A Phase 1, Open-Label, Fixed-Sequence, Drug-Drug Interaction Study of Zanubrutinib with Rifabutin in Healthy Volunteers.

Zanubrutinib is a second-generation Bruton tyrosine kinase inhibitor that is primarily metabolized by CYP3A enzymes. Previous drug-drug interaction (DDI) studies have demonstrated that co-administration of zanubrutinib with rifampin, a strong CYP3A inducer, reduces zanubrutinib plasma concentrations, potentially impacting activity. The impact of the co-administration of zanubrutinib with less potent CYP3A inducers is unclear. This phase 1, open-label, fixed-sequence DDI study evaluated the pharmacokinetics, safety, and tolerability of zanubrutinib when co-administered with steady-state rifabutin, a known CYP3A inducer less potent than rifampin, in 13 healthy male volunteers (NCT04470908). Co-administration of zanubrutinib with rifabutin resulted in a less than 2-fold reduction of zanubrutinib exposures. Overall, zanubrutinib was well tolerated. The results of this study provide useful information for the evaluation of the DDI between rifabutin and zanubrutinib. In conjunction with safety and efficacy data from other clinical studies, these results will be taken into consideration to determine the appropriate dose recommendation of zanubrutinib when co-administered with CYP3A inducers.

Third-line and rescue therapy for refractory Helicobacter pylori infection: A systematic review.

BACKGROUND: Due to increasing resistance rates of Helicobacter pylori (H. pylori) to different antibiotics, failures in eradication therapies are becoming more frequent. Even though eradication criteria and treatment algorithms for first-line and second-line therapy against H. pylori infection are well-established, there is no clear recommendation for third-line and rescue therapy in refractory H. pylori infection. AIM: To perform a systematic review evaluating the efficacy and safety of rescue therapies against refractory H. pylori infection. METHODS: A systematic search of available rescue treatments for refractory H. pylori infection was conducted on the National Library of Medicine's PubMed search platform based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or non-randomized clinical trials and observational studies evaluating the effectiveness of H. pylori infection rescue therapies were included. RESULTS: Twenty-eight studies were included in the analysis of mean eradication rates as rescue therapy, and 21 of these were selected for analysis of mean eradication rate as third-line treatment. For rifabutin-, sitafloxacin-, levofloxacin-, or metronidazole-based triple-therapy as third-line treatment, mean eradication rates of 81.6% and 84.4%, 79.4% and 81.5%, 55.7% and 60.6%, and 62.0% and 63.0% were found in intention-to-treat (ITT) and per-protocol (PP) analysis, respectively. For third-line quadruple therapy, mean eradication rates of 69.2% and 72.1% were found for bismuth quadruple therapy (BQT), 88.9% and 90.9% for bismuth quadruple therapy, three-in-one, Pylera® (BQT-Pylera), and 61.3% and 64.2% for non-BQT) in ITT and PP analysis, respectively. For rifabutin-, sitafloxacin-, levofloxacin-, or metronidazole-based triple therapy as rescue therapy, mean eradication rates of 75.4% and 78.8%, 79.4 and 81.5%, 55.7% and 60.6%, and 62.0% and 63.0% were found in ITT and PP analysis, respectively. For quadruple therapy as rescue treatment, mean eradication rates of 76.7% and 79.2% for BQT, 84.9% and 87.8% for BQT-Pylera, and 61.3% and 64.2% for non-BQT were found in ITT and PP analysis, respectively. For susceptibility-guided therapy, mean eradication rates as third-line and rescue treatment were 75.0% in ITT and 79.2% in PP analysis. CONCLUSION: We recommend sitafloxacin-based triple therapy containing vonoprazan in regions with low macrolide resistance profile. In regions with known resistance to macrolides or unavailability of bismuth, rifabutin-based triple therapy is recommended.

Rifabutin as salvage therapy for Helicobacter pylori eradication: Cornerstones and novelties.

When several Helicobacter pylori eradication treatments fail, guidelines recommend a cultured guided approach; however, culture is not widely available. Therefore, a rifabutin based regimen could be the best solution. Rifabutin indeed shows a low rate of antibiotic resistance. Rifabutin is generally used in combination with amoxicillin in a triple therapy, with eradication rates about 80% in third-line regimens. The ideal duration of this therapy should range between 10 and 12 d. Combinations with antibiotics other than amoxicillin have demonstrated even better results, such as vonoprazan, which is a type of novel acid suppressor drug. Finally, a new formulation of triple therapy in a single capsule is under investigation, which is a field that deserves further investigation. Some notes of caution about rifabutin should be mentioned. This drug is used to treat tuberculosis or atypical mycobacteria; therefore, before starting a rifabutin-based eradication regimen, Mycobacterium tuberculosis infection should be thoroughly tested, since its use could promote the development of antibiotic resistance, thus affecting its effectiveness against Koch's bacillus. Additionally, some serious side effects must be evaluated before starting any rifabutin-based therapy. Adverse effects include fever, nausea, vomiting and bone marrow suppression. For this reason, full blood count surveillance is required.

Efficacy and safety of low-dose rifabutin-based 7-day triple therapy as a third- or later-line Helicobacter pylori eradication regimen.

BACKGROUND: Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection. MATERIALS AND METHODS: Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a 13 C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene. RESULTS: Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%-99% and 92.7%, 95% CI: 86%-100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy. CONCLUSIONS: This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.

A Case Series of Rifabutin Use in Staphylococcal Prosthetic Infections.

This case series describes seven patients who received rifabutin in place of rifampin combined with conventional antimicrobial therapy for treatment of hardware-associated staphylococcal infections. Infection recurrence, defined as need for unplanned surgical intervention within the evaluable follow up period after starting rifabutin, occurred in two patients. Two patients experienced possible treatment-associated adverse effects. Findings support future work to examine rifabutin use, when rifampin is not suitable, for adjunctive treatment of staphylococcal hardware infections. IMPORTANCE This work evaluates real-world data and clinical outcomes when rifabutin is used in place of rifampin for adjunctive management of staphylococcal hardware-associated infections. This is the second case study looking at this specific use of rifabutin, signifying the current lack of clinical data in this area. Assessing use of rifabutin in this capacity is clinically important given its lower propensity for drug interactions compared to rifampin.

Drug-induced corneal deposits: an up-to-date review.

This review assesses different clinical aspects of the various known drug-induced corneal deposits, based on the corneal layer involved (epithelium, stroma and/or endothelium), and based on the drug class. The most well-known condition caused by drug deposits is vortex keratopathy, or corneal verticillata, which is a whorl-like opacity in the corneal epithelium. Vortex keratopathy is commonly caused by certain cationic amphiphilic drugs such as amiodarone, antimalarials, suramin, tamoxifen, chlorpromazine and non-steroidal anti-inflammatory drugs. These deposits usually occur once a certain dose of the drug is reached. Most cases present with mild to moderate symptoms with minimal visual impairment. Most of these deposits resolve automatically, after months to years of drug cessation. Notably, other drug classes can cause deposits in all three layers of the cornea. Chlorpromazine, gold, rifabutin, indomethacin and tyrosine kinase inhibitors can cause stromal deposits, with reduced visual acuity when the anterior stroma is involved. Chlorpromazine and rifabutin can also cause deposits in the endothelial layer of the cornea. Regardless of the type of corneal deposit, local therapies such as topical lubricants or corticosteroids may help improve symptoms. Drug cessation or modification can also be helpful but should be weighed against the systemic risks of the underlying disease.

Systematic review of drug-drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management.

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%-74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3-5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%-67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.

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.

Rifabutin pharmacokinetics and safety among TB/HIV-coinfected children receiving lopinavir/ritonavir-containing second-line ART.

BACKGROUND: Treatment options are limited for TB/HIV-coinfected children who require PI-based ART. Rifabutin is the preferred rifamycin for adults on PIs, but the one study evaluating rifabutin with PIs among children was stopped early due to severe neutropenia. METHODS: We evaluated rifabutin safety and plasma pharmacokinetics among coinfected children 3-15 years of age receiving rifabutin 2.5 mg/kg daily with standard doses of lopinavir/ritonavir. The AUC0-24 at 2, 4 and 8 weeks after rifabutin initiation was described using intensive sampling and non-compartmental analysis. Clinical and laboratory toxicities were intensively monitored at 12 visits throughout the study. RESULTS: Among 15 children with median (IQR) age 13.1 (10.9-14.0) years and weight 25.5 (22.3-30.5) kg, the median (IQR) rifabutin AUC0-24 was 5.21 (4.38-6.60) µg·h/mL. Four participants had AUC0-24 below 3.8 µg·h/mL (a target for the population average exposure) at week 2 and all had AUC0-24 higher than 3.8 µg·h/mL at the 4 and 8 week visits. Of 506 laboratory evaluations during rifabutin, grade 3 and grade 4 abnormalities occurred in 16 (3%) and 2 (0.4%) instances, respectively, involving 9 (60%) children. Specifically, grade 3 (n = 4) and grade 4 (n = 1) neutropenia resolved without treatment interruption or clinical sequelae in all patients. One child died at week 4 of HIV-related complications. CONCLUSIONS: In children, rifabutin 2.5 mg/kg daily achieved AUC0-24 comparable to adults and favourable HIV and TB treatment outcomes were observed. Severe neutropenia was relatively uncommon and improved with ongoing rifabutin therapy. These data support the use of rifabutin for TB/HIV-coinfected children who require lopinavir/ritonavir.

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.

Intraocular deposits and cataracts after long-term rifabutin intake: A case report.

RATIONALE: Rifabutin is a broad-spectrum antibiotic known to cause deposits on the corneal endothelium and lens. We report a patient in whom cataracts developed and progressive pigment deposits were seen on the corneal endothelium, lens, and iridocorneal angle. PATIENT CONCERNS: The patient was a 45-year-old woman who had been received long-term treatment with a combination of various anti-mycobacterial drugs for multidrug-resistant tuberculosis starting in 2004. Rifabutin was started in 2009, and she was referred to our department in 2017 for detailed ophthalmological examination. DIAGNOSES: Both eyes showed pigmented deposits over the entire corneal endothelium, the entire periphery of the iridocorneal angle, and the anterior surface of the lens. Mild cataracts were also diagnosed bilaterally. Pigment deposits on the anterior surface of the lens and the cataracts in both eyes gradually progressed. These lesions were assumed to be associated with long term rifabutin intake. INTERVENTIONS: Rifabutin intake was discontinued after progression of intraocular deposits, cataracts, and ERG deterioration. OUTCOMES: Visual acuity improved, although cataracts, deposits, and ERG deterioration remained. LESSONS: Rifabutin may induce not only corneal endothelial deposits, but also cataracts and iridocorneal angle deposits.

Drug-induced Uveitis in HIV Patients with Ocular Opportunistic Infections.

Purpose: To describe drug-induced uveitis in immunocompromised patients diagnosed with Human Immunodeficiency Virus (HIV) infection Methods: Narrative Review Results: Systemic and intraocular medications administered for the treatment of acquired immune deficiency syndrome (AIDS)-associated diseases in patients infected with HIV are a well-known cause of uveitis. Conclusions: Cidofovir and rifabutin, among other novel anti-retroviral therapies, are strongly associated with drug-induced uveitis. It is imperative to understand the pathogenesis, clinical findings, and management of HIV patients with uveitis induced by these agents.

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.