Antibiotic Resistance: Challenges and Solutions

Antibiotic Resistance: Challenges and Solutions Adam Castaño, Maggie Kober, Anuja Jain, John Prensner, Sara Haack, Sujal Parikh University of Michiga...
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Antibiotic Resistance: Challenges and Solutions

Adam Castaño, Maggie Kober, Anuja Jain, John Prensner, Sara Haack, Sujal Parikh University of Michigan Medical School Antibiotic Defense -- www.antibioticdefense.org

Sir Alexander Fleming Discovers Penicillin • •



1928: A mold on a petri dish was observed to inhibit growth of Staphylococcus bacteria. The active ingredient isolated from this mold was found to be a safe and effective bacteria-killing agent of enormous potency. 1945 Nobel Prize Acceptance Speech: Sir Alexander Fleming warns of the danger of resistance: “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body…”

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Notes on: Sir Alexander Fleming Discovers Penicillin

The improbable chain of events that led Alexander Fleming to discover penicillin in 1928 is what scientific lore is made of. On a brisk London day a wind carried a mold into his lab where it took root on a culture dish and would alter forever the world's treatment of bacterial infections. Staphylococcus bacteria grew over this culture dish like a lawn, covering the entire plate - except for a clear area surrounding the moldy contaminant. Alexander Fleming's recognition of this halo was his "Eureka" moment, an instant of great personal insight and deductive reasoning. He correctly deduced that the mold released a substance that inhibited the growth of the bacteria. The active ingredient in that mold, which Fleming named penicillin, turned out to be a bacteria-killing agent of enormous potency, and one that could be delivered to humans safely, or so we thought. Page 3

Resistance Emerges

Penicillins • •



1960s: Resistance seen worldwide Between 1979 and 1987 0.02% of S. pneumococcus penicillinresistant By 2008 ~40% S. pneumococcus in United States is resistant to penicillins

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Notes on: Resistance Emerges When the world finally recognized penicillin for what it was - the most efficacious life-saving drug in the world - it embraced it without question. By the middle of the century, Fleming's discovery had spawned a huge pharmaceutical industry, churning out synthetic penicillins that would treat some of mankind's most ancient scourges, including syphilis, and gangrene. Human society experienced decreased morbidity from warfare, increased food production, and increased life expectancy in large part due to the discovery of antibiotics. Although many improvements in public health and medicine and a decline in infectious disease mortality preceded the introduction of penicillin, antibiotics have made possible further reductions in deaths and disability from infectious disease. Perhaps equally important, they have facilitated the vast expansion of other medical interventions, such as kidney and heart transplants, by allowing clinicians to prevent surgical site infections and infections in immunosuppressed patients, such as organ recipients. Now, growing levels of bacterial resistance to antibiotics threaten our ability not just to treat infectious diseases but also to perform other procedures and treatments that fundamentally depend on affordable and effective antibiotics. Sources: Lewis R. “The Rise of Antibiotic-Resistant Infections”. http://www.fda.gov/Fdac/features/795_antibio.html Gold HS, Moellering RC, Jr. Antimicrobial-drug resistance. N Engl J Med. Nov 7 1996;335(19):14451453. Pitout JD, Sanders CC, Sanders WE, Jr. Antimicrobial resistance with focus on beta-lactam resistance in gram-negative bacilli. Am J Med. Jul 1997;103(1):51-59.

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A Widespread Problem

Cephalosporins

Vancomycin

Resistance [1980s]

Resistance [1996]

MRSA

HIV

VRSA

MDR-TB

VRE

Malaria

Global spread of penicillin-resistant Pneumococcus strain 23-F.

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Notes on: A Widespread Problem No region in the world has been excluded from the inexorable spread of increasingly drugresistant bacteria. Antimicrobial resistance (AMR) is now a serious global phenomenon. Deaths from acute respiratory infections, diarrheal diseases, measles, AIDS, malaria, and tuberculosis account for more than 85% of worldwide mortality from infectious disease. Resistance to first, second, and third-line drugs in most of the pathogens causing these diseases is increasing significantly. Associated costs of moving to second and third line therapy pose an additional economic burden. Added to this is the significant global burden of resistant hospital-acquired infections, the emerging problems of antiviral resistance and the increasing problems of drug resistance in neglected parasitic diseases of poor and marginalized populations. MRSA: Methicillin resistant S. aureus VRSA: Vancomycin resistant S. aureus VRE: Vancomycin resistant Enterococcus HIV: Human Immuno-deficiency virus MDR-TB: Multi-drug resistant tuberculosis Source: Cars, O., Nordberg, P. Antibiotic Resistance – The faceless threat. Published by ReAct, Sweden. 2004

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The Burden of Disease • Resistant infections increase the time patients stay in hospitals and patient mortality – 5.02 increase in mortality relative risk with a cephalosporin resistant Enterobacter infection • Methicillin resistant vs Methicillin susceptible S. aureus – 20.1% vs 6.7% for surgical wound site mortality • Multi-drug resistant Pseudomonas aeruginosa – 3-fold increase in mortality – 1.7-fold increase in hospital stay

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Notes on: The Burden of Disease Mortality from a resistant infection increases for multiple reasons, but, primarily, because of a delay in effective treatment of the resistant infection AMR, increased need for surgery, and other procedures. Comparing the onset of adequate treatment for susceptible versus resistant strains illustrates the how extensively delayed treatment affects patient outcomes. The median interval between obtaining a sample for culture and initiating antibiotics: 51 hours for resistant infections vs 16 hours for susceptible infections. The number of patients who receive effective treatment within 24 hours: 36% vs 68% for resistant to susceptible strains. The number of patients who receive effective treatment within 48 hours: 48% vs 90% for resistant to susceptible strains. These numbers show that within two days, less than half of the people with resistant infections receive the proper treatment. Without proper care, the infection can spread, making it even harder to eliminate (Cosgrove). -- One method to avoid misdiagnosing resistant infections is to identify patients at high risk for harboring antimicrobial resistant strains. These people include individuals in long-term care facilities and patients with a long or recent history of antimicrobial use. Patients falling into either category should alert the physician. When treating these patients, the doctor may elect to begin treatment with a stronger antimicrobial or, more ideally, perform a rapid susceptibility test to determine the resistance of the organism. In either case, being aware of the possibility of resistance may help to reduce the time to effective treatment. Sources:  Cosgrove, S. The Relationship between AMR and Patient Outcomes: Mortality, length of Hospital Stay and Health Care Costs. Clinical Infectious Disease, 2006, 42:S82–S89.  Lautencbach, Metlay, Biker, Edelstein, Fishman. Association between FQ Resistance and Mortality in E. Coli and Klebsiella pneumo infections: The Role of Inadequate Empirical AMR Therapy. Clinical Infectious Disease, 2005, 41: 923-929.  Image: http://healthypr.files.wordpress.com/2007/04/hospital-bed1.jpg

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Animal Reservoirs Definition: The continuation of a disease in animals that may transfer to humans under close contact and/or genetic mutation of the pathogen.

Common animal reservoirs: pigs and aquatic wildlife Pathogens with Reservoirs: Influenza, Lyme’s Disease, Ebola Virus How does transfer happen? •



Influenza: RNA virus with an avian reservoir – Influenza virus replicates in the intestinal tract of aquatic birds – Virus is spread in bird populations through faecal contact Intermediate from bird to human: swine – Swine serve as host for viruses from humans and birds – Humans contact swine infected with influenza and acquire the disease

Sources: Glass, G, et al. Satellite imagery characterizes local animal reservoir populations of Sin Nombre virus in the southwestern United States. Proceedings of the National Academy of Science. 2002, 99: 16817-16822; Donahue, J, et al. Reservoir Competence of White-Footed Mice for Lyme Disease Spirochetes. The American Journal of Tropical Hygiene and Medicine. 1987, 36: 92-96. Image: http://pigofknowledge.blogspot.com Page 10

Disease Localization • The prevalence of resistance varies between countries • MRSA prevalence by country - Japan - USA - Greece - UK 45% - Saudi Arabia > 39% - Russia - Trinidad - Germany - Netherlands

70% 63% 49%

36% > 29% 27% 1%

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Notes on: Disease Localization Many developed nations have implemented surveillance networks and monitoring systems to track the spread and increase of antimicrobial resistance in human and animal populations. Examples of these global networks include the European Antimicrobial Resistance Surveillance System (EARSS) and the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP). MRSA incidence rates in the Netherlands are among the lowest in the world - 1.1% - in contrast to more than 25% in France, Spain, and Belgium and 43.5% in the United Kingdom. This extremely low rate is attributable to a decade-old national "search and destroy" policy to limit the spread of MRSA. The implementing guidelines are based on the premise that the best way to fight MRSA is to identify it as early as possible and to isolate infected or possibly infected patients. Patients and health care workers are categorized according to risk and screened regularly based on those risk assessments. For example, all patients treated in a foreign hospital are considered at high risk of being MRSA carriers and thus are isolated until cultures prove negative. Most importantly, the policy requires the cooperation of all health care facilities and is enforced by the Dutch government. There are few numbers from the developing countries because monitoring resistant often requires laboratory equipment, trained personnel and financial resources, which many lower-income countries lack. It is important to strengthen the surveillance systems in these countries. Image Source: NASA. Sources:  Presentation by Dr. David Heyman. WHO. July 23, 2008.  Heiman, F, Wertheim, H, Grundmann, H, Tiemersesma, E. Global Prevalence of methicillin-resistant Staphylococcus aureus. Lancet, 2006, 2:1866.  Institute of Antimicrobial Chemotherapy, Smolensk, Russia. http://www.antibiotic.ru/en/iac/  Castaño, Adam. Antimicrobial Resistance, A Global Health Emergency. WHO Internal Document, Aug 2007.

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Economic Burden of Resistance • •

Resistance costs countries billions of dollars each year to contain and treat infections. These costs not only directly affect the healthcare sector but also the entire economy. Mechanisms of increased costs: – – – – – – – – – –

Additional labs and X-rays Alternative, more expensive treatments Longer hospital stay More elaborate infection control procedures Reduced quality of life Increases in private insurance coverage Increased overall healthcare expenditure Increased cost of disease surveillance Increased family burden of infected individual Increased cost to firms of absentee workers

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Notes on: Economic Burden of Resistance The economic burden continues to rise as the number of resistant infections increases as well as the number of drugs to which each microorganism is resistant. As evidenced by the calculations, antimicrobial resistance is taking a financial toll not only on our hospitals but on economies, as well. Examples of costs:    

Additional hospital charges for MRSA in the USA Median total cost for MSSA primary nosocomial infections = $9,661 Median cost for MRSA primary nosocomial infections = $27,083 Approximate 3-fold increase in hospital costs from resistance

Note: this is only the increase in hospital costs from MRSA; it does not include the costs associated with other resistance infections. Also, the number of resistant bugs continues to increase, making these numbers underestimates. Treatment for resistant infections in US = $4-7 billion per year, or £500,000 to contain a 5 week outbreak of MRSA in general hospitals. Sources:  Murray A. Abramson, Daniel J. Sexton. Nosocomial Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Primary Bacteremia: At What Costs? Infection Control Hospital Epidemiology,1999;20:408–411.  Richard Smith, Milton Yago, Michael Millar, Jo Coast. Assessing the macroeconomic impact of a healthcare problem: The application of computable general equilibrium analysis to antimicrobial resistance. Journal of Health Economics, 2005, 24:1055-1075.  React. Economic Impact of Antibiotic Resistance. Fact sheet from React, 2008.  Image Source: West Investments Ltd.

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Mechanisms of Resistance: Overview Methods of Resistance  Impermeability of the drug  Alteration in the drug’s target  Enzymatic drug modifications  Efflux of the drug Methods of Resistance Acquisition  Chromosomal mutations  Genetic transfer (ex: plasmids) Antimicrobials Discussed  S. pneumoniae  MRSA  VISA/VRSA  ESBLs  VRE  Neisseria gonorrhoeae  MDR Salmonella Typhi

Source: Todar K. Todar’s Online Textbook of Bacteriology. Online at: http://textbookofbacteriology.net/resantimicrobial.html

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S. pneumoniae Increased publications of drug-resistant pneumococci

• Leading cause of serious childhood illness • Causative agent for – Otitis Media – Pneumonia – Meningitis

This graph shows the number of publications each year, from 1966 to the present, under headings of Streptococcus pneumoniae, antibiotic, and resistance. Courtesy of Daniel M Musher, MD., Up-to-date, “Resistance of Streptococcus pneumoniae to beta-lactam antibiotics”

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Notes on: S. Pneumoniae S. pneumoniae is a universal bacteria that has the distinction of being the leading cause of serious childhood illness. In fact, prior to the pneumococcal vaccine, almost 17,000 cases of invasive S. pneumoniae occurred annually. S. pneumoniae is known mainly for its ability to cause three major diseases: otitis media, pneumonia, and meningitis. Of these, meningitis is the most lethal. As you can see in the graph, resistance to S. pneumoniae, as well as academic interest in this subject, has become increasing prevalent across the U.S. Fortunately most resistance of pneumococci to beta-lactams--which is the most common form of resistance--can be overcome by simply increasing the dose. Sources: Advisory Committee on Immunization Practices. MMWR Recomm Rep 6 Oct 2000;49(RR9):1-35

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S. pneumoniae •

Resistance strains to many antibiotics



Penicillins (late 1970s) – 40% of U.S. pneumococci • Over 70% resistance in parts of Asia – Resistance mechanism: • Decreased drug binding – More common in children



Macrolides – 29% of U.S. pneumococci – Resistance mechanisms: • Decreased drug binding – 1/3 of isolates

• Efflux pump ejects drug – 2/3 of isolates

See Notes

Source: Centers for Disease Control

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Methicillin-resistant S. Aureus (MRSA) • Up to 30-40% of people are asymptomatic S. aureus carriers • 70-80% of S. aureus is resistant to penicillins • Problem of disease localization: – HA-MRSA vs. CA-MRSA • e.g. quinalone-resistant HAMRSA in adult ICUs vs. quinalone-sensitive CA-MRSA in pediatric outpatient clinics Source: http://www.emedicinehealth.com/slideshow-mrsapictures/article_em.htm

See Notes

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MRSA (1) •

Resistance: – Staphylococcal cassette chromosome • mecA gene component – encodes penicillin binding protein 2 » Binds beta-lactams with low affinity

• beta-lactamase genes



Degrees of resistance – Determined by antibiotic resistance testing • Homogenous – Highest degree of resistance – Requires fem genes

» Interrupt peptidoglycan synthesis

Gordon RJ and Lowy FD. Clin Infect Dis. 2008(46):S350-359

• Heterogeneous • Borderline

See Notes

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MRSA (2) •





MRSA carriage in hospitals – 12% in pts with risk factors – 1.8% in pts without risk factors Patients colonized with MRSA – 10-30% rate of developing MRSA infection • either in-hospital or after discharge Active surveillance for MRSA – Can reduce incidence of HA-MRSA by up to 50%

Adapted from Moran G., et al. New Eng J Med 2006(355):666-674

•Treatment: Vancomycin HA-MRSA most commonly transmitted by the hands of healthcare workers

See Notes

–Daptomycin or linezolid if vancomycin is not an option –Hand hygiene, minimizing patient contact, wearing a gown, etc.

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Enterococcus • Gram-positive, facultative anaerobic cocci

• Two species are common commensal organisms in the intestines of humans: E. faecalis (90-95%) and E. faecium (5-10%). • Important clinical infections include urinary tract infections, bacteremia, bacterial endocarditis, diverticulitis, and meningitis • High level of endemic antibiotic resistance: – Some Enterococci are intrinsically resistant to β-lactam-based antibiotics (some penicillins and virtually all cephalosporins) as well as many aminoglycodies – In the last two decades, particularly virulent strains of Enterococcus which are resistant to vancomycin (vancomycin–resistant enterococcus or VRE) have emerged

Source: http://www.biologie.uni-hamburg.de/bonline/library/onlinebio/BioBookDiversity_2.html

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Notes on: Enterococcus Enterococci are the leading cause of nosocomial infection (or secondary infection acquired while in a hospital). They are responsible for approximately 110,000 cases of urinary tract infection, 25,000 cases of bacteremia, 40,000 wound infections, and 1,100 cases of endocarditis yearly in the United States. To infect hosts enterococci primarily colonize mucosal surfaces. They also must evade host defenses although little is known about the actual mechanism of evasion. The pathogenicity of the organism is believed to be closely associated with its ability to produce cytolysin, a toxin that causes rupture of a variety of target membranes, including bacterial cells, erythrocytes, and other mammalian cells. Enterococci inhabit the gastrointestinal tract, the oral cavity, and the vagina in humans as normal commensals. A potential reason for the emergence of E. faecalis as a causative agent of nosocomial infection is the robust nature of this organism. E. faecalis has an intrinsic ability to grow in hypotonic, hypertonic, acidic, or alkaline conditions and to withstand detergents, oxidative stress, and desiccation

Doe Joint Genome Institute. Organism Details, Enterococcus faecalis DO. March 22, 2005. Fischetti VA et al. (editors) Gram-Positive Pathogens. ASM Press 2000 Ryan KJ (editors) Sherris Medical Microbiology, 4th ed., McGraw Hill, 294–5 2004 http://www.cdc.gov/ncidod/dhqp/ar_vre.html

Murray, BE. The life and times of the Enterococcus. Clinical Microbiology Reviews. 1990; 3, 46-65

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Vancomycin Resistant Enterococcus (VRE) • Vancomycin normally complexes with Dalanyl-D-alanine termini of normal peptidoglycan cell wall precursors, inhibiting cell wall synthesis • The genes associated with VRE encode a ligase responsible for the synthesis of the D-alanyl-D-lactate which is incorporated into the terminal portion of the peptidoglycan cell wall precursor - limits vancomycin-peptidoglycan precursor binding • 6 glycopeptide-resistant enterococcal phenotypes have been described: - VanA and VanB are most clinically relevant - VanA is the most widely-distributed

Source: http://www.nature.com/nrg/journal/v4/n6/fig_tab/nrg1084_F1.html

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Notes on: Vancomycin Resistant Enterococcus (VRE) Of the six phenotypes for VRE resistance that have been reported, VanA and VanB are most clinically relevant: VanA phenotype, induces high level resistance to both vancomycin and teicoplanin while VanB induces variable levels of resistance to vancomycin but is sensitive to teicoplanin. Van A and Van B are usually associated with E.faecalis and E.faecium, but Van A is more widely distributed and thus the predominant type of resistance reported. Moreover, vancomycin resistance has appeared preferentially in E.faecium, which is inherently more resistant to multiple drugs making therapy extremely problematic.  http://www.cdc.gov/ncidod/dhqp/ar_vre.html  http://www.hopkinsmedicine.org/heic/ID/vre/  Wood, AJ. Vancomycin resistant enterococcal infections. New England Journal of Medicine. 2000; 342, 710-721

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Clinical Significance of VRE Hospital Related Risk Factors • ICU Admission • Proximity to a patient with VRE • Length of hospitalization • Multiple unit stays • Enteral feedings Medication Related Risk Factors • Number, type, and duration of antibiotic therapy • Vancomycin use • 3rd Generation Cephalosporin utilization • Anti-anaerobic antibiotics (such as clindamycin) • Flouroquinolones (such as ciprofloxacin) • Preoperative bowel preparations

Most VRE infections can be treated with antibiotics other than vancomycin. People who are colonized (bacteria are present, but have no symptoms of an infection) with VRE do not usually need treatment.

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Notes on: Clinical Significance of VRE Enterococci are very tolerant organisms and can survive easily on the hands of health care personnel. Patient-to-patient spread by health care personnel has been documented. Strict observance of hand-washing policies would then be a key element in controlling the spread of epidemic strains of enterococci or any other organism. Cohorting of infected and colonized patients with poor hygiene has been used to prevent the spread of this organism. Proper barriers such as gloves and gowns when soiling is likely are important in preventing dissemination. Each health care facility through collaboration of its quality improvement and infection control programs such as pharmacy, reference microbiology laboratory, nursing, physicians, housekeeping services should develop a comprehensive, institutional-specific strategic plan to detect, prevent and control infection and colonization with VRE.

Recommendations for preventing the spread of vancomycin resistance: recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC) Centers for Disease Control and Prevention. MMWR (1995); 44 (RR-12):1-13 Noskins, GA. Recovery of vancomycin-resistant enterococci on fingertips and environmental surfaces. Infection Control Hospital Epidemiology. 1995: 16; 577-581

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VISA/VRSA (1) S. Aureus •



VRE

Vancomycin resistance and susceptibility – VISA  “vancomycin intermediate”  AKA glycopeptide-intermediate (GISA)  Reduced vancomycin susceptibility  First noted in 1996 vanA gene cassette – VRSA  vancomycin resistance  First noted in 2002 Epidemiology – RARE!  0.3% of S. Aureus infections  Only 7 cases of VRSA in the US from 2002-2006 – 5 of 7 had a history of MRSA or VRE, or previous exposure to vancomycin – Thought to originate from transfer of vanA resistance genes from VRE to MRSA

See Notes

Gene transfer

VRSA

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VISA/VRSA (2)



VISA – –

Exact mechanism of resistance is unknown Abnormal increased thickening of D-ala D-ala cell wall dipeptides •





Figures from Applebaum PC. Clin Microbiol Infect 2006(12):16-23

Decreased penetrance of antibiotics

Lacks the vanA gene

VRSA –

vanA gene cluster • Plasmid-mediated transfer – Mobile genetic element Tn1546 from VRE

• Results in production of D-ala D-lac cell wall dipeptide – Decreased binding to vancomycin

See Notes

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ß-lactam antibiotics and ß-lactamase •

β-lactam antibiotics are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, and carbapenems.



Production of plasma encoded ßlactamases (e.g., TEM-1, TEM-2, and SHV-1 ) by gram negative bacteria is the main mechanism of bacterial resistance to ß-lactam antibiotics



Inactivated by hydrolysis of the amide bond of the β -lactam ring



Resistance is NOT conferred to expanded-spectrum cephalosporins

Source: http://www.cic.klte.hu/~gundat/betalaca.htm

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Notes on: ß-lactam antibiotics and ß-lactamase β-lactam antibiotics are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, and carbapenems. These antibiotics are bactericidal and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. β-lactam antibiotics are analogues of D-alanyl-D-alanine - the terminal amino acid residues on the peptide subunits of the nascent peptidoglycan layer. The structural similarity between β-lactam antibiotics and D-alanyl-D-alanine facilitates their binding to the active site of penicillin-binding proteins (PBPs), transpeptidases that facilitate the final step in the synthesis of the peptidoglycan. This irreversible inhibition of the PBPs prevents the final crosslinking of the nascent peptidoglycan layer, disrupting cell wall synthesis. Unfortunately, many gram-negative bacteria have found a way to resist the effects of β-lactam antibiotics. The most common mechanism of β-lactam resistance is due to enzymatic hydrolysis of the β-lactam ring. If the bacteria produces β-lactamase, the enzymes will break open the β-lactam ring of the antibiotic, rendering the antibiotic ineffective. The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer. Abraham EP, Chain E. An enzyme from bacteria able to destroy penicillin. Nature 1940; 46:837 George A et al. Mechanism of disease: The New Beta-Lactamases. N Engl J Med 2005; 352:380-91

Bush K et al. A functional classification scheme for beta-lactamases and its correlations with molecular structure. Antimicrob Agents Chemother 1995;39: 1211-33

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Extended Spectrum ß-lactamase Producing (ESBL) Gram negatives • ESBLs confer resistance to expanded-spectrum cephalosporins (e.g. ceftriaxone, cefotaxime, and ceftazidime ), aztreonam, and related oxyiminobeta lactams. • 1983: First documentation of plasmid-encoded ß-lactamases capable of hydrolyzing the extendedspectrum cephalosporins with an oxyimino side chain, collectively termed the extended spectrum beta-lactamases • Derived from mutations in plasmid-encoded genes for TEM-1, TEM-2, or SHV-1 that extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes.

Source: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=2941

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Notes on: Extended Spectrum ß-lactamase Producing (ESBL) Gram negatives Gram negatives 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 . However, in Germany in 1983, the extended-spectrum b-lactamases (ESBLs) were detected. ESBLs are beta-lactamases that hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam aztreonam. Typically, 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. Emery, CL. Detection and clinical significance of extended-spectrum β-lactamases in a tertiary-care medical center. Clin. Microbiol. 1997; 35:2061-2067 Bradford PA. Extended-spectrum β-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev. 2001; 48:933-51 Bush K et al. A functional classification scheme for beta-lactamases and its correlations with molecular structure. Antimicrob Agents Chemother 1995;39: 1211-33 Page 33

ESBL Clinical Significance • ESBLs are commonly found in Klebsiella, E.Coli , Enterobacter, Proteus, Citrobacter, Pseudomonas • Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides) – Treatment is limited • Risk factors – Critically ill patients – Long hospitalization (median 11-67 d) – Invasive medical devices – Heavy antibiotic treatment

Source: http://www.medscape.com/viewarticle/413080_30

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Notes on: ESBL Clinical Significance 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 ESBLproducing 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. Known risk factors for colonization and/or infection with organisms harboring ESBLs include admission to an intensive care unit, recent surgery, instrumentation, prolonged hospital stay and antibiotic exposure, especially to extendedspectrum beta-lactam antibiotics. Use of extended-spectrum antibiotics exerts a selective pressure for emergence of ESBL producing gram negatives. The resistance plasmids can then be transferred to other bacteria of a variety of species. Giske, CG et al. Clinical and economic impact of common multidrug-resistant gram-negative bacilli. Antimicrob. Agents Chemother 2008; 52: 813-821 Fung, HB et al. Current Issues in Gram-Negative Resistance: Extended-Spectrum Beta-Lactamases and Inducible BetaLactamases. Journal of Pharmacy Practice 2001; 14: 6-17 Yang, K. Diagnosis and Treatment of Extended-Spectrum and AmpC ß-Lactamase-Producing Organisms. The Annals of Pharmacotherapy 2007; 41: 1427-1435 Paterson, DL. Extended-Spectrum ß-Lactamases: a Clinical Update. Clin. Microbiol. Rev. 2005; 18: 657-686

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Neisseria gonorrhoeae • Gram-negative bacteria responsible for the sexually transmitted disease gonorrhea • Infections are acquired by sexual contact or direct content (in the context of neonates) and usually affect the mucous membranes of the urethra in males and the endocervix and urethra in females • Symptoms include purulent discharge from the genitals which may be foul smelling and a burning sensation during urination and conjunctivitis in neonates • Patients with N. gonorrhoeae should also be tested for Chlamydia infections, since co-infection is frequent

See Notes

Source: http://www.textbookofbacteriology.net/neisseria.html

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Resistance in Neisseria gonorrhoeae Antimicrobial resistance in N. gonorrhoeae occurs as: • Plasmid-mediated resistance to - Penicillin - Tetracycline • Chromosomally mediated resistance to - Penicillins - Tetracyclines - Spectinomycin - Fluoroquinolones • Cephalosporins are the treatment of choice. As a precaution, treatment for Chlamydia is usually included as well.

See Notes

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Salmonella Typhi and Typhoid Fever • Strain of Salmonella enterica and the cause of the disease typhoid fever • Transmitted by the fecal-oral route-- excreted by humans in feces and may be transmitted by contaminated water, food, or by person-to-person contact • Symptoms usually develop 1–3 weeks after exposure; include high fever, malaise, headache, constipation or diarrhea, rose-colored spots on the chest, and enlarged spleen and liver. • Healthy carrier state may follow acute illness. • Can be treated with antibiotics-- BUT resistance to common antimicrobials is widespread.

Source:http:// web.uconn.ed u/mcbstaff/gra f/Student%20 presentations/ Salmonellatyp hi/Salmonellat yphi.html

Source:http://w ww.migrantclinic ian.org/excellen ce/environment al/waterandsanit ation

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Notes on: Salmonella Typhi and Typhoid Fever Typhoid fever is a bacterial infection of the intestinal tract and bloodstream. Symptoms can be mild or severe and include sustained fever as high as 39°-40° C, malaise, anorexia, headache, constipation or diarrhoea, rosecolored spots on the chest area and enlarged spleen and liver. Most people show symptoms 1-3 weeks after exposure. Typhoid is caused by the bacteria S. typhi. Typhoid germs are passed in the feces and urine of infected people. People become infected after eating food or drinking beverages that have been handled by a person who is infected or by drinking water that has been contaminated by sewage containing the bacteria. Once the bacteria enter the person’s body they multiply and spread from the intestines, into the bloodstream. Even after recovery from typhoid, a small number of individuals (called carriers) continue to carry the bacteria. These people can be a source of infection for others. The transmission of typhoid in less-industrialized countries may be due to contaminated food or water. Where water quality is high, and chlorinated water piped into the house is widely available, transmission is more likely to occur via food contaminated by carriers handling food. • • •

http://www.cdc.gov/ncidod/dbmd/diseaseinfo/typhoidfever_g.htm http://www.who.int/mediacentre/factsheets/fs139/en/ http://www.healthinternetwork.com/topics/typhoid_fever/en/

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Multi-Drug Resistant Salmonella Typhi • Resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole and streptomycin is common-- these agents have not been used as first line treatment now for almost 20 years • Typhoid that is resistant to these agents is known as multidrug-resistant typhoid (MDR typhoid) • Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia

In geographic areas where MDR S. typhi is common, the recommended first line treatment is ciprofloxacin or ceftriaxone. There is also a vaccine available for travelers to these areas.

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Notes on: Multi-Drug Resistant Salmonella Typhi

Multidrug-resistant (MDR) strains of Salmonella are encountered frequently and the rates of multidrug-resistance have increased considerably in recent years. Even worse, some variants of Salmonella have developed multidrug-resistance as an integral part of the genetic material of the organism, and are therefore likely to retain their drug-resistant genes even when antimicrobial drugs are no longer used, a situation where other resistant strains would typically lose their resistance.

Drug-resistant Salmonella emerge in response to antimicrobial usage in food animals. Selective pressure from the use of antimicrobials is a major driving force behind the emergence of resistance, but other factors also need to be taken into consideration. The flouroquinolones - ofloxacin and ciprofloxacin, the third generation cephalosporins -ceftriazone and cefixime, and azithromycin, a macrolide antibiotic, are the drugs of choice for MDR typhoid fever. Flouroquinolones achieve excellent penetration in macrophages and bile, important sites of infection. However, resistance to flouroquinolones has also developed and represents a significant threat to the treatment of typhoid fever. The presence of ciprofloxacin resistance is a marker for decreased susceptibility to flouroquinolones and should be tested for when dealing with MDR strains. Switching to ceftriaxone or azithromycin may be preferable in these patients. These agents should be given for at least 7 days. There are also vaccines that are available for typhoid fever. The oral vaccine (Vivotif) contains a live but weakened strain of Salmonella typhi. The single-dose injectable vaccine (Typhim Vi) contains capsular polysaccharide antigen.   

Karmakar, SD. Plasmid-Encoded Multidrug Resistance of Salmonella typhi and some Enteric Bacteria in and around Kolkata, India: A Preliminary Study. J. Med. Microbiol . 1991; 34:149–151 Thong, KL. Integron-Associated Antibiotic Resistance in Salmonella enterica Serovar Typhi from Asia. Int. J. Infect. Dis. 2000, 4:194–197 Mirza S et al. Epidemiologic analysis of sporadic Salmonella typhi isolates and those from outbreaks by pulsed-field gel electrophoresis. J Clin Microbiol. 2000; 38:1449-1452

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Epidemiology of Multi-Drug Resistant Salmonella Typhi

With an estimated 16-33 million cases of MDR S. Typhi annually resulting in 500,000 to 600,000 deaths in endemic areas, the World Health Organization identifies typhoid as a serious public health problem. Its incidence is highest in children between 5 and 19 years old. http://www.who.int/infectious-disease-report/2000/ch4.htm http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index7.html Page 42

Factors affecting the development and spread of resistance • • • • • • • • • •

Rapid urbanization Pollution and environmental degradation Demographic changes AIDS epidemic Growth of global trade and travel Role of poverty Easy access w/o Rx Animal feed Antibacterial Cleaning Products Counterfeit medications

Image Source: United Nations - Trend towards Urbanization of the World's Population

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Rapid Urbanization •







Asia and Africa are expected to double their urban populations to roughly 3.4 billion by 2030 When a population grows beyond its resources, overcrowding and poor hygiene and sanitation result Poor hygiene and sanitation increase disease prevalence

Isolates from E. coli strains in urban Nigeria (Lagos) showed significantly more antimicrobial resistance than ones in rural/suburban SW Nigeria

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Notes on: Rapid Urbanization Africa now has 350 million urban dwellers, more than the populations of Canada and the United States combined, and in 2008, for the first time in history, half of the earth’s population will live in urban areas. This rapid urbanization is often not accompanied by a rapid increase in resources, especially in developing countries. Complicating this situation is the negative impact of poverty, which also plagues many developing country urban dwellers. These factors create settings that encourage the spread of infection. For instance, more than 1/3 of the world’s population lacks access to proper excreta disposal, which is discouraging since proper sanitation has been shown to prevent disease, especially diarrhea, trachoma and intestinal diseases. Improper sewage disposal, on the other hand, encourages AMR transmission and exchange of AMR genes among bacteria. It is not difficult to see why disease and AMR transmit so easily in situations with improper sewage systems, such as the case in Nairobi's slums, where plastic bags, or "floating toilets," are commonly used as containers for excreta disposal and then thrown into the street. Sources: • Aiello AE, Larson EL. What is the evidence for a causal link between hygiene and infections? The Lancet Infectious Diseases, 2002, 2(2):103-10. • Byarugaba DK. A view on antimicrobial resistance in developing countries and responsible risk factors. International Journal of Antimicrobial Agents, 2004, 24(2):105-10. • Cairncross S. Sanitation in the developing world: current status and future solutions. International Journal of Environmental Health Research, 2003, 13 Suppl 1:S123-31. • Okeke IN, Lamikanra A, Edelman R. Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerging Infectious Diseases, 1999, 5(1):18-27. • State of the world 2007: our urban future. Washington, DC, Worldwatch Institute, 2006 (http://www.worldwatch.org/taxonomy/term/467, accessed 22 July 2008).

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Pollution Fecal contamination of water supply •

Contamination can occur from leaking septic tanks, run-off of manure from fields



Feces in the water brings human or animal pathogens in contact with potentially resistant bacteria



This water is used for drinking or irrigation for agriculture

Increased levels of ozone air pollution •

Hastened by warmer temperature



More micro-organisms enter drinking water from associated increase in rainfall and run-off



Higher risk for resistance transfer

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Notes on: Pollution Applying manure to crops has the potential for runoff into surrounding water supplies. Antibiotics present in the manure, therefore, also end up in the water. A study of rivers across the US found that 50% of surface water was contaminated with antibiotics. Year-long monitoring of manure runoff from fields showed that small quantities (>5%) of dissolved antibiotics (chlorotetracycline, tylosin, and monensin) were lost through leaching and runoff. This study also concluded that the majority of runoff occurred during the fall. A simple strategy to minimize the runoff is spring manure application instead of fall. Sources: • Harakeha, S, et al. Antimicrobial-resistance of Streptococcus pneumoniae isolated from the Lebanese environment. Marine Environmental Research, 2006, 62: 181-193. • Berg,G, et al. The rhizosphere as a reservoir for opportunistic human pathogenic bacteria. Environmental Microbiology, 2005, 7:1673-1685. • Dolliver, H. et al. Antibiotic losses in leaching and surface runoff from manure-amended agricultural land. Journal of Environmental Quality, 2008, 37:1227-1237. • Martins da Costa, P, et al. Antimicrobial Resistance in Enterococcus spp. Isolated in inflow, effluent and sludge from municipal sewage water treatment plants. Water Research, 2006, 40: 1735-1740. Image: feww.wordpress.com

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AIDS Epidemic and Demographic Changes People living with HIV/AIDS (PLWHA), the young, and the elderly have a diminished natural ability to fight off infection.

More immunocompromised patients in a population

Infections are more easily caught and spread Resistance is more likely to occur and spread Page 48

Notes on: AIDS Epidemic and Demographic Changes The AIDS epidemic is a strong risk factor for the formation of AMR. Because HIV diminishes a body’s ability to fight infections, many PLWHA frequently use antimicrobials prophalactially and to treat infections. Indeed, it is likely that HIV is impacting the state of AMR. An Italian study found that individual exposure to beta-lactams, multiple hospitalizations, and low CD4+ cell number were all independent risk factors for MRSA infections in PLWHA. Since CD4+ cells are used by the body to fight infection, the lower the CD4+ number, the more immunocompromised one is. Notably, once highly active antiretroviral therapy (HAART) usage increased, the prevalence of MRSA bacteraemia in PLWHA decreased, indicating that bolstering a PLWHA’s immune system could correlate with a lower prevalence of AMR infections. A frequently overlooked social factor that can exacerbate AMR is the effect of a high concentration of very young and old patients in a health care system. Since it is easier for infection to take root in these populations, the effects of the shifting patient population on the spread of infection should be examined. Sources: Byarugaba DK. A view on antimicrobial resistance in developing countries and responsible risk factors. International Journal of Antimicrobial Agents, 2004, 24(2):105-10. Livermore DM. Bacterial resistance: origins, epidemiology, and impact. Clinical Infectious Diseases, 2003, 36(Suppl 1):S11-23.

Tumbarello M et al. Risk factors and predictors of mortality of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in HIV-infected patients. The Journal of Antimicrobial Chemotherapy, 2002, 50(3):375-82.

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Globalization of Trade and Travel • Globalization has enabled microbes to travel fast and far, leaving no region unaffected • AMR is more pronounced in developing countries – AMR commensal organisms are often part of the normal gut flora in developing country residents – Urban migration, inadequate sewage disposal and overcrowding encourage AMR dissemination Direst cargo flights leaving from Vancouver, Canada go to four continents. Source: Vancouver Airport Authority

• Most strains of multi-drug resistant typhoid in the US come from 6 developing countries

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Notes on: Globalization of Trade and Travel Globalization requires that efforts be made on an international, coordinated level. National initiatives will be ineffective if neighboring countries do not engage in similar measures. To date, no country has fully implemented the WHO's 2001 Global Strategy for Containment of AMR, with varying levels of commitment in different nations. In addition to MDR-typhoid in the US, many other instances of resistant infections spreading globally exist. Two examples include MRSA outbreaks in Canada that originated in an Indian village and genetically-identical strains of resistant S. pneumoniae that have been found in Iceland, Europe, and Latin America. Source: Cargo air carrier routes. Vancouver, British Columbia, Canada, Vancouver Airport Authority, 2008. (http://www.yvr.ca/business/cargo/routes.asp#, accessed 23 July 2008). Memish ZA, Venkatesh S, Shibl AM. Impact of travel on international spread of antimicrobial resistance. International Journal of Antimicrobial Agents. 2003 Feb;21(2):135-42. Okeke IN et al. Antimicrobial resistance in developing countries. Part II: strategies for containment. The Lancet Infectious Diseases, 2005, 5(9):568-80.

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Animal Husbandry

Sub-clinical doses of antibiotics in animal feed select for resistance microorganisms, including Campylobacter, Salmonella, E.coli and E. faecium

Use of antibiotics in animals creates reservoirs of resistance

Humans eat meat or poultry contaminated with resistant organisms

Ingesting AMR bacteria changes the normal intestinal microbiota

Potentially acquisition of a resistant infection

ANTIBIOTIC RESISTANCE

See Notes

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Aquaculture • Similar to antibiotics in animal feed, antibiotics are frequently given to prevent infection in aquaculture, commercial farms of seafood. • Mechanisms that spread antibiotic resistant organisms: – Transporting fish and consequently the antibiotic bacteria they carry between environments – Uneaten fish food and fish faeces, both containing antibiotics, settle with the natural sediment at the bottom of the pen; antibiotics leach from the sediment and travel to distant sites – Contamination of fisheries with untreated sewage containing normal intestinal flora and pathogens

See Notes

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Antibacterial Cleaning Products •Antibacterial soaps commonly contain triclosan – Have not shown any added infection protection – Effect on resistance is unknown •Antibacterial cleaning products commonly contain quaternary ammonium products –Have been used for decades –Households with high use have shown increased resistance •More research is needed on these compounds: it is likely that common usage encourages AMR

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Notes on: Antibacterial Cleaning Products Antibacterial soaps containing the common ingredients triclosan or trilocarban have not been shown to offer any added infection protection and their effects on resistance are unknown. Their potential harm should be further researched: although no increase in AMR was shown in three community settings, these soaps increased in vitro resistance in ten of eleven studies. The usage of antibacterial cleaning products containing quaternary ammonium compounds, such as benzalkonium chloride, has also correlated with increased resistance. Little literature on this subject exists, however, and more is needed to definitively determine the impact on resistance. Image source: http://www.flickr.com/photos/pbouchard/2807076457/ Sources: Aiello AE et al. Antibacterial cleaning products and drug resistance. Emerging Infectious Diseases, 2005, 11(10):1565-70.

Aiello AE, Larson EL, Levy SB. Consumer antibacterial soaps: effective or just risky? Clinical Infectious Diseases, 2007, 45(Suppl 2):S137-47. Page 55

Over-the-counter access to pharmaceuticals •





In many developing countries, antibiotics are readily available from hospitals, pharmacies, patent medicine stalls, roadside stalls and hawkers. Common issues with OTC drugs that contribute to AMR: – Substandard quality – Sub-therapeutic doses – Improper self-medication Internet/ mail-order pharmacies present a new, easy way to obtain OTC antibiotics – Few regulations monitor internet drug sales – Difficult to impose restrictions on the sale of these drugs given the nature of the internet and international sales

See Notes

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Counterfeit and Substandard Medicines •

Antimicrobials appear to be the most counterfeited product in developing countries

Genuine artusenate hologram

– TB, malaria, and HIV drugs are the most common – 'Old' antibiotics are also targeted: penicillin, tetracycline, cotrimoxazole, chloramphenicol •

20-90% of antimalarials were found to be counterfeit in a WHO survey of 7 African nations



Many laws in developing countries are ineffective, which more easily enable the sale of counterfeit drugs



Many storage and transport conditions in developing countries lead to the degradation of medication and a loss of efficacy

Silver foil copy

Fake

Source: Aldhous, P. Nature, 2005.

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Notes on: Counterfeit and Substandard Medicines

While it seems logical that a high prevalence of sub-therapeutic medications will increase the selective pressure for resistance to form, and thus add to the problem of AMR, evidence proving this series of events is lacking. The lack of studies examining this link should not be mistaken for a lack of causation, however. Several studies do cite cases of resistance likely hastened by a high presence of substandard medications. For instance, Kelesidis et al. concludes that the high prevalence of substandard chloramphenicol and co-trimoxazole in Burma could have contributed to the high rate of typhoid antibiotic resistance in the region. The lack of direct evidence speaks to the need for further studies on the extent of the effects of counterfeit and substandard drugs on AMR. Sources:  Aldhous P. Counterfeit pharmaceuticals: murder by medicine. Nature, 2005, 434: 132-136.  Byarugaba DK. A view on antimicrobial resistance in developing countries and responsible risk factors. International Journal of Antimicrobial Agents, 2004, 24(2):105-10.  Kelesidis T et al. Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence. The Journal of Antimicrobial Chemotherapy, 2007, 60(2):214-36.  Newton PN et al. Counterfeit anti-infective drugs. The Lancet Infectious Diseases, 2006, 6(9):602-13.  Okeke IN, Lamikanra A, Edelman R. Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerging Infectious Diseases, 1999, 5(1):18-27.

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Poverty Poverty impairs infection prevention and control

FACTORS THAT CHALLENGE INFECTION PREVENTION:

FACTORS THAT CHALLENGE INFECTION CONTROL:

 Decreased caloric and nutrient intake  Poor hygiene and sanitation  Crowded conditions

 Inaccessible health facilities  Inaccessible drugs  Lack of education about antimicrobials  Lack of money to buy full courses of drugs

The more infections, the more chances that AMR can emerge and spread

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Notes on: Poverty These co-factors affect infection prevention and control in the following ways:  Malnutrition and starvation affect the body’s natural ability to fight infection.  Poor hygiene and sanitation significantly increase the risk of infection (see Rapid Urbanization slide). Crowded conditions that outgrow resources can lead to poor sanitation and increase the probability of coming in contact with infections due to increased close contact with others. Inaccessible health facilities decrease one’s ability to get an accurate diagnosis and treat their infection. In developing countries rural communities are especially affected, like in Uganda where only 49% of the population lives within 5 km of a health care facility. When drugs are inaccessible, infection is allowed to continue and spread. Having insufficient funds to buy drugs can lead to the sharing of prescriptions among families or not buying the full course of antimicrobials, and both of these actions can increase AMR.

Sources:  Byarugaba DK. Antimicrobial resistance in developing countries and responsible risk factors. International Journal of Antimicrobial Agents 2004, 24(2): 105-10.  Okeke IN, Lamikanra A, Edelman R. Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerging Infectious Diseases, 1999, 5(1):18-27.

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Global Action Areas for Containing AMR

Adapted from WHO, Alliance for Patient Safety, departmental report, 2007

See Notes

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What Can We Do? INDIVIDUALS • Personal hygiene • Educate others about the problem

HOSPITALS • Improve hospital infection control • Enforce regulations by patient safety oversight committees

DOCTORS • Judicious use of drugs • Educate patients about the proper use of antibiotics • Collect more data on the extent of resistance

GOVERNMENTS • Increase worldwide access to the appropriate drugs • Revive R&D on antibiotic innovation • Revive innovation of rapid diagnostic technologies • Revive R&D for vaccines that target AMR organisms

Adapted from WHO, Alliance for Patient Safety, departmental report, 2007 Page 62

Quiz • We regret that this website cannot accommodate the 24-question quiz that was developed for this module. In time we hope it will be possible to include the quiz.

Credits Adam Castaño, Maggie Kober, Anuja Jain, John Prensner, Sara Haack, Sujal Parikh University of Michigan Medical School Antibiotic Defense

Acknowledgements We would like to thank Dr. Anthony So, Dr. Carol Kauffman, Dr. Laraine Washer, and Dr. R. Alexander Blackwood for their critical review of this module.

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The Global Health Education Consortium gratefully acknowledges the support provided for developing these teaching modules from:

Sponsors

Margaret Kendrick Blodgett Foundation The Josiah Macy, Jr. Foundation Arnold P. Gold Foundation

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

Notes on: S. pneumoniae Fortunately, most resistance of pneumococci to beta-lactams--which is the most common form of resistance--can be overcome by simply increasing the dose. Unfortunately, meningitis caused by S. pneumoniae does not, and so all meningitis is treated urgently with vancomycin. That said, resistance among S. pneumoniae is common and widespread. Some resistance is seen to many of the main classes of antibiotics: penicillins, macrolides, tetracyclines, fluoroquinolones, etc. Each of these has a distinct mechanism of resistance. Pencillins show decreased binding to the peptidyl transferase molecules in the bacterial cell wall, whereas macrolide resistance relates to the presence of either the erm(B) gene, which prevents macrolide binding through methylation of the 23S rRNA subunit, or the mef(A), which encodes an efflux pump that ejects the drug from the cell. The erm(B) gene also conveys resistance to clindamycin, which operates in a similar manner to macrolides. Globally, the threat of S. pneuomoniae can be greatly reduced by vaccinated children with the multivalent pneumococcal vaccine. This vaccine contains the 7 most common serotypes: 4 6B, 9V, 14, 18C, 19F, 23F, although many developing countries harbor a varying cast of serotypes and require a modified combination. Employment of this vaccine has led to a 30-50% reduction in penicillin-resistant isolates. However, the vaccine is also selecting for other resistant serotypes of S. pneumoniae, such as 19A. That said, these remain a minor fraction of the total S. pneumoniae infections seen. Image: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5706a2.htm Sources: Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med. Dec 28 2000;343(26):1917-1924. Thornsberry C, Sahm DF, Kelly LJ, et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999-2000. Clin Infect Dis. Mar 1 2002;34 Suppl 1:S4-S16. Hyde TB, Gay K, Stephens DS, et al. Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA. Oct 17 2001;286(15):1857-1862. Karlowsky JA, Thornsberry C, Jones ME, Evangelista AT, Critchley IA, Sahm DF. Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program (1998-2002). Clin Infect Dis. Apr 15 2003;36(8):963-970. Doern GV, Richter SS, Miller A, et al. Antimicrobial resistance among Streptococcus pneumoniae in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis. Jul 15 2005;41(2):139-148. Shortridge VD, Doern GV, Brueggemann AB, Beyer JM, Flamm RK. Prevalence of macrolide

resistance mechanisms in Streptococcus pneumoniae isolates from a multicenter antibiotic resistance surveillance study conducted in the United States in 1994-1995. Clin Infect Dis. Nov 1999;29(5):1186-1188. Pelton SI, Huot H, Finkelstein JA, et al. Emergence of 19A as virulent and multidrug resistant Pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine. Pediatr Infect Dis J. Jun 2007;26(6):468-472. Talbot TR, Poehling KA, Hartert TV, et al. Reduction in high rates of antibiotic-nonsusceptible invasive pneumococcal disease in tennessee after introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. Sep 1 2004;39(5):641-648. Stephens DS, Zughaier SM, Whitney CG, et al. Incidence of macrolide resistance in Streptococcus pneumoniae after introduction of the pneumococcal conjugate vaccine: population-based assessment. Lancet. Mar 5-11 2005;365(9462):855-863. Return to Slide 18

Notes on: Methicillin-resistant S. Aureus (MRSA) Perhaps the most epidemiologically important of all the antibiotic-resistant bacteria. With up to 40-60% of S. aureus carriers having a form resistant to penicillins (depending on the country), it medical problem of truly global proportions. In the U.S. alone, there are an estimated 90,000 cases of invasive S. aureus a year, contributing to the cause of death in an estimated 18,000 people. In fact, nearly 7% of patients coming into the hospital test positive for MRSA on admission--with the anterior nares being the most common site for MRSA inhabitance. This raises the point of community-acquired MRSA with hospital-acquired MRSA. In contrast to earlier years, in which clinical distinction was made between these diseases, they are now consider to be one and the same. While they may differ in exposure and etiology, they are the same clinical disease, and may present in the same fashion--most often as small, red skin lesions that progress to ulceration. Moreover, they are defined by the same criteria: namely, the S. aureus strain must have an oxacillin minimum inhibitory concentration of greater than or equal to 4 mcg/mL. Nevertheless, differing local resistance patterns continues to cause problems with MRSA. Examples of localized resistance have lead to reports to quinalone resistance in MRSA from inpatients when outpatients display quinalone-sensitivity. Such examples demonstrate the complexity of antibiotic resistance patterns (especially when considered on a national and international scale). Sources: Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. Oct 17 2007;298(15):1763-1771. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. Aug 1 2004;39(3):309-317. Sanford MD, Widmer AF, Bale MJ, Jones RN, Wenzel RP. Efficient detection and long-term persistence of the carriage of methicillin-resistant Staphylococcus aureus. Clin Infect Dis. Dec 1994;19(6):1123-1128. Eveillard M, de Lassence A, Lancien E, Barnaud G, Ricard JD, Joly-Guillou ML. Evaluation of a strategy of screening multiple anatomical sites for methicillin-resistant Staphylococcus aureus at admission to a teaching hospital. Infect Control Hosp Epidemiol. Feb 2006;27(2):181-184. Huang SS, Rifas-Shiman SL, Warren DK, et al. Improving methicillin-resistant Staphylococcus aureus surveillance and reporting in intensive care units. J Infect Dis. Feb 1 2007;195(3):330338. Furuno JP, McGregor JC, Harris AD, et al. Identifying groups at high risk for carriage of antibiotic-resistant bacteria. Arch Intern Med. Mar 13 2006;166(5):580-585. Return to Slide 19

Notes on: MRSA (1) The genetics behind MRSA have been well studied. All MRSA isolates have a mobile chromosomal element called the staphylococcal cassette chromosome, which contains the mec gene. The mec gene contains the structural component, mecA, and two regulatory components, the beta-lactamase genes and the negative regulators of mecA transcription. There are actually several different forms of the regulators and beta-lactamases, which correlate somewhat with CA-MRSA vs HA-MRSA, but these differences have only nominal impact on MRSA as a clinical entity. While these regulatory genes do contribute to MRSA virulence--indeed, the beta-lactamase genes assist in cleaving the functional component of penicillins, it is the mecA gene that is most prominent. It encodes penicillin binding protein 2a (PBP2a). The penicillin binding proteins are peptidase enzymes in the bacterial membrane. Typically, these catalyze cell wall synthesis, and it is these molecules that pencillin will bind in order to disarm bacteria. However, PBP2a has low affinity for penicillins, allowing S. aureus isolates with the mecA gene to gain penicillin resistance. The degrees of MRSA resistance are defined as the homogenous, heterogenous, and borderline phenotypes. Borderline is exactly what it sounds like: S. aureus isolates that have very mild resistance (oxacillin MIC of 4-8 mg/mL). Heterogenous and homogenous phenotypes refer to the fem genes, which also function to disrupt cell wall synthesis. Isolates that are homogenous for the fem genes tend to have the greatest level of resistance, whereas heterogenous isolates are less resistant. Sources: De Lencastre H, Tomas A. Reassessment of the number of auxiliary gene essential for expression of high-level methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. Nov 1994;38(11):2590-8 Inglis B, Matthews PR, Stewart PR. The expression in Staphylococcus aureus of cloned DNA encoding methicillin resistance. J Gen Microbiol. Jun 1988;134(6):1465-1469. Zhang HZ, Hackbarth CJ, Chansky KM, Chambers HF. A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci. Science. Mar 9 2001;291(5510):19621965. Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev. Oct 1997;10(4):781-791. Berger-Bachi B. Expression of resistance to methicillin. Trends Microbiol. Oct 1994;2(10):389393. Henze UU, Berger-Bachi B. Staphylococcus aureus penicillin-binding protein 4 and intrinsic betalactam resistance. Antimicrob Agents Chemother. Nov 1995;39(11):2415-2422. Return to Slide 20

Notes on: MRSA (2) As previously mentioned, over 6% of patients have MRSA isolates already upon admission. In the hospital, that risk only increases. In fact, the percent of patients with MRSA isolates may double to a full 12%--with 10 - 30% of these patients likely to develop an MRSA infection-especially if these patients qualify as having several different risk factors. Risk factors include antibiotic usage in the last 3 months, hospitalization in the past 12 months, diagnosis of skin or soft tissue infections on presentation (which is often the first sign of MRSA), of a known HIV infection. By contrast, less than 2% of patients who lack these risk factors will test positive for MRSA isolates. With such prominence in the healthcare system, MRSA treatment is crucial. Medically, vancomycin is the drug of choice, although linezolid or daptomycin may be used if vancomycin is not an option. Otherwise, the most important precautions are astounding simple, and really ought to be a part of all clinical care. Most importantly, hand washing: HA-MRSA has been proven to be directly related to the hand hygiene of medical professionals. In addition, minimizing patient contact, wearing a gown and gloves, and other similar common-sense measures are critical. Using these standards, the incidence of HA-MRSA can be reduced by up to 50%. Sources: Inglis B, Matthews PR, Stewart PR. The expression in Staphylococcus aureus of cloned DNA encoding methicillin resistance. J Gen Microbiol. Jun 1988;134(6):1465-1469. Zhang HZ, Hackbarth CJ, Chansky KM, Chambers HF. A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci. Science. Mar 9 2001;291(5510):19621965. Inglis B, et al. J Gen Microbiol 1988; 134:1465 Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev. Oct 1997;10(4):781-791. Berger-Bachi B. Expression of resistance to methicillin. Trends Microbiol. Oct 1994;2(10):389393. Henze UU, Berger-Bachi B. Staphylococcus aureus penicillin-binding protein 4 and intrinsic betalactam resistance. Antimicrob Agents Chemother. Nov 1995;39(11):2415-2422. De Lencastre H, Tomas A. Reassessment of the number of auxiliary gene essential for expression of high-level methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. Nov 1994;38(11):2590-8 Return to Slide 21

Notes on: VISA/VRSA (1) Recently, newer, more deadly forms of S. aureus infections have been surfacing around the world. Termed vancomycin-intermediate and vancomycin-resistant, these bacteria are frequently also methicillin-resistant, as vancomycin resistance is often discovered when MRSA isolates are unresponsive to vancomycin. VISA and VRSA associated with rapid death, with nearly 100% mortality occurring within 6 months of infection, although death in these cases can not be attributed to S. aureus alone. As with MRSA, vancomycin resistance is determined by evaluating the responsiveness of a strain to increasing concentrations of vancomycin. In certain cases, colonies of vancomycin-sensitive S. aureus may contain subpopulations of resistant S. aureus, a phenomenon termed “heteroresistance”. Heteroresistant isolates should be considered vancomycin-resistant for treatment purposes. Vancomycin resistance in S. aureus is thought to have originated from horizontal gene transfer of the vanA resistance cluster from Vancomycin-Resistant enterococci to MRSA. In 1992, scientists showed that, in fact, conjugal transfer of the vanA gene cluster from VRE to MRSA could create VRSA in laboratory mice. Thankfully, vancomycin resistance is exceedingly rare, with only a handful of cases reported. In fact, only 0.3% of S. aureus isolates demonstrate vancomycin resistance, with only some of these displaying total vancomycin resistance. From 2002-2006, only 7 cases of VRSA were recorded in the US, most of which occurred in patients with a previous history of vancomycin exposure as well as MRSA or VRE colonization. Sources: Noble WC, Virani Z, Cree RG. Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbiol Lett. Jun 1 1992;72(2):195-198. Sievert DM, Rudrik JT, Patel JB, McDonald LC, Wilkins MJ, Hageman JC. Vancomycin-resistant Staphylococcus aureus in the United States, 2002-2006. Clin Infect Dis. Mar 1 2008;46(5):668674. Hubert SK, Mohammed JM, Fridkin SK, Gaynes RP, McGowan JE, Jr., Tenover FC. Glycopeptideintermediate Staphylococcus aureus: evaluation of a novel screening method and results of a survey of selected U.S. hospitals. J Clin Microbiol. Nov 1999;37(11):3590-3593. Hiramatsu K, Aritaka N, Hanaki H, et al. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet. Dec 6 1997;350(9092):1670-1673. Hiramatsu K, Hanaki H, Ino T, Yabuta K, Oguri T, Tenover FC. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob

Chemother. Jul 1997;40(1):135-136. Return to Slide 28 Notes on: VISA/VRSA (2) As with MRSA, the genetics behind vancomycin resistance have been well studied. VRSA, like MRSA, contains a prominent gene cluster--known as vanA--that is not active in normal S. aureus isolates. vanA is harbored in a mobile genetic element originally found in vancomycin-resistant enterococci (VRE). This mobile genetic element finds its way to S. aureus via a plasmidmediated transfer from VRE. Once inside the S. aureus bacteria, vanA encodes for an alternative cell wall dipeptide composed of D-ala D-lac, rather than the normal D-ala D-ala. This D-ala D-lac dipeptide prevents vancomycin from binding to S. aureus, thereby granting the bacteria resistance. It would be logical to think that VISA shared a similar mechanism of resistance. Interestingly, it does not. VISA, in fact, has a resistance signature distinct from not only VRSA but also MRSA and VRE as well. Whereas the other three contain a vanA gene, VISA does not. Rather, VISA resistance is not well understood, but it seems to rely on increased synthesis of normal D-ala Dala dipeptides, resulting in an abnormally thickened cell wall. This increased synthesis may be due to a polymorphism in the accessory gene regulator, agr, but this is not universal among VISA isolates. Given that vancomycin is one of the most powerful antibiotics at our disposal, the question of treatment for VISA/VRSA is still a great debate. Unfortunately, there is no easy treatment, and no existing treatment has been particularly effective. Chloramphenicol, rifampin, TMX-SMX, and ciprofloxacin, among many other options, have been tried with varying degrees of success. Sources: Noble WC, Virani Z, Cree RG. Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbiol Lett. Jun 1 1992;72(2):195-198. Clark NC, Weigel LM, Patel JB, Tenover FC. Comparison of Tn1546-like elements in vancomycinresistant Staphylococcus aureus isolates from Michigan and Pennsylvania. Antimicrob Agents Chemother. Jan 2005;49(1):470-472.Courvalin P. Clin Infect Dis 2006; 42:Suppl 1:S25 Courvalin P. Vancomycin resistance in gram-positive cocci. Clin Infect Dis. Jan 1 2006;42 Suppl 1:S25-34. Howden BP, Johnson PD, Ward PB, Stinear TP, Davies JK. Isolates with low-level vancomycin resistance associated with persistent methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. Sep 2006;50(9):3039-3047.

Walsh TR, Howe RA. The prevalence and mechanisms of vancomycin resistance in Staphylococcus aureus. Annu Rev Microbiol. 2002;56:657-675. Staphylococcus aureus resistant to vancomycin--United States, 2002. MMWR Morb Mortal Wkly Rep 2002; 51:565 Return to Slide 29

Notes on: Neisseria gonorrhoeae The family Neisseriaceae consists of Gram-negative aerobic bacteria from fourteen genera, including Neisseria, Chromobacterium, Kingella, and Aquaspirillum. The genus Neisseria contains two important human pathogens, N. gonorrhoeae and N. meningitidis. N. gonorrhoeae causes gonorrhea, an infection with a high prevalence and low mortality. The disease gonorrhea is a specific type of urethritis that practically always involves mucous membranes of the urethra, resulting in a copious discharge of pus, more apparent in the male than in the female. Gonorrheal infection is generally limited to superficial mucosal surfaces lined with columnar epithelium. The areas most frequently involved are the urethra, cervix, rectum, pharynx, and conjunctiva. Uncomplicated gonorrhea in the adult male is an inflammatory and pyogenic infection of the mucous membranes of the anterior urethra. The most common symptom is a discharge that may range from a scanty, clear or cloudy fluid to one that is copious and purulent. Dysuria (difficulty in urination)is often present. Inflammation of the urethral tissues results in the characteristic redness, swelling, heat, and pain in the region. There is intense burning and pain upon urination. Endocervical infection is the most common form of uncomplicated gonorrhea in women. Such infections are usually characterized by vaginal discharge and sometimes by dysuria. About 50% of women with cervical infections are asymptomatic. Asymptomatic infections occur in males, as well. Males with asymptomatic urethritis are an important reservoir for transmission and are at increased risk for developing complications. Asymptomatic males and females are a major problem as unrecognized carriers of the disease, which occurs in the U.S. at an estimated rate of over one million cases per year. Ocular infections by N. gonorrhoeae can have serious consequences of corneal scarring or perforation. Ocular infections (ophthalmia neonatorum) occur most commonly in newborns who are exposed to infected secretions in the birth canal. Part of the intent in adding silver nitrate or an antibiotic to the eyes of the newborn is to prevent ocular infection by N. gonorrhoeae. http://www.cdc.gov/std/gonorrhea/arg/ YT van Duynhoven. The epidemiology of Neisseria gonorrheae in Europe. Microbes and Infection 1999; 1 (6): 455–464 Return to Slide 36

Notes on: Resistance in Neisseria gonorrhoeae N. Gonorrhoeae, originally highly susceptible to antibiotics can adapt to adverse conditions. A hostile environment in which antibiotics are present may select for the multiple changes which result in resistance and treatment failure. Mechanisms of antibiotic resistance in N. Gonorrhoeae may be conveniently grouped as those that involve reduced access of the antibiotic to the target site and those that involve alteration of the target site itself. Access of antibiotics to the target site may be limited by: reduced permeability of the cell envelope caused by changes in porin proteins; active export of antibiotics from the cell by means of efflux pumps; and destruction of the antibiotic before it can interact with the target. Alteration or deletion of the target site of the antibiotic results in a reduction of its affinity for the antibiotic. Genetically, these changes may be mediated by either chromosomal or extra-chromosomal elements (plasmids). Multiple resistance determinants may coexist in a single organism so that the level of resistance can increase incrementally and a single strain can be resistant to a number of different antibiotics. In gonococci, chromosomally mediated resistance is generally slow to emerge and disseminate. While genetic transformation, the mechanism of acquisition of these determinants, is common in N. gonorrhoeae, clinically relevant resistance requires multiple gene transfers. Plasmid-mediated resistance, at present limited to penicillins and tetracyclines, is transmitted by means of conjugation. This process requires the presence of a conjugative plasmid to mobilize the plasmid carrying the resistance determinants. Since not all strains possess conjugative plasmids, the rate of spread of resistance may be limited to some extent. However, conjugative plasmids are also transferable during conjugation, so that some recipient strains then become donors themselves. Different rates of dissemination of extrachromosomally mediated resistance have thus been observed. Health Protection Agency. “The gonnococal resistance to antimicrobials surveillance programme: Annual Report 2005.” http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5316a1.htm Johnson SR. Antibiotic resistance in Neisseria gonorrhoeae: genetics and mechanisms of resistance. Sex Transm Dis 1988; 15:217–224 Ison CA. Antimicrobial agents and gonorrhoea: therapeutic choice, resistance and susceptibility testing. Genitourin Med 1996;72:253–257. Return to Slide 37

Notes on: Animal Husbandry To prevent infection in animals, many farms add antibiotics to animal feed at sub-clinical doses, selecting for resistat bacteria. . (22) Once bacteria are resistant, they have the potential of spreading this resistant to a variety of other bacteria living in a diverse range of environments, including the human digestive tract.. When an individual ingests exogenous bacteria containing AMR genes, AMR genes transfer to bacteria that comprise the mircobiota of the intestine and to other foreign microorganisms with which it comes in contact. A study showed the transfer of vanA resistance gene (VRE) from E. faecium strain of animal origin to an E. faecium strain of human origin in the human intestine. Since no selective antimicrobial pressure was applied during the study, colonization with resistant bacteria was transient. However, it is reasonable to assume that if a selective pressure of antimicrobials is introduced, colonization with resistant bacteria would have persisted. Since enterococci are typically found in meat and milk products ranging from 10*2 to 10*5 per gram (30), the potential AMR transfer is high. This poses increased risk for immunocompromised patients, who are more susceptible (22). Fortunately, studies show that removing antimicrobials from animal feed decreases the rate of antimicrobial resistance. Denmark, like the rest of Europe, has banned the use of certain growth promoting antimicrobials, avoparcin in 1995, virginiamycin in 1998 and in 1999 producers voluntarily stopped the use of all antimicrobial growth promoters. Because the Danish surveillance system is well-developed, many trends seen around the EU have been quantified by the Danish. After stopping the use of antimicrobial growth promoters, there has been a decrease in the amount of resistance to all antibiotics. For instance, the erythromycin resistant E. faecium reached a peak among broilers in 1997 at 76.3%. However, after restricting use of virginiamycin, resistance decreased to 12.7% in 2000 (27). Similar resistance trends are seen for vancomycin and avilamycin. Similar results have been seen throughout Europe; resistance prevalence has declined rapidly following the removal of growth promoters in pigs and chickens, suggesting that in the absence of selective pressure, a susceptible population begins to replace resistant strains (26). Extensive guidelines in this area have been made in the past year by a joint commission of the FAO/WHO/OIE. The interventions that the commission recommends are continued monitoring of AMR in foodborne pathogens as well as risk management measures, including the use of guidelines, vaccinations policies, and development of alternative treatments. Other possible interventions consist of standardizing international methods, namely the MIC, frequently updating risk assessments, and employing resources to help developing countries contain and monitor AMR. Sources: Robin Bywater, Malcolm McConville, Ian Phillips and Thomas Shyrock. The susceptibility to growht-promotion antibiotics of E. faecium isolates from pigs and chickens in Europe. Journal of Antimicrobial Chemotherapy, 2005, 56: 538-543.

Frank Aarestrup, Anne Mette Seyfarth, Hanne-Dorthe Emborg, Karl Pedersen, Rene Hendriksen, Flemming Bager. Effect of Abolishment of the Use of Antimicrobial Agents for Growth Promotion on Occurrence of AMR in Fecal Enterococci from Food Animals in Denmark. Anitmicrobial Agents and Chemotherapy, 2001, 45: 2054-2059. Lester, Moller, Sorensen, Monnet, Hammerum. In Vivo Transfer of the van A Resistance Gene from an Enterococcus faecium isolate of animal origin to an E. faecium isolate of human origin in the intestines of human volunteers. Antimicrobial Agents and Chemotherapy, 2006, 50: 596599. Return to Slide 52

Notes on: Aquaculture In the past 20 years, industrial aquaculture has quadrupled in size, and a faster rate of growth in the industry has been predicted for the future. However, responsible practices in aquaculture have not evolved like the industry itself. Developing countries around the globe currently use prophylactic antibiotics indiscriminately, selecting for not only resistant fish pathogens but human pathogens, as well. The main concern with prophylactic antibiotics in aquaculture is the spread of resistance from fish pathogens to human pathogens. Several cases have been well documented, strongly suggesting that this transfer has taken place. The drug-resistant outbreaks of Salmonella enterica serotype Typhimurium DT104 in the United States and Europe was traced to the Far East (Angulo). The plasmid in Salmonella enterica contained genes for tetracycline and flouroquinolone resistance, which were traced to the fish pathogens Vibrio damsela and Vibrio anduillarum. Not an isolated case, other fish pathogens have been shown to transfer resistance to human pathogens, as well. Aeromonas salmonicida through the plasmid IncU, containing resistance to sulfonamides, trimethoprims, and tetracycline, have transferred resistance to the human pathogens around the globe, including Aeromonas hydrophila, Aeromonas caviae and E. coli (Rhodes). The use of antibiotics in aquaculture increase rates of AMR in human pathogens, posing a threat to our current treatment of human infections. Several techniques have been suggested to decrease the dependence on antimicrobial agents, including vaccines and improved water sanitation. Vaccines exist for more than 15 fish pathogens. Vaccines are not a substantial upfront cost, and the economic impact of the vaccine favors the investment, to the extent that only a marginal improvement in survival is necessary to pay for the investment of the vaccine. When choosing between vaccines, minor differences in the overall vaccine efficacy produce substantially greater profits (Ragnar). Sanitation measures aim to eliminate or reduce the number of fish pathogens present in the water. Current techniques include UV light radiation, chemicals such as hypochlorous acid and ozone. Furthermore, new technologies continue to be developed to improve the quality and sanitation of industry water in economical manners. Sources: Rhodes,et all. Distribution of Oxytetracycline Resistance Plasmids between Aeromonads in Hospital and Aquaculture Environments: Implications of Tn1721 in Dissemination of the Tetracycline Resistant Determinant TetA. Applied and Environmental Microbiology, 2000, 66: 3883-3890. Angulo,et al. Changes in antimicrobial resistance in Salmonella enterica serovar Typhimurium. Emerging Infectious Disease, 2006, 6:436-8. Ragnar, et al. Effects of disease risk, vaccine efficacy and market price on the economics of fish vaccination. Aquaculture, 2006, 256:42-49.

Fortt A et al. The Use and Abuse of Antibiotics in Salmon Farming. Oceana Publication, 2007, 23. Return to Slide 53

Notes on: Over-the-counter access to pharmaceuticals In many situations legal and illegal over-the-counter access to antimicrobials leads to injudicious drug use. Often antimicrobials are frequently obtained without the guidance of a physician or other knowledgeable prescriber in developing countries. This may cause consumers to erroneously determine their need for antimicrobials, as well as the optimal dose and length of treatment. Even if they seek outside advice on using antimicrobials for their symptoms, like from a pharmacist or untrained drug seller, this information can easily be inaccurate. Inappropriate over-the-counter drug use is not restricted to indigent people in developing countries. Larson and Grullon-Figueroa found that in Manhattan, New York, 34 of 34 pharmacies in a Hispanic neighbourhood sold OTC antibiotics, even though antibiotic sales require a prescription in the US. Additionally, antibiotics for fish, which have the same active ingredients as the ones that humans use, are widely sold OTC in pet stores across the US. Recently, a new method of drug acquisition has been created through internet pharmacies. While some online pharmacies obey the laws of their place of residence, many do not. Online pharmacies are capable of selling substandard or counterfeit drugs, as well as good quality drugs for which the consumer has no legitimate use for. Effective regulation of these pharmacies is still a new and relatively untested field. Some interventions, such as a seal of pharmaceutical quality issued by the national pharmaceutical licensing board, are in progress and provide consumers with a stronger security that they will receive quality medications. In general, though, internet pharmacies will be difficult to effectively regulate due to their nonphysical nature and international reach. Sources: Chalker J et al. Effectiveness of a multi-component intervention on dispensing practices at private pharmacies in Vietnam and Thailand--a randomized controlled trial. Social Science & Medicine, 2005, 60(1):131-41. Grigoryan L, et al. and Self-Medication with Antibiotics and Resistance (SAR) Consortium. Determinants of self-medication with antibiotics in Europe: the impact of beliefs, country wealth and the healthcare system. The Journal of Antimicrobial Chemotherapy, 2008, 61(5):1172-9. Internet pharmacy logo. London, England, Royal Pharmaceutical Society, 2008. (http://www.rpsgb.org/registrationandsupport/registration/internetpharmacylogo.html, accessed 22 July 2008). Larson E, Grullon-Figueroa L. Availability of antibiotics without prescription in New York City. Journal of Urban Health : Bulletin of the New York Academy of Medicine, 2004, 81(3):498-504. Okeke IN et al. Antimicrobial resistance in developing countries. Part II: strategies for containment. The Lancet Infectious Diseases, 2005, 5(9):568-80.

Okeke IN, Lamikanra A, Edelman R. Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerging Infectious Diseases, 1999, 5(1):18-27. Reeves D. The 2005 Garrod Lecture: the changing access of patients to antibiotics--for better or worse? The Journal of Antimicrobial Chemotherapy, 2007, 59(3):333-41. Statement of William K. Hubbard Commissioner for Policy, Planning and Legislation, Food and Drug Administration. Washington, DC, United States Food and Drug Administration, and Consumer Affairs, Foreign Commerce, and Tourism, on Commerce, Science and Transportation, 2001. (http://www.fda.gov/ola/2001/importation0905.html, accessed 22 July 2008). Return to Slide 56

Notes on: Global Action Areas for Containing AMR Currently, there is a lack of data on AMR. An international coalition of stakeholders (policy makers, epidemiologists and economists) -- already begun at WHO -- should assemble to outline a strategy to collect national surveillance data, collect national and global burden of disease data, and national and global economic burden data. A paradigm shift is needed in how we view antibiotics. The working group should develop a strategy: -that builds public perception of antibiotic effectiveness as a natural resource and global public good -that changes the public's perception of antibiotics from "magic bullets" or "miracle drugs" to dangerous blunt instruments with indiscriminate targets like healthy bowel flora -that emphasizes rather than war, disarmament, equilibrium, and coexistence with bacteria Major contributors to the irrational use of antibiotics are doctors, the public, and industry. The working group should utilize the WHO Rational Drug Use strategy to revive new actions: -that encourages doctors to use antibiotics responsibly, including behavior modification surrounding administration of broad spectrum and prophylactic antibiotics -that educates the public about the dangers of indiscriminate antibiotic use, over the counter use, and animal use -that eliminates direct-to-consumer marketing in nations that currently allow it There is a lack of new technologies to rapidly diagnose resistant infections. (see pg.14) The working group should develop a strategy: -that encourages governments to provide incentives for industry to develop rapid diagnostic technologies -that creates incentives for doctors to fine tune prescription habits to narrower spectrum regimens The antibiotic pipeline has dried up (see pg.14). The working group should develop a strategy: -that helps governments to treat antibiotics as a natural resource, like oil, fisheries, and

clean water -that encourages governments to pull antibiotics out of the private sector and into the public domain -that encourages governments to provide incentives for industry to revive R&D on antibiotic vaccines and new antibiotic drugs -that encourages innovative infection control practices Return to Slide 61

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