scholarly journals Analysis of the clinical pipeline of treatments for drug resistant bacterial infections: despite progress, more action is needed

2022 ◽  
Author(s):  
Mark S. Butler ◽  
Valeria Gigante ◽  
Hatim Sati ◽  
Sarah Paulin ◽  
Laila Al-Sulaiman ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antibacterial Agents ◽  
Phase 1 ◽  
Clinical Development ◽  
World Health ◽  
Drug Resistant ◽  
Antibacterial Drugs ◽  
Clostridioides Difficile ◽  
Differentiated Candidates ◽  
Health Organization

There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes ‘traditional’ and ‘non-traditional’ antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

IL-10-592 A/C Gene Polymorphism and Cytokine Levels are Associated with Susceptibility to Drug Resistance in Tuberculosis

2020 ◽  
Vol 8 (3) ◽  
pp. 103-112
Author(s):  
Atefeh SADEGHI SHERMEH ◽  
Majid KHOSHMIRSAFA ◽  
Ali-Akbar DELBANDI ◽  
Payam TABARSI ◽  
Esmaeil MORTAZ ◽  
...  
Keyword(s):  
Serum Levels ◽  
World Health ◽  
Control Group ◽  
Drug Resistant ◽  
Nucleotide Polymorphisms ◽  
Genotype Frequencies ◽  
Cytokine Levels ◽  
Ifn Γ ◽  
Health Organization ◽  
And Function

Introduction: Tuberculosis (TB) and especially resistant forms of it have a substantial economic burden on the community health system for diagnosis and treatment each year. Thus, investigation of this field is a priority for the world health organization (WHO). Cytokines play important roles in the relationship between the immune system and tuberculosis. Genetic variations especially single nucleotide polymorphisms (SNPs) impact cytokine levels and function against TB. Material and Methods: In this research SNPs in IFN-γ (+874 T/A) and IL-10 (-592 A/C) genes, and the effects of these SNPs on cytokine levels in a total of 87 tuberculosis patients and 100 healthy controls (HCs) were studied. TB patients divided into two groups: 1) 67 drug-sensitive (DS-TB) and 2) 20 drug-resistant (DR-TB) according to drug sensitivity test using polymerase chain reaction (PCR). For the genotyping of two SNPs, the PCR-based method was used and IFN-γ and IL-10 levels were measured by ELISA in pulmonary tuberculosis (PTB) and control group. Results: In -592A/C SNP, only two genotypes (AA, AC) were observed and both genotypes showed statistically significant differences between DR-TB and HCs (p=0.011). IL-10 serum levels in PTB patients were higher than HCs (p=0.02). The serum levels of IFN-γ were significantly higher in DS-TB patients than that of the other two groups (p<0.001); however, no significant differences were observed for allele and genotype frequencies in IFN-γ +874. Conclusions: Our results suggest that the SNP at -592 position of IL-10 gene may be associated with the susceptibility to DR-TB. However, further investigation is necessary. Keywords: Polymorphism, IFN-γ, IL-10, tuberculosis, drug-resistant tuberculosis

scholarly journals Treatment of COVID-19 with Chloroquine: Implication for Malaria Chemotherapy Using ACTs in Disease Endemic Countries

2020 ◽  
Author(s):  
Neils Ben Quashie ◽  
Nancy Odurowah Duah-Quashie
Keyword(s):  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
World Health ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Combination Therapies ◽  
Parasite Resistance ◽  
Demand And Supply ◽  
First Choice ◽  
Health Organization

Abstract Based on reports of parasite resistance and on World Health Organization recommendation, chloroquine was replaced with the artemisinin-based combination therapies (ACTs) as the first choice of drugs for the treatment of uncomplicated malaria. Disuse of chloroquine led to restoration of drug-sensitive parasite to some extent in certain countries. Ever since chloroquine and hydroxychloroquine were touted as potential treatment for coronavirus disease 2019 (COVID-19), there has been a dramatic surge in demand for the drugs. Even in areas where chloroquine is proscribed, there has been an unexpected increase in demand and supply of the drug. This situation is quite worrying as the indiscriminate use of chloroquine may produce drug-resistant parasites which may impact negatively on the efficacy of amodiaquine due to cross-resistance. Amodiaquine is a partner drug in one of the ACTs and in some of the drugs used for intermittent preventive treatment. We herein discuss the consequences of the escalated use of chloroquine in the management of COVID-19 on chemotherapy or chemoprevention of malaria and offer an advice. We speculate that parasite strains resistant to chloroquine will escalate due to the increased and indiscriminate use of the drug and consequently lead to cross-resistance with amodiaquine which is present in some drug schemes aforementioned. Under the circumstance, the anticipated hope of reverting to the use of the ‘resurrected chloroquine’ to manage malaria in future is likely to diminish. The use of chloroquine and its derivatives for the management of COVID-19 should be controlled.

Phytoconstituents in the Management of Covid-19: Demystifying the Fact

Drug Research ◽  
2022 ◽  
Author(s):  
Md. Abul Barkat ◽  
Pawan Kaushik ◽  
Harshita Abul Barkat ◽  
Mohammad Idreesh Khan ◽  
Hazrina Ab Hadi
Keyword(s):  
Therapeutic Agent ◽  
Clinical Development ◽  
World Health ◽  
Therapeutic Drug ◽  
Scientific Communities ◽  
Synthetic Drugs ◽  
Naturally Occurring ◽  
Deadly Disease ◽  
Novel Coronavirus ◽  
Health Organization

AbstractThe 2019-nCoV (COVID-19; novel coronavirus disease-2019) outbreak is caused by the coronavirus, and its continued spread is responsible for increasing deaths, social and economic burden. COVID-19 created a chaotic situation worldwide and claimed the lives of over 5,027,183 and 248,467,363 confirmed cases have been reported so far as per the data published by WHO (World Health Organization) till 5th November 2021. Scientific communities all over the world are toiling to find a suitable therapeutic drug for this deadly disease. Although till date no promising drug has been discovered for this COVID-19. However, as per the WHO, over 102 COVID-19 vaccines are in clinical development and 185 in pre-clinical development. Naturally occurring phytoconstituents possess considerable chemical richness in the form of anti-viral and anti-parasitic potential and have been extensively exploited for the same globally. Still, phytomedicine-based therapies are considered as the best available treatment option to minimize and treat the symptoms of COVID-19 because of the least possible side effects compared to synthetic drugs recommended by the physicians/clinicians. In this review, the use of plant chemicals as a possible therapeutic agent for severe acute respiratory syndrome coronavirus 2 (SARS CoV2) is highlighted with their proposed mechanism of action, which will prove fruitful and effective in finding a cure for this deadly disease.

scholarly journals Barriers and Solutions to Developing Future Therapies for Pulmonary Hypertension

2018 ◽  
Vol 17 (4) ◽  
pp. 159-165
Author(s):  
Brian Graham ◽  
Peter Fernandes ◽  
Sue Gu
Keyword(s):  
Clinical Trials ◽  
Pulmonary Hypertension ◽  
Phase 1 ◽  
Unmet Need ◽  
Orphan Drugs ◽  
World Health ◽  
Vasodilator Therapy ◽  
Scarce Resources ◽  
Pulmonary Arterial ◽  
Health Organization

Pulmonary hypertension (PH) and its subset, pulmonary arterial hypertension (PAH), are rare diseases with a significant unmet need. Between the 1980s and 2010s, the 5-year survival rate for PAH after diagnosis improved from 34% to 65%,12 but remains unacceptably low. Since the introduction of vasodilator therapy, 34 important advances have been made in the understanding of the disease pathophysiology and development of targeted therapies. There are now 14 US Food and Drug Administration (FDA)-approved therapies that target 3 distinct pathways that contribute to PAH, and additional therapeutic targets are currently under investigation in phase 1, 2, and 3 clinical trials.5 However, there have been major challenges in PH medication development to date, including: 1) only one medication approved for pediatric PAH; 2) focusing on vasodilator therapy rather than targeting the underlying pathogenesis of the disease; 3) no medications approved for PH World Health Organization (WHO) Groups 2, 3, and 5; and 4) several recent high-profile clinical failures after promising preclinical studies.The focus and goal of the PH research community should be directed at identifying new options and solutions for patients. The field must ensure that the approaches used for clinical trials to develop orphan drugs maximize the scarce resources available for recruiting subjects, and are directed toward making safe and effective therapies available in a timely manner. Therefore, there is a critical need to coordinate and harmonize innovative approaches within the field, including strengthening translational research to deliver promising candidates and optimize the designs, endpoints, and biomarkers to conduct safe and efficient clinical trials.

scholarly journals TB Elimination Requires Discovery and Development of Transformational Agents

2020 ◽  
Vol 10 (7) ◽  
pp. 2605 ◽  
Author(s):  
Christian Lienhardt ◽  
Mario C. Raviglione
Keyword(s):  
Rapid Detection ◽  
Susceptibility Testing ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
New Drugs ◽  
World Health ◽  
Drug Resistant ◽  
The World ◽  
Health Organization ◽  
Combination Regimens

The World Health Organization (WHO) End Tuberculosis (TB) Strategy has set ambitious targets to reduce 2015 TB incidence and deaths by 80% and 90%, respectively, by the year 2030. Given the current rate of TB incidence decline (about 2% per year annually), reaching these targets will require new transformational tools and innovative ways to deliver them. In addition to improved tests for early and rapid detection of TB and universal drug-susceptibility testing, as well as novel vaccines for improved prevention, better, safer, shorter and more efficacious treatments for all forms of TB are needed. Only a handful of new drugs are currently in phase II or III clinical trials, and a few combination regimens are being tested, mainly for drug-resistant TB. In this article, capitalising on an increasingly rich medicine pipeline and taking advantage of new methodological designs with great potential, the main areas where progress is needed for a transformational improvement of treatment of all forms of TB are described.

scholarly journals GeneXpert MTB/RIF Assay for Rapid Identification of Mycobacterium Tuberculosis and Rifampicin Resistance Directly from Sputum Sample

2017 ◽  
Vol 7 (2) ◽  
pp. 86-89 ◽  
Author(s):  
Nourjahan Laskar ◽  
Md Akram Hossain ◽  
Jannatul Fardows ◽  
Mominur Rahman
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Sputum Sample ◽  
Rapid Identification ◽  
Rapid Diagnosis ◽  
World Health ◽  
Multi Drug Resistance ◽  
Drug Resistant ◽  
Resistant Tuberculosis ◽  
The World ◽  
Health Organization

Background: The World Health Organization has endorsed the use of molecular methods for the detection of tuberculosis (TB) and drug resistant TB as a rapid method. In Bangladesh, the Xpert MTB/RIF assay has been implemented into reference laboratories for diagnosis of TB and also MDR TB.Objective: Drug resistant tuberculosis has long been a common problem prevailing in our country. The present study focused on the rapid identification of Mycobacterium tuberculosis as well as drug resistance.Materials and Methods: Sputum samples from a total of 107 cases, assumed as multi-drug resistance tuberculosis, were studied through GeneXpert assay.Results: Out of 107 cases, 91 (85.05%) were detected having M. tuberculosis ? 64 (59.81%) were rifampicin sensitive and 27 (25.23%) were rifampicin resistant. The sensitivity and specificity of the GeneXpert are 87.64% and 75% respectively.Conclusion: GeneXpert assay can be considered for the rapid diagnosis of drug resistant tuberculosis.J Enam Med Col 2017; 7(2): 86-89

scholarly journals Adjuvant Strategies for More Effective Tuberculosis Vaccine Immunity

2019 ◽  
Vol 7 (8) ◽  
pp. 255 ◽  
Author(s):  
Stewart ◽  
Triccas ◽  
Petrovsky
Keyword(s):  
Infectious Agent ◽  
Mechanisms Of Action ◽  
Clinical Development ◽  
World Health ◽  
Effective Vaccine ◽  
Bacillus Calmette Guerin ◽  
Mycobacterium Tuberculosis Infection ◽  
Future Directions ◽  
Vaccine Protection ◽  
Health Organization

Tuberculosis (TB) caused by Mycobacterium tuberculosis infection is responsible for the most deaths by a single infectious agent worldwide, with 1.6 million deaths in 2017 alone. The World Health Organization, through its “End TB” strategy, aims to reduce TB deaths by 95% by 2035. In order to reach this goal, a more effective vaccine than the Bacillus Calmette-Guerin (BCG) vaccine currently in use is needed. Subunit TB vaccines are ideal candidates, because they can be used as booster vaccinations for individuals who have already received BCG and would also be safer for use in immunocompromised individuals in whom BCG is contraindicated. However, subunit TB vaccines will almost certainly require formulation with a potent adjuvant. As the correlates of vaccine protection against TB are currently unclear, there are a variety of adjuvants currently being used in TB vaccines in preclinical and clinical development. This review describes the various adjuvants in use in TB vaccines, their effectiveness, and their proposed mechanisms of action. Notably, adjuvants with less inflammatory and reactogenic profiles that can be administered safely via mucosal routes, may have the biggest impact on future directions in TB vaccine design.

scholarly journals Comparison of the efficacy of artemether-lumefantrine vs. artesunate plus sulfadoxine-pyrimethamine in children with uncomplicated falciparum malaria

2010 ◽  
Vol 50 (2) ◽  
pp. 113 ◽  
Author(s):  
Rachmawati Rachmawati ◽  
Novie H Rampengan ◽  
Suryadi N N Tatura ◽  
Tonny H Rampengan
Keyword(s):  
Parasite Clearance ◽  
World Health ◽  
Drug Resistant ◽  
Limited Information ◽  
Clearance Time ◽  
Cure Rate ◽  
Fever Clearance Time ◽  
Significant Difference ◽  
Health Organization

Background World Health Organization (WHO) has recommendedthat countries with drug resistant malaria problem usecombination therapies, especially artemisinin-based combinationtherapy (ACT). However, there is limited information on theefficacy of ACT in North Sulawesi.Objective To compare the efficacy of artemether-lumefanttine andartesunate plus sulfadoxine-pyrimethamine (SP).Methods This was a randomized experimental study, conducted inProf. Dr. R. D. Kandou General Hospital, Manado from Januaryuntil July 2009. There were 42 patients aged less than 13 yearstreated with artemether-lumefanttine and artesunate plus SP. Bodytemperature, parasite and gametocyte count were recorded everyday until day 7 and follow-up reviews were done on day 14 and28.Results Fever clearance time showed a significant differencebetween artemether-lumefanttine group (median 27 hours) andartesunate plus SP group (median 18 hours), P<0.05). There wasno significant difference in parasite clearance time (P>0.05) andgame tocyte clearance time (P > 0. 05) . The 28 day cure rate were100% in the two groups. No side effect was found.Conclusion Both artemether-lumefanttine and artesunate plus SPcombination are effective and safe for the treatment of falciparummalaria in children.

scholarly journals Diagnosing isolated hepatosplenic tuberculosis in an immunocompetent patient: a case report

2018 ◽  
Vol 48 (3) ◽  
pp. 232-234
Author(s):  
Om Dawani ◽  
Raja Samir Khan ◽  
Mujtaba Jamal Syed ◽  
Abdul Moid Shehzad ◽  
Ahmed Alratoot ◽  
...  
Keyword(s):  
Case Report ◽  
Early Diagnosis ◽  
World Health Organization ◽  
Immunocompetent Patient ◽  
Clinical Suspicion ◽  
World Health ◽  
Drug Resistant ◽  
Health Organization ◽  
Specific Symptoms ◽  
Strong Suspicion

For many years, tuberculosis (TB) has been endemic in Pakistan; many rare and unusual presentations have been reported. There is a myriad of non-specific symptoms which always requires a high index of clinical suspicion for TB. World Health Organization data suggest that Pakistan ranks as the fifth highest country burdened with TB and has the fourth highest prevalence of multi-drug resistant TB globally. With an annual incidence of 277 cases per 100,000, the importance of early diagnosis and treatment is self-evident. We present a case where a strong suspicion of isolated hepatosplenic TB in an immunocompetent patient justified a directed approach.

scholarly journals Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report

2019 ◽  
Vol 54 (6) ◽  
pp. 1901522 ◽  
Author(s):  
Sergey Borisov ◽  
Edvardas Danila ◽  
Andrei Maryandyshev ◽  
Margareth Dalcolmo ◽  
Skaidrius Miliauskas ◽  
...  
Keyword(s):  
Adverse Events ◽  
Active Drug ◽  
Clinical Information ◽  
World Health ◽  
Drug Resistant ◽  
Serious Adverse Events ◽  
Resistant Tuberculosis ◽  
Drug Safety Monitoring ◽  
Grade 3 ◽  
Health Organization

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

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