Combination Of Isoniazid Research Articles

Isoniazid potentiates tigecycline to kill methicillin-resistant Staphylococcus aureus

ABSTRACT Therapeutic option for treating methicillin-resistant Staphylococcus aureus (MRSA) infection is urgently required since its resistance to a broad spectrum of currently available antibiotics. Here, we report that isoniazid is able to potentiate the killing efficacy of tigecycline to MRSA. Combination of isoniazid and tigecycline reduce the minimal inhibitory concentration of clinic MRSA strains to tigecycline. The killing activity of tigecycline is further confirmed by killing experiments and murine infection model. We further demonstrate the mechanism that isoniazid increases intracellular accumulation of tigecycline by promoting the influx but limiting the efflux of tigecycline through proton motive force. We also show that isoniazid and tigecycline synergize to increase the abundance of isoniazid-NAD adduct, which in turn damage cell membrane, possibly contributing to the disruption of PMF. Whereas phosphatidylethanolamine and cardiolipin are able to abrogate the synergistic effect of isoniazid plus tigecycline. Thus, our study provide a new perspective that antibiotics, e.g. isoniazid, once recognized only to target Mycobacterium tuberculosis, can be repurposed as antibiotic adjuvant to tigecycline, expanding our choice of antibiotic-antibiotic combinations in treating bacterial infectious diseases.

EVALUASI PENGGUNAAN OBAT ANTITUBERKULOSIS PARU DIPUSKESMAS: NARRATIVE LITERATURE REVIEW

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. While it primarily affects the lungs, it can also impact other organs. In Indonesia, pulmonary TB remains a significant health issue. This study aims to evaluate the use of anti-tuberculosis medications at various community health centers (puskesmas) in Indonesia through a literature review. The research method employed involves a literature review with searches conducted on Google Scholar and PubMed databases. Out of 360 articles found on Google Scholar and 13,026 articles on PubMed, 8 relevant articles were identified for this study. The results indicate that the most commonly used treatment regimen is Category 1, which includes a 2-month intensive phase with a combination of Isoniazid 75 mg, Rifampicin 150 mg, Pyrazinamide 400 mg, and Ethambutol 275 mg, followed by a 4-month continuation phase with Rifampicin 150 mg and Isoniazid 150 mg. This medication regimen aligns with the Tuberculosis Control Guidelines issued by the Indonesian Ministry of Health in 2016. The evaluation shows that Indonesian puskesmas generally adhere to the established treatment guidelines but still require further monitoring to ensure adherence and effectiveness of the treatment.

Apramycin kills replicating and non-replicating Mycobacterium tuberculosis

IntroductionMycobacterium tuberculosis (Mtb) has the capability to dodge the immune system by escaping into alternate physiological forms by forming drug tolerant populations under the immune pressure in the host. New drugs are urgently needed to treat these non-replicating persisters. In the past, aminoglycoside antibiotics have played a pivotal role in TB chemotherapy.MethodsHere, we explored the therapeutic potential of a monosubstituted deoxystreptamine aminoglycoside, apramycin (APR) which is different in its chemical structure from the other clinically relevant aminoglycoside antibiotics that are all disubstituted, e.g., amikacin (AMI). We determined the APR MIC as 0.25-1 µg/ml for sensitive and multidrug-resistant Mtb (MDRTB), including amikacin (AMI) resistant strains.ResultsIn standard time-kill kinetic assays, the bactericidal activity of APR was similar to that of AMI demonstrating dose-dependent killing of planktonic Mtb. However, in biofilm and macrophage intracellular killing assays, APR appeared significantly more potent than AMI. Further, APR monotherapy was efficacious in a mouse chronic TB lung infection model (~0.92 log10 CFU/lung reduction). APR combination therapy with the current 1st line standard of care (SoC) antibiotic combination of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z) was found to be additive (HREZ=1.88 vs. HREZ-APR=2.78 log10CFU/lung reduction).DiscussionThe results indicate the potential of apramycin-based combinations for the treatment of human tuberculosis.

A Single Centre Quality Improvement Project for Tuberculosis Preventive Therapy in People Living with HIV

Persons living with HIV should receive tuberculosis preventive therapy at least once in their lifetimes. Current practice at the Matron Roberts Polyclinic II (Belize City, Belize) is of a six-month course of isoniazid in combination with pyridoxine. A medical records audit was conducted for April 2021 with the objective of analyzing the initiation and completion of tuberculosis preventive therapy for people living with HIV seen in the polyclinic. This study was inconclusive due to a lack of standardization of the tuberculosis screening methods used, varied duration of tuberculosis preventive therapy and inconsistencies found in the documentation of the progress and completion of tuberculosis preventive therapy. In order to address these areas, a quality improvement project was conducted utilizing the Plan, Do, Study, Act methodology. The objectives were standardizing the tuberculosis screening methodology, the duration of therapy and the documentation. The following measures were taken: 1) four-question screening was standardized as the method of choice for tuberculosis screening; 2) tuberculosis preventive therapy was established as a six-month duration of isoniazid and pyridoxine; and 3) a documentation insert was added to the clinical notes to document tuberculosis screening and the progress of tuberculosis preventive therapy, among other parameters. Of the targets measured during the three months of the project, the outcomes were: 1) an average usage rate of 74.4% of the documentation insert; and 2) an average rate of initiation or continuation of tuberculosis preventive therapy of 64.3% for persons living with HIV seen over the duration of the project.

Real-world experience of adverse reactions-necessitated rifampicin-sparing treatment for drug-susceptible pulmonary tuberculosis

Rifampicin is an important agent for tuberculosis treatment; however, it is often discontinued because of adverse reactions. The treatment regimen then can be administered as that for rifampicin-resistant tuberculosis, which can be toxic. We retrospectively reviewed 114 patients with drug-susceptible pulmonary tuberculosis who discontinued rifampicin due to adverse reactions during an 18 year period at a tertiary referral center, of which 92 (80.7%) exhibited favorable response. Hepatotoxicity was the leading cause of intolerance. Patients with a favorable response were younger and less likely to have comorbidities. The majority of patients were administered four medications during the intensive phase and three to four during the consolidative phase. For those with a favorable response, the median duration of treatment was 10.2 months and the most common intensive regimen was a combination of isoniazid, ethambutol, pyrazinamide, and fluoroquinolone (25%). The most common consolidation regimen was a combination of isoniazid, ethambutol, and fluoroquinolone (22.8%). Among the patients with a favorable response, two (2.2%) experienced recurrence after a follow-up of 3.4 (interquartile range 1.8–6.8) years. For patients with drug-susceptible pulmonary tuberculosis who do not tolerate rifampicin owing to its toxicity, a shorter regimen may be a useful alternative.

Efficacy of Preventive Chemotherapy of Tuberculosis in HIV Infected Patients in Novosibirsk Oblast

The objective: to study the efficacy of tuberculosis preventive chemotherapy in HIV infected patients based on the data of AIDS Prevention and Control Center, which is a part of City Infectious Clinical Hospital no. 1, Novosibirsk.Subjects and Methods. 236 HIV infected patients aged 33-48 years old were enrolled in the study, they all were registered in AIDS Prevention and Control Center, City Infectious Clinical Hospital no. 1, Novosibirsk. All patients were at the stage of secondary diseases (4A, 4B, 4C), and had a pronounced degree of immunodeficiency (CD4+ from 200 to 349 cells/µl), and the ongoing ART was virologically successful. The efficacy of tuberculosis preventive chemotherapy (CTX) was analyzed in 147 patients versus 89 patients who received no tuberculosis CTX due to various reasons. For tuberculosis preventive chemotherapy, a combination drug was used, which contained isoniazid and pyrazinamide, for 3 months with daily intake. The groups of those receiving and not receiving CTX were comparable in terms of the gender, age and degree of immunodeficiency.Results. In the group receiving CTX within a year after completion of CTX, tuberculosis was diagnosed in 7/147 (4.8%) patients including: focal pulmonary tuberculosis - in 71.4% (5/7), and infiltrative pulmonary tuberculosis - in 28.6% (2/7 patients). In the group receiving no CTX, during the year, 17/89 (19.1%) tuberculosis cases were detected: focal pulmonary tuberculosis – in 29.4% (5/17), infiltrative pulmonary tuberculosis - in 47.1% (8/17), and disseminated pulmonary tuberculosis - in 23.5% (4/17). Disseminated pulmonary tuberculosis was registered only in the group who received no CTX. The relative risk (RR = 0.442 (<1)) when comparing the number of cases in the groups indicates lower likelihood to develop tuberculosis in the patients taking CTX. The odds ratio (OR = 0.212; CI 0.084-0.534) indicates that the chances of developing tuberculosis are higher in the group receiving no CTX.Conclusion. The use of a combination of isoniazid and pyrazinamide for tuberculosis preventive chemotherapy in HIV infected patients significantly reduces the risk of developing tuberculosis. Patients with severe immunodeficiency who have contraindications to tuberculosis preventive chemotherapy should be followed up jointly with a phthisiologist, the follow-up should include computed tomography for early detection of tuberculosis signs in the lungs.

PREVALENCE OF LATENT TUBERCULOSIS INFECTION AMONG MEDICAL WORKERS

The analysis of the results of immunological tests (skin test with tuberculosis recombinant allergen in standard dilution, hereinafter referred to as the test with ATP) and laboratory immunological test IGRA, delivered in 2019-2022 to employees of medical organizations of the Moscow Department of Health, working in four administrative districts of Moscow (Central, Western, South-Western, Troitsk and Novomoskovsk, next – CAD, WAD, SWAD/T&NAD). Among the average annual number of employees over 5 years – 43,452 people, with medical examination and exclusion of tuberculosis, the prevalence of persons with latent tuberculosis infection (LTI) was 2.6, 6.1 and 1.8%, in the CAD, WAD and SWAD/T&NAD, respectively, or 3.4% in general to these districts. At the same time, the average annual frequency of detection of cases of LTI («first detected LTI») was 0.6, 1.3 and 0.6% in these districts, respectively, and 0.75% in all districts as a whole. 95.4% of the employees were assigned a course of preventive therapy (PT), 45.8% of which the course was started. Among the latter, 85.0% successfully completed the course, 14.1% – the course was interrupted by the patient, and 0.9% – canceled by the doctor due to adverse events. The main PT regimen used (78.4%) included 3 months of taking a combination of isoniazid and pyrazinamide (INN: isoniazid 150 mg + pyrazinamide 500 mg), which showed a low proportion of adverse events – 3.1%. The identification of workers of medical organizations of LTI allows to determine a group high risk for tuberculosis and to allocate a group of persons for preventive therapy

1433. Factors Associated with Unsuccessful Treatment Outcomes among Patients with Rifampicin Resistant Tuberculosis - Tajikistan, 2015-2020

Abstract Background Tajikistan has a high burden of multidrug resistant TB, including rifampicin-resistant TB (RR-TB). Treatment options are more limited and include standard treatment (T1), bedaquiline/delamanid contained individual treatment (T2), short treatment (T3), modified short treatment (T4), and bedaquiline/pretomanid/linezolid treatment (T5). To inform national treatment plans, we assessed trends in RR-TB and determined factors associated with unsuccessful treatment. Methods We conducted a retrospective cohort study in Dushanbe, Tajikistan, from 2015 to 2020 using patient records. Patients had successful treatment outcomes if they completed treatment or were cured, and unsuccessful if they had treatment failure, were lost-to-follow-up, or died. We report relative risk (RR) and 95% confidence interval from multivariable Poisson regression. Results From 2015 to 2020, there was a decrease in incidence of TB (68.6 to 47.2 per 100,000) and RR-TB (10.6 to 7.2) with a 33% drop 2019 to 2020. Proportion of unsuccessful outcomes also decreased (30% to 15% 2015-2020). Of 522 patients, 515 had RR-TB. Of these, 39% received T1, 43% T2, 15% T3, 2% T4, and 0.4% T5 (Table 1). Overall, 23% had unsuccessful treatment outcomes. Patients on T1 had higher unsuccessful outcome compared to those on T2 - T5 (31% vs 19%, 14%, 0% and 0%, respectively). Unsuccessful outcomes were associated with combined isoniazid, rifampin and streptomycin resistance, alcohol and drug use. For patients receiving T1, unsuccessful outcome was associated with unemployment (RR: 2.7; 1.1-6.8), HIV (RR: 2.3, 1.5-3.4), hepatitis C (RR: 2.2, 1.4-3.4), and concomitant disease (RR: 2.1, 1.4-3.1). For patients receiving T2, risk of unsuccessful outcome was lower for females (RR: 0.4, 0.2-0.7) (Table 2). Conclusion Decrease in incidence is promising. Results highlight the need to transition RR-TB patients to non-standard treatment. Closer follow-up of patients with combined resistance, alcohol or drug use, HIV, hepatitis C, and concomitant diseases may contribute to successful outcome. Disclosures All Authors: No reported disclosures.

Isoniazid pharmacokinetics/pharmacodynamics as monotherapy and in combination regimen in the hollow fiber system model of Mycobacterium kansasii

BackgroundThere is limited high quality evidence to guide the optimal doses of drugs for the treatment of Mycobacterium kansasii pulmonary disease (Mkn-PD). MethodsWe performed (1) minimum inhibitory concentration experiment, (2) isoniazid dose-response study using the hollow fiber system model (HFS-Mkn) to determine PK/PD optimized exposure, and (3) another HFS-Mkn study to determine the efficacy of high dose isoniazid (15 mg/kg/day) with standard dose rifampin (10 mg/kg/day) and ethambutol (15 mg/kg/day). Inhibitory sigmoid maximal effect model and linear regression was used for data analysis. ResultsMIC of the 20 clinical isolates ranged between 0.5 mg/L to 32 mg/L. In the HFS-Mkn, isoniazid monotherapy failed to control the bacterial growth beyond day 7. On day 7, when the maximal Mkn kill was observed, the optimal isoniazid exposure for Mkn kill was calculated as 24hr area under the concentration-time curve to the MIC of 12.41. Target attainment probability of 300 mg/day dose fell below 90% above the MIC of 1 mg/L. High dose isoniazid combination sterilized the HFS-Mkn in 30-days with a kill rate of −0.15 ± 0.02 log10 CFU/mL/day. ConclusionDespite initial kill, isoniazid monotherapy failed due to resistance emergence. Our pre-clinical model derived results suggest that higher than currently recommended 300 mg/day isoniazid dose may achieve better clinical efficacy against Mkn-PD.

TB screening, prevention and treatment cascade in a Malawi prison.

BACKGROUND Incarcerated individuals, especially in high HIV and TB burden settings, are at increased risk of latent TB infection and/or TB disease. We implemented a comprehensive HIV-TB intervention in a Malawi prison and studied its feasibility.METHODS Between February and December 2019, consenting individuals underwent screening for HIV, TB infection and TB disease. HIV-positive individuals without TB disease were treated with a fixed-dose combination of isoniazid, cotrimoxazole and vitamin B6 (INH-CTX-B6). HIV-negative persons with TB infection received 12 weeks of isoniazid and rifapentine (3HP).RESULTS Of 1,546 consenting individuals, 1,498 (96.9%) were screened and 1,427 (92.3%) included in the analysis: 96.4% were male, the median age was 31 years (IQR 25-38). Twenty-nine (2.1%) participants were diagnosed with TB disease, of whom 89.7% started and 61.5% completed TB treatment. Of the 1,427 included, 341 (23.9%) were HIV-positive, of whom 98.5% on antiretroviral therapy and 95% were started on INH-CTX-B6. Among 1,086 HIV-negative participants, 1,015 (93.5%) underwent the tuberculin skin test (TST), 670 (65.9%) were TST-positive, 666 (99.4%) started 3HP and 570 (85.5%) completed 3HP treatment.CONCLUSION A comprehensive TB screening and treatment package among incarcerated individuals was acceptable and feasible, and showed high prevalence of HIV, TB disease and TB infection. Treatment uptake was excellent, but treatment completion needs to be improved. Greater investment in comprehensive HIV-TB services, including access to shorter TB regimens and follow-up upon release, is needed for incarcerated individuals.

Synthesis, characterization, anti-mycobacterial activity and in silico study of new 2,5-disubstituted-1,3,4-oxadiazole derivatives.

A series of new 2,5-disubstituted-1,3,4-oxadiazole derivatives (5a-j and 6a-j) have been designed and synthesized in four-steps. Sixteen compounds among the twenty compounds are reported for the first time. The compounds were characterized and confirmed by the FTIR, 1D- and 2D-NMR and HRMS analyses, and were tested against Mycobacterium smegmatis and Mycobacterium tuberculosis H37Ra. Compound 5d was the most active against M. smegmatis with MIC value of 25 µM, and exhibited cidal activity with MBC of 68 µM, respectively. The time-kill assay showed the good killing rate at 77% with the combination of isoniazid (INH). In addition, checkboard assay confirmed the interaction of compound 5d was categorised as additive. Docking simulation has been performed to position 5d into the pantothenate synthetase active site with binding free energy value -8.6 kcal mol-1. It also occupied the same active site as that of standard native ligand with similar interactions, which clearly indicate their potential as pantothenate synthetase inhibitor.

Systematic review with network meta-analysis on the treatments for latent tuberculosis infection in children and adolescents

BackgroundWe aimed to synthesize the evidence on the efficacy and safety of different treatment regimens for latent tuberculosis infection (LTBI) in children and adolescents. MethodsA systematic review with network meta-analysis was performed (CRD142933). Searches were conducted in Pubmed and Scopus (Nov-2021). Randomized controlled trials comparing treatments for LTBI (patients up to 15 years), and reporting data on the incidence of the disease, death or adverse events were included. Networks using the Bayesian framework were built for each outcome of interest. Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Rank probabilities were calculated via the surface under the cumulative ranking analysis (SUCRA) (Addis-v.1.16.8). GRADE approach was used to rate evidence's certainty. ResultsSeven trials (n = 8696 patients) were included. Placebo was significantly associated with a higher incidence of tuberculosis compared to all active therapies. Combinations of isoniazid (15–25 mg/kg/week) plus rifapentine (300–900 mg/week), followed by isoniazid plus rifampicin (10 mg/kg/day) were ranked as best approaches with lower probabilities of disease incidence (10% and 19.5%, respectively in SUCRA) and death (20%). Higher doses of isoniazid monotherapy were significantly associated to more deaths (OR 18.28, 95% ICr [1.02, 48.60] of 4–6 mg/kg/day vs. 10 mg/kg/3x per week). ConclusionsCombined therapies of isoniazid plus rifapentine or rifampicin for short-term periods should be used as the first-line approach for treating LTBI in children and adolescents. The use of long-term isoniazid as monotherapy and at higher doses should be avoided for this population.

A high content screening assay for discovery of antimycobacterial compounds based on primary human macrophages infected with virulent Mycobacterium tuberculosis

Drug resistance in Mycobacterium tuberculosis is an emerging threat that makes the discovery of new candidate drugs a priority. In particular, drugs with high sterilizing activity within host cells are needed to improve efficacy and reduce treatment duration. We aimed to develope and validate a High Content Screening assay based on Mycobacterium tuberculosis-infected primary human monocyte-derived macrophages as its natural reservoir. Infected primary human monocyte-derived macrophages were exposed to control antibiotics or tested compounds on 384 well plates. Intracellular bacterial growth and macrophage numbers were evaluated using an ImageXpress High Content Screening system and Z′-factor was calculated to assess the reproducibility. The combination of isoniazid and rifampicin as a positive control rendered a Z′-factor above 0.4, demonstrating suitability of the assay for screening and compound profiling purposes. In a validation experiment, isoniazid, rifampicin, moxifloxacin and levofloxacin all effectively inhibited intracellular growth as expected. Finally, a pilot screening campaign including 5700 compounds from diverse libraries resulted in the identification of three compounds with confirmed antimycobacterial activity in the low micromolar range and low host cell toxicity. The assay represents an attractive screening platform for both academic research on host-pathogen mechanisms in tuberculosis and for the identification and characterization of novel antimycobacterial compounds.

Pharmacokinetics of isoniazid in Wistar rats exposed to ethanol

Tuberculosis treatment consists of a drug combination, where isoniazid is the core drug and alcoholism is a factor highly related to poor patient compliance with the therapy. CYP2E1 is an enzyme involved both in the metabolism of ethanol and in the formation of hepatotoxic compounds during the metabolism of isoniazid. The shared metabolism pathway accounts for the possibility of pharmacokinetic interaction in cases of concomitant alcohol use during tuberculosis treatment. The aim of this study was to evaluate the effect of repeated exposure of Wistar rats (males, 250 g, n=6) to ethanol on the pharmacokinetics of a single dose of isoniazid in combination with pyrazinamide and rifampicin (100 mg/kg, 350 mg/kg and 100 mg/kg, respectively). An animal group received the combination of drugs and ethanol and was compared to a control group, which received the combination of drugs without exposure to ethanol. The plasma concentrations of isoniazid were determined by a UHPLC/UV bioanalytical method that was previously validated. Biochemical markers of liver function were measured to assess potential damage. A lower elimination half-life of isoniazid was observed in the ethanol group than in the control group (t1/2 0.91 h versus 1.34 h). There was no evidence of hepatotoxicity through the biomarker enzymes evaluated. The results allow us to infer that although there are no biochemical changes related to liver damage, there is a slight influence of ethanol exposure on the pharmacokinetic profile of isoniazid. This change may have a relevant impact on the efficacy of isoniazid in the outcome of tuberculosis treatment.

Combination of Isoniazid and Rifampin for the Prevention of Failure of Standard Therapy for Latent Tuberculosis Infection in Children: Evidence Base Case Report

Tuberculosis (TB) control program in children is carried out with three strategies: finding and treating adult TB cases (as a source of transmission), treating latent TB infection, and administering the BCG vaccine. There is a high risk of transmission in children in close contact and living at home with adult patients. After Mycobacterium is inhaled through the respiratory tract, then the body's resistance to Mycobacterium tuberculosis occurs. Furthermore, there are two possibilities: only TB infection occurs, or the child has TB disease. We report one case: a boy, age four years, diagnosed with latent TB infection. This diagnosis is based on the findings of the 13 mm tuberculin test (positive). There is a history of contact with adult TB patients. On physical examination, no abnormalities were found. Likewise, the chest X-ray examination also found no abnormalities. Due to the diagnosis of latent TB infection, prophylaxis with Isoniazid was planned for six months. In the first month, the child still wants to take medication according to the rules. However, entering the second month, children sometimes do not want to take medication. This situation raises concerns about the possibility of therapy failure. His mother was very worried about this condition. Therefore, doctors offer to provide a combination pattern of therapy in isoniazid with rifampicin, with a span of 3 months. Standard therapy with INH alone was discontinued. This therapeutic decision was based on a study that combined INH with rifampin for three months gave better results than single prophylactic therapy with INH.

In vitro Synergism of Six Antituberculosis Agents Against Drug-Resistant Mycobacterium tuberculosis Isolated from Retreatment Tuberculosis Patients

BackgroundRetreatment tuberculosis (TB) has become a major source of drug-resistant TB. In contrast to the combination of isoniazid (INH) and rifampicin (RIF), that of pasiniazid (Pa) and rifabutin (RFB) or rifapentine (RFP) appears to have better activity in vitro against drug-resistant Mycobacterium tuberculosis (MTB), especially when combined with moxifloxacin (MXF). However, there has been limited study of potential synergism among Pa, RFB, RFP, and MXF, or simultaneous comparison with the standard INH and RIF combination.MethodsIn vitro synergism of four two-drug combinations (INH and RIF, Pa and RFB, Pa and RFP, MXF and Pa) and two three-drug combinations (MXF and Pa combined with RFB or RFP) was evaluated against 90 drug-resistant MTB strains isolated from retreatment TB patients by the checkerboard method. The fractional inhibitory concentration index (FICI) was calculated for each combination.ResultsThe synergistic activity of the combination of Pa with RFB or RFP was higher than that of INH and RIF or MXF and Pa, and the synergistic activity of Pa in combination with RFP was even higher than that of RFB, although RFP yielded an MIC90 of 64 mg/liter, higher than that of RFB of 8 mg/liter against 90 drug-resistant MTB strains. Meanwhile, for three-drug combinations, the synergistic effects of MXF and Pa combined with RFB or RFP were similar. Further stratification analysis showed that, for XDR-MTB strains, the synergistic effect of the Pa and RFP combination was also better than those of other two-drug combinations.ConclusionThe combination of Pa with RFP shows better in vitro synergism than Pa with RFB and standard INH with RIF combinations, which can provide a reference for new regimens for retreatment TB patients.

Effect of Alcornea cordifolia Aqueous and Methanolic Leaf Extracts against Antituberculosis Drugs Induced Liver Damage in Rats

The hepatoprotective properties of Alchornea cordifolia, a medicinal plant was studied in hepatotoxicity induced animal model with a high dose of paracetamol or carbon tetrachloride. Knowing that antituberculosis drugs also represent a risk factor for hepatotoxicity, could A. cordifolia play a key role to limit their hepatotoxicity? The objective of this study was to assess the histological changes of antituberculosis drugs in rat livers and their evolution after administration of an aqueous and a methanolic leaf extracts of A. cordifolia and therefore estimate their polyphenol and flavonoid contents. Rats were divided into three (3) groups: group 1 was treated with isoniazid; group 2 received the combination of isoniazid and rifampicin and group 3 was given the combination of isoniazid, rifampicin and pyraziamide. For each group of rats, the hepatotoxicant was either administered alone or two hours before administration of an aqueous (200, 400, or 800 mg/kg) or a methanolic (200, 400, or 800 mg/kg) leaf extracts of A. cordifolia each day for 10 days. Animals were sacrificed on day 11 and their livers removed for histolopathological analysis. In addition, total polyphenol and flavonoid contents were estimated in both extracts. Antituberculosis drug combinations caused peliosis lesions, steatosis and hepatocyte necrosis. The liver histology of rats that received extracts after administration of antituberculosis drug combinations showed the ability of extracts to annihilate or alleviate hepatocellular damage caused by such drugs. The methanolic extract, richer in total polyphenols (0.55 ± 0.02 mg EGA) than the aqueous extract (0.35 ± 0.01 mg EGA) demonstrated a greater hepatoprotective effect. Thus, according to liver histological analysis, the aqueous and methanolic leaf extracts of A. cordifolia could attenuate the hepatotoxicity induced by antituberculosis drugs in rats.

Graphene Oxide-Linezolid Combination as Potential New Anti-Tuberculosis Treatment.

Global pandemic management represents a serious issue for health systems. In some cases, repurposing of existing medications might help find compounds that have the unexpected potential to combat microorganisms. In the same way, changing cell–drug interaction by nanotechnology could represent an innovative strategy to fight infectious diseases. Tuberculosis (TB) remains one of the most alarming worldwide infectious diseases and there is an urgent need for new drugs and treatments, particularly for the emergence and spread of drug-resistant Mycobacterium tuberculosis (Mtb) strains. New nanotechnologies based on carbon nanomaterials are now being considered to improve anti-TB treatments, and graphene oxide (GO) showed interesting properties as an anti-TB drug. GO, which preferentially accumulates in the lungs and is degraded by macrophagic peroxidases, can trap Mycobacterium smegmatis and Mtb in a dose-dependent manner, reducing the entry of bacilli into macrophages. In this paper, combinations of isoniazid (INH), amikacin (AMK) and linezolid (LZD) and GO anti-mycobacterial properties were evaluated against Mtb H37Rv by using a checkerboard assay or an in vitro infection model. Different GO effects have been observed when incubated with INH, AMK or LZD. Whereas the INH and AMK anti-mycobacterial activities were blocked by GO co-administration, the LZD bactericidal effect increased in combination with GO. GO-LZD significantly reduced extracellular mycobacteria during infection and was able to kill internalized bacilli. GO-LZD co-administration is potentially a new promising anti-TB treatment at the forefront in fighting emerging antibiotic-resistant Mtb strains where LZD administration is suggested. This innovative pharmacological approach may lead to reduced treatment periods and decreased adverse effects. More importantly, we demonstrate how nanomaterials–drugs combinations can represent a possible strategy to quickly design drugs for pandemics treatment.

Comparison of a Novel Regimen of Rifapentine, Tedizolid, and Minocycline with Standard Regimens for Treatment of Pulmonary Mycobacterium kansasii.

The combination of isoniazid, rifampin, and ethambutol is recommended by the American Thoracic Society (ATS) for treatment of pulmonary Mycobacterium kansasii, while the British Thoracic Society (BTS) recommends clarithromycin, rifampin and ethambutol. Unfortunately, therapy duration for both regimens lasts for years. In this study, we administered tedizolid, minocycline, clarithromycin, and rifapentine as monotherapy as well as novel combinations in the intracellular hollow-fiber model system of M. kansasii (HFS-Mkn) in a 28-day study. The ATS and BTS regimens were used as comparators. Repetitive sampling was used to validate the intended intrapulmonary pharmacokinetics of each drug and to monitor changes in M. kansasii burden. As monotherapy, tedizolid at an observed area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC of 5.85 and minocycline at an AUC0-24/MIC of 5.77 failed to kill the bacteria below day 0 (stasis), clarithromycin at an AUC0-24/MIC of 2.4 held the bacterial burden at stasis, but rifapentine at an AUC0-24/MIC of 140 killed 2 log10 CFU/ml below stasis. The BTS regimen kill slope was -0.083 ± 0.035 CFU/ml/day, which was significantly superior to the ATS regimen slope of -0.038 ± 0.038 CFU/ml/day. The rifapentine-tedizolid-minocycline combination kill slope was -0.119 ± 0.031 CFU/ml/day, superior to that of the ATS regimen and comparable to that of the BTS regimen. In conclusion, the BTS regimen and the novel rifapentine-tedizolid-minocycline regimen showed better kill of intracellular bacteria in the HFS-Mkn However, the efficacy of the new combination regimen remains to be tested in clinical settings.

Antibiotic Treatment Shapes the Antigenic Environment During Chronic TB Infection, Offering Novel Targets for Therapeutic Vaccination

The lengthy and complicated current regimen required to treat drug-susceptible tuberculosis (TB) reflects the ability of Mycobacterium tuberculosis (Mtb) to persist in host tissues. The stringent response pathway, governed by the dual (p)ppGpp synthetase/hydrolase, RelMtb, is a major mechanism underlying Mtb persistence and antibiotic tolerance. In the current study, we addressed the hypothesis that RelMtb is a “persistence antigen” presented during TB chemotherapy and that enhanced immunity to RelMtb can enhance the tuberculocidal activity of the first-line anti-TB drug, isoniazid, which has reduced efficacy against Mtb persisters. C57BL/6 mice and Hartley guinea pigs were aerosol-infected with M. tuberculosis (Mtb) and, 4 weeks later, received either human-equivalent daily doses of isoniazid alone, or isoniazid in combination with a DNA vaccine targeting relMtb. After isoniazid treatment, there was a significant reduction in dominant antigen ESAT6-reactive CD4+ or TB10.4-reactive CD8+ T cells in the lungs and spleens of mice. However, the total number of RelMtb-reactive CD4+ T cells remained stable in mouse lungs and spleens, as did the number of RelMtb-reactive CD8+T cells. Therapeutic vaccination with relMtb DNA vaccine enhanced the activity of isoniazid in Mtb-infected C57BL/6 mice and guinea pigs. When treatment with isoniazid was discontinued, mice immunized with the relMtb DNA vaccine showed a lower mean lung bacterial burden at relapse compared to the control group. Our work shows that antitubercular treatment shapes the antigenic environment, and that therapeutic vaccination targeting the Mtb stringent response may represent a novel approach to enhance immunity against Mtb persisters, with the ultimate goal of shortening curative TB treatment.