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  • Ignaz Philipp Semmelweis (1818-1865), a Hungarian obstetrician, introduced antiseptic hand hygiene techniques Semmelweis noted that postpartum women examined by medical students who did not wash their hands after performing autopsies had high mortality rates He required students to clean their hands with chlorinated lime before examining patients Maternal mortality declined from 12% to less than 1% after this hand hygiene intervention was implemented
  • Daptomycin chemical structure.
  • Daptomycin mechanism of action. Hypothetical steps: step 1, daptomycin binds to the cytoplasmic membrane in a calcium-dependent manner; step 2, daptomycin oligomerizes, disrupting the membrane; step 3, the release of intracellular ions and rapid cell death.
  • Once a pathogen produces infection, antimicrobial treatment may be essential However, antimicrobial use promotes selection of antimicrobial-resistant strains of pathogens As the prevalence of resistant strains increases in a population, subsequent infections are increasingly likely to be caused by these resistant strains Fortunately, this cycle of emerging antimicrobial resistance/multidrug resistance can be interrupted Preventing infections in the first place will certainly reduce the need for antimicrobial exposure and the emergence and selection of resistant strains Effective diagnosis and treatment will benefit the patient and decrease the opportunity for development and selection of resistant microbes; this requires rapid accurate diagnosis, identification of the causative pathogen, and determination of its antimicrobial susceptibility Optimizing antimicrobial use is another key strategy; optimal use will ensure proper patient care and at the same time avoid overuse of broad-spectrum antimicrobials and unnecessary treatment Finally, preventing transmission of resistant organisms from one person to another is critical to successful prevention efforts
  • The “12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults” intervention program is the first 12-step program to be launched because hospital patients are at an especially high risk for serious antimicrobial-resistant infections Each year nearly 2 million patients in the United States get an infection in a hospital Of those patients, about 90,000 die as a result of their infection More than 70% of the bacteria that cause hospital-acquired infections are resistant to at least 1 of the drugs most commonly used to treat them Persons infected with antimicrobial-resistant organisms are more likely to have longer hospital stays and to require treatment with second- or third-choice drugs that may be less effective, more toxic, and/or more expensive
  • The proportion of pathogens causing hospital-acquired infections that are resistant to target antimicrobial drugs continues to increase at an alarming rate Currently, more than 50% of Staphylococcus aureus isolates causing infections in intensive care units are resistant to methicillin; more than 40% are resistant in other hospital units Vancomycin-resistant enterococci (VRE) emerged in the late 1980s and are now endemic in many hospitals In many hospitals, more than 25% of enterococcal infections are caused by vancomycin-resistant strains
  •   Background.      The prevalence of multidrug resistance (MDR) among gram-negative bacilli is rapidly increasing. Quantification of the prevalence and the common antimicrobial coresistance patterns of MDR gram-negative bacilli (MDR-GNB) isolates recovered from patients at hospital admission, as well as identification of patients with a high risk of harboring MDR-GNB, would have important implications for patient care.       Methods.      Over a 6-year period, patients who harbored MDR-GNB (i.e., patients who had MDR-GNB isolates recovered from clinical cultures within the first 48 h after hospital admission) were identified. "MDR-GNB isolates" were defined as Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, and Klebsiella species isolates with resistance to at least 3 antimicrobial groups. A case-control study was performed to determine the independent risk factors for harboring MDR-GNB at hospital admission.       Results.      Between 1998 and 2003, the prevalence of MDR-GNB isolates recovered from patients at hospital admission increased significantly for all isolate species ( P < .001), with the exception of P. aeruginosa ( P = .09). Of 464 MDR-GNB isolates, 12%, 35%, and 53% of isolates were coresistant to 5, 4, and 3 antimicrobial groups, respectively. Multivariable analysis identified age 65 years (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.1 7.4; P < .04), prior exposure to antibiotics for 14 days (OR, 8.7; 95% CI, 2.5 30; P < .001), and prior residence in a long-term care facility (OR, 3.5; 95% CI, 1.3 9.4; P < .01) as independent risk factors for harboring MDR-GNB at hospital admission.       Conclusion.      A substantial number of patients harbor MDR-GNB at hospital admission. Identification of common coresistance patterns among MDR-GNB isolates may assist in the selection of empirical antimicrobial therapy for patients with a high risk of harboring MDR-GNB

Antibiotics ppt Antibiotics ppt Presentation Transcript

    • ANTIBIOTICS
  • Antibiotics
    • Topics
    • - Antimicrobial Therapy
    • - Selective Toxicity
    • - Survey of Antimicrobial Drugs
    • - Microbial Drug Resistance
    • - Drug and Host Interaction
  • Key Words Sterilization/disinfection/antisepsis Antibiotic Selective toxicity Bactericidal Bacteriostatic Minimal inhibitory concentration (MIC) Susceptibility testing Penicillin binding proteins Penicillinase/beta lactamas Resistance
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  • Selective Toxicity
    • Drugs that specifically target microbial processes, and not the human host cellular processes.
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  • Improved Patient Outcomes Associated With Proper Hand Hygiene Semmelweis Chlorinated lime hand antisepsis
  • Antibiotics
    • Naturally occurring antimicrobials
      • Metabolic products of bacteria and fungi
      • Reduce competition for nutrients and space
    • Bacteria that produce them:
      • Streptomyces, Bacillus,
    • Molds
      • Penicillium, Cephalosporium
  • History
    • Ancient remedies
    • Ehrlich
    • Domagk
    • Fleming
  • Neem Plant
  • Neem Plant
    • Uses: Arthritis, blood purifier and detoxifier, convalescence after fever, cough, diabetes, eczema, fever (used with black pepper and gentian), inflammation of muscles and joints, jaundice, leukorrhea, malaria, mucus membrane ulcerations, nausea, obesity, parasites, rheumatism, skin diseases/inflammations, cleanses liver, syphilis, thirst, tissue excess, tumors, vomiting, worms, drowsiness, loss of appetite. Leaves—heal ulcers in urinary passage, emmenagogue, skin diseases. Fruit—skin diseases, bronchitis. Kernel powder —washing hair. Effective as a pesticide .
  • Propolis
  • Propolis
    • Propolis is plant resin compound, different fabric compositions, wax, essential oils, iron, microelements – copper, zinc, manganese, cobalt, plus pollen, flavonoids, salivary gland secretions of bees. Propolis is used as a bio-stimulator which enhances endurance and eliminate fatigue. Because its antiviral properties, antitoxic and anti-inflammatory propolis finds more and more uses. Recovery is a good stimulator of affected tissue injuries, cuts. .. 
  • Ehrlich’s Magic Bullets
  • Gerhard Domagk - Prontosil
  • Fleming and Penicillin
  • Selman Waksman
  • Between 1962 and 2000, no major classes of antibiotics were introduced Fischbach MA and Walsh CT Science 2009
  • A Changing Landscape for Numbers of Approved Antibacterial Agents Bars represent number of new antimicrobial agents approved by the FDA during the period listed. 1983-87 1988-92 1993-97 1998-02 2003-05 2008 Infectious Diseases Society of America. Bad Bugs, No Drugs . July 2004; Spellberg B et al. Clin Infect Dis . 2004;38:1279-1286; New antimicrobial agents. Antimicrob Agents Chemother . 2006;50:1912 Resistance 0 0 2 4 6 8 10 12 14 16 18 Number of agents approved
  • Azamulin
  • Daptomycin chemical structure . Steenbergen J N et al. J. Antimicrob. Chemother. 2005;55:283-288 JAC vol.55 no.3 © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved
  • Daptomycin mechanism of action . Steenbergen J N et al. J. Antimicrob. Chemother. 2005;55:283-288 JAC vol.55 no.3 © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved
  • Linezolid
  •  
  • Ideal Antimicrobial Attributes
    • Solubility
    • Selective toxicity
    • Stable toxicity level
    • Allergenicity
    • Tissue stability
    • Resistance Acquisition
    • Shelf Life
    • Cost
  •  
  • ANTIBIOTICS
    • Selectively toxic for bacteria
      • bactericidal (killing)
      • bacteriostatic (growth inhibition)
    • no harm to patient
  • Antibiotic/Antimicrobial
    • Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism
    • Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms
  • Microbial Sources of Antibiotics
  • Administration of Antibiotics
  • Spectrum of Activity
  • Determining Microbial Sensitivities
    • Disk Diffusion Method
    • Dilution Method
    • Serum Killing Power
    • Automated Methods
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  • Drug Mechanisms of Action
    • Penicillin (over 50 compounds)
      • Share 4-sided ring (  lactam ring)
    • Natural penicillins
        • Narrow range of action
        • Susceptible to penicillinase (  lactamase)
    Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis
  • Prokaryotic Cell Walls
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  •  
  • Cell wall synthesis
    • Bactericidal
      • Penicillin and cephalosporins – binds and blocks peptidases involved in cross-linking the glycan molecules
      • Vancomycin – hinders peptidoglycan elongation
      • Cycloserine – inhibits the formation of the basic peptidoglycan subunits
  • Antibiotics weaken the cell wall, and cause the cell to lyse .
  • Penicillin
    • Penicillin chrysogenum
    • A diverse group (1 st , 2 nd , 3 rd generations)
      • Natural (penicillin G and V)
      • Semisynthetic (Ampicillin, Carbenicillin)
    • Structure
      • Thiazolidine ring
      • Beta-lactam ring
      • Variable side chain (R group)
  • - 4C – 28C - 38C water activity 0.98
  • The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive. Chemical structure of penicillins
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  •  
  •  
  • Penicillins Figure 20.6
  •  
    • Penicilinase-resistant penicillins
        • Carbapenems: very broad spectrum
        • Monobactam: Gram negative
    • Extended-spectrum penicillins
    • Penicillins +  -lactamase inhibitors
    Semisynthetic Penicillins
  • Penicillinase (  Lactamase)
    • Cephalosporins
      • 2 nd , 3 rd , and 4 th generations more effective against gram-negatives
    Other Inhibitors of Cell Wall Synthesis Figure 20.9
  • Cephalosporin
    • Cephalosporium acremonium (mold)
    • Widely administered today
      • Diverse group (natural and semisynthetic)
    • Structure
      • similar to penicillin except
        • Main ring is different
        • Two sites for R groups
  • The different R groups allow for versatility and improved effectiveness.
  •  
  • Other Inhibitors of Cell Wall Synthesis
    • Mycobacteria: interfere with mycolic acid synthesis or incorporation
      • Isoniazid (INH)
      • Ethambutol
    • Polypeptide antibiotics
      • Bacitracin
        • Topical application
        • Against gram-positives
      • Vancomycin
        • Glycopeptide
        • Important "last line" against antibiotic resistant S. aureus
    Other Inhibitors of Cell Wall Synthesis
    • Broad spectrum, toxicity problems
    • Examples
      • Aminoglycosides: Streptomycin, neomycin, gentamycin
      • Tetracyclines
      • Macrolides: Erythromycin
      • Chloramphenicol
    Inhibitors of Protein Synthesis
  •  
  • Aminoglycosides
    • From Streptomyces
    • Inhibit protein synthesis
    Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin.
  •  
  • Sites of inhibition on the procaryotic ribosome
  •  
  •  
  • Tetracycline
    • Inhibits proteins synthesis
    • Broad spectrum and low cost
    • Commonly used to treat sexually transmitted diseases
    • Minor side effect – gastrointestinal disruption
  •  
  • Tetracyclines (bacteriostatic) tetracycline , minocycline and doxycycline
    • Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.
    • Spectrum of activity - Broad spectrum; Useful against intracellular bacteria
    • Resistance - Common
    • Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth. Not used in children.
  •  
  •  
  • Spectinomycin (bacteriostatic)
    • Mode of action - Spectinomycin reversibly interferes with m-RNA interaction with the 30S ribosome. It is structurally similar to the aminoglycosides but does not cause misreading of mRNA. Does not destabilize membranes, and is therefore bacteriostatic
    • Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae
    • Resistance - Rare in Neisseria gonorrhoeae
  • Erythromycin
    • Inhibits protein synthesis
    • Broad-spectrum
    • Commonly used as prophylactic drug prior to surgery
    • Side effects - low toxicity
  •  
  •  
  • Streptomycin - treat Plague
  • Chloramphenicol
    • Broad-spectrum
    • Treat typhoid fever, brain abscesses
    • Rarely used now due to side effects – aplastic anemia
  • Chloramphenicol
  • UDP-glucuronyl transferase
  • Aminoglycoside
    • Polymyxin B (Gram negatives)
      • Topical
      • Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation
    Injury to the Plasma Membrane
    • Polymyxin B (Gram negatives)
      • Topical
      • Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation
    Injury to the Plasma Membrane
  •  
  •  
  •  
    • Rifamycin
      • Inhibits RNA synthesis
      • Antituberculosis
    • Quinolones and fluoroquinolones
      • Ciprofloxacin
      • Inhibits DNA gyrase
      • Urinary tract infections
    Inhibitors of Nucleic Acid Synthesis
  •  
  •  
  •  
  • Inhibition of Nucleic Acid Synthesis
    • Rifampin binds to DNA-dependent RNA polymerase and inhibits intiation of RNA synthesis
  •  
  •  
  • Antibacterials — Antimetabolites
    • Sulfonamides
    • Isoniazid
    • Ethambutol
    • Nitrofurans
  • Folic acid synthesis
    • Sulfonamides (sulfa drug) and trimethoprim
      • Analogs
      • Competitive inhibition of enzymes
      • Prevents the metabolism of DNA, RNA, and amino acid
      • Sulfonamides (Sulfa drugs)
        • Inhibit folic acid synthesis
        • Broad spectrum
    Competitive Inhibitors Figure 5.7
  • Sulfonamides compete with PABA for the active site on the enzyme. The sulfonamide Sulfamethoxazole is commonly used in combination with trimethoprim
  •  
  •  
  • Necrotizing Fasciitis
    • Group A hemolytic streptococci and Staphylococcus aureus, alone or in synergism, are frequently the initiating infecting bacteria. However, other aerobic and anaerobic pathogens may be present, including Bacteroides, Clostridium, Peptostreptococcus, Enterobacteriaceae, coliforms, Proteus, Pseudomonas, and Klebsiella .
  •  
  •  
  •  
  • Summary of Targets
  • Antibiotic Resistance Figure 20.20
  • Antimicrobial Resistance
    • Relative or complete lack of effect of antimicrobial against a previously susceptible microbe
    • Increase in MIC
      • Enzymatic destruction of drug
      • Prevention of penetration of drug
      • Alteration of drug's target site
      • Rapid ejection of the drug
    Mechanisms of Antibiotic Resistance
  • Antibiotic Selection for Resistant Bacteria
  • What Factors Promote Antimicrobial Resistance?
    • Exposure to sub-optimal levels of antimicrobial
    • Exposure to microbes carrying resistance genes
  • Inappropriate Antimicrobial Use
    • Prescription not taken correctly
    • Antibiotics for viral infections
    • Antibiotics sold without medical supervision
    • Spread of resistant microbes in hospitals due to lack of hygiene
  • Inappropriate Antimicrobial Use
    • Lack of quality control in manufacture or outdated antimicrobial
    • Inadequate surveillance or defective susceptibility assays
    • Poverty or war
    • Use of antibiotics in foods
  • Antibiotics in Foods
    • Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth
    • Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef fed antibiotics
  • Consequences of Antimicrobial Resistance
    • Infections resistant to available antibiotics
    • Increased cost of treatment
  •  
  • Multi-Drug Resistant TB
  • MRSA “mer-sah”
    • Methicillin-Resistant Staphylococcus aureus
    • Most frequent nosocomial (hospital-acquired) pathogen
    • Usually resistant to several other antibiotics
  • Proposals to Combat Antimicrobial Resistance
    • Speed development of new antibiotics
    • Track resistance data nationwide
    • Restrict antimicrobial use
    • Direct observed dosing (TB)
  • Proposals to Combat Antimicrobial Resistance
    • Use more narrow spectrum antibiotics
    • Use antimicrobial cocktails
    • Antimicrobial peptides
      • Broad spectrum antibiotics from plants and animals
        • Squalamine (sharks)
        • Protegrin (pigs)
        • Magainin (frogs)
    The Future of Chemotherapeutic Agents
  • Side Effects
  • Resistance to Drugs
    • Chromosomal
    • Plasmid borne
  • Mechanisms of Drug Resistance
    • Mutations in Target molecules
    • Alterations in membrane permeability
    • Enzyme development
  • Mechanisms of Drug Resistance
    • Enzyme Activity Changes
    • Alterations in Anabolic Pathways
  • Generations of Drugs
    • First/Second/Third Line Drugs
    • Cross Resistance
  • Limiting Drug Resistance
    • E ffective Drug Concentrations
    • Simultaneous Drug Administration
        • Synergism
        • Antagonism
    • Restricting Drug Prescriptions
  • Antibiotic Resistance
    • Inactivation of the antibiotic by a microbial enzyme
    • Prevention of the antibiotic from reaching its target cell structure
    • Alteration of the target cell structure so that it is no longer affected by the antibiotic
  • Mechanisms of Resistance
    • Failure of the antibiotic to penetrate the outer membrane
    • Failure to bind to the target site (penicillin binding protein)
    • Hydrolysis of the antibiotic by beta lactamases
  • Drug Resistance
    • Intrinsic as well as acquired
    • Intrinsic drug resistance exists naturally and is not acquired through specific genetic changes
  • How does drug resistance develop?
    • The genetic events most often responsible for drug resistance are either chromosomal mutations or transfer of extrachromosomal DNA from a resistant species to a sensitive one.
  •  
  • Resistance Factors – R Factors
    • Transferred through conjugation, transformation or transduction
    • Many bacteria also maintain transposable drug resistance sequences – tansposons that are duplicated and inserted from one plasmid to another or from a plasmid to a chromosome
  • Conjugation – plasmids and chromosomal elements, conjugative transposons plasmids
    • Conjugative plasmid – plasmids that transfer themselves by conjugation must carry a number of genes encoding proteins needed for the conjugation process itself (tra genes)
    • Self-transmissable plasmids (STP) are usually at least 25kb
    • Mobilize plasmids – much smaller than STP because they need only 1 or 2 genes (mob genes)
  • Resistance Genes
    • Acquire sequential transposon insertions
    • Integrons are probably responsible for evolution of many of the plasmids that carry multiple resistance genes
  • Integrons
    • Integrons like transposons are linear DNA segments that insert into DNA
    • Unlike transposons, integrons integrate at a single site and do not encode a transposase
    • Conjugative transposons – located in the bacterial chromosome, also integrate into plasmids
  • Mechanism of Transfer
    • Excise themselves from the donor genome to form a covalently closed circle that does not replicate
    • The circular intermediate transfers similarly to a plasmid
    • In the recipient, the circular intermediate integrates in the chromosome by a mechanism that does not duplicate the target site
  •  
  • Origin of Antibiotic Resistant Genes
    • First it was assumed that antibiotic resistance genes appeared only after antibiotics began to be widely used in medicine
    • The genetic diversity within some classes of resistance makes it clear that these genes have been evolving for a much longer time
  • Origin of resistance
    • Hypothesis: resistance genes first evolved in the antibiotic-producing bacteria such as Streptomyces spp. As a mechanism for protecting them from the antibiotics they produce.
    • Genes for antibiotic production are frequently found in the same gene clusters with genes encoding resistance proteins
  • Specific mechanisms of drug resistance
    • Bacteria lose its sensitivity to a drug by expressing genes that stop the action of the drug.
  • Gene expression
    • Synthesis of enzymes that inactivate the drug
    • Decrease in cell permeability and uptake of the drug
    • Change in the number or affinity of the drug receptor sites, or
    • Modification of an essential metabolic pathway
  • Resistance
    • Some bacteria can become resistant indirectly by lapsing into dormancy, or, in the case of penicillin, by converting to a cell-wall-deficient form (L form) that penicillin cannot affect.
  • Drug Inactivation Mechanisms
    • Produce enzymes that permanently alter drug structure (beta lactamases)
  • Decreased Drug Permeability or Increased Drug Transport
    • Prevent drug from entering the cell and acting on the target
    • Gram negative – natural blockade for some of the penicillin drugs
    • Resistance to the tetracyclines can arise fro plasmid-encoded proteins that pump the drug out of the cell
  • Resistance
    • Resistance to the aminoglycoside antibiotics is a specific case in which microbial cells have lost the capacity to transport the drug intracellulary
  • Multidrug Resistant (MDR) Pumps
    • Actively transport drugs and other chemicals out of the cell
    • These pumps are proteins encoded by plasmids and chromosomes
    • They are located in the cell membrane and expel molecules by a protonmotive force similar to ATP synthesis
  • PUMPS
    • Because they lack selectivity, one type of pump can expel a broad array of antimicrobic drugs, detergents and other toxic substances.
  • Change of Drug Receptors
    • Alter nature of target site
    • On bacteria resistant to rifampin and streptomycin, the structure of key proteins has been altered so that these antibiotics can no longer bind.
  • Changes in Metabolic Patterns
    • Sulfonamide and trimethoprim resistance develops when microbes deviate from the usual patterns of folic acid synthesis
  • Natural selection and drug resistance
    • When a population of bacteria is exposed to a drug, sensitive cells are inhibited or destroyed and resistant forms survive and proliferate
    • In ecological terms, the environmental factor has put selection pressure on the population, allowing the more fit microbe to survive, and the population has evolved to a condition of drug resistance.
  • Antimicrobial Resistance: Key Prevention Strategies Susceptible Pathogen Optimize Use Prevent Transmission Prevent Infection Effective Diagnosis and Treatment Antimicrobial-Resistant Pathogen Antimicrobial Resistance Antimicrobial Use Infection
  • 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults 12 Contain your contagion 11 Isolate the pathogen 10 Stop treatment when cured 9 Know when to say “no” to vanco 8 Treat infection, not colonization 7 Treat infection, not contamination 6 Use local data 5 Practice antimicrobial control 4 Access the experts 3 Target the pathogen 2 Get the catheters out 1 Vaccinate Prevent Transmission Use Antimicrobials Wisely Diagnose and Treat Effectively Prevent Infection
  • Antimicrobial Resistance Among Pathogens Causing Hospital-Acquired Infections Methicillin (oxacillin)-resistant Staphylococcus aureus Vancomycin-resistant enterococci Non-Intensive Care Unit Patients Intensive Care Unit Patients Source: National Nosocomial Infections Surveillance (NNIS) System
  • Prevalence of Isolates of Multidrug-Resistant Gram Negative Rods Recovered Within The First 48 h After Admission to the Hospital Pop-Vicas and D'Agata CID 2005;40:1792-8 .
  •  
  • Conjugative transposons
    • Responsible for at least as much resistance gene transfer as plasmids, especially among G+, and they have a broad host range
    • G+  G+ ; G -  G - ; G+  G -
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