Search

OBJECTIVE: Antibiotic prophylaxis is one of the most important steps to reduce surgical site infections. First-generation cephalosporin (cefazolin) is used prophylactically in the majority of operations. Rifamycin is a broad-spectrum semisynthetic antibiotic that is bactericidal against gram (+) and gram (˗) microorganisms. To the best of our knowledge, there are no studies on the use of rifamycin in antibiotic prophylaxis. In this study, we aimed to analyze whether there is a difference between the use of only cefazolin and only rifamycin in terms of surgical site infections. STUDY DESIGN: One hundred patients were included in this case-control study during the last quarter period of 2017. These patients (n=100) were divided into two groups according to their antibiotic use; 50 patients who received only 1 g cefazolin constituted Group 1, 50 patients who received only 250 mg topical rifamycin over the incision line based on surgeon’s preference constituted Group 2. RESULTS: The use of prophylactic topical rifamycin reduced the incidence of wound infection. compared with cefazolin. Surgical site infection was detected in 5 (10%) of the patients who received cefazolin, whereas surgical site infection was not observed in patients who received rifamycin (p=0.022). CONCLUSIONS: The use of topical rifamycin is effective but does not imply that systemic antibiotics should replace prophylaxis. The use of rifamycin would aid in systemic antibiotic prophylaxis.

Opioids are one of the most prescribed classes of analgesic medications. Their narrow therapeutic index and metabolism through cytochrome p450 (CYP) enzymes can result in a drug interaction when used concomitantly with rifamycins. In clinical scenarios where concurrent therapy with an opioid and a rifamycin occurs, there is no standardized guidance for managing the interaction. The objective of this review was to examine literature which evaluates the concomitant use of opioids and rifamycins with clinically relevant CYP-inducing properties. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria was performed. PubMed, Scopus, and OVID Embase were queried for studies from database inception to January 2020 related to rifamycin and opioid medications. Only full-text, peer-reviewed, English language articles addressing clinical outcomes from concomitant rifamycin and opioid therapy were included. The review isolated 12 articles for data extraction from an original 2260 citations identified. Rifampin (11; 92%) and rifabutin (2; 17%) were the rifamycins studied along with seven different opioids. Decreased effect of opioids with concomitant rifampin therapy manifested as withdrawal in numerous patients on methadone and a decreased analgesic effect from tramadol, morphine, and, most notably, oxycodone. Only the combinations of rifampin with buccal fentanyl and rifabutin with buprenorphine and methadone were found to have no clinically measurable interaction. Available literature suggests that a decrease in opioid clinical effects is appreciated with concomitant rifamycin therapy. Further research is needed to focus on specific mitigation strategies beyond opioid agent selection, such as dosing adjustment recommendations.

Fecal transplant is associated with reduction in the expression of antibiotic‐resistance genes in patients with decompensated cirrhosis. Genes focused on beta‐lactamase and vancomycin resistance reduced after fecal transplant regardless of pre‐procedure antibiotics and concurrent use of lactulose, rifaximin or PPIs., Antibiotic resistance leads to poor outcomes in cirrhosis. Fecal microbiota transplant (FMT) is associated with reduction in antibiotic resistance gene (ARG) burden in patients without cirrhosis; however, the impact in cirrhosis is unclear. We aimed to study the effect of capsule and enema FMT on ARG abundance in fecal samples, which were collected during two published FMT trials in patients with cirrhosis on rifaximin, lactulose, and proton pump inhibitors. ARGs were identified using metagenomics and mapped against the Comprehensive Antibiotic Resistance Database. Changes in ARG abundance were studied within/between groups. The capsule FMT trial involved a one‐time FMT or placebo capsule administration with stool collection at baseline and week 4 postintervention. Antibiotics+enema FMT included preprocedure antibiotics followed by FMT enema versus standard‐of‐care (SOC). Stool was collected at baseline, postantibiotics, and day 7/15 postintervention. Both trials included 20 patients each. There was no safety/infection signal linked to FMT. In the capsule trial, beta‐lactamase (OXY/LEN) expression decreased post‐FMT versus baseline. Compared to placebo, patients who were post‐FMT had lower abundance of vancomycin (VanH), beta‐lactamase (ACT), and rifamycin ARGs; the latter was associated with cognitive improvement. No changes were seen within patients treated with placebo. In the antibiotics+enema trial for postantibiotics at day 7 versus baseline, there was an increase in vancomycin and beta‐lactamase ARGs, which decreased at day 15. However, quinolone resistance increased at day 15 versus baseline. Between SOC and FMT, day 7 had largely lower ARG (CfxA beta‐lactamase, VanW, and VanX) that continued at day 15 (cepA beta‐lactamase, VanW). No changes were seen within the SOC group. Conclusion: Despite differences in routes of administration and preintervention antibiotics, we found that ARG abundance is largely reduced after FMT compared to pre‐FMT baseline and non‐FMT groups in decompensated cirrhosis.

The list of clinically important nontuberculous mycobacteria (NTM) is growing as new species continue to be identified and older ones are found to be pathogenic. Molecular techniques such as real-time PCR and gene amplification and restriction length polymorphism are promising tools for rapid identification of NTM. Optimal therapy for a documented Mycobacterium gordonae infection remains undefined. The majority of isolates tested have been resistant in vitro to isoniazid and pyrazinamide, whereas many are susceptible to ethambutol, rifampin, clarithromycin, linezolid, and the fluoroquinolones. Unlike other nontuberculous mycobacteria, M. simiae produces niacin and thus may be confused with M. tuberculosis. M. simiae can colonize the respiratory tract, and the lung is the most commonly reported site of infection. The majority of reported infections have occurred in persons living near rivers or stagnant bodies of water. A recent open-label randomized trial conducted in Ghana compared two regimens for early, limited M. ulcerans infections. In this study, 73 of 76 patients who received streptomycin and rifampin for 8 weeks and 68 of 75 patients who received 4 weeks of streptomycin and rifampin followed by 4 weeks of rifampin and clarithromycin had healed lesions at 1 year after the start of treatment. Infections with M. xenopi have shown variable responses to drug therapy. Recommendations for initial therapy include isoniazid, a rifamycin, ethambutol, and clarithromycin with or without an initial course of streptomycin. Pyrazinamide and ciprofloxacin have been included in some successful regimens.

The divalproex (DVP) package insert states that rifampin may increase the oral clearance of valproate by 40% and that valproic acid derivative dose adjustments may be required when starting or stopping rifampin. However, the overall clinical significance of this drug-drug interaction remains unclear given that limited clinical outcome data has been published. This case describes a 52-year-old female with bipolar disorder, borderline personality disorder, and PTSD who was previously stable on a medication regimen consisting of DVP delayed-release 500 mg every morning and 1500 mg every evening (baseline steady-state trough 99.8 mcg/mL). Throughout rifampin therapy for latent tuberculosis treatment, she required an increase in both the frequency of DVP administration, from 2 to 3 times daily, and DVP dose by 75% to maintain clinical stability. Valproic acid trough concentrations ranged from 56.4 to 75.9 mcg/mL during the 4-month course of rifampin. This report supports that the DVP-rifampin interaction may be clinically significant and of a greater magnitude than suggested by the package insert.

Introduction: Tuberculosis, a disease of antiquity continues to cause high morbidity and mortality. In Sustainable Development Goals and End Tb Strategy proposed by WHO includes Drug Susceptibility Testing as major component. Conventional methods are time consuming and molecular methods are rapid but expensive and demanding. Resazurin assay is a rapid colorimetric redox indicator method of Drug Susceptibility Testing. Materials and Methods: 67 strains of M. tuberculosis isolated from pulmonary tuberculosis patients were tested using indirect absolute concentration method by resazurin assay and compared with drug incorporated Lowenstein – Jensen media for Isoniazid and Rifamycin. Results: There was 91.5 % and 91.7% concordance between both methods for INH and Rifamycin respectively. Resazurin assay for INH was 100% sensitive and 61.54% specific. Sensitivity and specificity for RMP was 98.04% and 62.5% respectively. The duration required for INH was 7.0 ± 2.07 and for RMP 6.58 ± 1.58 days. Conclusions: Resazurin assay is sensitive, rapid, cheap, technically simple drug susceptibility method. Keywords: M. tuberculosis, resazurin assay, drug susceptibility.

Objectives: To assess differential effects of different materials combined with allograft on bone-to-implant contact and newly formed bone formation in dental implants with coronal defects histomorphometrically. Materials and Methods: The study was conducted on 24 male New Zealand white rabbits. Dental implants (3.0 × 10 mm) were placed at the center of defects (9 mm diameter, 4 mm depth) created in the tibial bones of the rabbits. Graft (GF, n=8), graft + rifamycin (GR, n=8), and graft + black cumin oil via orogastric route (GB, n=8) were applied on the coronal aspects of the implants for 28 days. Undecalcified histomorphometric analyses were conducted on slides stained with toluidine blue. Results: Bone-to-implant contact was 46.57% ± 3.59% in the graft, 67.12% ± 3.64% in the graft+rifamycin, and 55.62% ± 4.37% in the graft+black cumin oil groups. The percentage of new bone formation at the defect area was 34.71% ± 4.11% in the graft, 55.37% ± 4.89% in the graft + rifamycin, and 45.75% ± 3.69% in the graft + black cumin oil groups. In terms of new bone formation and bone-to-implant contact, graft + rifamycin and graft + black cumin oil groups were significantly different from the graft group. The differences between the graft + rifamycin and graft + black cumin oil groups were also statistically significant. Conclusion: Allogreft + rifamycin and orogastric black cumin oil were found to have positive effects on bone healing at sites with coronal defects. Rifamycin showed significantly greater favorable effects on bone-to-implant contact and new bone formation compared to black cumin oil.

Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an important cause of disease. The most common species causing pulmonary disease are members of Mycobacterium avium complex (MAC). MAC pulmonary disease (MAC-PD) can be chronic, debilitating, costly, and associated with a high mortality. However, MAC diagnoses are often delayed due to the nonspecific presentation of MAC-PD and radiological findings that overlap with other pulmonary diseases. Patients with risk factors and who meet the diagnostic criteria—which include clinical, radiological, and microbiologic criteria—should be considered for treatment. Diagnosis requires 2 or more positive sputum cultures or 1 bronchoscopic specimen culture. The recommendation for those who are treated is a 3-drug regimen including macrolide, rifamycin, and ethambutol that is continued for 12 months beyond sputum culture conversion to negative. MAC-PD is difficult to treat, with frequent drug-related side effects and suboptimal treatment outcomes. Refractory and recurrent disease is common, leading to lifelong follow-up of patients. There are limited treatment options for patients with macrolide-resistant or refractory disease. Amikacin liposome inhalation suspension is recommended for treatment-refractory patients whose cultures remain positive after 6 months of guideline-based therapy. Among the research priorities to improve patient outcomes and quality of life are developing new, more rapid diagnostic tests, investigating biomarkers associated with disease progression, and identifying new drugs and routes of administration as well as new, shorter, and better-tolerated regimens.

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1. Its use in combination with rifapentine (RPT), an antituberculosis (TB) antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV-1 co-infected with TB. We conducted a prospective, phase I, open label, two-period, fixed sequence, drug interaction study to evaluate the effect of once-weekly RPT and isoniazid (INH) on the pharmacokinetics (PKs) of DOR in healthy volunteers. DOR 100 mg was administered alone twice-daily for 4 days in period 1. In period 2, once-weekly RPT + INH were co-administered with multiple doses of DOR 100 mg twice-daily for study days 7, 14, and 21. Plasma was obtained for DOR PKs when given alone and co-administered with RPT + INH. Eleven healthy volunteers enrolled and completed the study. The geometric mean ratios and 90% confidence intervals for DOR area under the concentration-time curve from zero to 12 hours (AUC0-12 ) and C12 in the presence of RPT + INH compared with DOR alone were 0.71 (0.60-0.85) and 0.69 (0.54-0.89), respectively. Although exposures were moderately reduced in the presence of RPT + INH, trough DOR values were within the concentration range associated with virological suppression. These results demonstrate that a modest decrease in DOR exposure would unlikely be clinically relevant in a virally suppressed patient co-administered once-weekly RPT + INH.

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis–bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.

Background: The incidence of Mycobacterium avium complex (MAC) increases as immunosuppressed conditions become more common. MAC's standard treatment regimen includes a macrolide, ethambutol, and a rifamycin, among which rifampin and rifabutin are the most commonly used. Although current guidelines recommend initial therapy for MAC with rifampin, it has been theorized to be less efficacious than rifabutin.Methods: We reviewed the relevant scientific literature published up to February 18, 2020. Statistical analyses were performed with Comprehensive Meta-Analysis Software Version 2.0 (Biostat, Englewood, NJ). The pooled frequency with 95% confidence intervals (CI) was assessed using a random-effect model. We considered P Results: After reviewing 3665 records, we identified 24 studies that satisfied the inclusion criteria. Among these studies, 8 had rifabutin in their regimens (rifabutin group) and 16 had rifampin in their regimens (rifampin group). The estimated pooled treatment success rate was found to be 54.7% (95% CI 41.0-67.0%) in rifabutin groups and 67.5% (95% CI 55.7-77.4%) in rifampin groups. There was no evidence of publication bias among the included studies (Egger’s test p-value was 0.7).Conclusion: In this study, it was shown that in comparison to Rifabutin, rifampin has similar treatment success rates in treating MAC. In order to determine the exact preference of each of these drugs, double-blind clinical trial studies are recommended.

After staphylococci, streptococci and enterococci are the most frequent causes of periprosthetic joint infection (PJI). MICs and minimum biofilm bactericidal concentrations of rifampin, rifabutin, and rifapentine were determined for 67 enterococcal and 59 streptococcal PJI isolates. Eighty-eight isolates had rifampin MICs of ≤1 μg/ml, among which rifabutin and rifapentine MICs were ≤ 8 and ≤4 μg/ml, respectively. There was low rifamycin in vitro antibiofilm activity except for a subset of Streptococcus mitis group isolates. IMPORTANCE Rifampin is an antibiotic with antistaphylococcal biofilm activity used in the management of staphylococcal periprosthetic joint infection with irrigation and debridement with component retention; some patients are unable to receive rifampin due to drug interactions or intolerance. We recently showed rifabutin and rifapentine to have in vitro activity against planktonic and biofilm states of rifampin-susceptible periprosthetic joint infection-associated staphylococci. After staphylococci, streptococci and enterococci combined are the most common causes of periprosthetic joint infection. Here, we investigated the in vitro antibiofilm activity of rifampin, rifabutin, and rifapentine against 126 Streptococcus and Enterococcus periprosthetic joint infection isolates. In contrast to our prior findings with staphylococcal biofilms, there was low antibiofilm activity of rifampin, rifabutin, and rifapentine against PJI-associated streptococci and enterococci, apart from some Streptococcus mitis group isolates.

Tuberculosis (TB) remains the leading cause of death among people with human immunodeficiency virus (PWH). The diagnosis of latent TB infection (LTBI) and treatment with TB preventative therapy (TPT) can reduce morbidity and mortality in this population. Historically, isoniazid has been recommended for TPT in PWH due to the absence of drug-drug interactions with most antiretroviral therapy (ART). However, newer rifamycin-based regimens are safer, shorter in duration, associated with improved adherence, and may be as or more effective than isoniazid TPT. Current guidelines have significant heterogeneity in their recommendations for TPT regimens and acceptability of drug interactions with modern ART. In this Infectious Diseases learning unit, we review common questions on diagnosis, treatment, and drug interactions related to the management of LTBI among PWH., The repertoire of data-driven medication regimens to treat latent tuberculosis infection (LTBI) among people with HIV (PWH) is rapidly evolving, leading to heterogeneity in published guidelines. We review the emerging data regarding LTBI management among PWH to support patient-centered care.

Introduction Short‐course preventive therapy with 1‐month course of daily administration of isoniazid (300‐mg) plus rifapentine (600‐mg) (1HP) and 3‐month course of weekly administration of isoniazid (900‐mg) plus rifapentine (900‐mg) (3HP) has higher completion rates than 9‐month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Methods PLWH testing positive by interferon‐gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL)

We evaluated the in vitro activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, rifabutin showed the lowest MICs against all NTM species, including Mycobacterium avium complex, M. abscessus , and M. kansasii .

Rifamycins are integral part of the combination regimen for treatment of pulmonary Mycobacterium avium-complex [MAC] infection, but different practitioners prefer different rifamycins. The objective of the study was to compare microbial kill and resistance emergence of rifamycins using principles of pharmacokinetics/pharmacodynamics. First, we identified rifamycin MICs in 20 MAC isolates from patients followed by concentration-response studies in test-tubes. Next, we examined efficacy and resistance suppression of three doses of each rifamycin in the hollow fiber system model of pulmonary MAC [HFS-MAC], mimicking human like concentration-time profile of the drugs. HFS-MAC units were repetitively sampled for total and drug-resistant MAC burden and for drug concentration measurements. Inhibitory sigmoid E max model, linear regression, and analysis of variance was used for data analysis. For rifabutin 90% of isolates had MIC ≤ 0.125 mg/L while for both rifampin and rifapentine this was ≤2.0 mg/L. There was no statistically significant difference (p > 0.05) in maximal kill and effective concentration mediating 50% of the bacterial kill among three rifamycins in the static concentration experiment. In the HFS-MAC, the bactericidal kill (day 0–4) for rifampin was 0.89 (95% Confidence Interval (CI): 0.43–1.35), for rifapentine was 1.05 (95% CI: 0.08–1.23), and for rifabutin was 0.92 (95% CI: 0.61–1.24) log10 CFU/ml, respectively. Rifamycins monotherapy failed after just 4-days of treatment and entire MAC population was drug resistant on day 26 of the study. There was no dose dependent difference in MAC kill or resistance suppression among the three rifamycins tested in the HFS-MAC. Therefore, replacing one rifamycin, due to emergence of drug-resistance, with other may not be beneficial in clinical setting.

Rifamycin antibiotics were discovered during the 1950s, and their main representative, rifampicin, remains a cornerstone treatment for TB. The clinical use of rifamycin is restricted to mycobacteria and Gram-positive infections because of its poor ability to penetrate the Gram-negative outer membrane. Rifabutin, a rifamycin antibiotic approved for the prevention of Mycobacterium avium complex disease, makes an exception to this rule by hijacking the iron uptake system of Acinetobacter baumannii, resulting in potent activity against this important Gram-negative pathogen. Here, we describe recent findings on the specific activity of rifabutin and provide evidence of the need for the development of an intravenous formulation of rifabutin (BV100) for the treatment of difficult-to-treat carbapenem-resistant A.baumannii infections.

Mycobacterium abscessus exhibits arr (ADP-ribosyltransferase)-dependent rifampicin (RIF) resistance. In apparent contrast, rifabutin (RBT) has demonstrated promising activity in M. abscessus infection models implying that RBT might not be inactivated by Arr. RBT susceptibility testing of M. abscessus Δarr revealed a strongly decreased minimal inhibitory concentration (MIC). Our findings therefore suggest that the efficacy of RBT might be enhanced by rendering RBT resilient to Arr-dependent modification or by blocking M. abscessus Arr activity.

The tale of abate in antibiotics continued defense mechanisms that chaperone the rise of drug-defying superbugs—on the other hand, the astray in antibacterial drug discovery and development. Our salvation lies in circumventing the genesis of resistance. Considering the competitive advantages of antibacterial chemotherapeutic agents equipped with multiple warheads against resistance, the development of hybrids has rejuvenated. The adoption of antibiotic hybrid paradigm to macrocycles has advanced novel chemical entities to clinical trials. The multi-targeted TD-1792, for instance, retained potent antibacterial activities against multiple strains that are resistant to its constituent, vancomycin. Moreover, the antibiotic conjugation of rifamycins has provided hybrid clinical candidates with desirable efficacy and safety profiles. In 2020, the U.S. FDA has granted an orphan drug designation to TNP-2092, a conjugate of rifamycin and fluoroquinolone, for the treatment of prosthetic joint infections. DSTA4637S is a pioneer antibacterial agent under clinical development and represents a novel class of bacterial therapy, that is, antibody–antibiotic conjugates. DSTA4637S is effective against the notorious persistent S. aureus bacteremia, a revelation of the abracadabra potential of antibiotic hybrid approaches.

Staphylococcus epidermidis is a major cause of periprosthetic joint infection (PJI); its intracellular persistence within osteoblasts may compromise therapy if that therapy is not intracellularly active. The intracellular activity of rifampin, rifapentine, and rifabutin was assessed against five rifampin-susceptible and two rifampin-resistant S. epidermidis isolates. Compared to no treatment, treatment resulted in a ≥2-fold log(10) reduction of intracellular rifampin-susceptible, but not rifampin-resistant, S. epidermidis. These findings show activity of rifampin, rifapentine, and rifabutin against intraosteoblast PJI-associated S. epidermidis.

AIM Rifaximin is recommended as treatment for hepatic encephalopathy (HE) that targets intestinal bacterial flora. Although combined use with synthetic disaccharides is the standard of care worldwide, the therapeutic effects of rifaximin for overt encephalopathy (OHE) in Japanese patients have not been examined sufficiently. We examined the therapeutic effects of rifaximin for OHE in Japanese patients. METHODS A total of 76 patients who developed OHE of West Haven grade II or higher at least once within the 12 months before starting rifaximin were included. Blood ammonia levels and the incidence of OHE during the 12 months before and after starting rifaximin therapy were compared in a before-and-after study. Rifaximin efficacy and predictors of efficacy were also examined. RESULTS Post-treatment blood ammonia levels were significantly lower than pretreatment levels. The mean annual number of OHE incidents and intravenous branched-chain amino acid preparations used per patient were significantly lower after starting rifaximin therapy (2.51 vs. 0.76 times/year, p

The combination of rifamycin (RFP), ethambutol (EB), and macrolides is currently the standard regimen for treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). However, poor adherence to the standardized regimens recommended by current guidelines have been reported. We undertook a single-centred retrospective cohort study to evaluate the long-term outcomes in 295 patients with MAC-PD following first line treatment with standard (RFP, EB, clarithromycin [CAM]) or alternative (EB and CAM with or without fluoroquinolones (FQs) or RFP, CAM, and FQs) regimens. In this cohort, 80.7% were treated with standard regimens and 19.3% were treated with alternative regimens. After heterogeneity was statistically corrected using propensity scores, outcomes were superior in patients treated with standard regimens. Furthermore, alternative regimens were significantly and independently associated with sputum non-conversion, treatment failure and emergence of CAM resistance. Multivariate cox regression analysis revealed that older age, male, old tuberculosis, diabetes mellitus, higher C-reactive protein, and cavity were positively associated with mortality, while higher body mass index and M. avium infection were negatively associated with mortality. These data suggest that, although different combination regimens are not associated with mortality, first line administration of a standard RFP + EB + macrolide regimen offers the best chance of preventing disease progression in MAC-PD patients.

Aldosterone-producing adenoma (APA) is a main cause of primary aldosteronism (PA). Given that a large benign-appearing unilateral masse (>1 cm in diameter) may represent an aldosterone and cortisol-co-secreting adenoma, dexamethasone suppression testing is required in such patients to exclude or confirm the diagnosis of hypercortisolism. Tuberculosis is highly prevalent in China, and rifamycins are often used in these patients. Rifapentine belongs to the rifamycin family, and we herein for the first time report a case of misdiagnosis of hypercortisolism due to rifapentine use in a patient with APA. Thus, in patients treated with rifapentine, diagnosis of hypercortisolism based on dexamethasone suppression tests can be very misleading.

Background The treatment of tuberculosis (TB) in solid organ transplant (SOT) recipients is challenging owing to interactions between rifampin and immunosuppressive drugs. Rifabutin, a rifamycin with excellent activity against Mycobacterium tuberculosis and that induces cytochrome p450 less, may facilitate treatment. We report our experience with rifabutin for treating TB in SOT recipients and review the available literature. Methods A retrospective observational study of all SOT recipients with TB between January 2000 and December 2019. The clinical characteristics and outcomes of patients treated with and without rifabutin-containing regimens were compared and a literature review was conducted. Results We included 31 SOT recipients with TB, among whom 22 (71%) were men and the median age was 62 years (interquartile range 50-20). There were no significant differences between patients treated with rifabutin (n = 12), rifampin (n = 14), and non-rifamycins (n = 5) in clinical cure rates (83.3%, 64.3%, and 100%, respectively; P = .21), side effects (25%, 37.5%, and 20%, respectively; P = .74), or mortality (16.7%, 35.7%, and 0%, respectively; P = .21). Only one patient, treated with rifampin, suffered graft rejection. The literature review identified 59 SOT recipients with TB treated with rifabutin-containing regimens from 8 publications. Overall, the clinical cure, graft rejection, and mortality rates were 93.2%, 5.1%, and 6.8%, respectively. Conclusions Rifabutin-containing regimens offer a reliable alternative to rifampin when treating TB in SOT recipients.

Background Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered. Objectives To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated. Methods We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0–24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575. Results The effect on rifapentine least squares mean AUC0–24 in black participants overall decreased by –10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10). Conclusions Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.

Tuberculosis (TB) is a communicable airborne infectious disease caused by the Mycobacterium tuberculosis (MTB) that primarily affects the lungs, and can disseminate to other parts of the body. MTB is one of the most dangerous pathogens, killing about 1.4 million people annually worldwide. Although the standard treatment of TB is comprised of four anti-TB drugs, the emergence of multidrug-resistant (MDR) and extensive drug-resistant (XDR) strains in the recent past and associated side effects have affected the tailor-made regimens. Notably, existing therapies approved by the World Health Organisation (WHO) can only treat less than 50% of drug-resistant TB. Therefore, an expeditious pace in the TB research is highly needed in search of effective, affordable, least toxic novel drugs with shorter regimens to reach the goals viz. 2020 milestones End TB strategy set by the WHO. Currently, twenty-three drug-like molecules are under investigation in different stages of clinical trials. These newer agents are expected to be effective against the resistant strains. This article summarizes the properties, merits, demerits, and the probability of their success as novel potential therapeutic agents.

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.

Background The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug–drug interactions with concomitantly used ART. Objectives To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. Methods Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. Results Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13–66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266–9302) ng/mL; week 2, 5537 (3552–8462) ng/mL; and week 4, 5388 (3516–8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58–2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81–3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26–1.33). Conclusions The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug–drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

Is to study the efficacy of treatment of exacerbation of chronic tubotympanic purulent otitis media with Otofa drug with the active substance Rifamycin.Performed a retrospective analysis of 37 medical histories of patients who applied to the otorhinolaryngology clinic with a diagnosis of exacerbation of chronic purulent tubotympanic otitis media in the period from January 2019 to December 2019.Noted relief of symptoms such as throbbing noise and pain in patients receiving the topical Otofa drug (active ingredient Rifamycin) by the 3th day of therapy. Otofa also reduced otorrhea by the 5th day of therapy.The study showed the high clinical efficacy of Otofa ear drops containing the Rifamycin antibiotic.Изучить эффективность лечения обострения хронического туботимпанального гнойного среднего отита препаратом Отофа с действующим веществом рифамицин (Rifamycin).Проведен ретроспективный анализ 37 историй болезни пациентов, обратившихся в клинику оториноларингологии с диагнозом «обострение хронического гнойного туботимпанального среднего отита» в период с января 2019 г. по декабрь 2019 г.У пациентов, получающих местно препарат Отофа (действующее вещество — рифамицин), уже к 3-му дню терапии было отмечено купирование таких симптомов, как пульсирующий шум и боль, а также снижение выраженности отореи к 5-му дню терапии.Исследование показало высокую клиническую эффективность ушных капель Отофа, содержащих антибиотик рифамицин.

Background Treatment of latent tuberculosis (LTBI) is important for tuberculosis (TB) prevention, and short course rifamycin-based therapies are preferred. Once-weekly isoniazid-rifapentine by self-administered therapy (3HP-SAT) has never been compared with 4 months of daily rifampin (4R). Methods Retrospective cohort study of adults ≥18 years of age initiating LTBI treatment with either 3HP-SAT or 4R in a United States (US)–based TB clinic between 11 April 2016 and 31 December 2018. We evaluated treatment completion through pharmacy fills and reviewed charts for reasons of noncompletion, including adverse events (AEs). The χ 2 test and a log-binomial multivariable model were used to compare treatment completion and AEs. Results Five hundred sixty individuals (42%) initiated 3HP-SAT and 773 (58%) initiated 4R. Median age was 38, 55% were female, and 89% were born outside of the US. Among those aged 18–49 years, treatment completion with 3HP-SAT was 79% compared to 68% with 4R (adjusted risk ratio [aRR], 1.17 [95% CI, 1.17–1.27]; P < .0001). Among individuals aged ≥50 years, treatment completion with 3HP-SAT was 87% compared to 64% with 4R (aRR, 1.35 [95% CI, 1.19–1.52]; P < .0001). Compared to 4R, there was no difference in risk of AEs in the 18–49 age group (aRR, 0.93 [95% CI, .58–1.48]; P = .75). Reduced risk of AEs was noted among patients aged ≥50 years who received 3HP-SAT (aRR, 0.37 [95% CI, .16–.85]; P = .02). Conclusions 3HP-SAT was associated with higher LTBI treatment completion and lower rates of AEs compared to 4R in individuals aged 50 and older. Expanding 3HP-SAT as an option for patients with LTBI may enhance TB prevention strategies in the US.

Mycobacterium avium complex (MAC) is the major pathologic nontuberculous mycobacteria causing lung disease (LD) in humans worldwide. Although the burden of MAC-LD has increased over the past two decades, treatment remains difficult because of intolerance of long-term antibiotics, lack of adherence to guidelines, and disease recurrence. The current guidelines recommend antibiotic initiation for patients with MAC-LD and severe disease and in those with disease progression. Thus, physicians should consider antibiotic treatment for patients with MAC-LD and cavitary pulmonary lesions or symptomatic non-cavitary nodular bronchiectasis pattern at initial visits and also for those with clinical deterioration during follow-up. The standard three-drug regimen should be macrolide, rifamycin, and ethambutol. Physicians should monitor side effects in patients and maintain the regimen for 12 months, beginning from when sputum conversion has been obtained. With adherence to guideline-based therapy, treatment is successful in two thirds of treatment-naive patients without macrolide resistance. Without adherence, macrolide resistance can occur, which leads to poor outcomes in patients with MAC-LD. Although the discovery of new treatment options is warranted, adherence to guidelines remains most crucial in treating patients with MAC-LD. It is worth mentioning that the majority of current recommendations are based on observational studies or small-scale clinical trials.

There is an urgent need to identify safe and effective combination treatments for multidrug-resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug-resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N-monodesmethyl metabolite, M2, and further desmethylated into an N-didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400 mg) of bedaquiline on days 1 and 29. Oral rifabutin (300 mg) or rifampin (600 mg) were given daily on days 20-41. In the rifabutin group maximum M2 concentrations (Cmax ) increased significantly (P < .001) from 47.59 to 79.53 ng/mL, and clearance slowed slightly (P = .01). This resulted in significantly (P < .001) increased overall exposure (area under the concentration-time curve [AUC0-τ ]). Peak concentrations of M3 increased approximately 3-fold with little decline thereafter. In rifampin recipients M2 Cmax doubled (48.44 to 101.52 ng/mL), but M2 clearance and time to Cmax significantly (P < .001) increased, and AUC0-∞ and mean residence time significantly decreased (P < .001). Peak M3 concentrations increased 4-fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.

Mycobacterium haemophilum is increasingly being recognized as a human pathogen and has been described as an important, albeit uncommon cause of cutaneous mycobacterial disease. We sought to review disease manifestations and recent reports of successful treatment outcomes. M. haemophilum has been reported to cause cutaneous disease in both immunocompetent and immunocompromised hosts. Diagnosis can be difficult due to its specific growth requirements of incubation at 32 °C on chocolate agar. In immunocompetent individuals, it has been associated with tattooing. In immunocompromised individuals, an inciting event may not be readily apparent. The optimal treatment regimen is not well defined; however, most patients are managed with combination therapy consisting of a macrolide, a rifamycin, and a fluoroquinolone. Treatment duration is usually several months. M. haemophilum can be challenging to isolate in culture if not suspected initially. Improved recognition of this pathogen will likely lead to earlier diagnosis and management.

Background Rifamycin antibiotics are commonly used for treatment of tuberculosis, but may reduce the effectiveness of hormonal contraception (HC). Objectives To determine whether interactions between rifamycins and HC result in decreased effectiveness or increased toxicity of either therapy. Search strategy We searched MEDLINE, Embase, Cochrane and clinicaltrials.gov through May 2017. Selection criteria We included trials, cohort, and case-control studies addressing pregnancy rates, pharmacodynamics or pharmacokinetic (PK) outcomes when HC and rifamycins were administered together versus apart. Of 7291 original records identified, 11 met inclusion criteria after independent review by two authors. Data collection and analysis Two authors independently abstracted study details and assessed study quality using the United States Preventive Services Task Force grading system. Findings are reported descriptively. Main results Studies only addressed combined oral contraceptives (COCs) and none reported pregnancy rates. Quality ranged from good to poor. Rifampin increased the frequency of ovulation in two of four studies, and reduced estrogen and/or progestin exposure in five studies. Rifabutin led to smaller PK changes than rifampin in two studies. In one study each, rifaximin and rifalazil did not alter hormone PK. Conclusions No studies evaluated pregnancy risk or non-oral HCs. PK and ovulation outcomes support a clinically concerning drug interaction between COCs and rifampin, and to a lesser extent rifabutin. Data are limited for other rifamycins. Tweetable abstract Rifampin and rifabutin reduce systemic exposure of oral contraceptives, but no studies have evaluated pregnancy risk.

The last decade has seen publication of more robust data for shorter course regimens for tuberculosis infection. These regimens are associated with higher completion rates than the traditional 6- to 9-month course of daily isoniazid (INH). These shorter regimens include 4 months of daily rifampin (RIF) and 12 once-weekly doses of INH and a long-acting rifamycin and rifapentine. In addition, a widely used regimen in the United Kingdom is 3 or 4 months of daily INH and RIF. All regimens have demonstrated efficacy in the ideal conditions of clinical studies, and all have very low rates of hepatotoxicity in children. These newer regimens likely are more effective than longer courses of INH once patient and family adherence is considered. Clinicians need to be cognizant of poor completion rates with traditional INH therapy and how the use of rifamycin-containing regimens offers more palatable options for children and their families.

Rifapentine is a rifamycin derivate approved by the US Food and Drug Administration in 1998 for the treatment of active, drug-susceptible tuberculosis (TB). In 2014, rifapentine was approved for the treatment of latent TB infection in patients at high risk of progression to active disease and is currently under evaluation by the European Medicines Agency. Expanding indications of rifapentine largely affect diabetes patients, since about one-third of them harbor latent TB. Clinical consequences of rifapentine use in this population and potentially harmful interactions with hypoglycemic agents are widely underexplored and generally considered similar to the ones of rifampicin. Indeed, rifapentine too may decrease blood levels of many oral antidiabetics and compete with them for protein-binding sites and/or transporters. However, the two drugs differ in protein-binding degree, the magnitude of cytochrome P450 induction and auto-induction, the degree of renal elimination, and so on. Rifapentine seems to be more suitable for use in diabetes patients with renal impairment, owing to the fact that it does not cause renal toxicity, and it is eliminated via kidneys in smaller proportions than rifampicin. On the other hand, there are no data related to rifapentine use in patients >65 years, and hypoalbuminemia associated with diabetic kidney disease may affect a free fraction of rifapentine to a greater extent than that of rifampicin. Until more pharmacokinetic information and information on the safety of rifapentine use in diabetic patients and drug–drug interactions are available, diabetes in TB patients treated with rifapentine should be managed with insulin analogs, and glucose and rifapentine plasma levels should be closely monitored.

In high prevalence settings, tuberculosis and HIV dual infection and co-treatment is frequent. Rifamycins, especially rifampicin, in combination with isoniazid, ethambutol and pyrazinamide are key components of short-course antituberculosis therapy. Areas covered: We reviewed available data, for which articles were identified by a Pubmed search, on rifamycin-antiretroviral interactions in HIV-infected children. Rifamycins have potent inducing effects on phase I and II drug metabolising enzymes and transporters. Antiretroviral medications are often metabolised by the enzymes induced by rifamycins or may suppress specific enzyme activity leading to drug-drug interactions with rifamycins. These may cause significant alterations in their phamacokinetic and pharmacodynamic properties, and sometimes that of the rifamycin. Recommended strategies to adapt to these interactions include avoidance and dose adjustment. Expert opinion: Despite the importance and frequency of tuberculosis as an opportunistic disease in HIV-infected children, current data on the management of co-treated children is based on few studies. We need new strategies to rapidly assess the use of rifamycins, new anti-tuberculosis drugs and antiretroviral drugs together as information on safety and dosing of individual drugs becomes available.

Background Owing to patient intolerance or drug interactions, alternative agents to rifampin are needed for management of staphylococcal periprosthetic joint infection. In the current study, we evaluated rifabutin, rifapentine and rifampin, with and without vancomycin, in a rat model of foreign body osteomyelitis. Methods Proximal tibiae were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and a Kirschner wire (K-wire) implanted in each. After 4 weeks of infection, rifampin, rifabutin, or rifapentine were administered, alone or with vancomycin. Tibiae and K-wires were cultured, and medians were reported as log10 colony-forming units (CFUs) per gram of bone or log10 CFUs per K-wire, respectively. Results Rifampin, rifabutin or rifapentine administered with vancomycin yielded less MRSA from bones (0.10, 3.02, and 0.10 log10 CFUs/g, respectively) than did no treatment (4.36 log10 CFUs/g) or vancomycin alone (4.64 log10 CFUs/g) (both P ≤ .02). The K-wires of animals receiving no treatment or vancomycin monotherapy recovered medians of 1.76 and 2.91 log10 CFUs/g per K-wire, respectively. In contrast, rifampin, rifabutin and rifapentine administered with vancomycin yielded medians of 0.1 log10 CFUs per K-wire, respectively. Rifampin resistance was detected in a single animal in the rifampin monotherapy group. Conclusions Rifabutin or rifapentine with vancomycin were as active as rifampin with vancomycin against MRSA in rat foreign body osteomyelitis, suggesting that rifabutin and/or rifapentine may be alternatives to rifampin in the clinical management of staphylococcal periprosthetic joint infections.

There is no reliable cure for Mycobacterium abscessus lung disease. Rifampin is not used clinically due to poor in vitro potency. In contrast, we have shown that rifabutin, another approved rifamycin used to treat tuberculosis, is potent in vitro against M. abscessus. Here, we report that rifabutin is as active as clarithromycin against M. abscessus K21 in NOD.CB17-Prkdcscid/NCrCrl mice. This suggests that rifabutin should be considered a repurposing candidate for patients with M. abscessus disease.

Current strategies to treat tuberculosis (TB) and co-morbidities involve multidrug combination therapies. Rifamycin antibiotics are a key component of TB therapy and a common source of drug–drug interactions (DDIs) due to induction of drug metabolizing enzymes (DMEs). Management of rifamycin DDIs are complex, particularly in patients with co-morbidities, and differences in DDI potential between rifamycin antibiotics are not well established. DME profiles induced in response to tuberculosis antibiotics (rifampin, rifabutin and rifapentine) were compared in primary human hepatocytes. We identified rifamycin induced DMEs, cytochrome P450 (CYP) 2C8/3A4/3A5, SULT2A, and UGT1A4/1A5 and predicted lower DDIs of rifapentine with 58 clinical drugs used to treat co-morbidities in TB patients. Transcriptional networks and upstream regulator analyses showed FOXA3, HNF4α, NR1I2, NR1I3, NR3C1 and RXRα as key transcriptional regulators of rifamycin induced DMEs. Our study findings are an important resource to design effective medication regimens to treat common co-conditions in TB patients.

Tuberculosis (TB) treatment was revolutionized in 1965 with the discovery of rifamycins by Sensi et al. [1]. With the introduction of rifamycins, treatment duration drastically decreased from 18 to...

Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the bc1:aa3 oxidase inhibitor Q203 (now named telacebec), was recently described against Mycobacterium tuberculosis. Recognizing that M. tuberculosis mutants lacking the alternative bd oxidase are hypersusceptible to Q203 and that Mycobacterium ulcerans is a natural bd oxidase-deficient mutant, we tested the in vitro susceptibility of M. ulcerans to Q203 and evaluated the treatment-shortening potential of novel 3- and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 μg/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIF+STR) and RPT and CFZ (RPT+CFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIF+STR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.

Introduction: Rifabutin, a rifamycin of equivalent potency to rifampicin, has several advantages in its pharmacokinetic and toxicity profile, particularly in HIV co-infected patients on combined antiretroviral therapy (cART). In this commentary we evaluate evidence supporting increased global use of rifabutin and highlight key recommendations for action. Discussion: Although extrapolation of data from HIV uninfected patients would suggest non-inferiority, there has been no randomized controlled study comparing rifabutin versus rifampicin in the outcomes of relapse-free cure, in drug susceptible tuberculosis, in HIV co-infected patients on currently utilized cART regimens or in paediatric populations. An important advantage of rifabutin is that compared to the dose adjustments required with rifampicin, it can be co-administered with the integrase strand inhibitors (INSTIs) raltegravir or dolutegravir without the need for dose adjustments. This strategy would be easier to implement in a programmatic setting and save costs. We have assessed cost incentives to utilize rifabutin and have estimated generic costs for a range of rifabutin dosage scenarios. Where facilities are present for drug re-challenge and monitoring for drug toxicity and cross-reactivity, rifabutin offers a switch alternative for adverse drug reactions (ADR)s attributed to rifampicin. This would negate the need to prolong treatment in the absence of a rifamycin as part of short-course multi-drug therapy. There is evidence of incomplete cross-resistance to rifampicin and rifabutin. Rifabutin may be useful in rifampicin-resistant tuberculosis, in an estimated 20% of cases, based on phenotypic or genotypic rifabutin susceptibility testing. Conclusions: Rifabutin should be available globally as a first line rifamycin in HIV co-infected individuals and as a switch option in cases of rifampicin associated ADRs. Further studies are needed to ascertain the utility of rifabutin in rifampicin-resistant rifabutin-susceptible tuberculosis.

Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. Areas covered: In this review, the authors discuss the rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.

Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response., Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.

Introduction Patients undergoing orthotopic heart transplant (OHT) have a 0.2 to 2.8% rate of infection with nontuberculous mycobacteria (NTM) in the year after transplant. Rifamycins, particularly rifampin, remain the backbone of NTM therapy; rifampin therapy can be especially challenging in solid organ transplant (SOT) due to potent CYP3A4 induction. Rifabutin, an alternative rifamycin, though less studied, is commonly substituted for rifampin in SOT due to less drug-drug interactions (DDI). Rifabutin is also a CYP3A4 substrate which can be impacted by concomitant CYP3A4 inhibitors. We report a case of an OHT recipient requiring systemic fungal prophylaxis while on rifabutin for pulmonary NTM. Case Report He is a 44-year old Caucasian male on 12 months of NTM treatment with rifabutin, azithromycin, and ethambutol who presented for OHT in his final month of treatment for pulmonary Mycobacterium kansasii. After OHT, he was started on high-dose steroids and triple-drug immunosuppression (IS). His NTM regimen was extended for another month. In addition to his IS regimen, isavuconazole was initiated for fungal prophylaxis rather than standard protocol posaconazole, for less CYP3A4 inhibition of rifabutin. Due to DDI, he required close therapeutic drug monitoring (TDM) to attain tacrolimus levels of 10-12ng/mL, requiring 10-15 mg/day (0.11-0.16 mg/kg/day) on the CYP3A4 inhibitor/inducer regimen. Rifabutin also remained therapeutic (0.3mcg/ml) on 300mg daily despite isavuconazole inhibition. After completion of rifabutin, tacrolimus requirements reduced to 6mg/day (0.06 mg/kg/day) with isavuconazole CYP3A4 inhibition alone. No breakthrough fungal infections occurred during isavuconazole prophylaxis despite the potential for rifabutin CYP3A4 induction. Summary Use of moderate CYP3A4 inhibitor isavuconazole with rifabutin did not result in rifabutin toxicity, particularly the shared ocular effects of ethambutol, and permitted effective systemic fungal prophylaxis. The degree of reduced exposure of isavuconazole inhibition due to a concomitant CYP3A4 induction of rifabutin remains unknown and requires monitoring for breakthrough infections. Close TDM may permit concomitant administration of significantly interacting CYP3A4 inhibitors, inducers, and substrates in complicated SOT patients.