Antimicrobial Resistance in Bacteria Chapter Abstracts
Introduction
Carlos Amábile-Cuevas
Abstract
No Abstract is available, however we pesent the first paragraph of the introduction: Antibiotic resistance is now definitely in the realm of public health issues all people know and discuss. While preparing this volume, an article in the Los Angeles Times, devoted to the threat posed by methicillin-resistant Staphylococcus aureus, not only made it to the main section of the newspaper's website, but also was the top e-mailed story for two or three days. However, the reasons behind this bacterial trend to gain more and more resistance traits, is not that clear. Physicians are starting to realize, some decades late, that antibiotics are not drugs that can be dispensed without risks; governments are starting to realize, also decades late, that antibiotics added to the food of farm animals pose a terrible risk of selecting resistant bacteria that can go along the food chain, and/or transfer their resistance genes to clinically-relevant organisms that can cause infections. Despite the fact that clinical antibiotic usage is diminishing (although wide-spectrum drugs are now used more) and that the agricultural use is being banned at more countries, resistance continues to evolve and to cause the clinical failure of antimicrobial treatments. We haven't got the entire picture of bacterial resistance.
Chapter 1: New Antibiotics and the Threat of Antibiotic Resistant Bacteria
Anibal Sosa
Abstract
Since its discovery, antibiotics are essential drugs to treat bacteria-producing infectious diseases. Many of the available antibiotics are no longer effective because of emerging resistance, which is mainly caused by inappropriate antibiotic use by prescribers, self-prescription by consumers, counterfeit sale and dispensing by unsanctioned dealers, etc. In addition, lack of standard treatment guidelines, training for prescribers, and pressure from the pharmaceutical industry are important determinants influencing resistance acquisition. Resistant clones are widely disseminated and continue to increase around the world. In last few years, the pharmaceutical industry has either slow down or completely stopped the research for new antibiotics. More profitable incentives exist when developing new drugs for chronic diseases or lifestyle conditions. Policy makers and clinicians need to convene and examine the root causes of resistance and devise new strategies that guarantee not only the development of new molecules but also the preservation of existing ones.
Chapter 2: The Prevalence of Plasmids and Other Mobile Genetic Elements in Clinically Important Drug-Resistant Bacteria
Elizabeth M. Moritz and Paul J. Hergenrother
Abstract
The "golden age" of antibiotics is over. Infectious bacteria now exist that are resistant to all clinically used antibiotics, severely complicating treatment strategies. Although some of this resistance is due to chromosomal mutation, large portions of bacteria become drug-resistant through the acquisition of a foreign piece of DNA that harbors the genes encoding resistance-mediating proteins. Such lateral DNA transfer allows for the rapid dissemination of antibiotic resistance genes throughout bacterial populations. The major classes of antibiotics used in the clinic target a handful of operations within the bacterial cell: protein synthesis, cell wall biosynthesis, or DNA gyrase. As resistance is observed to all of these classes of antibiotics, new macromolecular targets for antibacterial therapy are desperately needed. One intriguing new approach involves the explicit targeting of drug-resistant bacteria through exploitation of the DNA that has been laterally transferred and is so critical to the bacterial resistance. For example, the genes for resistance-mediating proteins are often transferred from one bacterium to another on plasmids, small circular pieces of DNA. If one had a compound that could induce plasmid elimination, the resulting bacteria would be once again be sensitive to antibiotics. Many of these large plasmids have intricate systems for maintaining themselves in their host, often involving the use of a toxin-antitoxin (TA) protein system. This TA system might also be an attractive target for antibacterial therapy. However, before such plasmid-targeting strategies can be used in the clinic, the prevalence and identity of plasmids in the most infectious bacteria must first be defined. This chapter summarizes the data on plasmid-mediated resistance in some of the most untreatable bacterial infections: β-lactam resistant Enterobacteriaceae, quinolone resistant Enterobacteriaceae, vancomycin-resistant enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA), and macrolide and tetracycline resistant Streptococcus pneumoniae. The prospect for treating these and other similar bacteria through plasmid targeting strategies is discussed in the final section.
Chapter 3: Regulation of Efflux pumps in Enterobacteriaceae: Genetic and Chemical Effectors
Anne Davin-Regli and Jean-Marie Pagès
Abstract
In Enterobacteriaceae, the expel of antibiotics (quinolones, tetracyclines and phenicols) and redox-cycling compounds is currently associated to the overproduction of a major efflux pump belonging to the AcrAB-TolC family. This pump contributes to a Multi-Drug Resistance (MDR) phenotype often associated to the modification of the outer membrane permeability. The expression of efflux components is controlled by several positive regulators, e.g. MarA, SoxS or Rob, that activate transcription, directly or from a regulation cascade of specific genes. These activators could be expressed in response to bacterial exposure to salicylic acid, antibiotics, antiseptics, oxidative stress agents, bile salts or phenolic compounds. In addition, Enterobacter aerogenes, Klebsiella pneumoniae and Salmonella Typhimurium, exhibit a disctinct regulator termed RamA, belonging to the same AraC-XylS transcriptional activator family; RamA enhances the transcription of the marRAB operon and is also a self-governing activator of the MDR cascade. The presence of this additional regulator generate an advantage in the level and the induction rate of the MDR phenotype in these bacteria. The redundancy and overlap, the respective interactions and the cross-activations generated by activators coupled to the induction fromexternal stimuli, clearly participate in the emergence and dissemination of MDR strains.
Chapter 4: Biofilms, Multi-Resistance and Persistence
Peter Gilbert, Andrew McBain and Sharon Lindsay
Abstract
Microbial biofilm has become inexorably linked with man's failure to control them by treatment regimes that are effective against suspended bacteria. This failure has been related to a localised concentration of bacteria and their extracellular products (exopolymers and extracellular enzymes), that moderates the access of treatment agents and starves the more deeply placed cells. Biofilms, therefore present gradients of physiology, and of concentration for the imposed treatment agent, where small sub-populations sometimes survive inimical treatments, and death is generally delayed for the least susceptible cells. Such cells must either possess innate insensitivity to a wide variety of treatment agents or they must adopt resistant phenotypes during the sub-lethal phases of treatment. Sub-lethal exposure to chemical antimicrobial agents has been shown to induce expression of multi-drug efflux pumps and to favour efflux mutants within populations. Since not all antimicrobial agents are substrates for energetic efflux, then this cannot provide a singular explanation of biofilm-resistance. Indeed, it is the diversity of action mechanisms within those agents towards which biofilms are resistant that makes singular explanations of resistance phenomena difficult. Recently, a number of concepts have been introduced that impinge greatly upon this area of research. The first recognises that it is generally only a small subset of cells that survive inimical treatments and that these survivors, termed "persisters", may regenerate the biofilm community after antimicrobial stress (Lewis, 2000; 2001; Spoering and Lewis, 2001). The second recognises that materials lost from damaged cells may act as signals, alarmones that induce a less susceptible phenotype in the vicinity of the stress damage. The global operation of such mechanisms would be of particular interest within biofilm communities and could further contribute to our understanding of the breadth of unrelated antimicrobials to which biofilms demonstrate their extreme recalcitrance (Gilbert et al., 2002). These and the more classical explanations of the resistance of microbial biofilms will be presented and discussed in the light of up-to-date literature.
Chapter 5: A Latin American "Point de Vue" on the Epidemiology, Control and Treatment Options of Infections Caused by Extended-Spectrum Beta-Lactamase Producers
Jos Maria Casellas and Mirta G. Quinteros
Abstract
Soon after the introduction of the third generation cefalosporins (3GC) in the 1980s, plasmidic beta-lactamases derived from the so-called broad spectrum beta-lactamases (BSBLs, which are able to hydrolyze 1st and some 2nd generation cephalosporins, amino-, ureido- and carboxy-penicillins) such as TEM-1, SHV-1 and others, appeared and were shown to be capable to hydrolyze monobactams, beta-lactam/beta-lactamase inhibitor combinations and in some instances 4th generation cephalosporins (4GC) as well. These new enzymes were denominated extended-spectrum beta lactamases (ESBLs) and they are derived from BSBLs. Three ESBLs families are predominant: TEM-derived (Europe and US); SHV-derived (worldwide) and CTX-M which were first detected in Argentina and later on in East Europe and are nowadays globally extended. While TEM-derived ESBLs hydrolyze preferentially ceftazidime, SHV-type hydrolyze both ceftazidime and cefotaxime; CTX-M preferentially hydrolyze cefotaxime and 4GC. ESBLs are frequently present in megaplasmids and carry several genes determining resistance to other antibiotics. Difficulties in screening for ESBLs lasted a decade and were due to the fact that NCCLS was reluctant to recommend phenotypic methods including cefotaxime, and also considered that investigation of ESBLs should only be performed in Escherichia coli and Klebsiella spp. isolates. Latin America is presently the region showing the higher incidence of ESBLs. Low-income level and other social issues, crowed hospitals, prolonged hospital stay, as well as the increasing use of invasive devices are factors increasing the risk for ESLB-producer infections. Previous use of 3GC, 4GC, fluoroquinolones and aminoglycosides are also important factors. Perhaps even high inocula in infections such as abscesses, could also be responsible for the selection of ESBL-producing organisms causing difficulties in clinical treatments. ESBL-producers are only uniformely susceptible, in human infections, to carbapenems and tigecycline.
Chapter 6: Monitoring Antimicrobial Resistance
Thomas F. O'Brien and John M. Stelling
Abstract
After an antimicrobial agent is widely used genes expressing resistance to it eventually emerge somewhere in the world's bacterial populations. They spread on genetic elements and in bacterial strains, preferentially through hosts treated with such agents, to strains causing infections that the agent then fails to cure. To block spread of resistance genes, by avoiding selection for it and interposing barriers to it, we need to know where they are. The local, national and global distribution of resistance genes is reflected in the routine tests of tens of thousands of microbiology laboratories, but few put their results into a database for clinical laboratory surveillance or send strains for reference laboratory surveillance. Available software analyzes resistance databases to guide empirical therapy, infection control, antimicrobial policy and guidelines, and to issue sentinel alerts, discern resistance processes and build laboratory capacity. Each database can be analyzed for local management of resistance, and all can be linked into a network for national management, as recommended by W.H.O. Implementation of such surveillance has progressed slowly, but faster where public health agencies with responsibility for but little direct contact with resistance problems have collaborated with caregivers, who have abundant contact but lack responsibility for networking.
Chapter 7: Predicting the Evolution and Emergence of New Antibiotic-Resistance Genes: An Important Element in Developing Antibiotics and Antibiotic Therapeutic Policy
Barry G. Hall
Abstract
The antibiotic resistance field has focused almost exclusively on describing the problem, but has devoted little attention to predicting the emergence, evolution and spread of antibiotic resistance genes. The lack of predictive power means that public health policies concerning antibiotic use are largely based on assumptions. Those policies not only affect patient care, they affect the willingness of pharmaceutical companies to invest in antibiotic development. This article describes an experimental system, the Barlow-Hall method, for predicting how known drug resistance genes will evolve expanded substrate ranges and/or increased activity toward current substrates in response to selection imposed by clinical use of those antibiotic substrates. The results show that the method accurately mimics natural evolution, that in at least one case it has correctly predicted the appearance of a new resistance allele, and that it is able to predict when a particular resistance gene does not have the potential to increase its activity toward a specific substrate. The article also describes a system, the GeneHunter method, for identifying and characterizing previously unknown cryptic (silent) genes within microbial geneomes on the basis of their ability to confer resistance to novel drugs.
Chapter 8: Ecology and Economics of Cycling Antibiotics: Insights from Mathematical Modeling
Ramanan Laxminarayan and David L. Smith
Abstract
In recent years, there has been much discussion of cycling between two or more antibiotics as an approach to minimize drug resistance in nosocomial infections. We evaluate a strategy of periodically rotating between two or more antibiotics and characterize the economic and biological criteria under which a cycling strategy may be superior to simultaneous use of two or more antibiotics. The paper also describes a simple method to determine the optimal rotation time to switch from between one antibiotic to another.
Chapter 9: The Social Context of Drug Discovery and Safety Testing
Jack A. Heinemann and Joanna Goven
Abstract
The productive life of antibiotics is determined not just by the biology of the host and pathogen, but by the social context in which drugs are discovered, tested and used. We extrapolate from previous work on how the social shaping of the development and use of antibiotics has influenced the evolution of bacteria, to discuss the tradeoffs in human and environmental health that come from the (social and political) decision to commercialize drug discovery and development. We examine how the structure and context of the pharmaceutical/biotechnology industries may slow long-term efforts to produce a safe, reliable and secure drug supply if they are not properly balanced by a strong independent research community. An expectation that research and development for the public good will generally also be commercially viable may significantly reduce options and may from time-to-time compromise safety. An alternative model to supplement the commercial model for drug discovery and delivery is presented.
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