Rifabutin triple therapy for first-line and rescue treatment of Helicobacter pylori infection: A systematic review and meta-analysis.

BACKGROUND AND AIM: Due to the increasing resistance of Helicobacter pylori, there is a need for novel antibiotic treatment protocols. We aimed to perform a systematic review and meta-analysis in order to determine the effectiveness and safety of rifabutin triple therapy for H. pylori infection. METHODS: We performed a systematic review of prospective clinical trials with a treatment arm consisting of proton pump inhibitor, amoxicillin, and rifabutin and a meta-analysis of randomized controlled trials (RCTs). RESULTS: Thirty-three prospective studies including 44 datasets were identified. Meta-analysis of four RCTs for rescue treatment found no difference between treatment groups (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.437-1.791, I2  = 68.1%, P = 0.733). Only one RCT compared rifabutin therapy with control for first-line treatment of H. pylori infection (OR 3.78, 95% CI 2.44-5.87, P < 0.0001). Treatment was more likely to be successful in Asian versus non-Asian populations (81.0% vs 72.4%, P = 0.001) and when daily amoxicillin dose was ≥ 3000 mg or proton pump inhibitor dose was ≥ 80 mg or treatment duration was 14 days (80.6% vs 66.0%, P = 0.0001). The overall event rate for adverse effects was 24.8% (729/2937) (95% CI 0.23-0.26), and the pooled OR for adverse effects in the treatment versus control group was 0.93 (95% CI 0.50-1.75) (I2  = 79.76, P = 0.82). CONCLUSION: Evidence for the effectiveness of rifabutin for the first-line treatment of H. pylori infection in adults is limited, and studies comparing rifabutin with conventional first-line treatments are lacking.

Efficacy and safety of a new rifabutin-based triple therapy with vonoprazan for refractory Helicobacter pylori infection: A prospective single-arm study.

BACKGROUND: A small proportion of Helicobacter pylori-infected individuals in Japan suffer failure of eradication therapy with third-line regimens containing the potent acid suppressor, vonoprazan, and a quinolone. OBJECTIVES: This prospective study evaluated the efficacy and safety of rifabutin-based triple therapy with vonoprazan for refractory H pylori infection. METHODS: Patients who failed H pylori eradication by clarithromycin-based first-line, metronidazole-based second-line, and sitafloxacin-based third-line therapies were recruited. After obtaining informed consent, patients received eradication therapy with vonoprazan (20 mg), amoxicillin (750 mg), and rifabutin (150 mg) twice daily for 10 days. Eradication was confirmed by a negative H pylori stool antigen or urea breath test at least 8 weeks after the end of therapy. RESULTS: Nineteen patients were included in the study. All of the patients completed the course of medication. Eradication of H pylori was confirmed in all of the patients (19/19; 100%, 95% confidence interval; 83-100%). The most common adverse event was soft stool/diarrhea (4/19, 21%). No severe adverse event was observed. CONCLUSIONS: Ten-day rifabutin with amoxicillin and vonoprazan triple therapy appears to be effective and safe for refractory H pylori infections. However, considering the recent publications showing high eradication rates with vonoprazan amoxicillin dual therapy, confirmation will require future studies comparing our new therapy with vonoprazan-amoxicillin dual with similar doses and duration and with vonoprazan-rifabutin dual therapy.

Pharmacokinetic study of two different rifabutin doses co-administered with lopinavir/ritonavir in African HIV and tuberculosis co-infected adult patients.

BACKGROUND: This study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day (every 48 h) versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection. METHODS: This is a two-arm, open-label, pharmacokinetic, randomised study conducted in Burkina Faso between May 2013 and December 2015. Enrolled patients were randomised to receive either 150 mg RBT EOD (arm A, 9 subjects) or 300 mg RBT EOD (arm B, 7 subjects), both associated with LPV/r taken twice daily. RBT plasma concentrations were evaluated after 2 weeks of combined HIV and TB treatment. Samples were collected just before drug ingestion and at 1, 2, 3, 4, 6, 8, and 12 h after drug ingestion to measure plasma drug concentration using an HPLC-MS/MS assay. RESULTS: The Cmax and AUC0-12h medians in arm A (Cmax = 296 ng/mL, IQR: 205-45; AUC0-12h = 2528 ng.h/mL, IQR: 1684-2735) were lower than those in arm B (Cmax = 600 ng/mL, IQR: 403-717; AUC0-12h = 4042.5 ng.h/mL, IQR: 3469-5761), with a statistically significant difference in AUC0-12h (p = 0.044) but not in Cmax (p = 0.313). No significant differences were observed in Tmax (3 h versus 4 h). Five patients had a Cmax below the plasma therapeutic limit (< 300 ng/mL) in the 150 mg RBT arm, while the Cmax was above this threshold for all patients in the 300 mg RBT arm. Additionally, at 48 h after drug ingestion, all patients had a mycobacterial minimum inhibitory concentration (MIC) above the limit (> 64 ng/mL) in the 300 mg RBT arm, while 4/9 patients had such values in the 150 mg RBT arm. CONCLUSION: This study confirmed that the 150 mg dose of rifabutin ingested EOD in combination with LPV/r is inadequate and could lead to selection of rifamycin-resistant mycobacteria. TRIAL REGISTRATION: PACTR201310000629390, 28th October 2013.

Pharmacokinetics of plasma lopinavir and ritonavir in tuberculosis-HIV co-infected African adult patients also receiving rifabutin 150 or 300 mg three times per week.

BACKGROUND: To evaluate the pharmacokinetic of plasma lopinavir (LPV) and ritonavir (RTV) when co-administered with three times weekly (TPW) rifabutin (RBT) at a dose of either 150 or 300 mg in African tuberculosis (TB) and HIV co-infected adult patients. METHODS: This is a pharmacokinetic study conducted in Ouagadougou among patients treated with a standard dosage of LPV/RTV 400/100 mg twice daily and RBT 150 mg TPW (arm A = 9 patients) or rifabutin 300 mg TPW (arm B = 7 patients) based regimens. Patients were recruited from the Bogodogo and Kossodo district hospitals in Ouagadougou from May 2013 to December 2015. Study inclusion criteria were that the patients were between 18 and 60 years of age, HIV-1 infected with pulmonary tuberculosis confirmed or suspected. Subsequent blood samples for pharmacokinetic monitoring were collected at 1, 2, 3, 4, 6, 8 and 12 h after combined drug ingestion for plasma drug monitoring using HPLC/MS assays. RESULTS: The medians LPV Cmax and Tmax were respectively, 20 µg/mL and 4 h for the RBT 150 mg group (arm A) and 7.7 µg/mL and 3 h for the RBT 300 mg group (arm B). The AUC0-12 of LPV was 111.8 µg h/mL in patients belonging to arm A versus 69.9 µg/mL for those in arm B (p = 0.313). The C0 of LPV was lower than 4 µg/mL in three patients receiving RBT 300 mg. Of note, the RTV plasma concentrations were nearly halved among patients on RBT 300 mg compared to those on lower RBT doses. The AUC0-12 of RTV in arm A was 12.7 µg h/mL versus 6.6 µg h/ml in arm B (p = 0.313). CONCLUSION: In our study, the pharmacokinetic of LPV and RTV was found to be highly variable when coadministrated with RBT 150 mg or 300 mg three times per week. There is a need for specific large study to verify clinical and virological effects of this variation, especially when coadministrated with RBT of 300 mg TPW, and to prevent viral resistance in response to under-dosing of LPV. Trial registration PACTR201310000629390. Registered 28 October 2013, http://www.pactr.org/.

Safety and efficacy of rifabutin among HIV/TB-coinfected children on lopinavir/ritonavir-based ART.

BACKGROUND: TB is the leading cause of death among HIV-infected children, yet treatment options for those who require PI-based ART are suboptimal. Rifabutin is the preferred rifamycin for adults on PI-based ART; only one study has evaluated its use among children on PIs and two of six children developed treatment-limiting neutropenia. METHODS: Since 2009, rifabutin has been available for HIV/TB-coinfected children requiring PI-based ART in the Harvard/APIN programme in Nigeria. We retrospectively analysed laboratory and clinical toxicities at baseline and during rifabutin therapy, and examined HIV/TB outcomes. RESULTS: Between 2009 and 2015, 48 children received rifabutin-containing TB therapy with PI (lopinavir/ritonavir)-based ART: 50% were female with a median (IQR) baseline age of 1.7 (0.9-5.0) years and a median (IQR) CD4+ cell percentage of 15% (9%-25%); 52% were ART experienced. Eighty-five percent completed the 6 month rifabutin course with resolution of TB symptoms and 79% were retained in care at 12 months. Adverse events (grade 1-4) were more common at baseline (27%) than during rifabutin treatment (15%) (P = 0.006). Absolute neutrophil count was lower during rifabutin compared with baseline (median = 1762 versus 2976 cells/mm3, respectively), but only one instance (2%) of grade 3 neutropenia occurred during rifabutin treatment. CONCLUSIONS: With clinical and laboratory monitoring, our data suggest that rifabutin is a safe option for TB therapy among children on PI-based ART. By contrast with the only other study of this combination in children, severe neutropenia was rare. Furthermore, outcomes from this cohort suggest that rifabutin is effective, and a novel option for children who require PI-based ART. Additional study of rifabutin plus PIs in children is urgently needed.

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

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

Inhalable chitosan microparticles for simultaneous delivery of isoniazid and rifabutin in lung tuberculosis treatment.

The direct delivery of antibiotics to the lung has been considered an effective approach to treat pulmonary tuberculosis, which represents approximately 80% of total cases. In this sense, this work aimed at producing inhalable chitosan microparticles simultaneously associating isoniazid and rifabutin, for an application in pulmonary tuberculosis therapy. Spray-dried chitosan microparticles were obtained with adequate flow properties for deep lung delivery (aerodynamic diameter of 4 µm) and high drug association efficiencies (93% for isoniazid and 99% for rifabutin). The highest concentration of microparticles that was tested (1 mg/mL) decreased the viability of macrophage-differentiated THP-1 cells to around 60% after 24 h exposure, although no deleterious effect was observed in human alveolar epithelial (A549) cells. The release of LDH was, however, increased in both cells. Chitosan microparticles further evidenced capacity to activate macrophage-like cells, inducing cytokine secretion well above basal levels. Moreover, the propensity of macrophages to internalize microparticles was demonstrated, with uptake levels over 90%. Chitosan microparticles also inhibited bacterial growth by 96%, demonstrating that the microencapsulation preserved drug antibacterial activity in vitro. Overall, the obtained data suggest the potential of chitosan microparticles for inhalable lung tuberculosis therapy.

Rifabutin Triple Therapy is Effective in Patients With Multidrug-resistant Strains of Helicobacter pylori.

INTRODUCTION: Eradicating Helicobacter pylori continues to be a challenge, and no treatment regimen is uniformly successful in all treated patients. Triple therapy with rifabutin and amoxicillin is a successful rescue therapy after consecutive treatment failures. We designed this study to test the efficacy of 12-day rifabutin-based triple therapy in patients infected with multidrug-resistant strains. METHODS: Consecutive patients with dyspeptic symptoms after at least 1 antibiotic therapy course for H. pylori infection harboring triple-resistant (clarithromycin, metronidazole, levofloxacin) strains were enrolled. They received triple therapy with esomeprazole 40 mg bid, amoxicillin 1 g bid, and rifabutin 150 mg od for 12 days. Patients who failed rifabutin therapy were treated empirically on the basis of the judgment of the treating physician. RESULTS: A total of 254 out of 756 tested patients were found to be infected with a triple-resistant H. pylori strains after at least 1 antibiotic therapy course. Overall, the infection was eradicated in 213 patients, corresponding to a cure rate of 82.9% (95% CI, 78.3-87.5) by intention-to-treat analysis and 88.7% (95% CI, 84.7-92.7) at per-protocol analysis. In multivariate analysis, no factor was identified as an independent predictor of bacterial eradication. CONCLUSIONS: There is no current standard for the growing population of patients with multidrug-resistant strains of H. pylori. The 12-day low-dose rifabutin/high-dose proton pump inhibitor regimen is a safe and reliable option for patients infected with triple-resistant strains.

Therapeutic implications of nano-encapsulated rifabutin, azithromycin & ethambutol against experimental Mycobacterium avium infection in mice.

Background & objectives: Mycobacterium avium causes atypical infection in both immunocompetent and immunocompromised individuals. Conventional chemotherapy for M. avium infection is not efficient due to lengthy course of treatment and drug-associated toxic side effects. The present study was aimed at reducing dosing frequency of antimicrobial regimen consisting of azithromycin (AZM), rifabutin (RBT) and ethambutol (EMB) by encapsulation of drugs in nanoparticles (NPs) in experimental M. avium infection in mice. Methods: Poly (DL-lactide-co-glycolide) NPs containing anti-M. avium drugs were prepared, characterized and studied for their pharmacokinetics and pharmacodynamics parameters. Drug-loaded NPs were further analyzed for their therapeutic efficacy against experimental M. avium infection in mice. Results: Drug-loaded NPs were of size 227.3±16.4 for RBT, 334.35±11.7 for AZM and 509.85±20.5 for EMB with smooth surface morphology and negative zeta potential. AZM, EMB and RBT from NPs were detectable for 6, 4 and 5 days, respectively, in the mice plasma, whereas free drugs were cleared from mice circulation within 24 h. Chemotherapeutic effects of weekly administered drug-loaded NPs were equivalent to daily administered free drugs. Interpretation & conclusions: Our findings showed that NPs gave sustained release of drugs inside plasma and organs, thus decreasing dosage frequency, and their weekly dosage had therapeutic efficacy equivalent to daily dosage of free drugs.

Spray-dried fucoidan microparticles for pulmonary delivery of antitubercular drugs.

Pulmonary tuberculosis accounts for 80% of cases and the delivery of antitubercular drugs into the lungs allows targeting the infected organ and, possibly, reducing systemic drug toxicity. This work aimed at using fucoidan as matrix of inhalable microparticles that associate two first-line antitubercular drugs, for an application in pulmonary tuberculosis therapy. Fucoidan is composed of fucose and sulphated sugar residues, moieties described as being recognised by surface receptors of alveolar macrophages, which host mycobacteria. Inhalable fucoidan microparticles loaded with antitubercular drugs were successfully produced with high association efficiencies of either isoniazid (95%) or rifabutin (81%). The microparticles evidenced no cytotoxicity on lung epithelial cells (A549). However, rifabutin-loaded microparticles showed a certain degree of toxicity on macrophage-like cells (THP-1) at the highest tested concentration (1 mg/mL). Furthermore, microparticles showed favourable aerodynamic properties for deep lung delivery (MMAD 2.0-3.8 µm) and, thus, show potential for an application as inhalable tuberculosis therapy.

A novel ceftazidime/avibactam, rifabutin, tedizolid and moxifloxacin (CARTM) regimen for pulmonary Mycobacterium avium disease.

OBJECTIVES: To compare the efficacy of ceftazidime/avibactam plus tedizolid-based combination regimens with the standard therapy of azithromycin, ethambutol and rifabutin for the treatment of pulmonary Mycobacterium avium complex (MAC) disease. METHODS: We mimicked the human pulmonary concentration-time profiles of ceftazidime/avibactam and tedizolid in combination, ceftazidime/avibactam, rifabutin, tedizolid and moxifloxacin (CARTM), and the standard regimen and examined microbial kill in triplicate hollow-fibre system model of intracellular pulmonary MAC (HFS-MAC) units. The tedizolid and moxifloxacin doses used were non-optimized; the tedizolid dose was that associated with bacteriostasis. Drugs were administered daily for 28 days. Each HFS-MAC was sampled in the central and peripheral compartment to ascertain that the intended drug exposures had been achieved. The peripheral compartments were sampled at regular intervals over the 28 days to quantify the burden of MAC. RESULTS: MAC-infected macrophages in the HFS-MAC achieved multi-fold higher intracellular versus extracellular concentrations of rifabutin, moxifloxacin, ceftazidime/avibactam. The non-optimized ceftazidime/avibactam plus tedizolid dual therapy held the bacterial burden at the same level as day 0 (stasis) throughout the 28 days. The standard therapy reduced the bacterial load 2 log10 cfu/mL below stasis on day 14 but started failing after that. The CARTM regimen achieved 3.2 log10 cfu/mL kill below stasis on day 21, but had started to fail by day 28. CONCLUSIONS: The CARTM regimen promises to have kill rates better than standard therapy. Experiments to identify exposures of each of the four drugs associated with optimal effect in the CARTM combination are needed in order to design a short-course chemotherapy regimen.

Microencapsulated Solid Lipid Nanoparticles as a Hybrid Platform for Pulmonary Antibiotic Delivery.

Solid lipid nanoparticles (SLN) containing rifabutin (RFB), with pulmonary administration purposes, were developed through a technique that avoids the use of organic solvents or sonication. To facilitate their pulmonary delivery, the RFB-loaded SLN were included in microspheres of appropriate size using suitable excipients (mannitol and trehalose) through a spray-drying technique. Confocal analysis microscopy showed that microspheres are spherical and that SLN are efficiently microencapsulated and homogeneously distributed throughout the microsphere matrices. The aerodynamic diameters observed an optimal distribution for reaching the alveolar region. The dry powder's performance during aerosolization and the in vitro drug deposition were tested using a twin-impinger approach, which confirmed that the microspheres can reach the deep lung. Isothermal titration calorimetry revealed that SLN have higher affinity for mannitol than for trehalose. Upon microsphere dissolution in aqueous media, SLN were readily recovered, maintaining their physicochemical properties. When these dry powders reach the deep lung, microspheres are expected to readily dissolve, delivering the SLN which, in turn, will release RFB. The in vivo biodistribution of microencapsulated RFB-SLN demonstrated that the antibiotic achieved the tested organs 15 and 30 min post pulmonary administration. Their antimycobacterial activity was also evaluated in a murine model of infection with a Mycobacterium tuberculosis strain H37Rv resulting in an enhancement of activity against M. tuberculosis infection compared to nontreated animals. These results suggest that RFB-SLN microencapsulation is a promising approach for the treatment of tuberculosis.

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis.

Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).

Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-ß-catenin axis.

The essential roles of overexpression of eukaryotic translation initiation factor 4E (eIF4E) and aberrant activation of ß-catenin in lung cancer development have been recently identified. However, whether there is a direct connection between eIF4E overexpression and ß-catenin activation in lung cancer cells is unknown. In this study, we show that antibiotic drug rifabutin targets human lung cancer cells via inhibition of eIF4E-ß-catenin axis. Rifabutin is effectively against lung cancer cells in in vitro cultured cells and in vivo xenograft mouse model through inhibiting proliferation and inducing apoptosis. Mechanistically, eIF4E regulates ß-catenin activity in lung cancer cells as shown by the increased ß-catenin phosphorylation and activity in cells overexpressing eIF4E, and furthermore that the regulation is dependent on phosphorylation at S209. Rifabutin suppresses eIF4E phosphorylation, leads to decreased ß-catenin phosphorylation and its subsequent transcriptional activities. Depletion of eIF4E abolishes the inhibitory effects of rifabutin on ß-catenin activities and overexpression of ß-catenin reverses the inhibitory effects of rifabutin on cell growth and survival, further confirming that rifabutin acts on lung cancer cells via targeting eIF4E- ß-catenin axis. Our findings identify the eIF4E- ß-catenin axis as a critical regulator of lung cancer cell growth and survival, and suggest that its pharmacological inhibition may be therapeutically useful in lung cancer.

Inhalable Particles for "Pincer Therapeutics" Targeting Nitazoxanide as Bactericidal and Host-Directed Agent to Macrophages in a Mouse Model of Tuberculosis.

Nitazoxanide (NTZ) has moderate mycobactericidal activity and is also an inducer of autophagy in mammalian cells. High-payload (40-50% w/w) inhalable particles containing NTZ alone or in combination with antituberculosis (TB) agents isoniazid (INH) and rifabutin (RFB) were prepared with high incorporation efficiency of 92%. In vitro drug release was corrected for drug degradation during the course of study and revealed first-order controlled release. Particles were efficiently taken up in vitro by macrophages and maintained intracellular drug concentrations at one order of magnitude higher than NTZ in solution for 6 h. Dose-dependent killing of Mtb and restoration of lung and spleen architecture were observed in experimentally infected mice treated with inhalations containing NTZ. Adjunct NTZ with INH and RFB cleared culturable bacteria from the lung and spleen and markedly healed tissue architecture. NTZ can be used in combination with INH-RFB to kill the pathogen and heal the host.

Facial Skin Lesions in Children Caused by Nontuberculous Mycobacteria.

BACKGROUND: Nontuberculous mycobacteria rarely cause facial skin lesions in immunocompetent children. AIM: I describe the clinical features and treatment of nontuberculous mycobacteria facial lesions. MATERIALS AND METHODS: The diagnosis of a facial nontuberculous mycobacteria infection was established using polymerase chain reaction. RESULTS: Of 286 children with confirmed nontuberculous mycobacteria infection, 14 (4.9%; median age 50 mos, range 9-156 mos; 5 [36%] male, 9 [64%] female) had nontuberculous mycobacteria facial skin lesions. Six (43%) had lesions on the cheek and five (36%) in the medial eye corner. Polymerase chain reaction results confirmed the presence of Mycobacterium haemophilum in eight patients (57%) and Mycobacterium avium in six patients (43%). The facial lesions were treated using a combination of clarithromycin and rifabutin for 12 weeks, with a median healing time of 4 months. CONCLUSION: Nontuberculous mycobacteria facial lesions are rare in immunocompetent children. The diagnosis requires a high index of suspicion. Nonsurgical treatment is preferable, because surgical excision of the cutaneous lesions might lead to undesirable visible facial scars.

Pharmacokinetics and safety of rifabutin in young HIV-infected children receiving rifabutin and lopinavir/ritonavir.

OBJECTIVES: Co-treatment of HIV and TB in young children is complicated by limited treatment options and complex drug-drug interactions. Rifabutin is an alternative to rifampicin for adults receiving a ritonavir-boosted PI. We aimed to evaluate the short-term safety and pharmacokinetics of rifabutin when given with lopinavir/ritonavir in children. PATIENTS AND METHODS: We conducted an open-label study of rifabutin dosed at 5 mg/kg three times a week in HIV-infected children≤5 years of age receiving lopinavir/ritonavir. Intensive steady-state pharmacokinetic sampling was conducted after six doses. The Division of AIDS 2004, clarification 2009, table for grading severity of adverse events was used to classify drug toxicities. The study was registered with ClinicalTrials.gov, number NCT01259219. RESULTS: Six children completed the study prior to closure by institutional review boards. The median (range) AUC0-48 of rifabutin was 6.91 (3.52-8.67) µg ·â€Šh/mL, the median (range) Cmax of rifabutin was 0.39 (0.19-0.46) µg/mL, the median (range) AUC0-48 of 25-O-desacetyl rifabutin was 5.73 (2.85-9.13) µg ·â€Šh/mL and the median (range) Cmax of 25-O-desacetyl rifabutin was 0.17 (0.08-0.32) µg/mL. The neutrophil count declined in all children; two children experienced grade 4 neutropenia, which resolved rapidly without complications. There was strong correlation between AUC0-48 measures and neutrophil counts. CONCLUSIONS: Rifabutin dosed at 5 mg/kg three times per week resulted in lower AUC0-48, AUC0-24 and Cmax values for rifabutin and 25-O-desacetyl rifabutin compared with adults receiving 150 mg of rifabutin daily, the current recommended dose. We observed high rates of severe transient neutropenia, possibly due to immaturity of CYP3A4 in young children. It remains unclear whether a safe and effective rifabutin dose exists for treatment of TB in children receiving lopinavir/ritonavir.

Helicobacter pylori first-line and rescue treatments in the presence of penicillin allergy.

BACKGROUND: Helicobacter pylori eradication is a challenge in penicillin allergy. AIM: To assess the efficacy and safety of first-line and rescue treatments in patients allergic to penicillin. METHODS: Prospective multicenter study. Patients allergic to penicillin were given a first-line treatment comprising (a) 7-day omeprazole-clarithromycin-metronidazole and (b) 10-day omeprazole-bismuth-tetracycline-metronidazole. Rescue treatments were as follows: (a) bismuth quadruple therapy; (b) 10-day PPI-clarithromycin-levofloxacin; and (c) 10-day PPI-clarithromycin-rifabutin. Eradication was confirmed by (13)C-urea breath test. Compliance was determined through questioning and recovery of empty medication envelopes. Adverse effects were evaluated by questionnaires. RESULTS: In total, 267 consecutive treatments were included. (1) First-line treatment: Per-protocol and intention-to-treat eradication rates with omeprazole-clarithromycin-metronidazole were 59 % (62/105; 95 % CI 49-62 %) and 57 % (64/112; 95 % CI 47-67 %). Respective figures for PPI-bismuth-tetracycline-metronidazole were 75 % (37/49; 95 % CI 62-89 %) and 74 % (37/50; 95 % CI (61-87 %) (p < 0.05). Compliance with treatment was 94 and 98 %, respectively. Adverse events were reported in 14 % with both regimens (all mild). (2) Second-line treatment: Intention-to-treat eradication rate with omeprazole-clarithromycin-levofloxacin was 64 % both after triple and quadruple failure; compliance was 88-100 %, with 23-29 % adverse effects (all mild). (3) Third-/fourth-line treatment: Intention-to-treat eradication rate with PPI-clarithromycin-rifabutin was 22 %. CONCLUSION: In allergic to penicillin patients, a first-line treatment with a bismuth-containing quadruple therapy (PPI-bismuth-tetracycline-metronidazole) seems to be a better option than the triple PPI-clarithromycin-metronidazole regimen. A levofloxacin-based regimen (together with a PPI and clarithromycin) represents a second-line rescue option in the presence of penicillin allergy.

[Biodistribution of Rifabutin Polymeric Transport Form].

BACKGROUND: One way to increase drug efficacy is to provide a drug delivery transport system to the target organ. A widely used method is to incorporate the drug in a biodegradable polymer composition with forming nanosized drug's transport forms. Objective: Our aim was to investigate the tissue biodistribution of antibiotic rifabutin transport system based on lactic and glycolic acids copolymer, and to compare it with the pure substance of rifabutin. METHODS: These substances were administered to two groups of rats intragastrically in the doses of 10 mg/kg. After a certain period of time, the animals were sacrificed by cervical dislocation. Samples preparation for analysis was carried out of the liquid-liquid extraction. Active substance's concentrations were measured by high performance liquid chromatography method. RESULTS: The study included 8-week-aged Wistar rats of both sexes weighing 0.22 ± 0.02 kg. Animals were divided into 2 groups. The study group received polymer form of antibiotic, and the comparison group received substance of rifabutin. In intervals of 10 min, 30 min, 1 h, 2 h, 4 h, 7h, 15 h, 24 h after drug administration liver, lung, spleen, kidney, intestines, stomach, heart and brain were resected respectively. Organs were measured by their weight. The drug was not detected in the brain. Rifabutin was determined in other examined tissues within 10 minutes and the maximum drug concentration in organs was fixed in 1.5-3.5 hours after administration. The rifabutin concentrations defined in the lungs were significantly higher in polymerform (p < 0.05). The polymer form's distribution coefficient was higher in the liver and lungs (15.83 and 10.14 µg/g respectively) in comparison with the substance one. The minimum amount of the active ingredient was observed in the heart (0.02 µg/g). CONCLUSION: It is shown that the inclusion of the drug in a polymeric form substantially alters its localization in organs and tissues. Extensive biodistribution nanorifabutin in lung tissue, liver and spleen is established.

Pharmacokinetic evaluation of the interaction between etravirine and rifabutin or clarithromycin in HIV-negative, healthy volunteers: results from two Phase 1 studies.

OBJECTIVES: Drug-drug interactions between etravirine and rifabutin or clarithromycin were examined in two separate open-label, randomized, two-period, crossover trials in HIV-negative, healthy volunteers. METHODS: Rifabutin study: 16 participants received 300 mg of rifabutin once daily (14 days) and then 800 mg of etravirine twice daily (Phase 2 formulation; 21 days) plus 300 mg of rifabutin once daily (days 8-21). Clarithromycin study: 16 participants received 200 mg of etravirine twice daily (commercial formulation; 8 days) and then 500 mg of clarithromycin twice daily (13 days) plus 200 mg of etravirine twice daily (days 6-13). A 14 day washout period between treatments was mandatory in both studies. Full pharmacokinetic profiles of each drug and safety/tolerability were assessed. RESULTS: Rifabutin decreased etravirine exposure by 37%; etravirine decreased rifabutin and 25-O-desacetyl rifabutin exposure by 17%. Clarithromycin increased etravirine exposure by 42%, whereas etravirine decreased clarithromycin exposure by 39% and increased 14-OH clarithromycin exposure by 21%. No serious adverse events were reported in either trial. CONCLUSIONS: Short-term etravirine coadministration with rifabutin or clarithromycin was well tolerated. Etravirine can be coadministered with 300 mg of rifabutin once daily in the absence of an additional potent cytochrome P450 inducer. No dose adjustments are required upon etravirine/clarithromycin coadministration, but alternatives to clarithromycin are recommended when used for Mycobacterium avium complex prophylaxis or treatment.