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Appendix D Glossary Acquired immune deficiency syndrome (AIDS): a disease of the human immune system caused by the human immunodeficiency virus (HIV). This con- dition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk. Acinetobacter baumannii: A species of pathogenic bacteria, referred to as an aerobic Gram-negative bacterium, which is resistant to most antibiotics. As a result of its resistance to drug treatment, some estimates state the disease is kill - ing tens of thousands of U.S. hospital patients each year. The illness can cause severe pneumonia and infections of the urinary tract, bloodstream, and other parts of the body. Actinobacteria: A group of Gram-positive bacteria with high G+C ratio. These organisms may be terrestrial or aquatic. Adhesins: Bacterial proteins that promote adherence to host-cell membranes; see http://www.nature.com/nrm/journal/v3/n10/glossary/nrm932_glossary.html (accessed August 3, 2010). Antibiogram: The result of laboratory testing for the sensitivity of an isolated bacterial strain to different antibiotics. It is by definition an in vitro sensitivity. 

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 ANTIBIOTIC RESISTANCE Antibiotic: Class of substances that can kill or inhibit the growth of some groups of microorganisms. Originally antibiotics were derived from natural sources (e.g., penicillin from molds), but many currently used antibiotics are semisynthetic and modified with additions of man-made chemical components. See Antimicrobial. Antimicrobial: In this document, the term “antimicrobial” is used inclusively to refer to any agent (including an antibiotic) used to kill or inhibit the growth of microorganisms (bacteria, viruses, fungi, or parasites). This term applies whether the agent is intended for human, veterinary, or agricultural applications. Antimicrobial Resistance: Most commonly, this refers to infectious microbes that have acquired the ability to survive exposures to clinically relevant concen - trations of antimicrobial drugs that would kill otherwise sensitive organisms of the same strain. The phrase is also used to describe any pathogen that is less susceptible than its counterparts to a specific antimicrobial compound (or com - bination thereof). β-Lactam Antibiotics: A broad class of antibiotics that include penicillin deriva- tives (penams), cephalosporins (cephems), monobactams, and carbapenems, that is, any antibiotic agent that contains a β-lactam nucleus in its molecular structure. They are the most widely used group of antibiotics. β-Lactamase: A type of enzyme produced by some bacteria that is responsible for their resistance to β-lactam antibiotics, such as penicillins, cephalosporins, cephamycins, and carbapenems. Bacteria: Microscopic, single-celled organisms that have some biochemical and structural features different from those of animal and plant cells. Bacteriophange: A virus that infects bacteria. Biocontrol: Method of controlling pests (including insects, mites, weeds and diseases) in plants that relies on predation, parasitism, herbivory, or other natural mechanisms. Biofilms: Bacterial communities that become established on surfaces and are encased by an exopolymer matrix; see Lewis, K. 2007. Persister cells, dormancy and infectious disease. Nature Reviews Microbiology 5(1):48–56. Biomedical Advanced Research and Development Authority (BARDA): Housed within the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services, this agency provides an integrated, systematic approach to the development and purchase of the neces -

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 APPENDIX D sary vaccines, drugs, therapies, and diagnostic tools for public health medical emergencies; see http://www.phe.gov/about/barda/Pages/default.aspx (accessed August 3, 2010). Cefotaximase (CTX-M): β-lactamases enzyme named for its greater activity against cefotaxime than other oxyimino-β-lactam substrates (e.g., ceftazidime, ceftriaxone, cefepime). Rather than arising by mutation, cefotaximases represent examples of plasmid acquisition of β-lactamase genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic commensal organisms. Cephalosporins: A class of β-lactam antibiotics originally derived from Acre- monium, which was previously known as “Cephalosporium.” They have the same mode of action as other β-lactam antibiotics (such as penicillins) but are less susceptible to enzymes that break down penicillin (penicillinases). Commensals: Organisms in a mutually symbiotic relationship where both live peacefully together while not being completely dependent on one another (exam- ple: the gut microbiome); see http://www.bacteriamuseum.org/cms/Evolution/ bacteria-are-needed-for-life.html (accessed July 19, 2010). Conjugation: A process whereby two cells come in contact and exchange genetic material; see http://www.everythingbio.com/glos/definition.php?word=conjugation (accessed June 14, 2010). Deoxyrobinucleic acid (DNA): A nucleic acid that contains the genetic instruc- tions used in the development and functioning of all known living organisms with the exception of some viruses. The main role of DNA molecules is the long-term storage of information. Diagnosis-related group (DRG): A system to classify hospital cases into one of approximately 500 groups, also referred to as DRGs, expected to have similar hospital resource use, developed for Medicare as part of the prospective payment system. DRGs are assigned by a “grouper” program based on ICD diagnoses, procedures, age, sex, discharge status, and the presence of complications or comorbidities. Enterobacter: A genus of common Gram-negative, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of these bacteria are pathogenic and cause opportunistic infections in immunocompromised (usually hospitalized) hosts and in those who are on mechanical ventilation. The urinary and respiratory tracts are the most common sites of infection.

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0 ANTIBIOTIC RESISTANCE Enterococcus faecium: An enteric, Gram-positive, coccoid-shaped bacteria that can be found in the digestive and urinary tracts of some humans. It can be a com - mensal in the human intestine, but may also be a pathogen—causing diseases like neonatal meningitis. Fungicides: Chemical compounds or biological organisms used to kill or inhibit the growth of fungi or fungal spores. Gene Regulation: The process through which a cell determines—through inter- actions among DNA, RNA, proteins, and other substances—when and where genes will be activated and how much gene product will be produced; see http:// pubs.niaaa.nih.gov/publications/arh26-3/165-171.htm (accessed July 19, 2010). Genome: The complete genetic composition of an organism (e.g., human, bacterium, protozoan, helminth, fungus), contained in a chromosome or set of chromosomes or in a DNA or RNA molecule (e.g., a virus). Gentamicin: An aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative bacteria. The Global Fund to Fight AIDS, Tuberculosis and Malaria : Often referred to as “The Global Fund” or “GFATM,” this financing mechanism was estab - lished in January 2002 to dramatically increase global financing for inter - ventions against the two pandemics (malaria is actually endemic). It is the largest international funder of programs to combat malaria and tuberculosis, providing two-thirds of all financing, and it provides 20 percent of all inter - national funding to combat HIV/AIDS. The Fund asserts that as of June 2007, 1.9 million lives have been saved thanks to efforts in 136 countries supported by the Global Fund. Gram-Negative Bacteria: Refers to the inability of a microorganism to accept a certain stain. This inability is related to the cell wall composition of the micro - organism and has been useful in classifying bacteria. Gram-Positive Bacteria: Refers to the ability of a microorganism to retain a certain stain. This ability is related to the cell wall composition of the microor- ganism and has been useful in classifying bacteria. Human immunodeficiency virus (HIV): A lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk.

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 APPENDIX D Horizontal Gene Transfer: Any process in which an organism incorporates genetic material from another organism without being the offspring of that organism. Immunoglobulins: A class of proteins produced in lymph tissue in vertebrates and that function as antibodies in the immune response; see http://wordnetweb. princeton.edu/perl/webwn?s=immunoglobulin (accessed August 2, 2010). Insertion Sequence: A mobile piece of bacterial DNA (several hundred nucleo- tide pairs in length) that is capable of inactivating a gene into which it inserts. Small simple transposons; see http://www.everythingbio.com/glos/definition. php?word=insertion+sequence+(IS) (accessed June 14, 2010). Integrative Conjugative Elements (ICEs): Chromosomally located gene clus- ters that encode phage-linked integrases and conjugation proteins as well as other genes associated with an observable phenotype, such as virulence or symbiosis. They can be transferred between cells and have some phage-like genes, but they do not lyse the cell or form extracellular particles; see http://www.nature.com/nrmi - cro/journal/v3/n9/glossary/nrmicro1235_glossary.html (accessed June 16, 2010). Integron: A mobile DNA element that can capture and carry genes, particularly those responsible for antibiotic resistance. It does this by site-specific recom - bination; see http://www.medterms.com/script/main/art.asp?articlekey=32273 (accessed June 14, 2010). Intrinsic Resistance Gene: A gene that code for traits that reduce an organism’s sensitivity to antibiotics, such as efflux pumps, but is not specifically a resistance gene. Klebsiella pneumonia: A species of Gram-negative, non-motile bacteria found in soil, water, cereal grains, and the intestinal tract of humans and other ani - mals. It is associated with several pathologic conditions, including pneumonia. It is commonly implicated in hospital-acquired urinary tract infections, espe - cially in immunocompromised patients; see Mosby’s Medical Dictionary. 2009. “Klebsiella pneumonia.” 8th edition. St. Louis, MO: Mosby. Lysogenic: The state of a bacterial cell that has an integrated phage (pro- phage) in its chromosome; see http://www.everythingbio.com/glos/definition. php?word=lysogenic (accessed June 18, 2010). Lysogenic Bacteriophage: A lysogenic phage is a “temperate” bacteriophage (such as lambda phage) that integrates its genome into the genome of the host without immediately transcribing and making new virus particles. However, at

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 ANTIBIOTIC RESISTANCE a later time, the integrated genome can be excised and begin to be actively tran - scribed, producing virus particles that eventually burst the cell. This is opposite to the “lytic” variety of bacteriophage (T4 phage) that immediately transcribe and make new virus after infecting the host cell, causing rapid lysis; see http://wiki. answers.com/Q/What_is_a_lysogenic_bacteriophage (accessed June, 23 2010). Macrolides: Family of bacteriostatic antibiotics that inhibit protein synthesis by binding to the large subunit of the bacterial ribosome; includes erythromycin, clindamycin, and the newer drugs clarithromycin and azithromycin. Metabolism: The organic processes (in a cell or organism) that are necessary for life; see http://wordnetweb.princeton.edu/perl/webwn?s=metabolism (accessed July 20, 2010). Methicillin-resistant Staphylococcus aureus (MRSA): A type of staph that is resis- tant to antibiotics called β-lactams. β-lactam antibiotics include methicillin and other more common antibiotics, such as oxacillin, penicillin, and amoxicillin; see http:// www.cdc.gov/ncidod/dhqp/ar_MRSA_ca_public.html#2 (accessed July 19, 2010). Microbe: A microorganism or biologic agent that can replicate in humans (including bacteria, viruses, protozoa, fungi, and prions). Microbiome: Term used to describe the collective genome of our indigenous microbes (microflora); see Hooper, L. V., and J. I. Gordon. 2001. Commensal host bacterial relationships in the gut. Science 292(5519):1115–1118. Monoclonal Antibodies: Antibodies produced against a single antigen in cells that are clones of a single parent (germ) cell. Mutation: Genetic change that can occur either randomly or at an accelerated rate through exposure to radiation or certain chemicals (mutagens) and may lead to change in structure of the protein coded by the mutated gene. Narrow-Spectrum Antibiotic: An antibiotic effective against a limited number of microorganisms; often applied to one that is active against either Gram-positive or Gram-negative bacteria. Neutropenia: The condition of having an abnormally low number of neutrophils, a type of white blood cell that defends the blood against bacterial infections. Nomogram: A graphical calculating device, a two-dimensional diagram designed to allow the approximate graphical computation of a function; it uses a coordinate system other than Cartesian coordinates.

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 APPENDIX D Noninferiority Clinical Trials: A clinical trial that shows that a new treatment is equivalent to standard treatment; see http://www.medterms.com/script/main/art. asp?articlekey=39072 (accessed August 3, 2010). Pathogen: An organism capable of causing disease. Penicillins: Any of the various antibiotics derived from Penicillium fungi. All penicillins are b-lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. They are historically significant because they are the first drugs that were effective against many previously serious diseases and are still widely used today, though many types of bacteria are now resistant. Persister Cells: Cells produced by bacterial populations that neither grow nor die in the presence of antibiotics. These cells are largely responsible for the high levels of tolerance to antimicrobial agents often observed in biofilms; see Keren, I., N. Kaldalu, A. Spoering, Y. Wang, and K. Lewis. 2004. Persister cells and tolerance to antimicrobials. FEMS Microbiology Letters 230(1):13–18. Pesticide: Any substance or mixture of substances intended for preventing, destroying, repelling or mitigating any pest. A pesticide may be a chemical substance, biological agent (such as a virus or bacterium), antimicrobial, dis - infectant, or device used against any pest. Pests include insects, plant patho - gens, weeds, mollusks, birds, mammals, fish, nematodes (roundworms), and microbes that destroy property, spread disease, are a vector for disease, or cause a nuisance. Phytopathogen: Any organism that is pathogenic to plants. Plasmid: A small cellular inclusion consisting of a ring of DNA that is not in a chromosome but is capable of autonomous replication; see http://wordnetweb. princeton.edu/perl/webwn?s=plasmid (accessed June 14, 2010). Polypeptide Antibiotics: A class of antibiotics used for eye, ear, or bladder infections in addition to aminoglycosides. They are toxic and are therefore not suitable for systemic administration. They are usually applied directly to the eye or skin or are inhaled into the lungs. Examples include actinomycin, bacitracin, colistin, and polymyxin B. Prodrug: A pharmaceutical substance that is inactive at the time of adminis- tration and activates once it diffuses into a cell and is modified into a reactive product by a specific enzyme.

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 ANTIBIOTIC RESISTANCE Propensity Score: The probability of a unit (e.g., person, classroom, school) being assigned to a particular condition in a study given a set of known covariates. Propensity scores are used to reduce selection bias by equating groups based on these covariates. Proto-Resistance Genes: Genes that have the potential to develop into resistance elements; see Wright, G. D., and M. Morar. 2010 (forthcoming). The genomic enzy- mology of antibiotic resistance. Annual Review of Genetics 44 (Forthcoming). Pseudomonas aeruginosa: A common bacterium that can cause disease in humans and animals. It is found in soil, water, skin flora, and most man-made environments throughout the world. It uses a wide range of organic material for food; in animals, this enables the organism to infect damaged tissues or people with reduced immu- nity. These infections cause generalized inflammation and sepsis and can be fatal if they occur in critical organs, such as the lungs, the urinary tract, and kidneys. Quinolones: Class of purely synthetic antibiotics that inhibit the replication of bacterial DNA; includes ciprofloxacin and fluoroquinolone. Reactive Oxygen Species (ROS): Chemically-reactive molecules containing oxygen. Examples include oxygen ions and peroxides. They can be either inor- ganic or organic. Recombination: A combining of genes or characters different from what they were in the parents; see http://wordnetweb.princeton.edu/perl/webwn?s=recombination (accessed July 19, 2010). Resistome: The collection of all genes that directly or indirectly result in anti- microbial resistance. Respiratory Syncytial Virus: A respiratory virus that infects the lungs and breathing passages. Most otherwise healthy people recover from a respiratory syncytial virus infection in 1 to 2 weeks; however, infection can be severe in some people, such as certain infants, young children, and older adults; see http://www. cdc.gov/rsv/ (accessed June 18, 2010). Ribonucleic acid (RNA): A biologically important type of molecule that consists of a long chain of nucleotide units. Each nucleotide consists of a nitrogenous base, a ribose sugar, and a phosphate. RNA is very similar to DNA, but differs in a few important structural details: in the cell, RNA is usually single-stranded, while DNA is usually double-stranded; RNA nucleotides contain ribose while DNA contains deoxyribose (a type of ribose that lacks one oxygen atom); and RNA has the base uracil rather than thymine that is present in DNA.

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 APPENDIX D Selective Pressure: Any phenomena which alters the behavior and fitness of living organisms within a given environment; see http://www.bookrags.com/ research/selective-pressure-wob/ (accessed July 19, 2010). SOS Response: A post-replication DNA repair system using the RecA protein that allows DNA replication to bypass lesions or errors in the DNA. It is an error- prone repair system. Staphylococcus aureus: A Gram-positive bacteria that is the most common cause of staph infections. It is frequently part of the skin flora found in the nose and on skin. About 20% of the human population are long-term carriers of S. aureus. Subsistome: A subset of genes in the resistome that permit microbes to degrade antibiotics and use them as an energy source. Sulfonamides: A group of synthetic antibiotics that contain the sulfonamide group. Allergies to sulfonamides are common, and they must be prescribed carefully. Superinfection: A secondary infection that occurs during treatment for an infec- tion of a different pathogen. Susceptibility Testing: Laboratory analyses used to determine whether microor- ganisms are susceptible or resistant to one or several antimicrobials. Tetracyclines: A group of broad-spectrum antibiotics that inhibit protein syn- thesis. They may be used in the treatment of infections of the respiratory tract, sinuses, middle ear, urinary tract, intestines, and also gonorrhoea, especially in patients allergic to β-lactams and macrolides. Their use for these indications is less popular than it once was due to widespread resistance development in the causative organisms. Transgenic Plants: Plants that have been created in a laboratory using recom- binant DNA technology and possess a single or multiple genes from another species. Transposon: A mobile piece of DNA flanked by terminal repeat sequences that can insert into a chromosome, exit, and relocate and typically bears genes coding for these functions; see http://www.everythingbio.com/glos/definition. php?word=transposon (accessed June 14, 2010).

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 ANTIBIOTIC RESISTANCE Vancomycin-Intermediate or Vancomycin-Resistant Staphylococcus aureus (VISA/VRSA): Specific types of antimicrobial-resistant staph bacteria. While most staph bacteria are susceptible to the antimicrobial agent vancomycin, some have developed resistance. VISA and VRSA cannot be treated successfully with vancomycin because these organisms are no longer susceptibile to vancomycin. However, to date, all VISA and VRSA isolates have been susceptible to other Food and Drug Administration-approved drugs; see http://www.cdc.gov/ncidod/ dhqp/ar_visavrsa_FAQ.html (accessed July 19, 2010). Vancomycin-Resistant Enterococcus (VCE): Bacteria from the genus Entero- coccus spp that are resistant to the antibiotic vancomycin. Though infection is uncommon in healthy individuals, the VCE is particularly dangerous to immu - nocompromised individuals. Virulence Factor: Intrinsic characteristic of an infectious bacteria that facilitates its ability to cause disease; see http://www.nature.com/scitable/definition/viru - lence-factor-53 (accessed August 3, 2010). Zoonoses: Infectious diseases that can be transmitted (in some instances, by a vector) from non-human animals, both wild and domestic, to humans.