scholarly journals Triple artemisinin-containing combination anti-malarial treatments should be implemented now to delay the emergence of resistance: the case against

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Sanjeev Krishna
Keyword(s):  
Multidrug Resistant ◽  
Triple Combination ◽  
Combination Therapies ◽  
Combination Treatments ◽  
Emergence Of Resistance

Abstract Managing multidrug resistant malaria can be problematic if currently available artemisinin-containing anti-malarial combination treatments are not used appropriately. Here, I debate that the best way to manage multidrug resistant malaria is to make best use of existing treatments and to develop new classes of anti-malarial drugs and not to make ‘triple combination therapies’ when there is already resistance to one or more proposed components.

Management of hypertension with fixed-dose triple-combination treatments

2013 ◽  
Vol 7 (5) ◽  
pp. 246-259 ◽  
Author(s):  
Benjamin J. Epstein ◽  
Niren K. Shah ◽  
Nancy L. Borja-Hart
Keyword(s):  
Fixed Dose ◽  
Triple Combination ◽  
Combination Treatments

Combination Treatments for Schizophrenia

CNS Spectrums ◽  
2004 ◽  
Vol 9 (S9) ◽  
pp. 19-23 ◽  
Author(s):  
Alexander L. Miller
Keyword(s):  
Electroconvulsive Therapy ◽  
Cognitive Deficits ◽  
Negative Symptoms ◽  
Current Evidence ◽  
Positive Symptoms ◽  
Combination Therapies ◽  
Safety And Efficacy ◽  
Combination Treatments ◽  
Improved Outcomes ◽  
Expert Recommendations

ABSTRACTCombination treatments, especially combinations of antipsychotics, are used frequently for schizophrenia, despite a paucity of evidence regarding their safety and efficacy. Because the literature basis is weak and expert recommendations are largely lacking, providers should be vigilant in documenting improved outcomes for patients thought to benefit from combination treatments. Target symptoms that have been studied include psychosis, cognitive deficits, and negative symptoms. The strongest evidence is for augmentation of clozapine with another antipsychotic or with electroconvulsive therapy for persistent positive symptoms. Combination treatments for cognitive deficits and negative symptoms are being actively investigated, but current evidence is insufficient to recommend available agents for these components of schizophrenia. It is important that appropriate monotherapies be given adequate trials before resorting to combination therapies.

Triple therapy in uncontrolled asthma: a network meta-analysis of Phase III studies

2021 ◽  
pp. 2004233
Author(s):  
Paola Rogliani ◽  
Beatrice Ludovica Ritondo ◽  
Luigino Calzetta
Keyword(s):  
Meta Analysis ◽  
Phase Iii ◽  
Fixed Dose ◽  
High Dose ◽  
Severe Exacerbation ◽  
Triple Combination ◽  
Combination Therapies ◽  
Uncontrolled Asthma ◽  
Long Acting ◽  
The Impact

Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS), long-acting β2-adrenoceptor agonist (LABA), and long-acting muscarinic receptor antagonist (LAMA) fixed-dose combination (FDC). Since meta-analyses allow settling controversies of apparently inconsistent results, we performed a network meta-analysis of Phase III randomised controlled trials including 9535 patients to assess the effect of ICS/LABA/LAMA combinations in uncontrolled asthma. Triple combination therapies with an ICS administered at high dose (HD) were more effective (p<0.05) than medium dose (MD) ICS/LABA/LAMA FDC and both MD and HD ICS/LABA FDCs against moderate to severe exacerbation (relative risk [RR] from 0.61 to 0.80) and increasing trough forced expiratory volume in the 1st second (mL from +33 to +114). Triple combination therapies including HD ICS were superior (p<0.05) than MD ICS/LABA/LAMA FDC in preventing severe exacerbation (RR from 0.46 to 0.65), but not with respect to moderate exacerbation (p>0.05). Triple combination therapies were equally effective on asthma control, with no safety concerns. This quantitative synthesis suggests that ICS/LABA/LAMA FDCs are effective and safe in uncontrolled asthma, and that the dose of ICS in the combination represents the discriminating factor to treat patients with a history of moderate or severe exacerbation.

Antibiotic adjuvants: a promising approach to combat multidrug resistant bacteria

2021 ◽  
Vol 22 ◽  
Author(s):  
Namita Sharma ◽  
Anil K. Chhillar ◽  
Sweety Dahiya ◽  
Pooja Choudhary ◽  
Aruna Punia ◽  
...  
Keyword(s):  
Drug Targets ◽  
Pathogenic Bacteria ◽  
Antibacterial Agents ◽  
Bacterial Resistance ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Antibacterial Drugs ◽  
Effective Strategies ◽  
The Impact ◽  
Emergence Of Resistance

The escalating emergence and prevalence of infections caused by multi-drug resistant (MDR) pathogenic bacteria accentuate the crucial need to develop novel and effectual therapeutic strategies to control this threat. Recent past surprisingly indicates a staggering decline in effective strategies against MDR. Different approaches have been employed to minimize the effect of resistance but the question still lingers over the astounding number of drugs already tried and tested to no avail, furthermore, the detection of new drug targets and the action of new antibacterial agents against already existing drug targets also complicate the condition. Antibiotic adjuvants are considered as one such promising approach for overcoming the bacterial resistance. Adjuvants can potentiate the action of generally adopted antibacterial drugs against MDR bacterial pathogens either by minimizing the impact and emergence of resistance or improving the action of antibacterial drugs. This review provides an overview of mechanism of antibiotic resistance, main types of adjuvants and their mode of action, achievements and progression.

scholarly journals Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2888 ◽  
Author(s):  
Buthaina Jubeh ◽  
Zeinab Breijyeh ◽  
Rafik Karaman
Keyword(s):  
Turning Point ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Medical Interventions ◽  
Gram Positive Bacteria ◽  
New Antibiotics ◽  
Vancomycin Resistant ◽  
New Treatments ◽  
Emergence Of Resistance

The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem.

scholarly journals Mechanistic Understanding Enables the Rational Design of Salicylanilide Combination Therapies for Gram-Negative Infections

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Janine N. Copp ◽  
Daniel Pletzer ◽  
Alistair S. Brown ◽  
Joris Van der Heijden ◽  
Charlotte M. Miton ◽  
...  
Keyword(s):  
Rational Design ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Combination Therapies ◽  
Diverse Range ◽  
Gram Negative ◽  
Mechanistic Understanding ◽  
Multiple Drugs

ABSTRACT One avenue to combat multidrug-resistant Gram-negative bacteria is the coadministration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we examine the molecular mechanisms of niclosamide, a clinically approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies. We discovered that Gram-negative bacteria possess two innate resistance mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was compromised, niclosamide became a potent antibiotic, dissipating the proton motive force (PMF), increasing oxidative stress, and reducing ATP production to cause cell death. These insights guided the identification of diverse compounds that synergized with salicylanilides when coadministered (efflux inhibitors, membrane permeabilizers, and antibiotics that are expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may have broad utility in combination therapies. We validate these findings in vivo using a murine abscess model, where we show that niclosamide synergizes with the membrane permeabilizing antibiotic colistin against high-density infections of multidrug-resistant Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase activity is a potential route to adaptive niclosamide resistance but show that this causes collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can rationally guide the discovery, development, and stewardship of novel combination therapies. IMPORTANCE There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in vitro against a diverse range of recalcitrant Gram-negative clinical isolates and in vivo in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.

scholarly journals Assessment of the Potential for Inducing Resistance in Multidrug-Resistant Organisms from Exposure to Minocycline, Rifampin, and Chlorhexidine Used To Treat Intravascular Devices

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Joel Rosenblatt ◽  
Nylev Vargas-Cruz ◽  
Ruth A. Reitzel ◽  
Issam I. Raad
Keyword(s):  
Antimicrobial Resistance ◽  
Clinical Setting ◽  
Multidrug Resistant ◽  
Antimicrobial Efficacy ◽  
Triple Combination ◽  
Surveillance Studies ◽  
Development Of Resistance ◽  
Multidrug Resistant Organisms ◽  
Intravascular Devices ◽  
Inducing Resistance

ABSTRACT To assess the potential for the induction of antimicrobial resistance following repeated subinhibitory exposures to the combination minocycline (MIN), rifampin (RIF), and chlorhexidine (CHX), a total of 29 clinical microbial pathogenic isolates were repeatedly exposed to subinhibitory concentrations of MIN, RIF, and CHX for 20 passages. MICs of the MIN, RIF, and CHX combination were assessed at each passage to evaluate the potential for resistance to have been induced. The combination of MIN, RIF, and CHX showed significant antimicrobial efficacy and synergy against organisms resistant to all 3 individual components (MIC of ≥16 μg/ml for MIN or MIC of ≥4 μg/ml for RIF or CHX). Among the organisms originally resistant to 2 or more individual components and the organisms originally susceptible to 2 or more individual components, there was no evidence that organisms became resistant following 20 repeated subinhibitory exposure cycles to the triple combination. The risk of resistance developing to the triple combination is extremely low because microbes are inhibited or killed before resistance can simultaneously emerge to all three agents. Surveillance studies monitoring the development of resistance should be conducted in a clinical setting.

scholarly journals Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

2015 ◽  
Vol 59 (12) ◽  
pp. 7805-7810 ◽  
Author(s):  
Johana Rueda ◽  
Teresa Realpe ◽  
Gloria Isabel Mejia ◽  
Elsa Zapata ◽  
Juan Carlos Rozo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Content Type ◽  
Genotypic Analysis ◽  
Mdr Tb ◽  
Proportion Method ◽  
Emergence Of Resistance ◽  
Phenotypic Susceptibility

ABSTRACTEthionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in theMycobacterium tuberculosispopulation. ETH resistance inM. tuberculosisis phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in theinhApromoter and in the following genes:katG,ethA,ethR,mshA,ndh, andinhA. We sequenced the above genes in 64M. tuberculosisisolates (n= 57 ETH-resistant MDR-TB isolates;n= 3 ETH-susceptible MDR-TB isolates; andn= 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% inkatG, 72% inethA, 45.6% inmshA, 8.7% inndh, and 33.3% ininhAor its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations inkatG; one had a mutation inethA, and another, inmshAandinhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations inmshAgene unrelated to the resistance. Mutations not previously reported were found in theethA,mshA,katG, andndhgenes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in theM. tuberculosisisolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

scholarly journals Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

Parasite ◽  
2018 ◽  
Vol 25 ◽  
pp. 24 ◽  
Author(s):  
Manel Ouji ◽  
Jean-Michel Augereau ◽  
Lucie Paloque ◽  
Françoise Benoit-Vical
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistant ◽  
Sub Saharan Africa ◽  
High Rate ◽  
Combination Therapies ◽  
Parasite Resistance ◽  
The Past ◽  
Sub Saharan ◽  
Treatment Policies ◽  
Related Mortality

The use of artemisinin-based combination therapies (ACTs), which combine an artemisinin derivative with a partner drug, in the treatment of uncomplicated malaria has largely been responsible for the significant reduction in malaria-related mortality in tropical and subtropical regions. ACTs have also played a significant role in the 18% decline in the incidence of malaria cases from 2010 to 2016. However, this progress is seriously threatened by the reduced clinical efficacy of artemisinins, which is characterised by delayed parasitic clearance and a high rate of recrudescence, as reported in 2008 in Western Cambodia. Resistance to artemisinins has already spread to several countries in Southeast Asia. Furthermore, resistance to partner drugs has been shown in some instances to be facilitated by pre-existing decreased susceptibility to the artemisinin component of the ACT. A major concern is not only the spread of these multidrug-resistant parasites to the rest of Asia but also their possible appearance in Sub-Saharan Africa, the continent most affected by malaria, as has been the case in the past with parasite resistance to other antimalarial treatments. It is therefore essential to understand the acquisition of resistance to artemisinins by Plasmodium falciparum to adapt malaria treatment policies and to propose new therapeutic solutions.

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