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BACKGROUND: We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin. METHODS: Infants with HIV aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported. RESULTS: Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough

Rifampicin (RF) is a potent antibiotic, but its clinical effectiveness is limited by poor water solubility and stability. To overcome these limitations, RF is encapsulated in solid‐lipid nanoparticles (SLNs) using a one‐pot microwave microemulsion method. This study aimed to synthesize and characterize RF‐loaded SLNs, evaluating their physicochemical characteristics and antimicrobial efficacy. The synthesized SLNs exhibit particle sizes ranging from 150 to 200 nm, with a high encapsulation efficiency of ≈55% and high loading capacity. The particles are imaged by cryogenic‐transmission electron microscopy and found to be circular and elongated, with RF homogenously distributed throughout the particles. The RF‐loaded SLNs demonstrate potent antimicrobial activity, as evidenced by disc diffusion assays. The SLNs exhibits a sustained drug release profile, highlighting their potential as an effective drug delivery system for antimicrobial treatment. These findings suggest that SLNs can enhance the stability, bioavailability, and therapeutic efficacy of hydrophobic drugs like RF. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a serious, life‐threatening infectious disease that mostly affects the lungs and is caused by Mycobacterium tuberculosis (MTB). Still, in 2024, because of its widespreadness, contagious nature, and an increasing number of patients with other diseases, it is hard to cure, and leftovers as the deadliest disease to mankind across the world. In recent years, abundant efforts have been made to cure and eradicate TB, but drug‐resistant TB (DR‐TB) or multidrug‐resistant TB (MDR‐TB) surges the rate of mortality. Recently, World Health Organization (WHO) released the Global Tuberculosis (TB) Report 2022, in which the millions of infections and deaths stretched a line of serious concern to the scientists. In pursuit of searching for novel anti‐TB agents, several derivatives of sulfonamides have been synthesized and tested for their anti‐TB activity. It is noteworthy that lead compounds contain sulfonamide functionalities, which are the privileged motifs that act as crucial pharmacophores in many bioactive compounds and have diverse biological activities, including analgesics, antitubercular, antifungal, antidepressant, anti‐inflammatory, antihypertensive, antidiabetic, anticancer, antimalarial, antioxidant, antimicrobial, etc. The review encapsulates the latest methods for preparing sulfonamide derivatives and their groundbreaking medicinal applications from 2007 to 2020. [ABSTRACT FROM AUTHOR]

The interest in transporter‐mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion‐transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration‐dependent manner for both CP I and CP III in human hepatocytes (PXB‐cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild‐type ICR mice. Plasma concentrations (AUC0‐8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24‐h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP‐mediated drug interactions in PXB mice. [ABSTRACT FROM AUTHOR]

Rifaximin and rifampicin are good broad-spectrum antimicrobials. The irrational use of antimicrobial drugs in veterinary clinics could threaten public health and food safety. It is necessary to develop a reliable detection method of the residue for enhancing the rational supervision of the use of such drugs, reducing and slowing down the generation of bacterial resistance, and promoting animal food safety and human health. So, this study developed an LC-MS/MS method for the detection of rifaximin and rifampicin residues in animal-origin foods. The residual rifaximin and rifampicin of homogenized test materials were extracted with acetonitrile-dichloromethane solution or acetonitrile in the presence of anhydrous sodium sulfate and vitamin C, purified by dispersible solid phase extraction, determined by LC-MS/MS, and quantified by the internal standard method. The specificity, sensitivity, matrix effect, accuracy, and precision of the method were investigated in the edible tissues of cattle, swine, or chicken. In addition, the stability of the standard stock solution and the standard working solution was also investigated. The method was suitable for the muscle, liver, kidney, fat, milk, and eggs of cattle, swine, or chicken, as well as fish and shrimp. The specificity of the method was good, and the detection of the analytes was not affected by different matrices. Both the LOD and LOQ of the two analytes were 5 μg/kg and 10 μg/kg, respectively. The results of matrix effects in each tissue were in the range of 80–120%; there were no significant matrix effects. The average accuracy of rifaximin and rifampicin in different foodstuffs of animal origin was between 80% and 120%, and the method precision was below 20% (RSD). The proposed method showed good performance for determination, which could be employed for the extraction, purification, and detection of residual rifaximin and rifampicin in edible animal tissues. The pretreatment procedure of tissue samples was simple and feasible. The method was highly specific, stable, reliable, and with high sensitivity, accuracy, and precision, which met the requirements of quantitative detection of veterinary drug residues. [ABSTRACT FROM AUTHOR]

Drug biotransformation studies emerges as an alternative to pharmacological investigations of metabolites, development of new drug candidates with reduced investment and most efficient production. The present study aims to evaluate the capacity of biotransformation of rifampicin by the filamentous fungus Aspergillus niger ATCC 9029. After incubation for 312 h, the drug was metabolized to two molecules: an isomer (m/z 455) and the rifampicin quinone (m/z 821). The monitoring of metabolite formation was performed by high‐performance liquid chromatography, followed by their identification through ultra‐high‐performance liquid chromatography coupled to tandem mass spectrometer. In vitro antimicrobial activity of the proposed metabolites was evaluated against Staphylococus aureus microorganism, resulting in the loss of inhibitory activity when compared with the standards, with minimum inhibitory concentration of 7.5 μg/ml. The significant biotransformation power of the ATCC 9029 strain of A. niger was confirmed in this study, making this strain a candidate for pilot studies in fermentation tanks for the enzymatic metabolization of the antimicrobial rifampicin. The unprecedented result allows us to conclude that the prospect of new biotransforming strains in species of anemophilic fungi is a promising choice. [ABSTRACT FROM AUTHOR]

The intricate process of protein binding orchestrates crucial drug interactions within the bloodstream, facilitating the formation of soluble complexes. This research endeavours to improve the dissolution and oral bioavailability of Rifampicin (RMP) by strategically manipulating drug-protein binding dynamics and the hydrophobic characteristics of human serum albumin (HSA). Various precipitation techniques leveraging methanol, ammonium sulfate, and heat treatment were meticulously employed to tailor the properties of colloidal albumin (HSA NPs). The resultant complexes underwent comprehensive characterization encompassing evaluations of hydrophobicity, size distribution, surface charge, and structural analyses through FTIR, TG-DSC, XRD, and morphological examinations. The findings revealed a significant binding affinity of 78.07 ± 6.6% with native albumin, aligning with prior research. Notably, the complex RMP-HSA NPs-M13, synthesized via the methanolic precipitation method, exhibited the most substantial complexation, achieving a remarkable 3.5-fold increase, followed by the ammonium sulfate (twofold) and heat treatment (1.07-fold) methods in comparison to native albumin binding. The gastric simulated media exhibited accelerated drug release kinetics, with maximal dissolution achieved within two hours, contrasting with the prolonged release observed under intestinal pH conditions. These findings translated into significant improvements in drug permeation, as evidenced by pharmacokinetic profiles demonstrating elevated Cmax, AUC, t1/2, and MRT values for RMP-HSA NPs-M13 compared to free RMP. In summary, this innovative approach underscores the potential of precipitation methods in engineering stable colloidal carrier systems tailored to enhance the oral bioavailability of poorly soluble drugs, offering a pragmatic and scalable alternative to conventional surfactants, polymers, or high-energy methods for complex formation and production. Highlights: Colloidal albumin produced by methanol exhibits superior physiochemical and pharmaceutical performance. Albumin-Rifampicin conjugates are thought to be a potential method for improving drug release and oral bioavailability. Albumin-Rifampicin complex shows better pharmacokinetic characteristics compared to free Rifampicin. [ABSTRACT FROM AUTHOR]

Drug-resistant Tuberculosis (TB) is a global public health problem. Resistance to rifampicin, the most effective drug for TB treatment, is a major growing concern. The etiological agent, Mycobacterium tuberculosis (Mtb), has a cluster of ATP-binding cassette (ABC) transporters which are responsible for drug resistance through active export. Here, we describe studies characterizing Mtb Rv1217c-1218c as an ABC transporter that can mediate mycobacterial resistance to rifampicin and have determined the cryo-electron microscopy structures of Rv1217c-1218c. The structures show Rv1217c-1218c has a type V exporter fold. In the absence of ATP, Rv1217c-1218c forms a periplasmic gate by two juxtaposed-membrane helices from each transmembrane domain (TMD), while the nucleotide-binding domains (NBDs) form a partially closed dimer which is held together by four salt-bridges. Adenylyl-imidodiphosphate (AMPPNP) binding induces a structural change where the NBDs become further closed to each other, which downstream translates to a closed conformation for the TMDs. AMPPNP binding results in the collapse of the outer leaflet cavity and the opening of the periplasmic gate, which was proposed to play a role in substrate export. The rifampicin-bound structure shows a hydrophobic and periplasm-facing cavity is involved in rifampicin binding. Phospholipid molecules are observed in all determined structures and form an integral part of the Rv1217c-1218c transporter system. Our results provide a structural basis for a mycobacterial ABC exporter that mediates rifampicin resistance, which can lead to different insights into combating rifampicin resistance. [ABSTRACT FROM AUTHOR]

Leprosy remains a significant neglected tropical disease despite the goal of elimination having been achieved in various endemic nations over the past two decades. Reactional episodes complicate the disease course, resulting in deformities and disability. The main aim of treatment is to kill Mycobacterium leprae and decrease the bacterial load, which could help prevent further bacilli transmission. A major concern in breaking the chain of transmission and possibly for recurrent reactions is the role of drug‐resistant bacilli. Though some data is available on the background prevalence of drug resistance in leprosy, there is a paucity of studies that look for resistance specifically in leprosy reactions. Administration of long‐term steroids or immunosuppressants for chronic and recurrent responses in the presence of drug resistance has the twin effect of perpetuating the multiplication of resistant bacilli and encouraging the dissemination of leprosy. The increasing trend of prescribing second‐line drugs for leprosy or type 2 reactions without prior assessment of drug resistance can potentially precipitate a severe public health problem as this can promote the development of resistance to second‐line drugs as well. A comprehensive multicenter study, including drug resistance surveillance testing in cases of reactions, is necessary, along with the current measures to stop the spread of leprosy. Here, we have detailed the history of drug resistance in leprosy, given pointers on when to suspect drug resistance, described the role of resistance in reactions, methods of resistance testing, and the management of resistant cases with second‐line therapy. [ABSTRACT FROM AUTHOR]

Despite the large number of works on the synthesis of polylactide-co-glycolide (PLGA) nanoparticles (NP) loaded with antituberculosis drugs, the data on the influence of various factors on the final characteristics of the complexes are quite contradictory. In the present study, a comprehensive analysis of the effect of multiple factors, including the molecular weight of PLGA, on the size and stability of nanoparticles, as well as the loading efficiency and release of the antituberculosis drug rifampicin (RIF), was carried out. Emulsification was carried out using different surfactants (polyvinyl alcohol, Tween 80 and Pluronic F127), different aqueous-to-organic phase ratios, and different solvents (dichloromethane, dimethyl sulfoxide, ethyl acetate). In this research, the PLGA nanoemulsion formation process was accompanied by ultrasonic dispersion, at different frequencies and durations of homogenization. The use of the central composite design method made it possible to select optimal conditions for the preparation of PLGA-RIF NPs (particle size 223 ± 2 nm, loading efficiency 67 ± 1%, nanoparticles yield 47 ± 2%). The release of rifampicin from PLGA NPs was studied for the first time using the flow cell method and vertical diffusion method on Franz cells at different pH levels, simulating the gastrointestinal tract. For the purpose of the possible inhalation administration of rifampicin immobilized in PLGA NPs, their mucoadhesion to mucin was studied, and a high degree of adhesion of polymeric nanoparticles to the mucosa was shown (more than 40% within 4 h). In the example of strain H37Rv in vitro, the sensitivity of Mycobacterium tuberculosis to PLGA-RIF NPs was proven by the complete inhibition of their growth. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) remains a significant global health challenge, particularly with the rise of drug-resistant strains. Heteroresistance, where subpopulations of bacteria show varying levels of resistance within the same patient, complicates diagnosis and treatment. This study aims to assess the prevalence of heteroresistance to rifampicin and isoniazid in clinical samples from patients with presumptive drug-resistant tuberculosis. Materials and Methods A cross-sectional study was conducted from January to June 2024 at a tertiary care hospital. Clinical samples, including sputum and bronchial lavage, were collected from 200 patients suspected of having drug-resistant TB. Samples were processed using the GeneXpert MTB/RIF assay and Löwenstein-Jensen culture for drug susceptibility testing. Isolates were tested for heteroresistance to rifampicin and isoniazid using the BACTEC MGIT 960 system and molecular techniques like whole-genome sequencing. Results Out of 200 samples, 150 (75%) were confirmed to have Mycobacterium tuberculosis complex. Among these, 60 samples (40%) exhibited heteroresistance to rifampicin, while 45 samples (30%) showed heteroresistance to isoniazid. Dual heteroresistance to both drugs was observed in 20 samples (13.3%). Whole-genome sequencing revealed mutations in the rpoB and katG genes associated with resistance. The presence of heteroresistant populations was associated with prior TB treatment history and poor treatment outcomes. Conclusion The study highlights a substantial prevalence of heteroresistance to rifampicin and isoniazid in patients with presumptive drug-resistant TB. This underscores the need for advanced diagnostic techniques to detect heteroresistant strains and guide effective treatment regimens. Tailored therapeutic strategies are crucial to managing and controlling the spread of drugresistant TB. [ABSTRACT FROM AUTHOR]

Purpose: Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). Methods: Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600 mg of rifampicin separated by a wash-out period of at least 9 days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. Results: A one-compartment model with nonlinear (Michaelis–Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. Conclusion: Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin. [ABSTRACT FROM AUTHOR]

Ritonavir (RTV), which is used in combination with nilmatrelvir (NMV) to treat coronavirus disease 2019 (COVID-19), inhibits cytochrome P450 (CYP) 3A, thereby increasing blood tacrolimus (TAC) levels through a drug–drug interaction (DDI). We experienced a case in which a DDI between the two drugs led to markedly increased blood TAC levels, resulting in vasospastic angina (VSA) and acute kidney injury (AKI). Rifampicin (RFP) was administered to induce CYP3A and promote TAC metabolism. A 60-year-old man with dermatomyositis who was taking 3 mg/day TAC contracted COVID-19. The patient started oral NMV/RTV therapy, and he was admitted to the hospital after 4 days because of chest pain and AKI. On day 5, his blood TAC level increased markedly to 119.8 ng/mL. RFP 600 mg was administered once daily for 3 days, and his blood TAC level decreased to the therapeutic range of 9.6 ng/mL on day 9, leading to AKI improvement. Transient complete atrioventricular block and nonsustained ventricular tachycardia were present during chest pain. In the coronary spasm provocation test, complete occlusion was observed in the right coronary artery, leading to a diagnosis of VSA. VSA and AKI are possible side effects of high blood TAC levels caused by DDI, and attention should be paid to cardiovascular side effects such as VSA and AKI associated with increased blood levels of TAC when it is used together with NMV/RTV. When blood levels of TAC increase, oral RFP can rapidly decrease TAC blood levels and potentially reduce its toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Nucleotide-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry (nucleotide MALDI-TOF MS) is an emerging molecular technology used for the diagnosis of tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB)and its drug resistance. This study aimed to compare the ability of nucleotide MALDI-TOF MS to detect rifampicin (RIF) resistance in drug-resistant TB (DR-TB) patients with Xpert MTB/RIF and to analyze the disparate results individually. Additionally, potential factors associated with rifampicin resistance among DR-TB patients in Qingdao were investigated. Patients and Methods: A retrospective study was conducted at Qingdao Chest Hospital, and patients with DR-TB were enrolled. Corresponding frozen isolates were recovered and subjected to nucleotide MALDI-TOF MS, Xpert MTB/RIF, and phenotypic drug susceptibility testing (pDST). Sanger sequencing was performed for the discordant results of nucleotide MALDI-TOF MS and Xpert MTB/RIF. Univariate and multivariate logistic regression analyses were used to identify potential factors associated with rifampicin resistance among patients with DR-TB. Results: A total of 125 patients with DR-TB (18.8%, 125/668) were enrolled in this study from May 1 to July 31, 2023. Rifampicin-resistant (DR-TB/RR, 29) and rifampicin-sensitive (DR-TB/RS, 96) groups were divided according to the pDST results. Nucleotide MALDI-TOF MS performed better than Xpert MTB/RIF in terms of sensitivity, specificity, accuracy, and agreement with pDST. Only six cases had inconsistent results, and the sequencing results of five cases were identical to nucleotide MALDI-TOF MS. Furthermore, chest pain (aOR=12.84, 95% CI, 2.29– 91.97, p=0.005), isoniazid sensitivity (aOR=0.14, 0.02– 0.59, p=0.013), and ethambutol sensitivity (aOR=0.02, 0.00– 0.10, p=0.000) were potential factors associated with rifampicin resistance among DR-TB patients in Qingdao. Conclusion: The overall concordance between nucleotide MALDI-TOF MS and Xpert MTB/RIF was 95.2%, with the former performing better in determining rifampicin susceptibility among DR-TB cases in Qingdao. Chest pain, isoniazid, and ethambutol resistance might be factors associated with RIF resistance among patients with DR-TB in Qingdao. [ABSTRACT FROM AUTHOR]

A 64-year-old man presented with diffuse patchy alopecia for one month. He had a 17-year history of moderate to severe plaque psoriasis. Significant resolution of psoriasis lesions occurred during preventive anti-tuberculosis therapy using isoniazid and rifampicin. However, diffuse patchy alopecia areata developed. After withdrawal of anti-tuberculosis drugs and administration of glucocorticoids, alopecia areata was in remission gradually. However, psoriatic lesions returned. Anti-tuberculosis drugs may exert anti-inflammatory and immunomodulatory effects through multiple key factors. [ABSTRACT FROM AUTHOR]

Rifampicin is a frontline antibiotic in the management of tuberculosis. Since no spectrofluorimetric methods are reported for this drug, this approach was challenged to craft a sensitive, reliable, valid, fast, and green methodology. In recent years, fluorescence spectroscopy has received a lot of interest. Its benefits include ecological greenness and analytical performance. The pharmaceutical industries greatly like this approach because of its low energy and decreased solvent usage, which make it both economical and environmentally friendly. This methodology was based on utilizing the enhanced native fluorescence of the rifampicin at 341 nm after excitation at 241 nm in a beta‐cyclodextrin micellar system. Modern developments in analytical chemistry have been applied to reduce risks to the workplace and environment by using distilled water as a dilution solvent for method application and optimization. The method was found excellent green with 97 eco‐scale and 0.86 AGREE scores besides an 89.6 overall whiteness score. The range of linearity for rifampicin raw material was 0.2–1.5 μg·mL−1, and the average recoveries for raw material and spiked plasma were 100.15% and 99.64%, respectively. The suggested technique worked well for the commercial oral syrup of Rimactane® and did not conflict with any common additives. [ABSTRACT FROM AUTHOR]

Background: Drug-resistant tuberculosis (DR-TB) poses a major global challenge to public health and therapeutics. It is an emerging global concern associated with increased morbidity and mortality mostly seen in the low- and middle-income countries. Molecular techniques are highly sensitive and offer timely and accurate results for TB drug resistance testing, thereby positively influencing patient management plan. Methods: The study was carried out at the National Tuberculosis Reference Laboratory (NTRL) in Kenya in the period between January and October 2022. A total of 243 Mycobacterium tuberculosis (M.tb) clinical isolates were included in the study. These isolates comprised of 50 isolates with mutations in rpoB, 51 isolates with katG mutations, 51 isolates with mutations in inhA, and 91 M.tb isolates lacking mutations in these genes based on Genotype MTBDRplus results. DNA from the isolates was extracted using the FluoroLyse extraction kit. Real-time polymerase chain reaction targeting the rpoB, InhA, and katG genes was performed using the FluoroType MTBDR amplification mix. Isolates with discordant results between Genotype MTBDRplus and FluoroCycler® MTBDR assays underwent targeted sequencing for the respective genes, then, sequences were analyzed for mutations using Geneious version 11.0 software. Results: The sensitivity of the Fluorocycler XT MTBDR assay for the detection of mutations that confer drug resistance was 86% (95% confidence interval [CI] 73.0–94.0) for rpoB, 96% (95% CI 87–100) for katG and 92% (95% CI 81–98) for inhA. The assay’s specificity was 97% (95% CI 93–99) for rpoB, 98% (95% CI 96–100) for katG, and 97% (95% CI 93–99) for inhA. Conclusion: The diagnostic accuracy of FluoroType MTBDR for the detection of mutations conferring resistance to rifampicin and isoniazid was high compared with that of Genotype MTBDRplus and demonstrates its suitability as a replacement assay for Genotype MTBDRplus.

Background: Tuberculosis (TB), one of the deadliest infectious diseases globally, is increasingly exacerbated in China by the emergence of resistant Mycobacterium tuberculosis (MTB) strains. Drug-resistant TB, including mono-drug-resistant TB, multidrug-resistant TB (MDR-TB), and extensively drug-resistant TB (XDR-TB), presents significant public health challenges. Methods: We conducted a systematic literature review from January 2010 to February 2024 using databases such as PubMed, Embase, Web of Science, and Google Scholar. Our focus was on empirical data related to drug resistance patterns in newly diagnosed TB cases. Non-empirical studies were excluded through meticulous filtering. For the meta-analysis, we used Review Manager (RevMan) 5.2 and assessed evidence quality using the Newcastle-Ottawa Scale (NOS). Results: Our search strategy identified 40 studies that met the inclusion criteria, encompassing a total sample size of 87,667 participants. Among new TB cases, the estimated prevalence of MDR-TB in China was 6.9% (95% CI: 5.6–8.1%). Prevalence rates for mono-drug resistance to first-line anti-TB medications were as follows: isoniazid at 18.2% (95% CI: 16.4–20.6%), rifampicin at 10.5% (95% CI: 8.6–12.8%), and ethambutol at 5.7% (95% CI: 4.1–7.3%). The prevalence of streptomycin resistance, a former first-line anti-TB drug, was 17.1% (95% CI: 14.6–19.1%). The prevalence of other types of mono-drug resistance was 15.2% (95% CI: 13.9–17.3%), and for XDR-TB, it was 0.9% (95% CI: 0.6–1.4%). Conclusions: The high prevalence of drug-resistant TB in China poses a significant public health challenge. There is an urgent need for targeted interventions and continued surveillance to combat the spread of drug-resistant TB.

Increasing environmental issues have emerged due to various pharmaceutical wastes. These wastes are difficult to remove by treatment due to their continuous consumption and long-term persistence. We have synthesized two different shapes of zinc oxide (ZnO) nanoparticles as catalysts—nanorod (ZnO–NR) and oval-shape (ZnO–OS). A comparative performance of these two catalyst shapes on photocatalytic degradation of rifampicin (RIF) in water—a first-line anti-tuberculosis drug, was carried out. ZnO–NR showed three times higher normalized first-order degradation rate constant of RIF under UV light than that with ZnO–OS. This is due to: (i) specific surface area and specific pore volume of ZnO–NR being 25 and six times higher, respectively, than ZnO–OS; (ii) oxygen vacancy in ZnO–NR being 1.7 times higher than ZnO–OS; (iii) slightly lower band gap energy in ZnO–NR than ZnO–OS, adding to carrier concentration; and (iv) ZnO–NR additionally showing 12.4% chemisorbed oxygen also. Towards RIF degradation, ZnO–NR shows a much improved synergistic effect than ZnO–OS under UV light, as ZnO–NR under UV light is found to give 2.7 times higher degradation than when the catalyst and UV act independently and hence only additively. Therefore, this study is helpful in tuning the shape-dependent chemical reactivity of nanoparticles in water treatment. [ABSTRACT FROM AUTHOR]

Abstract Fluoroquinolone resistance is a major challenge in treating Multidrug-Resistant Tuberculosis globally. The GenoType MTBDRsl Ver 2.0, endorsed by the WHO, was used to characterize fluoroquinolone resistance. The fluoroquinolone resistance rates in the MDR-TB, Rifampicin-Resistant TB, and non-MDR-TB were 33%, 16.5%, and 5.4%, respectively. The most common mutation found in fluoroquinolone-resistant isolates was D94G (49.5%) in the gyrA gene. Of the 150 MDR-TB isolates, the prevalence of Extensively Drug-Resistant Tuberculosis and pre-XDR-TB was 1.33% and 30%, respectively. Among the 139 RR-TB isolates, pre-XDR-TB prevalence was 15.8%. The fluoroquinolone resistance rates were 5.12% among the 1230 isoniazid-monoresistant isolates. The study found that MDR-TB and RR-TB have higher risk of fluoroquinolone resistance than non-MDR tuberculosis. Rifampicin-resistant isolates with a mutation at codon S450L have a higher risk (RR = 12.96; 95%CI: 8.34–20.13) of developing fluoroquinolone resistance than isolates with mutations at other codons in the rpoB gene. Isoniazid-resistant isolates with a mutation at codon S315T have a higher risk (RR = 2.09; 95%CI: 1.25–3.50) of developing fluoroquinolone resistance. The study concludes that rapid diagnosis of fluoroquinolone resistance before starting treatment is urgently needed to prevent the spread and increase of resistance and to achieve better treatment outcomes in areas where it is higher.

Objective(s): Tuberculosis (TB) is one of the most common infectious diseases in the world and requires novel medications or existing ones should be improved. Nanotechnology is a modern science that helps to avoid adverse reactions and resistance to drugs. The current regimen for standard therapy calls for routine administration of medications over six months. Since the noncompliance of patients and the emergence of drug-resistant strains, therapies become more challenging. The objective of the current study was to develop Isoniazid-Rifampicin-loaded (INH-RIF-NPs) nanoparticles to improve release properties and drug encapsulation efficiency.Materials and Methods: Box-Behnken Design (BBD) was used for optimizing the nanoparticles. Eudragit was used in the preparations in varying concentrations (1-2% w/v). The compatibility of the drug and excipients was shown. The existence of the nanoparticles was confirmed by the analytical results of the transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). Results: The optimized nanoparticles showed no drug-polymer interaction. The mean size of the INH-RIF-NPs was around 112±8.73 nm, and they were sphere-like, smooth, fairly uniform in size, and well-dispersed, and entrapment efficiencies were high at 98.7±0.68%. Drug release was slow and sustained with 66.91% INH cumulative release and 80.06 of RFP after 24 hr. Conclusion: Significant drug uptake with higher encapsulation efficiency, uniform size, good dispersion, and prolonged release characteristics are all present in INH-RIF-NPs. This suggests the existence of a delivery system capable of effectively encapsulating and delivery of combined drug formulation in polymeric nanoparticles.

Hong Lu,* Yanmei Mao,* Ying Zeng, Pengyu Li, Pan Yan, Qunzhi Shi, Lin Liu Department of Pharmacy, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, People’s Republic of China*These authors have contributed equally to this workCorrespondence: Hong Lu, Department of Pharmacy, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, People’s Republic of China, Email 1430368@qq.comPurpose: Voriconazole, a first-line therapeutic agent for chronic pulmonary aspergillosis, is metabolized by the cytochrome 450 enzymes, specifically CYP2C19 and CYP3A4. Rifampicin and rifapentine act as inducers of the cytochrome P450 enzyme. The current study explored the potential drug interactions arising from the co-administration of voriconazole with either rifampicin or rifapentine, as well as the duration of this effect on serum voriconazole levels after discontinuation of rifampicin or rifapentine.Patients and Methods: A retrospective study was conducted in tuberculosis patients with chronic pulmonary aspergillosis. These patients underwent a combination therapy involving voriconazole and rifampicin or rifapentine, or they were treated with voriconazole after discontinuation of rifampicin or rifapentine. The serum concentrations of voriconazole at steady-state were monitored. Data on demographic characteristics and the serum voriconazole levels were used for statistical analyses.Results: A total of 124 serum voriconazole concentrations from 109 patients were included in the study. The average serum concentration of voriconazole fell below the effective therapeutic range in patients treated with both voriconazole and rifampicin or rifapentine. Notably the co-administration of rifapentine led to a substantial (> 70%) decrease in serum voriconazole levels in two patients. Moreover, this interfering effect persisted for at least 7 days following rifampicin discontinuation, while it endured for 5 days or more after discontinuation of rifapentine.Conclusion: Concomitant use of voriconazole and rifampicin or rifapentine should be avoided, and it is not recommended to initiate voriconazole therapy within 5 or 7 days after discontinuation of rifapentine or rifampicin. Therapeutic drug monitoring not only provides a basis for the adjustment of clinical dose, but also serves as a valuable tool for identifying drug interactions.Keywords: voriconazole, rifampicin, rifapentine, serum concentration, discontinuation

Background: On a global scale, India holds the distinction of having the greatest number of tuberculosis (TB) cases caused by Mycobacterium tuberculosis (MTB) complex. The study aimed at evaluating the sensitivity, specificity, accuracy, cost, rapidity, and feasibility of the performance of the colorimetric nitrate reductase-based antibiotic susceptibility (CONRAS) test against the indirect proportion method (IPM) on Lowenstein–Jensen media as the gold standard. Methods: A comparative cross-sectional study was performed on 51 MTB isolates. Fresh subcultures were used for drug susceptibility testing by IPM on the Lowenstein–Jensen medium and the CONRAS method in liquid medium. Quality control for drug susceptibility testing was done using a known sensitive strain of MTB (H37Rv) and strains resistant to both isoniazid (INH) and rifampicin (RIF) – multidrug-resistant (MDR), mono-resistant to RIF, streptomycin (STM), and ethambutol (EMB). Statistical analysis was performed using MedCalc software (Version 20.027). Results: CONRAS, carried out in microfuge tubes, was cost-efficient and easy to perform/interpret with most results being available in 10 days compared to 42 days in the case of IPM. The sensitivity, specificity, and accuracy of RIF and INH were 100%, 97.37%, and 98.04 and 93.33%, 97.59%, and 96.08%, respectively, which translates into an almost perfect agreement between the two methods as indicated by κ value of 0.905 and 0.949, respectively, for the two drugs. The performance of CONRAS was less satisfactory for STM and EMB when compared to IPM. Conclusions: CONRAS may serve as a useful test for the detection of MDR-TB because of its accuracy, low cost, ease of performance/interpretation, and rapidity when compared to IPM on LJ medium. It does not involve the use of expensive reagents and equipment, as is the case with molecular methods like GeneXpert and line probe assay, making it a suitable option for the detection of MDR-TB in resource-poor settings.

Background: Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%–25%. Similarly, glomerular disease increases the risk of TB due to diminished glomerular filtration rate, proteinuria, and immunosuppression use. Further, the first-line anti-TB drugs are associated with acute kidney injury (AKI) even in patients with normal kidney functions. Methods: We retrospectively identified 10 patients hospitalized with unusual adverse effects of antituberculosis therapy (ATT) from 2013 to 2022. Results: We found three cases of AKI caused by rifampicin: acute interstitial nephritis, crescentic glomerulonephritis, and heme pigment-induced acute tubular necrosis. We observed rifampicin-induced accelerated hypertension and thrombocytopenia in two patients on maintenance hemodialysis. Isoniazid caused pancreatitis and cerebellitis in two CKD patients, respectively. In a CKD patient, we detected acute gout secondary to pyrazinamide-induced reduced uric acid excretion. We also observed cases of drug rash with eosinophilia and systemic symptoms and hypercalcemia due to immune reconstitution inflammatory syndrome in patients with glomerular disease on ATT. Immediate discontinuation of the offending drug, along with specific and supportive management, led to a recovery in all cases. Conclusion: The adverse effects of ATT may be unusually severe and varied in kidney patients due to decreased renal elimination. Early recognition of these adverse effects and timely discontinuation of the offending drug is essential to limit morbidity and mortality.

Abstract The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well‐established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89‐year‐old female, diagnosed with epidermal growth factor receptor (EGFR)‐mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis.

Fluoroquinolone resistance is a major challenge in treating Multidrug-Resistant Tuberculosis globally. The GenoType MTBDRsl Ver 2.0, endorsed by the WHO, was used to characterize fluoroquinolone resistance. The fluoroquinolone resistance rates in the MDR-TB, Rifampicin-Resistant TB, and non-MDR-TB were 33%, 16.5%, and 5.4%, respectively. The most common mutation found in fluoroquinolone-resistant isolates was D94G (49.5%) in the gyrA gene. Of the 150 MDR-TB isolates, the prevalence of Extensively Drug-Resistant Tuberculosis and pre-XDR-TB was 1.33% and 30%, respectively. Among the 139 RR-TB isolates, pre-XDR-TB prevalence was 15.8%. The fluoroquinolone resistance rates were 5.12% among the 1230 isoniazid-monoresistant isolates. The study found that MDR-TB and RR-TB have higher risk of fluoroquinolone resistance than non-MDR tuberculosis. Rifampicin-resistant isolates with a mutation at codon S450L have a higher risk (RR = 12.96; 95%CI: 8.34–20.13) of developing fluoroquinolone resistance than isolates with mutations at other codons in the rpoB gene. Isoniazid-resistant isolates with a mutation at codon S315T have a higher risk (RR = 2.09; 95%CI: 1.25–3.50) of developing fluoroquinolone resistance. The study concludes that rapid diagnosis of fluoroquinolone resistance before starting treatment is urgently needed to prevent the spread and increase of resistance and to achieve better treatment outcomes in areas where it is higher. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus, a Gram-positive bacterium, is a predominant pathogen associated with various infections. The rapid emergence of antibiotic resistance has intensified the challenge of managing fracture-related infections in severe osteoporotic patients. Rifampicin, a potent antimicrobial agent employed against fracture and implant-related infections, necessitates combination therapies due to its susceptibility to antibiotic resistance. In this study, we explored the potential of baicalein, a bioactive flavonoid from Oroxylum indicum and Scutellaria baicalensis, in combination with rifampicin against S. aureus biofilms invitro. The minimum inhibitory concentration of baicalein and rifampicin were determined as 500 µg/mL and 12.5 ng/mL respectively. The synergistic activity of baicalein and rifampicin was determined by the fractional inhibitory concentration index (FICI) using checkerboard assay. The results showed the FICI of baicalein and rifampicin was lesser than 0.5, demonstrating synergistic effect. Furthermore, the efficacy of baicalein and rifampicin, both individually and in combination, was evaluated for biofilm inhibition and eradication. Scanning electron microscopy and confocal laser microscopy also confirmed that the synergistic combinations effectively removed most of the biofilms and partially killed pre-formed biofilms. In conclusion, the findings demonstrate that baicalein is as effective as rifampicin in inhibiting and eradicating S. aureus biofilms. Their combination exhibits synergistic effect, enhancing their bactericidal effect in completely eradicating S. aureus biofilms. The findings of this research underscore the research potential of combining baicalein and rifampicin as a novel therapeutic strategy against S. aureus biofilms, offering a promising direction for future research in the treatment of fracture-related S. aureus infections. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculosis is a communicable illness and one of the leading causes of death, especially in developing countries like Turkey. One of the problems that must be managed well in the treatment of tuberculosis is drug hypersensitivity. The first-line agents are very important for the success of treatment. Alternative drugs are more toxic and less successful in treatment. Therefore, it is very important to be able to include first-line drugs in the post-hypersensitivity regimen. At this point, the success of desensitization comes to the fore. There are fewer studies on rapid drug desensitization in delayed-type drug hypersensitivity to anti-tuberculosis drugs. Aim: The primary aim of the study was to determine the prevalence of delayed-type hypersensitivity reactions in drug-sensitive cases; the secondary aim was to determine the appropriate treatment management. Material and methods: This was a retrospective study. Demographic features, tuberculosis diagnostic indicator, clinical signs of developing a hypersensitivity reaction, reaction time, desensitization scheme and treatment were evaluated. Results: A total of 41 tuberculosis cases were included in the study. Twenty-six of the cases were male; mean age (mean ± SD) 55.44 ±16.93 years; 70.7% of them were diagnosed bacteriologically; 70.7% of them were diagnosed with pulmonary tuberculosis. The most common skin finding was maculopapular drug eruption. The development time (mean ± SD) of the reaction in patients who developed a reaction was 34.93 ±39.62 days. The responsible agent could be identified in 15 reactions. The most common drug responsible for the reaction was rifampicin. Successful desensitization was achieved in 19 (46.3%) cases with the sensitive regimen. The duration of treatment was 8.97 ±3.44 months. When evaluated in terms of treatment results, cure and treatment completion were accepted as treatment success. In this case, 30 (73.2%) patients successfully completed the treatment. Conclusions: Our study is one of the largest series in which delayed-type hypersensitivity develops under tuberculosis treatment and the desensitization scheme is recommended. A practical, easy desensitization scheme had been shared in this paper. [ABSTRACT FROM AUTHOR]

The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetyl-rifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual variation in the exposure to RIF. Pharmacokinetic, clinical, and demographic data from TB patients with (TB-HIV+ group; n = 18) or without HIV (TB-HIV− group; n = 15) who were receiving RIF as part of a four-drug fixed-dose combination (FDC) regimen (RIF, isoniazid, pyrazinamide, and ethambutol) were analysed, along with the published literature data on the relative bioavailability of different formulations. A population pharmacokinetic model, including the formation of desRIF, was developed and compared to a model based solely on the parent drug. HIV co-infection does not alter the plasma exposure to RIF and the desRIF formation does not contribute to the observed variability in the RIF disposition. The relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard regimen with FDC tablets. Furthermore, participants weighting less than 50 kg do not reach the same RIF plasma exposure as compared to those weighting >50 kg. In conclusion, as no covariate was identified other than body weight on CL/F and Vd/F, low systemic exposure to RIF is likely to be caused by the low bioavailability of the formulation. [ABSTRACT FROM AUTHOR]

Rifampicin is a strong inducer of cytochrome P450 (CYP3A4) and P-glycoprotein (P-gp/ABCB1), leading to profound drug–drug interactions. In contrast, the chemically related rifabutin does not show such pronounced induction properties in vivo. The aim of our study was to conduct a comprehensive analysis of the different induction potentials of rifampicin and rifabutin in primary human hepatocytes and to analyze the mechanism of potential differences. Therefore, we evaluated CYP3A4/ABCB1 mRNA expression (polymerase chain reaction), CYP3A4/P-gp protein expression (immunoaffinity–liquid chromatography–mass spectrometry, IA-LC-MS/MS), CYP3A4 activity (testosterone hydroxylation), and considered intracellular drug uptake after treatment with increasing rifamycin concentrations (0.01–10 µM). Furthermore, rifamycin effects on the protein levels of CYP2C8, CYP2C9, and CYP2C19 were analyzed (IA-LC-MS/MS). Mechanistic analysis included the evaluation of possible suicide CYP3A4 inhibition (IC50 shift assay) and drug impact on translational efficiency (cell-free luminescence assays). Rifabutin accumulated 6- to 15-fold higher in hepatocytes than rifampicin, but induced CYP3A4 mRNA comparably to rifampicin (e. g. rifampicin 61-fold vs. rifabutin 44-fold, 72 h). While rifampicin for example enhanced protein (10 µM: 21-fold) and activity levels considerably (53-fold), rifabutin only slightly increased CYP3A4 protein expression (10 µM: 3.3-fold) or activity (11-fold) compared to rifampicin after 72 h. Both rifamycins similarly influenced expression of other eliminating proteins. A potential CYP3A4 suicide inhibition by a specific rifabutin metabolite or disruption of ribosome function were excluded experimentally. In conclusion, the lack of protein enhancement, could explain rifabutin's weaker induction-related drug–drug interaction risk in vivo. [ABSTRACT FROM AUTHOR]

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause significant economic losses to the global swine industry, yet effective prevention and control measures remain elusive. The development of novel antivirals is thus urgently needed. Rifampicin (RFP), a semisynthetic derivative of rifamycin, has been previously reported to inhibit the replication of certain mammalian DNA viruses as well as RNA viruses. In this study, we unveil RFP as a potent inhibitor of PRRSV both in Marc-145 cells (half-maximal inhibitory concentration 61.26 µM) and porcine alveolar macrophages (half-maximal inhibitory concentration 53.09 µM). The inhibitory effect of RFP occurred during viral replication rather than binding, internalization and release. We also demonstrated that RFP inhibits PRRSV proteins production in the early stage of infection, without inhibiting host protein synthesis. Moreover, RFP effectively restricted porcine epidemic diarrhea virus (PEDV) and porcine enteric alphacoronavirus (PEAV) infection in Vero cells. In summary, these findings indicate the promising potential of RFP as a therapeutic agent for PRRSV, PEDV and PEAV infection in pig farms. [ABSTRACT FROM AUTHOR]

Background/Aim: Patients with rifampicin resistant-tuberculosis (RR-TB) may remain a source of infection longer than patients with rifampicin sensitive-tuberculosis (RS-TB). This study aimed to detect active cases of RS-TB and RR-TB through systematic screening among household contacts of RR-TB patients in Dhaka, Bangladesh. Methods: This cross-sectional study was conducted among the 355 household contacts (HHCs) of 93 RR-TB primary cases identified from various centres in Dhaka, diagnosed between November 2020 and October 2021. For the identification of active cases of tuberculosis (TB), systematic screening among HHCs was done, where verbal screening was performed to check the presence of symptoms of TB. Those who had at least one symptoms of TB were considered as symptomatic contacts. Later GeneXpert analysis of sputum was done among the screened symptomatic contacts. Data was collected using a pretested, semi-structured, interviewer-administered questionnaire. Results: An estimated 30.4 % of respondents were ≤ 15 years of age. TB-like symptoms were prevalent among 9.9 % of respondents. Loss of appetite (45.7 %), unexplained weight loss (40.0 %) and cough (37.1 %) were the most common symptoms. Among the contacts with TB-like symptoms, 6.7 % were diagnosed as a case of TB (3.35 % were RR-TB and 3.35 % were RS-TB). The number needed to be screened to find an active case of TB was established at 178 among the HHCs of RR-TB. Conclusions: About one in ten RR-TB HHCs showed TB-like symptoms. One in fifteen HHCs with TB-like symptoms was an active case of TB. Regular, effective screening of RR-TB contacts is needed to stop the transmission. [ABSTRACT FROM AUTHOR]

Objective(s): Tuberculosis (TB) is one of the most common infectious diseases in the world and requires novel medications or existing ones should be improved. Nanotechnology is a modern science that helps to avoid adverse reactions and resistance to drugs. The current regimen for standard therapy calls for routine administration of medications over six months. Since the noncompliance of patients and the emergence of drug-resistant strains, therapies become more challenging. The objective of the current study was to develop Isoniazid-Rifampicin-loaded (INH-RIF-NPs) nanoparticles to improve release properties and drug encapsulation efficiency. Materials and Methods: Box-Behnken Design (BBD) was used for optimizing the nanoparticles. Eudragit was used in the preparations in varying concentrations (1-2% w/v). The compatibility of the drug and excipients was shown. The existence of the nanoparticles was confirmed by the analytical results of the transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). Results: The optimized nanoparticles showed no drug-polymer interaction. The mean size of the INH-RIFNPs was around 112±8.73 nm, and they were sphere-like, smooth, fairly uniform in size, and well-dispersed, and entrapment efficiencies were high at 98.7±0.68%. Drug release was slow and sustained with 66.91% INH cumulative release and 80.06 of RFP after 24 hr. Conclusion: Significant drug uptake with higher encapsulation efficiency, uniform size, good dispersion, and prolonged release characteristics are all present in INH-RIF-NPs. This suggests the existence of a delivery system capable of effectively encapsulating and delivery of combined drug formulation in polymeric nanoparticles. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is a major pathogen in hospital‐acquired infections notorious for its strong acquired resistance and complex drug resistance mechanisms. Owing to the lack of effective drugs, the mortality rate of extensively drug‐resistant A. baumannii pneumonia can reach as high as 65%. This article analyzes a case where a combination of cefoperazone‐sulbactam, polymyxin B, and minocycline with rifampicin successfully treated XDR‐AB pulmonary infection. Combination therapy is effective and has a particular clinical value. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a major causative pathogen of osteomyelitis. Intracellular infections of resident bone cells including osteocytes can persist despite goldstandard clinical intervention. The mechanisms by which intracellular S. aureus evades antibiotic therapy are unknown. In this study, we utilised an in vitro S. aureus infection model of human osteocytes to investigate whether antibioticmediated dysregulation of autophagy contributes to this phenomenon. Infected or non-infected osteocyte-like cells were exposed to combinations of rifampicin, vancomycin, and modulators of autophagy. Intracellular bacterial growth characteristics were assessed using colony-forming unit (CFU) analysis, viable bacterial DNA abundance, and the rate of escape into antibiotic-free medium, together with measures of autophagic flux. Rifampicin, alone or in combination with vancomycin, caused a rapid decrease in the culturability of intracellular bacteria, concomitant with stable or increased absolute bacterial DNA levels. Both antibiotics significantly inhibited autophagic flux. However, modulation of autophagic flux did not affect viable bacterial DNA levels. In summary, autophagy was shown to be a factor in the host--pathogen relationship in this model, as itsmodulation affected the growth state of intracellular S. aureus with respect to both their culturability and propensity to escape the intracellular niche. While rifampicin and vancomycin treatments moderately suppressed autophagic flux acutely, this did not explain the paradoxical response of antibiotic treatment in decreasing S. aureus culturability whilst failing to clear bacterial DNA and hence intracellular bacterial load. Thus, offtarget effects of rifampicin and vancomycin on autophagic flux in osteocyte-like cells could not explain the persistent S. aureus infection in these cells. [ABSTRACT FROM AUTHOR]

Background The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. Methods We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. Results Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. Conclusions Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation. [ABSTRACT FROM AUTHOR]

The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well‐established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89‐year‐old female, diagnosed with epidermal growth factor receptor (EGFR)‐mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis. [ABSTRACT FROM AUTHOR]

Persister cells are transiently tolerant to antibiotics and are associated with recalcitrant chronic infections due to recolonization of host cells after antibiotic removal. Brucella spp. are facultative pathogens that establish intracellular infection cycles in host cells which results in chronic persistent infections. Brucella abortus forms multi-drug persister cells which are promoted by the (p) ppGpp synthetase Rsh during rifampicin exposure. Here, we confirmed that Rsh promoted persister cells formation in B. abortus stationary phase treated with rifampicin and enrofloxacin. Deletion of the gene for Rsh decreased persister cells level in the presence of these drugs in different growth phases. However, persister cells formation by deletion strain varied in different growth phases in the presence of other antibiotics. Rsh also was involved in persister cells formation during rifampicin treatment under certain stress conditions, including acidic conditions, exposure to PBS, and heat stress. Moreover, Rsh impacted persister cell levels during rifampicin or enrofloxacin treatment in RAW264.7 macrophages. Certain typeIItoxin-antitoxin modules were upregulated under various stress conditions in B. abortus. We established that Rsh positively regulated the type II toxin-antitoxin mbcTA. Moreover, rifampicin-tolerant persister cells formation was elevated and ATP levels were decreased when mbcTA promoter was overexpressed in Rsh deletion background in stationary phase. Our results establish that (p)ppGpp synthetase Rsh plays a key role in B. abortus persistence and may serve as a potent novel target in combination with rifampicin in the development of new therapeutic approaches and prevention strategies to treat chronic infections of Brucella. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effect of the combination of carotegrast methyl with rifampicin, a potent inhibitor of organic anion transporter polypeptide, on the pharmacokinetics (PKs), safety and tolerability of carotegrast methyl. Methods: In this 2 × 2 crossover study in 20 healthy Japanese adults, 10 subjects received carotegrast methyl 960 mg and rifampicin 600 mg on day 1 and received carotegrast methyl 960 mg on day 8. The subjects in the other sequence received the same treatments but in the opposite order. The 90% confidence interval (CI) of the geometric mean ratio of the Cmax and AUC0‐t for carotegrast, the main active metabolite of carotegrast methyl, with/without rifampicin was calculated. If the 90% CI fell within the range of 0.80‐1.25, this indicated the absence of any drug‐drug interaction. Adverse events (AEs) were monitored. Results: The geometric mean ratios (90% CI) of the Cmax and AUC0‐t for carotegrast with/without rifampicin were 4.78 (3.64‐6.29) and 5.59 (4.60‐6.79), respectively, indicating that carotegrast has a PK interaction with rifampicin. The combination with rifampicin increased the exposure of carotegrast and also that of its metabolites. The incidence of any AEs with/without rifampicin was five (25.0%) and one (5.0%), respectively. Conclusions: Coadministration of carotegrast methyl with rifampicin significantly increased the exposure of carotegrast compared with carotegrast methyl administration alone. In this single dose study, the incidence of AEs of carotegrast methyl with rifampicin increased compared with carotegrast methyl alone, but the incidence of adverse drug reactions did not increase with combination administration. [ABSTRACT FROM AUTHOR]

Although the incidence of infections in orthopedic surgeries, including periprosthetic surgeries, remains low at approximately 1–2%, the number of surgeries and the incidence of drug-resistant bacteria is increasing. The cost and morbidity associated with revision surgeries are huge. More effective drug combinations and delivery methods are urgently needed. In this paper, three anti-infective drugs (vancomycin, rifampicin, and silver sulfadiazine) have been jointly and effectively electrospun in thin (0.1 mm) flexible nanofiber mats of either poly (methyl methacrylate) (PMMA) or poly (lactic-co-glycolic acid) (PLGA). The inclusion of poly (ethylene glycol) (PEG) enabled optimal drug release with a reduced water contact angle for wetting. The controlled release of these three agents from 20% PEG (w/w to polymer)-blended PMMA or PLGA nanofiber mats may allow for the prophylactical prevention of implant-related infections or provide methods to treat orthopedic infections at the time of revision surgeries. These combinations of drugs provide excellent additive or synergistic antibiotic action against a broader spectrum of bacteria than each drug alone. [ABSTRACT FROM AUTHOR]

In the present work, graphene oxide covalently functionalized with l-lysine (LSN@GO)-based electrochemical sensor has been developed for the ultrasensitive individual as well as the first ever simultaneous detection of Rifampicin (RIFA) and Acetaminophen (APAP) drugs. The synthesized LSN@GO composite, as well as its precursors LSN and GO, were characterized using FT-IR, XRD, TGA, XPS, SEM and EDAX. The electrochemical studies were performed using Cyclic Voltammetry (CV), Linear Sweep Voltammetry (LSV), and Electrochemical Impedance Spectroscopy (EIS). The fabricated LSN@GO/GCE electro-sensor's interface exhibited efficient electrical activity for the analysis of RIFA and APAP under the optimized conditions, owing to its substantial electrochemically active surface area and exceptional electron transport capabilities. The detection of RIFA and APAP in various pH environments entailed a proton-dependent mechanistic approach. The sensor displayed a robust linear correlation over a broad range (0.5 to 10 µM) for both RIFA and APAP, with low detection limits of 4.3 nM for RIFA and 5.8 nM for APAP (S/N = 3), along with quantification limits of 14.6 nM for RIFA and 19.4 nM for APAP (S/N = 10) for their individual detection. For simultaneous detection, the detection limit of 4.2 nM for RIFA and 6.0 nM for APAP were observed. We successfully detected spiked RIFA and APAP in real drug and urine samples without pre-treatment, demonstrating significant detection limits and no notable interference from excipients with satisfactory recovery data. The developed sensing platform demonstrated exceptional electrochemical performance for the detection of RIFA and APAP, showcasing significant potential for applications in clinical diagnosis and pharmaceuticals. [ABSTRACT FROM AUTHOR]

Cytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas. Based on consumption data, the kinetics after daily intake of retrorsine were simulated with concomitant rifampicin treatment. Strongest impact on retrorsine kinetics (plasma AUC 24 and C max reduced to 67% and 74% compared to the rifampicin-free reference) was predicted directly after withdrawal of rifampicin. At this time point, the competitive inhibitory effect of rifampicin stopped, while CYP3A4 induction was still near its maximum. Due to the impacted metabolism kinetics, the cumulative formation of intestinal retrorsine CYP3A4 metabolites increased to 254% (from 10 to 25 nmol), while the cumulative formation of hepatic CYP3A4 metabolites was not affected (57 nmol). Return to baseline PA toxicokinetics was predicted 14 days after stop of a 14-day rifampicin treatment. In conclusion, the PBTK model showed to be a promising tool to assess the dynamic interplay of enzyme induction and toxification pathways. [ABSTRACT FROM AUTHOR]

Objectives: Dolutegravir + lamivudine (DTG + 3TC) is a first‐line regimen for people with HIV. However, there are still concerns about its efficacy in people with tuberculosis (TB)/HIV due to the lack of available evidence and drug–drug interaction with rifampicin. Methods: A single‐centre retrospective observational case series was conducted in Guangxi Zhuang Autonomous Region, China. We included all people with TB/HIV on combined use of once‐daily (q.d.) dosing DTG + 3TC and rifampicin (RIF)‐containing anti‐TB regimens between 2020 and 2022. HIV‐RNA, CD4 cell counts were collected and analysed. Results: In all, 21 people with HIV (PWH) were included in this study. All the PWH were treatment‐naïve and told to take DTG + 3TC q.d. with food. The median age was 53 years, and 71.43% were male. A total of 71.43% PWH had baseline viral load (VL) > 100 000 copies/mL, and 33.33% had baseline VL greater than 500 000 copies/mL. Only one PWH had CD4 cell count greater than 200 cells/μL, and the median CD4 count was 20 cells/μL. A total of 16 PWH started DTG + 3TC after initiation of the RIF‐based anti‐TB regimen, and the other five PWH initiated DTG + 3TC before the treatment of TB. All the PWH had at least 24 weeks of follow‐up visits and all of the TB treatments were successful. A total of 20 PWH (95.24%) achieved viral suppression (VL <50 copies/mL). All detected viral loads between weeks 24 and 48 were less than 200 copies/mL. Among the PWH who started DTG + 3TC after the initiation of RIF‐based anti‐TB regimen, all achieved viral suppression by week 24 except the non‐suppressed PWH. CD4 counts were greatly improved after antiretroviral treatment: the median CD4 counts were raised from 20 to 171 cells/μL at week 48. No serious adverse events were reported. Conclusions: This case series preliminarily validates the efficacy of DTG + 3TC q.d. with food when combined with RIF‐based anti‐TB regimens in people with TB/HIV. [ABSTRACT FROM AUTHOR]

Anti-tuberculosis drugs rifampicin and pyrazinamide combination in pregnancy can cause morphological, visceral and skeletal damage. Several studies showed that propolis improves pregnancy outcomes. This study aims to determine the fetal protective effect of propolis in BALB/c mice given the anti-tuberculosis drug combination rifampicin and pyrazinamide. A total of 21 pregnant mice were randomly divided into three groups: the normal group (N) was given distilled water as a vehicle, the positive control group (RP) were given rifampicin 15 mg/kg BW, pyrazinamide 35 mg/kg BW and the treatment group (IP) were given rifampicin 15 mg/kg BB, pyrazinamide 35 mg/kg BW and propolis 400 mg/kg BW. The treatment was given during the period of organogenesis, from day 6 to day 15. Laparotomy was performed on the 18th day of pregnancy. Maternal and fetal body weight, fetal length, number of fetuses, and skeletal defects of fetuses were used as parameters to identify the teratogenic effect. All data were analyzed using the ANOVA. All groups significantly differed between maternal and fetal body weights (p<0.05). The administration of rifampicin-pyrazinamide and propolis during pregnancy did not significantly affect the number of fetuses (p>0.05). The administration of propolis protects the fetus from skeletal abnormalities. While in the RP and IP groups, we can find resorption sites and haemorrhagic. This study may suggest the protective effects of propolis against rifampicin pyrazinamide-induced impaired pregnancy. [ABSTRACT FROM AUTHOR]

The aim of this study was to characterize the antimicrobial and antibiofilm activities of ciprofloxacin (CIP) and rifampicin (RMP) loaded on a calcium alginate (CaAlg) scaffold via electrostatic interaction of CaAlg/antibiotic (s) and chitosan-TPP nanoparticles (Cs-TPP NPs). The identification of the shape and functional groups was carried out using scanning electron microscope (SEM) and Fourier transform infrared (FT-IR) spectroscopy. SEM images show that the nanoparticles are spherical and granular with an average size of about 100–500 nm. FT-IR results revealed bonds that corresponded to the Cs-TPP NPs and CaAlg-antibiotics (CaAlg-CIP, CaAlg-RMP) after the loading process. The tube adherence method (TM) was employed to identify potential biofilm producers. The antibiofilm capacity of Cs/CaAlg-CIP and Cs/CaAlg-RMP as well as free antibiotics was used against clinical strains in a test tube method and the results showed that the use of sub-MICs of nanodrugs (1/2 MIC) inhibited biofilm formation in the tested strains compared to free CIP and RMP (P < 0.05). The potential antimicrobial effects of Cs/CaAlg-CIP and Cs/CaAlg-RMP NPs against clinical strains were also evaluated using the minimum inhibitory concentration (MICs) and a time-dependent killing method. A robust inhibitory effect on bacterial growth was observed even at low concentrations of Cs/CaAlg-CIP and Cs/CaAlg-RMP NPs (CONC 4 and 2 μg.mL─1) compared to free drugs (CIP at 32 and RMP at 8.0 μg.mL─1), (P < 0.05). The kinetics assay indicated that the Cs/CaAlg-CIP and Cs/CaAlg-RMP NPs had faster and lasting antibacterial effects than those of the free drug(s) on the tested strains. This study shows that loading CIP and RMP into CaAlg scaffolds and complexes with chitosan-TPP nanoparticles via the emulsification/internal gelation increases the antimicrobial activity of antibiotics against clinical strains of S. aureus and thus might serve as a novel type of antimicrobial compounds for the treatment of bacterial infections. [ABSTRACT FROM AUTHOR]

Abstract The interest in transporter‐mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion‐transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration‐dependent manner for both CP I and CP III in human hepatocytes (PXB‐cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild‐type ICR mice. Plasma concentrations (AUC0‐8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24‐h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP‐mediated drug interactions in PXB mice.

Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15–60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.

Background: In recent years, various phytomedicines have been used in the treatment of hepatic disorders. The aim of this study is to find out whether Peltophorum pterocarpum bark and leaves can help rats that have been exposed to isoniazid and rifampicin-induced hepatotoxicity. Materials and Methods: The rats were divided into 10 groups each with 6 rats. The liver damage is induced by isoniazid and rifampicin. The leaf and bark of P. pterocarpum extracted with ethanol are freshly mixed in sterile water (100, 200 and 400 mg/kg body weight), and given to rats orally in the early morning as a single dosage per day until the study period. The animals were sacrificed and the tissue and serum samples were collected for further investigations. Results: The liver damage induced by isoniazid and rifampicin altered the various biochemical parameters levels, but after the treatment of P. pterocarpum barks and leaves the levels were significantly altered when compared to the negative control rats. The drug silymarin was used as a standard. Conclusion: The extracts have the protective effect of liver markers and membrane-bound enzymes against the toxin-treated rats. This result highlights the hepatoprotective properties of the leaves and barks of the plant in a similar manner and the formulation (Group 10) have high beneficial effects than other groups.