a GuIde To suPerbuGs and anTIbIoTIC resIsTanCe 2 Superbugs and Antibiotic Resistance: A Guide Table of Contents Introduction...........................................................................................................3 Bacteria basics...................................................................................................... 4 How are bacteria classified?.................................................................................... 4 The burden of nosocomial bacterial infections................................................. 6 How are bacterial infections treated?.................................................................. 7 What is antibiotic resistance?................................................................................. 9 How do bacteria develop resistance to medicines?......................................... 9 The impact of antibiotic resistance..................................................................... 10 A closer look at Gram-negative bacteria......................................................... 12 Drug-resistant Gram-negative infection.............................................................13 Resistance in Pseudomonas aeruginosa...............................................14 Resistance in Klebsiella pneumoniae.....................................................15 Resistance in Enterobacteriaceae...........................................................15 Resistance in Acinetobacter baumannii................................................15 What does the future hold for treatment of MDR bacteria?......................... 16 Glossary................................................................................................................ 18 Resources............................................................................................................ 22 References........................................................................................................... 23 Superbugs and Antibiotic Resistance: A Guide 3 Introduction Bacteria can be beneficial or harmful. Beneficial bacteria co-exist with us, living in our gut and on our skin, without causing disease. However, even “good” bacteria can become harmful when they find their way to a different part of the body. They may also do harm when they infect someone who has a compromised immune system, such as a hospitalized patient or someone with an underlying condition like cancer or diabetes. Harmful bacteria can cause significant illness and even death. Infectious diseases, including bacterial infections, are the second leading cause of death worldwide.1 Until recently, serious bacterial infections were almost always associated with hospitalization. More than 1.7 million patients in the United States develop a bacterial infection while in the hospital.2 Hospitalacquired – or “nosocomial” – infections cause more deaths than diabetes.2,3 A recent report from the Agency for Healthcare Research and Quality indicated that while surveillance and diagnosis of nosocomial infections has improved, rates of infection are not declining.4 In addition, serious infections contracted outside the hospital have become much more common in recent years.5 Serious bacterial infections – whether they are acquired in or outside of the hospital – are treated with antibiotics. However, the ability of bacteria to develop resistance to one or more antibiotics is a growing concern. Methicillin-resistant Staphylococcus aureus, or MRSA, is a particularly worrisome form of Gram-positive bacteria that was first seen only in hospitalized patients but can now be contracted outside the hospital setting.5,6 Multi-drug resistance (MDR), which occurs when a bacterium becomes resistant to three or more classes of antibiotics, is becoming especially common in certain types of Gram-negative bacteria.7 The threat of MDR Gram-negative bacterial infections is escalating, with more of these organisms appearing in hospital settings as well as exhibiting resistance to almost all available treatment options.8-10 Treatment of these so-called “superbugs” remains challenging because the pool of effective drugs is shrinking and few new Gram-negative antibiotics are in development.8,10 This handbook provides background on bacterial infections and MDR, with additional information on Gram-negative bacteria. Our intent is to provide context for research and public policy initiatives designed to understand, prevent, and manage this group of potentially life-threatening infections. For additional information, please contact Francis McLoughlin at Cubist Pharmaceuticals (781) 860-8777 or [email protected] Superbugs and Antibiotic Resistance: A Guide 4 Bacteria basics How are bacteria classified? Bacteria are primarily classified using a laboratory test known as Gram staining. The Gram stain, developed by Hans Christian Gram in the late 1800s, identifies two main types of bacteria: Gramnegative and Gram-positive. The original designation was determined by the extent to which the stain could be washed out of the cell; bacteria that didn’t keep the stain were pink and termed Gramnegative.11 Gram-positive bacteria retain the color of the stain and appear purple.11 The amount of stain that can be retained is determined by the composition of the outermost part of the bacterium, known as the cell wall. Even bacteria that cannot be stained by the traditional method are now classified into these categories.11 Select examples of Gram-negative and Gram-positive bacteria and the diseases they cause are listed in Tables 1 and 2. The make-up of the bacterial cell wall not only affects Gram staining but also protects the bacteria from medicines and a person’s immune system. Although the cell wall composition differs between Gramnegative and Gram-positive bacteria (see Figure 1), both structures form a tight barrier against the outside environment.11 Few enzymes in the human body are capable of cutting through the cell wall to destroy the bacterium. The medicine penicillin prevents the formation of a “water-tight” Gram-positive cell wall, which leads to the destruction of certain bacteria.11 The complex structure of the Gramnegative cell wall protects the bacterium from immune system attack and prevents many antibiotics from working. Bacteria also differ in their pathogenicity and virulence, and these differences can be used to classify them further. Pathogenicity is defined as the ability of the bacteria to cause disease in a human, whereas virulence is the degree to which the bacterium causes disease.11 Some bacteria that are normally found in the body, such as Escherichia coli (E. coli) in the colon, can be pathogenic but are only moderately virulent because they typically only cause disease when they are transferred to another part of the body.11 Species of bacteria can exist as different strains, with slightly different genetic makeup. Strains can differ in their pathogenicity and virulence, as well as their response to treatment. For example, when ingested, certain strains of E. coli can cause deadly food poisoning outbreaks. Superbugs and Antibiotic Resistance: A Guide 5 peptidoglycan layer (cell wall) pore protein Figure 1. The bacterial cell wall.12 This figure illustrates the differences in complexity between outer membrane the Gram-positive (A) and Gram-negative (B) cell walls. Peptidoglycans are molecules composed of sugars and space proteins and are a common drug target. The Gram-positive peptidoglycan cell wall is composed of peptidoglycans and has two layers. inner membrane The Gram-negative cell wall is more complex, with an outer membrane proteins Gram-negative cell wall also contains pore proteins, which membrane, a space and a layer of peptidoglycans. The can pump things back out of the bacterium. GRAM-POSITIVE GRAM-NEGATIVE A B Bacterium/Species Table 1. Examples* of Gram-positive bacteria Mycobacterium tuberculosis (M. tuberculosis) Tuberculosis Staphylococcus aureus (S. aureus) Skin infections and abscesses, bloodstream infections, pneumonia, toxic shock syndrome (TSS) Clostridium difficile (C. difficile) Diarrhea Streptococcus pyogenes (S. pyogenes) “Strep throat,” scarlet fever, serious deep tissue infections Streptococcus pneumoniae (S. pneumoniae) Pneumonia and meningitis Enterococcus faecium (E.faceium) Meningitis in infants and the diseases they cause.11 *There are many disease-causing bacteria and not Disease all are represented within this table. Superbugs and Antibiotic Resistance: A Guide 6 Bacterium/Species Disease Escherichia coli (E. coli) Food poisoning, urinary tract infections, various hospitalacquired infections Treponema pallidum (T. pallidum) Syphilis Vibrio cholerae (V. cholerae) Watery diarrhea (cholera) Helicobacter pylori (H. pylori) Chronic gastritis, ulcers Neisseria meningitidis (N. meningitides) Meningitis and blood infections Neisseria gonorrhoeae (N. gonorrhoeae) Gonorrhea Pseudomonas aeruginosa (P. aeruginosa) Pneumonia, septic shock, urinary tract infections, intra-abdominal infections, skin infections The burden of nosocomial bacterial infections During a hospital stay, a patient can develop a nosocomial infection through several means, including:10 • Person-to-person transmission between patients or between hospital staff and patients. • Implantation of a device, such as a catheter or tube that can support the growth of bacteria. • Transfer of a typically harmless bacterium from the skin or gut to another site of the body during or after a surgical procedure. Klebsiella pneumoniae (K. pneumoniae) Pneumonia, urinary tract infections • Inhalation of bacteria that can cause disease in someone who has poor immune system function. Acinetobacter baumannii (A. baumannii) Necrotizing fasciitis, pneumonia, urinary tract and bloodstream infections •L oss of the protective skin barrier due to bedsores, burns or surgical incisions. Enterobacter cloacae (E. cloacae) Respiratory and urinary tract infections Urinary tract infections (UTIs) and lower respiratory tract infections are among the most common nosocomial infections.10,13,14 Blood infections (bacteremia) can also occur when bacteria enter through openings created for catheters or tag along when devices are implanted. Along with lower respiratory infections, these pose the greatest risk to patients.14 In some instances, blood infections can develop after the original infection; these infections are particularly dangerous. It is estimated that up to 15 percent of bacterial Table 2. Examples* of Gram-negative bacteria and the diseases they cause.11 *There are many disease-causing bacteria and not all are represented within this table. 7 Superbugs and Antibiotic Resistance: A Guide blood infections originate from a UTI.10 Skin infections can also lead to blood infections. These infections can be caused by Gram-negative and Gram-positive bacteria and may develop following exposure via any of the means described above. Hospital-acquired bacterial infections place a great burden on patients and the healthcare system. The most recent estimate from the Centers for Disease Control indicates that direct cost of hospitalacquired infections, when adjusted for inflation, exceeds 30 billion dollars each year.15 In addition, mortality and morbidity rates associated with infection in intensive care units (ICUs) are significant.16 Infections can account for more than 30 percent of the death rate after being hospitalized.17 Even with treatment, bacterial infections result in longer hospital stays, the need for more medication and increased risk of morbidity and death.10 For example, patients with hospital-acquired bacterial infections spend, on average, 15 more days in the hospital and have an additional $156,000 in medical costs compared to patients who do not develop an infection.18 How are bacterial infections treated? Medicines that treat bacterial infections can act in multiple ways to help clear the infection, such as by improving the immune system response, reducing inflammation caused by infection or directly acting on the bacteria to kill it or stop it from reproducing (antibiotics). Antibiotics are a type of medicine often derived from compounds produced by other bacteria or molds; they are effective in treating many bacterial infections.11 Antibiotics are only effective in stopping the growth of bacteria, not other infectious agents such as viruses and fungi. Antibiotics may be bactericidal, meaning that they not only inhibit the growth of the bacteria but are also able to kill it.11 Antibiotics can have different mechanisms-of-action that work against the infecting pathogen. The vast majority of antibiotics fall into the same class and work by preventing the cell wall of the bacteria from forming (e.g., the beta-lactams, including penicillin) or inhibit the creation of bacterial proteins needed for survival or reproduction.11 Antibiotics may also prevent bacterial genes from being copied, which keeps the bacterium from reproducing.11 Figure 2 illustrates the general targets of antibiotics. Table 3 identifies drugs that fall into the two classes of antibiotics (beta-lactams and non-beta-lactams) that target the cell wall to prevent it from forming or break it apart. Superbugs and Antibiotic Resistance: A Guide 8 gene synthesis quinolones rifampin cell membrane polymixins Figure 2. Targets of antibiotics.12 cell wall synthesis. vancomycin, penicillins, cephalosporins DNA protein synthesis. tetracycline, streptomycin erythromycin, chloramphenicol Beta-lactams Penicillin Vancomycin Methicillin Bacitracin Amoxicillin Table 3. Antibiotics that work on the cell wall: the beta-lactams and non-beta-lactams.11 Non-beta lactams Cephalosporins Carbapenems 9 box 1. How.is.resistance.measured? resistance to specific antibiotics is determined by measuring “minimum SuperbugS and antibiotic reSiStance: a guide antibiotics vary in their ability to treat infections caused by different strains and species of bacteria. the spectrum of an antibiotic is used to define its potency against different bacterial infections.11 broad-spectrum antibiotics are active against many organisms and, depending on the agent, may be active against both gram-negative and gram-positive infections.11 narrow-spectrum antibiotics are only effective against a few types of bacteria.11 inhibitory concentration” (Mic).11 the Mic corresponds to the lowest More details on medicines used to treat gram-negative infections can be found on page 14 (see table 4). concentration of drug that can be used to treat the infection in a What is antibiotic resistance? laboratory setting.11 the Mic of an bacteria can acquire the ability to survive in the presence of drugs that would normally kill them. bacteria that are no longer susceptible to antibiotics and can survive in the presence of the drug are called antibiotic-resistant.11 Various strains of the same bacteria may be present in an infected person; treatment with an antibiotic kills susceptible but not resistant strains. this leads to the “selection” of resistant strains. in some instances, bacteria can be resistant to multiple drugs; these strains are considered multi-drug resistant (Mdr).7 Mdr bacteria are often referred to as “superbugs”. existing medicines may no longer be effective in treating these infections. antibiotic should fall within a range that is tolerated by patients. using this measurement,.susceptible. bacteria have a Mic that falls within the normal dosing range of the antibiotic.11 bacteria can exhibit different levels of susceptibility to How do bacteria develop resistance to medicines? different antibiotics. bacteria develop antibiotic resistance through genetic changes that can occur when:19 unlike susceptible bacteria, resistant. bacteria require doses of antibiotic that have not been shown to be safe or tolerable for patients.11 • genes move between different bacterial strains or between species. • Mutations (genetic changes) happen that help confer resistance. • genes that aid in survival are picked up from the host or environment. (See box 1: How is resistance measured?) More specifically, these changes can help the bacterium acquire resistance by:11 • Making it more difficult for the medicines to pass through the cell wall and get inside. • actively pumping medicines out of the bacterium. • changing the target of the antibiotic to prevent the drug from binding and having an effect. • inactivating the antibiotic with bacterial enzymes. 10 Superbugs and Antibiotic Resistance: A Guide These infections may be resistant to the normal medicines prescribed to treat them. Improper use and over-prescription of antibiotics to treat humans, along with misuse of antibiotics given to animals and used in agriculture, promotes development of resistance in these fast-growing, adaptable organisms because it selects for those that can’t be killed by the antibiotic being used for treatment.19,20 The impact of antibiotic resistance Antibiotic resistance is a serious global public health concern.20 The first antibiotic-resistant strains of bacteria were identified more than 60 years ago.20 MDR has been identified in globally-prevalent infections such as tuberculosis and S. aureus.20 Emerging antibiotic resistance is now being seen in Gram-negative pathogens including P. aeruginosa. In addition, drug-resistant pathogens that were previously only seen in hospital settings, such as MRSA, are becoming more common in the community at large (see Box 2).6 There are few medicines in development to treat resistant forms of bacteria.8,10 Of particular importance are the so-called ESKAPE bacteria because many of them are resistant to multiple medications:21,22 • Enterococcus, including E. faecium • Staphylococcus aureus (S. aureus) • Klebsiella, including K. pneumoniae • Acinetobacter baumannii (A. baumannii) • Pseudomonas aeruginosa (P. aeruginosa) • Enterobacter species, including E. cloacae The remainder of this guide will discuss resistance in Gram-negative bacteria as well as the growing burden of MDR Gram-negative infections on the healthcare system. SuperbugS and antibiotic reSiStance: a guide 11 box 2. Case.study:.Trends.in.S. Aureus.antibiotic.resistance S. aureus is known for its ability to rapidly develop resistance to antibiotics.6 penicillin was introduced as a treatment for S. aureus infections after World War ii. by the 1960s, more than which led to the development and use of a second generation penicillin, methicillin to treat this infection.8 by 2002, 57 percent of S. aureus infections were resistant to methicillin (i.e MrSa).8 different strains of MrSa, with different types of resistance, have emerged over the past two decades. these strains may be resistant to penicillin, methicillin, and another antibiotic used to treat these infections, vancomycin.6 the trends in MrSa resistance are illustrated in the graph to the right.6 the first strain of MrSa, MrSa-1, was identified in the 1960s. Subsequent resistant strains were found in the 1970s and 1990s. Historically, MrSa epidemics have been primarily associated increasing burden of S. aureus resistance 80 percent of S. aureus infections were resistant to penicillin, with healthcare and hospital-acquired infections, but now ca-MrSa Methicillin introduced penicillin introduced MrSa-iV MrSa-i MrSa-ii & -iii penicillin resistance community-acquired MrSa infections in otherwise healthy individuals are becoming more prevalent.6 community-acquired MrSa (ca-MrSa) was first observed in the 2000s, as shown in the graph to the right. recent evidence suggests that epidemics of MrSa come in waves as more pathogenic and virulent strains appear, and that community-acquired infections will place a greater burden on patients and the healthcare system in the coming years.6 1940 1960 1980 2000 Superbugs and Antibiotic Resistance: A Guide 12 A closer look at Gram-negative bacteria Gram-negative bacteria are a source of both community and hospital-acquired infections. Overall, infections caused by Gram-negative bacteria now account for more than 30 percent of common hospital-acquired infections.23 In addition they are the leading causes of nosocomial pneumonia and UTIs.14 In a 2009 study, 62 percent of patients hospitalized in an intensive care unit with a respiratory infection had a Gram-negative infection.16 Patients who had been in the hospital for a longer time period had not only higher rates of infection, but higher rates of drug-resistant infections with Gram-negative species such as Pseudomonas and Acinetobacter.16 As described earlier, the structure of the Gram-negative cell wall provides a unique barrier to antibiotics, which are often not able to cross it. The Gram-negative cell wall also contains proteins called efflux pumps, or pore proteins, that push medicines back out of the bacterium before they can have an effect. In addition, some Gram-negative species, such as Pseudomonas, are able to form a grouping of bacterial cells called a biofilm.24 The biofilm provides a further defense against antibiotics.24 Gram-negative bacteria are also proficient at developing drug resistance.14 In many instances, Gramnegative species can use multiple mechanisms to protect themselves against one antibiotic.7,14 MDR Gram-negative infections are associated with pneumonia and catheter-related bloodstream infections, co-infections with other bacteria and fungi, and higher mortality in hospitalized patients.25 Rates of drug-resistant Gram-negative infections are rising and likely will continue rising, placing an increasing burden on the healthcare system (See Figure 3).8,10,24,26 SuperbugS and antibiotic reSiStance: a guide 13 Key gram-negative culprits in nosocomial infection include E. coli and four of the six eSKape bacteria: % incidence • Klebsiella, including K. pneumoniae 60 • A. baumannii 50 • P. aeruginosa 40 MrSa 30 FQrp 20 10 0 1980 1985 1990 1995 2000 • Enterobacter species, including E. cloacae Drug-resistant Gram-negative infections resistance is a growing problem with infections caused by gram-negative bacteria, particularly those found in hospital settings.21 treatment of these infections varies between species. common treatments and mechanisms of resistance to those treatments are shown in table 4. Like gram-positive bacteria, gram-negative bacteria can acquire resistance through multiple means. the type of resistance determines which class of drug will no longer be effective. For example:14,24 FIGuRe. 3.. Rising. incidence. of. drugresistant. infections. in. the. united. States. .incidence of the gram-positive 8 infection MrSa and the gram-negative infection fluoroquinolone-resistant P. aeruginosa (FQrp) have been steadily rising since the 1990s. • changes to the cell wall that prevent antibiotics from entering or limit their activity against the cell wall affect penicillins, including methicillin. • changes to the pumps (pore proteins) found in the bacterial cell wall can affect most classes of drugs. • acquisition of genes that produce extendedspectrum beta lactamases (eSbLs), enzymes that break down antibiotics and prevent them from working.11 antibiotics sensitive to eSbLs include penicillins and cephalosporins, along with some carbapenems. SuperbugS and antibiotic reSiStance: a guide 14 • production of enzymes that modify aminoglycoside antibiotics, or break down cephalosporin antibiotics (cephalosporinases) or carbapenem antibiotics (carbapenemases). • changes to proteins that help make bacterial genetic material can confer resistance to quinolones or other compounds. in many instances, gram-negative bacteria have combinations of these resistance mechanisms, making treatment difficult. they are considered Mdr when they have picked up three or more resistance mechanisms.7 TABle.4..examples.of.treatments. and. resistance. mechanisms. of. Treatment Resistance.Seen Mechanisms.of.resistance Gram-negative.bacteria.14,24,27 box 3. Pseudomonas aeruginosa:. The.next.superbug? recent surveillance data has indicated that various antibiotic- Beta lactams penicillins cephalosporins carbapenems P. aeruginosa Enterobacter Klebsiella Acinetobacter • cephalosporinases • extended spectrum-beta lactamases (eSbLs) • carbapenemases Quinolone/ Fluoroquinolones P. aeruginosa Acinetobacter • Mutations in target of antibiotic Aminoglycosides P. aeruginosa Acinetobacter • Modification of aminoglycoside by bacterial enzymes resistant forms of P. aeruginosa are becoming more prevalent in u.S. hospitals. 28 Since the last measurements were taken from 1998-2002, resistance to antibiotics in this species has increased nine to 20 percent Resistance in Pseudomonas aeruginosa depending on the antibiotic.28 P. aeruginosa can cause disease at multiple sites in the body. it is a common cause of blood infections, utis, pneumonia, and can also cause intra-abdominal infections.14 resistance to beta-lactams is most common in P. aeruginosa.24 Mechanisms of resistance can be picked up not only from other bacteria, but from the environment, making prevention uniquely challenging. Multiple resistance mechanisms within one bacterium are also common and combinations of antibiotics are typically used as first-line therapy to circumvent potential resistance.24 resistance to specific antibiotics can range from one to 31 percent in P. aeruginosa strains isolated from hospitals.28,29 Superbugs and Antibiotic Resistance: A Guide 15 Risk factors for a resistant Pseudomonas infection include:24 • Patients in hospital settings, including intensive care units and burn victims. • Patients with previous exposure to broad-spectrum antibiotics. • Patients with cystic fibrosis are very susceptible because they are prone to lung infections and are aggressively treated with a variety of antibiotics. • Nursing home residents. Pseudomonas resistance to currently available antibiotics is rising in hospital settings and new medicines are needed to treat these potentially life-threatening infections (see Box 3: Pseudomonas aeruginosa: The Next Superbug?). Resistance in Klebsiella pneumoniae K. pneumoniae is most often associated with pneumonia and occasionally with UTIs.14 However, it is also commonly seen as a cause of blood infections.14 K. pneumoniae often shows resistance to cephalosporins and carbapenems.24,27 Resistance in Enterobacteriaceae The Enterobacteriaceae species, including E. cloacae, can cause pneumonia, UTIs and blood stream infections.14 Common types of resistance seen with this group of bacteria include production of ESBLs and carbapenemases.14,27 Carbapenem-resistant Enterobacteriaceae are particularly difficult to treat.9 Resistance in Acinetobacter baumannii A. baumannii is a significant cause of pneumonia in intensive care units (ICUs), but rarely causes UTIs.14,30 These bacteria are particularly resistant to carbapenems and treatment is further complicated by their ability to form biofilms.14,31 Wounded military personnel returning from combat zones are particularly at risk for contracting MDR A. baumannii infections.31 In one study performed at a military hospital, the percentage of MDR A. baumannii isolated rose from four percent to 55 percent over a seven-year span.32 Superbugs and Antibiotic Resistance: A Guide 16 What does the future hold for the treatment of MDR bacteria? As resistance in several Gram-negative species, such as P. aeruginosa, becomes more prevalent, doctors are turning to older treatments since few other options exist. These older antibiotics, such as the polymixins, are currently being used to treat carbapenem-resistant Gram-negative bacteria despite potential toxic side effects for patients.14,21 Not only are new, safer agents needed to treat these infections, but novel agents that work in different ways than existing medicines are necessary to prevent cross-resistance to drugs in the same class.8,10 Since 1998, only two novel antibiotics have been approved in the U.S.33 In addition, a 2009 report from the Infectious Disease Society of America (IDSA) found that of all compounds in development for the treatment of MDR infections, none had an entirely Gram-negative spectrum.21 16 Figure 4. New antibacterial agents approved in the United States, 1983–2007, per 5-year period33 Number of new antibacterials 14 12 10 8 6 4 2 0 1983-1987 1988-1992 1993-1997 1998-2002 2003-2007 SuperbugS and antibiotic reSiStance: a guide 17 overall, a steady decline has been observed in the approval of new antibacterial agents in the u.S. (See Figure 4).33 While there is a small pipeline of investigational antibacterial agents, they are progressing slowly through clinical development, limiting the availability of new agents to treat emerging Mdr bacterial strains. there are several well-known factors that contribute to the delay in development of antibacterials, including: box 4. New.Antibiotic.Development. Call.to.Action21 in 2009, idSa published a follow-up report to its 2004 call-to-action for researchers, • the high cost of antibiotic development.8,19 policy makers and government institutions, “bad bugs, no drugs: as antibiotic discovery • the short treatment length with antibiotics compared to medicines used to treat chronic conditions, which reduces the return on investment for developers.8,19 • the difficulty of conducting clinical trials to determine the efficacy and safety of investigational antibacterial compounds.19 Studies are typically required for each potential indication (i.e. uti, pneumonia) and investigators have difficulty enrolling large numbers of patients infected with Mdr bacteria.8 also, placebo-controlled studies, the original gold standard for evaluation of new antibiotics, are not feasible in patients with Mdr bacterial infections, who would likely die with no treatment.19 For these reasons, the idSa has proposed that new regulatory approaches are needed to facilitate the development and approval of new antibiotics.34 in an effort to remedy these and other concerns, the Food and drug administration, the centers for disease control, and the national institutes of Health released a draft “public Health action plan to combat antimicrobial resistance” in March 2011 that includes recommendations and roles for the government agencies in surveillance, prevention and control, research, and product development.35 in addition, the idSa released updated policy recommendations in February 2011 highlighting the importance of adopting economic incentives for antibiotic developers, the need for new regulatory approaches to antibiotic development and the requirement for cooperation between federal agencies, researchers and drug developers.34 it is critical for resources to be invested by all parties, including academic researchers, governmental agencies, policy makers, and pharmaceutical companies, to develop novel, safe and effective treatments for the life-threatening diseases caused by Mdr bacteria (see box 4: new antibiotic development call-to-action).21 Stagnates…a public Health crisis brews.” in this newer report, idSa urges: “now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure – one that can respond to current antibacterial resistance now and anticipate evolving resistance. this challenge requires that industry, academia, the national institutes of Health, the Food and drug administration, the centers for disease control and prevention, the u.S. department of defense, and the new biomedical advanced research and development authority at the department of Health and Human Services work productively together.” interagency engagement will help raise awareness of the threat of Mdr bacteria; promote research and development of novel compounds to treat these potentially deadly infections; and aid in the development of surveillance and prevention protect against Mdr outbreaks. measures to Superbugs and Antibiotic Resistance: A Guide 18 Glossary Acinetobacter baumannii (A. baumannii) A Gram-negative bacterium that is also one of the ESKAPE bacteria.21,22 Antibiotics Medicines that kill a bacterium or stop it from reproducing to limit an infection. Antibiotic-resistant bacteria Bacteria that are no longer susceptible to antibiotics and survive in the presence of a drug used to treat the infection.11 Bacteremia A bacterial blood infection. Bactericidal Describes antibiotics that kill a bacterium, rather than simply stop its growth.11 Beta-lactams A class of antibiotics that act on the cell wall to kill bacteria.11 Specific types of beta-lactam antibiotics are the penicillins, cephalosporins and carbapenems.11 Biofilm A grouping of bacterial cells that forms a film on a surface and provides extra protection against antibiotics.24 P. aeruginosa is a species of bacteria that forms biofilms.24 Broad-spectrum Describes antibiotics that are active against many organisms. Depending on the agent, may be active against both Gram-negative and Gram-positive infections.11 19 Superbugs and Antibiotic Resistance: A Guide Cell wall The outer barrier of a bacterium. The composition of the cell wall determines whether bacteria are Gram-positive or Gram-negative.12 Some antibiotics are unable to easily cross the cell wall to gain entry into the bacterium. Enterobacteriaceae A Gram-negative bacteria species that is also one of the ESKAPE bacteria.21,22 ESKAPE bacteria Six Gram-negative and Gram-positive bacteria that not only cause the majority of nosocomial infections, but are also becoming increasingly resistant to available antibiotics.22 The ESKAPE bacteria include: Enterococcus, including E. faecium; Staphylococcus aureus; Klebsiella, including K. pneumoniae; Acinetobacter baumannii; Pseudomonas aeruginosa; and the Enterobacter species, including E. cloacae.22 Gram-negative bacteria Bacteria that have a complex cell wall and do not retain the color of the gram stain.11 Examples of Gramnegative bacteria are Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). Gram-positive bacteria Bacteria that retain the color of the gram stain.11 Examples of Gram-positive bacteria are Staphylococcus aureus (S. aureus) and Clostridium difficile (C. difficile). Klebsiella pneumoniae (K. pneumoniae) A Gram-negative bacterium that is also one of the ESKAPE bacteria.21,22 Minimum inhibitory concentration (MIC) The lowest concentration of drug needed to inhibit bacterial growth in a laboratory setting.11 Methicillin-resistant Staphylococcus aureus, or MRSA A Gram-positive bacterium that is often multi-drug resistant. Superbugs and Antibiotic Resistance: A Guide 20 Multi-drug resistance (MDR) Resistance of a bacterium to multiple antibiotics. Typically defined as resistance to three or more antibiotic classes.7 Narrow-spectrum Antibiotics that are only effective against a few types of bacteria.11 Nosocomial infection A hospital-acquired infection.13 Pathogenicity The ability of a bacterium to cause disease in a human.11 Pseudomonas aeruginosa (P. aeruginosa) A Gram-negative bacterium that is also one of the ESKAPE bacteria.21,22 Resistant bacteria Bacteria that have a high MIC and require doses of antibiotic that have not been demonstrated to be safe or tolerable for patients.11 Selection When treatment kills susceptible strains of bacteria, but not resistant strains, leaving the resistant strains to survive and replicate.20 Spectrum A term used to define the potency of an antibiotic against different bacterial infections. Antibiotics may have broad or narrow spectrums.11 Strains A group of bacteria within a species that have a slightly different genetic makeup. Strains can differ in susceptibility and resistance to antibiotics. 21 Superbugs and Antibiotic Resistance: A Guide Susceptible bacteria Bacteria with a MIC that falls within the range where drug levels are achieved with normal dosing of an antibiotic.11 Superbugs Bacteria that have a high MIC and require doses of antibiotic that have not been demonstrated to be safe or tolerable for patients; these bacteria are resistant to multiple antibiotics and may no longer treatable with available medicines. Also see resistant bacteria and multi-drug resistant bacteria. Virulence The degree to which a bacterium causes disease.11 Superbugs and Antibiotic Resistance: A Guide 22 Resources American Society for Microbiology (ASM) http://www.asm.org/ Centers for Disease Control and Prevention (CDC): Antibiotic/Antimicrobial Resistance website http://www.cdc.gov/drugresistance/index.html Food and Drug Administration (FDA): Antibiotic Resistance website http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/ AntibioticsandAntibioticResistance/default.htm Infectious Disease Society of America (IDSA) http://www.idsociety.org/default.aspx Institute of Medicine (IOM) http://www.iom.edu/ National Institutes of Health (NIH) http://www.nih.gov/ National Institute of Allergy and Infectious Diseases (NIAID): Antimicrobial Resistance http://www.niaid.nih.gov/topics/antimicrobialresistance/Pages/default.aspx Society for Healthcare Epidemiology of America (SHEA) http://www.shea-online.org/ World Health Organization http://www.who.int/en/ Superbugs and Antibiotic Resistance: A Guide 23 References 1. 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