Early detection of MDR Mycobacterium tuberculosis mutations in Pakistan

AbstractThe result of improper treatment has led to the rise of Multidrug-resistant (MDR) strains. This concern still exists in Pakistan. In order to save energy, time and resources an early detection of resistant cases is imperative. Thus, a treated group of 100 isolates and a control group of 56 untreated isolates were studied. PCR and gene sequencing showed mutations at codon 531 and 513 in the rpoB gene. 12% of cases showed a double mutation in the rpoB gene. katG gene showed mutations at codon 315 and 299. 28.6% of the control group cases were positive for MDR whereas 100% of the treated group were positive for MDR. This study explores the significantly increasing ratio of MDR-TB among Pakistani population. This study provides prevalent MDR mutations among Pakistanis and suggests developing such molecular assays that are time and cost effective. Importance: Pakistan is a developing country and has fourth highest incidence rate of MDR-TB. The treatment of MDR-TB is the use of second line drugs that has severe side effects as well as it requires long time span. One of the strategies to control the spread of MDR-TB is to decipher the aberrations at molecular level in order to formulate potent drugs that can treat the patients within short span of time. Determining the mutation profile of MDR in Pakistani populations will open new horizons for the improvement of drug treatment regimens to make it more effective or for the development of novel potent drugs and vaccines to better treat the drug-resistant TB. Moreover, this study will be help in disease control program.

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Laboratory evaluation of the efficacy of Liastene application in complex therapy of multiresistant pulmonary tuberculosis

Infusion & Chemotherapy ◽

10.32902/2663-0338-2021-4-25-31 ◽

2021 ◽

pp. 25-31

Author(s):

I.L. Platonova ◽

M.I. Sakhelashvili ◽

G.D. Shtybel ◽

O.I. Sakhelashvili-Bil

Keyword(s):

Pulmonary Tuberculosis ◽

Dynamic Balance ◽

Multidrug Resistant ◽

Redox Activity ◽

Laboratory Evaluation ◽

Phagocytic Index ◽

Control Group ◽

Treatment Regimens ◽

Mdr Tb ◽

Experimental Group

OBJECTIVE. Evaluating according to laboratory tests the effectiveness of Liasten in the treatment of patients with multidrug-resistant pulmonary tuberculosis (MDR-TB). MATERIALS AND METHODS. Evaluation of the effectiveness of etiotropic and etiopathogenetic therapy in 57 patients with MDR-TB was performed. According to the treatment schemes, patients were divided into groups. The control group (n=22) received individualized antimycobacterial therapy (AMBT) regimens. The experimental group (n=35) received AMBT in combination with Liasten. Evaluation of the effectiveness of treatment regimens was performed on the basis of indicators of general clinical blood tests, immunological and bacteriological studies. RESULTS AND DISCUSSION. In patients of the experimental group, compared with the control in 1.5 times more often found positive changes in the hemogram of blood and ESR (p<0.05-0.001), the establishment of a dynamic balance between the pools of lymphocyte cells CD4+ and СD8+ (immunoregulatory index, p<0.05), an increase in the number of phagocytosis active cells (phagocytic index, p<0.05), the content of cationic lysosomal proteins of granulocyte leukocytes (p<0.05), a 1.4-fold decrease in the cytochemical coefficient of neutrophils (p<0.05), the number of proliferated under the action of PPD-L lymphocytes (p<0.05), normalization of phagocytic counts and total redox activity of neutrophils (p<0.05), increase in frequency and reduction of anesthesia was stated. CONCLUSIONS. Restoration of the body’s immune status, blood hemogram, increase in frequency and reduction of the time of decontamination were more active and occurred 1.5 times more often in patients receiving a complex combination of AMBT with Liasten.

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The epidemiologic impact and cost-effectiveness of new tuberculosis vaccines on multidrug-resistant tuberculosis in India and China

BMC Medicine ◽

10.1186/s12916-021-01932-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Chathika K Weerasuriya ◽

Rebecca C Harris ◽

C Finn McQuaid ◽

Fiammetta Bozzani ◽

Yunzhou Ruan ◽

...

Keyword(s):

Cost Effectiveness ◽

Cost Effective ◽

Multidrug Resistant ◽

Second Line ◽

Second Line Therapy ◽

China And India ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Line Therapy ◽

Mdr Tb

Abstract Background Despite recent advances through the development pipeline, how novel tuberculosis (TB) vaccines might affect rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is unknown. We investigated the epidemiologic impact, cost-effectiveness, and budget impact of hypothetical novel prophylactic prevention of disease TB vaccines on RR/MDR-TB in China and India. Methods We constructed a deterministic, compartmental, age-, drug-resistance- and treatment history-stratified dynamic transmission model of tuberculosis. We introduced novel vaccines from 2027, with post- (PSI) or both pre- and post-infection (P&PI) efficacy, conferring 10 years of protection, with 50% efficacy. We measured vaccine cost-effectiveness over 2027–2050 as USD/DALY averted-against 1-times GDP/capita, and two healthcare opportunity cost-based (HCOC), thresholds. We carried out scenario analyses. Results By 2050, the P&PI vaccine reduced RR/MDR-TB incidence rate by 71% (UI: 69–72) and 72% (UI: 70–74), and the PSI vaccine by 31% (UI: 30–32) and 44% (UI: 42–47) in China and India, respectively. In India, we found both USD 10 P&PI and PSI vaccines cost-effective at the 1-times GDP and upper HCOC thresholds and P&PI vaccines cost-effective at the lower HCOC threshold. In China, both vaccines were cost-effective at the 1-times GDP threshold. P&PI vaccine remained cost-effective at the lower HCOC threshold with 49% probability and PSI vaccines at the upper HCOC threshold with 21% probability. The P&PI vaccine was predicted to avert 0.9 million (UI: 0.8–1.1) and 1.1 million (UI: 0.9–1.4) second-line therapy regimens in China and India between 2027 and 2050, respectively. Conclusions Novel TB vaccination is likely to substantially reduce the future burden of RR/MDR-TB, while averting the need for second-line therapy. Vaccination may be cost-effective depending on vaccine characteristics and setting.

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Reversion of antibiotic resistance in multidrug-resistant pathogens using non-antibiotic pharmaceutical benzydamine

Communications Biology ◽

10.1038/s42003-021-02854-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Yuan Liu ◽

Ziwen Tong ◽

Jingru Shi ◽

Yuqian Jia ◽

Tian Deng ◽

...

Keyword(s):

Cost Effective ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Treatment Regimens ◽

Development Of Resistance ◽

Metabolic States ◽

Animal Infection ◽

Life Threatening

AbstractAntimicrobial resistance has been a growing concern that gradually undermines our tradition treatment regimens. The fact that few antibacterial drugs with new scaffolds or targets have been approved in the past two decades aggravates this crisis. Repurposing drugs as potent antibiotic adjuvants offers a cost-effective strategy to mitigate the development of resistance and tackle the increasing infections by multidrug-resistant (MDR) bacteria. Herein, we found that benzydamine, a widely used non‐steroidal anti‐inflammatory drug in clinic, remarkably potentiated broad-spectrum antibiotic-tetracyclines activity against a panel of clinically important pathogens, including MRSA, VRE, MCRPEC and tet(X)-positive Gram-negative bacteria. Mechanistic studies showed that benzydamine dissipated membrane potential (▵Ψ) in both Gram-positive and Gram-negative bacteria, which in turn upregulated the transmembrane proton gradient (▵pH) and promoted the uptake of tetracyclines. Additionally, benzydamine exacerbated the oxidative stress by triggering the production of ROS and suppressing GAD system-mediated oxidative defensive. This mode of action explains the great bactericidal activity of the doxycycline-benzydamine combination against different metabolic states of bacteria involve persister cells. As a proof-of-concept, the in vivo efficacy of this drug combination was evidenced in multiple animal infection models. These findings indicate that benzydamine is a potential tetracyclines adjuvant to address life-threatening infections by MDR bacteria.

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Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice

British Journal Of Nutrition ◽

10.1017/s0007114510004824 ◽

2010 ◽

Vol 105 (8) ◽

pp. 1218-1225 ◽

Cited By ~ 63

Author(s):

Zhuo Fu ◽

Wei Zhen ◽

Julia Yuskavage ◽

Dongmin Liu

Keyword(s):

Type 1 Diabetes ◽

Cell Mass ◽

Epigallocatechin Gallate ◽

Nod Mice ◽

Cost Effective ◽

Treated Group ◽

Control Group ◽

Plasma Insulin Levels ◽

Glucose Lowering Effect

Type 1 diabetes (T1D) results from the autoimmune-mediated destruction of pancreatic β-cells, leading to deficiency of insulin production. Successful islet transplantation can normalise hyperglycaemia in T1D patients; however, the limited availability of the islets, loss of islet cell mass through apoptosis after islet isolation and potential autoimmune destruction of the transplanted islets prevent the widespread use of this procedure. Therefore, the search for novel and cost-effective agents that can prevent or treat T1D is extremely important to decrease the burden of morbidity from this disease. In the present study, we discovered that ( − )-epigallocatechin gallate (EGCG, 0·05 % in drinking-water), the primary polyphenolic component in green tea, effectively delayed the onset of T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, eight (66·7 %) out of twelve mice in the control group developed diabetes, whereas only three (25 %) out of twelve mice in the EGCG-treated group became diabetic (P < 0·05). Consistently, mice supplemented with EGCG had significantly higher plasma insulin levels and survival rate but lower glycosylated Hb concentrations compared with the control animals. EGCG had no significant effects on food or water intake and body weight in mice, suggesting that the glucose-lowering effect was not due to an alteration in these parameters. While EGCG did not modulate insulitis, it elevated the circulating anti-inflammatory cytokine IL-10 level in NOD mice. These findings demonstrate that EGCG may be a novel, plant-derived compound capable of reducing the risk of T1D.

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Advantages of IT-based clinical pathways in surgical treatment of non-specific spondylodiscitis

Journal of Hospital Administration ◽

10.5430/jha.v5n6p19 ◽

2016 ◽

Vol 5 (6) ◽

pp. 19

Author(s):

N. Homagk ◽

T. Jarmuzek ◽

H.J. Meisel ◽

G.O. Hofmann ◽

L. Homagk

Keyword(s):

Surgical Therapy ◽

Clinical Pathway ◽

Clinical Pathways ◽

Total Duration ◽

Infectious Agent ◽

Cost Effective ◽

Control Group ◽

Personnel Costs ◽

Treatment Regimens ◽

Cost Effective Treatment

Objective: The German health care system increasingly incorporates clinical pathways as a tool to organize surgical, intervention or conservative therapies. Does a computerized clinical pathway offer advantages in severity-based surgical therapy of spondylodiscitis?Methods: A hospital has adopted a computerized system based on three severity grades of spondylodiscitis. From 01/01/2012 to 12/31/2013, 32 patients with spondylodiscitis were randomly chosen at admission and prospectively analysed with regard to duration, costs of treatment, pain level and inflammatory markers.Results: Of the 32 patients treated for spondylodiscitis who had not been transferred from another facility, 17 (53%) were treated according to a clinical pathway based on three well-established treatment regimens dependent on severity. The SponDT, as a parameter for the course of disease, was initially slightly higher in the pathway patient’s group (6.82) than in the control group (6.2). Compared to a control group (n = 15) there were differences in the total duration of stay (17.2 vs. 26.0) and the number of blood samples taken (7 vs. 10). No differences could be shown for the extent of documentation, the physical and neurological outcome, the level of pain and or the course of inflammatory markers. The most prevalent germ was Staphylococcus aureus (18.8%). In 43.8% of the patients, no infectious agent could be detected. Material costs and personnel-costs were significantly reduced in the pathway group (12,076 €) compared to 21,341 € in the control group.Conclusions: An IT-based clinical pathway is preferable for surgical therapy of spondylodiscitis based on three grades of severity and offers various advantages as a clinical and administrative regulative mechanism. The cost-effective treatment particularly stands out.

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Multidisciplinary advisory teams to manage multidrug-resistant tuberculosis: the example of the French Consilium

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.18.0779 ◽

2019 ◽

Vol 23 (10) ◽

pp. 1050-1054

Author(s):

L. Guglielmetti ◽

J. Jaffré ◽

C. Bernard ◽

F. Brossier ◽

N. El Helali ◽

...

Keyword(s):

Multidrug Resistant ◽

New Drugs ◽

World Health ◽

Advisory Committees ◽

Treatment Regimens ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Health Organization

SETTING: The World Health Organization (WHO) recommends that multidrug-resistant tuberculosis (MDR-TB) treatment should be managed in collaboration with multidisciplinary advisory committees (consilia). A formal national Consilium has been established in France since 2005 to provide a centralised advisory service for clinicians managing MDR-TB and extensively drug-resistant (XDR-TB) cases.OBJECTIVE: Review the activity of the French TB Consilium since its establishment.DESIGN: Retrospective description and analysis of the activity of the French TB Consilium.RESULTS: Between 2005 and 2016, 786 TB cases or contacts of TB cases were presented at the French TB Consilium, including respectively 42% and 79% of all the MDR-TB and XDR-TB cases notified in France during this period. Treatment regimens including bedaquiline and/or delamanid were recommended for 42% of the cases presented at the French TB Consilium since 2009. Patients were more likely to be presented at the French TB Consilium if they were born in the WHO Europe Region, had XDR-TB, were diagnosed in the Paris region, or had resistance to additional drugs than those defining XDR-TB.CONCLUSION: The French TB Consilium helped supervise appropriate management of MDR/XDR-TB cases and facilitated implementation of new drugs for MDR/XDR-TB treatment.

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Direct Detection of Pyrazinamide Resistance in Mycobacterium tuberculosis by Use of pncA PCR Sequencing

Journal of Clinical Microbiology ◽

10.1128/jcm.00145-19 ◽

2019 ◽

Vol 57 (8) ◽

Author(s):

Kingsley King-Gee Tam ◽

Kenneth Siu-Sing Leung ◽

Gilman Kit-Hang Siu ◽

Kwok-Chiu Chang ◽

Samson Sai-Yin Wong ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Direct Detection ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Activity Data ◽

Content Type ◽

Treatment Regimens ◽

Mdr Tb ◽

Resistant Strains ◽

Respiratory Specimens

ABSTRACT An in-house-developed pncA sequencing assay for analysis of pyrazinamide (PZA) resistance was evaluated using 162 archived Mycobacterium tuberculosis complex (MTBC) isolates with phenotypic PZA susceptibility profiles that were well defined by analysis of Bactec MGIT 960 PZA kit and PZase activity data. Preliminary results showed 100% concordance between pncA sequencing and phenotypic PZA drug susceptibility test (DST) results among archived isolates. Also, 637 respiratory specimens were prospectively collected, and 158 were reported as MTBC positive by the Abbott Realtime MTB assay (96.3% sensitivity [95% confidence interval {CI}: 92.2% to 98.7%]; 100% specificity [95% CI: 99.2% to 100.0%]). Genotypic and phenotypic PZA resistance profiles of these 158 MTBC-positive specimens were analyzed by pncA sequencing and Bactec MGIT 960 PZA kit, respectively. For analysis of PZA resistance, pncA sequencing detected pncA mutations in 5/5 (100%) phenotypic PZA-resistant respiratory specimens within 4 working days. No pncA mutations were detected among PZA-susceptible specimens. Combining archived isolates with prospective specimens, 27 were identified as phenotypic PZA resistant with pncA mutation. Among these 27 samples, 6/27 (22.2%) phenotypic PZA-resistant strains carried novel pncA mutations without rpsA and panD mutations. These included 5 with mutations (a deletion [Del] at 383T [Del383T], Del 380 to 390, insertion of A [A Ins] at position 127, A Ins at position 407, and G Ins at position 508) in pncA structural genes and 1 with a mutation (T-12C) at the pncA promoter region. All six of these strains had no or reduced PZase activities, indicating that the novel mutations might confer PZA resistance. Additionally, 25/27 phenotypic PZA-resistant strains were confirmed multidrug-resistant tuberculosis (MDR-TB) strains. As PZA is commonly used in MDR-TB treatment regimens, direct pncA sequencing will rapidly detect PZA resistance and facilitate judicious use of PZA in treating PZA-susceptible MDR-TB.

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Time for a change: considering regimen changes in analyses of observational drug-resistant TB treatment cohort data

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.20.0076 ◽

2020 ◽

Vol 24 (11) ◽

pp. 1151-1155

Author(s):

M. F. Franke ◽

C. D. Mitnick

Keyword(s):

Observational Studies ◽

Drug Exposure ◽

Randomized Clinical Trials ◽

Multidrug Resistant ◽

Drug Resistant ◽

Treatment Regimens ◽

Tb Treatment ◽

Mdr Tb ◽

Therapeutic Research ◽

Do So

Randomized clinical trials represent the gold standard in therapeutic research. Nevertheless, observational cohorts of patients treated for multidrug-resistant TB (MDR-TB) or rifampin-resistant TB (RR-TB) also play an important role in generating evidence to guide drug-resistant TB care. Generally, summary exposure classifications (e.g., ‘ever vs. never´, ‘exposed at baseline´) have been used to characterize drug exposure in the absence of detailed longitudinal data on MDR-TB regimen changes. These summary classifications, along with an absence of data on covariates that change throughout the course of treatment, constrain researchers´ ability to answer the most relevant questions while accounting for known biases. In this paper, we highlight the importance of regimen changes in improving inference from observational studies of longer MDR-TB treatment regimens, and offer an overview of the data and analytic strategies required to do so.

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Assessing the impacts of short-course multidrug-resistant tuberculosis treatment in the Southeast Asia Region using a mathematical modeling approach

PLoS ONE ◽

10.1371/journal.pone.0248846 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248846

Author(s):

Win Min Han ◽

Wiriya Mahikul ◽

Thomas Pouplin ◽

Saranath Lawpoolsri ◽

Lisa J. White ◽

...

Keyword(s):

Southeast Asia ◽

Treatment Initiation ◽

Multidrug Resistant ◽

Treatment Regimens ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Short Course ◽

Mdr Tb ◽

The Impact

This study aimed to predict the impacts of shorter duration treatment regimens for multidrug-resistant tuberculosis (MDR-TB) on both MDR-TB percentage among new cases and overall MDR-TB cases in the WHO Southeast Asia Region. A deterministic compartmental model was constructed to describe both the transmission of TB and the MDR-TB situation in the Southeast Asia region. The population-level impacts of short-course treatment regimens were compared with the impacts of conventional regimens. Multi-way analysis was used to evaluate the impact by varying programmatic factors (eligibility for short-course MDR-TB treatment, treatment initiation, and drug susceptibility test (DST) coverage). The model predicted that overall TB incidence will be reduced from 246 (95% credible intervals (CrI), 221–275) per 100,000 population in 2020 to 239 (95% CrI, 215–267) per 100,000 population in 2035, with a modest reduction of 2.8% (95% CrI, 2.7%–2.9%). Despite the slight reduction in overall TB infections, the model predicted that the MDR-TB percentage among newly notified TB infections will remain steady, with 2.4% (95% CrI, 2.1–2.9) in 2020 and 2.5% (95% CrI, 2.3–3.1) in 2035, using conventional MDR-TB treatment. With the introduction of short-course regimens to treat MDR-TB, the development of resistance can be slowed by 38.6% (95% confidence intervals (CI), 35.9–41.3) reduction in MDR-TB case number, and 37.6% (95% CI, 34.9–40.3) reduction in MDR-TB percentage among new TB infections over the 30-year period compared with the baseline using the standard treatment regimen. The multi-way analysis showed eligibility for short-course treatment and treatment initiation greatly influenced the impacts of short-course treatment regimens on reductions in MDR-TB cases and percentage resistance among new infections. Policies which promote the expansion of short-course regimens and early MDR-TB treatment initiation should be considered along with other interventions to tackle antimicrobial resistance in the region.

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Active surveillance for adverse events in patients on longer treatment regimens for multidrug-resistant tuberculosis in Viet Nam

PLoS ONE ◽

10.1371/journal.pone.0255357 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0255357

Author(s):

Nguyen Bao Ngoc ◽

Hoa Vu Dinh ◽

Nguyen Thi Thuy ◽

Duong Van Quang ◽

Cao Thi Thu Huyen ◽

...

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Bayesian Model Averaging ◽

Multidrug Resistant ◽

Treatment Regimens ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

Objective Management of multidrug-resistant tuberculosis (MDR-TB) is a significant challenge to the global healthcare system due to the complexity and long duration of the MDR-TB treatment. This study analyzed the safety of patients on longer injectable-based MDR-TB treatment regimens using active pharmacovigilance data. Method We conducted an observational, prospective study based on active pharmacovigilance within the national TB program. A total of 659 MDR-TB patients were enrolled and followed up at 9 TB- hospitals in 9 provinces of all 3 regions in Vietnam between 2014 and 2016. Patients received a treatment regimen (standardized or individualized) based on their drug susceptibility test result and their treatment history. Baseline and follow-up information was collected at the start and during treatment. Adverse events (AE) were defined and classified as serious adverse events (SAEs) or otherwise. Multivariate Cox regression following the Iterative Bayesian Model Averaging algorithm was performed to identify factors associated with AE occurrence. Results Out of 659 patients assessed, 71.3% experienced at least one AE, and 17.5% suffered at least one SAE. The most common AEs were gastrointestinal disorders (38.5%), arthralgia (34.7%), and psychiatric disorders (30.0%). The proportion of patients with nephrotoxicity and hearing loss or vestibular disorders were 7.4% and 15.2%, respectively. 13.1% of patients required modifications or interruption of one or more drugs. In 77.7% of patients, treatment was completed successfully, while 9.3% lost to follow-up, in 3.0% treatment failed, and 7.4% died. Some significant risk factors for nephrotoxicity included diabetes mellitus (HR = 8.46 [1.91–37.42]), renal dysfunction (HR = 8.46 [1.91–37.42]), alcoholism (HR = 13.28 [5.04–34.99]), and a higher average daily dose of injectable drugs (HR = 1.28 [1.14–1.43]). Conclusion While a majority of patients on the longer injectable-based regimens experienced non-serious AEs during MDR-TB treatment, one in six patients experienced at least an SAE. Active TB drug-safety monitoring is useful to understand the safety of MDR-TB treatment and explore the risk factors for toxicity. All-oral, shorter MDR-TB regimens might be able to reduce the inconvenience, discomfort, and toxicity of such regimens and increase adherence and likelihood of successful completion.

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