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156 Cards in this Set

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Examples of Eukaryotic Cells:
algae, fungi, protozoa, plants, animals
Examples of Prokaryotic Cells:
bacteria, blue green algae(cyanobacteria)
is a virus eukaryote or prokaryote?
neither, not a living thing
typical size of euk. cell?
2-100 microns diameter
typical size of prok. cell?
0.5=2 microns diameter
avg. size of E. coli?
1 x 2 microns
what does the small size of prok. cells allow for?
small prok. cells allow for INTRACELLULAR bacteria b/c much smaller than euk. cells
describe organism nomenclature techniques
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
4 major classifications of bacteria
aerobic
anaerobic
gram +
gram -
electron transfer in AEROBIC prok. metabolism?
O2 --> H2O

Oxygen dependent
electron transfer in ANAEROBIC prok. metabolism?
NO3 --> N2
SO4 --> H2S
CO2 -->CH4

Not O2 dependent
defn. "Obligate" an/aerobic
obligate anerobe must live under anaerobic conditions or it will die if put in aerobic environment (opposite for obligate aerobe)
defn. "facultative" anaerobe
preferes anaerobic environments, but CAN live if exposed to aerobic environment
2 main parts of prok. cell structure
cell envelope

cell wall
components of cell envelope
plasma membrane
cell wall
features of cell wall
composed primarily of peptidoglycans

provides structural stability and shape to the cell
benefit of unusual D-amino acids in bacterial cell walls?
specificity for antibiotics
features of gram + cell walls
THICK cell wall
no outer membrane
features of gram - cell walls
THIN cell wall
inner (cytoplasmic) and outer (external) membrane
bacterial capsule
a thick poly-saccharide layer that forms a viscous gel outside the cell envelope in some bacteria
peptidoglycan structure
linear
polysaccharide chains are cross linked by short peptides
prok. slime layer?
Some organisms lack a well-defined capsule but have a loose, amorphous slime layer outside the cell envelope
what are capsules and slime layers composed of?
Capsules and slime layers are generally composed of polysaccharides, but may also contain amino sugars, peptides, and DNA
examples of encapsulated bacteria?
Streptococcus pneumoniae (G+)

Haemophilus influenzae (G-)

Moraxella catarrhalis (G-)
what is the periplasmic space?
space b/w the inner and outer membrane in Gram - bacteria
Fxn of capsules and slime
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
how does S. pneumoniae inhibit phagocytosis?
Streptococcus pneumoniae synthesizes a polysaccharide capsule that prevents ingestion by alveolar macrophages
how does B. anthracis inhibit phagocytosis?
Bacillus anthracis synthesizes a poly-D-glutamate capsule that prevents damage by macrophage lysosomal enzymes
what is a biofilm?
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
what do Quorum sensors do?
“Quorum sensor” molecules secreted by the bacteria induce a number of genes that result in cellular aggregation and biofilm formation
How is Dental Plaque an example of a biofilm?
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
how is cystic fibrosis an example of a biofilm?
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
what are flagella?
flexible, corkscrew-shaped protein filament that is used for locomotion
what are pili?
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
what is cytoplasm?
• Cytosol, a gel-like aqueous
phase containing enzymes,
metabolites, amino acids,
nucleotides, RNA, inorganic ions, etc.

• Insoluble, suspended
particles (e.g., ribosomes,
polysomes)
do prok. cells have nuclei?
NO, DNA is free floating, no nuclear membrane
what is nucleoid?
• Double-stranded DNA genome
• Genome not separated from cytoplasm by a nuclear membrane as in mammalian cells
Desc. E. coli genome
• 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
features of prok. genome under microscope?
• Electron-transparent nuclear region (n)

• Dense distribution of ribosomal particles in the cytoplasm

• Absence of intracellular membranous organelles
what does DNA gyrase do?
help supercoil and densely pack genetic material/DNA
what are bacterial plasmids?
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
Desc. bacterial pathogenesis?
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
pathogenesis of bacteria that do not penetrate body tissues (vibrio, bordatella, bacillus)
(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
Adherence
microbial attachment to host cells, the first step in killing cells and toxic delivery (provides tropism)
tropism
very specific in terms of what bacteria attach to, mediated through adhesins(which bind to specific cell receptors)
what are exotoxins?
Exotoxins = protein toxins released from viable bacteria
features of exotoxins
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
what are virulence enhancing enzymes?
promote tissue dysfunctions/destruction

ex: coagulase, catalase
groups of exotoxins
(know)
neurotoxins

cytotoxins

enterotoxins (GI tract)
endotoxins
toxic lipopolysaccharide components of the outer membrane of Gram-negative bacteria

***Gram - only
features of endotoxins
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
biologic activity of endotoxin
Biologic activity of endotoxin:
Pyrogenicity
Leukopenia followed by leukocytosis
Complement activation
Hypotension
Hypothermia
what can endotoxin events lead to?
sepsis/lethal shock
when does bacterial lysis occur?
after death of cell, or during replication
Mechs of bacterial pathogenesis
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)
pathogenesis of Rickettsiae?
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
pathogenesis of Chlamydophila?
Chlamydophila spp. are small, obligate intracelluar parasites

C. trachomatis: urethritis
C. pneumoniae: pneumonia
normal flora of the body: how many cells?
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
normal flora of the body: what type of cells are they?
Normal flora are predominantly anaerobic bacteria, but aerobic bacteria also common as well as some yeasts
microbes on skin
Staphylococcus epidermidis, S. aureus
Propionobacterium acnes
microbes on nose/nasopharynx
S. epidermidis, S. aureus
H. influenzae
microbes in mouth and tooth surfaces
S. aureus, S. epidermidis,
Streptococcus mitis,& alpha-hemolytic strep
Haemophilus Influenzae,
Lactobacilus, Bacteroides fragilis, Fusobacterium nucleatum,
C. Albicans
microbes in large intestine
Escherichia coli, Klebsiella spp., Proteus spp.
B. fragilis, F. nucleatum,
Enterococcus,
Candida. albicans
microbes in vagina and uterin cervix
Bacteroides spp., Clostridium spp.
S. epidermidis,
C. albicans, Trichomonas vaginalis
functions of normal flora
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:
How do normal flora provide protection against potentially pathogenic organisms:
“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)
KNOW Bacterial Identification Chart (See IOS 10 Quiz 1 notecards)
bacterial chart from bacterial ID lecture:
Classify shapes, gram +/-, an/aerobic, etc.
Guidelines for Specimen Collection
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
How long for specimen collection results?
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
Reasons for Failing to successfully ID a pathogen?
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
what percent of culture results are positive/useful?
50%
functions of normal flora
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:
How do normal flora provide protection against potentially pathogenic organisms:
“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)
Bacterial Identification Chart
KNOW
See IOS 10 Quiz #1 notecards
know how to classify shapes, an/aerobic, gram +/-, etc.
guidelines to specimen collection
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
how long do specimen results take?
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
Reasons for failing to successfully ID a pathogen
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
what percent of specimen results are positive/useful?
50%
why is it important to obtain specimen collecction before initiating/changing antibiotics?
to get a higher yield and better results,
if already exposed to antimicrobial, numbers will be suppressed and results may not come back positive
defn cocci
sphere like
defn bacilli
rod shape
defn spirilla
spiral
defn strepto
chain
defn diplo
pair
defn staph
cluster
which microbe shows up as diplococcus gram +?
Streptococcus pneumoniae
what is example of coccobacillus?
gram - haemophilus
chemical strructure of macrolides: erythromycin
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
what is the decosamine part of macrolides used for?
PK parameters
what is the cladinose part of macrolides used for?
antimicrobial activity
ALSO, resistance inducer
what are the problems with erythromycin?
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
what is the half life of erythromycin in the stomach pH 2)
9.3 seconds
what are the complications caused by hemiketal and ketal products of erythromycin
poor tolerability after oral administration

ketal rxn product is inactive, and may be hepatotoxic
list the methods used to improve oral bioavailability of erythromycin
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%
how does enteric coating improve F of erythromycin
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
MOA macrolides
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
KNOW!!!
What is the main MOA of the macrolides???
"Block protein synthesis at the 50s ribosomal subunit"
Mechs. of resistance for macrolides
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
what are the 2 most important/relevant mechs of resistance for macrolides?
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
which main mech of macrolide resistance is Relative resistance?
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
which mech of macrolide resistance is Absolute resistance?
Methylation of adenine residues in 23S subunit of 50S ribosome causes profound alteration in drug binding
S. aureus, S. pneumoniae, Enterococcus
PK of erythromycin
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
PK of clarithromycin
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)
PK azithromycin
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
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
what are the main types of microbes macrolides are active against?
Gram + (staph, strep)
NOT MRSA, NOT enterococcus

Atypicals--traditional drugs of choice
side effects of macrolides
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
most common SE macrolides
GI: ab. pain, N/V, diarrhea
what is a relative CI for macrolides?
pregnancy b/c risk of hepatotoxicity
what causes macrolide drug drug interactions?
b/c macrolides inhibit hepatic CYP 450 metabolism
esp CYP 3A4
list some drugs that interact with erythromycin (3A4)
Alfentanil, buspirone, carbamazepine, clomipramine + respiradone, clozapine, cyclosporine, digoxin, disopyamide, felodipine, lovastatin, methylprednisolone, midazolam, phenytoin, tacrolimus, theophylline, trazolam, valproate, warfarin
list some drugs that interact with clarithromycin (3A4)
Carbamazepine, cyclosporine, digoxin, rifampin, rifabutin, ritonavir, zidovudine
drugs that interact with azithromycin
cyclosporine
azithro is the lowest drug interactino risk for macrolides, but still need to monitor for potential interactions
clinical uses of macrolides
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
why were the ketolides developed?
Need for new antibiotics in respiratory tract infections (RTIs)
what caused need for new antibiotics in respiratory tract infections
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
azithromycin was drug of choice for RTI, what is its percent resistance?
28.8%
what were ketolides SPECIFICALLY developed for?
to overcome problems of S. pneumoniae resistance macrolides and other antibiotics
what is the difference b/w macrolides and ketolides?
ketolides DO NOT have a cladinose sugar, which is responsible for resistance in macrolides
MOA ketolides
Mechanism similar to that of macrolides
Inhibition of peptidyl transferase activity & protein synthesis
what is the difference b/w macrolides and ketolides in the ribosomal binding of their MOA?
macrolides bind to only one place on ribosome (domain v)

ketolides bind 2 places on the ribosome (domain II and V)
what is the only ketolide available in the US?
telithromycin
how does telithromycin overcome macroliode (Erm b) resistance?
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)
what is the %susceptibility for telithromycin for S. pneumoniae?
99.8%
what is the % susceptibility for azithromycin for S. penuemoniae?
70.7%
ketolide resistance???
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
mech of ketolide resistance?
Resistance related to alterations in telithromycin-binding sites
Either chromosomal point mutations or ribosomal methylation

possibly by efflux
telithromycin PK
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
what is telithromycins effect on CYP enzyme?
strong inhibitor of CYP 3A4
SE of ketolides(telithromycin)
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%
what is a BAD side effect of telithromycin that limits its use?
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
what drugs should be avoided with telithromycin?
Simvastatin, atorvastatin, lovastatin (increase AUC 890%)

Rifampin (decrease TEL AUC 86%)
why should simvastatin (lovastatin, atorvastatin) be avoided with telithromycin?>
statin AUC incrases 890%
why should rifampin be avoided with telithromycin?
rifampin is CYP inducer and decreases the conc. of telithro A LOT
clincal uses for telithromycin
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
structure of clindamycin??
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)
MOA clindamycin?
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
resitance to clindamycin?
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)
what is themost common mech of clindamycin reistance?
chromosomal alteration of single AA residue at the receptor site of the 50S ribosome
what is absolute resistance mech for clindamycin?
Plasmid-mediated resistance involving alteration in the 23S ribosomal RNA of the 50S ribosomal subunit by methylation of adenine residue at the receptor site
PK clindamycin?
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
what can clindamycin be used to treat that many ABs cant?
bone infections (60-80% serum conc.)
spectrum of activity for clindamycin?
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
most common microbes clindamycin treats?
gram + (some MRSA)
anaerobes
chlamidophila

(infections ABOVE the diaphragm)
SEs clindamycin?
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
common Se clindamycin?
diarrhea (20%) b/c kill anaerobes in GI tract
rash (10%)
candida superinfections
clostridium difficile infections
Gram + aerobes clindamycin DOESN"T have activity against?
clostridium difficile
clindamycin interactinos??
no significant drug drug, drug food or drug lab interactions
clincal uses of clindamycin?
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
structure/derivation of metronidazole?
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
MOA metronidazole?
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
what enzyme does metronidazole act on?
ferridoxin oxidoreductase
what microbes utilize ferridoxin oxidoreductase?
obligate anaerobes
spectrum of activity metronidazole?
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
what microbes does metronidazole work best against?
nearly all anaerobic gram --

gram + anaerobe, clostridium
resistance to metronidazole
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