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.

Antibiotic Resistance Surviving An Uncertain Future Summary


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Global Perspectives of Antibiotic Resistance

Abstract The threat of antibiotic resistance is growing at an alarming pace, perhaps more rapidly in developing countries. Aside from the abuse of antibiotics, a number of circumstances converge to this rapid growth and spread, ranging from the biological traits that bacteria deploy to face antibiotics, which we are still trying to understand, to regulatory and financial issues behind antibiotic abuse. And, aside from the more-difficult-to-cure side of resistance, which is bad enough, bacteria are evolving to be more competent to face environmental stress, which includes antibiotics, present and future ones. In developing countries, we face peculiarities that go from antibiotic self-prescription to poor sanitary conditions, even at hospitals, that foster the threat of particular multi-resistant pathogens that are not common in developed countries and against which no new antibiotics are being investigated. In addition to the local repercussions of these peculiarities upon resistance...

Antibiotic Resistance Protects Pathogens

Antibiotic resistance is the capability of a particular pathogen population to grow in the presence of a given antibiotic when the antibiotic is used according to a specific regimen. Such a long, detailed definition is important for several reasons. First, pathogens differ in their susceptibility to antibiotics thus, pathogen species are considered individually. Second, resistance to one antibiotic may not affect susceptibility to another. This means that the antibiotics must also be considered separately. Third, dose is determined as a compromise between effectiveness and toxicity dose can be changed to be more or less effective and more or less dangerous. Consequently, the definition of resistance must consider the treatment regimen. Antibiotic resistance is a natural consequence of evolution. Microbes, as is true for all living organisms, use DNA molecules to store genetic information. (Some viruses use RNA rather than DNA both acronyms are defined in Appendix A, Molecules of Life....

Antibiotic Resistance Is Widespread

The seriousness of antibiotic resistance depends on perspective. For most diseases, we still have at least one effective drug. If we instantly stopped all resistance from increasing, our healthcare system could continue to perform well. But clinical scientists see resistance increasing and call the situation dire. 13 For some pathogens, such as MRSA and Acinetobacter, physicians are forced to turn to antibiotics abandoned decades ago due to their toxic side effects. Our collective task is to develop attitudes and policies that enable all of us to use antibiotics without causing resistance to increase. Data replotted from Johnson, A.P. Antibiotic Resistance Among Clinically Important Gram-Positive Bacteria in the UK. Journal of Hospital Infection (1998) 40 17-26. Data replotted from Johnson, A.P. Antibiotic Resistance Among Clinically Important Gram-Positive Bacteria in the UK. Journal of Hospital Infection (1998) 40 17-26.

Antibiotic Resistance Is Divided into Three Types

Antibiotic resistance is categorized into several types that require different solutions. One is called acquired resistance. As a natural part of life, mutant cells arise either spontaneously (about one in a million cells per generation) or from the transfer of resistance genes from other microbes (see Chapter 6). When a mutant is less susceptible to a particular antibiotic than its parent, mutant growth is favored during treatment. Eventually, the mutant becomes the dominant member of the pathogen population. One way to slow this process is to limit antibiotic use or use doses that block mutant growth.

Aspects of Virulence Antibiotic Resistance

There are numerous miscellaneous reports linking antibiotic resistance with a worse clinical outcome, although it must be borne in mind that increased morbidity and mortality due to infections caused by resistant organisms may only be due to the fact that they are more difficult to manage, and not necessarily because they are more virulent (Dancer 2004). Here are a few examples. Antimicrobial-resistant nontyphoidal salmonella is associated with excess bloodstream infections and hos-pitalizations than patients with pan-susceptible infection (Varma etal. 2005). Another food-poisoning organism, campylobacter, causes prolonged diarrhea if it is resistant to ciprofloxacin (Nelson etal. 2004). Quinolones are commonly prescribed for the treatment of campylobacteriosis in adults and usually reduce the duration of diarrhea associated with campylobacter infection. In a multivariable analysis-of-variance model, however, patients with ciprofloxacin-resistant infection had a longer mean duration...

Antibiotic Resistance Plus Toxin Production Equals Death

Why have we had this sudden increase in cases and in severity of C. diff disease Part of the explanation is that much of this increase is related to one or two strains now spreading worldwide that seem to be better able to disseminate and are more virulent. This seems also to be a disease of antibiotic resistance coupled with the other normal effect of antibiotics - a perturbation in the normal flora of the gut. The Infectious Diseases Society is worried. They have even formed a Task Force to deal with the conundrum of rapidly growing antibiotic resistance and the lack of new products available to treat these infections. We will discuss this in more detail in a later chapter.

Rise in antibiotic resistance

Over the last 20 years, gram-positive cocci have become the commonest pathogens causing hospital infections, mainly due to their capacity to develop antibiotic resistance.2 The most obvious example is methicillin resistant Staphylococcus aureus (MRSA).3 The prevalence of MRSA colonisation and infection are lower in countries with a more restrictive approach to antibiotic use, where infection control measures are rigorously enforced, and where nurse-to-patient ratios are higher. Infection control measures, including the routine use of gloves, gowns, hand antisepsis and the decolonisation of MRSA carriers, have met with varying degrees of success.4 Most strains of MRSA are resistant to the majority of antibiotics, such that glycopeptides antibiotics, for example vancomycin, are the treatment of choice for systemic infection. Recently, there have been treatment failures in Japan and the USA caused by strains that were vancomycin intermediate methicillin-resistant 5. aureus or VISA.5,8...

Emergence Of Antibiotic Resistance During Treatment With Specific Drugs

Antibiotic resistance in P. aeruginosa is an increasing problem, posing many therapeutic challenges. In addition, initially susceptible strains may acquire drug resistance during treatment, often with a relatively high frequency (21-23). This emergence of resistance has been reported with virtually all classes of drugs including beta-lactams, aminoglycosides, and quinolones (24,25).

The impact of antibiotic policies and antibiotic consumption on antibiotic resistance

Controlling antibiotic resistance requires not only improved antibiotic usage but also better compliance with infection control practices in particular, hand disinfection. Emergence of antibiotic resistance in the ICU setting may be due to the development of resistance during therapy, or to the selection and overgrowth of preexisting resistant flora. These processes can be prevented by reducing the use of antibiotics, selecting narrow-spectrum drugs with low ecological impact, or by using bactericidal drugs that discourage mutations. However, the spread of resistant clones of, for example, MRSA, ESBL, or VRE from patients already colonised or infected with these resistant bacteria on admission or acquired within the ICU (Bonten and Mascini, 2003) has to be controlled by hygiene measures such as isolation and improved hand hygiene. Various strategies have been tried to limit antibiotic resistance (Diaz and Rello, 2002). However, some basic requirements must first be met and Adverse...

Antibiotic Resistance

FGAs can be used to detect virtually any gene of interest including those encoding pathogenicity and virulence factors such as antibiotic resistance (Korczak et al., 2005). In contrast with traditional antibiotic resistance assays, which require isolation and growth of the organisms of interest, microarrays have the potential to rapidly screen a sample for the presence of multiple antibiotic resistance genes without the need for culturing. However, direct detection without amplification may be more applicable to antibiotic efflux- or modification-based resistance mechanisms than to mutation-based resistance given the difficulty in differentiating single (or a few) nucleotide differences with the longer probes, which provide better sensitivity. Very short oligo ( 20-mers) are more appropriate for detecting resistance due to mutations but will likely require amplification of these specific genes. Once the antibiotic resistant organisms are isolated, FGAs can be used to genotype the...

Microorganisms and Antibiotic Resistance

A detailed description of the underlying mechanisms of antibiotic resistance is beyond the scope of this chapter. In brief, alterations in the bacterial proteins that bind penicillin can decrease binding affinity and antimicrobial susceptibility to penicillins in S. pneumoniae. Such strains are also more likely to be resistant to other antibiotics, such as macrolides, tetracyclins, and fluoroquinolones. For the treatment of pneumococcal pneumonia, (3-lactam antibiotic concentrations should exceed the MIC for at least 40 of the time.59 When strains with reduced Importantly, prevalence of antibiotic resistance varies geographically. For instance, prevalence of reduced susceptibility to penicillin among S. pneumoniae is around 40 in Spain and 1 in the Netherlands (http Furthermore, over 50 of macrolide resistance in Europe is caused by mutations in the ermB gene,63 whereas presence of an efflux pump is the predominant resistance mechanism of S. pneumoniae to...

Influenza and Antibiotic Resistance

Summary Influenza is a viral disease that displays rapid dissemination of antibiotic resistance. The seasonal form of influenza moves around the world each winter, causing a mild, self-limiting infection for most persons. Vaccines are generally quite effective, but some patients fail to mount an adequate immune response. For such persons, antibiotics specific to flu virus have been developed. The adamantanes block productive infection of cells, whereas the neuraminidase inhibitors interfere with virus release and cell-to-cell spread. Resistance to the adamantanes has been extensive since 2005 resistance became significant for the neuraminidase inhibitors in the 2007-08 season. Pandemic influenza, exemplified by the 1918-19 outbreak and more recently by the 2009 H1N1 swine flu, sweeps around the world in a less predictable manner. Because vaccine can be produced only after human transmission is firmly established and the circulating virus strain is identified, antiviral agents are...

Effect Of Interventions On Antibiotic Resistance

Among the 39 studies reviewed, only 4 studies simultaneously assessed the effect of the interventions on bacterial antimicrobial resistance in the study communities (Belongia et al., 2001 Hennessy et al., 2002 Perz et al., 2002 Seppala et al., 1997). Seppala et al. (1997) examined the effect of a reduction in consumption of macrolides on the rate of isolation of macrolide-resistant Group A streptococci from throat swabs and pus specimens. The reduction in macrolide use in Finland was observed following a published recommendation against use of macrolides as first-line agents for Group A streptococcal infections. For the analysis of the trend in macrolide resistance, they used data from 1992 as the recommendations were issued in late 1991 and early 1992. This data could not be subjected to time-series analysis as there were an insufficient number of pre-intervention data points with which to perform such an analysis. Using logistic regression, it was determined that the odds of an...

Box 113 Detecting Viral Antibiotic Resistance

Detecting antibiotic resistance by virus growth requires more steps than with bacteria. Three methods are commonly used, although none was available in 2009 for routine commercial work with patient samples.230 In one method, human or animal cells, grown in culture, are infected with virus in the presence or absence of antibiotic, and virus number is measured. Often, the drug concentration that reduces virus yield by 50 is determined (IC50). A second method involves the target protein of the neuraminidase inhibitors (neuraminidase). Viral RNA is obtained from a patient sample, converted to a DNA form, and used to express the protein in vitro. The protein is then added to assays for neuraminidase, as are various amounts of the inhibitors. If the inhibitors fail to block neuraminidase activity, the virus is judged resistant.

Genesis of antibiotic resistance on the ICU

Antibiotic resistance occurs as a direct consequence of antibiotic use.1,2 An ICU provides an ideal location for the selection, maintenance and spread of antibiotic resistance in the hospital. An average ICU in a large teaching hospital will use about 10 of the antibiotic budget of the entire hospital, despite comprising only 1 of the total number of beds. This serves to illustrate the extent of antibiotic use and provides a tremendous selection pressure for bacteria to become resistant to multiple antibiotics. The problem of containing this level of resistance is now of major concern. In terms of the patient, the genesis, maintenance and spread of antibiotic resistance is fostered by a number of circumstances particularly common to ICU patients. There has been concern about overprescribing of antibiotics for essentially as long as antibiotics have been on the market, and most doctors now accept that antibiotic resistance is a problem for everyone, and this problem is owned by most...

Surveillance of Antibiotic Resistance in Developing Countries Needs Constraints and Realities

Abstract Surveillance for antimicrobial resistance is important in terms of defining prevention and treatment strategies. While surveillance is routinely and efficiently carried out in developed countries, several major constraints often make it impossible for developing countries to carry out major surveillance programmes in this field. This chapter reviews the problems faced by the developing world in carrying out effective surveillance for antibiotic resistance and briefly describes the available data.

Transfer Of Antibiotic Resistance

Anaerobes acquire and disseminate mobile DNA transfer factors by conjugation, that can harbor antibiotic resistance genes. Opportunities for the rapid disseminate of antibiotic resistance determinants are in the gut flora, as well as in polymicrobial infections. Transfer of resistance genes has been found in the B. fragilis group and in Prevotella, Clostridium, and Fusobacterium spp. (24). Bacterial conjugation, is the most common method of antibiotic resistance genes transmission in anaerobes. The resistance genes are located in DNA transfer factors that can harbor mobile transposons, plasmids and chromosomal elements (144,145). The transfer from one cell to cell of the DNA requires a connector bridge that is encoded by much larger transferable conjugative transposons (144). Two biochemical processes are required for horizontal transmission of the transmissible DNA (145, 146). The conjugative transposons are called Tet elements, because of their ability to harbor a tetracycline...

The widespread and often inappropriate use of antibiotics has consequences for antibiotic resistance

In addition to the examples listed above and elsewhere in this book, Wenzel and Edmond (2000) caution that epidemiologic studies indicate that the incidence of pneumococcal pneumonia went up in young children, over a 15-year period ending in 1998 in West Virginia, from 21 100,000 to 45 100,000. This increase was not restricted to the pediatric population. The geriatric group, aged 70 to 79 years, also saw a more than doubling of incidence, from 15 100,0000 to 39 100,000. Further, human immunodeficiency virus-infected patients with invasive pneumonia had an almost eight-fold higher mortality rate if the Streptococcus pneumoniae was penicillin resistant, reinforcing the deadly interactions between new and old pathogens. Wenzel and Edmond also note that nosocomial infections of the bloodstream have high rates of mortality 21 in coagulase-negative staphylococcal infections, 25 in Staphylococcus aureus infections, and 25 in enterococcal infections. The high incidences of antibiotic...

Antibiotic Resistance And Bacterial Variation

Geriatric medicine has certainly contributed to the growing problem of microbial antibiotic resistance. As a group, elderly patients in hospitals and long-term care facilities (LTCFs) are the major recipients of antibiotics. It has been estimated that among residents of LTCFs approx 40 of prescribed drugs for systemic use are antibiotics (68). A distressing result is the promotion and spread of antibiotic-resistant microorganisms (69). The types and origins of antibiotic-resistant pathogens in LTCFs have been carefully reviewed in a recent publication (70). Information about antibiotic resistance in the population of elderly who reside in LTCFs is probably the most reliable available. As stated in the review article (70), the antibiotic resistant bacteria of greatest concern to geriatricians are 1) p-lactam resistant organisms, especially penicillin-resistant pneumococci and aerobic Gram-negative bacilli resistant to third-generation cephalosporins 2) vanco-mycin-resistant enterococci...

Global Regulators Of Antibiotic Resistance In Escherichia Coli

Undoubtedly, the best-characterized global antibiotic resistance regulatory system is the mar (multiple antibiotic resistance) system in E. coli. An excellent review of the molecular genetics of this system has been published 1 . Much of the detailed work described in that review is only summarized here, and the reader is encouraged to look to that source for additional detailed information. The mar locus was first described in 1983 in the pioneering studies of George and Levy. As a component of an ongoing effort to understand the mechanisms contributing to tetracycline resistance, these investigators identified a locus on the E. coli chromosome that was associated with the frequent emergence of low-level resistant strains 2 . Moreover, it was shown that these tetracycline-resistant (tetr) strains had also acquired a concomitant resistance to other structurally unrelated antibiotics including chloram-phenicol, rifampicin, and fluoroquinolones 2 mechanistically this phenotype was...

Box 81 Surveillance Networks for Antibiotic Resistance

Many of the major surveillance networks were established in the late 1990s,182 a time when resistance became recognized as a widespread problem. However, nosocomial infections had been recognized for decades, as evidenced by establishment of the National Healthcare Safety Network (NHSN) in 1970 for U.S. hospitals.182 By the end of the 1990s, several networks were in place for European hospitals (HELICS, 1994 EARSS, 1998) and U.S. intensive care facilities ((ICARW, 1995). Respiratory infections also received attention in the U.S. (TRUST, 1996) and elsewhere (Alexander Project, 1992 PROTEKT, 1999). Community care centers in Canada and Europe began collating data for resistant urinary infections (ECO-SENS, 1999). As the resistance problem increased in severity, surveillance expanded to cover common pathogens in medical centers and outpatient facilities, initially in 30 countries worldwide (SENTRY, 1997). To study the relationship between antibiotic use and resistance, German intensive...

Disinfectant Usage And Antibiotic Resistance

Following the evidence of a possible linkage between biocide and antibiotic resistance in bacteria, several authors have claimed that the usage of biocides was deemed to cause the emergence of antibiotic resistance. There are a number of cases whereby the use of a biocide was associated with emerging antibiotic resistance in bacteria. The use of silver sulphadiazine for the treatment of burn infection which was somewhat successful (Lowbury et al., 1976) in decreasing patient mortality, was also linked to the emergence of plas-mid- mediated sulphonamide resistance (Bridges and Lowbury, 1977). Newsom et al. (1990) observed that although the use of chlorhexidine scrub-based preoperative showers effectively decreased skin flora, it might also promote the growth of staphylococci post-surgery, and notably those presenting high-resistance to methicillin. However, similar observations were made when antibiotic prophylaxis was used instead of biocide (Archer and Armstrong, 1983). Triclosan has...

What do we mean by resistance

The term antibiotic resistance is used frequently but influences on resistance are rarely considered. The concept that resistance is also dependent on pharmacodynamics and clinical outcome is often ignored. For example a strain of Escherichia coM which produces fi-lactamase (an enzyme related to penicillinase which destroys benzyl penicillin and confers resistance to penicillin) is resistant to ampicillin. This means that although a patient with a chest infection caused by such a strain cannot be treated, such strains can easily be killed by ampicillin concentrations of around 2000 mg 1 in the laboratory which may be clinically achievable in the urinary tract. Susceptibility to an antibiotic varies with bacterial species. Clinical resistance is a complex interaction between the infecting bacteria, the infection site, the distribution and concentration of antibiotic and the immune status of the patient (Box 6.1). The mechanisms encoding antibiotic resistance can be divided into four...

Antibiotic rotation or cycling

It used to be thought that if the selection pressures for antibiotic resistance are lowered the organisms would revert to a sensitive form but we now know that that is clearly optimistic. Rapid removal of selection pressure may result in reversion to sensitivity, but this is likely to take longer than the original process of resistance. Resistant survivors may also undergo mutations over hundreds of generations to favour maintenance of the resistant gene. This seems to have happened for example with MRSA and vancomycin-resistant enterococci (VRE). Mathematical models suggest that compensation is more likely than reversion.5

Containing resistance

Over the past 30 years the literature has been full of anecdotes supporting the concept that cycling through the different classes of antibiotic is able to control antibiotic resistance, although there is no long-term evidence available. We should be cautious of extrapolating from short-term studies, such as the study from Iceland addressing the problem of resistant pneumococci in the community where reduction in antibiotic prescribing lead to decrease in the rate of incidence of resistant pneumococci. It is known that in the community, multiresistant clones can come and go with a natural cycle of an epidemic, even without altered antibiotic prescribing, such that it may just be pure chance that resistance patterns change. Certainly in the community it is much more difficult to influence antibiotic resistance. In a hospital and particularly in the ICU the rapid flux of patients means that resistance clones are diluted. During the 1970s there were major aminoglycoside resistance...


Compliance of healthcare staff with basic infection control protocols such as hand-washing regimens is generally poor, and staff shortages lead to difficulties in compliance with isolation precautions. The successful implementation of guidelines for optimising antibiotic use and slowing the emergence of antibiotic resistance, requires a multidisciplinary approach including managers, clinicians, general and specialist nurses, infectious diseases specialists, infection control teams, microbiologists and pharmacists (see Chapter 7). Despite the fact that infection control guidelines are based more on expert opinion than on the results of randomised controlled trials in many instances, it is clear that effective solutions to antibiotic resistance should be geared to the specific local epidemiological circumstances, and the available facilities and resources.

Setting the scene

Patients on the ICU are at a higher risk of hospital-acquired infection than other hospitalised patients, and are subjected to invasive procedures facilitating the entry of micro-organisms. Outcome is dependent not only on the severity of the underlying condition but also on the vulnerability of the patients to infection. Accordingly the acquisition of antibiotic resistance has marked implications for treatment options in the infected ICU patient. Antibiotic resistance varies in both type and extent between ICUs and the rational choice of antibiotic has to reflect resistance patterns in individual units. Procedures must be in place to assess the prevalence of potentially pathogenic organisms, which should be used to design pathogenic organisms and local treatment strategies,1

Introduction to the Resistance Problem

Summary As a normal part of life, we are all exposed to pathogens, the tiny microbes and viruses that cause infectious disease. Many pathogen varieties exist. Some are even harmless inhabitants of our bodies most of the time. A common feature of pathogens is their microscopic size. Another is the huge numbers their populations can reach during infection, often in the millions and billions. Human bodies have natural defense systems, but those systems sometimes fail to control infection. For such occasions, pharmaceutical companies have developed antibiotics, chemicals that interfere with specific life processes of pathogens. As a natural response, antibiotic resistance emerges in pathogen populations. Resistance is a condition in which the antibiotic fails to harm the pathogen enough to cure disease. Emergence of resistance often begins with a large pathogen population in which a tiny fraction is naturally resistant to the antibiotic, either through spontaneous changes or through the...

Humans Live with Many Pathogens

MRSA is one type of pathogen, the collective word applied to microbes and viruses that cause disease. (The term microbe includes bacteria, some types of fungi, and protozoans.) Each type of microbe has a distinct lifestyle. Bacteria are single-celled organisms that reproduce by binary fission each cell grows and then divides to form two new cells. Bacteria cause many of the diseases that make headlines tuberculosis, flesh-eating disease, and anthrax. Pathogenic fungi include yeasts and molds. Yeasts are single-celled, whereas molds tend to grow as thread-like structures composed of many cells. (Some pathogenic fungi switch between the forms in response to the environment.) Yeasts and molds cause pneumonia, and in immuno-suppressed persons yeasts and molds can cause deadly systemic infections. Pathogenic protozoans, such as the types that cause malaria, are single-celled microbes that are often spread by insect bites. In tropical and subtropical regions, protozoan diseases are among...

The Biological Side of Resistance

In addition to the quinolone story, we have learned during the past 20 years or so about the many ways bacteria can successfully face the threat of antibiotics. Some of these include (a) global responses to environmental stress, which include the mar regulon earlier mentioned, and the somehow related oxidative-stress response system, the soxRS regulon of Escherichia coli and Salmonella enterica (Demple and Amabile-Cuevas 2003), along with several other efflux-mediated resistance mechanisms (Davin-Regli and Pages 2007), but also including the SOS response (Miller et al. 2004), which can, additionally, promote the horizontal dissemination of resistance genes (Beaber et al. 2003) (b) biofilm growth and its conferred resistance, or tolerance, the mechanism of which is still a matter of debate (Gilbert et al. 2007), but that is clearly causing antibiotic treatment failure. Also, biofilms are playgrounds for bacteria in terms of exchanging and concentrating canonical resistance traits...

Antibiotics Block Growth and Kill Pathogens

Antibiotics are drugs, taken orally, intermuscularly, or intravenously, that counter an infection. They include agents such as penicillin, tetracycline, ciprofloxacin, and erythromycin. Common bacterial diseases treated with antibiotics are tuberculosis and gonorrhea. Fungal and protozoan diseases are also treatable, but with agents specific for these organisms. (The biochemistry of fungi and protozoa differs substantially from that of bacterial cells.) Antiviral agents constitute a third set of specialized compounds. In general, little cross-reactivity exists among the categories, that is, agents used for fungi do not cure infections caused by viruses, bacteria, or protozoa. However, the principles underlying action and resistance are the same consequently, in Antibiotic Resistance we lump all these agents together as antibiotics. Combining all the agents into a single category risks confusion, because the public has been told repeatedly not to use antibiotics for viral diseases. In...

Establishing the problem

There is little point in attempting to improve a process of care that is already highly achieved. For example, is trying to improve oxygenation assessment within 24 hr of admission likely to be cost-effective, when it is already performed in 94 of patients Before embarking on QI therefore, it is essential to consider the question What is currently happening and do we need to improve it Surprisingly, this is not always done. In many UK hospitals, the clinical governance agenda is largely being achieved by the local development and implementation of treatment algorithms that have not been informed by pre-implementation audit. Even if a multidisciplinary approach to development is used, which is not always the case, there is a risk that the resulting intervention may focus on areas of ongoing good practice, while neglecting important processes of care that are sub-optimally achieved. The decision about which aspects of process to measure in CAP has been discussed above and is helped by...

Aspects of Virulence Horizontal Transfer of Virulence and Resistance Genes

Bacterial DNA damage occurs when bacteria are subjected to unfavorable environmental conditions. The global response to such damage is called the SOS system, and its function is to upregulate genes involved in DNA repair and cell survival. It is well known that exposure to antibiotics will initiate the SOS response but it has only recently been shown that the response itself is capable of generating the horizontal transfer of mobile genetic elements, such as plasmids, bacteriophages, pathogenicity islands, transposons, and various insertion sequences (Hastings, Rosenberg and Slack 2004). These elements play a crucial role in spreading antibiotic resistance and virulence genes among bacterial populations. Exposure to ciprofloxacin, for example, will induce the SOS response in Vibrio cholerae, which then promotes the horizontal dissemination of antibiotic resistance genes via an integrating conjugative element (ICE) (Beaber, Hochhut and Waldor 2004). This element encodes genes that...

Aspects of Virulence Bacterial Adhesion

Exposure of highly fluoroquinolone-resistant S. aureus to subinhibitory levels of ciprofloxacin significantly increases the expression of fibronectin adhesins. This leads to increased attachment of the bacterial cells to immobilized fibronectin in an in vitro model (Bisognano et al. 1997). Increased adhesion also occurs with other strains of staphylococci, including MRSA and methicillin-susceptible S. aureus. Indeed, staphylococcal expression of surface adhesins is altered following the acquisition of the methicillin resistance element mecA (Vaudaux et al. 1998). It is tempting to hypothesize that this antibiotic-promoted increase in adhesion might contribute towards the emergence of staphylococci expressing increased levels of antibiotic resistance. Certainly, there are a number of clinical and laboratory-based studies that suggest an association between ciprofloxacin consumption and acquisition of MRSA (Weber et al. 2003, Venezia et al. 2001, LeBlanc et al. 2006).

The Development of New Antibiotics Is Slowing

For many years, pharmaceutical companies developed new antibiotics to replace old ones whose effectiveness was seriously reduced by resistance. The new drugs were often more potent versions of earlier compounds. Unfortunately, finding completely new antibiotic classes becomes progressively more difficult as we exhaust the available drug targets in pathogens. Early in the Twenty-First Century, pharmaceutical companies placed considerable hope on genomic technology as a way to find new bacterial drug targets and thereby new antibiotics. In this approach, computer-based analyses examine the information in bacterial DNA and gene expression profiles to identify potential targets for new antibiotics. So far, that approach has not panned out. At the same time, pharmaceutical executives realized that more money could be made from quality-of-life drugs and drugs for managing chronic diseases. For example, heart disease requires life-long therapy to lower cholesterol. In contrast, antibiotics...

Local Surveillance And Future Directions

In conclusion, benchmarking can be a valuable and powerful tool in the fight against antibiotic resistance, but it is only as effective as the data used. Data from large multinational surveillance programs are of great value to understanding patterns of antibacterial resistance, and to date, these data have been under-utilized. The evaluation of MIC distributions using statistical tools that can accommodate quantitative MICs (including the pattern of MIC censoring) will allow for a better understanding of the impact of institution-, patient-, and microorganism-specific factors on changes in MIC, before high-level resistance develops in multiple regions. Future endeavors will require broad-based quality data from surveillance programs that are not dependent solely on funding from the pharmaceutical industry.

How Can We Make the Best Use of Existing Antibiotics and Pesticides

Considering the effectiveness of antibiotics (or pesticides) as a natural resource that is much the same as a stock of fish or a forest can help us explore ways of making better use of this resource. The concept of pest susceptibility to pesticides as a natural resource was first introduced 30 years ago (Carlson and Castle 1972). Since then, there has been sporadic interest in applying the tools of economics to understanding how these agents might be better used given that resistance is a likely consequence of using them (Hueth and Regev 1974 Comins 1977a,b Brown and Layton 1996 Laxminarayan and Brown 2001). Although the literature on pest resistance dates back to the 1970s, interest in antibiotic resistance is more recent. Interest in determining the kinds of strategies that would maximize the value from current antibiotics and pesticides has been accompanied by discussions of how economic incentives could be used to induce individuals who use these products to make better use of...

How Can We Encourage the Development of New Antibiotics and Pesticides

Other policy options that have received attention in the antibiotics context include mechanisms to exchange patent length extensions for use restrictions. The OTA report on antibiotic resistance suggests that an arrangement could be worked out between the Food and Drug Administration (FDA), the Patent Office, and the pharmaceutical firm to increase the patent length while limiting the number of uses for which the antibiotic may be used. However, extensive analyses of off-label drug use have shown that antibiotics are not necessarily prescribed for only the conditions for which they received FDA approval (Christopher 1993). Therefore, such an agreement may not necessarily work without some way of enforcing restrictions on antibiotic use. These problems are likely to arise in the pesticide arena as well.

Directions for Further Research

Another area in which public policy could be illuminated by more economic analysis is what often has been characterized as inappropriate use of antibiotics for farm animal feed. The science of how the use of antibiotics for growth promotion in animals results in resistant infections in humans is still in development, and there is disagreement on the relative importance of this causal factor when compared to inappropriate use of antibiotics in humans. Regardless, the need for public policy is evident. For instance, there has been a great deal of controversy surrounding FDA approval of fluoroquinolones, an antibiotic used in humans that is also approved for use in animals. In recent months, FDA has withdrawn permission for this drug to be marketed for animal use, a move that was opposed by Bayer, one of the two manufacturers of this drug. FDA's case was made on the basis of a risk analysis that showed that fluoroquinolone use in animals posed an increased risk of...

Mixed Species Biofilms

Bacterial biofilm development in co-culture experiments (e.g., Ghigo 2001), and biofilm formation increases the chance for lateral gene transfer and thus the risk for interspecies gene transfer and the consequent spread of virulence factors and antibiotic resistance (e.g., Weigel et al., 2007). In fact, many examples of synergistic induction of biofilm formation were observed when a large collection of nondomesticated E. coli strains were individually cocultivated with a laboratory strain or with each other. This was most often precipitated by conjugal transfer of natural plasmids carried by the isolates.

Antibiotic Resistant Bacterial Pathogens Why IDSA Is Concerned

New treatments, preventions, and diagnostics are clearly needed in all areas of ID medicine. However, IDSA is particularly concerned that the pharmaceutical pipeline for new antibiotics is drying up. ID clinicians are alarmed by the prospect that effective antibiotics may not be available to treat seriously ill patients in the near future. There simply are not enough new drugs in the pharmaceutical pipeline to keep pace with drug-resistant bacterial infections, so-called superbugs. Antibiotics, like other antimicrobial drugs, have saved millions of lives and eased patients' suffering. The withdrawal of companies from antibiotic R and D is a frightening twist to the antibiotic resistance problem and, we believe, one that has not received adequate attention from federal policymakers.

Patients Are Media Scared and Ill Informed

The increasing incidence or prevalence of antibiotic resistance is now an issue of major public concern. Newspaper headlines frequently carry feature stories of the impact on individuals as the doomsday scenario of widespread and untreatable drug-resistant infections in our hospitals. The extent and significance of antibiotic-resistant bacteria is clearly becoming increasingly apparent. Reports of antibiotic resistance and concerns highlighted by ID specialists over the last half century were generally unheeded until partway through the last decade (mid-1990s) when the importance of the issue finally achieved political recognition. In 1995, the American Society for Microbiology and three years later the U.K. Select Committee of the House of Lords published reports that were influential in developing national strategies. Soon after these initiatives the European Union and the WHO presented their approaches to this global problem. The latter currently has a six-part strategy for...

Antibiotics for Animals and Crops Lead to Resistance for People

A more dramatic example comes from an organism called Enterococcus. Starting in 1989, US hospitals have experienced an outbreak of Enterococcus resistant to what was our last line antibiotic at the time, vancomycin (they were frequently already resistant to everything else). About 50 of US hospital strains are now resistant to all but our latest two last line antibiotics, daptomycin and linezolid. During the late 1980s and early 1990s, there was no daptomycin and no linezolid for infected patients. There was nothing that worked. It turns out that the resistance seems to have been derived from animals in Europe where they were fed low concentrations of an antibiotic called avoparcin to promote growth. Avoparcin is closely related to vancomycin and the vancomycin-resistance genes found in enterococci infecting people are essentially identical to those found in animals fed avoparcin. Although this is one dramatic and threatening example of the transmission of antibiotic resistance from...

Timothy D McHugh 1 Introduction

There has been a significant increase in the number of genes associated with antibiotic resistance that have been described. For many antimicrobials all of the principal genes associated with their action have been identified (1). There is increasing interest in the epidemiological distribution of resistance mutations of these genes and research into their origin and routes of transmission. At the more fundamental level, there is interest in the impact of such mutations on the fitness survivability of the pathogen (2). We have described the strategies for selection of mutants in the mycobacteria (3) and also a polymerase chain reaction single-stranded conformational polymorphism (PCR-SSCP) approach to investigation of the distribution of such mutants. In this method PCR amplimers are denatured to form single-stranded nucleic acids and then submitted to gel electrophoresis to identify sequence polymorphisms. Sequencing of clones remains relatively expensive and time consuming for...

Bambos M Charalambous and Ndeky M Oriyo Abstract

To study the dynamics and diversity of pneumococcal carriage and antibiotic resistance, a more thorough and systematic approach has been employed compared with routine surveillance of serotype and antibiotic resistance. Up to ten pneumococcal isolates from pernasal (nose) and oropharyngeal (throat) sites are isolated and characterised. Our carriage studies have revealed a diverse community of pneumococci with multiple strains colonising the nasopharynx of children. In Tanzanian children less than 6 years of age, up to six serotypes and up to six different antibiotic sensitivities (as distinguished by at least a fourfold difference in the minimum inhibitory concentration) have been found. Serotyping by the Quelling reaction is prone to inaccuracy and requires expensive serological reagents. To improve the accuracy and reduce the costs, an alternative capsular typing DNA-based method has been developed. This chapter will describe the methods we have employed with emphasis on the...

Multiple Drug Resistance And Cross Resistance

Genetic analysis of this phenomenon showed that the genes for these antibiotic resistance properties resided on the bacterial genome, yet were transmissible between strains albeit at low frequency. Further study showed that the transfer of these genes was mediated by a conjugal plasmid and that the resistance genes could associate with the conjugal plasmid it was suggested that the resistance gene could be horizontally transmitted to other strains in a fashion similar to that for the integrative recombination for the temperate phage lambda 34 . It soon became clear, however, that the F-episome F-lac system in E. coli was a better analogous genetic system. In some cases, the resistance genes and the transfer genes could be separated both genetically and physically 35 . Because of the promiscuous nature of the RTF, once a gene for drug resistance evolves, it can rapidly spread to other organisms. Additionally, because the R-factor plasmids replicate to high copy number, probably as a...

Contaminated beef recalled from King Soopers

Antibiotic resistance in bacteria is often carried on segments of DNA that can jump from one organism to another. One recent report documented that these DNA segments carrying multiple antibiotic-resistance genes were identical in E. coli from humans and animals and in Salmonella from humans and animals. Our environment in general is becoming polluted with antibiotics. Runoff from farms and from our own sewers (yes, antibiotics are excreted in urine and in feces) exposes more and more of the worlds bacteria to low concentrations of antibiotics. The world, in the words of Julian Davies, one of the original and most important researchers in antibiotic resistance, is a dilute solution of antibiotics. This will continue to select for antibiotic resistance among environmental organisms. A Pseudomonas with a new gene causing resistance to our last line antibiotics for these bacteria and associated with multiple other antibiotic resistance genes was recently fished out of the Seine River in...

Survey of Antibiotics

Each antibiotic has its own features that influence its suitability for a particular pathogen. This chapter introduces the major antibiotic classes. We then use fluoroquinolones to illustrate how antibiotics evolve. We also briefly consider antiseptics and disinfectants, because they help us kill pathogens on surfaces and because their use may contribute to the emergence of antibiotic resistance. If you are unfamiliar with the synthesis of DNA, RNA, and protein, you may find Appendix A, Molecules of Life, and Appendix B, Microbial Life, useful when considering processes blocked by antibiotics.

Activities Collating Antibiotic Use Data

As already mentioned, the formation of comparable, local and national databases of antibiotic-use data are essential to inform those exploring the problem of antibiotic resistance. Use of the ATC DDD system, as the leading consensus method, is essential for benchmarking and evaluating the impact of intervention studies. Numerous projects and surveillance programmes appear to be using the system appropriately, including the following 3. The VIRESIST project aims to study relationships between antibiotic consumption and resistance and to forecast future behaviour. VIRESIST is a Spanish acronym, which stands for Resistance Surveillance using Time Series Analysis Techniques. This is a hospital-level project which models monthly antibiotic consumption data broken down by ward against monthly antibiotic resistance data. Through its participation in this project, Aberdeen Royal Infirmary has shown that its MRSA outbreak is driven by

Monitoring Antibiotic

To investigate the epidemiology of antibiotic use and its relationship with antibiotic resistance, antibiotic use and resistance data must be monitored over time to take account of seasonal variations and to be able to accurately monitor Because patient mix is crucial to antibiotic use, it is best to analyse local antibiotic use by discipline or unit. This is especially true for ICUs (Fridkin et al, 1999 White et al., 2000). The VIRESIST project demonstrates the usefulness of such monitoring schemes (Lopez-Lozano et al., 2000 MacKenzie et al., 2004 Monnet et al., 2001), allowing the statistical analysis of trends in use, the effects of interventions, the study of relationships to antibiotic resistance, and the prediction of antibiotic susceptibilities based on predicted antibiotic use and previous rates of resistance. Comparison of trends within similar units of a hospital and between hospitals is probably useful although there are limited publications on this (see Chapter 8 by H....

Control Group Selection in Studies of Antimicrobial Resistance

Numerous studies have focused on identifying risk factors for antimicrobial resistance. The majority of these studies have been case-control designed studies and how controls are selected in such studies is critical in ensuring the validity of study results. Recent work has highlighted this issue of control group selection specifically for studies of antibiotic resistance (5,17-20).

The Socioeconomic Perspective

Misconceptions about antibiotic use and its ecologic consequences are common among the general public.25 In 2000, the Programme for International Student Assessment (PISA) study, which assessed knowledge and skills attained by 265,000 adolescents in 32 countries, asked whether the use of antibiotics may lead to antibiotic resistance. Only 59 of students answered this question correctly. In 2001, a Eurobarometer survey showed that large variations existed among Europeans as per their knowledge that antibiotics were active against bacteria but not viruses.20 A low level of understanding and knowledge about antibiotics is likely to influence usage of these drugs.

Microorganismmediated Antimicrobial Resistance

Antibiotic resistance that results from altered cellular physiology and structure caused by changes in a microorganism's usual genetic makeup is known as acquired resistance. Unlike intrinsic resistance, acquired resistance may be a trait assodated with only some strains of a particular organism group or spedes, but not others. Therefore, the presence of this type of resistance in any clinical isolate is unpredictable, and this unpredictability is the primary reason why laboratory methods to detect resistance are necessary.

The Association Between Resistance and Mortality

The choice of control group is also relevant in studies of outcomes (36). Since studies addressing outcomes related to infection are primarily cohort studies, controls in these studies are more appropriately referred to as the unexposed or reference group. As in case-control studies of antibiotic resistance, there are effectively two choices for a reference group. In the first, patients with a resistant infection (e.g., FQREC) are compared with patients with the susceptible counterpart (e.g., FQSEC). In the second type of control group, patients with a resistant infection (e.g., FQREC) are compared with patients with no infection. Although either approach is valid, they address slightly different clinical questions. In the first, the result provides an assessment of the added impact of harboring a resistant infection versus a susceptible infection. In the second, the impact of having a resistant infection versus no infection is ascertained. It has been demonstrated that the latter...

Emergence And Dissemination Of Antimicrobial Resistance

Therefore, antibiotic resistance mechanisms always have been part of the evolution of bacteria as a means of survival among antibiotic-producing competitors. However, with the introduction of antibiotics into medical practice, clinically relevant bacteria have had to adopt resistance mechanisms as part of their survival strategy. With our use of antimicrobial agents, a survival of the fittest strategy has been used by bacteria to adapt to the pressures of antimicrobial attack (Figure 11-11).

Integrons and Mobile Gene Cassettes

Integrons are genetic elements that contain the determinants of the components of a site-specific recombination system, which capture and promote expression of mobile gene cassettes. A basic integron consists of an integrase gene (int) of the tyrosine recom-binase family (82) and a proximal recombination site, called the attl site. A gene cassette is a discrete mobile genetic unit that contains one ORF (or more) followed by a recombination site (attC) belonging to a family of sites known as 59-base elements (83). A gene cassette often contains an antibiotic resistance gene and can be integrated into an integron by a site-specific recombination reaction between the attl site and the attC site catalyzed by the integrase. Cassettes have been shown to exist as free cova-lent circular DNA molecules generated by excision through an Intl-mediated reaction from an existing integron with an integrated cassette. The covalent circular DNA cassettes are not able to replicate, but are able to...

Additional Reading

Pharmacol 91 Berlin, 1989, Springer-Verlag. Courvalin P Transfer of antibiotic resistance genes between gram-positive and gram-negative bacteria, Antimicrob Agents Chemother 38 1447,1994. Davies J Inactivation of antibiotics and the dissemination of Neu HC The crisis in antibiotic resistance, Science 257 1064, 1992.

Movement Of Ctns Between Species Of Human Colonic Bacteroides Spp

The patterns of antibiotic resistance genes seen in the clinical and community isolates were indeed similar. A striking difference was apparent, however, when the pre-1970 and post-1990 strains were compared. The older strains had a much lower rate of carriage of tetQ and the erm genes than the strains isolated after 1990. So, something had happened in the two-decade period that separated the two sets of strains, a period characterized by extensive use of antibiotics, such as tetracycline and the macrolides 30 . It is also surprising how high the carriage rate was in the isolates obtained prior to 1970, before the onset of intensive use of antibiotics in the treatment of human disease. This type of anomaly has been seen in other cases, such as detection of antibiotic-resistant bacteria in pristine environments 31,32 . This raises the question of whether antibiotics are the only force selecting for antibiotic-resistant bacteria, a still-unanswered question to which we will return at...

The Triclosan Quandry

Whatever the impact of triclosan use on antibiotic resistance patterns, the sudden popularity of antibacterial products is a cautionary tale. Public health officials were unprepared for the sudden advent of such products, and it remains unclear what the appropriate response to such changes in public consumption patterns is and how best the implications of such usage changes can be evaluated for safety.

The Ecology Of The Future

Although the ecology of antibiotic resistance genes is still a relatively new area, some problems and challenges are evident. First, very few systematic studies of the distribution and movement of resistance genes in nature have been done. Comparisons of the incidence of resistant strains in farms that do or do not use antibiotics are misleading if variables such as the proximity of water supplies that might be contaminated with antibiotics or the movement of wild birds and rodents between the farms are not taken into account. The finding of significant concentrations of antibiotics in some water sources has demonstrated what should have been obvious all along antibiotics do not necessarily stay in the location where they are used. Antibiotics used in the hospital or in agriculture can appear later in water released from sewage treatment plants 46,47 . Or water recovered from animal manure and used to irrigate vegetable crops can spread antibiotics to locations where antibiotics are...

Innate and Induced Resistance Mechanisms of Bacterial Biofilms

Abstract Bacterial biofilms are highly recalcitrant to antibiotic treatment, which holds serious consequences for therapy of infections that involve biofilms. The genetic mechanisms of this biofilm antibiotic resistance appear to fall into two general classes innate resistance factors and induced resistance factors. Innate mechanisms are activated as part of the biofilm developmental pathway, the factors being integral parts of biofilm structure and physiology. Innate pathways include decreased diffusion of antibiotics through the biofilm matrix, decreased oxygen and nutrient availability accompanied by altered metabolic activity, formation of persisters, and other specific molecules not fitting into the above groups. Induced resistance factors include those resulting from induction by the antimicrobial agent itself. Biofilm antibiotic resistance is likely manifested as an intricate mixture of innate and induced mechanisms. Many researchers are currently trying to overcome this...

Resistance Summing Up

Antibiotic resistance is a societal problem. It derives from the way we use antibiotics, the way we dispose of our garbage and our sewage and our hygienic practices at home, at work, in schools, in long term care facilities and in hospitals. Resistance costs us lives of loved ones, lost productivity and real dollars in terms of the increased care required for these patients. We can only truly address the problem as a society. Even if we improve our approach to antibiotic use and improve our hygienic practices, it is unlikely that we will be able to solve the problem of the continued selection of antibiotic resistance. We just do not have enough information to know how to halt this natural progression entirely. Therefore, as it stands today, antibiotic resistance also requires that we constantly have new, effective antibiotics coming on line in the marketplace so we can treat patients with resistant bacterial infections. No one ever wants to be in the place of Drs. Elemam, Rahimian,...

Innate Mechanisms Why Wait

Research has identified the influence of several different innate biofilm factors affecting antibiotic resistance (Costerton et al. 1999 Donlan and Costerton 2002 Dunne 2002 Mah and O'Toole 2001 Patel 2005 Stewart and Costerton 2001). First, the biofilm matrix may act as a diffusion barrier, preventing antibiotics from reaching their targets. Second, establishment of microenvironments within biofilms, such as reduced oxygen zones, leads to slow growth of the bacteria. Third, a small subpopulation of bacteria within the biofilm seems to differentiate into per-sisters, with greatly reduced susceptibility to antibiotics. Finally, several resistance genes have been identified that are specifically regulated within biofilms. Studies have only recently begun to elucidate the genetic regulation of these innate biofilm antibiotic resistance mechanisms. These molecular details are vital to our understanding of the ability of biofilms to thwart treatment.

Limited Growth Potential

While disagreement remains about the efficacy of the biofilm matrix as a diffusion barrier to antibiotics, altered microenvironments within the biofilm clearly play a role in antibiotic protection. Oxygen limitation in particular has been extensively investigated, and numerous studies have revealed the presence of hypoxic zones deep within biofilms. A recent microarray study of E. coli biofilms found an upregulation of the cydAB and b2997-hybABC gene clusters, which are known to be transcribed in oxygen-limiting conditions (Schembri et al. 2003). Similarly, nutrient diffusion through biofilms is restricted. Oxygen and nutrient deprivation consequently result in a decrease in bacterial metabolic activity and cessation of bacterial growth (Donlan and Costerton 2002 Dunne 2002). Indeed, experimental measurements have revealed a severe reduction in bacterial growth rates within biofilms compared to planktonic cultures (Anderl et al. 2003 Borriello et al. 2004). Even in planktonic cultures...

Lessons Learned and the Future

However, appropriate antibiotic advice alone is insufficient. Some balance between the gain of covering treatment and antibiotic costs must be achieved. The major cost to consider is the impact of the antibiotic choice on future antibiotic resistance. However, this component is largely missing in existing systems. No model currently exists to quantify the ecological impact of antibiotic treatment. Such a model should include the differential effect of the different antibiotics on the individual, on the environment, on resistance to the same antibiotic, and on resistance to other classes of antibiotics. It should be sensitive to temporal and local changes in resistance, since the ability of an antibiotic to induce resistance probably reaches a plateau at some resistance level. Only three decision support systems included an explicit representation of ecological costs in this balance. Two systems broadly Comprehensive computerized antibiotic decision support should be used to fight...

Aac2ia In Providencia Stuartii

Namely, the role of ubiquinone and or electron transport, are understood in less detail. The simplest model, proposed earlier, is that aac(2')-Ia expression is also coupled to electron transport via regulatory protein(s) that sense the redox status of the cell. The AarG AarR two-component system may have a role in this process. At the present time, interplay among the aar genes, electron transport, and quorum sensing in controlling aac(2)-Ia expression is being investigated. The mechanisms identified may serve as a model for the regulation of other chromosomally encoded acetyl-transferases. In addition, the identification of physiological roles for the other intrinsic acetyltransferases will allow us to better predict how the modification of intrinsic genes can lead to antibiotic resistance.

Emergence of Resistance

Summary Resistance is a natural response of pathogen populations to antibiotic treatment. Changes in pathogen DNA can affect genes involved in drug uptake, drug efflux, drug inactivation, and drug-target interactions. Some changes occur spontaneously others are induced as a response to the stress of antibiotic treatment. Still others involve the movement of whole resistance genes from one microbe to another. The enormous size of pathogen populations makes even rare events noticeable when antibiotic pressure is applied. Although many mutations are probably harmful to the organism, those that confer antibiotic resistance can be the difference between life and death for the pathogen. Consequently, they are tolerated. Subsequent mutations may then improve the fitness of mutant pathogens. The relationship between antibiotic concentration and emergence of resistance is described by the mutant selection window hypothesis. The hypothesis maintains that resistant mutant subpopulations...

Spontaneous Mutations Are Nucleotide Sequence Changes

Mutation frequencies may seem to be small numbers, but they are large enough for some bacterial infections to contain resistant mutants prior to therapy. During pneumonia or tuberculosis, a patient may contain more than one hundred million pathogen cells. For the antituberculosis drug called isoniazid, the mutation frequency is about one in one million. Consequently, a patient with tuberculosis could contain 100 resistant mutants before therapy begins (108 divided by 106 102 10 x 10 100). Such calculations cause many health professionals to accept antibiotic resistance as being inevitable.

Multidrug Efflux Pumps Structure Mechanism and Inhibition

The world of antibiotic drug discovery and development is driven by the necessity to overcome antibiotic resistance in common Gram-positive and Gram-negative pathogens. However, the lack of Gram-negative activity among both recently approved antibiotics and compounds in the developmental pipeline is a general trend. It is despite the fact that the plethora of covered drug targets is well conserved in both Gram-positive and Gram-negative bacteria. Multidrug resistance (MDR) efflux pumps play a prominent and proven role in Gram-negative intrinsic resistance. Moreover, these pumps also play a significant role in acquired clinical resistance. Together, these considerations make efflux pumps attractive targets for inhibition in that the resultant efflux pump inhibitor (EPI) antibiotic combination drug should exhibit increased potency, enhanced spectrum of activity, and reduced propensity for acquired resistance. To date, at least one class of broad-spectrum EPI has been extensively...

The Dynamic Analysis of Rowthorn and Brown

As a newcomer to the area of antibiotic resistance, I do not know what progress has been made since 1927 in numerically implementing the discrete-time counterpart to the Kermack-McKendrick model. But I can well imagine that some distinguished economists are very knowledgeable about the empirical implementation of this model (at least for some infections and some sets of antibiotics), just as others are well informed about dynamic optimization. One problem is getting practitioners from different disciplines to communicate effectively. I would think an accessible, user-friendly simulation model that could be manipulated online or in an electronic worksheet would facilitate such communication. One constrained optimization package (Solver) is standard equipment in most Microsoft Excel versions1 and greatly enhanced versions can seamlessly replace the standard package within Excel at reasonable prices (http ). Rowthorn and Brown emphasized that the dynamic problem they...

The Prospects for Microbial Genomics Providing Novel Exploitable Antibacterial Targets

Introduction - Antibiotics have been a major triumph in applied medical science since their introduction in the last century. The rapid improvement of patients afflicted with heretofore deadly infections led to these compounds being termed miracle drugs . Unfortunately, it has become increasingly clear that bacterial resistance to these compounds is rising at a rate that threatens to undermine their future utility (1,2). In this sense, antimicrobials stand in a somewhat unique position among drug classes. Compounds that affect human physiology, such as lipid-lowering agents, ACE inhibitors, and anti-inflammatory agents, do not engender resistance to their pharmacological targets in the human population. However, in the case of infectious agents we are dealing with rapidly evolving populations of organisms placed under selective pressure by antibiotics (3). Exacerbating the situation is the fact that many of the existing antimicrobial classes are derived from natural products, and...

Multidrug Resistance and Multidrug Tolerance Two Mechanistically Distinct Menaces

Numerous mechanisms of drug resistance have been described, and in most cases we have a fairly good understanding of these processes at the molecular level. The main types of resistance are target modification by mutation target modification by specialized enzymatic changes target substitution, such as expressing an alternative target antibiotic modification antibiotic efflux and restricted antibiotic permeation (Lewis et al. 2002 Levy and Marshall 2004). It is interesting to note that all theoretically logical possibilities of antibiotic resistance seem to have been realized in nature. Importantly, all of these mechanisms do essentially the same thing prevent the antibiotic from binding to the target (Fig. 3) . Each of these resistance mechanisms allows cells to grow at an elevated level of antibiotic. It is important to note that bactericidal antibiotics kill the cell not by merely inhibiting Fig. 3 Antibiotic resistance vs tolerance. Resistance mechanisms prevent an antibiotic from...

Bacteriological Uses Of Tetracyclines

The use of tetracyclines in medicine is limited to those that have been isolated by fermentation broths or by chemical modification through semisynthesis to produce chemically stable and effective compounds. Two clinically used tetracyclines are presented below, along with their primary and secondary usages against bacterial pathogens (34). Natural products Oxytetracycline tetracycline 3, and demeclocycline 4, are used to a lesser extent, while the semisynthetic tetracyclines, minocycline 17 and doxycycline 18, are some of the most widely used antibiotics in medicine, animal health and agriculture, although antibiotic resistance has curtailed the use of these agents.

[4 Identification of Essential Genes in Bacteria

The arrival of antibiotic-resistance strains of pathogenic bacteria has forced a major push for the development of novel drugs to combat these resistant strains. Identification of essential genes in any bacterial species is an important step for the identification of targets for new generations of

Which Interventions to Choose

Harris recently published a useful paradigm for determining which infection control interventions should be used for MDR-GNB (58). He asserts that we need organism-specific data on the proportion of antibiotic resistance that is attributable to antibiotic-selective pressure versus patient-to-patient transmission. These data would help to decide whether to focus effort and resources primarily on antimicrobial management strategies or on interventions designed to interrupt transmission (58). Knowledge about the undetected ratio (undetected by clinical cultures alone) could be used to predict the efficacy of ASC, and data on the duration of colonization would help to predict the efficacy of isolation precautions. Currently there are insufficient data to make these decisions or to evaluate the cost-effectiveness of various strategies. Almost all reports of successful control of MDROs use

Recombination Involves Breaking and Rejoining of DNA Molecules

Homologous recombination enables sections of DNA from the environment to be incorporated into microbial chromosomes if the resident and incoming DNA share regions of nucleotide sequence similarity. Homologous recombination also permits mutations, such as those responsible for antibiotic resistance, to move from the chromosome to a plasmid and vice versa, providing that the two DNA molecules contain similar sequences for strand invasion and complementary base pairing.

Plasmids Are Molecular Parasites

Plasmids are autonomous DNA molecules that are molecular parasites. They are the major DNA vehicles that move antibiotic resistance genes among bacteria. Each plasmid contains its own origin of replication and a gene encoding a specific replicator protein. These two elements give plasmids control over their own DNA replication, over their own lives. Plasmids can be small (on the order of 3,000 base pairs) or large (chromosome-size or about 3,000,000 base pairs). Many are circular, but linear forms are found. Some plasmids are present at only one or a few copies per cell, whereas others maintain hundreds of copies. The low-copy-number plasmids have special mechanisms for assuring that after cell division each daughter cell receives a plasmid copy. One mechanism, based on addiction modules, is briefly discussed in Box 6-1. Many plasmids contain a variety of antibiotic-resistance genes, which enables them to

Mechanisms Of Resistance To Specific Drugs

To multiple antimicrobial drug classes is multifactorial. Most small hydrophilic molecules, including antibiotics, enter the cell via nonspecific porin channels present in the outer membrane. The outer membrane permeability of P. aeruginosa has been shown to be 10- to 100-fold less efficient than, e.g., in Escherichia coli (28). This high intrinsic antibiotic resistance that typifies P. aeruginosa is recognized to be the result of synergy between this highly impermeable outer membrane and the expression of broad-spectrum multidrug efflux systems (Table 2). These efflux systems serve the physiological function of preventing toxic compounds from entering the cell in significant concentrations. They actively remove biocides, dyes, detergents, organic solvents, and metabolites as well as antibiotics from the cytoplasm or periplasmic space (29). The most important and well-studied family of these is the resistance-nodulation-cell division (RND)-type family of pumps. There are, in addition,...

Antimicrobial Resistance in Enteric Pathogens in Developing Countries

Abstract Bacterial enteric infections exact a heavy toll on human populations, particularly among children and immunosuppressed individuals in developing countries, where malnutrition, HIV AIDS and poor sanitation abound. Despite the explosion of knowledge on the pathogenesis of enteric diseases during the past two decades, the number of diarrhoeal episodes and human deaths reported especially among the poor populations in developing countries remain of apocalyptic dimensions. With several studies from developing countries showing worrying trends in multiple resistance among key enteric pathogens such as Escherichia coli, Klebsiella, Salmonella spp., Vibrio cholerae and Shigella spp. to nearly all commonly available antibiotics, it is imperative that this trend should be reversed. Many countries in the developing world lack a formal surveillance system for antibiotic resistance and often treatment is given empirically based on clinical diagnosis alone. Availability of antibiotics over...

Some Plasmids Move by Conjugation

Some bacterial plasmids encode a mating apparatus that enables them to move from one cell to another. The process, called conjugation, is the principal way in which antibiotic resistance genes and virulence factors move among bacteria. During conjugation a male plasmid-containing cell binds to a plasmid-free female cell. Plasmid DNA in the male is copied, and a copy of the male DNA is transferred to the female cell. Conjugation can be observed in a simple way. If a male cell is resistant to one antibiotic and a female cell is resistant to another, conjugation can be detected by placing a drop of male culture and a drop of female culture together on an agar plate containing both drugs. The two Mutations in genes that confer antibiotic resistance can move from one bacterial cell to another by conjugation if the genes are part of a conjugative plasmid. When conjugation is followed by recombination, the resistance mutations can move to the bacterial chromosome of the recipient cell....

IT and benchmarking to improve antibiotic prescribing

Interventions aimed at controlling the use of antibiotics require education and access to local data on antibiotic resistance and consumption. Therefore, a national ICU-surveillance programme, ICU-STRAMA was developed in Sweden in 1999, with the aim of aiding clinicians by providing feedback on local antibiotic consumption data and bacterial resistance patterns (ICU-STRAMA, 1999-2000). Local multidisciplinary ICU groups consisting of specialists in intensive care, infectious diseases, and infection control, as well as pharmacists, microbiologists, and others have formulated local policies using the information in the database which is easily accessible through a website. Person-to-person interactions are likely to be too time-consuming and unsustainable in the long term. By using the Internet, it will be possible to create a sustainable programme for the coordinated collection of information about antibiotic policy, antibiotic use, antibiotic resistance, infection control, and...

Multiple Mutations And Multidrug Resistance

One of the most striking characteristics of P. aeruginosa is its extraordinary ability for acquisition of antibiotic resistance determinants (31). No mutation has the capacity to single-handedly compromise every antipseudomonal antibiotic. However, comprehensive resistance to therapeutically useful agents is possible as a result of the convergence of multiple factors. Efflux-based resistance may have an additive or even multiplicative effects with decreased permeability, beta-lactamase expression, or target-mediated resistance so as to enhance drug resistance (54). The accumulation of sequential mutations is more common in hypermutator strains. These strains either lack the ability to perform DNA proofreading or mismatch repair, or use DNA polymerases with a reduced copying fidelity (55). The genetic backgrounds of these strains are primed for selecting some antibiotic-resistance mutations since mutation frequencies up to 1000-fold higher than in normal strains have been reported...

Outbreaks of Multidrug Resistant Shigellosis in Africa and Other Developing Countries

In another study on surveillance on antibiotic susceptibility in Shigella spp. (Kariuki et al. 1996) found all isolates multiply resistant to nearly all commonly available antibiotics including ampicillin, co-trimoxazole, co-amoxyclav, cefur-oxime, chloramphenicol and tetracycline however, no resistance to ciproflox-acin and minimal resistance to nalidixic acid were reported. Other studies also found little resistance to nalidixic acid and no resistance to ciprofloxacin among Shigella spp. in other parts of East Africa (Brooks et al. 2003). However, in areas where nalidixic acid has been introduced as the drug of choice to treat presumptive shigellosis, a marked increase in corresponding resistance has been observed (Mutwewingabo and Mets 1987). The ease with which antibiotics can be obtained without prescription may add further to selective pressure. Thus, although nalidixic acid is an attractive choice for treating bloody diarrhoea where antibiotic resistance limits other options,...

The Cost Of Antimicrobial Resistance

Infections with resistant pathogens lengthen the stay in hospital, likely to be one of the most significant contributors towards the economic consequences of resistant bacteria (Brooklyn Antibiotic Resistance Task Force, 2002 Kollef and Fraser, 2001 Nathwani, 2003). Managerial costs are increased when infection involves these organisms, as well as unnecessary and prolonged therapy (Niederman, 2001a). Treatment of resistant bacteria is associated with increased drug costs, as the newer, broad spectrum and often far more potent drugs are usually far more expensive than the narrower spectrum agents employed for less-resistant pathogens (Janknegt, 1997). These powerful drugs bring their own particular adverse effects, including the problems generated by overgrowth or superinfection of naturally resistant organisms (Drew et al., 2000 Khare and Keady, 2003 Sanyal and Mokaddas, 1999). Other factors to consider are the prohibitive costs required to develop new antimicrobial agents, and the...

Transposition Moves Genes from One DNA to Another

Transposons are mobile DNA elements that reside in DNA molecules. They have discrete ends that help define and identify each element, and they usually carry one or more gene that helps them move to other DNA molecules. (To move from one DNA to another, the donor and recipient DNA must break and rejoin specific proteins are involved in this process.) When transposons contain an antibiotic resistance gene, they can be easily followed because they cause bacterial cells to be drug resistant. Transposons enable resistance genes to hop from chromosome to plasmid and vice versa. When transposons hop into each other, they can create multidrug-resistant mobile DNA elements.

Antibiotic Susceptibility Pattern of the Organisms

The rapid latex agglutination test for mecA, encoding methicillin resistance, can only be used once S. aureus has been cultured. Many other molecular tests for antibiotic resistance genes, such as PCR and FISH, also rely on the cultured organism. However, to provide sensitivity results within the goal of 1-2 hours, direct analysis of clinical samples is imperative. The large number of resistance genes potentially involved limits the application of some techniques, for example realtime PCR can only detect a certain number of fluorophores simultaneously. Theoretically, DNA microarrays, genome-scanning approaches, rapid sequencing methods, and whole-genome amplification techniques could detect the required number of resistance genes. These have limitations, such as the detection of single nucleotide polymorphisms (SNPs) by some microarrays, but the biggest hurdles are the cost and technology, which are prohibitive to most diagnostic laboratories. We welcome initiatives to translate the...

What Is A Betalactamase

Beta-lactamases are enzymes produced by the great majority of clinically important bacteria. In addition to their relatively well-known job of destroying antibiotics like penicillins, cephalosporins, and carbapenems, they probably also serve other cellular maintenance roles involving the bacterial cell wall. It is hypothesized that beta-lactamases are distant relatives of bacterial cell wall synthesis and cross-linking enzymes called penicillin-binding proteins, which are the actual targets of beta-lactam antibiotics that we use commonly in the clinical setting (1). In terms of antibiotic resistance, the production of beta-lactamases is most important in Gramnegative bacteria like Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aerugi-nosa. However, some Gram-positive bacteria also produce beta-lactamases e.g., penicillin resistance in Staphylococcus aureus is partly mediated by an enzyme called PC1, which the bacterium secretes into the surrounding environment.

[5 Isolation of Transposon Insertions

Most transposons have low target-site specificity, allowing insertions in many sites throughout the bacterial genome. Antibiotic-resistant transposons are particularly useful genetic tools because the antibiotic resistance provides a selectable marker within the transposon. This chapter will focus on antibiotic-resistant transposons transposons derived from Tn10. A few of the applications of antibiotic resistant transposon insertions are summarized in Chapter 2. pools can then be used to transfer the transposon insertions into a new strain background by selection for the transposon-associated antibiotic resistance, in this case tetracycline resistance. Assuming a random distribution of insertion of the transposon throughout the genome, roughly 1 in 2000 of the mutants will have an insertion in any given nonessential gene. The desired mutants can thus be obtained by selection for a particular pheno-type, or by screening through several thousand independent tetracycline-resistant...

Class A Beta Lactamases

Figure 1 shows how the ESBL mutations open the active site, leading to greater rates of cephalosporin hydrolysis, causing antibiotic resistance. An interesting property, or phenotype, of these ESBLs was noted despite their ability to hydrolyze our most potent antibiotics of the time, they were inhibited even more effectively than their progenitors by drugs like clavulanic acid and tazobactam. These inhibitor drugs had been developed specifically to target the wild-type TEM and SHV Class A type enzymes, and were designed to be given together with extended spectrum penicillins like amoxicillin, ampicillin, and piperacillin. This inhibitor-sensitive phenotype is being used in the clinical microbiology laboratory to detect ESBL production in Enterobacteraciae reviewed in (12) .

The FDA Makes It Difficult for Them to Obtain Good Advice

Europe has been much more forward thinking than the US regarding the dilemma now facing antibiotics and the pharmaceutical industry. With the caveat that thinking is one thing and acting is another, we should explore what Europe has been doing, as it could be a model for all of us. Sweden, which assumed the rotating European Presidency during 2009, has been particularly active in this regard and just held a large meeting on this subject in September where the Obama administration was represented. Three documents have been published and are available on the web for those that are truly interested Policies and incentives for promoting innovation in antibiotic research, commissioned by the Swedish Government and written by Professor Elias Mossialos and his co-workers at the London School of Economics and Political Science on behalf of the European Observatory for Health Systems and Policies and The bacterial challenge Time to react. A call to narrow the gap between multidrug-resistant...

Bacterial Resistant Infections in Resource Limited Countries

Abstract Considering that antibiotics play a crucial role in reducing morbidity and mortality due to bacterial infections, antibiotic resistance is a major problem in resource-limited countries (RLCs) where there is a high burden of infectious diseases, resistance rates are even higher than in industrialized countries, and therapeutical options are often unavailable or too expensive. Multidrug-resistant organisms - e.g. Streptococcus pneumoniae, Salmonella Typhi, Shigella spp., Neisseria gonorrhoeae, Mycobacterium tuberculosis - have been increasingly documented. Many factors contributing to antibiotic resistance in RLCs are strongly related to poverty lack of knowledge or information of health-care professionals, lack of laboratory facilities, inadequate access to health system, lack of money available to pay for the appropriate amount of antibiotics, dispensation of drugs by untrained people, availability of substandard and counterfeit drugs, etc. Moreover, in RLCs, transmission of...

Local Knowledge of the Epidemiology of Resistance

More detailed epidemiological information to discriminate between resistant isolates may be gleaned from methods such as restriction fragment length polymorphism (RFLP), pulsed field gel electrophoresis (PFGE), rapid amplified polymorphic DNA (RAPD), microarrays, and multi-locus sequence typing (MLST). Only by detailed analysis of antibiotic resistance genes and their context, and by investigating how they spread both within and between species, can we begin to understand the complex, dynamic nature of the population of resistance genes and try to tackle the problem of antibiotic resistance (Bergeron and Ouellette 1998). Microarrays consist of thousands of nucleic acid targets immobilized on a solid substrate such as a glass slide or silicon wafer. Fluorescently labeled probes made from nucleic acids in a test sample are hybridized to these targets, allowing analysis of relative concentrations of DNA or mRNA in a sample. Microarrays have many applications in infectious diseases...

Identification of Virulence Factors

While this is not directly related to reducing antibiotic resistance, timely identification of virulence factors or certain serotypes would direct patient management and the use of isolation facilities. Examples include molecular tests to differentiate serotypes such as E. coli 0157, toxin producing strains such as Panton-Valentine leucocidin-positive S. aureus, and ribotypes such as C. difficile 027.

Optimization of Local Prescribing Behavior

Once the clinical diagnosis of infection is made or suspected, or the need for antibiotic prophylaxis for surgery identified, the hospital prescriber must select which antibiotic(s) to prescribe. There is an overwhelming plethora of guidelines and policies on prescribing antibiotics available in hospitals. However, their actual implementation at the bedside requires new approaches, which deal with both the starting, and the stopping, of antibiotics. These initiatives must consider the working environment, local logistics, the cultural context of prescribing, interprofessional and cross specialty working, clinical roles and accountability, the level of organizational understanding, senior management support, and the clinical role models and leadership. A systems-based approach is required to ensure a hospital can deliver and monitor a program of antibiotic stewardship, beyond having a highly efficient microbiology laboratory that delivers a first class modern service. This...

Transmission of Resistant Disease

Summary Transmission of antibiotic resistance occurs through the spread of resistant pathogens from one person to another. Disseminated resistance is easily seen as disease outbreaks that are unresponsive to particular antibiotics. Resistant pathogens are typically as effective at causing disease as susceptible ones consequently, transmission of resistance is similar to transmission of disease. Controlling outbreaks of infection relies on local surveillance and interventions such as patient isolation, identification of effective antibiotics, and in some cases, vector control. For most diseases, hand hygiene is crucial. Some pathogens are spread by air (tubercle bacillus, influenza virus) some by contact (S. aureus) some by food and water (Salmonella, Vibrio cholerae) some by exchange of body fluids (some hepatitis viruses) and some by insects (malaria parasite, yellow fever virus). Tuberculosis is an example of a treatable airborne infection that has been exhibiting outbreaks of...

Spread of Pathogens Is Highly Evolved

As long as a resistant infection is limited to its initial patient, disease can be controlled by isolating the patient. But when isolation is not achieved and the pathogen spreads, resistance also spreads. Resulting infections generally fail to respond to the antibiotic, and an outbreak of drug-resistant disease can occur. Indeed, outbreaks are what usually come to mind when we hear the term antibiotic resistance in reference to situations in hospitals.

Role of Surveillance Through Commensal Bacteria

There is increasing agreement about the importance of extending the surveillance of resistance to the commensal bacteria of humans and animals. Commensal bacteria, although not being a specific target, are continuously exposed to the selective pressure generated by antibiotic chemotherapy and may become a potential reservoir of resistant strains that can cause infections, and of resistant determinants that can be transferred to pathogenic bacteria (Levy et al. 1988 Leverstein-van Hall et al. 2002 Alliance for the Prudent Use of Antibiotics-APUA). Therefore, some members of the commensal microbiota, such as the faecal E. coli, are considered as sensitive indicator bacteria for surveillance of antibiotic resistance, to measure the selective pressure generated by antibiotic usage, to evaluate the impact of modifications in antibiotic prescription policies and to predict the emergence of resistance in pathogens (Lester et al. 1990 Calva et al. 1996 Bartoloni et al. 1998, 2006a, 2008a...

Box 71 Hospital Antibiotic Control Programs

In the remainder of the chapter, we describe examples of pathogen transmission and the response of infection control specialists. A broader view of the effort to control antibiotic resistance is presented in the next chapter. There we discuss surveillance that may span years and methods for determining resistance. The broader view reveals patterns of increasing prevalence of resistance, erosion of antibiotic effectiveness, and the need for policy changes and new antibiotics.

Resistance Should Create Opportunities

You would think that the emergence of antibiotic resistance would make it obvious to physicians that new antibiotics were needed, and that this need would result in brisk sales for any antibiotic that worked against resistant strains. Well its not so simple. The graph below (Fig. 6.2) illustrates the tremendous boost that the epidemic of MRSA provided the market for vancomycin. It also shows the beginning of vancomycin-resistance.

Box 79 Antibiotic Resistant Malaria

Another arthropod that spreads disease is the human body louse. This insect transmits typhus, which is caused by an obligate bacterial pathogen of the group called rickettsia.173 The rickettsial species that causes typhus invades epithelial cells of the louse digestive tract, reaching human skin via louse feces. Infection of humans then occurs through openings in the skin caused by louse bites. In humans, typhus causes severe headaches, high fever, rashes, and often death. (60 fatality if untreated). The lice, which are obligate parasites of man, are rarely found on persons in industrialized countries. (The last typhus outbreak in the United States occurred in 1922, before antibiotics were available.) However, crowded living conditions associated with war and famine still lead to outbreaks of typhus in Africa. (In 1997, an outbreak involving 100,000 persons occurred during a civil war in Burundi.) Rickettsia are readily controlled by tetracyclines. Although antibiotic resistance is...