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156 Cards in this Set
- Front
- Back
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Examples of Eukaryotic Cells:
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algae, fungi, protozoa, plants, animals
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Examples of Prokaryotic Cells:
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bacteria, blue green algae(cyanobacteria)
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is a virus eukaryote or prokaryote?
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neither, not a living thing
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typical size of euk. cell?
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2-100 microns diameter
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typical size of prok. cell?
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0.5=2 microns diameter
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avg. size of E. coli?
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1 x 2 microns
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what does the small size of prok. cells allow for?
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small prok. cells allow for INTRACELLULAR bacteria b/c much smaller than euk. cells
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describe organism nomenclature techniques
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One correct name for an organism
All names are in Latin or are latinized (given endings that agree in terms of proper usage and gender) Genus: the first word is always capitalized species: the second word is not capitalized Both the genus and species in print: underlined or italicized |
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4 major classifications of bacteria
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aerobic
anaerobic gram + gram - |
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electron transfer in AEROBIC prok. metabolism?
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O2 --> H2O
Oxygen dependent |
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electron transfer in ANAEROBIC prok. metabolism?
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NO3 --> N2
SO4 --> H2S CO2 -->CH4 Not O2 dependent |
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defn. "Obligate" an/aerobic
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obligate anerobe must live under anaerobic conditions or it will die if put in aerobic environment (opposite for obligate aerobe)
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defn. "facultative" anaerobe
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preferes anaerobic environments, but CAN live if exposed to aerobic environment
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2 main parts of prok. cell structure
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cell envelope
cell wall |
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components of cell envelope
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plasma membrane
cell wall |
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features of cell wall
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composed primarily of peptidoglycans
provides structural stability and shape to the cell |
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benefit of unusual D-amino acids in bacterial cell walls?
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specificity for antibiotics
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features of gram + cell walls
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THICK cell wall
no outer membrane |
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features of gram - cell walls
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THIN cell wall
inner (cytoplasmic) and outer (external) membrane |
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bacterial capsule
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a thick poly-saccharide layer that forms a viscous gel outside the cell envelope in some bacteria
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peptidoglycan structure
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linear
polysaccharide chains are cross linked by short peptides |
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prok. slime layer?
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Some organisms lack a well-defined capsule but have a loose, amorphous slime layer outside the cell envelope
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what are capsules and slime layers composed of?
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Capsules and slime layers are generally composed of polysaccharides, but may also contain amino sugars, peptides, and DNA
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examples of encapsulated bacteria?
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Streptococcus pneumoniae (G+)
Haemophilus influenzae (G-) Moraxella catarrhalis (G-) |
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what is the periplasmic space?
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space b/w the inner and outer membrane in Gram - bacteria
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Fxn of capsules and slime
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Bacterial adherence to surfaces
Protection from plant and animal antimicrobial agents Protection of soil bacteria from desiccation Protection from predatory protozoa or white blood cells (phagocytes) by decreased recognition Bacterial capsules may also inhibit phagocytosis |
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how does S. pneumoniae inhibit phagocytosis?
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Streptococcus pneumoniae synthesizes a polysaccharide capsule that prevents ingestion by alveolar macrophages
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how does B. anthracis inhibit phagocytosis?
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Bacillus anthracis synthesizes a poly-D-glutamate capsule that prevents damage by macrophage lysosomal enzymes
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what is a biofilm?
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Biofilm is a protected environment for themselves and other bacteria
Bacteria may attach to surface, produce complex slime layers, divide and produce micro-colonies within the slime layer “Quorum sensor” molecules secreted by the bacteria induce a number of genes that result in cellular aggregation and biofilm formation |
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what do Quorum sensors do?
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“Quorum sensor” molecules secreted by the bacteria induce a number of genes that result in cellular aggregation and biofilm formation
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How is Dental Plaque an example of a biofilm?
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Dental plaque constructed by the oral bacterium, Streptococcus mutans
The bacteria hydrolyze sucrose into glucose + fructose fructose is utilized as an energy source glucose is polymerized into an extracellular dextran polymer that cements the bacteria to tooth enamel and becomes the matrix of dental plaque (~300-500 cells in thickness) The dextran slime can be depolymerized to glucose which is used as a carbon source, resulting in production of lactic acid within the plaque The acid decalcifies the enamel and leads to dental caries and/or bacterial infection of the tooth |
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how is cystic fibrosis an example of a biofilm?
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Pseudomonas aeruginosa thrives in a “planktonic” free-living form, but also in biofilms
Biofilms coat rocks in streams, faucets -- and mucosal surfaces of the airways “Quorum sensor” molecules secreted by the bacteria induce a number of genes that result in cellular aggregation and biofilm formation Many protective enzymes are also induced Lab-based antibiotic sensitivity tests often indicate susceptibility, but this is for the free-living bacteria P. aeruginosa biofilms protect the bacteria from antibiotics via a number of mechanisms and may render organisms resistant to antibiotics |
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what are flagella?
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flexible, corkscrew-shaped protein filament that is used for locomotion
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what are pili?
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fine, hair-like structures used to attach to food sources as well as to other cells (host tissues)
sex pili are used by some bacteria to transfer genetic information -> conjugation |
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what is cytoplasm?
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• Cytosol, a gel-like aqueous
phase containing enzymes, metabolites, amino acids, nucleotides, RNA, inorganic ions, etc. • Insoluble, suspended particles (e.g., ribosomes, polysomes) |
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do prok. cells have nuclei?
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NO, DNA is free floating, no nuclear membrane
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what is nucleoid?
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• Double-stranded DNA genome
• Genome not separated from cytoplasm by a nuclear membrane as in mammalian cells |
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Desc. E. coli genome
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• E. coli genome is a 4,000 kb, circular duplex
• The extended length of chromosome is 100 µM • E. coli is 1 µM x 2 µM , so the genome must be highly condensed Bacterial DNA gyrase functions to supercoil DNA |
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features of prok. genome under microscope?
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• Electron-transparent nuclear region (n)
• Dense distribution of ribosomal particles in the cytoplasm • Absence of intracellular membranous organelles |
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what does DNA gyrase do?
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help supercoil and densely pack genetic material/DNA
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what are bacterial plasmids?
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Extrachromosal DNA
1,000 to 30,000 bp, circular duplex Plasmid replication occurs independent of genome replication Low-copy plasmids: 1-2 per cell High-copy plasmids: 1,000 per cell Plasmids encode proteins that are not essential to the cell, e.g. bacterial toxins, antibiotics, and proteins that confer resistance to antibiotics |
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Desc. bacterial pathogenesis?
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Most bacterial pathogens do not invade cells
Proliferation in the extracellular environment enriched by body fluids Some bacteria (Vibrio cholerae, Bordetella pertussis, Bacillus anthracis) do not penetrate any body tissues |
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pathogenesis of bacteria that do not penetrate body tissues (vibrio, bordatella, bacillus)
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(Vibrio cholerae, Bordetella pertussis, Bacillus anthracis) do not penetrate any body tissues
**Adherence to epithelial surfaces and secretion of potent protein toxins *damage from toxin production |
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Adherence
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microbial attachment to host cells, the first step in killing cells and toxic delivery (provides tropism)
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tropism
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very specific in terms of what bacteria attach to, mediated through adhesins(which bind to specific cell receptors)
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what are exotoxins?
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Exotoxins = protein toxins released from viable bacteria
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features of exotoxins
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Among the most potent of all known toxins
Some exotoxins are heat-stable peptides Produced by both Gram-positive and Gram-negative bacteria Functional purpose of these exotoxins for the bacteria are usually unknown |
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what are virulence enhancing enzymes?
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promote tissue dysfunctions/destruction
ex: coagulase, catalase |
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groups of exotoxins
(know) |
neurotoxins
cytotoxins enterotoxins (GI tract) |
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endotoxins
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toxic lipopolysaccharide components of the outer membrane of Gram-negative bacteria
***Gram - only |
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features of endotoxins
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Endotoxin exerts profound biologic effects on the host and may be lethal
Endotoxin is a class of toxic substances released after bacterial lysis (vs. exotoxins) Endotoxin is omnipresent in the environment and must be removed from all medical supplies intended for injection or use during surgical procedures Biologic activity of endotoxin: Pyrogenicity Leukopenia followed by leukocytosis Complement activation Hypotension Hypothermia These events can culminate in sepsis and lethal shock |
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biologic activity of endotoxin
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Biologic activity of endotoxin:
Pyrogenicity Leukopenia followed by leukocytosis Complement activation Hypotension Hypothermia |
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what can endotoxin events lead to?
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sepsis/lethal shock
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when does bacterial lysis occur?
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after death of cell, or during replication
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Mechs of bacterial pathogenesis
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Some bacteria are ingested by macrophages but actively block lysosomal fusion (Salmonella, Legionella, Chlamydophila)
Other bacteria can survive within the phagolysosome (Bacillus anthracis, Mycobacterium tuberculosis, S. aureus) |
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pathogenesis of Rickettsiae?
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Rickettsiae spp. are small, obligate intracellular parasites transmitted by arthropods (lice, fleas, ticks)
Phagocytized by macrophages but synthesize a phospholipase that destroys the phagosomal membrane prior to lysosome fusion Cause of typhus, Rocky Mountain Spotted Fever |
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pathogenesis of Chlamydophila?
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Chlamydophila spp. are small, obligate intracelluar parasites
C. trachomatis: urethritis C. pneumoniae: pneumonia |
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normal flora of the body: how many cells?
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The human body consists of ~10 trillion cells
The microbial normal flora consists of ~100 trillion cells Estimated 500 to 1,000 different species in gut and similar number on skin Estimated 30-40 species make up >95% of flora |
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normal flora of the body: what type of cells are they?
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Normal flora are predominantly anaerobic bacteria, but aerobic bacteria also common as well as some yeasts
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microbes on skin
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Staphylococcus epidermidis, S. aureus
Propionobacterium acnes |
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microbes on nose/nasopharynx
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S. epidermidis, S. aureus
H. influenzae |
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microbes in mouth and tooth surfaces
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S. aureus, S. epidermidis,
Streptococcus mitis,& alpha-hemolytic strep Haemophilus Influenzae, Lactobacilus, Bacteroides fragilis, Fusobacterium nucleatum, C. Albicans |
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microbes in large intestine
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Escherichia coli, Klebsiella spp., Proteus spp.
B. fragilis, F. nucleatum, Enterococcus, Candida. albicans |
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microbes in vagina and uterin cervix
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Bacteroides spp., Clostridium spp.
S. epidermidis, C. albicans, Trichomonas vaginalis |
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functions of normal flora
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Normal flora of GI tract aids in digestion and absorption of nutrients
Fermentation of carbohydrates Synthesis of folic acid, vitamin K Stimulates immune system activity to maintain constant “priming” Provides protection against potentially pathogenic organisms: |
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How do normal flora provide protection against potentially pathogenic organisms:
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“Colonization resistance” or “competitive exclusion”
Competition for space (i.e. binding sites) Competition for nutrients Produce substances to actively suppress other organisms Protein toxins (e.g. bacteriocins) Metabolic by-products (e.g. fatty acids, peroxides) |
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KNOW Bacterial Identification Chart (See IOS 10 Quiz 1 notecards)
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bacterial chart from bacterial ID lecture:
Classify shapes, gram +/-, an/aerobic, etc. |
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Guidelines for Specimen Collection
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Obtain before initiating or changing antibiotics
Minimize contamination… Use appropriate collection system… Label specimens… Indicate diagnostic test(s) to be performed… Rapidly transport specimen to lab… Wait for Results |
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How long for specimen collection results?
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1-2 hours for Gram-stain
Several hours for most “rapid” diagnostic tests 24-72 hours for bacterial culture results Often 7-10 days for fungal culture results |
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Reasons for Failing to successfully ID a pathogen?
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Incorrect diagnosis
Misinterpretations of Gram-stain Inadequate specimens Improper or delayed transport of specimens Antimicrobial exposure prior to collection Improper culture methods Unsuitable culture methods |
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what percent of culture results are positive/useful?
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50%
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functions of normal flora
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Normal flora of GI tract aids in digestion and absorption of nutrients
Fermentation of carbohydrates Synthesis of folic acid, vitamin K Stimulates immune system activity to maintain constant “priming” Provides protection against potentially pathogenic organisms: |
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How do normal flora provide protection against potentially pathogenic organisms:
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“Colonization resistance” or “competitive exclusion”
Competition for space (i.e. binding sites) Competition for nutrients Produce substances to actively suppress other organisms Protein toxins (e.g. bacteriocins) Metabolic by-products (e.g. fatty acids, peroxides) |
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Bacterial Identification Chart
KNOW See IOS 10 Quiz #1 notecards |
know how to classify shapes, an/aerobic, gram +/-, etc.
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guidelines to specimen collection
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Obtain before initiating or changing antibiotics
Minimize contamination… Use appropriate collection system… Label specimens… Indicate diagnostic test(s) to be performed… Rapidly transport specimen to lab… Wait for results |
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how long do specimen results take?
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1-2 hours for Gram-stain
Several hours for most “rapid” diagnostic tests 24-72 hours for bacterial culture results Often 7-10 days for fungal culture results |
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Reasons for failing to successfully ID a pathogen
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Incorrect diagnosis
Misinterpretations of Gram-stain Inadequate specimens Improper or delayed transport of specimens Antimicrobial exposure prior to collection Improper culture methods Unsuitable culture methods |
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what percent of specimen results are positive/useful?
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50%
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why is it important to obtain specimen collecction before initiating/changing antibiotics?
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to get a higher yield and better results,
if already exposed to antimicrobial, numbers will be suppressed and results may not come back positive |
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defn cocci
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sphere like
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defn bacilli
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rod shape
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defn spirilla
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spiral
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defn strepto
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chain
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defn diplo
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pair
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defn staph
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cluster
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which microbe shows up as diplococcus gram +?
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Streptococcus pneumoniae
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what is example of coccobacillus?
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gram - haemophilus
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chemical strructure of macrolides: erythromycin
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Erythromycin and its analogs are 12-16 membered cyclic esters (lactones) with complex functionality and glycosidically-linked sugars
Classic macrolide nucleus is a 14-membered ring Erythromycin consists of the Erythronolide-A nucleus and two attached deoxy sugars: Desosamine = influences PK properties Cladinose = critical for antimicrobial activity Numerous chemical modifications have been made |
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what is the decosamine part of macrolides used for?
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PK parameters
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what is the cladinose part of macrolides used for?
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antimicrobial activity
ALSO, resistance inducer |
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what are the problems with erythromycin?
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Erythromycin is inherently chemically unstable
Undergoes rapid formation of hemiketal and ketal decomposition products when exposed to an acidic environment Half-life of erythromycin at pH 2 is ~9.3 seconds Chemical instability leads to poor and unpredictable oral bioavailability (15-25%) Hemiketal and ketal products thought to be responsible for GI adverse effects and poor tolerability after oral administration Ketal reaction product is inactive and suspected to be hepatotoxic |
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what is the half life of erythromycin in the stomach pH 2)
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9.3 seconds
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what are the complications caused by hemiketal and ketal products of erythromycin
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poor tolerability after oral administration
ketal rxn product is inactive, and may be hepatotoxic |
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list the methods used to improve oral bioavailability of erythromycin
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Enteric coating
Cellulose acetate phthalate is water-insoluble at pH 2 At pH >5, the coating ionizes and disintegrates Gut esterases may facilitate the process True enteric coating (not film coating) significantly improves the stability of erythromycin in the gut Esterification of desosamine sugar Propionate, ethylsuccinate esters inactive and possibly hepatotoxic until hydrolyzed by serum esterases Formation of salts with desosamine sugar Erythromycin stearate, estolate Chemical modifications of reactive functionality Changes increase bioavailability up to 60-80% |
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how does enteric coating improve F of erythromycin
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Cellulose acetate phthalate is water-insoluble at pH 2
At pH >5, the coating ionizes and disintegrates Gut esterases may facilitate the process True enteric coating (not film coating) significantly improves the stability of erythromycin in the gut |
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MOA macrolides
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Work through inhibition of protein synthesis
Reversible binding to 50S ribosomal subunit Shares same binding site as clindamycin, chloramphenicol Inhibits translation through several actions Macrolides are generally considered to be bacteriostatic, but may be bactericidal against some rapidly dividing bacteria such as Streptococcus pyogenes and S. pneumoniae Impairs elongation cycle of peptidyl chain Drug binds at entrance of “exit tunnel” used by peptide chain to escape from the ribosome Blocks elongation of chain through steric hindrance of peptide chain in tunnel Other actions Promotes dissociation of peptidyl tRNA from ribosome Interferes with 50S ribosome subunit assembly Inhibition of peptide bond formation Desosamine sugar protrudes into peptidyl transferase center and inhibits positioning of substrate at the P-site |
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KNOW!!!
What is the main MOA of the macrolides??? |
"Block protein synthesis at the 50s ribosomal subunit"
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Mechs. of resistance for macrolides
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Resistance among many Gram-negatives due to impermeability of drug through outer membrane
Enterobacteriaceae, Pseudomonas, Acinetobacter Enzymatic inactivation of erythromycin by esterases or phosphotransferases Enterobacteriaceae Active efflux of drug Staphylococcus epidermidis, S. aureus Alteration of single amino acid in 23S subunit of 50S ribosome as a result of chromosomal mutation (adenine guanine) leading to decreased drug binding S. pyogenes, S. pneumoniae, Campylobacter, E. coli Methylation of adenine residues in 23S subunit of 50S ribosome causes profound alteration in drug binding S. aureus, S. pneumoniae, Enterococcus |
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what are the 2 most important/relevant mechs of resistance for macrolides?
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Resistance amon many gram - due to impermeability of drug through outer membrane
methylation of adenin residues in 23s subunit of 50s ribosome causes profound alteration in drug binding |
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which main mech of macrolide resistance is Relative resistance?
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Alteration of single amino acid in 23S subunit of 50S ribosome as a result of chromosomal mutation (adenine guanine) leading to decreased drug binding
S. pyogenes, S. pneumoniae, Campylobacter, E. coli |
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which mech of macrolide resistance is Absolute resistance?
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Methylation of adenine residues in 23S subunit of 50S ribosome causes profound alteration in drug binding
S. aureus, S. pneumoniae, Enterococcus |
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PK of erythromycin
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Absorption
Inactivated by gastric acids, administered as enteric-coated tablets or capsules that dissolve in duodenum Food in stomach delays absorption but may improve gastric tolerance Distributed well into all tissues (except CNS) Vd 0.65 L/kg Low serum concentrations but higher levels in tissues Serum half-life = 1.5 – 2.0 hours Primarily eliminated through hepatic P-450 metabolism and biliary excretion Dose adjustment required in severe dysfunction |
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PK of clarithromycin
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Superior acid stability and better absorption compared to erythromycin
Bioavailability = 55-60% Better gastric tolerance Extensive distribution into most tissues Vd = 3-4 L/kg Metabolism similar to erythromycin Half-life = 4 hrs 14-hydroxyclarithromycin is pharmacologically active and has additive or synergistic activity with parent drug (e.g., H. influenzae) |
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PK azithromycin
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Acid stable, 35-40% of dose absorbed
Absorption is reduced by presence of food Extensive distribution into most tissues Vd = 23 - 31 L/kg Ratio of [tissue]:[serum] = 50 to 1,150 Serum half-life = 11- 64 hrs Very complex pharmacokinetic profile Tissue elimination may require several weeks Metabolism similar to erythromycin |
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KNOW!!
macrolide spectrum of activity |
Gram + aerobes:
Good activity against streptococci, staphylococci Poor activity against MRSA, enterococci Gram – aerobes: Moderate activity against Neisseria gonorrhoeae, M. catarrhalis, H. influenzae Some activity against Enterobacteriaceae, particularly gastrointestinal pathogens (e.g. Shigella, Campylobacter, Vibrio) Anaerobes Little activity Atypicals Traditional drugs of choice for Legionella, Mycoplasma, Chlamydia Other Borrelia burgdorferi, Mycobacterium, H. pylori |
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what are the main types of microbes macrolides are active against?
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Gram + (staph, strep)
NOT MRSA, NOT enterococcus Atypicals--traditional drugs of choice |
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side effects of macrolides
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Gastrointestinal disturbances: abdominal pain, nausea/vomiting, diarrhea
Thrombophlebitis with IV erythromycin: avoided with adequate dilution (250 ml) and slow infusion (45-60 min) Allergic reactions: skin rash, fever, eosinophilia Hepatotoxicity: Hepatitis, cholestatic jaundice, LFTs May represent a hypersensitivity reaction Most commonly reported with erythromycin estolate in adults; may also be more common in pregnant women Ototoxicity: Tinnitus, hearing loss, vestibular dysfunction Risk factors = high doses of erythromycin (4 g/day), presence of renal or liver dysfunction, elderly, other ototoxins Usually reversible within 30 days of drug D/C Superinfections - Candida spp. Torsade de pointes - rare Clostridium difficile infection |
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most common SE macrolides
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GI: ab. pain, N/V, diarrhea
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what is a relative CI for macrolides?
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pregnancy b/c risk of hepatotoxicity
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what causes macrolide drug drug interactions?
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b/c macrolides inhibit hepatic CYP 450 metabolism
esp CYP 3A4 |
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list some drugs that interact with erythromycin (3A4)
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Alfentanil, buspirone, carbamazepine, clomipramine + respiradone, clozapine, cyclosporine, digoxin, disopyamide, felodipine, lovastatin, methylprednisolone, midazolam, phenytoin, tacrolimus, theophylline, trazolam, valproate, warfarin
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list some drugs that interact with clarithromycin (3A4)
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Carbamazepine, cyclosporine, digoxin, rifampin, rifabutin, ritonavir, zidovudine
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drugs that interact with azithromycin
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cyclosporine
azithro is the lowest drug interactino risk for macrolides, but still need to monitor for potential interactions |
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clinical uses of macrolides
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Erythromycin and other macrolides often used as alternatives to penicillin, particularly in children
Community-acquired respiratory tract infections, particularly those involving atypical bacteria Mycoplasma pneumoniae, Chylamydia pneumoniae, Legionella pneumophila STDs: gonorrhea, syphilis Uncomplicated skin and soft tissue infections Infectious gastroenteritis Misc: Lyme Disease, Rocky Mountain Spotted Fever |
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why were the ketolides developed?
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Need for new antibiotics in respiratory tract infections (RTIs)
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what caused need for new antibiotics in respiratory tract infections
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Driven by the emergence of multi-resistant bacterial strains
Availability of a new antibiotic class reduces resistance pressure on other classes Maintain coverage of all key RTI pathogens Simple, short course of therapy |
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azithromycin was drug of choice for RTI, what is its percent resistance?
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28.8%
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what were ketolides SPECIFICALLY developed for?
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to overcome problems of S. pneumoniae resistance macrolides and other antibiotics
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what is the difference b/w macrolides and ketolides?
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ketolides DO NOT have a cladinose sugar, which is responsible for resistance in macrolides
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MOA ketolides
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Mechanism similar to that of macrolides
Inhibition of peptidyl transferase activity & protein synthesis |
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what is the difference b/w macrolides and ketolides in the ribosomal binding of their MOA?
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macrolides bind to only one place on ribosome (domain v)
ketolides bind 2 places on the ribosome (domain II and V) |
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what is the only ketolide available in the US?
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telithromycin
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how does telithromycin overcome macroliode (Erm b) resistance?
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macrolide's affintiy for domain V is lost by methylation...
telithromycin maintains high affinity for domain II, so it has activity against macrolide resistant strains (the secondary point of attachment for the drug still works afer methylation) |
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what is the %susceptibility for telithromycin for S. pneumoniae?
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99.8%
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what is the % susceptibility for azithromycin for S. penuemoniae?
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70.7%
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ketolide resistance???
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Reports of ketolide resistance remain scarce
1999-2005: 99.8% of tested S. pneumoniae strains remain susceptible Resistance related to alterations in telithromycin-binding sites Either chromosomal point mutations or ribosomal methylation Ketolides may or may not be affected by efflux |
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mech of ketolide resistance?
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Resistance related to alterations in telithromycin-binding sites
Either chromosomal point mutations or ribosomal methylation possibly by efflux |
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telithromycin PK
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Bioavailability = 55 - 60%
Unaffected by food intake Vd = 2.9 L/kg Half-life = 10 hours Elimination 80% metabolized by the liver Mixture of CYP450 3A4 and non-CYP450 pathways 7% excreted unchanged in feces by biliary and/or intestinal secretion 13% excreted unchanged in urine by renal excretion Telithromycin is strong inhibitor of CYP450 3A4 |
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what is telithromycins effect on CYP enzyme?
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strong inhibitor of CYP 3A4
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SE of ketolides(telithromycin)
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Well tolerated overall
General pattern of adverse events similar to macrolides adverse event profile similar in different age groups GI events most common: Diarrhea 11% Nausea 8% |
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what is a BAD side effect of telithromycin that limits its use?
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Potential hepatotoxicity
Relatively low incidence of elevated transaminases, increased bilirubin observed during clinical trials Recent reports of severe hepatotoxicity Hepatitis, fulminant liver failure leading to transplantation and/or death Cause-effect relationship not definitely established, true incidence unknown Ocular toxicities in ≤2% of patients Blurred vision, diplopia, accommodation difficulties, decreased night vision Usually mild-moderate in severity, seen within first 1-3 doses, reversible after drug D/C Many patients |
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what drugs should be avoided with telithromycin?
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Simvastatin, atorvastatin, lovastatin (increase AUC 890%)
Rifampin (decrease TEL AUC 86%) |
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why should simvastatin (lovastatin, atorvastatin) be avoided with telithromycin?>
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statin AUC incrases 890%
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why should rifampin be avoided with telithromycin?
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rifampin is CYP inducer and decreases the conc. of telithro A LOT
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clincal uses for telithromycin
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Community-acquired respiratory tract infections
Acute exacerbations of chronic bronchitis Acute sinusitis Community-acquired pneumonia Recent reports of hepatotoxicity has severely limited clinical use of telithromycin |
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structure of clindamycin??
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Halogenation at the C-7 position of the sugar moiety of lincomycin yielded clindamycin
Broader spectrum of activity, greater potency, improved pharmacokinetics compared to lincomycin Clindamycin approved for human use in 1977 Cl added (= "CL"indamycin) |
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MOA clindamycin?
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Like macrolides...
Inhibition of protein synthesis through binding to the 50S ribosome Shares same mechanism as macrolides and chloramphenicol Although not structurally related, these drugs have common binding site and may demonstrate competitive inhibition Antagonism is possible when used together, but few good reasons to do so Like the macrolides, clindamycin usually considered to be bacteriostatic Demonstrates concentration-dependent activity against some staphylococci and streptococci |
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resitance to clindamycin?
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Chromosomal alteration of single amino acid residue at the receptor site on the 50S ribosomal protein
Similar to macrolides Plasmid-mediated resistance involving alteration in the 23S ribosomal RNA of the 50S ribosomal subunit by methylation of adenine residue at the receptor site This “MLSB phenotype” confers cross-resistance to all macrolide, lincosamide, and streptogramin B antibiotics Expression may be either constitutive or inducible 14- and 15-membered macrolides are potent inducers in staphylococci Macrolides, lincosamides, and streptogramins are all potent inducers in streptococci and enterococci Poor permeability of the cellular outer envelope Gram-negative bacteria (e.g., Enterobacteriaceae) |
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what is themost common mech of clindamycin reistance?
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chromosomal alteration of single AA residue at the receptor site of the 50S ribosome
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what is absolute resistance mech for clindamycin?
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Plasmid-mediated resistance involving alteration in the 23S ribosomal RNA of the 50S ribosomal subunit by methylation of adenine residue at the receptor site
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PK clindamycin?
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Excellent oral bioavailability
Rapid and complete absorption after oral dosing Food delays absorption, does not reduce extent Excellent distribution into most tissues Bone levels = 60-80% of serum concentrations CNS penetration is not great Good penetration of abscesses Extensively metabolized to inactive metabolites (N-demethylclindamycin and clindamycin sulfoxide) Small portion of dose excreted as unchanged drug 95% of total dose excreted through bile and feces Serum half-life = 2.7 hrs |
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what can clindamycin be used to treat that many ABs cant?
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bone infections (60-80% serum conc.)
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spectrum of activity for clindamycin?
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Gram + aerobes
Excellent activity against staphylococci, including some strains of MRSA Less activity against streptococci No activity against enterococci Gram – aerobes: overall poor activity Anaerobes Broad activity against many Gram-positive and Gram-negative anaerobes including Bacteroides fragilis Oropharyngeal strains of B. fragilis tend to be more susceptible; gut strains more resistant Clostridium tends to be more resistant than other anaerobes Active against Chlamydophila and many protozoa |
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most common microbes clindamycin treats?
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gram + (some MRSA)
anaerobes chlamidophila (infections ABOVE the diaphragm) |
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SEs clindamycin?
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Hypersensitivity reactions
Skin rash in approximately 10% of patients Rare Stevens-Johnson Syndrome Diarrhea in up to 20% of patients Hepatotoxicity: minor, reversible elevation of transaminase enzymes Rare cases of reversible neutropenia, thrombocytopenia, agranulocytosis Candida superinfections (vaginitis, cervicitis) Clostridium difficile infections |
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common Se clindamycin?
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diarrhea (20%) b/c kill anaerobes in GI tract
rash (10%) candida superinfections clostridium difficile infections |
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Gram + aerobes clindamycin DOESN"T have activity against?
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clostridium difficile
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clindamycin interactinos??
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no significant drug drug, drug food or drug lab interactions
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clincal uses of clindamycin?
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Anaerobic bacterial infections involving B. fragilis and most other anaerobes, including intra-abdominal infections
Anaerobic bronchopulmonary infections, e.g. lung abscess Head/neck and dental infections Skin and soft tissue infections involving staphylococci and streptococci Particularly in children and PCN-allergic patients Many protozoal infections Pneumocystis jerovici (carinii), malaria, toxoplasmosis Surgical prophylaxis |
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structure/derivation of metronidazole?
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Azomycin (2-nitroimidazole) found to possess trichomonacidal properties in 1955
Further research led to synthesis of metronidazole, introduced in 1959 for the treatment of Trichomonas vaginalis Anaerobic activity noted in 1962, but clinical effectiveness not demonstrated until 1972 |
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MOA metronidazole?
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Reductive activation of metronidazole’s nitro group by pyruvate:ferridoxin oxidoreductase
Enzyme catalyzes oxidative decarboxylation of pyruvate Found exclusively in obligate anaerobic bacteria Generation of short-lived toxic intermediates and free radicals Interact with DNA, cause strand breaks and helix destabilization and unwinding Metronidazole is bactericidal |
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what enzyme does metronidazole act on?
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ferridoxin oxidoreductase
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what microbes utilize ferridoxin oxidoreductase?
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obligate anaerobes
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spectrum of activity metronidazole?
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Highly active against nearly all anaerobic Gram-negative bacteria
Bacteroides spp., Prevotella spp., Fusobacterium spp. Active against Clostridium spp. and most other anaerobic Gram-positive bacteria Some species resistant (e.g. Actinomyces, Propionibacterium, Lactobacillus), tend to be found primarily in the oropharynx “Clindamycin above the belt, metronidazole below the belt” Other bacteria: Helicobacter pylori, Gardnerella vaginalis Many protozoa very susceptible Trichomonas vaginalis, Entamoeba hystolytica, Giardia lamblia |
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what microbes does metronidazole work best against?
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nearly all anaerobic gram --
gram + anaerobe, clostridium |
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resistance to metronidazole
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extremely RARE
Resistance to metronidazole extremely rare among most anaerobes Chromosomal resistance among Actinomyces, Propionibacterium Mechanism = decreased pyruvate:ferredoxin oxidoreductase Resistance found in H. pylori due to decreased drug uptake |
