The Antibiotic Epidemic Antibiotic Resistance

Antibiotic Resistance: Surviving An Uncertain Future

Antibiotic use can damage and weaken a healthy immune system and our reliance on them has been a double-edged sword. In fact, there are many, many powerful plant-based antimicrobials, scientifically tested, that can step up to the plate and help us face the growing threat of resistant bacteria. And you'll find them in this new eBook: The Antibiotic Epidemic: How to Fight Superbugs and Emerging Bacteria with Miracles from Mother Earth. This Ebook Shows You The Many Powerful Plant-based Antimicrobials And Provides Recipes To Help Diminish The Need For Antibiotics. ebooThis can be your guide during the coming antibiotic apocalypse.

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Overview global scope and cost of antibiotic resistance

Before discussing the social determinants of antibiotic resistance, we must place the problem into a context that considers its global scale, clinical importance, and economic impact. Gram-negative bacteria containing extended spectrum beta-lactamases (ESBLs), that hydrolyze third-generation cephalosporins and most other beta-lactam antibiotics, have a global presence. In 2003, the Study for Monitoring Antimicrobial Resistance Trends (SMART) collected intra-abdominal wound culture isolates from 74 medical centers, located in 23 different countries comprising five geographic regions. ESBLs were most prevalent within nosocomial Enterobacter isolates from the Asia Pacific region (Figure 9.3 Paterson Significant global rates of resistance and clinical and economic impact also have been demonstrated among Gram-positive bacteria. SENTRY reported susceptibility results for over 4900 enterococcal clinical isolates collected between 1997 and 1999, documenting a 17 percent US rate of vancomycin...

Isolation And Characterization Of Specific Organisms

Genetic markers that are incorporated into isolated organisms before soil reinoculation include antibiotic resistance, the lux operon for light emission, and genes that code for specific enzyme activities. Resistance to most currently used antibiotics is usually carried on a plasmid (see Chap. 5). The use of an appropriate vector makes it possible to transfer a plasmid containing an antibiotic resistance gene to soil isolates. These isolates can then be reintroduced into soil and recovered by placing soil dilutions on the appropriate medium containing that antibiotic. Only organisms carrying the antibiotic resistance gene(s) will be capable of growth.

Cloning and Recombinant DNA

Recall that bacteria possess a single circular chromosome. In addition, they, as well as some eukaryotes (e.g., yeast) and some plants, can also contain an additional piece of circular double-stranded DNA called a plasmid. In bacteria, the plasmid often contains genes for antibiotic resistance. Bacteria can exchange plasmids, and plasmids can exist outside the cell. Their possession of antibiotic genes makes it easy to select for bacteria that have been transfected by recombinant plasmid DNA. Whichever vector is used, it is transfected into an appropriate host cell using chemical and or physical techniques. It is somewhat of a random process only a fraction of the cells in a culture will be transfected successfully. Antibiotic resistance or other marker genes are included in the transfection to help select the desired cells. These are then cultured for further application.

Phylogeny And Function

This concept, with methodological and conceptual implications for our understanding of the development of distinct phylogenetic groups, evolution, and diversity. Prokaryotes can transfer genes by lateral (or horizontal) gene transfer (see Cell Structure), which bypasses standard evolutionary processes (mutation and selection), which can have an enormous influence on microbial community structure and activity. The most obvious example of this is the spread of plasmid-borne antibiotic resistance under selective pressure. Lateral gene transfer is not uncommon, particularly in highly active regions of the soil such as the rhizosphere. Nevertheless, all members of a particular (cultured) taxonomic unit (e.g., species) have many phe-notypic characteristics in common and this can help in relating their presence to their ecosystem function.

Transgenes and Microorganisms

The potential also exists for transfer of transgenes from crops to microorganisms and among microorganisms themselves. Oilseed rape (Brassica napus) carrying an antibiotic resistance gene was found to transfer the gene to Aspergillus niger, a soil fungus (Hoffman et al. 1994). Recent studies of bacterial genomes have shown that many bacterial genes are subject to horizontal gene transfer, that is, exchange between different bacterial species (Smalla and Sobecky 2002). Genetically engineered bacteria introduced into soil microcosms have been shown to transfer engineered genes to other soil bacteria (Doyle et al. 1995). RNA transgenes for plant resistance to specific viruses can also be incorporated into the genome of certain viruses by recombination (Greene and Allison 1994 Tepfer 2002).

Ronald Jay Lubelchek and Robert A Weinstein

The mid-twentieth century discovery and subsequent mass-production of antimicrobial agents ushered in a period during which previously deadly infectious diseases, such as Streptococcus pneumoniae meningitis and Staphylococcus aureus endocarditis, could at last be cured. Optimism abounded during the early days of the antibiotic era. By 1967, the US Surgeon General reportedly stated that we could close the book on infectious diseases (Fauci, 2001). Yet even as these apocryphal words were spoken, bacteria - driven by the selection pressure of antimicrobial exposure and enabled by an astounding degree of genetic mutability - had begun to develop antibiotic resistance, thus undermining the era's magic bullets. Today, despite our extensive armamentarium of antimicrobial agents, infectious diseases represent the second leading cause of death and a primary cause of disability worldwide (Fauci, 2001). Between 1980 and 1992, deaths attributed to infectious diseases increased by 58 percent....

Antibiotic use and resistance confirming the connection

Data linking VRE rates - nearly 29 percent in the CDC's latest National Nosocomial Infection Surveillance (NNIS) system - to antibiotic use paint a more nuanced picture than that described above for antibiotic resistance in Gram-negative bacteria (NNIS System, 2004). Results of studies linking antibiotic use with resistant pathogens, such as VRE, depend on factors such as when the study was conducted within the timeline of the pathogen's local emergence, whether the study is prospective or retrospective, patient-level or population-level, and whether it focuses on infection or colonization. Clearly, there has been a temporal relation between vancomycin use, which has increased as much as 20-fold in response to rising MRSA rates, and the emergence of VRE (Ena et al, 1993). For example, as part of the Intensive Care Antimicrobial Resistance Epidemiology (ICARE) project, researchers charted rates of VRE and antibiotic consumption for 120 US ICUs from 1996 to 1999. In their multivariate...

Agricultural antibiotic use and abuse

The agricultural use of antibiotics contributes significantly - perhaps more than use of antibiotics to treat human disease - to selection pressures driving the emergence of antibiotic resistance. As farming has become more commercial, with larger numbers of animals being housed in fewer, more densely populated farms, the role of agri-antibiotics has grown. Farmers and veterinarians use antibiotics for three primary reasons to treat sick animals, to halt the dissemination of infection, and to promote growth. While antibiotics are used at pharmacologic doses to treat or prevent infection in livestock, the common growth promotion-oriented practice uses sub-therapeutic doses, such as less than 200 grams per tonne of

Aging and nosocomial infections

LTCF residents acquire 2-4 million HAIs annually (Garibaldi, 1999), representing a rate of 4-8 infections per 1000 patient days (Capitano and Nicolau, 2003). The transfer into LTCFs of patients colonized or infected by resistant organisms during stays in acute-care hospitals, and selection pressure created by frequent LTCF use of antibiotics, lead to high rates of antimicrobial resistance. One survey of residents from 25 LTCFs found that 38 percent were receiving antibiotics bacterial isolates from those residents were resistant to the prescribed antibiotic in 65 percent of cases (Capitano and Nicolau, 2003). The combination of at-risk, elderly residents and frequent antibiotic use led a prominent antibiotic resistance researcher to label LTCFs as antibiotic-resistance factories (Levy and Marshall, 2004).

Antibiotic stewardship

Formulary restrictions have been used successfully to reduce rates of antibiotic resistance. Spurred on by a desire to reduce hospital antimicrobial expenditures, as well as a need to halt a resistant Acinetobacter bloodstream infection outbreak, Ben Taub County Hospital in Houston initiated a formulary restriction program in 1994. They required infectious disease approval before prescribing amikacin, ceftazidime, ciprofloxacin, fluconazole, ofloxacin, ticarcillin clavulanate, or piper-icillin tazobactam. By encouraging selection of less expensive antibiotics, without reducing overall quantity of antibiotic prescribing, the restriction led to a 430,000 (32 percent) decrease in expenditures for parenteral antimicrobial agents during a six-month period. The restrictions also led to increased rates of antimicrobial susceptibility - for example, rates of susceptibility for E. colito ticarcillin clavulanate increased from 77 to 97 percent for ICU patients. Although some have raised...

Improvements in infection control

In an attempt to reduce rates of antibiotic resistance and nosocomial infections, multifaceted interventions also have been directed at bolstering infection control practices. In 1996, officials from the Siouxland region of Iowa, Nebraska, and South Dakota noted increased rates of VRE. A taskforce requested CDC assistance to institute comprehensive surveillance and isolation precautions. Under CDC guidance, they enacted active screening, via perianal swabs, for VRE at the majority of the 32 Siouxland acute and long-term care facilities. By 1999, 92 percent of the facilities actively screened for VRE and 88 percent of the facilities had implemented strict barrier isolation precautions and environmental disinfection policies for VRE-infected or -colonized patients. The overall prevalence of VRE decreased from 2.2 percent in 1997 to 0.5 percent in 1999 (Ostrowsky et al, 2001).

Role of regulatory oversight

As reports of antibiotic resistance and HAIs have multiplied, the world's healthcare community has mobilized resources to respond to these problems. Large-scale surveillance projects, such as NNIS in the US and EARSS in Europe, have provided vital information about the scope of the problem. These alarming data

Mathematical Model of Gene Transfer in a Biofilm

The same models developed in this paper could also be used to study the important phenomena of horizontal spread of antibiotic resistance in the gut. Rather than assuming the plasmid codes for enhanced biofilm forming ability one would assume that it codes for antibiotic resistance. Selection for the resistant strain could, of course, be arranged by adding antibiotic. Ingestion of bacteria containing plasmid coding for antibiotic resistance could lead to the spread of resistance to the gut microflora. This phenomena may play a significant role in the proliferation of antibiotic resistant pathogens (Summers 1996).

Genetically modified weapons

The application of genomic science to bioterrorism may include the insertion of select genes for heightened infectivity, virulence, enhanced aerosol stability or antibiotic resistance into the agent's genome it may also involve modification of the sequences recognized by detection devices or the host immune response (Petro et al., 2003). One example is the concept of a multi-drug resistant anthrax strain created by the insertion of plasmids carrying multiple antibiotic-resistant genes. There is evidence that the Soviets had some success in developing such variants (Alibek, 1999) the STI-1 strain was engineered with plasmid-based resistance to penicillin, rifampicine, tetracycline, chloramphenicol, macrolides, and lincomycin (Stepanov et al., 1996). This strain was purportedly developed as a live bacterial vaccine for prophylaxis and treatment purposes in a bioterrorism setting, thus illustrating a dramatic example of dual-use technology.

Resistance Mechanisms

Besides the production of defensive compounds and enzymes that can be used against competitors, many microorganisms have developed a variety of protective mechanisms against the toxins from other organisms the cell membrane, drug exporters, restriction enzymes, or rapid mutational adaptation. The cell membrane of microorganisms together with extracellular enzymes provides a first line of protection against penetrating organisms or toxins. Drug exporters pump out poisonous compounds from the cells and thus prevent toxins to exert their destructive potential. Restriction enzymes destroy foreign DNA and thus kill organisms that have entered the cells. The short generation cycle of microorganisms allows them to rapidly adapt their genome to challenges from the environment. For example, antibiotic resistance is often quickly acquired (see Evolution of Defense Strategies).

Reproduction

The extremely high levels of genetic diversity in populations of the outcrossing monkey flower Mimulus guttatus have been attributed to long-term introgression of genes from the selfing congeneric M. nasutus into M. guttatus (Sweigart and Willis, 2003). Another example of this phenomenon has been found in populations of Darwin's ground finches (genus Geospiza), which experience regular bottlenecks often caused by environmental extremes such as drought or excessive rainfall. Despite these bottlenecks, populations show little evidence of depleted genetic diversity, and this seems to be at least attributable partly to ongoing hyridization among all six species (Freeland and Boag, 1999). The generation of genetic diversity following hybridization has been cited as one reason for the rapid evolutionary change that has led to adaptive radiation after species invade new environments, two examples of this being Darwin's finches on the Galapagos archipelago and African cichlid fish in Lake...

Discussion

The effect of quiescent states may be significant with respect to outcomes in specific biological systems. In fact, quiescent phases can have a quite surprising effect on the population as a whole. For example, quiescent states can induce taxis terms in movement equations. The extinction of populations (through washout) in river ecosystems can be prevented when there is a stationary phase weakly coupled to the mobile state. Cancer tumors can resist radiation treatment when cells have refuge in a quiescent state, which needs to be accounted for in radiation treatment planning. A similar effect is known for antibiotic resistance in bacteria. Balaban et al. (2004) have used a model involving a quiescent state (they called it persisters) to fit survival data of E. coli bacteria which were exposed to the antibiotic ampicillin. They show that the existence of a persisting compartment can explain population survival and re-growth after treatment.

Case study

The emergence of vancomycin-resistant S. aureus (VRSA) represents a cautionary tale. Although S. aureus displayed exquisite susceptibility to penicillin in the 1940s, it soon acquired a penicillin-hydrolyzing penicillinase enzyme, rendering it penicillin resistant. Only a year after the introduction of methicillin, a penicillinase-resistant penicillin derivative, nosocomial methicillin-resistant isolates of S. aureus emerged, and in the later 1990s MRSA began its run as a major community threat (Deresinski, 2005 see also Figure 9.1). From vancomycin's introduction in 1956 until 2002 this drug remained the agent of choice, and in some cases sole bactericidal option, for the treatment of invasive MRSA infections. Even as VRSA becomes a reality - five cases have been reported - S. aureus has also evolved resistance to novel agents such as quinupristin dalfopristin, lin-ezolid, and daptomycin (Malbruny et al., 2002 Hayden et al., 2005 Peeters and Sarria, 2005). Other microbes, such as...

Scope and magnitude

The threat that antibiotic resistance poses to human health seems even more dire when considered in the context of nosocomial infections. Ever since the 1840s, when Ignaz Semmelweis first demonstrated that hand hygiene by health-care workers could reduce rates of puerperal fever, there has been an awareness of both the importance of infection control and the impact of lapses in its application. Five percent of hospital patients, and 5-35 percent of patients in intensive care units (ICUs), acquire an infection during their stay (CDC, 1992 Roberts et al, 2003). Due to the selection pressure created by frequent antibiotic use in hospital environments, antibiotic-resistant organisms frequently cause nosocomial infections. From 1988 to 1994, the percent of hospitalized patients who received antibiotics increased from 32 percent to 53 percent (Pestotnik et al., 1996). The most recent NNIS System update reflects the consequences of increased use. NNIS reported antibiotic resistance rates for...

Conclusion

Alexander Fleming, the discoverer of penicillin and a father of modern anti-infective therapy, once said, A good gulp of hot whiskey at bedtime - it's not very scientific, but it helps (Creative Quotations, 2006). As the problem of antibiotic resistance grows, we find ourselves on the brink of a new era, a post-antibiotic era during which a shot of ampicillin may be less helpful than Fleming's suggested shot of whiskey. We have reviewed the global scope, clinical consequences, and economic impact of antibiotic resistance and nosocomial infections. We have also highlighted how human behaviors, such as the misuse of antibiotics for viral disorders and the overuse of antibiotics in agriculture, create selection pressures that contribute to these epidemics. Although new drug discovery, continued vaccine research, and technologic advances in infection control may help to alleviate these problems, ultimately only changes in human behavior, whether mandated by government oversight or driven...

Biofilm Formation

A biofilm offers multifaceted protection against attack First, the structure of the biofilm provides good shelter against toxic compounds because biocides cannot penetrate efficiently into the inside of the biofilm. Thus many cells are not exposed in high enough concentration to toxins that kill them. In addition, some microbial cells deep inside the biofilm differentiate into metabolically dormant states. Due to their downregulated metabolism, toxins that usually act by blocking the cell's metabolism become inefficient. Because of their high stability against drastic conditions, such cells have been named persisters. After the destruction of metabolically active cells in the biofilm, life in the biofilm may be reestablished by the persister cells. Also the diversity of mixed microbial communities helps the individual microorganisms to survive attack because deleterious foreign compounds are more likely to be detoxified by the combined enzymatic arsenal of many microorganisms....