Rifamycin Derivatives Research Articles

Experimental and Clinical Studies on Rifacinna® - The New Effective Antituberculous Drug (Review)

A new rifamycin derivative 3-(4-cinnamyl-piperazinyl iminomethyl) rifamycin SV (T9) and its sodium salt (T11, Rifacinna((R))) were in vitro, in vivo, toxicologically and clinically investigated in comparison with rifampicin, rifapentine, rifabutin, rifalazil. Our experiments showed that Rifacinna exhibits excellent in vitro activity against Gram(+), Gram (-) aerobic, anaerobic pathogens and mycobacteria. Rifacinna is active against Staphylococcus, Streptococcus spp. including MRSA, with MIC90- 0.06-0.5 mg/L; against Gram(+), Gram (-) anaerobes with MIC90 0.5 - 1 mg/L; against Mycobacterium tuberculosis (MTB) with MIC90 0.062 mg/L; against MDR resistant MTB (25%-30 %) and Mycobacterium avium complex (MAC) strains with MICs 0.6-1.0 mg/L. It shows high intraphagocytic activity against MAC strains (0.06 0.125mg/L). Single daily dose 10 mg/kg provides complete erradication of mycobacteria in experimental generalized tuberculosis. Pharmacological studies established: excellent pharmacokinetic profile following single oral dose 10mg/kg Tmax 5-6 h, C(max) 5-9 mg/L, T1/2 33-34 h; low toxicity; no teratogenic and embryotoxic effects. The clinical study of Rifacinna shows higher therapeutic efficacy than Rifampicin in patients with infiltrative, disseminated and cavitary form of pulmonary tuberculosis, good tolerability and safety profile. Some of the recent patents related to the treatment of tuberculosis are discussed in this review article.

Rifaximin in the management of colonic diverticular disease

Rifaximin is a rifamycin derivative that acts by inhibiting bacterial RNA synthesis. Since it is virtually unabsorbed after oral administration, its bioavailability within the GI tract is high, with intraluminal and fecal drug concentrations largely exceeding the minimum inhibitory concentration values observed in vitro against a broad spectrum of bacteria, including Gram-positive and Gram-negative bacteria, both aerobes and anaerobes. The GI tract, therefore, represents the primary therapeutic target and the disorders in which intestinal bacteria have a pathogenic role represent the main indication. This is the case with colonic diverticular disease. As a consequence, the broad antibacterial activity of rifaximin appears to be of value in the treatment of this clinical condition. Clinical trials have provided evidence of the substantial benefit of rifaximin in diverticular disease. Indeed, available data show the efficacy of the drug in achieving symptomatic relief in patients with uncomplicated disease. A therapeutic gain of approximately 30%, compared with fiber supplementation only, can be expected after cyclic administration of rifaximin for 12 months. However, its value in the prevention of inflammatory complications of the disease needs to be further explored. Recent studies have shown some evidence of synergy between rifaximin and mesalazine and suggest that a combined treatment could be worthwhile in selected subsets of patients with diverticular disease.

Interactions between Antiinfective Agents and Immunosuppressants

Interactions between Antiinfective Agents and Immunosuppressants

Fármacos con actividad frente a Mycobacterium tuberculosis

Treatment for Mycobacterium tuberculosis must be lengthy because populations of this bacillus differ in metabolic activity, and it must include various associated drugs, since spontaneous chromosome mutations can give rise to drug resistance. The multiresistant phenotype emerges with sequential acquisition of mutations in several independent loci. Thus, the main challenges in tuberculosis treatment are resistant strains and reductions in treatment duration and dose to facilitate adherence on the part of the patient. The drugs should be fast acting, active against resistant strains, and able to eradicate slowly metabolizing populations. Progress in recent years has led to the development of analogs of first-line antituberculosis drugs with longer dosing intervals (rifamycin derivatives) or shorter treatment courses (moxifloxacin, gatifloxacin). Nonetheless, new drugs that additionally have novel mechanisms of action and no cross-resistance to current first-line drugs are needed. This review describes the characteristics, activity, resistance mechanisms, and side effects associated with antituberculosis drugs.

Effects of interactions of antibacterial drugs with each other and with 6-mercaptopurine on in vitro growth of Mycobacterium avium subspecies paratuberculosis

Mycobacterium avium subspecies paratuberculosis (MAP) has been targeted for treatment with clarithromycin and rifamycin derivatives in numerous cases of Crohn's disease (CD). 6-Mercaptopurine and its pro-drug azathioprine are widely used as immunomodulators in the treatment of CD and have recently been shown to have anti-MAP activity in vitro. The objectives of the study were to evaluate the in vitro effects on MAP of (i) 6-mercaptopurine when combined with each of eight conventional antibacterial agents with in vitro anti-MAP activity and (ii) antibacterial combinations consisting of two drugs (clarithromycin combined with amikacin, rifampicin, ciprofloxacin or ethambutol) and three drugs (clarithromycin, rifabutin and clofazimine). The drug interaction effects on nine human isolates of MAP were determined by the chequerboard method adapted for the BACTECMGIT960 culture system and by calculation of the fractional inhibitory concentration index (FICI) for drug combinations. Synergism (FICI < or = 0.5) was observed between 6-mercaptopurine and azithromycin (seven isolates), clarithromycin, rifampicin, rifabutin (four isolates each) and ethambutol (two isolates). 6-Mercaptopurine was not antagonistic with any of the antibacterial agents tested. Among the combinations of two and three antibacterials tested, the clarithromycin/rifampicin combination was synergistic against four isolates, while all other combinations showed no interaction. This in vitro study suggests that 6-mercaptopurine may be synergistic with macrolides and rifamycin derivatives against MAP. The activity of clarithromycin against MAP seems to be enhanced by rifampicin.

Rifaximin for Hepatic Encephalopathy

Objective: To evaluate the efficacy of rifaximin for the treatment of hepatic encephalopathy (HE). Data Sources: All articles were accessed via PubMed (January 1960–December 2008), Cochrane Library, and Iowa Drug Information Service (1966–December 2008) using the terms rifaximin and hepatic encephalopathy. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: All articles in English identified from the data sources were evaluated. Fifteen studies that evaluated the efficacy, safety, and/or cost-effectiveness of rifaximin for the treatment of HE are reviewed in this article. Data Synthesis: HE is a neuropsychiatric syndrome that develops in patients with acute or chronic liver failure. There are a number of accepted theories explaining the pathophysiology of HE. Currently, pharmacologic therapies include nonabsorbable disaccharides (lactulose) and antibiotics (neomycin and metronidazole). Recent studies have shown a possible benefit with a newer, nonabsorbable rifamycin derivative, rifaximin. It has a broad spectrum of activity against aerobic and anaerobic gram-positive and gram-negative organism. Clinical trials have compared rifaximin with lactulose, neomycin, or metronidazole for the treatment of HE. There have also been review articles addressing the cost-effectiveness of rifaximin compared with lactulose, including the cost of hospitalization. To date there have been no randomized, placebo-controlled studies that have assessed the efficacy and long-term safety outcomes of rifaximin in the treatment of HE; however, rifaximin has demonstrated similar efficacy and better safety profiles compared with other therapies, in particular, neomycin and lactulose. Conclusions: Patients with HE who are refractory to lactulose therapy or who have decreased tolerability to lactulose therapy may benefit from rifaximin as either adjunct therapy or salvage therapy. ACPE Universal Program Numbers: 407-000-09-053-H01-P (Pharmacists); 407-000-09-053-H01-T (Technicians)

Rifampin and Rifaximin Resistance in Clinical Isolates of Clostridium difficile

Rifaximin, a poorly absorbed rifamycin derivative, is a promising alternative for the treatment of Clostridium difficile infections. Resistance to this agent has been reported, but no commercial test for rifaximin resistance exists and the molecular basis of this resistance has not been previously studied in C. difficile. To evaluate whether the rifampin Etest would be a suitable substitute for rifaximin susceptibility testing in the clinical setting, we analyzed the in vitro rifaximin susceptibilities of 80 clinical isolates from our collection by agar dilution and compared these results to rifampin susceptibility results obtained by agar dilution and Etest. We found rifaximin susceptibility data to agree with rifampin susceptibility; the MICs of both antimicrobials for all isolates were either very low or very high. Fourteen rifaximin-resistant (MIC, > or = 32 microg/ml) unique isolates from patients at diverse locations in three countries were identified. Molecular typing analysis showed that nine (64%) of these isolates belonged to the epidemic BI/NAP1/027 group that is responsible for multiple outbreaks and increased disease severity in the United Kingdom, Europe, and North America. The molecular basis of rifaximin and rifampin resistance in these isolates was investigated by sequence analysis of rpoB, which encodes the beta subunit of RNA polymerase, the target of rifamycins. Resistance-associated rpoB sequence differences that resulted in specific amino acid substitutions in an otherwise conserved region of RpoB were found in all resistant isolates. Seven different RpoB amino acid substitutions were identified in the resistant isolates, which were divided into five distinct groups by restriction endonuclease analysis typing. These results suggest that the amino acid substitutions associated with rifamycin resistance were independently derived rather than disseminated from specific rifamycin-resistant clones. We propose that rifaximin resistance in C. difficile results from mutations in RpoB and that rifampin resistance predicts rifaximin resistance for this organism.

Rifaximin for the treatment of hepatic encephalopathy

The use of rifaximin for the treatment of hepatic encephalopathy (HE) is reviewed. HE is observed in approximately 50-70% of all patients with cirrhosis. Clinical manifestations of HE range from altered mental status to deep coma. Most manifestations of this syndrome are reversible with medical treatment. Treatment measures focus on the resolution of ammonia accumulation and identification/ removal of precipitating factors. Lactulose has been the mainstay of HE treatment in the acute and chronic settings, though its use is limited by poor patient tolerance and compliance. Chronic administration of antibiotics has also proven to be effective in HE. Historically, neomycin or metronidazole has been used, but both carry the risk of serious adverse effects. Rifaximin is a nonabsorbed derivative of rifamycin with a broad spectrum of activity against aerobic and anaerobic gram-positive and gram-negative organisms. Clinical trials have compared rifaximin to lactulose or neomycin for the treatment of HE. Rifaximin shows a general trend toward better efficacy versus lactulose or neomycin. In addition, rifaximin seems to offer a better safety and tolerability profile than that of lactulose and possibly neomycin. While no randomized, placebo-controlled studies have assessed the efficacy and long-term safety outcomes of rifaximin in the treatment of HE, rifaximin has demonstrated better efficacy and safety profiles compared with lactulose and neomycin. Future studies should assess HE outcomes with more consistent indexes and measurements and should compare the efficacy and safety of rifaximin with those of metronidazole.

Effects of Rifaximin on Bacterial Virulence Mechanisms at Supra- and Sub-Inhibitory Concentrations

Rifaximin, a poorly absorbed rifamycin derivative, exhibited time-dependent bactericidal activity and at concentrations as low as 1/32 of the minimum inhibitory concentration (MIC) caused morphological alterations in both susceptible and resistant bacterial strains. Spontaneous rifaximin-resistant clones appeared with an incidence of 2.6×10−7. The percentage of Escherichia coli cells cured of various plasmids ranged from: 4.5-70% (Flac), 0-18% (pBP507), 7.7-43.8% (plasmid carrying ESBL genes) and 22.4-41.6% (plasmid encoding toxin from ETEC mex264). 8.4-18.2 and <0.1- 18% of Staphylococcus aureus cells were cured (plasmid-mediated penicillinase), 9.5-58.6% of Morganella morganii (ESBL), 10.6-47.1% Citrobacter freundii(ESBL), 2.3-38.7% of Proteus mirabilis (ESBL) and 14.3-66.6% of Klebsiella pneumoniae (ESBL). Rifaximin reduced plasmid transfer from donor to recipient strains by >99%. The MIC of ceftazidime was reduced (2-4 dilutions) in the presence of rifaximin (0.5xMIC) in ESBL producing strains. Rifaximin lowered the viability and virulence of the bacteria even though they developed resistance to the compound.In conclusion, the present findings add new features to the microbiological characteristics of rifaximin and suggest that if in vivo pathogens are exposed to sub-MICs of the drug, not only are their physiological functions compromised, but gene virulence and antibiotic resistance are not fully expressed.

Efficacy of a Novel Rifamycin Derivative, ABI-0043, against Staphylococcus aureus in an Experimental Model of Foreign-Body Infection

We compared the efficacy of a novel rifamycin derivative, ABI-0043, with that of rifampin, alone and in combination with levofloxacin, against methicillin-susceptible Staphylococcus aureus ATCC 29213 in a guinea pig tissue-cage infection model. The MIC, logarithmic-growth-phase minimal bactericidal concentration, and stationary-growth-phase minimal bactericidal concentration of ABI-0043 were 0.001, 0.008, and 0.25 microg/ml, respectively; the corresponding concentrations of rifampin were 0.016, 0.8, and 3.6 microg/ml, respectively. After a single intraperitoneal dose of 12.5 mg/kg of body weight, the peak concentration in cage fluid was 1.13 micarog/ml of ABI-0043 and 0.98 microg/ml of rifampin. Five days after completion of treatment, levofloxacin administered alone (5 mg/kg/12 h) resulted in bacterial counts in cage fluid that were similar to those for untreated controls (>8.0 log(10) CFU/ml), whereas rifampin and ABI-0043 administered alone (12.5 mg/kg/12 h) decreased the mean titers of bacteria +/- standard deviations to 1.43 +/- 0.28 log(10) and 1.57 +/- 0.53 log(10) CFU/ml, respectively, in cage fluid. In combination with levofloxacin, both rifamycins cleared bacteria from the cage fluid. The cure rates of cage-associated infections with rifampin and ABI-0043 administered alone were 46% and 58%, respectively, and increased to 88% and 92% in combination with levofloxacin. Emergence of rifamycin resistance was observed in 42% of cages after ABI-0043 therapy and in 38% of cages after rifampin therapy; no emergence of resistance occurred with combination treatment with levofloxacin. In conclusion, ABI-0043 had cure rates comparable to that of rifampin. ABI-0043 in combination with a quinolone has the potential for treatment of implant-associated infections caused by susceptible strains of S. aureus, potentially without drug-drug interactions.

Current Status of Some Antituberculosis Drugs and the Development of new Antituberculous Agents with Special Reference to their In Vitro and In Vivo Antimicrobial Activities

Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. In particular, the increasing prevalence of multidrug-resistant (MDR)-TB has greatly contributed to the increased difficulties in the control of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new anti-TB drugs without cross-resistance with known antimycobacterial agents is urgently needed. This article deals with the following areas. First, it briefly reviews some recent findings on the pharmacological status of fluoroquinolones and rifamycin derivatives. Second, it describes other types of new agents, such as oxazolidinones (linezolid, PNU-100480), nitroimidazoles (nitroimidazopyran PA-824, metronidazole), 2-pyridone, riminophenazines and diarylquinolines, which are being developed as anti-TB drugs. In addition, the future development of new antitubercular drugs is briefly discussed according to the potential pharmacological targets. New critical information on the whole genome of Mycobacterium tuberculosis (MTB) was recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on MTB genome, drug development using quantitative structure-activity relationship may be possible in the near future.

New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases

A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported.

New rifabutin analogs: Synthesis and biological activity against Mycobacterium tuberculosis

The synthesis, structure, and biological evaluation of a series of novel rifamycin derivatives, Rifastures (RFA) with potent anti-tuberculosis activity are presented. Some of these derivatives showed higher in vitro activity than rifabutin and rifampicin against not only Mycobacterium tuberculosis strains but also against MAC and Mycobacterium kansasii.

Study of the Reaction of 3‐Formylrifamycin SV with Gaseous Ammonia and Acetone

AbstractIn the second stage of our study concerning the search for new antibacterial rifamycin antibiotics, reaction of the aldehydes 3‐formylrifamycin SV (1) and 25‐O‐deacetyl‐3‐formylrifamycin SV with ammonia and acetone has been investigated. A new synthetic method for the preparation of a new group of rifamycin derivatives with a cyclic substituent at C‐3 having a 4‐piperidone structure, represented by compounds 6a, 6b, and 7a, has been developed. The structures of the compounds and a reaction mechanism have been proposed on the basis of mass spectrometry results as well as 1D and 2D 1H and 13C NMR analysis. The results of the in vitro tests confirm the antituberculous activity of the synthesized compounds. Furthermore, 6a, which is isolated in good yield, is a promising substrate for a new class of rifamycin derivatives. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2006)

Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection

Novel rifamycins (new chemical entities [NCEs]) having MICs of 0.002 to 0.03 microg/ml against Staphylococcus aureus and retaining some activity against rifampin-resistant mutants were tested for in vivo efficacy against susceptible and rifampin-resistant strains of S. aureus. Rifalazil and rifampin had a 50% effective dose (ED50) of 0.06 mg/kg of body weight when administered as a single intravenous (i.v.) dose in a murine septicemia model against a susceptible strain of S. aureus. The majority of NCEs showed efficacy at a lower i.v. dose (0.003 to 0.06 mg/kg). In addition, half of the NCEs tested for oral efficacy had ED50s in the range of 0.015 to 0.13 mg/kg, i.e., lower or equivalent to the oral ED50s of rifampin and rifalazil. NCEs were also tested in the septicemia model against a rifampin-resistant strain of S. aureus. Twenty-four of 169 NCEs were efficacious when administered as a single oral dose of 80 mg/kg. These NCEs were examined in the murine thigh infection model against a susceptible strain of S. aureus. Several NCEs dosed by intraperitoneal injection at 0.06 mg/kg caused a significant difference in bacterial titer compared with placebo-treated animals. No NCEs showed efficacy in the thigh model against a highly rifampin-resistant strain. However, several NCEs showed an effect when tested against a partially rifampin-resistant strain. The NCEs having a 25-hydroxyl moiety were more effective as a group than their 25-O-acetyl counterparts. These model systems defined candidate NCEs as components of potential combination therapies to treat systemic infections or as monotherapeutic agents for topical applications.

Infections associated with orthopedic implants

We review recent advances in the prevention, diagnosis and treatment of infections associated with joint prostheses and internal fixation devices. The perioperative antimicrobial prophylaxis should be administered 60-30 min before incision or before inflation of the tourniquet. New diagnostic approaches include sonication of removed implants to dislodge adherent microorganisms growing in biofilms and the use of molecular techniques to improve diagnostic yield. Treatment of implant-associated infections without removal of the device is an established option for selected patients. Treatment with rifampin combinations in staphylococcal infections is crucial for success. As demonstrated in vitro, in animal studies and in clinical trials, quinolones are suitable combination agents with rifampin against susceptible staphylococci, but increasing antimicrobial resistance requires evaluation of alternative combination agents, such as quinpristin-dalfopristin, linezolid, and daptomycin, although clinical experience is limited. New antimicrobial agents, such as dalbavancin, tigecycline, iclaprim, and novel rifamycin derivatives are studied. Better understanding of the interaction between microorganisms, the implant and the host may improve our current approach to the diagnosis and treatment of implant-associated infections. The treatment modality depends on duration of infection, stability of the implant, antimicrobial susceptibility of the pathogen and condition of the surrounding soft tissue.

Antimicrobial Activities of Cinnamyl Rifamycin Derivatives, T‐9 and T‐11, against Mycobacterium tuberculosis and Mycobacterium avium Complex (MAC) with Special Reference to the Activities against Intracellular MAC

The mycobacterial activities of cinamyl rifamycin derivatives, T-9 and T-11, especially against extracellular and intracellular Mycobacterium avium complex residing within macrophages and type II pneumocytes were compared with those of other rifamycins. The activities of test rifamycins were found to be in the order rifalazil, rifabutin, T-9, T-11, and rifampicin.

New Trends in Development of Antimycobacterial Compounds

The resurgence of tuberculosis and the surge of multidrug-resistant clinical isolates of Mycobacterium tuberculosis have reaffirmed tuberculosis as a primary public health concern. In this review we describe some new findings on the pharmacological status of fluoroquinolones derivatives (Gatifloxacin, Moxifloxacin and Sitafloxacin), new macrolides (Clarithromycin, Azithromycin and Roxithromycin), new rifamycin derivatives (Rifapentin, Rifabutin and Rifalazil) and new oxazolidinones (Linezolid and PNU 100480). We describe also other type of agents that are being developed as antimycobacterial drugs. Some of these are under clinical investigation, while others are considered to be promising candidates for future development. Among them, nitroimidazopyrans, new ketolides, Isoxyl (ISO), pyrroles derived from BM 212, Mefloquine and Diarylquinoline R207910 are discussed. We also describe the mechanism of drug resistance in mycobacteria, as well as new potential targets.

In Vitro Activity of Novel Rifamycins against Rifamycin-Resistant Staphylococcus aureus

We describe novel rifamycin derivatives (new chemical entities [NCEs]) that retain significant activity against a comprehensive collection of Staphylococcus aureus strains that are resistant to rifamycins. This collection of resistant strains contains 21 of the 26 known single-amino-acid alterations in RpoB, the target of rifamycins. Some NCEs also demonstrated a lower frequency of resistance development than rifampin and rifalazil in S. aureus as measured in a resistance emergence test. When assayed for activity against the strongest rifamycin-resistant mutants, several NCEs had MICs of 2 microg/ml, in contrast to MICs of rifampin and rifalazil, which were 512 microg/ml for the same strains. The properties of these NCEs therefore demonstrate a significant improvement over those of earlier rifamycins, which have been limited primarily to combination therapy due to resistance development, and suggest a potential use of these NCEs for monotherapy in several clinical indications.

Antimicrobial Agents in Orthopaedic Surgery

The pathogenesis of implant-associated infection involves interaction between the microorganisms (biofilm formation), the implant and the host. Despite improvement of perioperative prophylaxis, orthopaedic implants still remain highly susceptible to bacterial or fungal contamination, generally resulting in persistent implant-associated infection. Therefore, perioperative and life-long prevention of infection is important. For perioperative prophylaxis, a first- or second-generation cephalosporin is recommended, which should be administered between 60 and 30 minutes before incision. The duration of prophylaxis should not exceed 1 day. In centres with a low incidence of infection, a single dose is sufficient. Treatment of infections associated with orthopaedic devices usually requires appropriate surgical intervention combined with prolonged antimicrobial therapy. The choice of the antimicrobial regimen depends on the duration and pathogenesis of infection, stability of the implant, antimicrobial susceptibility of the pathogen and condition of the surrounding soft tissue. The role of rifampicin (rifampin), which has excellent activity on adherent staphylococci, in combination with beta-lactams, glycopeptides, fluoroquinolones, minocycline, cotrimoxazole or fusidic acid, in the treatment of staphylococcal infections is outlined. Increasing antimicrobial resistance requires the use of alternative agents, such as quinupristin/dalfopristin, linezolid and daptomycin, but results of clinical trials with these agents are limited. Also reviewed are potential new antimicrobial agents currently undergoing investigation, such as the novel oxazolidinone RWJ-416457, the new glycopeptide dalbavancin, the glycylcycline compound tigecycline, the new carbacephem BP-102 and novel rifamycin derivatives. Vaccination against Staphylococcus aureus with StaphVAX induced specific antibodies potentially preventing bacteraemia; however, there are no studies on efficacy in the prophylaxis of device-associated infections with this vaccine.