Nonabsorbable Antibiotics Research Articles

Microbiome: An Emerging New Frontier in Graft-Versus-Host Disease.

Hematopoietic cell transplantation is an intensive therapy used to treat high-risk hematological malignant disorders and other life-threatening hematological and genetic diseases. Graft-versus-host disease (GVHD) presents a barrier to its wider application. A conditioning regimen and medications given to patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) are capable of disturbing the homeostatic crosstalk between the microbiome and the host immune system and of leading to dysbiosis. Intestinal inflammation in the context of GVHD is associated with loss in microbial diversity that could serve as an independent predictor of mortality. Successful gastrointestinal decontamination using high doses of non-absorbable antibiotics likely affect allo-HCT outcomes leading to significantly less acute GVHD (aGVHD). Butyrate-producing Clostridia directly result in the increased presence of regulatory T cells in the gut, which are protective in GVHD development. Beyond the microbiome, Candida, a member of the mycobiome, colonization in the gut has been considered as a risk factor in pathophysiology of aGVHD and reduction in GVHD is observed with antifungal prophylaxis with fluconazole. Reduced number of goblet cells and Paneth cells havebeen shown to associate with GVHD and has a significant impact on the micro- and mycobiome density and their composition. Lower levels of 3-indoxyl sulfate at initial stages after allo-HCT are related with worse GVHD outcomes and increased mortality. Increased understanding of the vital role of the gut microbiome in GVHD can give directions to move the field towards the development of improved innovative approaches for preventing or treating GVHD followingallo-HCT.

A systematic review of the use of rifaximin for Clostridium difficile infections

Clostridium difficile infection (CDI) is an increasingly common occurrence in the hospital setting, and it is associated with significant morbidity and mortality. In vitro studies have found that rifaximin, a nonabsorbable rifamycin antibiotic, displays potent antimicrobial activity against C. difficile. This systematic review thus aimed to examine the clinical role of rifaximin in CDI. Using the keywords [clostridium OR difficile OR colitis] AND [rifaximin OR xifaxan OR rifagut], a preliminary search on the PubMed, EMBASE, Medline, Clinicaltrials.gov and Google Scholar databases yielded 6210 papers published in English between 1-Jan-1988 and 1-Jul-2018. A total of eight clinical trials were systematically reviewed. Of these, only two were randomized, controlled trials. In the treatment of mild-moderate CDI, rifaximin is a viable alternative to existing therapies (metronidazole or vancomycin). More importantly, rifaximin has a potential role in conjunction with other therapies, showing to be efficacious in reducing the rate of CDI recurrence. However, clinical studies have reported a resistance rate in the range of 29.1–48.9%, with a geographical variance in the distribution of rifaximin-resistant C. difficile strains. With its unique eubiotic properties and positive modulation of the gut flora, rifaximin has a potential therapeutic role in the management of CDI, especially in CDI recurrences. As there is a paucity of randomized, controlled trials to support its use, studies with larger and more diverse populations should be conducted before the efficacy of rifaximin can be conclusively stated. Rifaximin is also a relatively expensive antimicrobial, further studies should include cost-benefit analyses.

L-Carnitine for the Treatment of Overt Hepatic Encephalopathy in Patients with Advanced Liver Cirrhosis.

Hepatic encephalopathy is a major complication in patients with advanced cirrhosis and is associated with poor prognosis. To evaluate the effectiveness of L-carnitine supplementation in patients with overt hepatic encephalopathy (OHE), outcomes were retrospectively analyzed in patients with OHE who were treated with intravenous branched-chain amino acids (BCAA), with or without intravenous L-carnitine. Twenty-six patients were treated with intravenous BCAA in addition to conventional agents such as lactulose and non-absorbable antibiotics (Group A), and 19 patients were treated with these agents plus intravenous L-carnitine (Group L). Changes in blood ammonia concentrations, hepatic coma grade and the Glasgow Coma Scale (GCS) were compared in the two groups. Recurrence-free survival (RFS) was evaluated in the two groups and in patients who were and were not administered oral L-carnitine supplementation. At baseline, GCS scores were significantly lower and deterioration in liver function greater in Group L. After 3 d of intravenous L-carnitine, however, GCS showed a significantly greater improvement in Group L than in Group A. Blood ammonia levels improved stably over time in Group L. Overall survival and RFS were similar in Group L and Group A, but median RFS was significantly longer in patients who did than did not receive oral L-carnitine supplementation (735 versus 497 d, p=0.03). Although these findings are preliminary, L-carnitine supplementation may be a therapeutic option for patients with OHE and disturbed consciousness.

From the Editor’s Desk…: October 2018

From the Editor’s Desk…: October 2018

Novel perspectives in the management of decompensated cirrhosis.

The current approaches to the management of patients with decompensated cirrhosis are based on targeted strategies aimed at preventing or treating specific complications of the disease. The improved knowledge of the pathophysiological background of advanced cirrhosis, represented by a sustained systemic inflammation strictly linked to a circulatory dysfunction, provides a novel paradigm for the management of these patients, with the ambitious target of modifying the course of the disease by preventing the onset of complications and multiorgan failure; these interventions will eventually improve patients' quality of life, prolong survival and reduce health-care costs. Besides aetiological treatments, these goals could be achieved by persistently antagonizing key pathophysiological events, such as portal hypertension, abnormal bacterial translocation from the gut, liver damage, systemic inflammation, circulatory dysfunction and altered immunological responses. Interestingly, in addition to strategies based on new therapeutic agents, these targets can be tackled by employing drugs that are already used in patients with cirrhosis for different indications or in other clinical settings, including non-absorbable oral antibiotics, non-selective β-blockers, human albumin and statins. The scope of the present Review includes reporting updated information on the treatments that promise to influence the course of advanced cirrhosis and thus act as disease-modifying agents.

Does administration of broad-spectrum antibiotics in febrile neutropenic children trigger the emergence of BMR? A French experience

Background Blood stream infections (BSI) remain a major cause of morbidity and mortality in immunocompromised children and increase the length of hospitalisation as well as the cost of treatment. The difficulty of documenting bacteremia at the onset of fever in neutropenic patients led to an early administration of broad-spectrum antibiotics, without waiting for further clinical or microbiological evidence of infection. Furthermore, gut decontamination is performed in children with a high-risk of BSI. Does this practice trigger the emergence of multidrug resistant bacteria? Methods We performed a monocentric, retrospective and descriptive study between January 2014 and December 2017, using a large cohort of pediatric patients with hematological and oncological diseases in a tertiary care pediatric center in France, the Institute of Hematology and Oncology Pediatric (IHOPe) in Lyon. This includes patients with acute leukemia, lymphoma, children who underwent hematopoietic stem cell transplantation (HSCT) (allogenic and autogenic), children with severe combined immunodeficiency syndromes as well as children suffering from solid tumors. A bacteremia was defined by a positive blood culture sample, associated with fever. For coagulase-negative staphylococci (CoNS), two distinct positive blood cultures within 48 h were mandatory. The children were divided into 4 infectious risk groups regarding their immunosuppression level. Groups 3 and 4 received non-absorbable antibiotics for gut and oral decontamination. The empirical antibacterial therapy was adjusted to the risk group, as well as a prior identified bacteria colonisation: all patients with a central venous access received vancomycin (stopped after 48 hours in the absence of bacterial identification), amikacin and a broad-spectrum penicillin. Results During these 4 years, our institution recorded more than 8000 hospitalisations distributed within 3 units: 2 conventional hospitalisation wards and the HSCT unit. Our protected unit is equipped with spacious positive air pressure rooms, for child and parent, with high-efficiency particulate air (HEPA) filters where only a clean non-sterile outfit (gown and mask) are required. We identified 350 cases of BSI, thus an overall incidence of 4,5%. Fifteen to twenty per cent of these children suffered from a second or more re-infection. The incidence of BSI was stable throughout the four years of our study. Gram-positive bacteria represented more than 50% of BSI and CoNS was the most frequent pathogen agent found. Among the others gram-positive isolates, we counted around 5 to 6 cases/year of Streptococcus and Staphylococcus aureus. Among Gram-negative bacteria, enterobacteries accounted for 14 to 20 BSI per year and Pseudomonas aeruginosa for 2 to 4 cases per year. Among the identified bacteria, only 6.5% were multidrug resistant for all our study time. Three highly resistant bacteria were identified in 2 children priorly treated in Romania and Tunisia: 2 Klebsiella pneumoniae producing Carbapenemase (KPC), 1 Enterococcus faecium resistant to glycopeptides. Interestingly, 35% of the BSI occurred in the less immunocompromised group. The other cases were evenly distributed between the 3 more severely immunocompromised groups. Conclusion Our empirical initial broad-spectrum antimicrobial coverage is well adapted to the epidemiology of our bacterial agents and shortens hospitalisations. Furthermore, it is not associated with the emergence of antibiotic resistance patterns. The microbiological spectrum of incriminated bacteria is relatively stable over time and we do not observe the emergence of multidrug resistant gram-negative bacteria as well as the absence of vancomycin-resistant enterococci (VRE) in our tertiary center.

L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis.

L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis.

50 Years Ago in The Journal of Pediatrics: Comparison of Orally Absorbable and Nonabsorbable Antibiotics in Shigellosis: A Double-Blind Study with Ampicillin and Neomycin

50 Years Ago in The Journal of Pediatrics: Comparison of Orally Absorbable and Nonabsorbable Antibiotics in Shigellosis: A Double-Blind Study with Ampicillin and Neomycin

Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice

Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid-FXR-FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. (Hepatology 2018;67:2150-2166).

A Review of Microbiota and Irritable Bowel Syndrome: Future in Therapies

Irritable bowel syndrome (IBS), one of the most frequent digestive disorders, is characterized by chronic and recurrent abdominal pain and altered bowel habit. The origin seems to be multifactorial and is still not well defined for the different subtypes. Genetic, epigenetic and sex-related modifications of the functioning of the nervous and immune-endocrine supersystems and regulation of brain-gut physiology and bile acid production and absorption are certainly involved. Acquired predisposition may act in conjunction with infectious, toxic, dietary and life event-related factors to enhance epithelial permeability and elicit mucosal microinflammation, immune activation and dysbiosis. Notably, strong evidence supports the role of bacterial, viral and parasitic infections in triggering IBS, and targeting microbiota seems promising in view of the positive response to microbiota-related therapies in some patients. However, the lack of highly predictive diagnostic biomarkers and the complexity and heterogeneity of IBS patients make management difficult and unsatisfactory in many cases, reducing patient health-related quality of life and increasing the sanitary burden. This article reviews specific alterations and interventions targeting the gut microbiota in IBS, including prebiotics, probiotics, synbiotics, non-absorbable antibiotics, diets, fecal transplantation and other potential future approaches useful for the diagnosis, prevention and treatment of IBS.

Diagnosis and management of hepatic encephalopathy.

Overt and covert hepatic encephalopathy (HE) are debilitating complications of cirrhosis. HE results in a poor quality of life for patients and their caregivers and, unless there is access to liver transplantation, the prognosis is poor. The development of overt HE is often unpredictable, and its management, particularly in the ward, remains challenging. There is an urgent need for novel approaches to treat HE. Until recently, therapies for this complication were disappointing, with frequently intolerable side effects such as diarrhoea and faecal incontinence. However, a non-absorbable antibiotic, rifaximin, * has been approved for the prevention of recurrent overt HE. It aims to reduce hospitalisation and resource use, as well as improve patients' quality of life. This article describes the practical aspects of diagnosing, classifying and managing HE. It reviews the pharmacological options for the treatment and prophylaxis of overt HE, and explores the evidence base demonstrating that rifaximin reduces the recurrence of overt HE.

Reduction in hepatic secondary bile acids caused by short-term antibiotic-induced dysbiosis decreases mouse serum glucose and triglyceride levels

Antibiotic-caused changes in intestinal flora (dysbiosis) can have various effects on the host. Secondary bile acids produced by intestinal bacteria are ligands for specific nuclear receptors, which regulate glucose, lipid, and drug metabolism in the liver. The present study aimed to clarify the effect of changes in secondary bile acids caused by antibiotic-induced dysbiosis on the host physiology, especially glucose, lipid, and drug metabolism. After oral administration of non-absorbable antibiotics for 5 days, decreased amounts of secondary bile acid-producing bacteria in faeces and a reduction in secondary bile acid [lithocholic acid (LCA) and deoxycholic acid (DCA)] levels in the liver were observed. Serum glucose and triglyceride levels were also decreased, and these decreases were reversed by LCA and DCA supplementation. Quantitative proteomics demonstrated that the expression levels of proteins involved in glycogen metabolism, cholesterol, bile acid biosynthesis, and drug metabolism (Cyp2b10, Cyp3a25, and Cyp51a1) were altered in the liver in dysbiosis, and these changes were reversed by LCA and DCA supplementation. These results suggested that secondary bile acid-producing bacteria contribute to the homeostasis of glucose and triglyceride levels and drug metabolism in the host, and have potential as therapeutic targets for treating metabolic disease.

Periconceptional folate deficiency leads to autism-like traits in Wistar rat offspring

BackgroundFolates in their role as key one carbon donors, are essential for two major pathways: the synthesis of DNA and RNA precursors and DNA methylation. A growing body of evidence from epidemiological studies indicates a possible association between nutritional and functional deficiency in folates and Autism Spectrum Disorders (ASD). However, there are no available behavioral animal studies on periconceptional one‑carbon donor deficiency during gestation and the autistic phenotype. ObjectiveThe objective of this study was to determine if the periconceptional alteration of one‑carbon metabolism induced with a folate deficient diet would affect the behaviour of rat offspring. MethodsFemale Wistar rats were divided in two groups: control (basal diet, in compliance with standards of regular laboratory diets), or exposed during one month before breeding until Gestational Day 15 to a modified diet with no added folic acid (0.2mg/kg of food), reduced choline (750mg/kg of food), and added 1% SST (a non-absorbable antibiotic used to inhibit folate synthesis by gut bacteria). We administered behavioral tests to offspring, i.e., open field (P20), social interactions (P25), marble burying (P30), elevated plus maze (P35), and prepulse inhibition of the acoustic startle reflex (sensorimotor gating) (P45). Blood homocysteine levels were used to confirm the deficit in one‑carbon donors. ResultsCompared to controls, offspring with the periconceptional deficit in folate showed: (i) congenital body malformations; (ii) reduced social interactions, with a ~30% decrease in social sniffing behavior; (iii) reduced exploration of the open arm by 50% in the elevated plus maze test, indicating increased anxiety; (iv) a ~160% increased number of marbles buried, indicating repetitive behaviors; and (v) altered sensorimotor gating, with a global 50% decrease in startle inhibition. ConclusionMaternal periconceptional deficit in folate provokes alterations in the behavior of offspring relevant to the autistic-like phenotype.

Effect of non-absorbable antibiotic, rifaximin in patients with irritable bowel syndrome: A single-center randomized controlled study

Background: Irritable bowel syndrome (IBS), most common functional bowel disease, does not have a definite treatment. Studies revealed the involvement of bacterial overgrowth for its pathology. The aim of this study is to evaluate the effect of a non-absorbable antibiotic. Aims and Objectives: The primary objective of the study is to assess the efficacy of a 14 days course of oral rifaximin at 400 mg thrice daily in patients with IBS without constipation. The secondary objective of this study is to evaluate the safety of a 14 days course of rifaximin at 400 mg thrice daily as compared with placebo in patients with IBS without constipation. Materials and Methods: In this single-center, randomized, placebo-controlled study, we recruited patients, using Rome III criteria in 2 years. Treatment group received rifaximin 400 mg thrice daily for 2 weeks. All patients underwent symptom assessment and safety assessment before inclusion, at the end of the treatment and 1 week after the regimen. Primary endpoint (proportion of patients who achieved adequate relief of IBS symptoms) and Likert scales of symptoms of both groups were compared. Results: Proportion of subject, who achieved adequate relief of IBS symptoms in the rifaximin arm, is more than placebo (68% vs. 39.1%). At the end of 2 weeks therapy, both groups show significant improvement in bloating score (P < 0.002), pain score (P < 0.001), and overall score (P < 0.002) and it continued for 1 more week. There were no significant adverse effects reported. Conclusion: A 2 weeks course of 400 mg rifaximin thrice daily regimen provided a significant improvement in global IBS symptoms.

Oral Tobramycin Prophylaxis Prior to Colorectal Surgery Is Not Associated with Systemic Uptake.

Preoperative oral prophylaxis with nonabsorbable antibiotics has been reported to reduce the risk of surgical site infections after colorectal surgery. This prospective study was conducted to evaluate the risk of toxic side effects by measuring postoperative serum tobramycin levels in patients who received a 3-day prophylaxis with tobramycin and colistin prior to colorectal surgery. In all patients, serum tobramycin concentrations were below the detection limit (0.3 mg/liter), implying a low risk of toxicity.

Pharmacotherapy for Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a disorder of the brain-gut axis; the pathophysiological mechanisms include altered colonic motility, bile acid metabolism, neurohormonal regulation, immune dysfunction, alterations in the epithelial barrier and secretory properties of the gut. This article reviews the mechanisms, efficacy, and safety of current pharmacotherapy, and medications that are in phase III trials for the treatment of IBS. There remains a significant unmet need for effective treatments—particularly for the pain component of IBS—although the introduction of drugs directed at secretion, motility and a non-absorbable antibiotic provide options for the bowel dysfunction in IBS.

Rifamycin SV MMX for the treatment of traveler’s diarrhea

ABSTRACTIntroduction: Rifamycin SV MMX®, a non-absorbable rifamycin antibiotic formulated using the multi-matrix system, was designed to exhibit its pharmacological action on the distal small intestine and colon. Its clinical efficacy and safety profile in the treatment of traveler’s diarrhea were evaluated in several clinical studies.Areas covered: This review summarizes all available evidence regarding clinical trials of the efficacy and safety profile of rifamycin SV MMX for the treatment of traveler’s diarrhea.Expert opinion: Rifamycin SV MMX demonstrated an excellent pharmacokinetic profile with decreased systemic toxicity similar to rifaximin. In phase II and phase III clinical trials, concerns have been raised regarding the medicine’s efficacy in terms of the time to last unformed stool and cure rate compared to current recommended antibiotics in the treatment of acute diarrhea caused by diarrheagenic Escherichia coli and invasive pathogens. The significance of the increase in MICs after the use of rifamycin SV MMX warrants further examination.

Susceptibility to rifaximin and other antimicrobials of bacteria isolated in patients with acute gastrointestinal infections in Southeast Mexico.

Enteropathogenic bacteria isolated in Mexico City have shown a high rate of resistance to different antibiotics, with the exception of rifaximin (RIF). RIF is a nonabsorbable antibiotic that reaches high fecal concentrations (≈ 8,000μg/g). Susceptibility to antimicrobials can vary in different geographic regions. To study the susceptibility to rifaximin and other antimicrobials of enteropathogenic bacteria isolated in patients with acute diarrhea in the southeastern region of Mexico. A total of 614 strains of bacteria isolated from patients with acute diarrhea from 4 cities in Southeast Mexico were analyzed. An antibiogram with the following antibiotics was created: ampicillin (AMP), trimethoprim/sulfamethoxazole (T-S), neomycin (NEO), furazolidone (FUR), ciprofloxacin (CIP), chloramphenicol (CHL), and fosfomycin (FOS), assessed through the agar diffusion method at the standard concentrations recommended by the Clinical and Laboratory Standards Institute (CLSI) and the American Society for Microbiology (ASM), and RIF, assessed through microdilution at 4 concentrations. The bacteria were Escherichia coli (55%), as the majority, in all its pathogenic variants, Shigella (16.8%), Salmonella (15.3%), Aeromonas (7.8%), and less than 5% Campylobacter, Yersinia, Vibrio, and Plesiomonas. The accumulated overall susceptibility to RIF was 69.1, 90.8, 98.9, and 100% at concentrations of 100, 200, 400, and 800μg/ml, respectively. Overall susceptibility to other antibiotics was FOS 82.8%, CHL 76.8%, CIP 73.9%, FUR 64%, T-S 58.7%, NEO 55.8%, and AMP 23.8%. Susceptibility to RIF at 400 and 800μg was significantly greater than with the other antimicrobials (P<.001). The data of the present study were similar to those of a previous study carried out in Mexico City: susceptibility to RIF in > 98% of the bacterial strains and a high frequency of resistance to several common antimicrobials.

Current Trends in the Use of Bowel Preparation for Colorectal Surgery

This article reviews recent findings in the use of bowel preparation for preventing infectious complications after colorectal surgery. Whereas mechanical bowel preparation (MBP) was formerly used routinely in combination with prophylactic non-absorbable oral antibiotics (OAs) and prophylactic intravenous antibiotics, there was a trend toward omitting OAs in the 1990s and early 2000s. Since the mid-2000s, the use of MBP has declined given evidence of the limited role of MBP alone in preventing infectious complications. However, recent studies have demonstrated favorable outcomes after MBP when used in combination with OAs. Results from recent studies have prompted surgeons to reexamine the appropriate regimen for preoperative bowel preparation. The principal question that should now be addressed by future research is whether OAs alone reduce surgical infectious complications after colorectal surgery.

Management of diverticulosis: what's new?

The incidence of diverticulosis and diverticular disease (DD) of the colon, including acute diverticulitis, is increasing worldwide, and becoming a significant burden on national health systems in terms of direct and indirect costs. Thus, significant efforts are now being focused to identify the correct therapeutic approach to treat symptomatic patients and to prevent diverticulitis. Fiber, non-absorbable antibiotics, 5-aminosalicylic acid and probioticsare currently being investigated in this way. Unfortunately, current evidences on the effectiveness of some medical treatment in preventing acute diverticulitis recurrence are still lacking. The effectiveness and the future perspectives of these treatments are discussed herein.