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Antimicrobial Agents and Chemotherapy Mar 2021Recently, we reported rifabutin hyperactivity against We sought to characterize potential interactions between rifabutin and colistin, the last-resort drug for...
Recently, we reported rifabutin hyperactivity against We sought to characterize potential interactions between rifabutin and colistin, the last-resort drug for carbapenem-resistant infections. Rifabutin and colistin were synergistic and , and low-dose colistin significantly suppressed emergence of resistance to rifabutin. Thus, this combination is a promising therapeutic option for highly resistant infections.
Topics: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Microbial Sensitivity Tests; Rifabutin
PubMed: 33468472
DOI: 10.1128/AAC.02204-20 -
The Journal of Antimicrobial... Sep 2019TB 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...
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.
Topics: Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Biomarkers; Coinfection; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Lopinavir; Male; Retrospective Studies; Rifabutin; Ritonavir; Treatment Outcome; Tuberculosis
PubMed: 31139825
DOI: 10.1093/jac/dkz219 -
The Journal of Antimicrobial... Feb 2015Co-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... (Clinical Trial)
Clinical Trial
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 · h/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 · h/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.
Topics: Antiretroviral Therapy, Highly Active; Antitubercular Agents; Area Under Curve; Child, Preschool; Coinfection; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Lopinavir; Male; Rifabutin; Ritonavir; Treatment Outcome; Tuberculosis
PubMed: 25281400
DOI: 10.1093/jac/dku382 -
Antimicrobial Agents and Chemotherapy Jan 2021Current treatment options for lung disease caused by complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform...
Current treatment options for lung disease caused by complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the bactericidal activity of single drugs against actively multiplying and net nonreplicating populations in nutrient-rich and nutrient-starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing , respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and nonreplicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved Overall, these data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for infections. This rich data set of differential time- and concentration-dependent activity of drugs, alone and together, against also highlights several issues affecting interpretation and translation of findings.
Topics: Anti-Bacterial Agents; Diarylquinolines; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Nutrients; Pharmaceutical Preparations; Rifabutin
PubMed: 33168614
DOI: 10.1128/AAC.02179-20 -
Journal of Chromatography. B,... Nov 2022Breast milk is the preferred method of infant nutrition. Breastfeeding infants born to mothers treated for TB may be at risk of drug toxicity through breast milk...
Breast milk is the preferred method of infant nutrition. Breastfeeding infants born to mothers treated for TB may be at risk of drug toxicity through breast milk exposure, or potentially be vulnerable to select for drug resistance with low level drug exposure. Except for isoniazid, the quantification of first-line TB drugs including rifabutin in breast milk has not been previously described and will provide much-needed insight to TB drug exposure in breastfeeding infants. We developed and validated a novel method to quantify several first-line TB drugs and their major metabolites in breast milk. Accuracy and precision were assessed during three consecutive, independent validation batches over a calibration range of 0.300-30.0 µg/mL for isoniazid and ethambutol, 0.150-15.0 µg/mL for acetyl isoniazid, desacetyl rifampicin, rifampicin, and pyrazinamide, 0.0150-1.50 µg/mL for rifabutin, and 0.00751-0.751 µg/mL for deacetyl rifabutin in breast milk. The method was reproducible for all analytes when using breast milk from six different sources and was not influenced by matrix effects with a mean regression precision (CV(%)) ranging between 1.0 and 2.8. The average recovery of analytes from the matrix was 76.7-99.1%, with a CV(%) between 0.4 and 4.4, while the average process efficiency was between 74.4 and 93.1% with a CV(%) between 1.9 and 8.3. Although only acetyl isoniazid, isoniazid, ethambutol, and pyrazinamide were successfully assayed in breast milk, samples taken from mothers treated for rifampicin-resistant TB and the inclusion of all first-line TB drugs, including rifabutin in the assay development and validation process will allow future quantification of these analytes in breast milk.
Topics: Female; Humans; Antitubercular Agents; Isoniazid; Ethambutol; Pyrazinamide; Rifabutin; Rifampin; Chromatography, Liquid; Milk, Human; Tandem Mass Spectrometry
PubMed: 36215877
DOI: 10.1016/j.jchromb.2022.123489 -
Microbiology Spectrum Jun 2022Defining the precise relationship between resistance mutations and quantitative phenotypic drug susceptibility testing will increase the value of whole-genome sequencing...
Defining the precise relationship between resistance mutations and quantitative phenotypic drug susceptibility testing will increase the value of whole-genome sequencing (WGS) for predicting tuberculosis drug resistance. However, a large number of WGS data sets currently lack corresponding quantitative phenotypic data-the MICs. Using MYCOTBI plates, we determined the MICs to nine antituberculosis drugs for 154 clinical multidrug-resistant tuberculosis isolates from the Shenzhen Center for Chronic Disease Control in Shenzhen, China. Comparing MICs with predicted drug-resistance profiles inferred by WGS showed that WGS could predict the levels of resistance to isoniazid, rifampicin, streptomycin, fluoroquinolones, and aminoglycosides. We also found some mutations that may not be associated with drug resistance, such as EmbB D328G, mutations in the gene, and C-12T in the promoter. However, some strains carrying the same mutations showed different levels of resistance to the corresponding drugs. The MICs of different strains with the RpsL K88R, C-15T mutations and some with mutations in and , had MICs to the corresponding drugs that varied by 8-fold or more. This variation is unexplained but could be influenced by the bacterial genetic background. Additionally, we found that 32.3% of rifampicin-resistant isolates were rifabutin-susceptible, particularly those with mutations H445D, H445L, H445S, D435V, D435F, L452P, S441Q, and S441V. Studying the influence of bacterial genetic background on the MIC and the relationship between rifampicin-resistant mutations and rifabutin resistance levels should improve the ability of WGS to guide the selection of medical treatment regimens. Whole-genome sequencing (WGS) has excellent potential in drug-resistance prediction. The MICs are essential indications of adding a particular antituberculosis drug dosage or changing the entire treatment regimen. However, the relationship between many known drug-resistant mutations and MICs is unclear, especially for rarer ones. The results showed that WGS could predict resistance levels to isoniazid, rifampicin, streptomycin, fluoroquinolones, and aminoglycosides. However, some mutations may not be associated with drug resistance, and some others may confer various MICs to strains carrying them. Also, 32.3% of rifampicin (RIF)-resistant strains were classified as sensitive to rifabutin (RFB), and some mutations in the gene may be associated with this phenotype. Our data on the MIC distribution of strains with some rarer mutations add to the accumulated data on the resistance level associated with such mutations to help guide further research and draw meaningful conclusions.
Topics: Aminoglycosides; Antitubercular Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifabutin; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant
PubMed: 35658579
DOI: 10.1128/spectrum.02714-21 -
Helicobacter Aug 2022Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects...
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 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.
Topics: Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Humans; Proton Pump Inhibitors; Rifabutin; Treatment Outcome
PubMed: 35644041
DOI: 10.1111/hel.12900 -
Antimicrobial Agents and Chemotherapy Aug 2018Repurposing drugs may be useful as an add-on in the treatment of pulmonary infections, which are particularly difficult to cure. naturally produces a β-lactamase,...
Repurposing drugs may be useful as an add-on in the treatment of pulmonary infections, which are particularly difficult to cure. naturally produces a β-lactamase, Bla, which is inhibited by avibactam. The recommended regimens include imipenem, which is hydrolyzed by Bla and used without any β-lactamase inhibitor. Here, we determine whether the addition of rifabutin improves the activity of imipenem alone or in combination with avibactam against CIP104536. Rifabutin at 16 μg/ml was only bacteriostatic (MIC of 4 μg/ml) and was moderately synergistic in combination with imipenem (fractional inhibitory concentration [FIC] index of 0.38). Addition of rifabutin (16 μg/ml) moderately increased killing by a low (8 μg/ml) but not by a high (32 μg/ml) concentration of imipenem. Addition of avibactam (4 μg/ml) did not further increase killing by the former combination. In infected macrophages, rifabutin (16 μg/ml) increased the activity of imipenem at 8 and 32 μg/ml, achieving 3- and 100-fold reductions in the numbers of intracellular bacteria, respectively. Avibactam (16 μg/ml) improved killing by imipenem at 8 μg/ml. A 5-fold killing was obtained for a triple combination comprising avibactam (16 μg/ml) and therapeutically achievable doses of imipenem (8 μg/ml) and rifabutin (1 μg/ml). These results indicate that the imipenem-rifabutin combination should be further considered for the treatment of pulmonary infections in cystic fibrosis patients and that addition of a β-lactamase inhibitor might improve its efficacy. Mechanistically, the impact of Bla inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and a β-lactamase-deficient derivative.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Imipenem; Microbial Sensitivity Tests; Mycobacterium abscessus; Rifabutin
PubMed: 29866869
DOI: 10.1128/AAC.00623-18 -
World Journal of Gastroenterology Jan 2023Due to increasing resistance rates of () to different antibiotics, failures in eradication therapies are becoming more frequent. Even though eradication criteria and...
BACKGROUND
Due to increasing resistance rates of () 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 infection are well-established, there is no clear recommendation for third-line and rescue therapy in refractory infection.
AIM
To perform a systematic review evaluating the efficacy and safety of rescue therapies against refractory infection.
METHODS
A systematic search of available rescue treatments for refractory 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 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.
Topics: Humans; Helicobacter Infections; Anti-Bacterial Agents; Metronidazole; Helicobacter pylori; Bismuth; Levofloxacin; Proton Pump Inhibitors; Drug Therapy, Combination; Macrolides; Drug Resistance, Bacterial; Tetracycline; Rifabutin
PubMed: 36687120
DOI: 10.3748/wjg.v29.i2.390 -
Synergistic Effects of Omadacycline with Other Antimicrobial Agents against Mycobacterium abscessus.Antimicrobial Agents and Chemotherapy Jun 2023The clinical importance of Mycobacterium abscessus species (MABS) infections has been increasing. However, the standard treatment regimens recommended in the current...
The clinical importance of Mycobacterium abscessus species (MABS) infections has been increasing. However, the standard treatment regimens recommended in the current guidelines often result in unfavorable outcomes. Therefore, we investigated the activity of omadacycline (OMC), a novel tetracycline, against MABS to explore its potential as a novel therapeutic option. The drug susceptibilities of 40 Mycobacterium abscessus subsp. (Mab) clinical strains obtained from the sputum of 40 patients from January 2005 to May 2014 were investigated. The MIC results for OMC, amikacin (AMK), clarithromycin (CLR), clofazimine (CLO), imipenem (IPM), rifabutin (RFB), and tedizolid (TZD) alone and their combined effects (with OMC) were examined using the checkerboard method. Additionally, we studied the differences in the effectiveness of the antibiotic combinations based on the colony morphotype of Mab. The MIC and MIC of OMC alone were 2 and 4 μg/mL, respectively. The combinations of OMC with AMK, CLR, CLO, IPM, RFB, and TZD showed synergy against 17.5%, 75.8%, 25.0%, 21.1%, 76.9%, and 34.4% of the strains, respectively. Additionally, OMC combined with CLO (47.1% versus 9.5%, 0.023) or TZD (60.0% versus 12.5%, 0.009) showed significantly higher synergy against strains with rough morphotypes than those with smooth morphotypes. In conclusion, the checkerboard analyses revealed that the synergistic effects of OMC were observed most frequently with RFB, followed by CLR, TZD, CLO, IPM, and AMK. Furthermore, OMC tended to be more effective against rough-morphotype Mab strains.
Topics: Humans; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Clarithromycin; Amikacin; Anti-Infective Agents; Mycobacterium; Rifabutin; Tetracyclines; Microbial Sensitivity Tests
PubMed: 37154742
DOI: 10.1128/aac.01579-22