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Fulltext Antimycobacterial susceptibility evaluation of rifampicin and isoniazid benz-hydrazone in biodegradable polymeric nanoparticles against Mycobacterium tuberculosis H37Rv strain

Hakkimane SS, Shenoy VP, Gaonkar SL, Bairy I, Guru BR

Int J Nanomedicine, 2018;13:4303-4318.
PMID: 30087562 DOI: 10.2147/IJN.S163925

INTRODUCTION: Tuberculosis (TB) is the single largest infectious disease which requires a prolonged treatment regime with multiple drugs. The present treatment for TB includes frequent administration of a combination of four drugs for a duration of 6 months. This leads to patient's noncompliance, in addition to developing drug-resistant strains which makes treatment more difficult. The formulation of drugs with biodegradable polymeric nanoparticles (NPs) promises to overcome this problem.
MATERIALS AND METHODS: In this study, we focus on two important drugs used for TB treatment - rifampicin (RIF) and isoniazid (INH) - and report a detailed study of RIF-loaded poly lactic-co-glycolic acid (PLGA) NPs and INH modified as INH benz-hydrazone (IH2) which gives the same therapeutic effect as INH but is more stable and enhances the drug loading in PLGA NPs by 15-fold compared to INH. The optimized formulation was characterized using particle size analyzer, scanning electron microscopy and transmission electron microscopy. The drug release from NPs and stability of drug were tested in different pH conditions.
RESULTS: It was found that RIF and IH2 loaded in NPs release in a slow and sustained manner over a period of 1 month and they are more stable in NPs formulation compared to the free form. RIF- and IH2-loaded NPs were tested for antimicrobial susceptibility against Mycobacterium tuberculosis H37Rv strain. RIF loaded in PLGA NPs consistently inhibited the growth at 70% of the minimum inhibitory concentration (MIC) of pure RIF (MIC level 1 µg/mL), and pure IH2 and IH2-loaded NPs showed inhibition at MIC equivalent to the MIC of INH (0.1 µg/mL).
CONCLUSION: These results show that NP formulations will improve the efficacy of drug delivery for TB treatment.

Matched MeSH terms: Isoniazid/pharmacology*; Isoniazid/therapeutic use
Fulltext Synthesis, characterization, and efficacy of antituberculosis isoniazid zinc aluminum-layered double hydroxide based nanocomposites

Saifullah B, El Zowalaty ME, Arulselvan P, Fakurazi S, Webster TJ, Geilich BM, et al.

Int J Nanomedicine, 2016;11:3225-37.
PMID: 27486322 DOI: 10.2147/IJN.S102406

The chemotherapy for tuberculosis (TB) is complicated by its long-term treatment, its frequent drug dosing, and the adverse effects of anti-TB drugs. In this study, we have developed two nanocomposites (A and B) by intercalating the anti-TB drug isoniazid (INH) into Zn/Al-layered double hydroxides. The average size of the nanocomposites was found to bê164 nm. The efficacy of the Zn/Al-layered double hydroxides intercalated INH against Mycobacterium tuberculosis was increased by approximately three times more than free INH. The nanocomposites were also found to be active against Gram-positive and -negative bacteria. Compared to the free INH, the nanodelivery formulation was determined to be three times more biocompatible with human normal lung fibroblast MRC-5 cells and 3T3 fibroblast cells at a very high concentration of 50 µg/mL for up to 72 hours. The in vitro release of INH from the Zn/Al-layered double hydroxides was found to be sustained in human body-simulated buffer solutions of pH 4.8 and 7.4. This research is a step forward in making the TB chemotherapy patient friendly.

Matched MeSH terms: Isoniazid/pharmacology*
Fulltext A rare case of TB elbow synovitis in a patient with rheumatoid arthritis: a case report

Meryl Grace Lansing, Malehah Mohd Noh, Mohd Hakimi Nordin

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):96-96.
MyJurnal

Introduction: Tuberculosis (TB) of the elbow joint is uncommon. Prompt diagnosis and treatment are important to prevent joint destruction and preserve function. We present a case of TB synovitis of the elbow joint in a patient with active rheumatoid arthritis (RA). Case description: A 56-year-old woman with a known seropositive RA on metho-trexate and Leflunomide was seen in the outpatient rheumatology clinic as part of her monthly follow-up. She com-plained of persistent bilateral elbow pain and swelling, despite optimisation of her disease-modifying antirheumatic drugs (DMARD) and steroid therapy. The suspicion for another diagnosis for her elbow symptoms stems from the persistent pain and swelling amidst increased titration of methotrexate and prednisolone dosages. Ultrasound scan of her elbows revealed bilateral complex olecranon bursitis with active synovitis. The left elbow aspiration yielded cloudy yellowish synovial fluid and the sample was sent for fluid culture, acid-fast bacilli (AFB) stain, and GeneXpert. No AFB was seen but the GeneXpert test confirmed the presence of Mycobacterium Tuberculosis. Thus, a diagnosis of TB synovitis of the left elbow was made, and she was promptly started on anti-tubercular therapy (ATT) consisting of Rifampicin, Isoniazid, Ethambutol and Pyrazinamide with the aim to complete 9 months of ATT. Conclusion: The diagnosis of tuberculous synovitis is challenging. In the absence of constitutional or respiratory symptoms, joint TB is usually low on the initial differential diagnosis in patients presenting with joint pain and swelling. The diagnosis is made even more difficult in patients with concomitant rheumatoid arthritis. This case demonstrates the importance of a high index of suspicion for TB, particularly when evaluating patients in high TB prevalence area with an underlying immunosuppressive state.

Matched MeSH terms: Isoniazid
Fulltext A double-edged sword: a case report on liver injury side-effect of anti-tuberculosis drug on liver tuberculosis patient

Azlina Ibrahim, Alvin Oliver Payus

Borneo Journal of Medical Sciences, 2020;14(1):49-53.
MyJurnal

Hepatic involvement in extra-pulmonary tuberculosis (TB) is rare, even in the endemic area. It has a high mortality rate as it can easily be misdiagnosed due to its rarity and non-specific presentations, and the treatment can be challenging for its hepatotoxic side-effect. A 55-year old man who was newly diagnosed with AIDS and pulmonary TB which complicated with anti-TB-induced transaminitis, presented with a few weeks history of fever and persistent diarrhoea. It was initially treated as microsporidia infection but the symptoms persisted despite given antiparasitic agent for more than a week. He was subjected to computed tomography (CT) scan of the abdomen and noted multiple hypoechoic lesion at multiple segments of the liver, which later confirmed to be liver TB by liver biopsy. As he could not tolerate Akurit-4 (Rifampicin 150 mg, Isoniazid 75 mg, Pyrazinamide 400 mg and Ethambutol 275 mg), the second-line treatment was given instead. He is currently well on regular clinic appointment. The objective of this case report is to share the rare occurrence of hepatic TB and the difficulty to treat it as the hepatotoxic effect of anti-TB medications complicate the liver damage due to the infection.

Matched MeSH terms: Isoniazid
Fulltext Treatment Outcomes of Extensively Drug-Resistant Tuberculosis in Pakistan: A Countrywide Retrospective Record Review

Abubakar M, Ahmad N, Ghafoor A, Latif A, Ahmad I, Atif M, et al.

Front Pharmacol, 2021;12:640555.
PMID: 33867989 DOI: 10.3389/fphar.2021.640555

Background: The current study is conducted with the aim to the fill the gap of information regarding treatment outcomes and variables associated with unsuccessful outcome among XDR-TB patients from Pakistan. Methods: A total of 404 culture confirmed XDR-TB patients who received treatment between 1st May 2010 and June 30, 2017 at 27 treatment centers all over Pakistan were retrospectively followed until their treatment outcomes were reported. A p-value <0.05 reflected a statistical significant association. Results: The patients had a mean age 32.9 ± 14.1 years. The overall treatment success rate was 40.6% (95% confidence interval [CI]:35.80-45.60%). A total of 155 (38.4%) patients were declared cured, 9 (2.2%) completed treatment, 149 (36.9%) died, 60 (14.9%) failed treatment and 31 (7.7%) were lost to follow up (LTFU). The results of the multivariate binary logistic regression analysis revealed that the patients' age of >60 years (OR = 4.69, 95%CI:1.57-15.57) and receiving high dose isoniazid (OR = 2.36, 95%CI:1.14-4.85) had statistically significant positive association with death, whereas baseline body weight >40 kg (OR = 0.43, 95%CI:0.25-0.73) and sputum culture conversion in the initial two months of treatment (OR = 0.33, 95%CI:0.19-0.58) had statistically significant negative association with death. Moreover, male gender had statistically significant positive association (OR = 1.92, 95%CI:1.04-3.54) with LTFU. Conclusion: The treatment success rate (40.6%) of XDR-TB patients in Pakistan was poor. Providing special attention and enhanced clinical management to patients with identified risk factors for death and LTFU in the current cohort may improve the treatment outcomes.

Matched MeSH terms: Isoniazid
Fulltext Diagnostic challenges and Gene-Xpert utility in detecting Mycobacterium tuberculosis among suspected cases of Pulmonary tuberculosis

Kabir S, Parash MTH, Emran NA, Hossain ABMT, Shimmi SC

PLoS One, 2021;16(5):e0251858.
PMID: 34015016 DOI: 10.1371/journal.pone.0251858

The incidence of pulmonary tuberculosis (PTB) can be reduced by preventing transmission with rapid and precise case detection and early treatment. The Gene-Xpert MTB/RIF assay is a useful tool for detecting Mycobacterium tuberculosis (MTB) with rifampicin resistance within approximately two hours by using a nucleic acid amplification technique. This study was designed to reduce the underdiagnosis of smear-negative pulmonary TB and to assess the clinical and radiological characteristics of PTB patients. This cross-sectional study included 235 participants who went to the Luyang primary health care clinic from September 2016 to June 2017. The demographic data were analyzed to investigate the association of patient gender, age group, and ethnicity by chi-square test. To assess the efficacy of the diagnostic test, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. The area under the curve for sputum for both AFB and gene-Xpert was analyzed to compare their accuracy in diagnosing TB. In this study, TB was more common in males than in females. The majority (50.71%) of the cases belonged to the 25-44-year-old age group and the Bajau ethnicity (57.74%). Out of 50 pulmonary TB cases (smear-positive with AFB staining), 49 samples were positive according to the Gene-Xpert MTB/RIF assay and was confirmed by MTB culture. However, out of 185 smear-negative presumptive cases, 21 cases were positive by Gene-Xpert MTB/RIF assay in that a sample showed drug resistance, and these results were confirmed by MTB culture, showing resistance to isoniazid. In comparison to sputum for AFB, Gene-Xpert showed more sensitivity and specificity with almost complete accuracy. The additional 21 PTB cases detection from the presumptive cases by GeneXpert had significant impact compared to initial observation by the routine tests which overcame the diagnostic challenges and ambiguities.

Matched MeSH terms: Isoniazid
Fulltext Treating More with Less: Effectiveness and Event Outcomes of Antituberculosis Fixed-dose Combination Drug versus Separate-drug Formulation (Ethambutol, Isoniazid, Rifampicin and Pyrazinamide) for Pulmonary Tuberculosis Patients in Real-world Clinical Practice

Lai JML, Yang SL, Avoi R

J Glob Infect Dis, 2019 3 1;11(1):2-6.
PMID: 30814828 DOI: 10.4103/jgid.jgid_50_18

Introduction: Conventionally, a combination of four separate drugs (ethambutol, isoniazid, rifampicin, and pyrazinamide [EHRZ]) is the first-line pharmacotherapy for pulmonary tuberculosis (TB). In recent years, fixed-dose combination (FDC) formulation, where a single tablet contains the active ingredients of four aforementioned drugs, is gaining popularity due to its ease of administration.
Objective: To compare the real-world effectiveness of EHRZ and FDC treatment groups on a cohort registry by investigating the sputum conversion rate and treatment outcomes of both groups.
Methods: A total of 11,489 patients' data were extracted from the Sabah TB registry between January 2012 and June 2016, including EHRZ (n = 4188) and FDC (n = 7301) patients. Then, 1:1 propensity score matching was adopted to reduce the baseline bias. Caliper matching was conducted with maximum tolerance score set at 0.001. Confounders included in the propensity score matching were gender, nationality, diabetes, HIV status, smoking status, and chest X-ray status. Successful matching provided 4188 matched pairs (n = 8376) for final analysis.
Results: In this matched cohort of 4188 pairs, the 2-month sputum conversion rate of FDC group was significantly higher than the EHRZ group (96.3% vs. 94.3%; P < 0.001) whereas 6-month sputum conversion of both groups showed no significant difference. Treatment outcomes such as noncompliance rate, failure rate, and success rate have no significant difference (P > 0.05) in both the treatment groups. There was an incidental finding of reduced death rate among FDC group compared to the EHRZ group (0.2% vs. 0.5%; P = 0.034).
Conclusion: The FDC formulation has better sputum conversion rate at 2 months compared to conventional EHRZ regime as separate-drug formulation. It was also observed that FDC has a slight protective effect against all-cause death among TB patients. This protective effect of FDC, however, still needs to be proven further.

Matched MeSH terms: Isoniazid
Fulltext Isoniazid Conjugated Magnetic Nanoparticles Loaded with Amphotericin B as a Potent Antiamoebic Agent against Acanthamoeba castellanii

Iqbal K, Abdalla SAO, Anwar A, Iqbal KM, Shah MR, Anwar A, et al.

Antibiotics (Basel), 2020 May 25;9(5).
PMID: 32466210 DOI: 10.3390/antibiotics9050276

The pathogenic free-living amoeba, Acanthamoeba castellanii, is responsible for a rare but deadly central nervous system infection, granulomatous amoebic encephalitis and a blinding eye disease called Acanthamoeba keratitis. Currently, a combination of biguanides, amidine, azoles and antibiotics are used to manage these infections; however, the host cell cytotoxicity of these drugs remains a challenge. Furthermore, Acanthamoeba species are capable of transforming to the cyst form to resist chemotherapy. Herein, we have developed a nano drug delivery system based on iron oxide nanoparticles conjugated with isoniazid, which were further loaded with amphotericin B (ISO-NPs-AMP) to cause potent antiamoebic effects against Acanthamoeba castellanii. The IC50 of isoniazid conjugated with magnetic nanoparticles and loaded with amphotericin B was found to be 45 μg/mL against Acanthamoeba castellanii trophozoites and 50 μg/mL against cysts. The results obtained in this study have promising implications in drug discovery as these nanomaterials exhibited high trophicidal and cysticidal effects, as well as limited cytotoxicity against rat and human cells.

Matched MeSH terms: Isoniazid
Mass-spectrometry based minisequencing method for the rapid detection of drug resistance in Mycobacterium tuberculosis

Ikryannikova LN, Afanas'ev MV, Akopian TA, Il'ina EN, Kuz'min AV, Larionova EE, et al.

J Microbiol Methods, 2007 Sep;70(3):395-405.
PMID: 17602768

A MALDI TOF MS based minisequencing method has been developed and applied for the analysis of rifampin (RIF)- and isoniazid (INH)-resistant M. tuberculosis strains. Eight genetic markers of RIF resistance-nucleotide polymorphisms located in RRDR of rpoB gene, and three of INH resistance including codon 315 of katG gene and -8 and -15 positions of the promoter region of fabG1-inhA operon were worked out. Based on the analysis of 100 M. tuberculosis strains collected from the Moscow region in 1997-2005 we deduced that 91% of RIF-resistant and 94% of INH-resistant strains can be identified using the technique suggested. The approach is rapid, reliable and allows to reveal the drug resistance of M. tuberculosis strains within 12 h after sample isolation.

Matched MeSH terms: Isoniazid/pharmacology
Synthesis, in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one schiff bases

Narender M, Jaswanth S B, Umasankar K, Malathi J, Raghuram Reddy A, Umadevi KR, et al.

Bioorg Med Chem Lett, 2016 Feb 01;26(3):836-840.
PMID: 26755393 DOI: 10.1016/j.bmcl.2015.12.083

Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in Mycobacterium tuberculosis (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB. The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15-73 μM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC50 <340 μM in LRP assay) and (MIC <9 μM in broth microdilution method).

Matched MeSH terms: Isoniazid/pharmacology

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