Multi Drug- Resistant Organisms (MDRO’s) in the ICU A Guide for RT’s

Multi Drug- Resistant Organisms (MDRO’s) in the ICU A Guide for RT’s
Terrence Shenfield BS, RRT- RPFT, NPS, AE-C Education Coordinator A & T Respiratory Lectures

Objectives Describe what is a MDRO’s
Review the history of antibiotics ( abuse/misuse) How do organisms become resistant What is the difference between gram negative and gram positive organisms Why is it important to control these organisms Strategies on prevention

What is a MDROs? Multidrug-Resistant Organisms (MDROs) are defined as microorganisms that are resistant to one or more classes of antimicrobial agents Three most common MDROs are: 1. Methicillin-Resistant Staph aureus (MRSA) 2.Vancomycin Resistant Enterococci: (VRE) 3.Extended Spectrum Beta - Lactamase producing Enterobacteria. (ESBLs)

History of Bacteria Been around for billions of years and actually predates mankind Fossil evidence dates back over 3.5 billion years Bacteria reproduce by binary fission One bacteria can reproduce up to one billion clones in ten hours Mutation is a natural process Bacteria grow in a wide variety of habitats and conditions. When most people think of bacteria, they think of disease-causing organisms, like the Streptococcus bacteria growing in culture in this picture, which were isolated from a man with strep throat. While pathogenic bacteria are notorious for such diseases as cholera, tuberculosis, and gonorrhea, such disease-causing species are a comparatively tiny fraction of the bacteria as a whole. Bacteria are so widespread that it is possible only to make the most general statements about their life history and ecology. They may be found on the tops of mountains, the bottom of the deepest oceans, in the guts of animals, and even in the frozen rocks and ice of Antarctica. One feature that has enabled them to spread so far, and last so long is their ability to go dormant for an extended period. Bacteria have a wide range of environmental and nutritive requirements. Most bacteria may be placed into one of three groups based on their response to gaseous oxygen. Aerobic bacteria thrive in the presence of oxygen and require it for their continued growth and existence. Other bacteria are anaerobic, and cannot tolerate gaseous oxygen, such as those bacteria which live in deep underwater sediments, or those which cause bacterial food poisoning. The third group are the facultative anaerobes, which prefer growing in the presence of oxygen, but can continue to grow without it. Bacteria may also be classified both by the mode by which they obtain their energy. Classified by the source of their energy, bacteria fall into two categories: heterotrophs and autotrophs. Heterotrophs derive energy from breaking down complex organic compounds that they must take in from the environment -- this includes saprobic bacteria found in decaying material, as well as those that rely on fermentation or respiration. The other group, the autotrophs, fix carbon dioxide to make their own food source; this may be fueled by light energy (photoautotrophic), or by oxidation of nitrogen, sulfur, or other elements (chemoautotrophic). While chemoautotrophs are uncommon, photoautotrophs are common and quite diverse. They include the cyanobacteria, green sulfur bacteria, purple sulfur bacteria, and purple nonsulfur bacteria. The sulfur bacteria are particularly interesting, since they use hydrogen sulfide as hydrogen donor, instead of water like most other photosynthetic organisms, including cyanobacteria. Bacteria play important roles in the global ecosystem. The ecosystem, both on land and in the water, depends heavily upon the activity of bacteria. The cycling of nutrients such as carbon, nitrogen, and sulfur is completed by their ceaseless labor. Organic carbon, in the form of dead and rotting organisms, would quickly deplete the carbon dioxide in the atmosphere if not for the activity of decomposers. This may not sound too bad to you, but realize that without carbon dioxide, there would be no photosynthesis in plants, and no food. When organisms die, the carbon contained in their tissues becomes unavailble for most other living things. Decomposition is the breakdown of these organisms, and the release of nutrients back into the environment, and is one of the most important roles of the bacteria. The cycling of nitrogen is another important activity of bacteria. Plants rely on nitrogen from the soil for their health and growth, and cannot acquire it from the gaseous nitrogen in the atmosphere. The primary way in which nitrogen becomes available to them is through nitrogen fixation by bacteria such as Rhizobium, and by cyanobacteria such as Anabaena,Nostoc, and Spirulina, shown at right. These bacteria convert gaseous nitrogen into nitrates or nitrites as part of their metabolism, and the resulting products are released into the environment. Some plants, such as liverworts, cycads, and legumes have taken special advantage of this process by modifying their structure to house the basteria in their own tissues. Other denitrifying bacteria metabolize in the reverse direction, turning nitrates into nitrogen gas or nitrous oxide. When colonies of these bacteria occur on croplands, they may deplete the soil nutrients, and make it difficult for crops to grow.

Brief History of Antibiotics
1928-Dr Fleming produces penicillin from bread mold 1930-Chain and Florey make it available to the medical community and patients 1943- Penicillin becomes available to pharmaceutical companies 1945- Fleming, Chain, and Florey receive the Nobel prize 1969- the US Surgeon General ( William Stewart) says that the infectious disease is a thing of the past and we should “close the books on infectious disease”

OH OH - Problems in Paradise MDROs Emerge
What Causes MDROs? Darwin's Theory of “ Survival of the Fittest” Mutation Destruction/Inactivation Efflux pumps Genetic Transfer

Types of Resistance Intrinsic resistance
Chromosomal genes of the organism's are “born” with innate resistance to antibiotics Resistant to a specific class of antibiotics by virtue of its genetic makeup Resistance is predictable Makes it easier for ordering the right antibiotic Examples all streptococci are intrinsically resistant to aminoglycosides (e.g., gentamicin and tobramycin) all gram-negative bacilli are intrinsically resistant to vancomycin. The genetics of antibiotic resistance Genes can encode proteins or ribosomal RNA that enables bacteria to evade the actions of antibiotics. Such antibiotic resistance may either be intrinsic or acquired (Box 2).3 Intrinsic resistance is associated with the “usual” chromosomal genes or determinants of the organism's characteristics. Thus, an organism can be resistant to a specific class of antibiotics by virtue of its inherent genetic makeup. This form of resistance is predictable, which makes antibiotic selection straightforward. For example, all streptococci are intrinsically resistant to aminoglycosides (e.g., gentamicin and tobramycin), and all gram-negative bacilli are intrinsically resistant to vancomycin. View larger version:In this page In a new window Download as PowerPoint Slide Box 2. However, antibiotic resistance may also be acquired. This involves a change in the organism's genetic composition. This may occur by 1 of 2 mechanisms: there may be a mutation in the bacterial chromosomal DNA, or there may be acquisition of new genetic material. Mutations are generally uncommon events, perhaps occurring at a frequency of 1 event per 107–1010 bacteria, but may result in the development of resistance during therapy in organisms that are initially susceptible. An important example of this type of resistance is isoniazid resistance that can occur in Mycobacterium tuberculosis. This form of resistance is not transferable to other organisms. The probability of multiple resistance mutations occurring in a single organism is equal to the product of their individual probabilities. This is the rationale behind the use of combination therapy for the management of tuberculosis. Perhaps of greater concern is the development of resistance because of the acquisition of new genetic material. Genes mediating antimicrobial resistance may be found on transferable segments of DNA such as plasmids, transposons or integrons (Box 2). Plasmids are extrachromosomal molecules of DNA that replicate independently from the bacterial chromosome. They may carry genes that convey resistance to antibiotics, as well as genes that may enhance bacterial fitness or virulence. Transposons carry antibiotic resistance genes along with genes that allow them to replicate and transpose, or “jump,” to other regions of the chromosome or to plasmids. An integron is a DNA structure capable of capturing genes. Although integrons are not themselves mobile, they may be carried by plasmids or transposons to other bacteria. These mobile genetic elements may be transferred from organism to organism, and even from one bacterial species to another. Multiple antibiotic resistance genes may be transferred at the same time. There are numerous examples of this type of resistance, including plasmid-mediated production of β-lactamase enzymes, which are capable of inactivating penicillins or cephalosporins in Staphylococcus aureus, Escherichia coli or Enterobacterspecies.

Types of Resistance Extrinsic Resistance
Antibiotic resistance is acquired by a change in the organism's genetic composition Occurs by 1 of 2 mechanisms either mutation or acquisition Mutations Mutation in chromosomal DNA Mutations are generally uncommon events occurring at a frequency of 1 event per 107–1010 bacteria Example: Resistance to isoniazid can occur in Mycobacterium tuberculosis Resistance is not transferable to other organisms Mechanisms of antibiotic resistance Antibiotics work by interacting with specific bacterial targets, inhibiting bacterial cell-wall synthesis, protein synthesis or nucleic acid replication. To accomplish this, the antibiotic must have access to and bind to its bacterial target site (Figure 1). Whether antibiotic resistance is intrinsic or acquired, the genetic determinants of resistance encode specific biochemical resistance mechanisms that may include enzymatic inactivation of the drug, alterations to the structure of the antibiotic target site, and changes that prevent access of an adequate concentration of the antimicrobial agent to the active site (Table 1).3 Download as PowerPoint Slide In a new window View larger version:In this page View this table:In this window Figure 1: Sites of action and potential mechanisms of bacterial resistance to antimicrobial agents. Modified with permission from the American Association for the Advancement of Science (>Science 1992;257:1064–73).3 Image by: Lianne Friesen and Nicholas Woolridge Enzymatic drug inactivation Table 1. Bacteria may produce enzymes that modify or destroy the chemical structure of an antibiotic, which renders it inactive. This mechanism of resistance is probably best exemplified by the β-lactamase family of enzymes, which act by hydrolyzing the β-lactam ring of penicillins, cephalosporins and carbapenems. There are hundreds of β-lactamase enzymes that may be distinguished by their substrate profiles and activities. Some β-lactamase genes are chromosomal, whereas others are located on plasmids or transposons. Penicillin resistance in S. aureus and Neissseria gonorrheae, ampicillin-resistance in Haemophilus influenzae, and resistance to extended-spectrum cephalosporins in E. coli and in Enterobacter species are all commonly mediated by the production of β-lactamases. Resistance to extended-spectrum cephalosporins (e.g., cefotaxime, ceftriaxone, and ceftazidime) has arisen primarily by 1 of 2 mechanisms, both of which involve the production of β-lactamases.4 In E. coli and Klebsiellaspecies, plasmid-mediated extended-spectrum β-lactamases have most often emerged as mutations of the TEM, SHV or CTX-M genes (Ambler class A β-lactamases). In the past decade, the CTX-M type of extended-spectrum β-lactamases has become predominant in many parts of the world, including Canada.5,6 In other gram-negative bacilli, such as Enterobacter, Citrobacter orSerratia species, this resistance most often arises because of selection of mutants that overproduce chromosomally encoded AmpC cephalosporinases (Ambler class C β-lactamases), although plasmid-mediated ampC genes have also been identified.7 Both resistance mediated by Ambler class A extended-spectrum β-lactamases and AmpC are associated with cross-resistance to penicillins and cephalosporins. In addition, these bacteria are often also resistant to other antibiotic classes, such as fluoroquinolones, trimethoprim-sulfamethoxazole and aminoglycosides. Broad-spectrum β-lactamases, called carbapenemases, are capable of degrading carbapenem antibiotics and may be responsible for resistance to imipenem and meropenem in Pseudomonas aeruginosa and other gram-negative bacilli. An important and rapidly emerging group of carbapenemases is the KPC (Klebsiella pneumoniae carbapenemase) family of enzymes, which are capable of inactivating all β-lactam drugs, including carbapenems.8 The KPC genes are found on plasmids that often carry determinants of resistance to other classes of antimicrobials. Although these enzymes are most commonly found in K. pneumoniae, they have spread to other Enterobacteriaceae. To date in Canada, there have been no reports of infections caused by organisms with K. pneumoniae carbapenemase enzymes, but outbreaks caused by these multidrug-resistant strains have been reported in the United States and in many countries in Europe, Asia and South America.8,9 For antibiotics to work, they must bind to a specific bacterial target site, which varies depending on the class of antibiotic. A change in the structure of the target may result in the inability of the antibiotic to bind to its target. For example, β-lactam antibiotics act by binding to structures in the bacterial cell wall called penicillin-binding proteins. Methicillin-resistant strains of S. aureus (MRSA) possess a genetic element called staphylococcal cassette chromosome mec (SCCmec), which contains the mecA gene that codes for the production of an altered penicillin -binding protein (PBP2a) that does not effectively bind β-lactam antibiotics.10 As a result, MRSA is resistant to all of the currently available penicillins, cephalosporins and carbapenems. Changes in penicillin-binding proteins also account for penicillin resistance inStreptococcus pneumoniae.11 Alteration of the antibiotic target site Another example of antimicrobial resistance caused by an altered target site is resistance to fluoroquinolones (e.g., ciprofloxacin, levofloxacin and moxifloxacin). Fluoroquinolones act by inhibiting proteins called DNA gyrases (encoded by gyrA and gyrB genes) and topoisomerases (encoded by parC andparE), which are essential for bacterial DNA replication. Mutations in specific regions of the gyrA or parC genes (known as the quinolone-resistance determinant region) result in alterations to DNA gyrase or topoisomerase, and therefore result in an altered target binding site.12 Typically, multiple step-wise mutations must occur for resistance to fluoroquinolones to emerge. For an antibiotic to bind to its target, it must arrive at its target site and achieve an adequate concentration. Therefore, another strategy that has evolved to counteract antimicrobial activity is to prevent access of the drug to its target site. This may occur because of a permeability barrier or because of the presence of an efflux pump mechanism. Prevention of antibiotic access to the target site The cell wall of gram-negative bacteria consists of inner and outer membranes that act as a permeability barrier. To allow movement of essential compounds through the outer membrane, the bacterial cell produces outer membrane proteins (porins), which allow diffusion of molecules, including antibiotics into the cytoplasm. Mutations that cause changes in the structure of the outer membrane proteins can result in a permeability barrier that impedes access of antimicrobial agents to their active site. This mechanism may account for resistance to β-lactams and aminoglycosides in P. aeruginosa and other gram-negative bacilli.13 Instead of preventing penetration of antibiotics to the active site, some organisms have evolved an active efflux mechanism that pumps out antibiotics from the cytoplasm before they can bind to their target.14 These efflux pumps have been found in both gram-positive and gram-negative organisms. Such pumps may be responsible for resistance to tetracyclines, macrolides (e.g., erythromycin), clindamycin, fluoroquinolones and aminoglycosides. Some pumps may be specific for only 1 class of antibiotics, but others may be associated with resistance to multiple drugs because they are capable of exporting many different classes of antimicrobials. The emergence and transmission of antimicrobial-resistant organisms Previous SectionNext Section A drug-resistant organism may be introduced into a health care facility with the admission of a patient who is infected with or who has been colonized by such a strain. Alternatively, antimicrobial resistance may emerge in bacteria as a response to selective antibiotic pressure, or a resistant organism may spread from person to person (Table 2). Often, a combination of these factors may be involved in the emergence and transmission of antimicrobial resistance within a health care facility. Selective pressure refers to the environmental conditions that allow organisms with certain characteristics to survive and proliferate. Exposure to an antibiotic, for example, may inhibit or kill the majority of the bacterial population who are susceptible. However, a resistant subset of organisms may not be inhibited or killed by the antibiotic (Figure 2). These bacteria may be intrinsically resistant to the antibiotic, or they may have acquired resistance. Thus, antimicrobial use selects for the emergence of resistant strains of organisms that may then proliferate and become predominant.15 Indeed, antimicrobial resistance in health care facilities and the community is largely determined and magnified by the selective pressure of antimicrobial use.16 Selective antibiotic pressure Table 2. There are numerous examples that illustrate the direct relation between antimicrobial use, both appropriate and inappropriate, and antimicrobial resistance at both the population and individual patient level. In Finland, a significant association was found between macrolide consumption and macrolide resistance rates for group A Streptococcus.17 Similar correlations have been identified for macrolide use and resistance in S. pneumoniaeisolates in the United States,18 and for fluoroquinolone use and decreased susceptibility of pneumococci to fluoroquinolones in Canada.19 In intensive care units and other hospital settings, increased use of fluoroquinolones is correlated with a greater incidence of ciprofloxacin resistance in gram-negative bacilli.20–22 Similarly, many studies have documented prior antimicrobial exposure as a significant risk factor for subsequent acquisition of an antibiotic-resistant organism at the patient level. For example, prior exposure to broad-spectrum cephalosporins has been associated with acquisition of vancomycin-resistant enterococci and organisms that produce extended-spectrum β-lactamases.23,24 Previous fluoroquinolone or carbapenem use is an important risk factor for infection due to gram-negative organisms resistant to fluoroquinolones or carbapenems.25–27 Figure 2: Effect of selective antibiotic pressure in bacteria. Image by: Lianne Friesen and Nicholas Woolridge However, the relation between antimicrobial use and resistance is complex. In a study involving 8 hospitals in the United States, high intensity of antimicrobial use was not necessarily associated with high rates of resistance.28 Moreover, facility-level and individual risk factors for antibiotic resistance may be different, especially with regards to antimicrobial exposure. In a parallel analysis of individual and aggregated data on antibiotic exposure and resistance, different results were obtained with facility-level and individual patient-level analyses.29 In an ecologic facility-wide analysis, there was no apparent relation between intensity of antibiotic use and rates of resistance. But when the same data were analyzed at the individual patient level, there were significant associations between antibiotic exposure and resistance. Clonal transmission of antibiotic-resistant organisms Organisms resistant to antimicrobial agents can be spread from patient to patient in health care facilities, often via the contaminated hands of health care personnel, contaminated medical or surgical equipment, or the inanimate hospital environment. This type of spread is generally clonal, involving the transmission of a single strain of the antibiotic-resistant organism. Outbreaks caused by clonal transmission of an antimicrobial-resistant organism have commonly been reported for MRSA, vancomycin-resistant enterococci, C. difficile and multidrug-resistant gram-negative bacilli.24,30–35 Clonal outbreaks at multiple institutions may also occur with transmission of a common strain in multiple health care facilities, even in diverse geographic regions.30,33,34,36 However, clonality is less likely to occur with sporadic disease in areas with a relatively low prevalence, or with certain organisms and mechanisms of resistance.37–39 In some settings, an outbreak of antimicrobial resistance may occur from transmission of a plasmid rather than dissemination of a single resistant strain.40 Methicillin-resistant Staphylococcus aureus Selected antibiotic-resistant organisms in hospitals Although there is considerable variation in the rates of MRSA from country to country, and even from hospital to hospital within a country, MRSA is currently the most commonly identified antibiotic-resistant pathogen among patients in hospital.41 Rates of MRSA infections have increased in both US and Canadian hospitals; however, the rates are much higher in the United States.42,43 Until recently, MRSA was considered to be primarily a nosocomial pathogen, affecting older adults with comorbidities in hospital or long-term care settings. However, in the past decade, community-associated MRSA (CA-MRSA), which involves a small number of unique MRSA strains (clones), has emerged in many parts of the world, including Canada.44–46 Patients affected by CA-MRSA often do not have commonly recognized health care–associated risk factors. CA-MRSA may cause infections at any site but are most often associated with skin and soft tissue infections, including pustulosis, furunculosis and abscesses. Invasive disease and fatal necrotizing pneumonia have also been reported.47 Not surprisingly, CA-MRSA strains have been introduced into health care settings and have been associated with hospital-acquired bacteremia, surgical-site infections and outbreaks in maternity units and hospital nurseries.48 Although generally less virulent than S. aureus, Enterococcus species (e.g.,Enterococcus faecalis, Enterococcus faecium) may also cause serious, life-threatening infections. Resistance to vancomycin in enterococci is caused by synthesis of modified cell-wall precursors that do not bind glycopeptides. This occurs with the acquisition of a plasmid-associated gene cluster, most commonly the vanA or vanB genes.49 These genes are transferable and may spread from enterococci to MRSA, thereby further complicating the treatment of infections caused by this organism.50 In Canada, 15% of inpatients with vancomycin-resistant enterococci were found to also be colonized with MRSA.51 Prior antimicrobial therapy with oral vancomycin, broad-spectrum cephalosporins or metronidazole has been identified as an important risk factor for vancomycin-resistant enterococcal infection or colonization.23,52Environmental contamination with vancomycin-resistant enterococci or exposure to contaminated medical equipment may also contribute to nosocomial transmission.53 Vancomycin-resistant Enterococcus Multidrug-resistance in gram-negative bacilli is generally defined as resistance to more than 2 classes of antimicrobial agents. Typically, multidrug-resistant gram-negative bacteria are resistant to penicillins (including those combined with a β-lactamase inhibitor), cephalosporins, fluoroquinolones, trimethoprim-sulfamethoxazole and aminoglycosides. However, some strains may also be resistant to the carbapenems, often leaving colistin as the only agent available for treatment of these infections.54 Multidrug-resistant gram-negative bacilli The major multidrug-resistant gram-negative pathogen in most Canadian hospitals is P. aeruginosa, which is most often isolated from patients in intensive care units. At present, about 30% of P. aeruginosa isolates from intensive care units in the United States and Canada are resistant to fluoroquinolones.42,55,56 In Canadian intensive care units, about 13% of isolates were found to be resistant to multiple antibiotics.56 Carbapenem-resistance was identified in 14% of P. aeruginosa isolates from intensive care units in Canada.56 About 21% of P. aeruginosa isolates from intensive care units in the United States were resistant to carbapenems.42 Acinetobacter baumannii is also an important nosocomial pathogen acquired in intensive care units. This pathogen may cause pneumonia or urinary tract, wound, or bloodstream infections. Acinetobacter are generally resistant to most classes of antimicrobials, leaving carbapenems, and possibly glycylcyclines (tetracycline derivatives such as tigecycline), as the only effective drugs. The emergence of carbapenem-resistant A. baumannii in many parts of the world is disturbing and poses a threat to the effective management of these infections.57 Multidrug-resistant A. baumannii is identified infrequently in Canadian hospitals, although an outbreak was reported in a burn unit of a tertiary care hospital in Toronto.58 Nosocomial outbreaks due to multidrug-resistant A. baumannii that originated with injured military personnel returning from Afghanistan and Iraq have recently been reported in the United States and the United Kingdom.59 Similarly, a number of injured Canadian soldiers returning from active duty in Afghanistan have received treatment for multidrug-resistant Acinetobacter respiratory and wound infections in Canadian hospitals.60 C. difficile is the major cause of diarrhea associated with antibiotic use and is the most common infectious cause of nosocomial diarrhea. A major outbreak of C. difficile infection occurred in many hospitals in Quebec beginning in ,61 Markedly increased disease rates (as high as 156 cases per people) and severity occurred, especially among elderly people. In this outbreak, there was often a poor response to metronidazole therapy.61,62 The emergence of such severe disease is thought to have occurred because of the presence of a hypervirulent epidemic strain of C. difficile, known as PCR ribotype 27, or North America pulso-type 1 (NAP1).63 The same strain of C. difficile has caused extensive and severe disease in the United States and Europe.33 It is not clear why this strain appeared and caused such severe disease in the past few years, but this may in part be related to changing patterns of antimicrobial use in hospitals. The NAP1 strain associated with these outbreaks is resistant to fluoroquinolones, and fluoroquinolone use was found to be a major risk factor for C. difficile-associated disease in the Quebec outbreak.32 The NAP1 strain has now been identified in most provinces, and it has become the predominant strain in many hospitals, indicating the potential for severe outbreaks in many parts of the country. Clostridium difficile The burden of antimicrobial resistance refers to the impact of events that would not have occurred if resistance had not been present. These outcome measures may include excess mortality, morbidity (e.g., length of hospital stay and complications) and attributable costs (e.g., costs to the hospital, patient and society). The risk of such adverse outcomes has been found to be higher in patients with infections caused by an antibiotic-resistant organism compared with infections caused by susceptible strains of the same pathogen, even after adjustment for underlying comorbidities.64–68 For example, in a meta-analysis performed to examine the impact of methicillin-resistance on mortality among patients with S. aureus bloodstream infections, a significant increase in mortality (nearly a double increase in risk) was found to be associated with MRSA bacteremia when adjusted in a random-effects model (odds ratio 1.93, 95% confidence interval 1.54–2.42, p < 0.001).69 In a multivariable model, MRSA bacteremia was associated with increased length of hospital stay (1.29-fold increase, p = 0.016), with an attributable length of stay of 2 days.64 Similarly, attributable prolonged excess hospital stay was identified for infections caused by resistant strains of extended-spectrum ß-lactamase-producing K. pneumoniae (median post-infection hospital stay of 11 days for susceptible strains compared with 29 days for resistant strains, p= 0.03) and for carbapenem-resistant P. aeruginosa (20 days v. 34 days, p = 0.002).68 Several studies have attributed these adverse outcomes to delays in instituting effective antimicrobial therapy and use of inadequate initial therapy.70,71 Impact of antimicrobial resistance Not surprisingly, adverse outcomes and prolonged hospital stays associated with antimicrobial-resistant organisms have been associated with increased costs. However the economic burden of antimicrobial resistance on the health care system has not been well defined. Thirteen years ago in the United States, cost estimates for managing antimicrobial resistance were between $0.1 billion and $10 billion per year.72 In 2001, the mean attributable cost associated per patient with MRSA infection in a Canadian hospital was $ The incremental cost for care of patients with enterococci in Canadian hospitals was estimated to be about $6700 per patient.74 Incremental costs were attributed to length of hospital or intensive care unit stay, lost revenue from private isolation rooms, need for more expensive antibiotics and increased laboratory testing, and the added expense of infection control interventions, including the use of antiseptic soaps, gloves and gowns. The burden of antibiotic resistance continues to increase and is acknowledged to be a major threat to the treatment of infectious diseases, particularly among patients in hospital. The reasons for the variability in resistance rates around the world and within different parts of Canada is unknown but may be related to differences in diagnostic procedures, patterns of antimicrobial use or infection prevention and control practices. Summary Other important gaps in our knowledge include uncertainty about how understanding specific mechanisms of resistance may lead to the identification of novel targets for new antimicrobial drug development. A better understanding of the relative importance of selective pressure related to antibiotic use compared to cross-infection as mechanisms for emergence and spread of antimicrobial resistance would also be important to design and evaluate effective infection prevention and control strategies. Infections caused by antimicrobial-resistant organisms are almost always associated with increased attributable mortality, prolonged hospital stays and excess costs. Although the rates of antibiotic resistance in Canada tend to be lower than those in many other parts of the world, complacency would be a mistake. Rates of antibiotic-resistant organisms have increased in Canadian health care facilities in the past 10 years, and the rates will continue to increase unless aggressive control measures are implemented.75 These interventions must include enhanced surveillance of antibiotic resistance, attention to hand hygiene and other standard infection prevention and control measures, and antibiotic stewardship to ensure appropriate use of antimicrobial agents.76,77 See related commentary by Nicolle and colleagues, page 371, and related analysis paper by Patrick and Hutchinson, page 416 Acquired antibiotic resistance may arise from bacterial chromosomal DNA mutations or as a result of transfer and acquisition of new genetic material. The incidence and adverse consequences of infections caused by antimicrobial-resistant organisms continue to increase. Key points The major mechanisms of antimicrobial resistance include enzymatic inactivation of the drug and bacterial changes that prevent access or binding to the drug's target. Enhanced infection prevention and control strategies need to be developed, implemented and evaluated to stem the rise of infections caused by antimicrobial-resistant organisms. Emergence and spread may be promoted by antibiotic selection pressure. The emergence and spread of antimicrobial-resistant organisms within health care facilities or the community may be related to clonal transmission of a common “epidemic” strain. Footnotes Competing interests: None declared. Contributors: Both of the authors contributed to the conception of this review, and participated in reviewing and analyzing the literature. Both of the authors drafted portions of the review, revised it critically and approved the version submitted for publication. This article has been peer reviewed. REFERENCES Previous Section

Acquisition of New Genetic Material- Plasmids
Bad News! Genes mediating resistance may be found on transferable segments of DNA called Plasmids Extra chromosomal piece of DNA that can be transferred from one cell to another Perhaps of because of the acquisition of new genetic material. Genes mediating antimicrobial resistance may be found on transferable segments of DNA such as plasmids, transposons or integrons (Box 2). Plasmids are extrachromosomal molecules of DNA that replicate independently from the bacterial chromosome. They may carry genes that convey resistance to antibiotics, as well as genes that may enhance bacterial fitness or virulence. Transposons carry antibiotic resistance genes along with genes that allow them to replicate and transpose, or “jump,” to other regions of the chromosome or to plasmids. An integron is a DNA structure capable of capturing genes. Although integrons are not themselves mobile, they may be carried by plasmids or transposons to other bacteria. These mobile genetic elements may be transferred from organism to organism, and even from one bacterial species to another. Multiple antibiotic resistance genes may be transferred at the same time. There are numerous examples of this type of resistance, including plasmid-mediated production of β-lactamase enzymes, which are capable of inactivating penicillins or cephalosporins in Staphylococcus aureus, Escherichia coli or Enterobacterspecies.

Transposons Transposons Smaller than plasmid
Capable to transferring DNA sequencing from one cell to another Sequence of DNA that can move to new positions within the genome of a single cell The new cell type will gain resistance it never had before Perhaps of because of the acquisition of new genetic material. Genes mediating antimicrobial resistance may be found on transferable segments of DNA such as plasmids, transposons or integrons (Box 2). Plasmids are extrachromosomal molecules of DNA that replicate independently from the bacterial chromosome. They may carry genes that convey resistance to antibiotics, as well as genes that may enhance bacterial fitness or virulence. Transposons carry antibiotic resistance genes along with genes that allow them to replicate and transpose, or “jump,” to other regions of the chromosome or to plasmids. An integron is a DNA structure capable of capturing genes. Although integrons are not themselves mobile, they may be carried by plasmids or transposons to other bacteria. These mobile genetic elements may be transferred from organism to organism, and even from one bacterial species to another. Multiple antibiotic resistance genes may be transferred at the same time. There are numerous examples of this type of resistance, including plasmid-mediated production of β-lactamase enzymes, which are capable of inactivating penicillins or cephalosporins in Staphylococcus aureus, Escherichia coli or Enterobacterspecies.

Integrons Integrons are DNA structures capable of capturing and incorporating gene site specific recombination's There are numerous examples of this type of resistance Plasmid-mediated production of β-lactamase enzymes Inactivating penicillin's or cephalosporin's in Staphylococcus aureus, Escherichia coli or Enterobacter species Perhaps of because of the acquisition of new genetic material. Genes mediating antimicrobial resistance may be found on transferable segments of DNA such as plasmids, transposons or integrons (Box 2). Plasmids are extrachromosomal molecules of DNA that replicate independently from the bacterial chromosome. They may carry genes that convey resistance to antibiotics, as well as genes that may enhance bacterial fitness or virulence. Transposons carry antibiotic resistance genes along with genes that allow them to replicate and transpose, or “jump,” to other regions of the chromosome or to plasmids. An integron is a DNA structure capable of capturing genes. Although integrons are not themselves mobile, they may be carried by plasmids or transposons to other bacteria. These mobile genetic elements may be transferred from organism to organism, and even from one bacterial species to another. Multiple antibiotic resistance genes may be transferred at the same time. There are numerous examples of this type of resistance, including plasmid-mediated production of β-lactamase enzymes, which are capable of inactivating penicillins or cephalosporins in Staphylococcus aureus, Escherichia coli or Enterobacterspecies.

Antibiotic selective pressure
Antibiotics kill receptive bacteria Bacteria that are hardy are not killed and flourish Selective antibiotic pressure Selective pressure refers to the environmental conditions that allow organisms with certain characteristics to survive and proliferate. Exposure to an antibiotic, for example, may inhibit or kill the majority of the bacterial population who are susceptible. However, a resistant subset of organisms may not be inhibited or killed by the antibiotic (Figure 2). These bacteria may be intrinsically resistant to the antibiotic, or they may have acquired resistance. Thus, antimicrobial use selects for the emergence of resistant strains of organisms that may then proliferate and become predominant.15 Indeed, antimicrobial resistance in health care facilities and the community is largely determined and magnified by the selective pressure of antimicrobial use.16 View larger version:In this page In a new window Download as PowerPoint Slide Figure 2: Effect of selective antibiotic pressure in bacteria. Image by: Lianne Friesen and Nicholas Woolridge There are numerous examples that illustrate the direct relation between antimicrobial use, both appropriate and inappropriate, and antimicrobial resistance at both the population and individual patient level. In Finland, a significant association was found between macrolide consumption and macrolide resistance rates for group A Streptococcus.17 Similar correlations have been identified for macrolide use and resistance in S. pneumoniaeisolates in the United States,18 and for fluoroquinolone use and decreased susceptibility of pneumococci to fluoroquinolones in Canada.19 In intensive care units and other hospital settings, increased use of fluoroquinolones is correlated with a greater incidence of ciprofloxacin resistance in gram-negative bacilli.20–22 Similarly, many studies have documented prior antimicrobial exposure as a significant risk factor for subsequent acquisition of an antibiotic-resistant organism at the patient level. For example, prior exposure to broad-spectrum cephalosporins has been associated with acquisition of vancomycin-resistant enterococci and organisms that produce extended-spectrum β-lactamases.23,24 Previous fluoroquinolone or carbapenem use is an important risk factor for infection due to gram-negative organisms resistant to fluoroquinolones or carbapenems.25–27 However, the relation between antimicrobial use and resistance is complex. In a study involving 8 hospitals in the United States, high intensity of antimicrobial use was not necessarily associated with high rates of resistance.28 Moreover, facility-level and individual risk factors for antibiotic resistance may be different, especially with regards to antimicrobial exposure. In a parallel analysis of individual and aggregated data on antibiotic exposure and resistance, different results were obtained with facility-level and individual patient-level analyses.29 In an ecologic facility-wide analysis, there was no apparent relation between intensity of antibiotic use and rates of resistance. But when the same data were analyzed at the individual patient level, there were significant associations between antibiotic exposure and resistance.

Bacterial resistance mechanisms
Efflux pumps Binding sites Beta lactamase enzymes Antibiotic target modifications

How MDRO’s are introduced in the hospital
Patient admitted from nursing homes, LTACS, etc… with resistant organisms Selective pressure from misuse of antibiotics Clonal dissemination

Bacteria summary who developed resistance

By 1946, 6% of S. aureus strains were resistant to penicillin
By 1960 up to 60% of S. aureus strains were resistant to penicillin From Wikipedia, the free encyclopedia Nalidixic acid Nalidixic acidSystematic (IUPAC) name1-ethyl-7-methyl-4-oxo-[1,8]naphthyridine-3-carboxylic acidClinical dataAHFS/Drugs.comConsumer Drug InformationPregnancy cat.B U.S.Legal status ?RoutesOralPharmacokinetic dataProtein binding90%MetabolismPartially HepaticHalf-life6-7 hours, significantly longer in renal impairmentIdentifiersCAS number ATC codeJ01MB02PubChemCID 4421DrugBankAPRD01133ChemSpider4268 UNII3B91HWA56M KEGGD00183 ChEBICHEBI:100147 ChEMBLCHEMBL5 Chemical dataFormulaC12H12N2O3 Mol. mass g/molSMILESeMolecules & PubChemInChI[show] (what is this?) (verify) Nalidixic acid (tradenames Nevigramon, Neggram, Wintomylon and WIN 18,320) is the first of the synthetic quinolone antibiotics. In the technical sense, it is a naphthyridone, not a quinolone: its ring structure is a 1,8-naphthyridines nucleus that contains two nitrogen atoms, unlike quinoline, which has a single nitrogen atom.[1] Synthetic quinolone antibiotics were discovered by George Lesher and coworkers as a byproduct of chloroquine manufacture in the 1960s.[1] Nalidixic acid is effective against both gram-positive and gram-negative bacteria. In lower concentrations, it acts in a bacteriostatic manner; that is, it inhibits growth and reproduction. In higher concentrations, it is bactericidal, meaning that it kills bacteria instead of merely inhibiting their growth. It is especially used in treating urinary tract infections, caused, for example, by Escherichia coli, Proteus, Shigella, Enterobacter, andKlebsiella.. It is also a tool in studies as a regulation of bacterial division. It selectively and reversibly blocks DNA replication in susceptible bacteria. Nalidixic acid and related antibiotics inhibit a subunit of DNA gyrase and induce formation of relaxation complex analogue. It also inhibits the nicking dosing activity on the subunit of DNA gyrase that releases the positive binding stress on the supercoiled DNA. It is the only FDA approved quinolone for treating UTI infections in children (3). Linezolid (INN) ( /lɪˈnɛzəlɪd/ li-nez-ə-lid) is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. A member of the oxazolidinone class of drugs, linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistantStaphylococcus aureus (MRSA).[1] The main indications of linezolid are infections of the skin and soft tissues and pneumonia (particularlyhospital-acquired pneumonia), although off-label use for a variety of other infections is becoming popular. Linezolid is marketed by Pfizerunder the trade names Zyvox (in the United States, United Kingdom, Australia, and several other countries), Zyvoxid (in Europe), andZyvoxam (in Canada and Mexico). Generics are also available in India, such as Linospan (Cipla). Discovered in the 1990s and first approved for use in 2000, linezolid was the first commercially available 1,3-oxazolidinone antibiotic. As of 2009, it is the only marketed oxazolidinone, although others are in development. As a protein synthesis inhibitor, it stops the growth of bacteria by disrupting their production of proteins. Although many antibiotics work this way, the exact mechanism of action of linezolid appears to be unique to the oxazolidinone class. Bacterial resistance to linezolid has remained very low since it was first detected in 1999, although it may be increasing. Cefotaxime (INN) ( /ˌsɛfɵˈtæksiːm/) is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria. In most cases, it is considered to be equivalent toceftriaxone in terms of safety and efficacy. Contents [hide] 1 Mechanism of action 3 Chemistry 2 Clinical use 4 References [edit]Mechanism of action Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.[1] Cefotaxime, like other β-lactam antibiotics does not only block the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the Glaucophytes, and the division of chloroplasts of bryophytes. In contrast, it has no effect on the plastids of the highly developed vascular plants. This is supporting the endosymbiotic theory and indicates an evolution of plastid division in land plants [2]. Cefotaxime is used for infections of the respiratory tract, skin, bones, joints, urogenital system, meningitis, and septicemia. It generally has good coverage against most Gram-negative bacteria, with the notable exception of Pseudomonas. It is also effective against most Gram-positive cocci except for Enterococcus.[1] It is active against penicillin-resistant strains of Streptococcus pneumoniae. It has modest activity against the anaerobic Bacteroides fragilis. [edit]Clinical use Dr.T.V.Rao MD 16

Gram Staining ( Grams method)
Differentiates between Gram positive and Gram negative organisms based on the chemical and physical properties of the cell wall Gram positive results in a purple/blue color Gram negative results in a pink/red color Gram staining (or Gram's method) is a method of differentiating bacterial species into two large groups (Gram-positive and Gram-negative). It is based on the chemical and physical properties of their cell walls. Primarily, it detects peptidoglycan, which is present in a thick layer in Gram positive bacteria.[1] A Gram positive results in a purple/blue color while a Gram negative results in a pink/red color. The Gram stain is almost always the first step in the identification of a bacterial organism, and is the default stain performed by laboratories over a sample when no specific culture is referred. While Gram staining is a valuable diagnostic tool in both clinical and research settings, not all bacteria can be definitively classified by this technique, thus forming Gram-variable and Gram-indeterminate groups as well. The word Gram is always spelled with a capital, referring to Hans Christian Gram, the inventor of Gram staining. History The method is named after its inventor, the Danish scientist Hans Christian Gram (1853–1938), who developed the technique while working with Carl Friedländer in the morgue of the city hospital in Berlin. Gram devised his technique not for the purpose of distinguishing one group of bacteria from another but to enable bacteria to be seen more readily in stained sections of lung tissue.[2] He published his method in 1884, and included in his short report the observation that the Typhus bacillus did not retain the stain.[3] Uses Gram staining is a bacteriological laboratory technique[4] used to differentiate bacterial species into two large groups (Gram-positive and Gram-negative) based on the physical properties of their cell walls.[5] Gram staining is not used to classify archaea, formally archaeabacteria, since these microorganisms yield widely varying responses that do not follow their phylogenetic groups.[6] The Gram stain is not an infallible tool for diagnosis, identification, or phylogeny, and it is of extremely limited use in environmental microbiology. It has been largely superseded by molecular techniques even in the medical microbiology lab. Some organisms are Gram-variable (that means, they may stain either negative or positive); some organisms are not susceptible to either stain used by the Gram technique. In a modern environmental or molecular microbiology lab, most identification is done using genetic sequences and other molecular techniques, which are far more specific and information-rich than differential staining. Medical See also: Gram-negative bacterial infection and Gram-positive bacterial infection Gram stains are performed on body fluid or biopsy when infection is suspected. Gram stains yield results much more quickly than culture, and is especially important when infection would make an important difference in the patient's treatment and prognosis; examples are cerebrospinal fluid for meningitis and synovial fluid for septic arthritis.[4][7] . Staining mechanism Gram-positive bacteria have a thick mesh-like cell wall made of peptidoglycan (50-90% of cell wall), which are stained purple by crystal violet, whereas Gram-negative bacteria have a thinner layer (10% of cell wall), which are stained pink by the counter-stain. There are four basic steps of the Gram stain: applying a primary stain (crystal violet) to a heat-fixed (death by heat) smear of a bacterial culture the addition of a trapping agent (Gram's iodine) rapid decolorization with alcohol or acetone, and counterstaining with safranin.[8] carbol fuchsin is sometimes substituted for safranin since it will more intensely stain anaerobic bacteria but it is much less commonly employed as a counterstain.[9] Crystal violet (CV) dissociates in aqueous solutions into CV+ and chloride (Cl−) ions. These ions penetrate through the cell wall and cell membrane of both Gram-positive and Gram-negative cells. The CV+ ion interacts with negatively charged components of bacterial cells and stains the cells purple. Iodine (I− or I− 3) interacts with CV+ and forms large complexes of crystal violet and iodine (CV–I) within the inner and outer layers of the cell. Iodine is often referred to as a mordant, but is a trapping agent that prevents the removal of the CV–I complex and, therefore, color the cell.[10] When a decolorizer such as alcohol or acetone is added, it interacts with the lipids of the cell membrane. A Gram-negative cell will lose its outer lipopolysaccharide membrane, and the inner peptidoglycan layer is left exposed. The CV–I complexes are washed from the Gram-negative cell along with the outer membrane. In contrast, a Gram-positive cell becomes dehydrated from an ethanol treatment. The large CV–I complexes become trapped within the Gram-positive cell due to the multilayered nature of its peptidoglycan. The decolorization step is critical and must be timed correctly; the crystal violet stain will be removed from both Gram-positive and negative cells if the decolorizing agent is left on too long (a matter of seconds). After decolorization, the Gram-positive cell remains purple and the Gram-negative cell loses its purple color. Counterstain, which is usually positively charged safranin or basic fuchsin, is applied last to give decolorized Gram-negative bacteria a pink or red color.[11][12] Some bacteria, after staining with the Gram stain, yield a Gram-variable pattern: a mix of pink and purple cells are seen. The genera Actinomyces, Arthobacter, Corynebacterium, Mycobacterium, and Propionibacterium have cell walls particularly sensitive to breakage during cell division, resulting in Gram-negative staining of these Gram-positive cells. In cultures of Bacillus, Butyrivibrio, and Clostridium, a decrease in peptidoglycan thickness during growth coincides with an increase in the number of cells that stain Gram-negative.[13] In addition, in all bacteria stained using the Gram stain, the age of the culture may influence the results of the stain.

Gram Positive Stained dark blue or violet
Gram-positive cell walls typically lack the outer membrane found in Gram-negative bacteria Most pathogens in humans are Gram-positive organisms Cocci ( sphere shaped) Streptococcus Staphylococcus

Gram Negative Gram-negative bacteria with a red or pink color
Cytoplasmic membrane Medically relevant Gram-negative bacilli include a multitude of species. Hemophilus influenzae Klebsiella pneumoniae Pseudomonas aeruginosa Escherichia coli Nosocomial infections Acinetobacter baumannii Bacteremia- secondary to meningitis Ventilator-associated pneumonia Gram-negative Both gram-positive and gram-negative bacteria have a cell wall made up of peptidoglycan and a phospholipid bilayer with membrane-spanning proteins. However, gram-negative bacteria have a unique outer membrane, a thinner layer of peptidoglycan, and a periplasmic space between the cell wall and the membrane. In the outer membrane, gram-negative bacteria have lipopolysaccharides (LPS), porin channels, and murein lipoprotein all of which gram-positive bacteria lack. As opposed to gram-positive cells, gram-negative cells are resistant to lysozyme and penicillin attack. The gram-negative outer membrane which contains LPS, an endotoxin, blocks antibiotics, dyes, and detergents protecting the sensitive inner membrane and cell wall. LPS is significant in membrane transport of gram-negative bacteria. LPS, which includes O-antigen, a core polysaccharide and a Lipid A, coats the cell surface and works to exclude large hydrophobic compounds such as bile salts and antibiotics from invading the cell. O-antigen are long hydrophilic carbohydrate chains (up to 50 sugars long) that extend out from the outer membrane while Lipid A (and fatty acids) anchors the LPS to the outer membrane. Examples of gram-negative bacteria: Spirochetes (spiral-shaped) - causes syphilis, lyme disease Neisseria (cocci) - causes meningococcus, gonorrhea

Microscopic Review Gram positive Gram negative

MDRO’s Gram Positive Gram negative MRSA VRE C- Diff
ESBLs (Extended Spectrum Beta- Lactamase producing Enterobacteria) CRE (Carbapenem- Resistant Enterobacteriaceae) Carbapenem-Resistant Enterobacteriaceae (CRE)? CRE are bacteria that are resistant to most antibiotics. Enterobacteriaceae is a family of bacteria. Many of these bacteria live in our environment (in soil or water). Some of them can get into our bodies and make us sick. Members of the Enterobacteriaceae family of bacteria can cause pneumonia, kidney and bladder infections, and bloodstream infections. Most of the Enterobacteriaceae can treated with antibiotics. However, because antibiotics have been overused, many of the Enterobacteriaceae have become resistant to most of the available antibiotics. The carbapenem antibiotics were developed to treat bacteria that had become resistant to most other antibiotics. About 10 years ago, we began to see bacteria from the Enterobacteriaceae familythat had become resistant to the carbapenem antibiotics. These are called Carbapenem-ResistantEnterobacteriaceae or CRE. Are CRE dangerous? They can be, because they are found in hospitals, and can cause infection in people who are very sick. Patients in intensive care units are at greatest risk, especially if they are on ventilators and have central intravenous catheters in place. Are CRE treatable? Yes, usually. However, because we have few antibiotics available to treat CRE, they can be difficult to treat. Patients can die from infections with CRE. What are hospitals doing to prevent CRE? Hospitals are very aware of CRE and are taking steps to prevent infection in their patients. Careful use of antibiotics can make it less likely that CRE will appear in a hospital. If a patient does become infected with CRE, hospitals take special precautions to prevent spread of the CRE to other patients. How can CRE be transmitted to other patients? CRE can be transferred from the patient to the environment and to the hands of the care provider (doctor or nurse or other person) when the care provider touches the patient or touches the patient with medical equipment, then touches another patient. What kind of precautions can the hospital use? Hospitals use “standard precautions” for all patient care activities. Standard precautions means that healthcare personnel wash their hands before they touch a patient and after they finishcaring for the patient, and they wear gloves and a gown for patient care activities that might result in exposure to blood or body fluids. If a patient is infected with CRE, additional infection control measures are taken. These are called “contact precautions”. The patient is usually placed in a private room. The care provider wears gloves and a gown any time he/she is in the patient’s room. The patient must stay in the room and visitors may be restricted. How can I prevent CRE in myself or a family member? As far as we know now, the greatest risk for acquiring a CRE is in a hospital, especially in an ICU. If you or a family member are hospitalized, you should follow instructions for hand washing and other infection control measures as requested. You should also expect your nurse and other care providers to wash their hands and wear gloves and gown if necessary. If you have questions, talk with your physician or nurse. What should I do if I think I have CRE? Talk to your health care provider. Where can I obtain additional information on CRE? The CDC website ( has some general information on drug resistant bacteria, and several pages of information on Klebsiella. Klebsiella is a member of the Enterobacteriaceaefamily. It was the first member of the family to develop carbapenem resistance. The other CRE are similar in their ways of making people sick, and their resistance to treatment with common antibiotics.

MRSA Images MRSA MRSA patient

MRSA Facts 2007 880,000 cases reported- not all fatal
2.4% of all patients have contacted MRSA in a hospital Around 25,000 deaths each year Hospital stay increases 6 days 33% of healthy people are colonized with staph aureus 1% of the above are colonized with MRSA MRSA infections are declining in the hospital setting According to the Centers for Disease Control (CDC), in the year 2005, MRSA was responsible for an estimated 94,000 invasive life-threatening infections and close to 19,000 deaths (more than AIDS). In the US in 2003, there were an estimated 12 million doctor or emergency room visits for skin and soft tissue infections suspected to be caused by staph aureus. Hospitals in England have seen a 548% increase in MRSA related deaths from 2003 to 2004! For more MRSA and Staph statistics, click here: Facts about MRSA MRSA Infection, U.S. Statistics Number MRSA infected each year: 880,000 (2007 numbers) % of hospital inpatients MRSA infected each year: 2.4% Additional cost per MRSA infection: at least $10,000 Total cost of MRSA infections per year: around $8 billion Average increased length of stay: 6 extra hospital days % of people with MRSA infection who die from it: 5% Number of MRSA infection deaths per year: 20,000 to 40,000 MRSA Infection, Globally The global situation of MRSA is a bit harder to get a handle on. In Europe, the problem doesn’t seem quite as bad as in the U.S., partly because of differences in the prescribing of antibioitics and partly because of control measures that have been put in place (such as mandatory MRSA screening for all patients in some settings). That said, an epidemic is still brewing and as MRSA travels from the U.S. to Europe, expect to see the rates increase there too.How Did This Happen? There are several reasons we have a MRSA problem today. The most basic reason is that the Staph bacteria has developed resistance to methicillin and other antibiotics. Why? Antibiotic resistance evolves through selective pressure and random mutations. While the bacteria are replicating, a portion of those reproduced (by chance) may be mutants and able to survive even in the presence of antibiotics. Those that survive may be fit enough to go on to reproduce and cause illness. There is also a lot of data that overuse of antibiotics for decades has contributed to the problem. Because we overused antibiotics for decades. For example, antibiotics are often prescribed for viruses (like when people have the cold or the flu), this causes strain on the bacteria. When exposed to the antibiotics, some bacteria naturally are “hardier” than others. These bacteria survive (especially when the patients don’t take their full dose of antibiotics). They survive, reproduce and create resistant offspring. Continue the cycle for a couple of decades and a new strain of bacteria appears that is resistant to the antibiotic.But it is not only the misuse of medications that is the problem, there is a lot of misuse of antibiotics in the animal industry. Those antibiotics end up in food and in the water supply, providing a low dose of antibiotics that helps create resistant bacteria. What Does the Future Hold? More of the same, lots more. There are no signs that MRSA and other infections are on the wane. As soon as one infection gets under control, it seems there are two to replace. While MRSA remains a huge concern (with no signs of slowing), two more superbugs are already poised to dethrone it: C. Diff. and A. Baumannii.Must Read: Protect Yourself From MRSA Infections Sources: Selected antibiotic-resistant organisms in hospitals Methicillin-resistant Staphylococcus aureus Although there is considerable variation in the rates of MRSA from country to country, and even from hospital to hospital within a country, MRSA is currently the most commonly identified antibiotic-resistant pathogen among patients in hospital.41 Rates of MRSA infections have increased in both US and Canadian hospitals; however, the rates are much higher in the United States.42,43 Until recently, MRSA was considered to be primarily a nosocomial pathogen, affecting older adults with comorbidities in hospital or long-term care settings. However, in the past decade, community-associated MRSA (CA-MRSA), which involves a small number of unique MRSA strains (clones), has emerged in many parts of the world, including Canada.44–46 Patients affected by CA-MRSA often do not have commonly recognized health care–associated risk factors. CA-MRSA may cause infections at any site but are most often associated with skin and soft tissue infections, including pustulosis, furunculosis and abscesses. Invasive disease and fatal necrotizing pneumonia have also been reported.47 Not surprisingly, CA-MRSA strains have been introduced into health care settings and have been associated with hospital-acquired bacteremia, surgical-site infections and outbreaks in maternity units and hospital nurseries.48

MRSA These are organisms that are not sensitive to common penicillin based drugs such as methicillin, amoxicillin, penicillin, oxacillin Normal flora- lives on human skin, noses, vaginal tract May cause infections if enters the body Contagious- through person to person contact Treatment - Vancomycin Overview Staphylococcus aureus, often referred to as "staph," is a very common bacteria. Approximately 25-30% of healthy people carry this organism on their skin or in their nose. Sometimes, staph causes an infection. Staph bacteria are the most common causes of skin infections in the United States. Infections caused by staph can appear as pimples, boils, and abscesses - staph infections may also be mistaken for bites from insects or spiders. Sometimes, staph can cause more severe infections inside the body. These are called invasive infections and include pneumonia, bone infections, and toxic shock syndrome. But the vast majority of staph infections are not invasive, and involve only the skin. MRSA Methicillin-resistant Staphylococcus aureus (MRSA) is a type of staph that is resistant to certain antibiotics. These antibiotics include methicillin and other [narrow-spectrum B-lactamase-resistant penicillin antibiotics] such as cloxacillin, dicloxacillin, oxacillin, and nafcillin, as well as a closely related class of drugs known as cephalosporins (e.g., cephalexin). Overuse of antibiotics and the use of more powerful drugs than necessary for less serious infections may be some of the causes of the development of MRSA. Approximately 1-2% of people carry MRSA on their skin or in their nose. Infections caused by MRSA, for the most part, are not different from any other staph infection, although some strains of MRSA may be more aggressive than regular staph. The diagnosis of a MRSA infection requires laboratory testing. Laboratory testing can also be important since MRSA's antibiotic resistance may make it more difficult to manage; testing can guide treatment. The diagnosis of a MRSA infection requires laboratory testing. Your doctor might recommend laboratory testing of a wound that looks infected and is not healing properly in order to confirm whether it is caused by MRSA and to determine which antibiotics might be useful in treating it. Transmission of Staph The main way that staph (including MRSA) is spread is from one person to another on hands. The bacteria may also be spread by contact with contaminated items (e.g., razors, sports equipment, towels) or environmental surfaces (e.g., athletic benches or mats). Factors contributing to transmission include close skin-to-skin contact, openings in the skin such as cuts and abrasions, the presence of contaminated items, crowded living conditions, and poor hygiene. Staph can cause mild to serious infections, and they are all spread the same way. Serious infections are not easier to spread than mild ones. MRSA is not easier to spread than other staph infections. Settings Where MRSA Occurs MRSA has traditionally been seen as associated with healthcare settings, both in hospitals and in non-hospital healthcare facilities (such as dialysis centers). Infections in these settings are referred to as healthcare-associated MRSA, or HA-MRSA. However, MRSA infections are increasingly occurring in people who have not recently been hospitalized or had a medical procedure. These infections are known as community-associated MRSA (CA-MRSA). Examples of groups that have experienced outbreaks of CA-MRSA include persons living in correctional facilities or participating on competitive sports teams. A person can carry MRSA, without symptoms, for a long time before getting sick. This can make it extremely difficult to determine where a person might have acquired his or her MRSA infection. The place of onset of illness may have nothing to do with the place where the bacterium was acquired. Colonization vs Infection The distinction between staph (including MRSA) colonization and infection is important. Colonization = the presence of the bacteria, but no signs of illness or infection. Staph thrives in warm, moist places; common sites of colonization include the nostrils, belly button, underarms, groin, etc. Infection = clinical signs of illness or inflammation (e.g., localized pain/tenderness, redness, warmth, swelling; pus; fever). These are due to tissue damage caused by invasion by the bacteria. Infection requires treatment - various treatment options exist. Treatment does not always require the use of an antibiotic. Management and Treatment No treatment is needed for colonization. Most people do not know they are colonized because the bacteria are present but not causing any symptoms. Everyone should practice good hand hygiene and proper wound care to help ensure that bacteria do not enter the body through breaks in the skin and potentially cause infections. Most minor skin infections (such as pimples and boils) can be treated with appropriate wound care at home through proper cleaning of wounds and covering them with bandages. Additional actions are needed for wounds that are not healing properly or that are draining (e.g., see a physician for possible drainage of pus with warm compresses or incision and sometimes, antibiotics). However, more serious infections (such as surgical wound infections, bloodstream infections, pneumonia) need to be treated aggressively. This may require hospitalization and/or the use of intravenous (IV) antibiotics. Laboratory testing of the organism is often necessary to make sure the right antibiotic is being used. Basic Steps for Prevention Frequent and thorough hand washing, not sharing personal items, and proper wound care are the key ways to reduce the risk of spreading the organism to others. Reduce the risk of spreading staph, including MRSA to others by following these steps: Cover wounds. Pus from infected wounds can contain staph. Cover wounds that are draining or have pus with clean, dry bandages. Follow your healthcare provider's instructions on proper care of the wound. Bandages or tape can be discarded with the regular trash. Keep hands clean. Wash bare hands frequently with soap and warm water, especially after changing a bandage or touching an infected wound (even if gloves are worn). Alcohol-based hand sanitizers may be used if hands are not visibly soiled. Do not share personal items. Avoid sharing personal items such as towels, washcloths, razors, clothing, or uniforms. Wash soiled sheets, towels, and clothes with warm/hot water and laundry detergent. Drying clothes in a hot dryer, rather than air-drying, also helps kill bacteria in clothes. Learn More About MRSA Talk to your doctor. Tell any healthcare providers who treat you if you have had a MRSA infection. MRSA Overview - Centers for Disease Control and Prevention (CDC) VDH Fact Sheet on MRSA More links and resources on MRSA will be available soon!

Vancomycin Resistant Enterococci (VRE)
Enterococci are bacteria that are naturally present in the intestinal tract of all people Vancomycin is an antibiotic to which some strains of enterococci have become resistant People in good health are not at risk of infection Health care workers may play a role in transmitting the organism Very contagious Vulnerable populations Children Elderly Immunocompromised VRE can live on surfaces for up to 7 days Vancomycin-resistant Enterococcus Although generally less virulent than S. aureus, Enterococcus species (e.g.,Enterococcus faecalis, Enterococcus faecium) may also cause serious, life-threatening infections. Resistance to vancomycin in enterococci is caused by synthesis of modified cell-wall precursors that do not bind glycopeptides. This occurs with the acquisition of a plasmid-associated gene cluster, most commonly the vanA or vanB genes.49 These genes are transferable and may spread from enterococci to MRSA, thereby further complicating the treatment of infections caused by this organism.50 In Canada, 15% of inpatients with vancomycin-resistant enterococci were found to also be colonized with MRSA.51 Prior antimicrobial therapy with oral vancomycin, broad-spectrum cephalosporins or metronidazole has been identified as an important risk factor for vancomycin-resistant enterococcal infection or colonization.23,52Environmental contamination with vancomycin-resistant enterococci or exposure to contaminated medical equipment may also contribute to nosocomial transmission.53 Multidrug-resistant gram-negative bacilli Multidrug-resistance in gram-negative bacilli is generally defined as resistance to more than 2 classes of antimicrobial agents. Typically, multidrug-resistant gram-negative bacteria are resistant to penicillins (including those combined with a β-lactamase inhibitor), cephalosporins, fluoroquinolones, trimethoprim-sulfamethoxazole and aminoglycosides. However, some strains may also be resistant to the carbapenems, often leaving colistin as the only agent available for treatment of these infections.54 The major multidrug-resistant gram-negative pathogen in most Canadian hospitals is P. aeruginosa, which is most often isolated from patients in intensive care units. At present, about 30% of P. aeruginosa isolates from intensive care units in the United States and Canada are resistant to fluoroquinolones.42,55,56 In Canadian intensive care units, about 13% of isolates were found to be resistant to multiple antibiotics.56 Carbapenem-resistance was identified in 14% of P. aeruginosa isolates from intensive care units in Canada.56 About 21% of P. aeruginosa isolates from intensive care units in the United States were resistant to carbapenems.42 Acinetobacter baumannii is also an important nosocomial pathogen acquired in intensive care units. This pathogen may cause pneumonia or urinary tract, wound, or bloodstream infections. Acinetobacter are generally resistant to most classes of antimicrobials, leaving carbapenems, and possibly glycylcyclines (tetracycline derivatives such as tigecycline), as the only effective drugs. The emergence of carbapenem-resistant A. baumannii in many parts of the world is disturbing and poses a threat to the effective management of these infections.57 Multidrug-resistant A. baumannii is identified infrequently in Canadian hospitals, although an outbreak was reported in a burn unit of a tertiary care hospital in Toronto.58 Nosocomial outbreaks due to multidrug-resistant A. baumannii that originated with injured military personnel returning from Afghanistan and Iraq have recently been reported in the United States and the United Kingdom.59 Similarly, a number of injured Canadian soldiers returning from active duty in Afghanistan have received treatment for multidrug-resistant Acinetobacter respiratory and wound infections in Canadian hospitals.60 What is VRE? Enterococci are bacteria that are normally present in the human intestines and in the female genital tract and are often found in the environment. These bacteria sometimes can cause infections. Vancomycin is an antibiotic that is often used to treat infections caused by enterococci. In some instances, vancomycin is no longer able to kill enterococci. These enterococci are then called vancomycin-resistant enterococci (VRE). Most VRE infections occur in hospitals. Who is at risk for VRE? The following individuals are at an increased risk becoming infected with VRE: • People who have been previously treated with vancomycin and combinations of other antibiotics, such as penicillin and gentamicin • People who are hospitalized, particularly when they receive antibiotic treatment for long periods of time • People with weakened immune systems, such as patients in intensive care units or in cancer or transplant wards • People who have undergone surgical procedures, such as abdominal or chest surgery • People with medical devices that stay in for some time, such as urinary catheters or central intravenous catheters What are the symptoms of VRE? The symptoms of VRE can vary. Among the infections that can be caused by VRE are urinary tract infections, blood stream infections and wound infections. How soon do symptoms appear? The period between being infected and developing symptoms is variable and not well understood. How is VRE spread? VRE usually is passed to others by direct contact with stool, urine or blood containing VRE. It also can be spread indirectly via the hands of health-care providers or on contaminated environmental surfaces. VRE usually is not spread through casual contact such as touching or hugging. VRE is not spread through the air by coughing or sneezing For more images of this bacterium, search the Public Health Image Library General Information What is vancomycin-resistant enterococci? Enteroccocci are bacteria that are normally present in the human intestines and in the female genital tract and are often found in the environment. These bacteria can sometimes cause infections. Vancomycin is an antibiotic that is used to treat some drug-resistant infections caused by enterococci. In some instances, enterococci have become resistant to this drug and thus are called vancomycin-resistant enterococci (VRE). Most VRE infections occur in hospitals. Top of page What types of infections does VRE cause? VRE can live in the human intestines and female genital tract without causing disease (often called colonization). However, sometimes it can cause infections of the urinary tract, the bloodstream, or of wounds associated with catheters or surgical procedures.

Other Drug Resistant Diseases
Extensively-Drug Resistant Tuberculosis (XDR-TB) This is a TB causing organism that is resistant to almost all drugs that are used to treat TB. Isoniazid Rifampin Fluoroquinolones The main causative organism is Mycobacterium tuberculosis3 Contagious through droplets but slower than viral infection such as flu Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to the most effective anti-TB drugs. Some contend that XDR-TB strains have emerged from the mismanagement of multidrug-resistant TB (MDR-TB) and once created, can spread from one person to another. The exact nature of this mismanagement is not yet known, but origin of XDR-TB may coincide with the institution of new policies to promote drug compliance, such as DOTS.[1] One in three people in the world is infected with TB bacteria.[2] Only when the bacteria become active do people become ill with TB. Bacteria become active as a result of anything that can reduce the person’s immunity, such as HIV, advancing age, or some medical conditions. TB can usually be treated with a course of four standard, or first-line, anti-TB drugs. If these drugs are misused or mismanaged, multidrug-resistant TB (MDR-TB) can develop. MDR-TB takes longer to treat with second-line drugs, which are more expensive and have more side-effects. XDR-TB can develop when these second-line drugs are also misused or mismanaged and therefore also become ineffective. XDR-TB raises concerns of a future TB epidemic with restricted treatment options, and jeopardizes the major gains made in TB control and progress on reducing TB deaths among people living with HIV/AIDS. It is therefore vital that TB control be managed properly and new tools developed to prevent, treat and diagnose the disease. The true scale of XDR-TB is unknown as many countries lack the necessary equipment and capacity to accurately diagnose it. It is estimated however that there are around 40,000 cases per year. As of June 2008, 49 countries have confirmed cases of XDR-TB.[3] By 2010, that number had risen to 58.[4]

Extended Spectrum Beta- Lactamase producing Enterobacteria. (ESBL)
Beta-lactamases are enzymes produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics Some antibiotics have a common element in their molecular structure ( beta lactam ring) Lactamase enzyme breaks down this structure (hydrolysis) Penicillin's Cephamycin’s Carbapenem’s Cephalosporin's Beta-lactamase Beta-lactamase Structure of a Streptomyces albus beta-lactamaseIdentifiersSymbolβ-lactamase domainPfamPF00144Pfam clanCL0013InterProIPR001466PROSITEPS00146SCOP56601SUPERFAMILY56601[show]Available protein structures:β-lactamase Action of β-lactamase and decarboxylation of the intermediateIdentifiersEC number CAS number DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO / EGO[show]Search From Wikipedia, the free encyclopedia Escherichia coli bacteria on the right are sensitive to two beta-lactam antibiotics, and do not grow in the semi-circular regions surrounding the antibiotics. E. coli bacteria on the left are resistant to beta-lactam antibiotics, and grow next to one antibiotic (bottom) and are less inhibited by another antibiotic (top). Core structure of penicillins (top) andcephalosporins (bottom). β-lactam ring in red. Beta-lactamases are enzymes (EC ) produced by some bacteria which provide resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems (ertapenem) (Carbapenems are relatively resistant to beta-lactamase). Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam. Through hydrolysis, the lactamase enzyme breaks the β-lactam ring open, deactivating the molecule's antibacterial properties. Contents Beta-lactamases produced by Gram-negative organisms are usually secreted, especially when antibiotics are present in the environment.[1] Beta-lactam antibiotics are typically used to treat a broad spectrum of Gram-positive and Gram-negative bacteria. [hide] 3 Classification 2 Penicillinase 1 Structure 3.1 Functional classification 3.1.3 Group 3 3.1.2 Group 2 3.1.1 Group 1 3.1.4 Group 4 4 Resistance in Gram-negative bacteria 3.2 Molecular classification 4.2 Types 4.1 Extended-spectrum beta-lactamase (ESBL) 4.2.3 CTX-M beta-lactamases (class A) 4.2.2 SHV beta-lactamases (class A) 4.2.1 TEM beta-lactamases (class A) 4.2.4 OXA beta-lactamases (class D) 4.3 Inhibitor-resistant β-lactamases 4.2.6 Treatment 4.2.5 Others 4.5 Carbapenemases 4.4 AmpC-type β-lactamases (Class C) 4.5.3 OXA (oxacillinase) group of β-lactamases) (Class D) 4.5.2 VIM (Verona integron-encoded metallo-β-lactamase) (Class B) 4.5.1 IMP-type carbapenemases (metallo-β-lactamases) (Class B) 4.5.6 SME, IMI, NMC and CcrA 4.5.5 CMY (Class C) 4.5.4 KPC (K. pneumoniae carbapenemase) (Class A) 5 Treatment of ESBL/AmpC/carbapenemases 4.5.7 NDM-1 (New Delhi metallo-β-lactamase) (Class B) 5.2 According to genes 5.1 General overview 5.2.2 Inhibitor-Resistant β-Lactamases 5.2.1 ESBLs 5.3 According to species 5.2.4 Carbapenemases 5.2.3 AmpC 5.3.2 Pseudomonas aeruginosa 5.3.1 Escherichia coli or Klebsiella 8 References 7 See also 6 Detection 9 External links [edit]Penicillinase The structure of a Streptomyces β lactamase is given by 1BSG. [edit]Structure Penicillinase was the first β-lactamase to be identified: It was first isolated by Abraham and Chain in 1940 from Gram-negative E. colieven before penicillin entered clinical use,[2] but penicillinase production quickly spread to bacteria that previously did not produce it or produced it only rarely. Penicillinase-resistant beta-lactams such as methicillin were developed, but there is now widespread resistanceto even these. Penicillinase is a specific type of β-lactamase, showing specificity for penicillins, again by hydrolysing the beta-lactam ring. Molecular weights of the various penicillinases tend to cluster near 50 kiloDaltons. [edit]Functional classification [edit]Classification The following functional classification for beta lactamases has been proposed:[3] [edit]Group 1 GROUP 2aPENICILLINASE, Molecular Class AThe 2a subgroup contains just penicillinases.GROUP 2bBROAD-SPECTRUM, Molecular Class A2b Opposite to 2a , 2b are broad-spectrum β-lactamases, meaning that they are capable of inactivating penicillins andcephalosporins at the same rate. Furthermore, new subgroups were segregated from subgroup 2b:GROUP 2beEXTENDED-SPECTRUM, Molecular Class ASubgroup 2be, with the letter "e" for extended spectrum of activity, represents the ESBLs, which are capable of inactivating third-generation cephalosporins (ceftazidime,cefotaxime, and cefpodoxime) as well as monobactams (aztreonam)GROUP 2brINHIBITOR-RESISTANT, Molecular Class A (diminished inhibition by clavulanic acid)The 2br enzymes, with the letter "r" denoting reduced binding to clavulanic acid and sulbactam, are also called inhibitor-resistant TEM-derivative enzymes; nevertheless, they are commonly still susceptible to tazobactam, except where an amino acid replacement exists at position met69.GROUP 2cCARBENICILLINASE, Molecular Class ALatersubgroup 2c was segregated from group 2 because these enzymes inactivate carbenicillin more than benzylpenicillin, with some effect on cloxacillin.GROUP 2dCLOXACILANASE, Molecular Class D or ASubgroup 2d enzymes inactivate cloxacillin more than benzylpenicillin, with some activity against carbenicillin; these enzymes are poorly inhibited by clavulanic acid, and some of them are ESBLsthe correct term is "OXACILLINASE". These enzymes are able to inactivate the oxazolylpenicillins like oxacillin, cloxacillin, dicloxacillin. The enzymes belong to the molecular class D not molecular class A.GROUP 2eCEPHALOSPORINASE, Molecular Class ASubgroup 2e enzymes are cephalosporinases that can also hydrolyse monobactams, and they are inhibited by clavulanic acidGROUP 2fCARBAPENAMASE, Molecular Class ASubgroup 2f was added because these are serine-based carbapenemases, in contrast to the zinc-based carbapenemases included in group 3[edit]Group 3 Group 2 are penicillinases, cephalosporinases, or both inhibited by clavulanic acid, corresponding to the molecular classes A and D reflecting the original TEM and SHV genes. However, because of the increasing number of TEM- and SHV-derived β-lactamases, they were divided into two subclasses, 2a and 2b. CEPHALOSPORINASE, Molecular Class C (not inhibited by clavulanic acid)Group 1 are cephalosporinases not inhibited by clavulanic acid, belonging to the molecular class C[edit]Group 2 METALLOENZYME, Molecular Class B (not inhibited by clavulanic acid)Group 3 are the zinc-based or metallo {beta}-lactamases, corresponding to the molecular class B, which are the only enzymes acting by the metal ion zinc, as discussed above. Metallo B-lactamases are able to hydrolyse penicillins, cephalosporins, and carbapenems. Thus, carbapenems are inhibited by both group 2f (serine-based mechanism) and group 3 (zinc-based mechanism)[edit]Group 4 The molecular classification of β-lactamases is based on the nucleotide and amino acid sequences in these enzymes. To date, four classes are recognised (A-D), correlating with the functional classification. Classes A, C, and D act by a serine-based mechanism, whereas class B or metallo-β-lactamases need zinc for their action[4] PENICILLINASE, No Molecular Class (not inhibited by clavulanic acid)Group 4 are penicillinases that are not inhibited by clavulanic acid, and they do not yet have a corresponding molecular class.[edit]Molecular classification "Penicillinase" was discovered in 1940 and renamed Beta-lactamase when the structure of the Beta-lactam ring was finally elucidated. Among Gram-negative bacteria, the emergence of resistance to expanded-spectrum cephalosporins has been a major concern. It appeared initially in a limited number of bacterial species (E. cloacae, C. freundii, S. marcescens, and P. aeruginosa ) that could mutate to hyperproduce their chromosomal class C β-lactamase. A few years later, resistance appeared in bacterial species not naturally producing AmpC enzymes (K. pneumoniae, Salmonella spp., P. mirabilis) due to the production of TEM- or SHV-type ESBLs. Characteristically, such resistance has included oxyimino- (for example ceftizoxime, cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam aztreonam), but not 7-alpha-methoxy-cephalosporins (cephamycins); in other words, (cefoxitin and cefotetan) have been blocked by inhibitors such as clavulanate, sulbactam, or tazobactam, and did not involve carbapenems. Chromosomal-mediated AmpC β-lactamases represent a new threat, since they confer resistance to 7-alpha-methoxy-cephalosporins (cephamycins) such as cefoxitin or cefotetan are not affected by commercially available β-lactamase inhibitors, and can, in strains with loss of outer membrane porins, provide resistance to carbapenems.[5] [edit]Resistance in Gram-negative bacteria Members of the family Enterobacteriaceae commonly express plasmid-encoded β-lactamases (e.g., TEM-1, TEM-2, and SHV-1). which confer resistance to penicillins but not to expanded-spectrum cephalosporins. In the mid-1980s, a new group of enzymes, the extended-spectrum b-lactamases (ESBLs), was detected. (first detected in Germany in 1983).[6] ESBLs are beta-lactamases that hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include cefotaxime, ceftriaxone, andceftazidime, as well as the oxyimino-monobactam aztreonam. Thus ESBLs confer resistance to these antibiotics and related oxyimino-beta lactams. In typical circumstances, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described.[7] The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. [edit]Extended-spectrum beta-lactamase (ESBL) TEM-1 is the most commonly encountered beta-lactamase in Gram-negative bacteria. Up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1.[8] Also responsible for the ampicillin and penicillin resistance that is seen in H. influenzae and N. gonorrhoeae in increasing numbers. Although TEM-type beta-lactamases are most often found in E. coli and K. pneumoniae, they are also found in other species of Gram-negative bacteria with increasing frequency. The amino acid substitutions responsible for the ESBL phenotype cluster around the active site of the enzyme and change its configuration, allowing access to oxyimino-beta-lactam substrates. Opening the active site to beta-lactam substrates also typically enhances the susceptibility of the enzyme to b-lactamase inhibitors, such as clavulanic acid. Single amino acid substitutions at positions 104, 164, 238, and 240 produce the ESBL phenotype, but ESBLs with the broadest spectrum usually have more than a single amino acid substitution. Based upon different combinations of changes, currently 140 TEM-type enzymes have been described. TEM-10, TEM-12, and TEM-26 are among the most common in the United States.[9][10][11] [edit]TEM beta-lactamases (class A) [edit]Types SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall structure. The SHV-1 beta-lactamase is most commonly found in K. pneumoniae and is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this species. ESBLs in this family also have amino acid changes around the active site, most commonly at positions 238 or 238 and 240. More than 60 SHV varieties are known. They are the predominant ESBL type in Europe and the United States and are found worldwide. SHV-5 and SHV-12 are among the most common.[9] [edit]SHV beta-lactamases (class A) These enzymes were named for their greater activity against cefotaxime than other oxyimino-beta-lactam substrates (e.g., ceftazidime, ceftriaxone, or cefepime). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. More than 80 CTX-M enzymes are currently known. Despite their name, a few are more active on ceftazidime than cefotaxime. They have mainly been found in strains of Salmonella enterica serovar Typhimurium and E. coli, but have also been described in other species of Enterobacteriaceae and are the predominant ESBL type in parts of South America. (They are also seen in eastern Europe) CTX-M-14, CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is currently (2006) the most widespread type in E. coli the UK and is widely prevalent in the community.[12] [edit]CTX-M beta-lactamases (class A) OXA beta-lactamases were long recognized as a less common but also plasmid-mediated beta-lactamase variety that could hydrolyze oxacillin and related anti-staphylococcal penicillins. These beta-lactamases differ from the TEM and SHV enzymes in that they belong to molecular class D and functional group 2d . The OXA-type beta-lactamases confer resistance to ampicillin and cephalothin and are characterized by their high hydrolytic activity against oxacillin and cloxacillin and the fact that they are poorly inhibited by clavulanic acid. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. While most ESBLs have been found in E. coli, K. pneumoniae, and other Enterobacteriaceae, the OXA-type ESBLs have been found mainly in P. aeruginosa. OXA-type ESBLs have been found mainly in Pseudomonas aeruginosa isolates from Turkey and France. The OXA beta-lactamase family was originally created as a phenotypic rather than a genotypic group for a few beta-lactamases that had a specific hydrolysis profile. Therefore, there is as little as 20% sequence homology among some of the members of this family. However, recent additions to this family show some degree of homology to one or more of the existing members of the OXA beta-lactamase family. Some confer resistance predominantly to ceftazidime, but OXA-17 confers greater resistance to cefotaxime and cefepime than it does resistance to ceftazidime. [edit]OXA beta-lactamases (class D) Other plasmid-mediated ESBLs, such as PER, VEB, GES, and IBC beta-lactamases, have been described but are uncommon and have been found mainly in P. aeruginosa and at a limited number of geographic sites. PER-1 in isolates in Turkey, France, and Italy; VEB-1 and VEB-2 in strains from Southeast Asia; and GES-1, GES-2, and IBC-2 in isolates from South Africa, France, and Greece. PER-1 is also common in multiresistant acinetobacter species in Korea and Turkey. Some of these enzymes are found in Enterobacteriaceae as well, whereas other uncommon ESBLs (such as BES-1, IBC-1, SFO-1, and TLA-1) have been found only in Enterobacteriaceae. [edit]Others While ESBL-producing organisms were previously associated with hospitals and institutional care, these organisms are now increasingly found in the community. CTX-M-15-positiveE. coli are a cause of community-acquired urinary infections in the UK,[12] and tend to be resistant to all oral β-lactam antibiotics, as well as quinolones and sulfonamides. Treatment options may include nitrofurantoin, fosfomycin, mecillinam and chloramphenicol. In desperation, once-daily ertapenem or gentamicin injections may also be used. [edit]Treatment Although the inhibitor-resistant β-lactamases are not ESBLs, they are often discussed with ESBLs because they are also derivatives of the classical TEM- or SHV-type enzymes. These enzymes were at first given the designation IRT for inhibitor-resistant TEM β-lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct inhibitor-resistant TEM β-lactamases. Inhibitor-resistant TEM β-lactamases have been found mainly in clinical isolates of E. coli, but also some strains of K. pneumoniae, Klebsiella oxytoca, P. mirabilis, and Citrobacter freundii. Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid andsulbactam, thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of amoxicillin-clavulanate (co-amoxiclav), ticarcillin-clavulanate (co-ticarclav), and ampicillin/sulbactam, they normally remain susceptible to inhibition by tazobactam and subsequently the combination of piperacillin/tazobactam, although resistance has been described. This is no longer a primarily European epidemiology, it is found in northern parts of America often and should be tested for with complex UTI's.[10] [edit]Inhibitor-resistant β-lactamases AmpC type β-lactamases are commonly isolated from extended-spectrum cephalosporin-resistant Gram-negative bacteria. AmpC β-lactamases (also termed class C or group 1) are typically encoded on the chromosome of many Gram-negative bacteria including Citrobacter, Serratia and Enterobacter species where its expression is usually inducible; it may also occur on Escherichia coli but is not usually inducible, although it can be hyperexpressed. AmpC type β-lactamases may also be carried on plasmids.[5] AmpC β-lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-β-lactams) but are not inhibited by β-lactamase inhibitors such as clavulanic acid. [edit]AmpC-type β-lactamases (Class C) Carbapenems are famously stable to AmpC β-lactamases and extended-spectrum-β-lactamases. Carbapenemases are a diverse group of β-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems. Aztreonam is stable to the metallo-β-lactamases, but many IMP and VIM producers are resistant, owing to other mechanisms. Carbapenemases were formerly believed to derive only from classes A, B, and D, but a class C carbapenemase has been described. [edit]Carbapenemases Plasmid-mediated IMP-type carbapenemases, 17 varieties of which are currently known, became established in Japan in the 1990s both in enteric Gram-negative organisms and inPseudomonas and Acinetobacter species. IMP enzymes spread slowly to other countries in the Far East, were reported from Europe in 1997, and have been found in Canada and Brazil. [edit]IMP-type carbapenemases (metallo-β-lactamases) (Class B) A second growing family of carbapenemases, the VIM family, was reported from Italy in 1999 and now includes 10 members, which have a wide geographic distribution in Europe, South America, and the Far East and have been found in the United States. VIM-1 was discovered in P. aeruginosa in Italy in 1996; since then, VIM-2 - now the predominant variant - was found repeatedly in Europe and the Far East; VIM-3 and -4 are minor variants of VIM-2 and -1, respectively. VIM enzymes occur mostly in P. aeruginosa, also P. putida and, very rarely, Enterobacteriaceae. [edit]VIM (Verona integron-encoded metallo-β-lactamase) (Class B) The OXA group of β-lactamases occur mainly in Acinetobacter species and are divided into two clusters. OXA carbapenemases hydrolyse carbapenems very slowly in vitro, and the high MICs seen for some Acinetobacter hosts (>64 mg/L) may reflect secondary mechanisms. They are sometimes augmented in clinical isolates by additional resistance mechanisms, such as impermeability or efflux. OXA carbapenemases also tend to have a reduced hydrolytic efficiency towards penicillins and cephalosporins.[13] [edit]OXA (oxacillinase) group of β-lactamases) (Class D) Amino acid sequence diversity is up to 10% in the VIM family, 15% in the IMP family, and 70% between VIM and IMP. Enzymes of both the families, nevertheless, are similar. Both are integron-associated, sometimes within plasmids. Both hydrolyse all β-lactams except monobactams, and evade all β-lactam inhibitors. A few class A enzymes, most noted the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Ten variants, KPC-2 through KPC-11 are known, and they are distinguished by one or two amino-acid substitutions (KPC-1 was re-sequenced in 2008 and found to be 100% homologous to published sequences of KPC-2). KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids. [edit]KPC (K. pneumoniae carbapenemase) (Class A) The class A Klebsiella pneumoniae carbapenemase (KPC) is currently the most common carbapenemase, which was first detected in North Carolina, US, in 1996 and has since spread worldwide.[14] A later publication indicated that Enterobacteriaceae that produce KPC were becoming common in the United States.[15] [edit]CMY (Class C) In general, these are of little clinical significance. [edit]SME, IMI, NMC and CcrA The first class C carbapenemase was described in 2006 and was isolated from a virulent strain of Enterobacter aerogenes.[16] It is carried on a plasmid, pYMG-1, and is therefore transmissible to other bacterial strains.[17] CcrA (CfiA). Its gene occurs in c. 1-3% of B. fragilis isolates, but fewer produce the enzyme since expression demands appropriate migration of an insertion sequence. CcrA was known before imipenem was introduced, and producers have shown little subsequent increase. Originally described from New Delhi in 2009, this gene is now widespread in Escherichia coli and Klebsiella pneumoniae from India and Pakistan. As of mid-2010, NDM-1 carrying bacteria have been introduced to other countries (including the United States and UK), most probably due to the large number of tourists travelling the globe, who may have picked up the strain from the environment, as strains containing the NDM-1 gene have been found in environmental samples in India.[18] Main article: New Delhi metallo-beta-lactamase [edit]NDM-1 (New Delhi metallo-β-lactamase) (Class B) [edit]Treatment of ESBL/AmpC/carbapenemases In general, an isolate is suspected to be an ESBL producer when it shows in vitro susceptibility to the second-generation cephalosporins (cefoxitin, cefotetan) but resistance to the third-generation cephalosporins and to aztreonam. Moreover, one should suspect these strains when treatment with these agents for Gram-negative infections fails despite reportedin vitro susceptibility. Once an ESBL-producing strain is detected, the laboratory should report it as "resistant" to all penicillins, cephalosporins, and aztreonam, even if it is tested (in vitro) as susceptible.[citation needed] Associated resistance to aminoglycosides and trimethoprim-sulfamethoxazole, as well as high frequency of co-existence of fluoroquinoloneresistance, creates problems. Beta-lactamase inhibitors such as clavulanate, sulbactam, and tazobactam in vitro inhibit most ESBLs, but the clinical effectiveness of beta-lactam/beta-lactamase inhibitor combinations cannot be relied on consistently for therapy. Cephamycins (cefoxitin and cefotetan) are not hydrolyzed by majority of ESBLs, but are hydrolyzed by associated AmpC-type β-lactamase. Also, β-lactam/β-lactamase inhibitor combinations may not be effective against organisms that produce AmpC-type β-lactamase. Sometimes these strains decrease the expression of outer membrane proteins, rendering them resistant to cephamycins. In vivo studies have yielded mixed results against ESBL-producing K. pneumoniae. (Cefepime, a fourth-generation cephalosporin, has demonstrated in vitro stability in the presence of many ESBL/AmpC strains.) Currently,carbapenems are, in general, regarded as the preferred agent for treatment of infections due to ESBL-producing organisms. Carbapenems are resistant to ESBL-mediated hydrolysis and exhibit excellent in vitro activity against strains of Enterobacteriaceae expressing ESBLs.[citation needed] [edit]General overview [edit]ESBLs [edit]According to genes Strains with some CTX-M–type and OXA-type ESBLs are resistant to cefepime on testing, despite the use of a standard inoculum. For organisms producing TEM and SHV type ESBLs, apparent in vitro sensitivity to cefepime and to piperacillin/tazobactam is common, but both drugs show an inoculum effect, with diminished susceptibility as the size of the inoculum is increased from 105to 107organisms. Strains producing only ESBLs are susceptible to cephamycins and carbapenems in vitro and show little if any inoculum effect with these agents. Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid and sulbactam, thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of amoxicillin-clavulanate (Co-amoxiclav), ticarcillin-clavulanate, and ampicillin/sulbactam, they remain susceptible to inhibition by tazobactam and subsequently the combination of piperacillin/tazobactam. [edit]Inhibitor-Resistant β-Lactamases AmpC-producing strains are typically resistant to oxyimino-beta lactams and to cephamycins and are susceptible to carbapenems; however, diminished porin expression can make such a strain carbapenem-resistant as well. [edit]AmpC Strains with IMP-, VIM-, and OXA-type carbapenemases usually remain susceptible. Resistance to non–b-lactam antibiotics is common in strains making any of these enzymes, such that alternative options for non–b-lactam therapy need to be determined by direct susceptibility testing. Resistance to fluoroquinolones and aminoglycosides is especially high. For infections caused by ESBL-producing Escherichia coli or Klebsiella species, treatment with imipenem or meropenem has been associated with the best outcomes in terms of survival and bacteriologic clearance. Cefepime and piperacillin/tazobactam have been less successful. Ceftriaxone, cefotaxime, and ceftazidime have failed even more often, despite the organism's susceptibility to the antibiotic in vitro. Several reports have documented failure of cephamycin therapy as a result of resistance due to porin loss. Some patients have responded to aminoglycoside or quinolone therapy, but, in a recent comparison of ciprofloxacin and imipenem for bacteremia involving an ESBL-producing K. pneumoniae,imipenem produced the better outcome [edit]Escherichia coli or Klebsiella [edit]According to species [edit]Pseudomonas aeruginosa Beta-lactamase enzymatic activity can be detected using nitrocefin, a chromogenic cephalosporin substrate which changes color from yellow to red upon beta-lactamase mediated hydrolysis.[19] [edit]Detection There have been few clinical studies to define the optimal therapy for infections caused by ESBL producing Pseudomonas aeruginosa strains. ESBL-producing E. coli [edit]See also

Extended Spectrum Beta- Lactamase producing Enterobacteria. (ESBL)
Mostly gram negative rod shaped bacteria Normally part of the gut flora found in the intestines 60% mortality rate with blood stream infections Common species that produce Beta- lactamases Escherichia coli Klebsiella Pseudomonas aeruginosa Salmonella Beta-lactamase Beta-lactamase Structure of a Streptomyces albus beta-lactamaseIdentifiersSymbolβ-lactamase domainPfamPF00144Pfam clanCL0013InterProIPR001466PROSITEPS00146SCOP56601SUPERFAMILY56601[show]Available protein structures:β-lactamase Action of β-lactamase and decarboxylation of the intermediateIdentifiersEC number CAS number DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO / EGO[show]Search From Wikipedia, the free encyclopedia Escherichia coli bacteria on the right are sensitive to two beta-lactam antibiotics, and do not grow in the semi-circular regions surrounding the antibiotics. E. coli bacteria on the left are resistant to beta-lactam antibiotics, and grow next to one antibiotic (bottom) and are less inhibited by another antibiotic (top). Core structure of penicillins (top) andcephalosporins (bottom). β-lactam ring in red. Beta-lactamases are enzymes (EC ) produced by some bacteria which provide resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems (ertapenem) (Carbapenems are relatively resistant to beta-lactamase). Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam. Through hydrolysis, the lactamase enzyme breaks the β-lactam ring open, deactivating the molecule's antibacterial properties. Beta-lactam antibiotics are typically used to treat a broad spectrum of Gram-positive and Gram-negative bacteria. [hide] Contents Beta-lactamases produced by Gram-negative organisms are usually secreted, especially when antibiotics are present in the environment.[1] 1 Structure 3 Classification 2 Penicillinase 3.1 Functional classification 3.1.2 Group 2 3.1.1 Group 1 3.2 Molecular classification 3.1.4 Group 4 3.1.3 Group 3 4 Resistance in Gram-negative bacteria 4.2 Types 4.1 Extended-spectrum beta-lactamase (ESBL) 4.2.3 CTX-M beta-lactamases (class A) 4.2.2 SHV beta-lactamases (class A) 4.2.1 TEM beta-lactamases (class A) 4.2.6 Treatment 4.2.5 Others 4.2.4 OXA beta-lactamases (class D) 4.3 Inhibitor-resistant β-lactamases 4.5 Carbapenemases 4.4 AmpC-type β-lactamases (Class C) 4.5.3 OXA (oxacillinase) group of β-lactamases) (Class D) 4.5.2 VIM (Verona integron-encoded metallo-β-lactamase) (Class B) 4.5.1 IMP-type carbapenemases (metallo-β-lactamases) (Class B) 4.5.6 SME, IMI, NMC and CcrA 4.5.5 CMY (Class C) 4.5.4 KPC (K. pneumoniae carbapenemase) (Class A) 5 Treatment of ESBL/AmpC/carbapenemases 4.5.7 NDM-1 (New Delhi metallo-β-lactamase) (Class B) 5.2 According to genes 5.1 General overview 5.2.1 ESBLs 5.2.2 Inhibitor-Resistant β-Lactamases 5.3 According to species 5.2.4 Carbapenemases 5.2.3 AmpC 5.3.1 Escherichia coli or Klebsiella 7 See also 6 Detection 5.3.2 Pseudomonas aeruginosa 9 External links 8 References [edit]Penicillinase The structure of a Streptomyces β lactamase is given by 1BSG. [edit]Structure Penicillinase was the first β-lactamase to be identified: It was first isolated by Abraham and Chain in 1940 from Gram-negative E. colieven before penicillin entered clinical use,[2] but penicillinase production quickly spread to bacteria that previously did not produce it or produced it only rarely. Penicillinase-resistant beta-lactams such as methicillin were developed, but there is now widespread resistanceto even these. Penicillinase is a specific type of β-lactamase, showing specificity for penicillins, again by hydrolysing the beta-lactam ring. Molecular weights of the various penicillinases tend to cluster near 50 kiloDaltons. [edit]Functional classification [edit]Classification The following functional classification for beta lactamases has been proposed:[3] [edit]Group 1 GROUP 2aPENICILLINASE, Molecular Class AThe 2a subgroup contains just penicillinases.GROUP 2bBROAD-SPECTRUM, Molecular Class A2b Opposite to 2a , 2b are broad-spectrum β-lactamases, meaning that they are capable of inactivating penicillins andcephalosporins at the same rate. Furthermore, new subgroups were segregated from subgroup 2b:GROUP 2beEXTENDED-SPECTRUM, Molecular Class ASubgroup 2be, with the letter "e" for extended spectrum of activity, represents the ESBLs, which are capable of inactivating third-generation cephalosporins (ceftazidime,cefotaxime, and cefpodoxime) as well as monobactams (aztreonam)GROUP 2brINHIBITOR-RESISTANT, Molecular Class A (diminished inhibition by clavulanic acid)The 2br enzymes, with the letter "r" denoting reduced binding to clavulanic acid and sulbactam, are also called inhibitor-resistant TEM-derivative enzymes; nevertheless, they are commonly still susceptible to tazobactam, except where an amino acid replacement exists at position met69.GROUP 2cCARBENICILLINASE, Molecular Class ALatersubgroup 2c was segregated from group 2 because these enzymes inactivate carbenicillin more than benzylpenicillin, with some effect on cloxacillin.GROUP 2dCLOXACILANASE, Molecular Class D or ASubgroup 2d enzymes inactivate cloxacillin more than benzylpenicillin, with some activity against carbenicillin; these enzymes are poorly inhibited by clavulanic acid, and some of them are ESBLsthe correct term is "OXACILLINASE". These enzymes are able to inactivate the oxazolylpenicillins like oxacillin, cloxacillin, dicloxacillin. The enzymes belong to the molecular class D not molecular class A.GROUP 2eCEPHALOSPORINASE, Molecular Class ASubgroup 2e enzymes are cephalosporinases that can also hydrolyse monobactams, and they are inhibited by clavulanic acidGROUP 2fCARBAPENAMASE, Molecular Class ASubgroup 2f was added because these are serine-based carbapenemases, in contrast to the zinc-based carbapenemases included in group 3[edit]Group 3 Group 2 are penicillinases, cephalosporinases, or both inhibited by clavulanic acid, corresponding to the molecular classes A and D reflecting the original TEM and SHV genes. However, because of the increasing number of TEM- and SHV-derived β-lactamases, they were divided into two subclasses, 2a and 2b. CEPHALOSPORINASE, Molecular Class C (not inhibited by clavulanic acid)Group 1 are cephalosporinases not inhibited by clavulanic acid, belonging to the molecular class C[edit]Group 2 METALLOENZYME, Molecular Class B (not inhibited by clavulanic acid)Group 3 are the zinc-based or metallo {beta}-lactamases, corresponding to the molecular class B, which are the only enzymes acting by the metal ion zinc, as discussed above. Metallo B-lactamases are able to hydrolyse penicillins, cephalosporins, and carbapenems. Thus, carbapenems are inhibited by both group 2f (serine-based mechanism) and group 3 (zinc-based mechanism)[edit]Group 4 "Penicillinase" was discovered in 1940 and renamed Beta-lactamase when the structure of the Beta-lactam ring was finally elucidated. The molecular classification of β-lactamases is based on the nucleotide and amino acid sequences in these enzymes. To date, four classes are recognised (A-D), correlating with the functional classification. Classes A, C, and D act by a serine-based mechanism, whereas class B or metallo-β-lactamases need zinc for their action[4] PENICILLINASE, No Molecular Class (not inhibited by clavulanic acid)Group 4 are penicillinases that are not inhibited by clavulanic acid, and they do not yet have a corresponding molecular class.[edit]Molecular classification Among Gram-negative bacteria, the emergence of resistance to expanded-spectrum cephalosporins has been a major concern. It appeared initially in a limited number of bacterial species (E. cloacae, C. freundii, S. marcescens, and P. aeruginosa ) that could mutate to hyperproduce their chromosomal class C β-lactamase. A few years later, resistance appeared in bacterial species not naturally producing AmpC enzymes (K. pneumoniae, Salmonella spp., P. mirabilis) due to the production of TEM- or SHV-type ESBLs. Characteristically, such resistance has included oxyimino- (for example ceftizoxime, cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam aztreonam), but not 7-alpha-methoxy-cephalosporins (cephamycins); in other words, (cefoxitin and cefotetan) have been blocked by inhibitors such as clavulanate, sulbactam, or tazobactam, and did not involve carbapenems. Chromosomal-mediated AmpC β-lactamases represent a new threat, since they confer resistance to 7-alpha-methoxy-cephalosporins (cephamycins) such as cefoxitin or cefotetan are not affected by commercially available β-lactamase inhibitors, and can, in strains with loss of outer membrane porins, provide resistance to carbapenems.[5] [edit]Resistance in Gram-negative bacteria Members of the family Enterobacteriaceae commonly express plasmid-encoded β-lactamases (e.g., TEM-1, TEM-2, and SHV-1). which confer resistance to penicillins but not to expanded-spectrum cephalosporins. In the mid-1980s, a new group of enzymes, the extended-spectrum b-lactamases (ESBLs), was detected. (first detected in Germany in 1983).[6] ESBLs are beta-lactamases that hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include cefotaxime, ceftriaxone, andceftazidime, as well as the oxyimino-monobactam aztreonam. Thus ESBLs confer resistance to these antibiotics and related oxyimino-beta lactams. In typical circumstances, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described.[7] The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. [edit]Extended-spectrum beta-lactamase (ESBL) [edit]Types TEM-1 is the most commonly encountered beta-lactamase in Gram-negative bacteria. Up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1.[8] Also responsible for the ampicillin and penicillin resistance that is seen in H. influenzae and N. gonorrhoeae in increasing numbers. Although TEM-type beta-lactamases are most often found in E. coli and K. pneumoniae, they are also found in other species of Gram-negative bacteria with increasing frequency. The amino acid substitutions responsible for the ESBL phenotype cluster around the active site of the enzyme and change its configuration, allowing access to oxyimino-beta-lactam substrates. Opening the active site to beta-lactam substrates also typically enhances the susceptibility of the enzyme to b-lactamase inhibitors, such as clavulanic acid. Single amino acid substitutions at positions 104, 164, 238, and 240 produce the ESBL phenotype, but ESBLs with the broadest spectrum usually have more than a single amino acid substitution. Based upon different combinations of changes, currently 140 TEM-type enzymes have been described. TEM-10, TEM-12, and TEM-26 are among the most common in the United States.[9][10][11] [edit]TEM beta-lactamases (class A) SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall structure. The SHV-1 beta-lactamase is most commonly found in K. pneumoniae and is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this species. ESBLs in this family also have amino acid changes around the active site, most commonly at positions 238 or 238 and 240. More than 60 SHV varieties are known. They are the predominant ESBL type in Europe and the United States and are found worldwide. SHV-5 and SHV-12 are among the most common.[9] [edit]SHV beta-lactamases (class A) [edit]CTX-M beta-lactamases (class A) These enzymes were named for their greater activity against cefotaxime than other oxyimino-beta-lactam substrates (e.g., ceftazidime, ceftriaxone, or cefepime). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. More than 80 CTX-M enzymes are currently known. Despite their name, a few are more active on ceftazidime than cefotaxime. They have mainly been found in strains of Salmonella enterica serovar Typhimurium and E. coli, but have also been described in other species of Enterobacteriaceae and are the predominant ESBL type in parts of South America. (They are also seen in eastern Europe) CTX-M-14, CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is currently (2006) the most widespread type in E. coli the UK and is widely prevalent in the community.[12] OXA beta-lactamases were long recognized as a less common but also plasmid-mediated beta-lactamase variety that could hydrolyze oxacillin and related anti-staphylococcal penicillins. These beta-lactamases differ from the TEM and SHV enzymes in that they belong to molecular class D and functional group 2d . The OXA-type beta-lactamases confer resistance to ampicillin and cephalothin and are characterized by their high hydrolytic activity against oxacillin and cloxacillin and the fact that they are poorly inhibited by clavulanic acid. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. While most ESBLs have been found in E. coli, K. pneumoniae, and other Enterobacteriaceae, the OXA-type ESBLs have been found mainly in P. aeruginosa. OXA-type ESBLs have been found mainly in Pseudomonas aeruginosa isolates from Turkey and France. The OXA beta-lactamase family was originally created as a phenotypic rather than a genotypic group for a few beta-lactamases that had a specific hydrolysis profile. Therefore, there is as little as 20% sequence homology among some of the members of this family. However, recent additions to this family show some degree of homology to one or more of the existing members of the OXA beta-lactamase family. Some confer resistance predominantly to ceftazidime, but OXA-17 confers greater resistance to cefotaxime and cefepime than it does resistance to ceftazidime. [edit]OXA beta-lactamases (class D) [edit]Others Other plasmid-mediated ESBLs, such as PER, VEB, GES, and IBC beta-lactamases, have been described but are uncommon and have been found mainly in P. aeruginosa and at a limited number of geographic sites. PER-1 in isolates in Turkey, France, and Italy; VEB-1 and VEB-2 in strains from Southeast Asia; and GES-1, GES-2, and IBC-2 in isolates from South Africa, France, and Greece. PER-1 is also common in multiresistant acinetobacter species in Korea and Turkey. Some of these enzymes are found in Enterobacteriaceae as well, whereas other uncommon ESBLs (such as BES-1, IBC-1, SFO-1, and TLA-1) have been found only in Enterobacteriaceae. While ESBL-producing organisms were previously associated with hospitals and institutional care, these organisms are now increasingly found in the community. CTX-M-15-positiveE. coli are a cause of community-acquired urinary infections in the UK,[12] and tend to be resistant to all oral β-lactam antibiotics, as well as quinolones and sulfonamides. Treatment options may include nitrofurantoin, fosfomycin, mecillinam and chloramphenicol. In desperation, once-daily ertapenem or gentamicin injections may also be used. [edit]Treatment Although the inhibitor-resistant β-lactamases are not ESBLs, they are often discussed with ESBLs because they are also derivatives of the classical TEM- or SHV-type enzymes. These enzymes were at first given the designation IRT for inhibitor-resistant TEM β-lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct inhibitor-resistant TEM β-lactamases. Inhibitor-resistant TEM β-lactamases have been found mainly in clinical isolates of E. coli, but also some strains of K. pneumoniae, Klebsiella oxytoca, P. mirabilis, and Citrobacter freundii. Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid andsulbactam, thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of amoxicillin-clavulanate (co-amoxiclav), ticarcillin-clavulanate (co-ticarclav), and ampicillin/sulbactam, they normally remain susceptible to inhibition by tazobactam and subsequently the combination of piperacillin/tazobactam, although resistance has been described. This is no longer a primarily European epidemiology, it is found in northern parts of America often and should be tested for with complex UTI's.[10] [edit]Inhibitor-resistant β-lactamases AmpC type β-lactamases are commonly isolated from extended-spectrum cephalosporin-resistant Gram-negative bacteria. AmpC β-lactamases (also termed class C or group 1) are typically encoded on the chromosome of many Gram-negative bacteria including Citrobacter, Serratia and Enterobacter species where its expression is usually inducible; it may also occur on Escherichia coli but is not usually inducible, although it can be hyperexpressed. AmpC type β-lactamases may also be carried on plasmids.[5] AmpC β-lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-β-lactams) but are not inhibited by β-lactamase inhibitors such as clavulanic acid. [edit]AmpC-type β-lactamases (Class C) Carbapenems are famously stable to AmpC β-lactamases and extended-spectrum-β-lactamases. Carbapenemases are a diverse group of β-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems. Aztreonam is stable to the metallo-β-lactamases, but many IMP and VIM producers are resistant, owing to other mechanisms. Carbapenemases were formerly believed to derive only from classes A, B, and D, but a class C carbapenemase has been described. [edit]Carbapenemases Plasmid-mediated IMP-type carbapenemases, 17 varieties of which are currently known, became established in Japan in the 1990s both in enteric Gram-negative organisms and inPseudomonas and Acinetobacter species. IMP enzymes spread slowly to other countries in the Far East, were reported from Europe in 1997, and have been found in Canada and Brazil. [edit]IMP-type carbapenemases (metallo-β-lactamases) (Class B) [edit]VIM (Verona integron-encoded metallo-β-lactamase) (Class B) A second growing family of carbapenemases, the VIM family, was reported from Italy in 1999 and now includes 10 members, which have a wide geographic distribution in Europe, South America, and the Far East and have been found in the United States. VIM-1 was discovered in P. aeruginosa in Italy in 1996; since then, VIM-2 - now the predominant variant - was found repeatedly in Europe and the Far East; VIM-3 and -4 are minor variants of VIM-2 and -1, respectively. VIM enzymes occur mostly in P. aeruginosa, also P. putida and, very rarely, Enterobacteriaceae. The OXA group of β-lactamases occur mainly in Acinetobacter species and are divided into two clusters. OXA carbapenemases hydrolyse carbapenems very slowly in vitro, and the high MICs seen for some Acinetobacter hosts (>64 mg/L) may reflect secondary mechanisms. They are sometimes augmented in clinical isolates by additional resistance mechanisms, such as impermeability or efflux. OXA carbapenemases also tend to have a reduced hydrolytic efficiency towards penicillins and cephalosporins.[13] [edit]OXA (oxacillinase) group of β-lactamases) (Class D) Amino acid sequence diversity is up to 10% in the VIM family, 15% in the IMP family, and 70% between VIM and IMP. Enzymes of both the families, nevertheless, are similar. Both are integron-associated, sometimes within plasmids. Both hydrolyse all β-lactams except monobactams, and evade all β-lactam inhibitors. A few class A enzymes, most noted the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Ten variants, KPC-2 through KPC-11 are known, and they are distinguished by one or two amino-acid substitutions (KPC-1 was re-sequenced in 2008 and found to be 100% homologous to published sequences of KPC-2). KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids. [edit]KPC (K. pneumoniae carbapenemase) (Class A) The first class C carbapenemase was described in 2006 and was isolated from a virulent strain of Enterobacter aerogenes.[16] It is carried on a plasmid, pYMG-1, and is therefore transmissible to other bacterial strains.[17] [edit]CMY (Class C) The class A Klebsiella pneumoniae carbapenemase (KPC) is currently the most common carbapenemase, which was first detected in North Carolina, US, in 1996 and has since spread worldwide.[14] A later publication indicated that Enterobacteriaceae that produce KPC were becoming common in the United States.[15] In general, these are of little clinical significance. [edit]SME, IMI, NMC and CcrA Main article: New Delhi metallo-beta-lactamase [edit]NDM-1 (New Delhi metallo-β-lactamase) (Class B) CcrA (CfiA). Its gene occurs in c. 1-3% of B. fragilis isolates, but fewer produce the enzyme since expression demands appropriate migration of an insertion sequence. CcrA was known before imipenem was introduced, and producers have shown little subsequent increase. Originally described from New Delhi in 2009, this gene is now widespread in Escherichia coli and Klebsiella pneumoniae from India and Pakistan. As of mid-2010, NDM-1 carrying bacteria have been introduced to other countries (including the United States and UK), most probably due to the large number of tourists travelling the globe, who may have picked up the strain from the environment, as strains containing the NDM-1 gene have been found in environmental samples in India.[18] In general, an isolate is suspected to be an ESBL producer when it shows in vitro susceptibility to the second-generation cephalosporins (cefoxitin, cefotetan) but resistance to the third-generation cephalosporins and to aztreonam. Moreover, one should suspect these strains when treatment with these agents for Gram-negative infections fails despite reportedin vitro susceptibility. Once an ESBL-producing strain is detected, the laboratory should report it as "resistant" to all penicillins, cephalosporins, and aztreonam, even if it is tested (in vitro) as susceptible.[citation needed] Associated resistance to aminoglycosides and trimethoprim-sulfamethoxazole, as well as high frequency of co-existence of fluoroquinoloneresistance, creates problems. Beta-lactamase inhibitors such as clavulanate, sulbactam, and tazobactam in vitro inhibit most ESBLs, but the clinical effectiveness of beta-lactam/beta-lactamase inhibitor combinations cannot be relied on consistently for therapy. Cephamycins (cefoxitin and cefotetan) are not hydrolyzed by majority of ESBLs, but are hydrolyzed by associated AmpC-type β-lactamase. Also, β-lactam/β-lactamase inhibitor combinations may not be effective against organisms that produce AmpC-type β-lactamase. Sometimes these strains decrease the expression of outer membrane proteins, rendering them resistant to cephamycins. In vivo studies have yielded mixed results against ESBL-producing K. pneumoniae. (Cefepime, a fourth-generation cephalosporin, has demonstrated in vitro stability in the presence of many ESBL/AmpC strains.) Currently,carbapenems are, in general, regarded as the preferred agent for treatment of infections due to ESBL-producing organisms. Carbapenems are resistant to ESBL-mediated hydrolysis and exhibit excellent in vitro activity against strains of Enterobacteriaceae expressing ESBLs.[citation needed] [edit]General overview [edit]Treatment of ESBL/AmpC/carbapenemases [edit]According to genes For organisms producing TEM and SHV type ESBLs, apparent in vitro sensitivity to cefepime and to piperacillin/tazobactam is common, but both drugs show an inoculum effect, with diminished susceptibility as the size of the inoculum is increased from 105to 107organisms. Strains producing only ESBLs are susceptible to cephamycins and carbapenems in vitro and show little if any inoculum effect with these agents. [edit]ESBLs Strains with some CTX-M–type and OXA-type ESBLs are resistant to cefepime on testing, despite the use of a standard inoculum. Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid and sulbactam, thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of amoxicillin-clavulanate (Co-amoxiclav), ticarcillin-clavulanate, and ampicillin/sulbactam, they remain susceptible to inhibition by tazobactam and subsequently the combination of piperacillin/tazobactam. [edit]Inhibitor-Resistant β-Lactamases AmpC-producing strains are typically resistant to oxyimino-beta lactams and to cephamycins and are susceptible to carbapenems; however, diminished porin expression can make such a strain carbapenem-resistant as well. [edit]AmpC Strains with IMP-, VIM-, and OXA-type carbapenemases usually remain susceptible. Resistance to non–b-lactam antibiotics is common in strains making any of these enzymes, such that alternative options for non–b-lactam therapy need to be determined by direct susceptibility testing. Resistance to fluoroquinolones and aminoglycosides is especially high. For infections caused by ESBL-producing Escherichia coli or Klebsiella species, treatment with imipenem or meropenem has been associated with the best outcomes in terms of survival and bacteriologic clearance. Cefepime and piperacillin/tazobactam have been less successful. Ceftriaxone, cefotaxime, and ceftazidime have failed even more often, despite the organism's susceptibility to the antibiotic in vitro. Several reports have documented failure of cephamycin therapy as a result of resistance due to porin loss. Some patients have responded to aminoglycoside or quinolone therapy, but, in a recent comparison of ciprofloxacin and imipenem for bacteremia involving an ESBL-producing K. pneumoniae,imipenem produced the better outcome [edit]Escherichia coli or Klebsiella [edit]According to species [edit]Pseudomonas aeruginosa Beta-lactamase enzymatic activity can be detected using nitrocefin, a chromogenic cephalosporin substrate which changes color from yellow to red upon beta-lactamase mediated hydrolysis.[19] [edit]Detection There have been few clinical studies to define the optimal therapy for infections caused by ESBL producing Pseudomonas aeruginosa strains. ESBL-producing E. coli [edit]See also In gram-negative bacteria, one of the important mechanisms of resistance is the, which inhibit protein transpeptidases participating in bacterial cell wall synthesis (Bradford, 2001; Paterson and Bonomo, 2005). Currently, numerous such enzymes are known and more continue to be described. Of particular clinical and epidemiological importance are ESBLs and AmpC beta lactamases, capable of inactivating the effects of broad-spectrum cephalosporins and penicillins. Production of these enzymes in clinically significant Enterobacteriaceaere presents an increasing problem resulting in higher patient morbidity and mortality (Paterson and Bonomo, 2005). For example, a recent study described a mortality rate of as high as 60% in patients with bloodstream infections due to ESBL-positive Enterobacteriaceae when adequate antibiotic therapy was not administered (Tumbarello et al., 2007). In humans, Enterobacteriaceae which produce ESBLs and AmpC broad-spectrum beta-lactamases have been studied for more than two decades (Bradford, 2001; Paterson and Bonomo, 2005). Similarly, articles describing their prevalence in food animals and foods of animal original have been published in recent years (Brinas et al., 2003; Liebana et al., 2004; Weill et al., 2004; Hasman et al., 2005; Jensen et al., 2006; Wu et al., 2008).In the Czech Republic, ESBLs and AmpC betalactamases were first described by Bardon et al. (2009) in samples from poultry. More detailed data, including the molecular characteristics of these enzymes are unavailable. Therefore, this study aimed at completing this gap. Enterobacter species, particularly Enterobacter cloacae and Enterobacter aerogenes, are important nosocomial pathogens responsible for various infections, including bacteremia, lower respiratory tract infections, skin and soft-tissue infections, urinary tract infections (UTIs), endocarditis, intra-abdominal infections, septic arthritis, osteomyelitis, and ophthalmic infections. Enterobacter species can also cause various community-acquired infections, including UTIs, skin and soft-tissue infections, and wound infections, among others. Risk factors for nosocomial Enterobacter infections include hospitalization of greater than 2 weeks, invasive procedures in the past 72 hours, treatment with antibiotics in the past 30 days, and the presence of a central venous catheter. Specific risk factors for infection with nosocomial multidrug-resistant strains of Enterobacter species include the recent use of broad-spectrum cephalosporins or aminoglycosides and ICU care. These "ICU bugs" cause significant morbidity and mortality, and infection management is complicated by resistance to multiple antibiotics.Enterobacter species possess inducible beta-lactamases, which are undetectable in vitro but are responsible for resistance during treatment. Physicians treating patients with Enterobacter infections are advised to avoid certain antibiotics, particularly third-generation cephalosporins, because resistant mutants can quickly appear. The crucial first step is appropriate identification of the bacteria. Antibiograms must be interpreted with respect to the different resistance mechanisms and their respective frequency, as is reported for Enterobacter species, even if routine in vitro antibiotic susceptibility testing has not identified resistance. Enterobacter species rarely cause disease in healthy individuals. This opportunistic pathogen, similar to other members of the Enterobacteriaceae family, possesses an endotoxin known to play a major role in the pathophysiology of sepsis and its complications. Although community-acquired Enterobacter infections are occasionally reported, nosocomial Enterobacter infections are, by far, most common. Patients most susceptible to Enterobacter infections are those who stay in the hospital, especially the ICU, for prolonged periods. Other major risk factors of Enterobacter infection include prior use of antimicrobial agents, concomitant malignancy (especially hemopoietic and solid-organ malignancies), hepatobiliary disease, ulcers of the upper gastrointestinal tract, use of foreign devices such as intravenous catheters, and serious underlying conditions such as burns, mechanical ventilation, and immunosuppression. The source of infection may be endogenous (via colonization of the skin, gastrointestinal tract, or urinary tract) or exogenous, resulting from the ubiquitous nature of Enterobacter species. Multiple reports have incriminated the hands of personnel, endoscopes, blood products, devices for monitoring intra-arterial pressure, and stethoscopes as sources of infection. Outbreaks have been traced to various common sources: total parenteral nutrition solutions, isotonic saline solutions, albumin, digital thermometers, and dialysis equipment. Enterobacter species contain a subpopulation of organisms that produce a beta-lactamase at low-levels. Once exposed to broad-spectrum cephalosporins, the subpopulation of beta-lactamase–producing organisms predominate. Thus, an Enterobacter infection that appears sensitive to cephalosporins at diagnosis may quickly develop into a resistant infection during therapy. Carbapenems and cefepime have a more stable beta-lactam ring against the lactamase produced by resistant strains of Enterobacter.

Clostridium difficile
Clostridium difficile (C. diff) is a gram positive bacteria of the clostridium genus. Contagious- especially in hospitals through contact Responsible for Clostridium difficile Infection (CDI) Infection types: Uncomplicated diarrhea (CDAD) Toxic megacolon Colitis These diseases can lead to sepsis and death Clostridium difficile C. difficile is the major cause of diarrhea associated with antibiotic use and is the most common infectious cause of nosocomial diarrhea. A major outbreak of C. difficile infection occurred in many hospitals in Quebec beginning in ,61 Markedly increased disease rates (as high as 156 cases per people) and severity occurred, especially among elderly people. In this outbreak, there was often a poor response to metronidazole therapy.61,62 The emergence of such severe disease is thought to have occurred because of the presence of a hypervirulent epidemic strain of C. difficile, known as PCR ribotype 27, or North America pulso-type 1 (NAP1).63 The same strain of C. difficile has caused extensive and severe disease in the United States and Europe.33 It is not clear why this strain appeared and caused such severe disease in the past few years, but this may in part be related to changing patterns of antimicrobial use in hospitals. The NAP1 strain associated with these outbreaks is resistant to fluoroquinolones, and fluoroquinolone use was found to be a major risk factor for C. difficile-associated disease in the Quebec outbreak.32 The NAP1 strain has now been identified in most provinces, and it has become the predominant strain in many hospitals, indicating the potential for severe outbreaks in many parts of the country. Clostridium difficile assocated Disease (CDAD) is now called clostridium difficile Toxic megacolon is characterized by extreme inflammation and distention of the colon. Symptoms are: pain, distention of the abdomen, fever, tarchycardia and dehydration. This is a medical emergency. 3. Pseudomembranous colitis: The Clostridium difficile bacteria is normally present in the intestine. However, it may overgrow when antibiotics are taken. The bacteria release a powerful toxin that causes the symptoms. The lining of the colon becomes inflamed and bleeds, and takes on a characteristic appearance called pseudomembranes.

CDC Guidelines For Reducing MDROs
Administrative Measures/Adherence Monitoring MDRO Education Judicious Antimicrobial Use Surveillance* Infection Control Precautions to Prevent Transmission Environmental Measures Administrative Measures/Adherence Monitoring Make MDRO prevention/control an organizational priority. Provide administrative support and both fiscal and human resources to prevent and control MDRO transmission. (IB) Identify experts who can provide consultation and expertise for analyzing epidemiologic data, recognizing MDRO problems, or devising effective control strategies, as needed. (II) Implement systems to communicate information about reportable MDROs to administrative personnel and state/local health departments. (II) Implement a multi-disciplinary process to monitor and improve HCP adherence to recommended practices for Standard and Contact Precautions.(IB) Implement systems to designate patients known to be colonized or infected with a targeted MDRO and to notify receiving healthcare facilities or personnel prior to transfer of such patients within or between facilities. (IB) Support participation in local, regional and/or national coalitions to combat emerging or growing MDRO problems.(IB) Provide updated feedback at least annually to healthcare providers and administrators on facility and patientcare unit MDRO infections. Include information on changes in prevalence and incidence, problem assessment and performance improvement plans. (IB) Provide education and training on risks and prevention of MDRO transmission during orientation and periodic educational updates for HCP; include information on organizational experience with MDROs and prevention strategies MDRO Education Provide education and training on risks and prevention of MDRO transmission during orientation and periodic educational updates for HCP; include information on organizational experience with MDROs and prevention strategies. (IB) Judicious Antimicrobial Use In hospitals and LTCFs, ensure that a multi-disciplinary process is in place to review local susceptibility patterns (antibiograms), and antimicrobial agents included in the formulary, to foster appropriate antimicrobial use. (IB) Implement systems (e.g., CPOE, susceptibility report comment, pharmacy or unit director notification) to prompt clinicians to use the appropriate agent and regimen for the given clinical situation. (IB) Provide clinicians with antimicrobial susceptibility reports and analysis of current trends, updated at least annually, to guide antimicrobial prescribing practices. (IB) In settings with limited electronic communication system infrastructures to implement physician prompts, etc., at a minimum implement a process to review antibiotic use. Prepare and distribute reports to providers. Surveillance Use standardized laboratory methods and follow published guidelines for determining antimicrobial susceptibilities of targeted and emerging MDROs. Establish systems to ensure that clinical micro labs (in-house and outsourced) promptly notify infection control or a medical director/designee when a novel resistance pattern for that facility is detected. (IB) In hospitals and LTCFs: ...develop and implement laboratory protocols for storing isolates of selected MDROs for molecular typing when needed to confirm transmission or delineate epidemiology of MDRO in facility. (IB) ...establish laboratory-based systems to detect and communicate evidence of MDROs in clinical isolates (IB) ...prepare facility-specific antimicrobial susceptibility reports as recommended by CLSI; monitor reports for evidence of changing resistance that may indicate emergence or transmission of MDROs (IA/IC) ...develop and monitor special-care unit-specific antimicrobial susceptibility reports (e.g., ventilatordependent units, ICUs, oncology units). (IB) ...monitor trends in incidence of target MDROs in the facility over time to determine if MDRO rates are decreasing or if additional interventions are needed. (IA) Infection Control Precautions to Prevent Transmission Follow Standard Precautions in all healthcare settings. (IB) Use of Contact Precautions (CP): --- In acute care settings : Implement CP for all patients known to be colonized/infected with target MDROs.(IB) --- In LTCFs: Consider the individual patient's clinical situation and facility resources in deciding whether to implement CP (II) --- In ambulatory and home care settings, follow Standard Precautions (II) ---In hemodialysis units: Follow dialysis specific guidelines (IC) No recommendation can be made regarding when to discontinue CP. (Unresolved issue) Masks are not recommended for routine use to prevent transmission of MDROs from patients to HCWs. Use masks according to Standard Precautions when performing splash-generating procedures, caring for patients with open tracheostomies with potential for projectile secretions, and when there is evidence for transmission from heavily colonized sources (e.g., burn wounds). Patient placement in hospitals and LTCFs: When single-patient rooms are available, assign priority for these rooms to patients with known or suspected MDRO colonization or infection. Give highest priority to those patients who have conditions that may facilitate transmission, e.g., uncontained secretions or excretions. When single-patient rooms are not available, cohort patients with the same MDRO in the same room or patient-care area. (IB) When cohorting patients with the same MDRO is not possible, place MDRO patients in rooms with patients who are at low risk for acquisition of MDROs and associated adverse outcomes from infection and are likely to have short lengths of stay. (II) Environmental Measures Follow recommended cleaning, disinfection and sterilization guidelines for maintaining patient care areas and equipment. Dedicate non-critical medical items to use on individual patients known to be infected or colonized with an MDRO. Prioritize room cleaning of patients on Contact Precautions. Focus on cleaning and disinfecting frequently touched surfaces (e.g., bed rails, bedside commodes, bathroom fixtures in patient room, doorknobs) and equipment in immediate vicinity of patient.

Prevention of MDROs Appropriate antibiotic use
Determine the pathogen Give appropriate therapy Removing medical equipment as soon as possible Catheters Ventilators Prevention of transmission to patients Environmental cleaning Hand hygiene Clonal transmission of antibiotic-resistant organisms Organisms resistant to antimicrobial agents can be spread from patient to patient in health care facilities, often via the contaminated hands of health care personnel, contaminated medical or surgical equipment, or the inanimate hospital environment. This type of spread is generally clonal, involving the transmission of a single strain of the antibiotic-resistant organism. Outbreaks caused by clonal transmission of an antimicrobial-resistant organism have commonly been reported for MRSA, vancomycin-resistant enterococci, C. difficile and multidrug-resistant gram-negative bacilli.24,30–35 Clonal outbreaks at multiple institutions may also occur with transmission of a common strain in multiple health care facilities, even in diverse geographic regions.30,33,34,36 However, clonality is less likely to occur with sporadic disease in areas with a relatively low prevalence, or with certain organisms and mechanisms of resistance.37–39 In some settings, an outbreak of antimicrobial resistance may occur from transmission of a plasmid rather than dissemination of a single resistant strain.40 Previous SectionNext Section Although there is considerable variation in the rates of MRSA from country to country, and even from hospital to hospital within a country, MRSA is currently the most commonly identified antibiotic-resistant pathogen among patients in hospital.41 Rates of MRSA infections have increased in both US and Canadian hospitals; however, the rates are much higher in the United States.42,43 Until recently, MRSA was considered to be primarily a nosocomial pathogen, affecting older adults with comorbidities in hospital or long-term care settings. However, in the past decade, community-associated MRSA (CA-MRSA), which involves a small number of unique MRSA strains (clones), has emerged in many parts of the world, including Canada.44–46 Patients affected by CA-MRSA often do not have commonly recognized health care–associated risk factors. CA-MRSA may cause infections at any site but are most often associated with skin and soft tissue infections, including pustulosis, furunculosis and abscesses. Invasive disease and fatal necrotizing pneumonia have also been reported.47 Not surprisingly, CA-MRSA strains have been introduced into health care settings and have been associated with hospital-acquired bacteremia, surgical-site infections and outbreaks in maternity units and hospital nurseries.48 Methicillin-resistant Staphylococcus aureus Selected antibiotic-resistant organisms in hospitals Although generally less virulent than S. aureus, Enterococcus species (e.g.,Enterococcus faecalis, Enterococcus faecium) may also cause serious, life-threatening infections. Resistance to vancomycin in enterococci is caused by synthesis of modified cell-wall precursors that do not bind glycopeptides. This occurs with the acquisition of a plasmid-associated gene cluster, most commonly the vanA or vanB genes.49 These genes are transferable and may spread from enterococci to MRSA, thereby further complicating the treatment of infections caused by this organism.50 In Canada, 15% of inpatients with vancomycin-resistant enterococci were found to also be colonized with MRSA.51 Prior antimicrobial therapy with oral vancomycin, broad-spectrum cephalosporins or metronidazole has been identified as an important risk factor for vancomycin-resistant enterococcal infection or colonization.23,52Environmental contamination with vancomycin-resistant enterococci or exposure to contaminated medical equipment may also contribute to nosocomial transmission.53 Vancomycin-resistant Enterococcus Multidrug-resistance in gram-negative bacilli is generally defined as resistance to more than 2 classes of antimicrobial agents. Typically, multidrug-resistant gram-negative bacteria are resistant to penicillins (including those combined with a β-lactamase inhibitor), cephalosporins, fluoroquinolones, trimethoprim-sulfamethoxazole and aminoglycosides. However, some strains may also be resistant to the carbapenems, often leaving colistin as the only agent available for treatment of these infections.54 Multidrug-resistant gram-negative bacilli The major multidrug-resistant gram-negative pathogen in most Canadian hospitals is P. aeruginosa, which is most often isolated from patients in intensive care units. At present, about 30% of P. aeruginosa isolates from intensive care units in the United States and Canada are resistant to fluoroquinolones.42,55,56 In Canadian intensive care units, about 13% of isolates were found to be resistant to multiple antibiotics.56 Carbapenem-resistance was identified in 14% of P. aeruginosa isolates from intensive care units in Canada.56 About 21% of P. aeruginosa isolates from intensive care units in the United States were resistant to carbapenems.42 Acinetobacter baumannii is also an important nosocomial pathogen acquired in intensive care units. This pathogen may cause pneumonia or urinary tract, wound, or bloodstream infections. Acinetobacter are generally resistant to most classes of antimicrobials, leaving carbapenems, and possibly glycylcyclines (tetracycline derivatives such as tigecycline), as the only effective drugs. The emergence of carbapenem-resistant A. baumannii in many parts of the world is disturbing and poses a threat to the effective management of these infections.57 Multidrug-resistant A. baumannii is identified infrequently in Canadian hospitals, although an outbreak was reported in a burn unit of a tertiary care hospital in Toronto.58 Nosocomial outbreaks due to multidrug-resistant A. baumannii that originated with injured military personnel returning from Afghanistan and Iraq have recently been reported in the United States and the United Kingdom.59 Similarly, a number of injured Canadian soldiers returning from active duty in Afghanistan have received treatment for multidrug-resistant Acinetobacter respiratory and wound infections in Canadian hospitals.60 C. difficile is the major cause of diarrhea associated with antibiotic use and is the most common infectious cause of nosocomial diarrhea. A major outbreak of C. difficile infection occurred in many hospitals in Quebec beginning in ,61 Markedly increased disease rates (as high as 156 cases per people) and severity occurred, especially among elderly people. In this outbreak, there was often a poor response to metronidazole therapy.61,62 The emergence of such severe disease is thought to have occurred because of the presence of a hypervirulent epidemic strain of C. difficile, known as PCR ribotype 27, or North America pulso-type 1 (NAP1).63 The same strain of C. difficile has caused extensive and severe disease in the United States and Europe.33 It is not clear why this strain appeared and caused such severe disease in the past few years, but this may in part be related to changing patterns of antimicrobial use in hospitals. The NAP1 strain associated with these outbreaks is resistant to fluoroquinolones, and fluoroquinolone use was found to be a major risk factor for C. difficile-associated disease in the Quebec outbreak.32 The NAP1 strain has now been identified in most provinces, and it has become the predominant strain in many hospitals, indicating the potential for severe outbreaks in many parts of the country. Clostridium difficile The burden of antimicrobial resistance refers to the impact of events that would not have occurred if resistance had not been present. These outcome measures may include excess mortality, morbidity (e.g., length of hospital stay and complications) and attributable costs (e.g., costs to the hospital, patient and society). The risk of such adverse outcomes has been found to be higher in patients with infections caused by an antibiotic-resistant organism compared with infections caused by susceptible strains of the same pathogen, even after adjustment for underlying comorbidities.64–68 For example, in a meta-analysis performed to examine the impact of methicillin-resistance on mortality among patients with S. aureus bloodstream infections, a significant increase in mortality (nearly a double increase in risk) was found to be associated with MRSA bacteremia when adjusted in a random-effects model (odds ratio 1.93, 95% confidence interval 1.54–2.42, p < 0.001).69 In a multivariable model, MRSA bacteremia was associated with increased length of hospital stay (1.29-fold increase, p = 0.016), with an attributable length of stay of 2 days.64 Similarly, attributable prolonged excess hospital stay was identified for infections caused by resistant strains of extended-spectrum ß-lactamase-producing K. pneumoniae (median post-infection hospital stay of 11 days for susceptible strains compared with 29 days for resistant strains, p= 0.03) and for carbapenem-resistant P. aeruginosa (20 days v. 34 days, p = 0.002).68 Several studies have attributed these adverse outcomes to delays in instituting effective antimicrobial therapy and use of inadequate initial therapy.70,71 Impact of antimicrobial resistance Not surprisingly, adverse outcomes and prolonged hospital stays associated with antimicrobial-resistant organisms have been associated with increased costs. However the economic burden of antimicrobial resistance on the health care system has not been well defined. Thirteen years ago in the United States, cost estimates for managing antimicrobial resistance were between $0.1 billion and $10 billion per year.72 In 2001, the mean attributable cost associated per patient with MRSA infection in a Canadian hospital was $ The incremental cost for care of patients with enterococci in Canadian hospitals was estimated to be about $6700 per patient.74 Incremental costs were attributed to length of hospital or intensive care unit stay, lost revenue from private isolation rooms, need for more expensive antibiotics and increased laboratory testing, and the added expense of infection control interventions, including the use of antiseptic soaps, gloves and gowns. The burden of antibiotic resistance continues to increase and is acknowledged to be a major threat to the treatment of infectious diseases, particularly among patients in hospital. The reasons for the variability in resistance rates around the world and within different parts of Canada is unknown but may be related to differences in diagnostic procedures, patterns of antimicrobial use or infection prevention and control practices. Summary Other important gaps in our knowledge include uncertainty about how understanding specific mechanisms of resistance may lead to the identification of novel targets for new antimicrobial drug development. A better understanding of the relative importance of selective pressure related to antibiotic use compared to cross-infection as mechanisms for emergence and spread of antimicrobial resistance would also be important to design and evaluate effective infection prevention and control strategies. Infections caused by antimicrobial-resistant organisms are almost always associated with increased attributable mortality, prolonged hospital stays and excess costs. Although the rates of antibiotic resistance in Canada tend to be lower than those in many other parts of the world, complacency would be a mistake. Rates of antibiotic-resistant organisms have increased in Canadian health care facilities in the past 10 years, and the rates will continue to increase unless aggressive control measures are implemented.75 These interventions must include enhanced surveillance of antibiotic resistance, attention to hand hygiene and other standard infection prevention and control measures, and antibiotic stewardship to ensure appropriate use of antimicrobial agents.76,77 The incidence and adverse consequences of infections caused by antimicrobial-resistant organisms continue to increase. Key points See related commentary by Nicolle and colleagues, page 371, and related analysis paper by Patrick and Hutchinson, page 416 Acquired antibiotic resistance may arise from bacterial chromosomal DNA mutations or as a result of transfer and acquisition of new genetic material. Emergence and spread may be promoted by antibiotic selection pressure. The emergence and spread of antimicrobial-resistant organisms within health care facilities or the community may be related to clonal transmission of a common “epidemic” strain. The major mechanisms of antimicrobial resistance include enzymatic inactivation of the drug and bacterial changes that prevent access or binding to the drug's target. Enhanced infection prevention and control strategies need to be developed, implemented and evaluated to stem the rise of infections caused by antimicrobial-resistant organisms. Contributors: Both of the authors contributed to the conception of this review, and participated in reviewing and analyzing the literature. Both of the authors drafted portions of the review, revised it critically and approved the version submitted for publication. This article has been peer reviewed. Footnotes Previous Section Competing interests: None declared. REFERENCES

Surveillance Monitor trends in ICU or patient care areas
Is it local, regional, national, or international Screening MRSA screening at UMDNJ Determine if treatment /intervention practices are working

CDC Recommendations for the Prevention of VAP
VAP is the 2nd most common nosocomial infection = 15% of all hospital acquired infections Incidence = 9% to 70% of patients on ventilators Increased ICU stay by several days Increased avg. hospital stay 1 to 3 weeks Mortality = 13% to 55% Added costs of $40,000 - $50,000 per stay

Types of VAP ( Early- Onset)
Early–Onset Pneumonia (< 96 hours of intubation or ICU admission) Community-acquired Pathogens: Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Antibiotic-sensitive

Types of VAP ( Late- Onset)
Late-Onset Pneumonia (> 96 hours of intubation or ICU admission) Hospital-acquired Pathogens: Pseudomonas aeruginosa Methicillin resistant Staphylococcus aureus (MRSA) Acinetobacter Enterobacter Antibiotic-resistant

VAP Prevention Semirecumbent positioning ( HOB 30%)
Sedation vacation and daily assessments of readiness for extubation New-generation endotracheal tubes and continuous subglottic-secretion drainage Oral, not nasal, gastric tubes Oral intubation / not nasal Aggressive oral hygiene DVT prophylaxis PUD prophylaxis

Q $100 Q $100 Q $100 Q $100 Q $100 Q $200 Q $200 Q $200 Q $200 Q $200
About MDRO’s Management of MDRO’s Fact or Fiction? Precautions For MDRO’s Things you should know Q $100 Q $100 Q $100 Q $100 Q $100 Q $200 Q $200 Q $200 Q $200 Q $200 Q $300 Q $300 Q $300 Q $300 Q $300 Q $400 Q $400 Q $400 Q $400 Q $400 Q $500 Q $500 Q $500 Q $500 Q $500 Final Question

$100 Question: About MDRO’s
Name two types of MDRO’s?

$100 Answer: About MDRO’s Bacteria: MRSA VRE

How is VRE most commonly spread?

$200 Answer: About VRE Colonized hands of health care workers from contact with clients/patients/residents infected or colonized with VRE, or from contact with equipment contaminated with VRE.

How do bacteria Reproduce?

$300 Answer: About MDRO’s Binary Fission

What year was the Nobel prize awarded to Fleming, Chain, and Florey?

$400 Answer: About MDRO’s 1945

True or False? Name two ways that bacteria become resistant?

$500 Answer: About MDRO’s Darwin's Theory of “ Survival of the Fittest” Mutation Destruction/Inactivation Efflux pumps

$100 Question: Management of MDRO’s
What is the CDC Guidelines For Reducing MDROs? Name two!

$100 Answer: Management of MDRO’s
Administrative Measures/Adherence Monitoring MDRO Education Judicious Antimicrobial Use Surveillance Infection Control Precautions to Prevent Transmission Environmental Measures

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Multi Drug- Resistant Organisms (MDRO’s) in the ICU A Guide for RT’s

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