Concentrations Of Rifampin Research Articles

Endogenously doped mixed-oxide CoO/Co2O3 in ZIF-derived carbon deposited on graphite felt for electrochemical oxidation of pharmaceutics

Some of the important goals in the development of the electro-Fenton (EF) process are to increase the performance of the electrodes while reducing their size as an alternative for expensive electrodes, expanding the active pH range, and also generating reactive oxygen species (ROSs) directly without using other homo/heterogeneous catalysts. This work modified graphite felt (GF) using a rapid and in-situ synthesis with Co/Zn doped mixed-metal ZIF. After calcination, various physicochemical analyses, including XRD, SEM, and XPS, confirmed that a carbonic material doped with mixed-oxide CoO/Co2O3 is embedded on the surface of GF fibers. LSV analysis showed that the modification significantly improved the electrode activity for O2 reduction. The modified CoZnCal-GF electrode showed good performance and higher kinetics in the EF process. It removed 87% of rifampin (RIF) in a short period of 30 min without any homo/heterogeneous catalysts. The selected conditions for this process were 1.0 V, 40 mg/L, and 5.6 for applied voltage, initial RIF concentration, and pH, respectively. The non-radical species 1O2 showed the most important role in removing RIF. LC-MS analysis was performed, and while confirming the complete removal of RIF, it was used to investigate the degradation pathway and identify the produced intermediates.

Estimating optimal therapeutic drug levels of anti-tuberculosis medications based on treatment safety and effectiveness.

Therapeutic drug ranges (TDR) for standard anti-tuberculosis (TB) treatment have been determined based on expected drug levels at least 2 hours after taking the dose. In this study we constructed TDR for TB drug levels based on minimizing drug toxicity and maximizing treatment effectiveness. Participants were followed prospectively in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil observational cohort study. We focused on participants with culture-confirmed drug-susceptible pulmonary TB who underwent standard TB therapy. TDR were estimated for each TB drug separately: isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA). TDR were defined as drug concentrations that were both safe and effective: safety was defined as the probability of having an ADR of at most 5%, while effectiveness was defined as a probability of at least 95% of not having either TB treatment failure or recurrence. There were 765 plasma samples from 448 patients; 110 (24.6%) were people with HIV, 9 (2.0%) had a grade 3 or higher ADR, and 15 (3.3%) had treatment failure/recurrence. Higher drug concentrations of INH, RIF and EMB were associated with increased odds of having ADR. High concentrations of INH suggested protection against treatment failure/recurrence. Estimated therapeutic drug range for INH (2.3-8.2 µg/ml) and for RIF (0.5-7.5 µg/ml) differed from the currently recommended drug ranges (3-5 µg/ml and 8-24 µg/ml, respectively). Estimates for PZA and EMB were similar to the currently recommended values. Our estimated upper end TDR were higher for INH and lower for RIF compared to currently recommended ranges.

Mechanically stable rifampin antibiotic cement inhibits Pseudomonas aeruginosa biofilm surface growth.

Rifampin has been proven to be effective in the treatment of prosthetic infections due to its ability to intercalate into biofilms. The use of rifampin in antibiotic spacers is not well described, which would be especially important in the local periprosthetic environment where parenteral doses have poor penetration. The null hypothesis tests if rifampin use in polymethyl methacrylate (PMMA) cement will show no clinically significant impact on mechanical strength at antibiotic concentrations that remain bactericidal. Test antibiotic cement samples supplemented with 0, 30, 50, 100, 150, or 200 mg of rifampin into a standard 40 g bag were tested for compression to failure using published ASTM standards. The samples were then inoculated with Pseudomonas aeruginosa and either evaluated for lipopolysaccharide (LPS) presence as a marker of biofilm or tested by elution as the Kirby Bauer assay. Rifampin concentrations of 30 and 50 mg, showed no statistically different mechanical characteristics from control PMMA (p > 0.05). The 100-mg sample fell within the acceptable range of compressive strength and had significantly less LPS and bacterial presence compared to the control at 12 and 24 h. The ability of PMMA with 100 mg of rifampin to maintain its structural integrity and have significant bacterial inhibition at 12 and 24 h makes it a great candidate as an antibiotic bone cement additive. PMMA loaded with up to 100 mg of rifampin shows promise in the treatment and prevention of periprosthetic joint infection for total knee and total hip arthroplasty.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Effects of sub-inhibitory concentration of antibiotic and heat stress on the expression of type II TA system genes in Brucella spp.

ObjectiveBacteria can react to stress conditions using the Toxin-Antitoxin (TA) system. This study investigated the expression of TA system genes under heat and antibiotic stresses in Brucella spp. MethodsTo determine the effects of sub-inhibitory concentration (sub-MIC) of rifampin on bacterial survival and growth, a colony-forming unit was quantitated, and turbidity was assessed following the treatment of Brucella isolates, with ½ minimum inhibitory concentration (MIC) of antibiotic at different time intervals. Also, Brucella isolates were exposed to heat stress (42 °C) compared to the control (37 °C). Finally, the expression of TA system genes in Brucella isolates was evaluated one hour after treatment using the quantitative reverse transcription PCR (qRT-PCR) method. ResultsOur results showed that the growth of the Brucella isolates reduced in the presence of the sub-MIC of antibiotics compared to the control. The results of the qPCR assay showed that, in the presence of rifampicin the expression of the TA system genes increased and, under the heat stress conditions, the expression of the TA system genes increased compared to controls expect brnT / brnA system. ConclusionAlthough the exact role of the TA system in response to various stresses is not yet fully understood, our study provided information on the effectiveness of the type II TA system under heat and antibiotic stress conditions by examining the gene expression of type II systems in Brucella isolates.

A Simple UPLC-MS/MS Assay of Rifampin in a Small Volume of Human Plasma.

Rifampin (RIF) is a typical cytochrome P450 (CYP) 3A inducer and inhibitor of organic anion transporting polypeptide (OATP) 1B1 to assess drug-drug interaction (DDI) via CYP3A or OATP1B1 in clinical settings. To ensure sufficient exposure of RIF in DDI studies, it is important to determine plasma RIF concentrations. In this study, we developed a simple RIF assay in a small volume of human plasma by ultraperformance liquid chromatography with tandem mass spectrometry. RIF in 0.02 mL of plasma was extracted using protein precipitation and separated on a reverse phase column under gradient elution of three mobile phases, where the mobile phase C containing 1% formic acid was exclusively used to reduce the carryover of RIF. RIF and the internal standard were detected by multiple reaction monitoring in positive-ion electrospray ionization. RIF was quantifiable at 0.025-10 μg/mL without the carryover issue. The intra- and inter-run assays confirmed the reproducibility of the assay. Stability assessments ensured that RIF in human plasma was stable for 6 h at room temperature and for 409 days at -15 °C or below. The assay was successfully applied to a pharmacokinetic study with successful incurred sample reanalysis.

Effects of sub-inhibitory concentration of antibiotic and heat stress on the expression of type II TA system genes in Brucella spp.

ObjectiveBacteria can react to stress conditions using the Toxin-Antitoxin (TA) system. This study investigated the expression of TA system genes under heat and antibiotic stresses in Brucella spp. MethodsTo determine the effects of sub-inhibitory concentration (sub-MIC) of rifampin on bacterial survival and growth, a colony-forming unit was quantitated, and turbidity was assessed following the treatment of Brucella isolates, with ½ minimum inhibitory concentration (MIC) of antibiotic at different time intervals. Also, Brucella isolates were exposed to heat stress (42 °C) compared to the control (37 °C). Finally, the expression of TA system genes in Brucella isolates was evaluated one hour after treatment using the quantitative reverse transcription PCR (qRT-PCR) method. ResultsOur results showed that the growth of the Brucella isolates reduced in the presence of the sub-MIC of antibiotics compared to the control. The results of the qPCR assay showed that, in the presence of rifampicin the expression of the TA system genes increased and, under the heat stress conditions, the expression of the TA system genes increased compared to controls expect brnT / brnA system. ConclusionAlthough the exact role of the TA system in response to various stresses is not yet fully understood, our study provided information on the effectiveness of the type II TA system under heat and antibiotic stress conditions by examining the gene expression of type II systems in Brucella isolates.

Antibiofilm effect of melittin alone and in combination with conventional antibiotics toward strong biofilm of MDR-MRSA and -Pseudomonas aeruginosa.

Multidrug-resistant (MDR) pathogens are being recognized as a critical threat to human health if they can form biofilm and, in this sense, biofilm-forming MDR-methicillin resistant Staphylococcus aureus (MRSA) and -Pseudomonas aeruginosa strains are a worse concern. Hence, a growing body of documents has introduced antimicrobial peptides (AMPs) as a substitute candidate for conventional antimicrobial agents against drug-resistant and biofilm-associated infections. We evaluated melittin's antibacterial and antibiofilm activity alone and/or in combination with gentamicin, ciprofloxacin, rifampin, and vancomycin on biofilm-forming MDR-P. aeruginosa and MDR-MRSA strains. Antibacterial tests [antibiogram, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC)], anti-biofilm tests [minimum biofilm inhibition concentration (MBIC), and minimum biofilm eradication concentration (MBEC)], as well as synergistic antibiofilm activity of melittin and antibiotics, were performed. Besides, the influence of melittin alone on the biofilm encoding genes and the cytotoxicity and hemolytic effects of melittin were examined. MIC, MBC, MBIC, and MBEC indices for melittin were in the range of 0.625-5, 1.25-10, 2.5-20, and 10-40 μg/ml, respectively. The findings found that the combination of melittin AMP with antibiotics was synergistic and fractional biofilm inhibitory concentration index (FBICi) for most tested concentrations was <0.5, resulting in a significant reduction in melittin, gentamicin, ciprofloxacin, vancomycin, and rifampin concentrations by 2-256.4, 2-128, 2-16, 4-64 and 4-8 folds, respectively. This phenomenon reduced the toxicity of melittin, whereby its synergist concentration required for biofilm inhibition did not show cytotoxicity and hemolytic activity. Our findings found that melittin decreased the expression of icaA in S. aureus and LasR in P. aeruginosa genes from 0.1 to 4.11 fold for icaA, and 0.11 to 3.7 fold for LasR, respectively. Overall, the results obtained from our study show that melittin alone is effective against the strong biofilm of MDR pathogens and also offers sound synergistic effects with antibiotics without toxicity. Hence, combining melittin and antibiotics can be a potential candidate for further evaluation of in vivo infections by MDR pathogens.

Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment: A physiologically based pharmacokinetic modeling and simulations study

Objective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted. ResultsThe rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing. ConclusionIn this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.

Design and preparation magnetic bio-surfactant rhamnolipid-layered double hydroxide nanocomposite as an efficient and recyclable adsorbent for the removal of Rifampin from aqueous solution

In this study, a magnetic core–shell rhamnolipid (MCSR) intercalated cobalt/aluminum layered double hydroxide (LDH) has been used for water remediation and rifampin (RIF) removal. Biosurfactants, including rhamnolipid (RL), exhibit advantages such as low toxicity and environmental compatibility. Moreover, rhamnolipid can promote the removal efficiency of the adsorbent. The effect of major factors on the adsorption process, including pH of the solution, initial RIF concentration, contact time, and adsorbent dosage were examined and optimized in detail. Accordingly, in acidic pH the adsorption efficiency was the highest because in this condition, OH functional groups of RIF molecules may be protonated leading to interacting with positively charged LDH layers. The results showed that the RIF removal efficiency is 96 %. According to the Langmuir model, the maximum adsorption capacity obtained for 0.67 g/L of adsorbent (20 mg of adsorbent in 30 mL of RIF solution) was 221.30 mg/g. In accordance with the modeling results, the Temkin isotherm better expresses the adsorption mechanism at the surface of MCSR-LDH. Furthermore, the kinetic data was better suited to the pseudo-first-order model, indicating that the solution reaches equilibrium between 20 and 30 min. Evaluation of thermodynamic parameters indicated the exothermic nature of adsorption process (ΔH° = −68362.70 J/mol). The magnetic property of MCSR-LDH leads to the easy recovery of the adsorbent by an external magnet at the end of the adsorption process, so that it can be regenerated for repeated cycles of at least four cycles without a significant decrease in efficiency.

Minimum inhibitory concentrations of rifampin and isoniazid among multidrug and isoniazid resistant Mycobacterium tuberculosis in Ethiopia.

Traditionally, single critical concentrations of drugs are utilized for Mycobacterium tuberculosis (Mtb) drug susceptibility testing (DST); however, the level of drug resistance can impact treatment choices and outcomes. Mutations at the katG gene are the major genetic mutations in multidrug resistant (MDR) Mtb and usually associated with high level resistance. We assessed the minimum inhibitory concentrations (MICs) of MDR or rifampin resistant (RR) and isoniazid (INH) resistant Mtb isolates to determine the quantification of drug resistance among key anti-tuberculosis drugs. The study was conducted on stored Mtb isolates collected as part of a national drug resistance survey in Ethiopia. MIC values were determined using Sensititre™ MYCOTB plates. A line probe assay (MTBDRplus) was also performed to identify genetic determinants of resistance for all isolates. MIC testing was performed on 74 Mtb isolates including 46 MDR, 2 RR and 26 INH phenotypically resistant isolates as determined by the Löwenstein Jensen (LJ) method. Four (15%) INH resistant Mtb isolates were detected as borderline rifampin resistance (MIC = 1 μg/ml) using MYCOTB MIC plates and no rifampin resistance mutations were detected by LPA. Among the 48 MDR/RR TB cases, 9 (19%) were rifabutin susceptible (MIC was between ≤0.25 and 0.5μg/ml). Additionally, the MIC for isoniazid was between 2-4 μg/ml (moderate resistance) for 58% of MDR TB isolates and 95.6% (n = 25) of the isolates had mutations at the katG gene. Our findings suggest a role for rifabutin treatment in a subset of RR TB patients, thus potentially preserving an important drug class. The high proportion of moderate level INH resistant among MDR Mtb isolates indicates the potential benefit of high dose isoniazid treatment in a high proportion of katG gene harboring MDR Mtb isolates.

SLCO1B1 and SLC10A1 polymorphism and plasma rifampin concentrations in patients with co-morbidity tuberculosis-diabetes mellitus in Baja California, Mexico

Rifampicin is one of the most important drugs for the treatment of tuberculosis (TB). Polymorphisms in SLCO1B1 and SLC10A1 genes are associated with impaired transporter function of drug compounds such as rifampicin. The relationship between genetic variation, clinical comorbidities, and rifampicin exposures in TB patients has not been completely elucidated. The aim of this study was to investigate the prevalence of SLCO1A1 and SLCO1B1 polymorphisms in TB and TB-DM patients and to determine their relationship with rifampicin pharmacokinetics on patients from México. Blood samples were collected in two hospitals in Baja California, Mexico from February through December 2017. Sampling included 19 patients with TB, 11 with T2DM and 17 healthy individuals. Polymorphisms genotype rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs72559746,rs2291075 and rs4603354 of SLCO1B1 and rs4646285 and rs138880008 of SLC10A1 were analyzed by Sanger's sequencing. None of the SLCO1B1 and SLC10A1 variants were significantly associated with rifampicin Cmax. TB and T2DM patients with suboptimal Cmax rifampicin levels showed wild alleles in rs11045819 and rs2291075 in SLCO1B1 SLC10A1 and SLC10A1. This is the first study to analyze SLC10A1 and SLCO1B1 polymorphisms in TB and TB-T2DM patients and healthy individuals in Mexico. Further research to confirm and extend these findings is necessary.

Facile preparation of sisal–Fe/Zn layered double hydroxide bio-nanocomposites for the efficient removal of rifampin from aqueous solution: kinetic, equilibrium, and thermodynamic studies

In the present study, sisal–Fe/Zn LDH bio-nanocomposite for efficiently removing rifampin was synthesized using a simple co-precipitation method. SEM, XRD, and FTIR analyses were applied to characterize the prepared composite. In the following, different factors that are affecting the adsorption of rifampin, including contact time, initial rifampin concentration, adsorbent dosage, and temperature were evaluated. Also, the kinetic, isotherm, and thermodynamic studies were investigated. The results indicated that Freundlich (R 2 = 0.9976) was a suitable model for describing the adsorption equilibrium and adsorption kinetic showed that the data are in maximum agreement with the pseudo-second-order kinetic model (R 2 = 0.9931). According to the Langmuir isotherm model, the maximum adsorption capacity of rifampin was found to be 40.00 mg/g. The main mechanisms for rifampin elimination were introduced as electrostatic attraction and physical adsorption. Moreover, the spontaneity and nature of the reaction were analyzed by elucidating thermodynamic factors that indicated the adsorption process was exothermic and spontaneous. Also, the batch process design indicated that for treating 10 L wastewater containing 100 mg/L rifampin with a removal efficiency of 96%, the needed amount of sisal–Fe/Zn LDH is 51.6 g. This study revealed that the sisal–Fe/Zn LDH bio-nanocomposites as a low-cost adsorbent have promising adsorption potential.

Highly Synergistic Effects of Melittin With Vancomycin and Rifampin Against Vancomycin and Rifampin Resistant Staphylococcus epidermidis.

Methicillin-resistant Staphylococcus epidermidis (MRSE) strains are increasingly emerging as serious pathogens because they can be resistant to many antibiotics called multidrug resistance (MDR) that limit the therapeutic options. In the case of vancomycin- and rifampin-resistant MDR-MRSE, the physicians are not allowed to increase the doses of antibiotics because of severe toxicity. Accordingly, we investigated the synergistic activity of melittin antimicrobial peptide with vancomycin and rifampin against vancomycin-resistant, and rifampin-resistant MDR-MRSE isolates. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), fractional inhibitory concentration index (FICi), and fractional bactericidal concentration index (FBCi) of antimicrobial agents against isolates were determined. Coagulate activities and serum and salt stability as well as melittin cytotoxicity on the human embryonic kidney (HEK) 293 cells and human red blood cells (RBCs) at their synergistic concentrations. MIC and MBC values for melittin were in the range of 0.312–2.5 and 0.312–5, respectively. Results also showed that the interaction of melittin with drugs was highly synergistic in which the geometric means of FICi and FBCi were < 0.5. Induced synergism led to a decrease in melittin, rifampin, and vancomycin concentrations by 8–1,020, 2–16, and 4–16-folds, respectively. This phenomenon caused a reduction in melittin toxicity by which the synergistic concentration of melittin needed to kill bacteria did not show cytotoxicity and hemolytic activity. Besides, no coagulation activity was found for the synergistic and alone concentrations of melittin in both Prothrombin Time (PT) and Partial Thromboplastin Time (PTT). Interestingly, the antibacterial activity of melittin in Mueller Hinton Broth (MHB) containing human serum did no significant differences between MIC and MBC values of melittin in MHB and MHB containing 10% human serum. The present findings showed that the therapeutic index of melittin was improved by 32.08- and 12.82-folds when combined with vancomycin and rifampin, respectively. Taken together, the obtained data show that melittin alone was effective against MDR-MRSE isolates and this antimicrobial peptide showed highly synergistic effects with vancomycin and rifampin without causing toxicity. Therefore, the combination of melittin and traditional antibiotics could be a promising strategy for the treatment of infections caused by MDR-MRSE.

Antimicrobial Activity of a Triple Antibiotic Combination Toward Ocular Pseudomonas aeruginosa Clinical Isolates.

Purpose Pseudomonas aeruginosa is a leading cause of corneal infections. Recently, we discovered an antimicrobial drug combination, polymyxin B/trimethoprim (PT) + rifampin, that displayed impressive efficacy toward P. aeruginosa in both in vitro and in vivo studies. As such, this combination was further evaluated as a potential keratitis therapeutic through testing the combination's efficacy against a diverse set of P. aeruginosa clinical isolates.MethodsMinimum inhibitory concentrations (MICs) of moxifloxacin, levofloxacin, erythromycin, tobramycin, PT, polymyxin B (alone), trimethoprim (alone), and rifampin were determined for 154 ocular clinical P. aeruginosa isolates, 90% of which were derived from corneal scrapings. Additionally, the efficacy of PT + rifampin was evaluated utilizing fractional inhibitory concentration (FIC) testing.ResultsWhile 100% of isolates were resistant to erythromycin (average MIC 224 ± 110 µg·mL−1) and trimethoprim (alone) (206 ± 67.3 µg·mL−1), antibiotic resistance was generally found to be low: moxifloxacin (2% of isolates resistant; average MIC 1.08 ± 1.61 µg·mL−1), levofloxacin (3.9%; 1.02 ± 2.96 µg·mL−1), tobramycin (1%; 0.319 ± 1.31 µg·mL−1), polymyxin B (0%; 0.539 ± 0.206 µg·mL−1), PT (0%; 0.416 ± 0.135 µg·mL−1), and rifampin (0%; 23.4 ± 6.86 µg·mL−1). Additionally, FIC testing revealed that PT + rifampin eradicated 100% of isolates demonstrating additive or synergistic activity in 95% of isolates (average FIC index 0.701 ± 0.132).ConclusionsThe drug combination of PT + rifampin was effective against a large panel of clinically relevant P. aeruginosa strains and, as such, may represent a promising therapeutic for P. aeruginosa keratitis.Translational RelevanceThis work furthers the preclinical development of a novel antibiotic combination for the treatment of corneal infections (bacterial keratitis).

Pre-clinical evaluation of a third generation absorbable antibacterial envelope

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Background An absorbable antibacterial envelope (TYRX), which stabilizes cardiac implantable electronic devices (CIEDs) was shown to significantly reduce infections in a large randomized controlled trial (WRAP-IT). A 3rd generation envelope (T3) is being developed to improve the implanter experience and enable smoother device insertion with a redesigned, multifilament mesh, an enhanced form factor, and identical polymer coating and antibiotic concentrations as the currently available 2nd generation envelope (T2). Purpose To compare drug elution profiles of T3 vs T2 and evaluate the efficacy of T3 against bacteria commonly known to be associated with CIED infections. Methods The T3 drug elution profile was assessed in vitro by evaluating the amount of each drug, minocycline and rifampin, released at a given timepoint using an accelerated dissolution method. For comparative analysis with T2, elution curve equivalency was based on similarity factor values (f2) of ≥50 per FDA guidance. An in vivo elution study was also conducted (per the Principles of Laboratory Animal Care [NIH Publication no. 85-23 revised 1985]) to ensure drug concentrations met the minimal inhibitory concentration (MIC) through 7 days. Substantial equivalence was defined as rifampin and minocycline concentrations above MIC at 2hr post-implant and sustained through 7 days. In a further animal model, 12 pockets were created in 6 rabbits, for CIED insertion with and without T3 envelopes, to evaluate efficacy against gram+ and gram- bacteria. At day 7, implant sites were evaluated for signs of infection via macroscopic observations and microbial recovery procedures. A Fisher’s Exact Test was used for comparisons. Results The T3 envelope showed a similar elution profile to T2 in vitro (Figure) with f2 &amp;gt;50 (range 76-84). In the in vivo assessment, the T3 envelope eluted both antibiotics above the MIC at 2hr post-implant with sustained elution through 7 days, consistent with historical T2 performance. Further bacterial challenge studies in vivo showed a statistically significant reduction (p&amp;lt;0.05) in infections with 0/6 infected pockets in the CIED + T3 group vs 6/6 infected pockets in the CIED only group consistent with T2 performance (Table). Conclusion The 3rd generation absorbable antibacterial envelope demonstrated equivalent pre-clinical performance compared to the 2nd generation envelope as antibiotic elution curves were equivalent, elution was sustained at concentrations above MIC for 7 days, and infection rates were significantly reduced compared to no envelope. These results suggest equivalent clinical performance could be expected with the newly designed envelope.

Evaluation of a novel inhibitor of aspartate semialdehyde dehydrogenase as a potent antitubercular agent against Mycobacterium tuberculosis.

The in vitro activity of IMB-XMA0038, a novel inhibitor targeting Mycobacterial tuberculosis (Mtb) aspartate semialdehyde dehydrogenase, was evaluated. Minimum inhibitory concentrations (MICs) of IMB-XMA0038 were against 20 Mtb isolates, including H37Rv (ATCC 27294), ten clinical pan-sensitive isolates, and nine clinical multidrug-resistant (MDR) isolates. In addition, minimum bactericidal concentrations (MBCs) were also determined against the H37Rv and 6 MDR isolates (the background information is same as above in order). A model was generated to evaluate IMB-XMA0038 activity against dormant Mtb. The post-antibiotic effect (PAE), an important indicator of antimicrobial drug dosing schedules to obtain efficacy, was determined based on time required for regrowth of Mtb to 50% of the OD600max value after treatment with various concentrations of IMB-XMA0038 and INH. In addition, interactions between IMB-XMA0038 and other anti-tuberculosis drugs, measured using a checkerboard assay, revealed that IMB-XMA0038 MICs of 0.5-1 μg/mL could be achieved in combinations. Synergistic effects were observed for IMB-XMA0038 when used together with almost all other anti-tuberculosis drugs against most Mtb isolates. IMB-XMA0038 exhibited greater activity than rifampin against Mtb under hypoxic conditions, as reflected by CFU decreases of 1.1-log-unit versus 0.8-log-unit, respectively, for IMB-XMA0038 and rifampin concentrations of 4 × MIC. IMB-XMA0038-induced PAEs (9, 10, 11 days) were comparable to INH PAEs (10, 11, 12 days). These findings suggest that addition of IMB-XMA0038 to current therapeutic regimens could be useful to improve the efficacy of treatments for drug-resistant and drug-susceptible TB.

Rifampin Pharmacokinetics/Pharmacodynamics in the Hollow-Fiber Model of Mycobacterium kansasii Infection.

ABSTRACTThere is limited high-quality evidence to guide the optimal treatment of Mycobacterium kansasii pulmonary disease. We retrospectively collected clinical data from 33 patients with M. kansasii pulmonary disease to determine the time-to-sputum culture conversion (SCC) upon treatment with a standard combination regimen consist of isoniazid-rifampin-ethambutol. Next, MIC experiments with 20 clinical isolates were performed, followed by a dose-response study with the standard laboratory strain using the hollow-fiber system model of M. kansasii infection (HFS-Mkn). The inhibitory sigmoid maximum effect (Emax) model was used to describe the relationship between the bacterial burden and rifampin concentrations. Finally, in silico clinical trial simulations were performed to determine the clinical dose to achieve the optimal rifampin exposure in patients. The SCC rate in patients treated with combination regimen containing rifampin at 10 mg/kg of body weight/day was 73%, the mean time to SSC was 108 days, and the mean duration of therapy was 382 days. The MIC of the M. kansasii laboratory strain was 0.125 mg/L, whereas the MICs of the clinical isolates ranged between 0.5 and 4 mg/L. In the HFS-Mkn model, a maximum kill (Emax) of 7.82 log10 CFU/mL was recorded on study day 21. The effective concentration mediating 80% of the Emax (EC80) was calculated as the ratio of the maximum concentration of drug in serum for the free, unbound fraction (fCmax) to MIC of 34.22. The target attainment probability of the standard 10-mg/kg/day dose fell below 90% even at the MIC of 0.0625 mg/L. Despite the initial kill, there was M. kansasii regrowth with the standard rifampin dose in the HFS-Mkn model. Doses higher than 10 mg/kg/day, in combination with other drugs, need to be evaluated for better treatment outcome.

Phenotypical and Genotypical Comparison of Clostridium difficile Isolated from Clinical Samples: Homebrew DNA Fingerprinting versus Antibiotic Susceptibility Testing (AST) and Clostridial Toxin Genes.

Background Clostridium (Clostridioides) difficile is recognized as the major cause of healthcare antibiotic-associated diarrhea. We surveyed a molecular epidemiological correlation between the clinical isolates from two general hospitals in Iran through clustering toxigenic types and antibiotic susceptibility testing (AST) accuracy. Methods Study population included 460 diarrhoeic specimens from inpatients with a history of antibiotic therapy. All samples underwent enriched anaerobic culture, confirmed by detection of gluD gene with PCR. Toxin status and AST were assessed by the disk diffusion method (DDM) and minimal inhibitory concentrations (MICs) of metronidazole, vancomycin, and rifampin. C. difficile outbreak was analyzed through conventional PCR by tracing toxin genes and Homebrew pulsed-field gel electrophoresis (PFGE) for characterizing isolates within our healthcare systems. Results A total of 29 C. difficile strains were isolated by enriched anaerobic culture from the clinical samples. Among them, 22 (4.8%) toxigenic profiles yielded toxins A and B (tcdA, tcdB) and binary toxins (cdtA, cdtB). The minimum inhibitory concentration (MIC) was 18.1% and 9% for vancomycin and metronidazole, and all isolates were susceptible to rifampicin and its minimum inhibitory concentration was at <0.003 μg/mL. The most dominant toxigenic and antibiotic-resistant “pulsotype F” was detected through PFGE combined with multiple Clostridial toxigenic pattern and AST. Conclusions DNA fingerprinting studies represent a powerful tool in surveying hypervirulent C. difficile strains in clinical settings. Resistance to vancomycin and metronidazole, as first-line antibiotics, necessitate accomplishment of proper control strategies and also prescription of tigecycline as a more appropriate option.

Tanshinone ⅡA may alleviate rifampin-induced cholestasis by regulating the expression and function of NTCP.

The Na+-taurocholate cotransporting polypeptide (NTCP) acts as the major hepatic basolateral uptake system, and plays a key role in balancing bile flow. The anti-tuberculosis drugs rifampin (RFP) can affect bile flow causing liver injury, while tanshinone IIA (TAN IIA) has the effect of protecting liver. This study aimed to investigate the effects of RFP and TAN IIA on the NTCP expression and activity, and explore the potential connections. Herein, we established sandwich-cultured primary rat hepatocytes, and quantified mRNA and protein levels of NRF2 and NTCP after treatment with RFP (10, 25, or 50 μM) or co-treatment with TAN IIA (5, 10, or 20 μM) for 12, 24, 48 h (n = 3). NTCP activity was assessed by measuring the initial uptake rates of known substrates taurocholate (TCA) (n = 3) after treatment with different concentrations of RFP, TAN ⅡA for 12, 24 and 48 h. We found that RFP had inhibition effects on NRF2, NTCP mRNA and protein expression, and co-administration of TAN IIA could reverse RFP inhibition. TCA cellular accumulation was significantly decreased by RFP (39.1%), and TAN IIA could significantly induce TCA uptake of NTCP (2.9-fold at 48 h). The TCA uptake activity was correlated with the NTCP mRNA expression, confirming the role of RFP or TAN IIA on NTCP expression and activity is synchronous, and we can predict NTCP activity by detecting its mRNA expression. In conclusion, our work will enrich the significance of NTCP in the liver protection, and provide theoretical basis for TAN IIA to prevent RFP induced cholestatic liver injury.