Rifamycin SV MMX for the treatment of traveler's diarrhea.

INTRODUCTION: 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.

Understanding pharmacokinetics to improve tuberculosis treatment outcome.

INTRODUCTION: Tuberculosis (TB) remains the leading cause of death from a curable infectious disease; drug-resistant TB threatens to dismantle all prior gains in global control. Suboptimal circulating anti-TB drug concentrations can lead to lack of cure and acquired drug resistance. AREAS COVERED: This review will introduce pharmacokinetic parameters for key anti-TB drugs, as well as the indications and limitations of measuring these parameters in clinical practice. Current and novel methodologies for delivering anti-TB pharmacokinetic-pharmacodynamic data are highlighted and gaps in operational research described. EXPERT OPINION: Individual pharmacokinetic variability is commonplace, underappreciated and difficult to predict without therapeutic drug monitoring (TDM). Pharmacokinetic thresholds associated with poor TB treatment outcome in drug-susceptible TB have recently been described and may now guide the application of TDM, but require validation in a variety of settings and comorbidities. Dried blood spots for TDM and prepackaged multidrug plates for minimum inhibitory concentration testing will overcome barriers of accessibility and represent areas for innovation. Operationalizing pharmacokinetics has the potential to improve TB outcomes in the most difficult-to-treat forms of the disease such as multidrug resistance. Clinical studies in these areas are eagerly anticipated and we expect will better define the rational introduction of novel therapeutics.

Rifaximin: a nonsystemic rifamycin antibiotic for gastrointestinal infections.

Use of nonsystemic antimicrobials with activity against enteropathogens is a promising approach for treatment of infectious diarrhea and other nonsystemic gastrointestinal infections. Rifaximin is approved by the US FDA for the treatment of travelers' diarrhea caused by noninvasive strains of Escherichia coli in patients aged 12 years and older, and for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients aged 18 years or older. Rifaximin has been available in Italy since 1987 and overall is approved in 33 countries for various conditions, such as acute and chronic infections, bacterial diarrhea, HE, and pre- and postsurgical prophylaxis. There is accumulating evidence on the benefit of rifaximin for nonsystemic gastrointestinal infections. This article will serve as an update on rifaximin. The pharmacology and pharmacodynamics of rifaximin along with an updated review on the bacterial susceptibility to rifaximin will be presented. Finally, clinical trials with rifaximin for nonsystemic gastrointestinal indications will be updated.

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.

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.

Development potential of rifalazil and other benzoxazinorifamycins.

Rifalazil and other benzoxazinorifamycins (new chemical entities [NCEs]) are rifamycins that contain a distinct planar benzoxazine ring. Rifalazil has excellent antibacterial activity, high intracellular levels and high tissue penetration, which are attributes that favour its use in treating diseases caused by the obligate intracellular pathogens of the genus Chlamydia. Recent studies have shown that rifalazil has efficacy in the treatment of human sexually transmitted disease caused by Chlamydia trachomatis. The extraordinary potency of rifalazil and other NCEs, such as ABI-0043, extends to the related microorganism, C. pneumoniae, a respiratory pathogen that can disseminate and persist chronically in the vasculature, resulting in increased plaque formation in animal studies. A pivotal clinical trial with rifalazil has been initiated for the treatment of peripheral arterial disease. Other opportunities include gastric ulcer disease caused by Helicobacter pylori and antibiotic-associated colitis caused by infection with Clostridium difficile in the colon. The NCEs could prove to be valuable as follow-on compounds in these indications, as rifampin replacements in antibacterial combination therapy or as stand-alone topical antibacterials (e.g., to treat acne). Neither rifalazil nor NCEs appear to induce the cytochrome P450 3A4, an attribute of rifampin that can result in adverse events due to drug-drug interactions.

Rifaximin in the treatment of infectious diarrhea.

Rifaximin matches the criteria for an ideal agent for the treatment of infectious diarrhea. It has excellent activity against a broad range of enteropathogens. It is nonabsorbable, which may help explain its excellent side effect profile and lack of emergence of resistance because of high stool levels that are not likely to reach subinhibitory levels before the target Gram-negative bacilli are killed. It has shown excellent efficacy in numerous clinical trials of bacterial diarrhea. Because of the lack of systemic absorption and minimal adverse reactions, rifaximin should be useful in treating hosts such as pregnant women in whom the currently favored fluoroquinolones are contraindicated. Uses limited to enteric indications and its inherently low propensity to induce sustainable resistance among Gram-negative flora favor the sustained usefulness of rifaximin in the treatment of enteric infectious syndromes.

Management of inflammatory bowel disease: does rifaximin offer any promise?

An increasing number of both clinical and laboratory-derived observations support the importance of luminal components in driving the inflammatory response in ulcerative colitis and Crohn's disease. Although its role is unclear, antibiotic therapy is commonly used in clinical practice for the treatment of moderately to severely active ulcerative colitis. Metronidazole and/or ciprofloxacin are currently employed in active Crohn's disease, particularly in patients with colonic involvement and with perianal disease. Rifaximin, a rifamycin-derived antibiotic, is characterized by a wide range of antibacterial activity and a very low systemic absorption. Some preliminary data show its efficacy in severe active ulcerative colitis, pouchitis and prevention of postoperative recurrence in Crohn's disease.

Development potential of rifalazil.

Rifalazil represents a new generation of ansamycins that contain a unique four-ring structure. Originally rifalazil was developed as a therapeutic agent to replace rifampin as part of a multiple drug regimen in the treatment of tuberculosis. As a result of its superior antimicrobial activity and high intracellular levels, rifalazil has potential to treat indications caused by the intracellular pathogen, Chlamydia trachomatis, which causes non-gonococcal urethritis and cervicitis, often leading to pelvic inflammatory disease. Rifalazil also has potential to treat the related microorganism, Chlamydia pneumoniae, which may be involved in chronic inflammatory processes thought to be partly responsible for atherosclerosis. Due to its favourable antimicrobial spectrum and other positive attributes, rifalazil may also prove valuable in the treatment of gastric ulcer disease, caused by Helicobacter pylori, and antibiotic-associated colitis, the result of toxin production following the growth of Clostridium difficile in the colon. The potential value of rifalazil in the treatment of these indications will be assessed in human clinical trials.

Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis.

BACKGROUND: Pouchitis is the major long-term complication after ileal pouch-anal anastomosis for ulcerative colitis. About 15% of patients have a chronic, treatment-resistant disease. AIMS: To evaluate the efficacy of an antibiotic combination for chronic active, treatment-resistant pouchitis. PATIENTS AND METHODS: Eighteen patients were treated orally with rifaximin 1 g b.d. + ciprofloxacin 500 mg b.d. for 15 days. Symptoms assessment, endoscopic and histological evaluations were performed at screening and after 15 days using the Pouchitis Disease Activity Index (PDAI). Improvement was defined as a decrease of at least 3 points in PDAI score, and remission as a PDAI score of 0. Systemic absorption of rifaximin was determined by high performance liquid chromatography. Faecal samples were collected before and after antibiotic treatment for stool culture. RESULTS: Sixteen out of 18 patients (88.8%) either improved (n=10) or went into remission (n=6); the median PDAI scores before and after therapy were 11 (range 9-17) and 4 (range 0-16), respectively (P < 0.002). No side-effects were reported. Rifaximin plasma levels and urinary excretion were negligible, confirming its mainly topical activity. A significant decrease in total anaerobes and aerobes, enterococci, lactobacilli, bifidobacteria and bacteroides in faecal samples was observed, while the reduction in number of coliforms and Clostridium perfringens did not reach a statistical significance. CONCLUSIONS: A combination of rifaximin and ciprofloxacin was effective in patients with active chronic, treatment-resistant pouchitis, suggesting the need, in these patients, for treatment using antibiotic agents with wide antibacterial spectrum of activity.

Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice.

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDS-associated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracellulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracellulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDS-associated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in present study.

[Preclinical research on drug forms containing rifamycin SV intended for intramammary use]. / Predklinichni izsledvaniia vurkhu lekarstveni formi, sudurzhashti rifamitsin SV, prednaznacheni za intramamarna upotreba.

It was established, that LD50 of rifamycin SV--sodium salt, produced by the Research Institute on Microbiological Industry--Razgrad (People's Republic of Bulgaria)--RM, at p.o. applying on albino mice, albino rats and broilers is correspondingly greater than 4100.0 mg/kg m., greater than 5740.0 mg/kg m. and 1951.6 (1355.5 divided by 2810.1) mg/kg m. and at s. c. introducing into albino mice--815.9 (756.9 divided by 879.9) mg/kg m. From the prepared on the basis of RM-4 intramammary medicaments--RM-1, RM-2 and RM-3 for lactating cows and RM-4 for cows in the dry period, a good bearing have RM-1, RM-3 and RM-4. RM-1, RM-2 and RM-3, applied intracisternally a single time on lactating cows, and RM-4 on cows in the dry period, create antimicrobial levels with duration correspondingly 168, 72 and 48 h, and 35 days. RM almost does not penetrate in the neighbouring not treated quarters. Appropriate medicament for the lactating cows with average duration of emission is RM-3 (term of action 96 h) and for cows in the dry period RM-4 when applied 35 days before the calving.