introduction to antimicrobials

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Khushbu    on Jul 14, 2012 Says :

knowledgeable presentation on antibiotics.
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Slide 1 : Chemotherapy
Slide 2 : Introduction
Slide 3 : Chemotherapy- Pharmacology, Selectively inhibit /destroy specific agents of diseases- bact, viruses, fungi and parasites. Relation – Neoplastic diseases due to anology b/w malignant cells and pathogenic microbes. Term coined – Poul Ehrlich, 1913. Drugs that attack invading organism without harming host cells.
Slide 4 : Terms Chemotherapeutic agents- Covers A/B, A/V, A/F, A/pro, A/H and A/Neo. Antibiotics-Misnomer Antimicrobials- Selective Toxicity-Ability of AMA to kill an invading organism without harming cells of host.
Slide 5 : Antimicrobial activity- Ability – react with microbial cell molecules- interferes with growth and multiplication of the m/o (Static) or killing m/o (Cidal ). Bacteriostatic Bactericidal Antimicrobial Spectrum- range of pathogenic organisms. Broad, Narrow
Slide 6 : Potency- AMA activity per mg/µg. Expressed as MIC, MBC, MAC MIC-Lowest conc of AMA prevents visible growth of m/o when grown against sequentially diminishing drug conc in vitro. Guides selection of AMA that can reach similar conc in vivo . Provides base for comparing the susceptibility of m/o to the other drugs. Factors- Host, methodology, m/o strain It is fixed to particular m/o.
Slide 7 : MIC 90- inhibit 90 % m/o tested MBC- to kill m/o MAC- Conc of AMA, reduces the growth of m/o in vitro by a factor of 10. It may be 1 quarter or 1/10th of the MIC depends on the drug and organism. PAE – persistence of AMA for longer period ( few hrs) after brief exposure to or in absence of detectable conc of AMA. Biphasic (Eagle’s) effect- phenomenon , Low dose-cidal whereas High dose - No effect Common in BLA because of differential sensitivity of the PBPs to high doses of BLA.
Slide 8 : Properties of good AMA Powerful action Specific in action Should not be inactivated by tissue enzyme or GI microflora Long elimination half life , should not excrete rapidly Good oral bioavailability Good penetration to various body tissues
Slide 9 : Should not interfere with host defense/immune mechanism Should not show cross resistance Should not have ADR Should not lead resistance Short withdrawal time Easily available Not induce hypersensitivity in the host.
Slide 10 : Rapid and extensive tissue distribution A relatively long half-life. Free of interactions with other drugs. Convenient for administration. Relatively inexpensive
Slide 11 : GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY Antibiotics - antibacterial substances produced by various species of microorganisms (bacteria, fungi, and actinomycetes) - suppress the growth of other microorganisms. Drugs that destroy microbes, prevent their multiplication or growth or prevent their pathogenic action. Differ in their physical, chemical, and pharmacological properties. Differ in their antibacterial spectrum of activity and their mechanism of action.
Slide 12 : Antibiotics = “against life” Antibiotics can be either natural products or man-made synthetic chemicals. Old : An antibiotic is a chemical substance produced by various species of microorganisms that is capable of inhibiting the growth of other microorganisms in small concentrations. New: An antibiotic is a product produced by a microorganism or a similar substance produced wholly or partially by chemical synthesis, which in low concentrations, inhibits the growth of other microorganisms.
Slide 13 : Antibiotics (i.e., anti-infective or antimicrobial drugs) may be directed at one of several disease-producing organisms including bacteria, viruses, fungi, helminthes, etc. The vast majority of antibiotics are bacteria fighters; although there are millions of viruses, there are only about half a dozen antiviral drugs. Bacteria are more complex than viruses (while viruses must “live” in a host (us), bacteria can live independently, and so are easier to kill.
Slide 14 : The impact of antibiotics on human health. The overall death rate from diseases such as pneumonia and tuberculosis has declined from 79.7 per 100,000 in 1900 to 59 per 100,000 in 1996, according to the Centers for Disease Control and Prevention (CDC). As a result, life expectancy during that period increased from 47.3 to 76.1 years. Assignment
Slide 15 : Impact of Modern Healthcare on Life Expectancy
Slide 16 : History Credit for the actual discovery of microorganisms is given to Antony Van Leeuwenhoek in Holland in 1676. Using a microscope of his own invention, he reported “animalcules” in various specimens, including scrapings from his own teeth.
Slide 17 : In 1861 Pasteur demonstrated that when organisms from the air were excluded from heat-sterilized liquids, such as sugar solutions and urine, fermentation failed to take place. Robert Koch was a German scientist - modern medical microbiology. Koch’s first major breakthrough in bacteriology - in 1870. He demonstrated - infectious disease anthrax in mice, only when the disease-bearing material injected into a mouse’s bloodstream contained viable rods or spores of Bacillus anthracis.
Slide 18 : In 1891, the Russian Romanovsky – suggested that usage of quinine to cure malaria. Ehrlich (1854–1915) coined the term chemotherapy. Ehrlich defined chemotherapy as “the use of drugs to injure an invading organism without injury to the host.”
Slide 19 : The Penicillins, a Historical Perspective… 15th century: Abess Hildegarde von Bingen (a madrigal composer) discovered penicillins while at a nunnery in Italy where they were making a poultice out of penicillium mold. Modern times: Alexander Fleming was first to characterize penicillin’s activity. He found mold contaminating his culture plates, with clearing of staphylococcal colonies all around the mold. Fleming then isolated penicillin from the mold. Florey developed penicillin during WWII when it was much needed; tons of mold was grown to produce it, and was even collected from the urine of people that had first been treated with it (because it is eliminated unchanged by the kidneys).
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Slide 30 : Ehrlich’s Magic Bullets
Slide 31 : Fleming and Penicillin
Slide 32 : 32 A tale by A. Fleming He took a sample of the mold from the contaminated plate. He found that it was from the penicillium family, later specified as Penicillium notatum. Fleming presented his findings in 1929, but they raised little interest. He published a report on penicillin and its potential uses in the British Journal of Experimental Pathology. BC Yang
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Slide 34 : Ehrlich’s first chemotherapeutic experiments, beginning in 1904, with organic dyes. During 1904, Ehrlich demonstrated the curative properties of trypan red against trypanosome. He concentrated his efforts in studying aromatic arsenicals meant to treat trypanosomiasis.
Slide 35 : In 1910, Ehrlich made a historic discovery of arsenicals, for syphilis and was referred as a “magic bullet”. The marketed form of the chemical, Salvarsan, ultimately proved to be too toxic for human use. Arsphenamine was the opening event in the chemotherapeutic revolution for the treatment of human infections.
Slide 36 : 1909 Paul Ehrlich Differential staining of tissue, bacteria Searched for magic bullet that would attack bacterial structures, not ours. Developed salvarsan, arsenic derivative used against syphilis.
Slide 37 : 1929-Penicillin discovered by Alexander Fleming 1940- Florey and Chain mass produce penicillin for war time use, became available to the public. 1935- Sulfa drugs discovered. 1943 -Streptomycin discovered.
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Slide 42 : Assignment
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Slide 48 : Assignment
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Slide 51 : Class III: Assembly of small molecules into macromolecules- proteins, RNA, DNA, polysaccharides and peptidoglycon. Other potential targets are the formed structures e.g., cell membrane microtubules other specific tissues muscle tissue in helminths).
Slide 52 : Bacterial Structures Flagella Pili Capsule Plasma Membrane Cytoplasm Cell Wall Lipopolysaccharides Teichoic Acids Inclusions Spores Chapter 4
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Slide 54 : Classification Based on chemical structure and proposed mechanism of action Inhibit synthesis of bacterial cell walls- the ß-lactam class e.g., penicillins, cephalosporins, carbapenems and Monobactums and dissimilar agents such as cycloserine, vancomycin, and bacitracin; Act directly on the cell membrane of the microorganism, increasing permeability and leading to leakage of intracellular compounds viz. detergents -polymyxin; polyene antifungal agents -nystatin and amphotericin B which bind to cell-wall sterols; and the lipopeptide daptomycin.
Slide 55 : Bind to the 30S ribosomal subunit and alter protein synthesis, which generally are bactericidal. e.g., aminoglycosides. Affect bacterial nucleic acid metabolism- rifamycins (e.g., rifampin and rifabutin), which inhibit RNA polymerase and the quinolones, which inhibit topoisomerases; Antimetabolites-trimethoprim and sulfonamides, which block essential enzymes of folate metabolism. Disrupt function of 30S or 50S ribosomal subunits to reversibly inhibit protein synthesis – bacteriostatic e.g., chloramphenicol, tetracyclines, erythromycin, clindamycin, streptogramins and linezolid.
Slide 56 : Classes of antiviral agents Nucleic acid analogs - acyclovir or ganciclovir, which selectively inhibit viral DNA polymerase and zidovudine or lamivudine, which inhibit HIV reverse transcriptase. Non-nucleoside HIV reverse transcriptase inhibitors- nevirapine or efavirenz. Inhibitors of other essential viral enzymes, e.g., inhibitors of HIV protease or influenza neuraminidase. Fusion inhibitors - enfuvirtide . Assignment
Slide 57 : Classification I; Bacterial Targets for Antibiotics
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Slide 60 : ß lactam AMA’s inhibit cell wall synthesis by blocking the action of transpeptidase (PBP’s) { PBP’s are membrane bound and produce peptidoglycon the major cell wall component}
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Slide 62 : Glycan chains cross-linked with amino acids 62 G- and G+ vary w/ DAP vs. lysine and at the interbridge. Note the presence of unusual “D” amino acids. Peptides attached to NAM.
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Slide 64 : Peptidoglycan is a 3D molecule 64 Cross links are both horizontal and vertical between glycan chains stacked a top one another.
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Slide 67 : Vankomycin also inhibits cell wall synthesis but it is not a ß lactam AMA. It does by interfering with the production of Peptidoglycon. It binds to D-Ala-D-Ala terminals of peptidoglycon precursors on the outer surface membrane. As a result precursors cannot incorporate into the peptidoglycon.
Slide 68 : Ribosomes: site of protein synthesis Prokaryotic ribosome's are 70S; Large subunit: 50 S 33 polypeptides, 5S RNA, 23 S RNA Small subunit: 30 S 21 polypeptides, 16S RNA Eukaryotic are 80S Large subunit: 60 S 50 polypeptides, 5S, 5.8S, and 28S RNA Small subunit: 40S 33 polypeptides, 18S RNA
Slide 69 : Assignment
Slide 70 : Assignment
Slide 71 : A. Conventional diagram used to depict a bacterial cell and chromosome (e.g. Escherichia coli). {Note that the E. coli chromosome is 1300 mm long and is contained in a cell envelope of 2µm to 1 µm; this is approximately equivalent to a 50-m length of cotton folded into a matchbox.} B. Chromosome folded around RNA core. C. Supercoiled by DNA gyrase (topoisomerase II). Quinolones interfere with the action of this enzyme. Assignment
Slide 72 : Sulpha’s Assignment
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Slide 74 : Miscellaneous AMA’s Acts against anaerobes. It diffuses into the bacterial cell and converted to reduced form by ferrodoxin ( mitochondrial electron transport protein). The free radicals /metabolites cause breakdown of DNA
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Slide 77 : Polymyxins Broad gram -negative agents Surface detergent like action. Penetrate into the cell membrane phospholipids- disrupt membrane causing cell death.
Slide 78 : Assignment
Slide 79 : Appropriate antibiotic use The World Health Organization -12 key interventions to promote more rational use Establishment of a multidisciplinary national body to coordinate policies on medicine use. Use of clinical guidelines. Development and use of national essential medicines list. Establishment of drug and therapeutics committees in districts and hospitals. Inclusion of problem-based pharmacotherapy training in undergraduate curricula. Continuing in-service medical education as a licensure requirement. Supervision, audit and feedback. Use of independent information on medicines. Public education about medicines. Avoidance of perverse financial incentives. Use of appropriate and enforced regulation. Sufficient government expenditure to ensure availability of medicines. .
Slide 80 : Check
Slide 81 : Selection of antimicrobial therapy Status of the patient Immune system Renal dysfunction Hepatic dysfunction Poor perfusion Pregnancy Lactation Age
Slide 82 : Combination therapy Indications To treat a broader spectrum of pathogens than a single agent could cover To prevent emergence of resistance to one of the agents To treat a suspected pathogen more effectively than either agent would do alone
Slide 83 : Synergy and Antagonism Synergy; If two antibiotics used in combination have an antibacterial effect much greater than either drug alone Ex.; beta-lactams and aminoglycosides Antagonism; When two drugs in combination have activity less than the better of the two Ex.; bactericidal and bacteriostatic
Slide 84 : Factors That Determine the Susceptibility and Resistance of Microorganisms to Antimicrobial Agents Concentration of antibiotic at the site of infection. This concentration must be sufficient to inhibit growth of the offending microorganism. If host defenses are intact and active, a minimum inhibitory effect, such as that provided by bacteriostatic agents (i.e., agents that interfere with growth or replication of the microorganism but do not kill it) may be sufficient.
Slide 85 :   If host defenses are impaired, antibiotic-mediated killing (i.e., a bactericidal effect) may be required to eradicate the infection. If an inhibitory or bactericidal concentration exceeds that which can be achieved safely in vivo, then the microorganism is considered resistant to that drug.
Slide 86 : Oral Absorption of Antibiotics Good: sulfonamides chloramphenicol clindamycin trimethoprim isoniazid, pyrazinamide ciprofloxacin doxycycline cycloserine metronidazole linezolid Bad or variable: penicillins (some are, many aren’t) cephalosporins (few are, most are not) erythromycin (estolate conjugate) (clarithromycin is better) Ugly: aminoglycosides: gentamicin tobramycin amikacin netilmicin vancomycin quinupristin/dalfopristin meropenem Kinetics
Slide 87 : Therapeutic levels in the CSF? Good: ciprofloxacin sulfonamides, trimethoprim chloramphenicol some 3rd generation cephalosporins (e.g. ceftriaxone, ceftizoxime) meropenem cycloserine, metronidazole pyrazinamide, isoniazid linezolid OK: (esp. when meninges inflamed) ampicillin, ticarcillin vancomycin rifampin Poor: aminoglycosides tetracyclines clindamycin erythromycin cefaclor quinupristin/dalfopristin (synercid)
Slide 88 : Distribution of drug into human cells? Pathogens can enter cells Require intracellular phase Rickettsia (cytoplasm) Chlamydia (phagosomes) Can survive both intra and extracellular environment Mycobacteria (cytoplasm & phagosomes) Legionella (phagosomes) Listeria (cytoplasm) Salmonella (phagosomes)
Slide 89 : Antibiotic metabolism and excretion excreted unchanged via kidney metabolized by liver metabolites excreted by kidney metabolites excreted thru bile Affected by renal/hepatic disease, developmental state, pharmacogenetic traits, and drug/drug interactions
Slide 90 : Drug Metabolism and Excretion Excretion by Kidney (primarily) penicillins/cephalosporins (both kidney and liver for some) aminoglycosides tetracyclines (except doxycycline) sulfonamides vancomycin ciprofloxacin trimethoprim pyrazinamide
Slide 91 : Chloramphenicol is metabolized in liver and then excreted by kidney
Slide 92 : Application of pharmacokinetic principles Bactrim: 400mg sulfamethoxazole + 80 mg trimethoprim in fixed dose---does this make sense? what basic properties of these two drugs are relevant? optimal plasma ratio and concentration t1/2 oral bioavailability volume of distribution drug interactions
Slide 93 : Antimicrobial susceptibility tests Minimum inhibitory concentration [MIC] The smallest concentration of antibiotic that inhibits the growth of organism Liquid media (dilution) allows MIC estimation Solid media (diffusion) Disk diffusion (Kirby-Bauer) E-tests Allows MIC estimation Beta lactamase production: quick screening method
Slide 94 : Dilution in liquid broth Tubes containing increasing antibiotic concentrations Incubation during 18 hr at 37°C Tedious 0 (Control) 0,25 0,50 1 2 4 8 mg/l Bacterial growth Inhibition
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Slide 96 : Kirby-Bauer disc testing Antibiotic-impregnated discs placed on an agar plate at the interface between test organism and susceptible control organism Resulting zones of inhibition compared, use of controls Susceptibility is inferred (standard tables)
Slide 97 : E-test Plastic strips with a predefined gradient of One antibiotic One antifungal Only one manufacturer One strip per antibiotic Wide range of antibiotics Easy to use Storage at -20°C Short shelf life, expensive
Slide 98 : Reading E-tests Susceptible < 1 Resistant > 4 ug/ml Ciprofloxacin for Yersinia pestis Intermediate 1-4 ug/ml Upper reading
Slide 99 : Common interpretation problems Results depends on the technique used Many factors influence results Lack of standardization of the inoculums Thickness and quality of the culture media Quality and conservation of the disks Wuality control with standardized strains Condition and duration of incubation
Slide 100 : An agar gel that is too thick leads to smaller zones Common interpretation problems Source: http://www.who.int/csr/resources/publications/drugresist/WHO_CDS_CSR_RMD_2003_6/en/
Slide 101 : Common interpretation problems Problem with the size of the inoculums Solution: Use McFarland 0.5 photometer Scale -> same tubes
Slide 102 : Common interpretation problems Contamination with another organism
Slide 103 : Common interpretation problems Bad manipulation Inoculation of the Muller Hinton Swabbing Not by flooding
Slide 104 : Problems with E-test reading Common interpretation problems
Slide 105 : Antimicrobial susceptibility tests Antimicrobial susceptibility testing is expensive (costs include all supplies) Kirby-Bauer 12 discs panel = $1.35 E-test (Performed only in certain situations) One strip = $2.50
Slide 106 : 106 In vitro: Factors for optimal antibiotic action pH of environment: Nitrofurantoin is more active in acid pH; sulfonamides and aminoglycoside are more active in alkaline pH. Components of medium: Anionic detergents inhibit aminoglycosides, serum proteins bind to penicillin in varying degrees. Stability of drug: Aminoglycosides and chloramphenical are stable for long period in vivo. Size of inoculums: The larger the bacterial inoculum, the greater the chance for resistnat mutant to emerge. Metablic activity of microorganisms: Actively and rapidly growing organisms are more susceptible to drug action BC Yang
Slide 107 : References Manual for the laboratory Identification and Antimicrobial Susceptibility Testing of Bacterial Pathogens of Public Health Importance in the Developing World WHO/CDS/CSR/RMD/2003.6 http://www.who.int/csr/resources/publications/drugresist/WHO_CDS_CSR_RMD_2003_6/en/
Slide 108 : Antibiotic Sensitivity Test Kirby-Bauer Test (disc diffusion test) Assignment
Slide 109 : Disk diffusion method Kirby-Bauer disk diffusion antibiotic susceptibility test
Slide 110 : Disk diffusion method Staphylococcus aureus Pseudomonas aeruginosa
Slide 111 : Antibiotic Sensitivity Test Etest (strip test) E-strips have a gradient of antibiotic, so the zone of inhibition forms an oval and the minimum inhibitory concentration (MIC) is where the clear zone hits the E strip.
Slide 112 : Antibiotic Sensitivity Test Broth Dilution Method antibiotic (dilution series) + bacterial suspension growth ? MIC – minimal inhibitory concentration (standard amount)
Slide 113 : Assignment
Slide 114 : Gram-negative rods (aerobic)
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Slide 121 : Natural & acquired resistance Natural resistance Chromosomic genetic support. Affect almost all species strains. Existed before antibiotic use (Enterobacter sp. - amoxicillin). Acquired resistance (mutation) Chromosomic, plasmidic or transposon genetic support Affects a fraction of strains. Increased with antibiotic use (extended spectrum beta-lactamase producing E. coli).
Slide 122 : Transferring resistance genes
Slide 123 : Horizontal transfer Simple selection isn’t the only means for resistance alleles to spread. Bacteria can acquire resistance genes by transformation, when they pick up DNA from the environment. They can also get resistance genes by conjugation: bacterial sex, when they exchange plasmids. Plasmids can have multiple resistance genes, conferring multiresistance.
Slide 124 : Mechanisms of resistance Hawkey, P. M BMJ 1998;317:657-660 Penicillins, Cephalosporins Tetracycline Streptococcus pneumoniae resistance to penicillins MRSA penicillin binding protein PBP2A Imipenem resistant Pseudomonas aeruginosae
Slide 125 : Cross-resistance Resistance to one antibiotic can confer resistance to others. Resistance to cephalosporins gives resistance to methicillin, even in bacteria that have never been exposed to methicillin.
Slide 126 : Mechanisms of resistance 1. Antibiotic modification: some bacteria have enzymes that cleave or modify antibiotics: e.g. b lactamase inactivates penicillin 2. Denied access: membrane becomes impermeable for antibiotic: e.g. imipenem 3. Pumping out the antibiotic faster than it gets in: e.g. tetracyclines 4. Altered target site: antibiotic cannot bind to its intended target because the target itself has been modified 5. production of alternative target (typically enzyme): e.g. Alternative penicillin binding protein (PBP2a) in MRSA
Slide 127 : FAILURE OF ANTIBIOTICS DUE TO BETA-LACTAMASE Am J Infect Control 1999;27:520-32
Slide 128 : SOLUTION b-lactamase inhibitors Tazobactam – irreversible ‘suicide inhibitor’ Clavulanic acid Sulbactam
Slide 129 : Status of the production of different antibiotics in India.
Slide 130 : Table 1. Outpatient antibiotic purchases from retail outlets in India Year 2005 2006 2007 2008 2009 Antibiotic purchases in crore rupees (INR) 3,763 4,484 5,075 5,886 6,414 Notes: One crore equals 100 lakhs, equals 10 million Source: Personal communication of IMS Health Information and Consulting Services-India data from Burzin Bharuch (Pfizer) to Ramanan Laxminarayan on July 30, 2009.
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Slide 138 : Brief History of Resistance
Slide 139 : Development of Resistance Animal with both sensitive and resistant bacteria Antibiotic is administered and selects for resistant bugs Antibiotic- resistant bacteria multiply Resistant bacteria spread among animals by contact Spread to humans in animal products Spread to farm workers or food processors Resistant bacteria released into environment
Slide 140 : Resistant microorganisms in the environment Resistant organism released into environment Spread to humans through contact or consumption of fruits or vegetables Spread to humans through contact or consumption of fish Non-pathogenic bacteria transfer resistant genes to pathogenic bacteria
Slide 141 : Present and future goals: AVMA recommends: Use of narrow spectrum drugs Tx only the sick or at risk for bacterial infections Further research before imposing bans Producer education Development of economically feasible chemotherapeutic and non chemotherapeutic alternatives to antibiotics Vaccines Probiotics Immune enhancers Better husbandry practices Improved biosecurity
Slide 142 : Examples Data from USDA National Animal Health Monitoring System: Only 32% of calves received recommended volume of colostrum during the first feeding Immunoglobulin concentration was less than ideal in 67% of 2,177 dairy cows sampled Frequency of vaccination for respiratory diseases inadequate in 86% of beef calves offered for sale in 1997
Slide 143 : Antibiotic Cycling a - add clindamycin for pneumonia if aspiration suspected b – imipenem or meropenem c- add ampicillin or vancomycin if Enterococcus is suspected Raymond DP, Crit Care Med 2001;29:1101
Slide 144 : Antibiotic Cycling Variable * Year 1 Year 2 p value Resistant GPC Infections 14.6 7.8 <0.001 Resistant GNB Infections 7.7 2.5 <0.001 Infection-related mortality 9.6 2.9 <0.001 Liver disease 19 (10.8%) 8 (5.6%) <0.001 Transplantation 27 (15.3%) 6 (4.2%) 0.001 * All variables per 100 admissions Limitations Concurrent ceftazidime to cefepime formulary switch Concurrent infection control interventions Raymond DP, Crit Care Med 2001;29:1101
Slide 145 : Antimicrobial Optimization Decrease unnecessary antibiotic use Develop / apply guidelines for antibiotic use Tailor empiric antibiotic selection to particular situation Patient specific Maintain broad choice of agents Several approaches Human Computer
Slide 146 : Antibiotics in Veterinary use more than 1 million tons released into biosphere in the last 50 years globally estimated: 50% for veterinary and agricultural purposes
Slide 147 : Antibiotics in Veterinary use veterinary use of antibiotics includes the use on: pets farm animals animals raised in aquaculture for farm animals, antibiotics are used: in therapy and prophylaxis to increase growth and feed efficiencies ? at subtherapeutical levels!
Slide 148 : Antibiotics in Veterinary use bacteria that develop antibiotic resistance in animals comprise: food-borne pathogens opportunistic pathogens commensal bacteria the danger: same antibiotic resistance genes and gene transfer mechanisms can be found in the microfloras of animals and humans the accumulation of resistant bacteria and the spread via agriculture and direct contamination by the use of antibiotics in agriculture and veterinary medicine are documented
Slide 149 : Acquired Resistance to Antibacterial Drugs Chromosomal mutation is random and spontaneous and occurs uninfluenced by in the presence of antibiotics; usually involves changes in bacterial structures May be a single-step mutation for antibiotics that affect a single target or multi-step if more than one target
Slide 150 : Acquired Resistance to Antibacterial Drugs Transferable drug resistance: Transduction – plasmid DNA is incorporated by a bacterial virus (bacteriophage) and transferred to another bacterium Conjugation – plasmid-mediated transfer of resistance genes through a sex pilus from a donor bacterium to a recipient (most common and most important)
Slide 151 : Acquired Resistance to Antibacterial Drugs Transposition – transposons (jumping genes) - short DNA sequences transpose to & between plasmids and chromosomes Simplest form is a resistance gene flanked on either side by an insertion sequence; potentially any bacterial gene can be moved by a transposon May also involve conjugation & integrons
Slide 152 : Acquired Resistance to Antibacterial Drugs Integrons – consist of an integrase gene & a site-specific integration site on a chromosome or plasmid into which an integrase can insert an antimicrobial drug resistance cassette with as many as 7 resistance genes 9 types of integrons and 60 different gene cassettes associated with multi-drug resistant GN enteric bacteria
Slide 153 : Acquired Resistance to Antibacterial Drugs Transformation – cells can take up free DNA from the environment (from dead or lysed cells) and the genes can be integrated into the chromosome or a plasmid; least important type
Slide 154 : Clinical Importance Acquired resistance is a major problem and has been found in most veterinary pathogens R (resistance) plasmids which carry genes for multiple drug resistance and the gene for sex pili for conjugation are the most common and most important
Slide 155 : Clinical Importance R plasmids are readily transferred to other bacteria, especially enteric bacteria Use of one of the antibiotics to which resistance is carried leads to a population of bacteria that is resistant to the other antibiotics which the plasmid carries Eventually the usefulness of many antibiotics becomes limited for pathogens
Slide 156 : Public Health Importance Not only pathogens, but also nonpathogens of the normal flora may acquire antibiotic resistance These organisms may colonize humans following contact with animals, through the food chain or from contaminated water sources and spread resistance genes to human pathogens and normal flora.
Slide 157 : Public Health Implications Increased scrutiny of antibiotics used for growth promotion and prophylaxis in food animals (enrofloxacin recently removed as an approved drug for poultry) Increased scrutiny before approval of new animal drugs that are similar to drugs important for human use Increased scrutiny of veterinary use of human drugs (off label)
Slide 158 : Antifungal Chemotherapy Fungal drug susceptibility testing is not widely available Many topical products are available Griseofulvin – dermatophytes, oral, incorporated into keratin tissues, inhibits fungal mitosis, fungistatic Nystatin – polyene, oral not absorbed or topical used to treat yeast infections
Slide 159 : Antifungal Chemotherapy Amphotericin B – polyene, binds ergosterol, damages membrane, fungicidal, broad spectrum; IV only & nephrotoxic. 5-Flucytosine – incorporated into mRNA & leads to faulty proteins, yeasts only Chitin inhibitors – good against major pathogens but not licensed yet Glucan inhibitors – IV Caspofungin licensed in 2001 shows limited promise in animals
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