Antibiotic Cycling and Marketing Into the 21st Century: A Perspective From the Pharmaceutical Industry

2000 ◽  
Vol 21 (S1) ◽  
pp. S32-S35 ◽  
Author(s):  
Bruce S. Lavin
Keyword(s):  
Antimicrobial Resistance ◽  
Pharmaceutical Industry ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Medical Community ◽  
Resistant Bacteria ◽  
Environmental Pressures ◽  
Development Of Resistance ◽  
Antibiotic Cycling

AbstractBefore the development of the first antimicrobial agents, bacteria already had demonstrated an ability to adapt to stress in the environment, resulting in the development of resistance that often makes the prevailing antibiotic treatment ineffective. The response to antimicrobial resistance in the medical community has been to use new or alternative antibiotics not previously used against the resistant bacteria. The pharmaceutical industry has responded to the resistance problem by producing newer antibiotics, either as modifications of currently existing compounds or as combinations of compounds that may inhibit or bypass the bacterial resistance mechanisms. The development of new antibiotics is a lengthy and costly process. To be successful, the pharmaceutical industry must anticipate the changing needs of the medical community, as well as the dynamic process of antimicrobial resistance. The marketing of new antimicrobial agents must be adaptable to the potential environmental pressures that induce bacterial resistance in order to ensure the longevity of the agents.

Bacterial Resistance: Antibiotics of Last Generation used in Clinical Practice and the Arise of Natural Products as New Therapeutic Alternatives

2020 ◽  
Vol 26 (8) ◽  
pp. 815-837 ◽  
Author(s):  
Rúbia C.G. Corrêa ◽  
Sandrina A. Heleno ◽  
Maria J. Alves ◽  
Isabel C.F.R. Ferreira
Keyword(s):  
Natural Products ◽  
Natural Resources ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Critical Discussion ◽  
Public Health Issue ◽  
Resistant Bacteria ◽  
Natural Agents ◽  
Development Of Resistance

Bacterial resistance to therapeutical drugs has been a serious issue over the last decades. In fact, the quick development of resistance mechanisms by the microorganisms has been fatal for millions of people around the world, turning into a public health issue. The major cause of the resistance mechanisms is the overuse of antimicrobials. European countries try to implement mechanisms to overcome antimicrobial resistance in the community through the rational use of antimicrobials. The scientific community has been exhaustively dedicated to the discovering of new, safer and efficient drugs, being the exploitation of natural resources, mainly plants and fungi, considered as a hot topic in the field of antimicrobial agents. Innumerous reports have already shown the promising capacity of natural products or molecules extracted from these natural resources, to act as bacteriostatic and bactericidal agents. More importantly, these natural agents present significantly lower harmful effects. Bearing that in mind, this review aims at giving a contribution to the knowledge about the synthetic antibiotics of the last generation. Moreover, it is intended to provide information about the last advances regarding the discovery of new antimicrobial agents. Thus, a compilation of the chemical characteristics, efficiency, harmful outcomes and resistance mechanisms developed by the microorganisms can be consulted in the following sections together with a critical discussion, in line with the recent approaches. Furthermore, modern strategies for the prospection of novel anti-infective compounds for tackling resistant bacteria have been considered as also a current synopsis of plants and mushrooms with relevant antimicrobial potentials.

scholarly journals Bacterial Resistance to Antimicrobial Agents

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 593
Author(s):  
Manuel F. Varela ◽  
Jerusha Stephen ◽  
Manjusha Lekshmi ◽  
Manisha Ojha ◽  
Nicholas Wenzel ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Drug Targets ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Health Sector ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Cellular Mechanisms ◽  
Causative Agents

Bacterial pathogens as causative agents of infection constitute an alarming concern in the public health sector. In particular, bacteria with resistance to multiple antimicrobial agents can confound chemotherapeutic efficacy towards infectious diseases. Multidrug-resistant bacteria harbor various molecular and cellular mechanisms for antimicrobial resistance. These antimicrobial resistance mechanisms include active antimicrobial efflux, reduced drug entry into cells of pathogens, enzymatic metabolism of antimicrobial agents to inactive products, biofilm formation, altered drug targets, and protection of antimicrobial targets. These microbial systems represent suitable focuses for investigation to establish the means for their circumvention and to reestablish therapeutic effectiveness. This review briefly summarizes the various antimicrobial resistance mechanisms that are harbored within infectious bacteria.

scholarly journals PROPAGATION OF ANTIMICROBIAL RESISTANT Salmonella spp. IN BIVALVE MOLLUSKS FROM ESTUARY AREAS OF BAHIA, BRAZIL

2016 ◽  
Vol 29 (2) ◽  
pp. 450-457 ◽  
Author(s):  
CARLA SILVA DA SILVEIRA ◽  
OSCARINA VIANA DE SOUSA ◽  
NORMA SUELY EVANGELISTA-BARRETO
Keyword(s):  
Nalidixic Acid ◽  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Index ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Bivalve Mollusks ◽  
Salmonella Spp ◽  
Development Of Resistance

ABSTRACT: In recent years, the emergence of resistant pathogens has complicated the treatment of bacterial infections in livestock production as well as in the medical field, due to the development of resistance mechanisms by microorganisms. The objective of this study was to delineate the antimicrobial resistance profile of Salmonella spp. strains isolated from bivalve mollusks (oysters and mussels) and from estuarine environment water of two regions of Bahia, Brazil. Twenty-seven strains, 12 isolated from bivalve mollusks and 15 from estuarine water, were tested. Eight antimicrobial agents (phenicol, beta-lactams, tetracyclines, quinolones and fluoroquinolones classes) were used for a susceptibility test, Minimum Inhibitory Concentration (MIC) and extended-spectrum beta-lactamases (ESBLs) production. Isolates showed high susceptibility to the classes of antimicrobial agents tested, with resistance only to nalidixic acid (27%), ampicillin (25%) and tetracycline (25%). Bacterial resistance was of chromosomal origin and the multidrug resistance index (MAR) among isolates of shellfish (mussels in natura) was 0.25. The MIC was found to be 100 µg/mL, 500 µg/mL and 350 µg/mL to nalidixic acid, ampicillin and tetracycline, respectively. None of the isolates presented ESBLs production. The presence of multidrug-resistant and high MIC Salmonella spp. is being conveyed in extraction areas of bivalve mollusks in the State of Bahia, Brazil.

Potential Role of Pharmacokinetics, Pharmacodynamics, and Computerized Databases in Controlling Bacterial Resistance

2000 ◽  
Vol 21 (S1) ◽  
pp. S18-S21 ◽  
Author(s):  
Judith M. Hyatt ◽  
Jerome J. Schentag
Keyword(s):  
Potential Role ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Bacterial Isolation ◽  
Ciprofloxacin Resistance ◽  
Antibiotic Cycling ◽  
The Impact ◽  
Emergence Of Resistance

AbstractBacterial resistance to antibiotics continues to be a problem, in spite of increased knowledge of resistance mechanisms. Due to the multifactorial nature of bacterial resistance, studies that evaluate the association between antimicrobial exposure and emergence of resistance may fail to find a relationship unless other factors, in particular the association between patient-pathogen pharmacokinetics (PK) and pharmacodynamics (PD) and the emergence of bacterial resistance, are evaluated as well. It has been hypothesized that, in conjunction with good infection control practices, cycling of antimicrobial agents may prove to be effective in reducing resistance emergence.There is some indication that there may be a relationship between the level of antibiotic exposure and the probability of emergence of bacterial resistance. As shown in our companion article in this supplement, factors associated with ciprofloxacin resistance in Pseudomonas aeruginosa included increased length of stay prior to isolation, exposure to ciprofloxacin, and respiratory tract site of bacterial isolation. However, in patients who received ciprofloxacin therapy, when exposure was at an area under the 24-hour inhibitory concentration curve (AUIC24)>110 (μg·h/mL)/μg/mL, resistance was decreased to 11%, a rate similar to that seen in respiratory isolates not exposed to ciprofloxacin (7%).While the length of time the patient spends in the hospital and the site of infection cannot be controlled, by using PK and PD principles for dosing of ciprofloxacin, the emergence of ciprofloxacin resistance in P aeruginosa may be reduced. Prospective antibiotic-cycling studies may help to determine not only the impact of antibiotic cycling on the institution's antibiogram but also, through the use of PK and PD principles, may help to determine appropriate dosing schedules for antibiotics in order to reduce the probability of emergence of bacterial resistance.

scholarly journals The Link between Antimicrobial Resistance and the Content of Potentially Toxic Metals in Soil and Fertilising Products

2019 ◽  
pp. 319-321
Author(s):  
Yngvild Wastson ◽  
Eystein Skjerve ◽  
Siamak Yazdankhah ◽  
Karl Eckner ◽  
Georg Kapperud ◽  
...  
Keyword(s):  
Food Safety ◽  
Antimicrobial Resistance ◽  
Toxic Metals ◽  
Working Group ◽  
Antimicrobial Agents ◽  
Land Application ◽  
Resistant Bacteria ◽  
Published Data ◽  
Potentially Toxic Metals ◽  
Development Of Resistance

Potentially toxic metals (PTM), along with PTM-resistant bacteria and PTM-resistance genes may be introduced to soil and water through sewage systems, direct excretion, land application of biosolids (organic matter recycled from sewage, especially for use in agriculture) or animal manures as fertilisers, and irrigation with wastewater or treated effluents. The Norwegian Food Safety Authority (NFSA) asked the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for an assessment of the link between antimicrobial resistance (AMR) and potentially toxic metals (PTM) in soil and fertilising products. The NFSA would like VKM to give an opinion on the following question related to the influence of potentially toxic metals on antimicrobial resistance: Can the content of arsenic (As), cadmium (Cd), chromium (CrIII + CrVI), copper (Cu), lead (Pb), mercury (Hg), nickel (Ni), and zinc (Zn) in soil and fertilising products that are relevant for Norway play a role in the development, spreading, and persistence of bacterial resistance to these elements, as well as cross or co-resistance to antimicrobial agents? VKM appointed a working group, consisting of two members of the Panel on Biological Hazards, to prepare a draft Opinion document and answer the questions. The Panel on Biological Hazards has reviewed and revised the draft prepared by the working group and approved the Opinion document “The link between antimicrobial resistance and the content of potentially toxic metals in soil and fertilising products”. In this report we assess the following PTM: arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), mercury (Hg), lead (Pb), and zinc (Zn), because of their possible presence in fertilisers and their potential to induce AMR in bacteria. This assessment is based on internationally published data. There is no systematic monitoring for toxic metals in soils in Norway, and the levels are expected to be highly variable depending on the input sources, previous and current agricultural practices, and the characteristics of the soil. Data on PTM in fertilising products added to soil are also fragmented and limited. Fertilising materials, in the form of sewage sludge or livestock manure, will add toxic metals to the existing levels in soil, and in areas of intensive agriculture, the levels will be expected to be highest. The additive effect of toxic metals in fertilising materials must be assessed from a long-term perspective, as these metals accumulate in the environment. Development of AMR can be partly regarded as a dose- and time-dependant response to exposure to different drivers for resistance. There is an indication that the presence of potentially toxic metals is a driver for development of AMR in exposed bacteria, but the dose and time exposure most likely to cause this effect is not known. Investigation of PTM-driven co-selection of AMR in environments impacted by agriculture and aquaculture should focus especially on Cu and Zn, which are added to animal feed, and on Cd because of its high concentration, in comparison with other PTM, in inorganic fertilising products. The naturally occurring background resistance in environmental bacteria complicates the estimation of the effect of PTM exposure on development of resistance. In addition, it is difficult to distinguish between the natural resistome and an elevated abundance of AMR in environmental samples. Spreading of resistance towards the PTM evaluated in this assessment involves cross- and co-resistance to antimicrobial agents used in prophylaxis and therapy in animals and people. Most important are those cases where toxic metal resistance is coupled to resistance towards highly important and critically important antibiotics. This has been described in some of the published articles included in this assessment. We do not fully understand the mechanisms behind persistence of AMR, and removing drivers for development and spread of resistance may result in a decrease in the levels of resistance, but not necessarily full disappearance. There is lack of knowledge regarding links between the level and concentration of PTM in fertilising products and soil and development of resistance in bacteria. Data regarding the routes and frequencies of transmission of AMR from bacteria of environmental origin to bacteria of animal and human origin were lacking in the published articles reviewed here. Due to the lack of such data, it is difficult to estimate the probability of development, transmission, and persistence of PTM resistance in the Norwegian environment. More research is needed to explain the relationship between development of resistance against potential toxic metals and resistance toward antimicrobial agents in bacteria.

Inhibition of Bacterial Biofilm Formation by Phytotherapeutics with Focus on Overcoming Antimicrobial Resistance

2020 ◽  
Vol 26 (24) ◽  
pp. 2807-2816 ◽  
Author(s):  
Yun Su Jang ◽  
Tímea Mosolygó
Keyword(s):  
Antimicrobial Resistance ◽  
Biofilm Formation ◽  
Antimicrobial Agents ◽  
Bacterial Biofilm ◽  
Experimental Investigations ◽  
Resistant Bacteria ◽  
Salmonella Spp ◽  
Food Borne ◽  
High Prevalence ◽  
Scientific Attention

: Bacteria within biofilms are more resistant to antibiotics and chemical agents than planktonic bacteria in suspension. Treatment of biofilm-associated infections inevitably involves high dosages and prolonged courses of antimicrobial agents; therefore, there is a potential risk of the development of antimicrobial resistance (AMR). Due to the high prevalence of AMR and its association with biofilm formation, investigation of more effective anti-biofilm agents is required. : From ancient times, herbs and spices have been used to preserve foods, and their antimicrobial, anti-biofilm and anti-quorum sensing properties are well known. Moreover, phytochemicals exert their anti-biofilm properties at sub-inhibitory concentrations without providing the opportunity for the emergence of resistant bacteria or harming the host microbiota. : With increasing scientific attention to natural phytotherapeutic agents, numerous experimental investigations have been conducted in recent years. The present paper aims to review the articles published in the last decade in order to summarize a) our current understanding of AMR in correlation with biofilm formation and b) the evidence of phytotherapeutic agents against bacterial biofilms and their mechanisms of action. The main focus has been put on herbal anti-biofilm compounds tested to date in association with Staphylococcus aureus, Pseudomonas aeruginosa and food-borne pathogens (Salmonella spp., Campylobacter spp., Listeria monocytogenes and Escherichia coli).

Development of Peptides that Inhibit Aminoglycoside-Modifying Enzymes and β-Lactamases for Control of Resistant Bacteria

2020 ◽  
Vol 21 (10) ◽  
pp. 1011-1026
Author(s):  
Bruna O. Costa ◽  
Marlon H. Cardoso ◽  
Octávio L. Franco
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Specific Chemical ◽  
Target Interaction ◽  
Multiresistant Bacteria ◽  
Acute Bacterial Infections

: Aminoglycosides and β-lactams are the most commonly used antimicrobial agents in clinical practice. This occurs because they are capable of acting in the treatment of acute bacterial infections. However, the effectiveness of antibiotics has been constantly threatened due to bacterial pathogens producing resistance enzymes. Among them, the aminoglycoside-modifying enzymes (AMEs) and β-lactamase enzymes are the most frequently reported resistance mechanisms. AMEs can inactivate aminoglycosides by adding specific chemical molecules in the compound, whereas β-lactamases hydrolyze the β-lactams ring, preventing drug-target interaction. Thus, these enzymes provide a scenario of multidrug-resistance and a significant threat to public health at a global level. In response to this challenge, in recent decades, several studies have focused on the development of inhibitors that can restore aminoglycosides and β-lactams activity. In this context, peptides appear as a promising approach in the field of inhibitors for future antibacterial therapies, as multiresistant bacteria may be susceptible to these molecules. Therefore, this review focused on the most recent findings related to peptide-based inhibitors that act on AMEs and β-lactamases, and how these molecules could be used for future treatment strategies.

scholarly journals Silver (I) N-Heterocyclic Carbene Complexes: A Winning and Broad Spectrum of Antimicrobial Properties

2021 ◽  
Vol 22 (5) ◽  
pp. 2497
Author(s):  
Filippo Prencipe ◽  
Anna Zanfardino ◽  
Michela Di Napoli ◽  
Filomena Rossi ◽  
Stefano D’Errico ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Antimicrobial Properties ◽  
Resistance Mechanisms ◽  
Heterocyclic Carbenes ◽  
Significant Activity ◽  
Bacterial Strains ◽  
Development Of Resistance ◽  
Starting Point ◽  
Catalytic Chemistry

The evolution of antibacterial resistance has arisen as the main downside in fighting bacterial infections pushing researchers to develop novel, more potent and multimodal alternative drugs.Silver and its complexes have long been used as antimicrobial agents in medicine due to the lack of silver resistance and the effectiveness at low concentration as well as to their low toxicities compared to the most commonly used antibiotics. N-Heterocyclic Carbenes (NHCs) have been extensively employed to coordinate transition metals mainly for catalytic chemistry. However, more recently, NHC ligands have been applied as carrier molecules for metals in anticancer applications. In the present study we selected from literature two NHC-carbene based on acridinescaffoldand detailed nonclassicalpyrazole derived mono NHC-Ag neutral and bis NHC-Ag cationic complexes. Their inhibitor effect on bacterial strains Gram-negative and positivewas evaluated. Imidazolium NHC silver complex containing the acridine chromophore showed effectiveness at extremely low MIC values. Although pyrazole NHC silver complexes are less active than the acridine NHC-silver, they represent the first example of this class of compounds with antimicrobial properties. Moreover all complexesare not toxic and they show not significant activity againstmammalian cells (Hek lines) after 4 and 24 h. Based on our experimental evidence, we are confident that this promising class of complexes could represent a valuable starting point for developing candidates for the treatment of bacterial infections, delivering great effectiveness and avoiding the development of resistance mechanisms.

scholarly journals The Lactococcal dgkB (yecE) and dxsA Genes for Lipid Metabolism Are Involved in the Resistance to Cell Envelope-Acting Antimicrobials

2021 ◽  
Vol 22 (3) ◽  
pp. 1014
Author(s):  
Aleksandra Tymoszewska ◽  
Tamara Aleksandrzak-Piekarczyk
Keyword(s):  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Cytoplasmic Membrane ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Membrane Targeting ◽  
Nucleotide Polymorphisms ◽  
Next Generation ◽  
Lipid Ii

The emergence of antibiotic-resistant bacteria led to an urgent need for next-generation antimicrobial agents with novel mechanisms of action. The use of positively charged antimicrobial peptides that target cytoplasmic membrane is an especially promising strategy since essential functions and the conserved structure of the membrane hinder the development of bacterial resistance. Aureocin A53- and enterocin L50-like bacteriocins are highly cationic, membrane-targeting antimicrobial peptides that have potential as next-generation antibiotics. However, the mechanisms of resistance to these bacteriocins and cross-resistance against antibiotics must be examined before application to ensure their safe use. Here, in the model bacterium Lactococcus lactis, we studied the development of resistance to selected aureocin A53- and enterocin L50-like bacteriocins and its correlation with antibiotics. First, to generate spontaneous resistant mutants, L.lactis was exposed to bacteriocin BHT-B. Sequencing of their genomes revealed single nucleotide polymorphisms (SNPs) in the dgkB (yecE) and dxsA genes encoding diacylglycerol kinase and 1-deoxy-D-xylulose 5-phosphate synthase, respectively. Then, selected mutants underwent susceptibility tests with a wide array of bacteriocins and antibiotics. The highest alterations in the sensitivity of studied mutants were seen in the presence of cytoplasmic membrane targeting bacteriocins (K411, Ent7, EntL50, WelM, SalC, nisin) and antibiotics (daptomycin and gramicidin) as well as lipid II cycle-blocking bacteriocins (nisin and Lcn972) and antibiotics (bacitracin). Interestingly, decreased via the SNPs accumulation sensitivity to membrane-active bacteriocins and antibiotics resulted in the concurrently increased vulnerability to bacitracin, carbenicillin, or chlortetracycline. It is suspected that SNPs may result in alterations to the efficiency of the nascent enzymes rather than a total loss of their function as neither deletion nor overexpression of dxsA restored the phenotype observed in spontaneous mutants.

scholarly journals Resistance and Adaptation of Bacteria to Non-Antibiotic Antibacterial Agents: Physical Stressors, Nanoparticles, and Bacteriophages

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 435
Author(s):  
Sada Raza ◽  
Kinga Matuła ◽  
Sylwia Karoń ◽  
Jan Paczesny
Keyword(s):  
Antimicrobial Resistance ◽  
Antibacterial Agents ◽  
Uv Light ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Physical Factors ◽  
Defense Systems ◽  
Drug Resistant Bacteria

Antimicrobial resistance is a significant threat to human health worldwide, forcing scientists to explore non-traditional antibacterial agents to support rapid interventions and combat the emergence and spread of drug resistant bacteria. Many new antibiotic-free approaches are being developed while the old ones are being revised, resulting in creating unique solutions that arise at the interface of physics, nanotechnology, and microbiology. Specifically, physical factors (e.g., pressure, temperature, UV light) are increasingly used for industrial sterilization. Nanoparticles (unmodified or in combination with toxic compounds) are also applied to circumvent in vivo drug resistance mechanisms in bacteria. Recently, bacteriophage-based treatments are also gaining momentum due to their high bactericidal activity and specificity. Although the number of novel approaches for tackling the antimicrobial resistance crisis is snowballing, it is still unclear if any proposed solutions would provide a long-term remedy. This review aims to provide a detailed overview of how bacteria acquire resistance against these non-antibiotic factors. We also discuss innate bacterial defense systems and how bacteriophages have evolved to tackle them.

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