. The most common symptom was abdominal distension (8/9, 88.9%), followed by abdominal discomfort (6/9, 66.7%). Rifaximin was prescribed to the nine patients with positive HBT, but two patients refused to take the medication. Four weeks later, six of the seven patients taking rifaximin (85.7%) reported symptom improvement, and none of them reported adverse events. CONCLUSIONS: More than one-third of the patients with inactive intestinal BD who had gastrointestinal symptoms were accompanied by SIBO using HBT. Rifaximin might be an effective and safe drug to treat these patients.

Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial.

BACKGROUND AND AIM: Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. METHODS: Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end-stage liver disease score 12 (± 3.9). Patients received rifaximin 550-mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing. RESULTS: Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-α, transforming growth factor ß-1, and high sensitivity C-reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin. CONCLUSION: Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).

Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis.

BACKGROUND: The primary and secondary prevention of spontaneous bacterial peritonitis (SBP) is recommended in high-risk patients with cirrhosis. Several studies evaluating the efficacy of rifaximin for SBP prophylaxis have yielded conflicting results. Rifaximin has the potential advantage of preventing bacterial overgrowth and translocation without the systemic side effects of broad-spectrum antibiotics. AIM: To evaluate the efficacy of rifaximin in the primary and secondary prevention of SBP. METHODS: A literature search using five databases was performed to identify studies on the association between rifaximin and SBP. We performed two meta-analyses: (1) rifaximin compared to systemic antibiotics and (2) rifaximin compared to no antibiotics. Random-effect modelling was conducted to determine overall pooled estimates and 95% confidence intervals (CIs). RESULTS: Five studies with 555 patients (295 rifaximin, 260 systemic antibiotics) compared rifaximin with systemic antibiotics. The pooled odds ratio (OR) for SBP was 0.45 (95% CI 0.16-1.27; P = .13) in patients receiving rifaximin and strengthened on sensitivity analysis (OR 0.38, 95% CI 0.19-0.76, P = .01). In the analysis comparing rifaximin with no antibiotics, there were five studies with 784 patients (186 rifaximin, 598 no antibiotics). The OR for SBP was 0.34 (95% CI 0.11-0.99; P < .05) in patients receiving rifaximin. In subgroup analysis, rifaximin reduced the risk of SBP by 47% compared to no antibiotics for primary prophylaxis and by 74% compared to systemic antibiotics for secondary prophylaxis. CONCLUSION: Rifaximin may be effective in preventing SBP in patients with cirrhosis and ascites compared to systemically absorbed antibiotics and compared to placebo.

Emergence of rifampin-resistant staphylococci after rifaximin administration in cirrhotic patients.

OBJECTIVES: Rifaximin, a poorly absorbed antibiotics, has gut-specific therapeutic effects. Although frequently prescribed to manipulate intestinal luminal bacterial population in various diseases, the possible induction of antibacterial cross-resistance to a target pathogen is a major concern in long-term rifaximin administration. We aimed to evaluate whether rifampin-resistant staphylococci could evolve after rifaximin treatment in cirrhotic patients. METHOD: A total of 25 cirrhotic patients who were administered rifaximin for the prevention of hepatic encephalopathy were enrolled. Swabs from both hands and the perianal skin were acquired on day 0 (before rifaximin treatment), period 1 (1-7 weeks after treatment), and period 2 (8-16 weeks after treatment) the staphylococcal strain identification and rifampin-resistance testing. RESULTS: A total of 198 staphylococcal isolates from 15 species were identified. Staphylococcus epidermidis was isolated most frequently, and Staphylococcus haemolyticus was the most common resistant species both from hands and perianal skin. Eleven patients (44.0%) developed rifampin-resistant staphylococcal isolates in period 1. Among these patients, only six (54.5%) were found to have rifampin-resistant isolates in period 2, with no significant infectious events. Rifampin-resistant staphylococcal isolates were more frequently found in perianal skin than from the hands. No patients acquired a newly resistant strain in period 2. CONCLUSIONS: About one-half of cirrhotic patients in this study developed rifampin-resistant staphylococcal isolates after rifaximin treatment. Although the resistant strains were no longer detected in about half of the patients in the short-term, the long-term influence of this drug treatment should be determined.