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Combination Therapy Against Multidrug Resistance

Combination Therapy Against Multidrug Resistance
A Book

by Mohmmad Younus Wani,Aijaz Ahmad

  • Publisher : Academic Press
  • Release : 2020-04-30
  • Pages : 268
  • ISBN : 0128205784
  • Language : En, Es, Fr & De
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Combination Therapy against Multidrug Resistance explores the potential of combination therapy as an efficient strategy to combat multi-drug resistance. Multidrug resistance (MDR) occurs when microorganisms such as bacteria, fungi, viruses, and parasites are excessively exposed to antimicrobial drugs such as antibiotics, antifungals, or antivirals, and in response the microorganism undergoes mutations or develops different resistance mechanisms to combat the drug for its survival. MDR is becoming an increasingly serious problem in both developed and developing nations. Bacterial resistance to antibiotics has developed faster than the production of new antibiotics, making bacterial infections increasingly difficult to treat, and the same is true for a variety of other diseases. Combination therapy proves to be a promising strategy as it offers potential benefits such as a broad spectrum of efficacy, greater potency than the drugs used in monotherapy, improved safety and tolerability, and reduction in the number of resistant organisms. This book considers how combination therapy can be applied in multiple situations, including cancer, HIV, tuberculosis, fungal infections, and more. Combination Therapy Against Multidrug Resistance gathers the most relevant information on the prospects of combination therapy as a strategy to combat multridrug resistance and helping to motivate the industrial sector and government agencies to invest more in research and development of this strategy as a weapon to tackle the multidrug resistance problem. It will be useful to academics and researchers involved in the development of new antimicrobial or antiinfective agents and treatment strtategies to combat multidrug resistance. Clinicians and medical nurses working in the field of infection prevention and control (IPC) will also find the book relevant Explores strategic methods with investigation of both short- and long-term goals to combat multidrug resistance Presents a broad scope to understand fully the ways to apply combined therapy to multidrug resistance Provides an overview of combination therapy, but also includes specific cases such as cancer, tuberculosis, HIV and malaria

Antibiotic Combination Therapy Against Multidrug-resistant Staphylococcus Epidermidis Biofilms and Broadening Antibiotic Spectrum Using Polyethylenimine

Antibiotic Combination Therapy Against Multidrug-resistant Staphylococcus Epidermidis Biofilms and Broadening Antibiotic Spectrum Using Polyethylenimine
A Book

by Anh Kim Lam

  • Publisher : Unknown Publisher
  • Release : 2020
  • Pages : 145
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components
Chapter 11. Medicinal Plants as Alternative Sources of Therapeutics against Multidrug-Resistant Pathogenic Microorganisms Based on Their Antimicrobial Potential and Synergistic Properties

by Kalpna D. Rakholiya,Mital J. Kaneria,Sumitra V. Chanda

  • Publisher : Elsevier Inc. Chapters
  • Release : 2013-05-24
  • Pages : 296
  • ISBN : 0128066822
  • Language : En, Es, Fr & De
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Antibiotics are antimicrobial agents that are used to treat infectious diseases. The outbreak of pathogenic antibiotic-resistant strains illustrates our urgent need to search for new alternative sources of treatment. Hence, an attempt has been made in this review to list some plant extracts, essential/volatile oils, and their antimicrobial activity against different microorganisms using different methods, as well as synergistic effects (plant extract-plant extract, plant extract-essential oils, plant extract-conventional antibiotics, phytochemical-antibiotics, and essential oil-essential oil). Plant products and their active constituents are useful in the treatment of infectious diseases caused by multidrug-resistant microbes, food borne diseases caused by food spoiling microbes, and oral pathogens. Products derived from plants have the potential to control microbial growth in diverse situations, and specifically in the treatment of disease. The various aspects of this review may be helpful for the food, cosmetic, and pharmaceutical industries.

Optimizing Polymyxin Antibiotics Using Combination Therapy and Mechanism-based Models

Optimizing Polymyxin Antibiotics Using Combination Therapy and Mechanism-based Models
A Book

by Neang S. Ly

  • Publisher : Unknown Publisher
  • Release : 2014
  • Pages : 443
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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The emergence of multidrug-resistant (MDR) Gram-negative 'superbugs' coupled with a rapid decline in the development of new antibiotics has led to a serious, global health crisis. Polymyxin antibiotics, which include polymyxin E (colistin) and polymyxin B, were introduced over 50 years ago and were seldom used due to nephrotoxicity. However, recently, the polymyxins have re-emerged in the clinic as an antibiotic of last-resort. There are increasing reports of polymyxin resistance and failure during polymyxin monotherapy. While polymyxin based combination therapies are a promising alternative, there are significant gaps regarding the optimal use of such combinations. The primary goal of this dissertation is to rationally optimize polymyxin combination therapy based on pharmacokinetic/pharmacodynamic (PK/PD) principles. Menchanism-based (PK/PD) models (MBMs) were employed to evaluate mechanisms of antibiotic synergy. A secondary goal is to define the mechanisms of polymyxin tolerance and resistance utilizing genetically modified knockout strains and to develop MBMs that quantify the impact of bacterial regulatory systems including quorum sensing mechanisms on antibiotic PD.

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components
Chapter 10. Combining Essential Oils with Antibiotics and other Antimicrobial Agents to Overcome Multidrug-Resistant Bacteria

by Kateryna Volodymyrivna Kon,Mahendra Kumar Rai

  • Publisher : Elsevier Inc. Chapters
  • Release : 2013-05-24
  • Pages : 296
  • ISBN : 0128066814
  • Language : En, Es, Fr & De
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High prevalence of multidrug-resistant microorganisms in the etiologic structure of different infectious processes significantly decreases the effectiveness of the treatment and enhances the probability of an unfavorable outcome from the infection. Combinations between antibiotics and other antimicrobial agents represent one of the most promising approaches for combating multidrug-resistant bacteria. A high therapeutic potential exists for combinations of antibiotics and natural antimicrobial substances with complex mechanisms of action and multiple healing properties, such as plant essential oils. The purpose of the present chapter is to review published studies on antibiotic-essential oil combinations and discuss the prospects for future studies. In general, many studies have shown the potential for essential oils to act synergistically with antibiotics in vitro. The main proposed mechanism of this beneficial effect is through inhibition of efflux pumps by some essential oils, which restores the activity of the antibiotic. Future efforts should be directed into further studies of antibiotic-essential oil combinations against multidrug-resistant bacteria, with an emphasis on understanding the mechanisms of the produced effect. Combinations of essential oils with different types of antimicrobial agents, such as bacteriophages, nanoparticles, and quorum-sensing inhibitors, require greater attention and are worthy of future investigations.

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components
Chapter 9. Botanicals for Adjunct Therapy and the Treatment of Multidrug-Resistant Staphylococcal Infections

by T.O. Lawal,K.K. Soni,B.A. Adeniyi,B.J. Doyle,G.B. Mahady

  • Publisher : Elsevier Inc. Chapters
  • Release : 2013-05-24
  • Pages : 296
  • ISBN : 0128066806
  • Language : En, Es, Fr & De
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High prevalence of multidrug-resistant microorganisms in the etiologic structure of different infectious processes significantly decreases the effectiveness of the treatment and enhances the probability of an unfavorable outcome from the infection. Combinations between antibiotics and other antimicrobial agents represent one of the most promising approaches for combating multidrug-resistant bacteria. A high therapeutic potential exists for combinations of antibiotics and natural antimicrobial substances with complex mechanisms of action and multiple healing properties, such as plant essential oils. The purpose of the present chapter is to review published studies on antibiotic-essential oil combinations and discuss the prospects for future studies. In general, many studies have shown the potential for essential oils to act synergistically with antibiotics in vitro. The main proposed mechanism of this beneficial effect is through inhibition of efflux pumps by some essential oils, which restores the activity of the antibiotic. Future efforts should be directed into further studies of antibiotic-essential oil combinations against multidrug-resistant bacteria, with an emphasis on understanding the mechanisms of the produced effect. Combinations of essential oils with different types of antimicrobial agents, such as bacteriophages, nanoparticles, and quorum-sensing inhibitors, require greater attention and are worthy of future investigations.

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components
Chapter 2. Natural Plant Products Used against Methicillin-Resistant Staphylococcus aureus

by Román Yesid Ramírez Rueda

  • Publisher : Elsevier Inc. Chapters
  • Release : 2013-05-24
  • Pages : 296
  • ISBN : 0128066733
  • Language : En, Es, Fr & De
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Methicillin-resistant Staphylococcus aureus (MRSA) is currently one of the most common causes of serious infections, in both hospital and community environments. This type of resistance was discovered in the 1960s, and now (50 years later) it has not been possible to develop an effective therapy to fight against it. This chapter compiles the results of several studies demonstrating the activity (mainly in vitro) of various extracts, essential oils, and plant-derived molecules that can act alone or in combination against MRSA. In addition, natural alternatives (other than from plants) being studied for the same purpose are described. Finally, the important role of phytotherapy in the development of new therapies against multidrug-resistant bacteria such as MRSA is emphasized.

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components
A Book

by Mahendra Rai,Kateryna Kon

  • Publisher : Academic Press
  • Release : 2013-05-24
  • Pages : 296
  • ISBN : 0124017088
  • Language : En, Es, Fr & De
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Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and their Components offers scientists a single source aimed at fighting specific multidrug-resistant (MDR) microorganisms such as bacteria, protozoans, viruses and fungi using natural products. This essential reference discusses herbal extracts and essential oils used or under investigation to treat MDR infections, as well as those containing antimicrobial activity that could be of potential interest in future studies against MDR microorganisms. The need to combat multidrug-resistant microorganisms is an urgent one and this book provides important coverage of mechanism of action, the advantages and disadvantages of using herbal extracts, essential oils and their components and more to aid researchers in effective antimicrobial drug discovery Addresses the need to develop safe and effective approaches to coping with resistance to all classes of antimicrobial drugs Provides readers with current evidence-based content aimed at using herbal extracts and essential oils in antimicrobial drug development Includes chapters devoted to the activity of herbal products against herpes, AIDS, tuberculosis, drug-resistant cancer cells and more

Use of Bedaquiline in the Treatment of Multidrug-Resistant Tuberculosis

Use of Bedaquiline in the Treatment of Multidrug-Resistant Tuberculosis
A Book

by World Health Organization

  • Publisher : Unknown Publisher
  • Release : 2015-03-31
  • Pages : 57
  • ISBN : 9789241505482
  • Language : En, Es, Fr & De
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WHO estimates that up to half a million new cases of multidrug-resistant tuberculosis (MDR-TB) occur worldwide, each year. Current treatment regimens for MDR-TB present many challenges: treatment lasts 20 months or more, requiring daily administration of drugs that are more toxic, less effective, and far more expensive than those used to treat drug-susceptible TB. Globally, less than half of all patients who start MDR-TB therapy are treated successfully. For the first time in over 40 years, a new TB drug with a novel mechanism of action - bedaquiline- is available, and was granted accelerated approval by the United States Food and Drug Administration in December 2012. There is considerable interest in the potential of this drug to treat MDR-TB. However, information about this new drug remains limited. It has only been through two Phase IIb trials for safety and efficacy. The World Health Organization (WHO) is therefore issuing "interim policy guidance". This interim guidance provides advice on the inclusion of bedaquiline in the combination therapy of MDR-TB in accordance with the existing WHO Guidelines for the Programmatic Management of Drug-resistant TB (2011 Update).

Dissemination, Suppression, and Evolution of Antibiotic Resistance in Human Pathogens

Dissemination, Suppression, and Evolution of Antibiotic Resistance in Human Pathogens
A Book

by Patrick Rolland Gonzales

  • Publisher : Unknown Publisher
  • Release : 2015
  • Pages : 152
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Multidrug-resistant (MDR) human pathogens represent a growing threat to human health. This threat is compounded by dissemination of antibiotic resistance genes from diverse microbial reservoirs. The selection of current antibiotic drugs that can clear bacterial infections with minimal human side effects is limited, and bacteria can rapidly evolve or acquire new resistance to these drugs on the order of weeks. Compounding this issue is the existence of an "innovation gap", where drug-discovery efforts of pharmaceutical companies to screen massive libraries of natural and synthetic compounds have reached practical limits. Concurrently with drug-discovery, synthetic tailoring methods with existing drug scaffolds, cycling of existing drugs to exploit collateral sensitivity, and lower-order combination therapies have slowed, but not stopped this rise. These strategies have, in the past, been successfully employed against the major MDR Gram-negative and Gram-positive human isolates, also known as ESKAPE pathogens, comprised of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and ESBL-producing Enterobacteriaceae species. These six ESKAPE strains are collectively responsible for a substantial percentage of nosocomial infections in the modern hospital and represent the vast majority of isolates whose increasing resistance to antibiotic agents presents serious therapeutic dilemmas for physicians, not to mention the considerable economic and social burdens placed. Attenuating this increase in multidrug resistance is crucial, as the pipeline of novel antibiotic compounds is rapidly drying up. In this work, I explore three aspects of antibiotic resistance, with particular focus on multidrug-resistant (MDR) human pathogens: 1) how antibiotic resistance genes have been disseminated in the clinic and the environment by Pseudomonas aeruginosa, a bacterial strain that can serve as a reservoir and vector of antibiotic resistance; 2) how existing antibiotic drugs can be combined to generate increased potency through synergy, and can also suppress the emergence of higher resistance in MRSA through collateral sensitivities of the components; and 3) how a novel bifunctional antibiotic resistance enzyme, AAC(6')-Ib-cr, can overcome fitness costs incurred by its acquired resistance function against ciprofloxacin, through mutational analysis of its variants in a diverse genomic library. We determined that the pseudomonads isolated from the clinical niche library were significantly enriched for all resistance gene functions in general, and all beta-lactamases in particular. Strikingly, these resistance genes were found on contigs with collinear resistance genes conferring resistance to multiple drug classes, and adjacent to mobilizable genomic elements like transposons and integrons. Also notable, many of the resistance genes have highest nucleotide and amino-acid identity to non-Pseudomonas species, indicating signatures of recent horizontal gene transfer (HGT). Collectively, these findings strongly suggest Pseudomonas aeruginosa to be a reservoir species and possible vector for the further dissemination of mobilizable antibiotic resistance genes. We identified multiple triple combinations of antibiotics with high synergy against P. aeruginosa DK2. This was not unexpected in this case, as prior work suggested that drugs targeting maximally orthogonal systems in bacteria would increase the likelihood of inducing a fragile state, where the bacterium is no longer capable of performing basic metabolic functions and is killed. In contrast to orthogonal drug components composing maximally synergistic combinations in Pseudomonas, we identified a new potential therapy against MRSA N315 consisting of a combination of clinically approved drugs from three distinct generations and subclasses of [beta]-lactam antibiotics, all targeting cell-wall synthesis: meropenem, piperacillin, and tazobactam (ME/PI/TZ). Because MRSA strains are highly resistant to most beta-lactam drugs, the remarkable synergy present in this triple combination was unexpected, and we found the synergy to derive from the differential targeting of multiple constituents of the cell wall synthesis system in MRSA, especially the allosteric triggering of the PBP2a enzyme by meropenem to open the active site for inhibition by the beta-lactams in the combination. The efficacy of the ME/PI/TZ combination in completely clearing aggressive MRSA infection in mice was also unexpected, as use of beta-lactams is not currently suggested for treating MRSA in the clinic because of the resistance conferred against beta-lactams given singly by the PBP2a enzyme. After generating libraries of barcoded, wild-type and mutant variants of the aac(6')-Ib-cr gene in an E. coli host, and exposing the libraries to high concentrations of kanamycin and ciprofloxacin, we found several clones that displayed increases in fitness toward both kanamycin and ciprofloxacin, thus refuting our hypothesis of increases in fitness toward one drug being anti-correlated with fitness to the other. However, we successfully generated libraries of the aac(6')-Ib-cr gene with unique barcodes for each clone and with endogenous ribosome binding sites for proper expression of the gene variants under arabinose-inducible expression in plasmid pBAD24. Initial high-throughput sequencing runs of libraries with MiSeq were of low efficiency, likely due to the large size of the gene construct and necessary adapter sequences for hybridization to the Illumina flow cells. Our attempts to subclone the construct, in order to generate sub-libraries more amenable to high-throughput sequencing with MiSeq, were unsuccessful. But, we successfully generated circularized aac(6')-Ib-cr constructs, bringing the necessary F and R barcodes in close proximity for short, direct sequencing with MiSeq. In sum, we have surveyed the dissemination of antibiotic resistance across global ecological niches in Pseudomonas aeruginosa, which we may consider a reservoir and vector of antibiotic resistance genes. We have sought out new ways to treat highly MDR human pathogens and discovered triple antibiotic drug combinations that are highly synergistic against Pseudomonas and MRSA strains, and especially an unexpected triple combination of beta-lactam drugs that strongly synergize to confer high potency against MRSA infections in vitro and in vivo, and also suppress emergence of higher antibiotic resistance through reciprocal collateral sensitivities of the components. Finally, we have focused on the potential of one novel gene conferring bifunctional resistance against aminoglycoside and fluoroquinolone antibiotics, aac(6')-Ib-cr, to assess whether this gene can acquire more mutations to become even more robust at resisting these drug classes in the clinic.

Carbapenems for Multi-drug Resistant Infections

Carbapenems for Multi-drug Resistant Infections
A Review of Guidelines

by Anonim

  • Publisher : Unknown Publisher
  • Release : 2016
  • Pages : 16
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Carbapenems are beta-lactam antibiotics with a very broad spectrum of activity and act by disrupting the synthesis of bacterial cell walls. Others in the family of beta-lactam antibiotics are cephalosporins, which include cefepime and ceftazidime. In contrast, beta-lactamase inhibitors have little antibacterial activity alone. They include tazobactam and clavulanate. When used with beta-lactams however, the combination therapy provides enhanced and extended spectrum of activity against bacteria containing plasmid-mediated and chromosomal beta-lactamases. In the literature, the terminology "combination therapy" varies. For instance, the combination product piperacillin-tazobactam is often referred to as monotherapy unless combined with other agents such as amikacin or tobramycin. The growing problem of multi-drug resistance (MDR) worldwide has led to efforts in restricting the use of carbapenems. MDR and gram-negative bacterial infections are especially predominant in febrile neutropenia (FN), where over 50% of patients have an established or occult infection, and over 20% have bacteremia. If FN patients are not treated immediately, bacterial infections become rapidly fatal. In such patient populations, there are questions of how carbapenems fit in the context of care given the availability of alternative therapies such as beta-lactam/ beta-lactamase inhibitor combinations, and the different strategies of implementation such as escalation and de-escalation. Escalation begins with monotherapy and escalates to a regimen with a broader spectrum. De-escalation begins with a broad regimen and de-escalates to a regimen with a narrower spectrum after laboratory confirmation of the pathogen. The purpose of this report is to review evidence-based guidelines on the appropriate indications or circumstances for the use of carbapenems and other empiric therapies in the context of MDR infections and FN.

Pharmacokinetics and Pharmacodynamics of Antimalarial Drugs Used in Combination Therapy

Pharmacokinetics and Pharmacodynamics of Antimalarial Drugs Used in Combination Therapy
A Book

by Qigui Li,Mark R. Hickman

  • Publisher : Bentham Science Publishers
  • Release : 2015-06-04
  • Pages : 550
  • ISBN : 1681080540
  • Language : En, Es, Fr & De
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Malaria takes a great toll on human health and well-being, particularly in tropical regions including Sub-Saharan Africa, Southeast Asia, Oceania and parts of the Americas. In recent years, some Plasmodium strains have become increasingly resistant to all classes of conventional antimalarial drugs currently in use. Researchers have, therefore, stepped up efforts to revise atimalarial drug policies, develop new drugs, and implement new strategies to combat this disease. In order to prevent widespread resistance, antimalarial combination therapies (ACTs) have been deployed and a World Antimalarial Resistance Network has been established as a means of anitimalarial drug resistance surveillance. Artemisinin-based combination therapies have proven to be useful as a replacement for standard regimens. Currently, these ACTs successfully cure patients suffering from uncomplicated malaria with superior efficacy and lower toxicity, but there remains a huge challenge (high mortality rate) associated with treatment of severe malaria. Studies of drug disposition and drug efficacy (PK/PD evaluations) are essential to understanding why drugs work as antimalarials as they illustrate issues with drug resistance, drug safety and drug toxicity that are critical to finding the appropriate drug dose for patients. This eBook illustrates how currently available combination antimalarial drugs can be optimized for effective malaria treatment. Chapters in this book explain methods to select combination drugs based on PK/PD evaluations followed by methods o reduce drug toxicity based on these evaluations. The book also summarizes efforts that are being made by the research community to improve ACT. It is, therefore, a handy reference for medical professionals and pharmacologists working on antimalarial drugs.

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components
Chapter 6. Use of Essential Oils and Their Components against Multidrug-Resistant Bacteria

by M.L. Faleiro,M.G. Miguel

  • Publisher : Elsevier Inc. Chapters
  • Release : 2013-05-24
  • Pages : 296
  • ISBN : 0128066776
  • Language : En, Es, Fr & De
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Aromatic and medicinal plants, through their secondary metabolism, provide a complex mixture of volatile molecules known as essential oils. These volatile molecules exert antibacterial activity that has been used in folk medicine for centuries. During the last few decades, the emergence of antibacterial resistance has forced us to search for new and efficient antimicrobial agents. The significant number of studies on the use of essential oils and their components against multidrug-resistant bacteria, such as Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, and Pseudomonas aeruginosa show the exceptional potential of these natural products to curb the development of antibacterial resistance. Moreover, the use of essential oils and their components in combination with antibiotics may increase bacterial susceptibility, thus limiting resistance.

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components

Fighting Multidrug Resistance with Herbal Extracts, Essential Oils and Their Components
Chapter 13. Use of Plant-Derived Extracts and Essential Oils against Multidrug-Resistant Bacteria Affecting Animal Health and Production

by Lyndy McGaw

  • Publisher : Elsevier Inc. Chapters
  • Release : 2013-05-24
  • Pages : 296
  • ISBN : 0128066849
  • Language : En, Es, Fr & De
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Many bacterial diseases affect animals, causing important economic losses in livestock. Subtherapeutic antibiotic use in production animals as antibiotic growth promoters has been implicated as a causative factor in the development of resistance of bacterial pathogens toward several classes of antimicrobials, some of which are used therapeutically in humans. This has led to the banning of antibiotic growth promoters by the European Union, and such a precedent may be followed in other countries. Alternatives to antibiotic growth promoters are necessary to enable the production of animal protein to keep pace with the expanding world population. One approach is to use plant extracts or essential oils as supplements to provide beneficial effects, including direct antibacterial activity and stimulation of the immune system, or enhancement of ruminal digestion. The risk of resistance developing to a combination of phytochemicals is lower than the risk of resistance against a single antibiotic, and synergistic effects of plant constituents may contribute to the overall activity of the preparation.

Formulation Approaches to Pulmonary Delivery of Colistin Combination Antibiotic Therapy

Formulation Approaches to Pulmonary Delivery of Colistin Combination Antibiotic Therapy
A Book

by Stephanie Wallace

  • Publisher : Unknown Publisher
  • Release : 2011
  • Pages : 712
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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AbstractAdvanced formulations such as liposomes are increasingly being employed to improve the therapeutic profile of existing drugs, and to facilitate appropriate delivery of combination drug products. This is particularly the case for antibiotic therapies, due to the development of bacterial resistance and consequent need for combination drug approaches.Multi-drug resistant (MDR) Gram-negative bacteria have become a major medical problem worldwide over the last decade, with rapidly diminishing therapeutic options and very few new agents in the drug development pipeline. This situation has forced the reintroduction of an old antibiotic, colistin, back into clinical use. Colistin inhalation therapy is being increasingly used as a salvage therapy for the treatment of MDR Gram-negative pulmonary infections; however, there is a dearth of information on its pharmacokinetics and pharmacodynamics. Importantly, current inhalable formulations have not been optimised. Combination therapy may be an important approach towards optimising the use of colistin in the treatment of MDR pulmonary infections. Inhalable formulations providing sustained concentrations of the combination of colistin and a second antibiotic within the lungs would offer a more effective inhalation therapy against MDR Gram-negative pulmonary infections. The research undertaken in this thesis investigates the use of colloidal-based drug delivery systems for the co-formulation of colistin and model poorly-water soluble co-drug, azithromycin. The surfactant-like structure of colistin and its prodrug, colistin methanesulphonate (CMS), has been suggested to impact on their solution behaviour and stability, however their self-assembly in solution has not been well studied. In this thesis dynamic light scattering studies have confirmed the formation of colistin and CMS association colloids at critical micelle concentrations of 2.1 and 6.1 mg/mL, respectively. The self- assembly of CMS impacted the rate of conversion of CMS to colistin in solution confirming that the concentration-dependent stability of CMS is attributable to micelle formation. Micelle formation by colistin and CMS in solution enabled solubilization of poorly-water soluble drugs, however the limited capacity of the micelles was deemed insufficient to use micellar solubilization solely as a means to co-formulate a poorly- water soluble antibiotic with either colistin or CMS. Consequently, liposomes were investigated as a drug delivery system with potential to co-formulate colistin and CMS with other antibiotics. Colistin was successfully incorporated into liposomes, and the incorporation of cholesterol into the liposome bilayer enhancing associations between colistin and the bilayer. However, it was found that CMS-loaded liposomes exhibited poor colloidal stability, resulting in particle size growth and changes in particle surface charge over time, and eventual phase separation. The formulation of CMS within a liposomal carrier also accelerated the conversion of the prodrug to colistin. The CMS-loaded liposome approach was therefore abandoned and further studies concentrated on colistin-loaded liposomes. Co-formulation of azithromycin and colistin in liposomes was consequently investigated. Remote-loading of liposomes using the pH gradient method enabled greater solubilization of azithromycin (azithromycin to lipid ratio 0.20:1) compared to passive loading (azithromycin to lipid ratio 0.16:1). In vitro release studies demonstrated that upon dilution, colistin rapidly re-established equilibrium associations with the liposome bilayer. Incorporation of colistin into the remotely-loaded azithromycin formulation accelerated the rate of azithromycin release from 'slow release' liposomes in a concentration-dependent manner, indicating that the association of colistin with liposomes modified bilayer fluidity. However, the rate of release of azithromycin from liposomes was also reduced by increasing the cholesterol composition in the lipid bilayer.Liposomes were investigated for their potential to provide co-localisation of colistin and azithromycin within the lungs following pulmonary delivery in a rat model. The temporal aspects of availability of drug in the lungs were investigated under the assumption that local drug availability was reflected by the rate of pulmonary absorption. Pulmonary absorptive drug clearance in turn was assumed to be reflected in plasma drug concentrations. Thus changes in plasma concentration profiles with changes in formulation were used as an indicator of drug availability in the lungs as a consequence of release of drug from the formulation. Liposomal encapsulation resulted in a 47% decrease in maximum plasma concentrations of colistin and a 26% reduction in systemic exposure, compared to unencapsulated colistin. The rate of pulmonary absorption of azithromycin, however, was not impeded by liposomal encapsulation. This thesis is the first study to investigate the potential of advanced drug delivery systems to provide co-localisation of colistin and azithromycin within the lungs following pulmonary delivery.

Exploiting Novel Combined Host- and Pathogen-Directed Therapies for Combating Bacterial Multidrug Resistance

Exploiting Novel Combined Host- and Pathogen-Directed Therapies for Combating Bacterial Multidrug Resistance
A Book

by Maurizio Fraziano,Roberto Nisini,Gian Maria Rossolini,Marco Rinaldo Oggioni

  • Publisher : Frontiers Media SA
  • Release : 2020-12-30
  • Pages : 129
  • ISBN : 2889663078
  • Language : En, Es, Fr & De
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Unraveling the Biology, Genetics, and Host/Environmental Interactions of Acinetobacter

Unraveling the Biology, Genetics, and Host/Environmental Interactions of Acinetobacter
A Book

by Maria Alejandra Mussi,Maria Soledad Ramirez

  • Publisher : Frontiers Media SA
  • Release : 2020-08-19
  • Pages : 129
  • ISBN : 2889639460
  • Language : En, Es, Fr & De
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Despite not being a disease in and of itself, antibiotic resistance could be considered the global epidemic of modern times, since it produces the failure to prevent and treat many infectious diseases. This can ultimately lead to untreatable microbial infections becoming more widespread and this will significantly increase morbidity and mortality. This worldwide problem is estimated to cause millions of deaths per year and could become an even more significant menace to humanity than established illnesses, such as cancer. In February 2017, the World Health Organization (WHO) published a list of antibiotic-resistant “priority pathogens” – a catalogue of 12 families of bacteria which pose the greatest threat to human health - and Acinetobacter baumannii is leading the list. The most critical group includes multidrug-resistant bacteria, which pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters. This group includes Acinetobacter, Pseudomonas, and various Enterobacteriaceae and they are often associated with deadly infections, such as bloodstream infections and pneumonia. Furthermore, these bacteria have become resistant to a large number of antibiotics, including carbapenems and third generation cephalosporins – the best available antibiotics for treating multidrug-resistant bacteria. A. baumannii is a particularly worrisome example and demands attention: This pathogen turned into a menace to humans during the late 70s, likely as a result of intense antibiotic use in hospital settings, and became one of the microorganisms that are challenging the antibiotic era. Its extreme genome plasticity, combined with mechanisms of horizontal genetic transfer, have played a key role in the evolution of this microorganism, as well as its adaptability to unfavorable environments. However, its pathophysiology, as well as the mechanisms leading to its success as a pathogen, are not that simple to unveil. However, what is clear is that the triad of host-pathogen-environment is crucial in selection and establishment of multidrug-resistant clones and outbreaks. Indeed, there are still many aspects of this pathogen that require a deeper understanding - not only regarding mechanisms of resistance but also its global pathophysiology. For example, basic understanding of transmission mechanisms; knowledge of ‘external’ factors modulating persistence of the pathogen; genetic effects on host susceptibility and infectiousness; mechanisms of pathogenicity and their dynamics; and genetic variation of the pathogen affecting virulence and transmissibility are some aspects that would require further study. Furthermore, the importance of other members of the genus as important nosocomial pathogens, such as Acinetobacter nosocomialis, has been increasingly recognized during the last few years.

Nosocomial and Ventilator-Associated Pneumonia

Nosocomial and Ventilator-Associated Pneumonia

by A. Torres,S. Ewig

  • Publisher : European Respiratory Society
  • Release : 2011
  • Pages : 169
  • ISBN : 1849840164
  • Language : En, Es, Fr & De
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Nosocomial and ventilator-associated pneumonia continue to be a major challenge in the management of intensive care patients. In particular, recent developments in microbial resistance are a cause of great concern. Internationally renowned experts provide comprehensive reviews on all the major topics within the field and, in particular, the recent insights into epidemiology, diagnosis and treatment surrounding this field. This Monograph is an essential reference book for both clinicians and researchers alike on this challenging subject.

Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases

Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases
2-Volume Set

by John E. Bennett, MD, MACP,Raphael Dolin, MD,Martin J. Blaser, MD

  • Publisher : Elsevier Health Sciences
  • Release : 2014-08-28
  • Pages : 3904
  • ISBN : 1455748013
  • Language : En, Es, Fr & De
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After thirty five years, Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition is still the reference of choice for comprehensive, global guidance on diagnosing and treating the most challenging infectious diseases. Drs. John E. Bennett and Raphael Dolin along with new editorial team member Dr. Martin Blaser have meticulously updated this latest edition to save you time and to ensure you have the latest clinical and scientific knowledge at your fingertips. With new chapters, expanded and updated coverage, increased worldwide perspectives, and many new contributors, Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition helps you identify and treat whatever infectious disease you see. Get the answers to questions you have with more in-depth coverage of epidemiology, etiology, pathology, microbiology, immunology, and treatment of infectious agents than you'll find in any other infectious disease resource. Find the latest diagnoses and treatments for currently recognized and newly emerging infectious diseases, such as those caused by avian and swine influenza viruses. Put the latest knowledge to work in your practice with new or completely revised chapters on influenza (new pandemic strains); new Middle East respiratory syndrome (MERS) virus; probiotics; antibiotics for resistant bacteria; antifungal drugs; new antivirals for hepatitis B and C; Clostridium difficile treatment; sepsis; advances in HIV prevention and treatment; viral gastroenteritis; Lyme disease; Helicobacter pylori; malaria; infections in immunocompromised hosts; immunization (new vaccines and new recommendations); and microbiome. Benefit from fresh perspectives and global insights from an expanded team of international contributors. Find and grasp the information you need easily and rapidly with newly added chapter summaries. These bulleted templates include diagnosis, therapy, and prevention and are designed as a quick summary of the chapter and to enhance relevancy in search and retrieval on Expert Consult. Stay current on Expert Consult with a thorough and regularly scheduled update program that ensures access to new developments in the field, advances in therapy, and timely information. Access the information you need easily and rapidly with new succinct chapter summaries that include diagnosis, therapy, and prevention. Experience clinical scenarios with vivid clarity through a richly illustrated, full-color format that includes 1500 photographs for enhanced visual guidance.

Alternative Therapeutics Against Antimicrobial-Resistant Pathogens

Alternative Therapeutics Against Antimicrobial-Resistant Pathogens
A Book

by Rebecca Thombre,Kamlesh Jangid,Ravi Shukla,Noton Kumar Dutta

  • Publisher : Frontiers Media SA
  • Release : 2019-12-19
  • Pages : 129
  • ISBN : 2889632164
  • Language : En, Es, Fr & De
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