Antiinfectives II

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Anti-infectives II

• Chloramphenicol
• Tetracyclines
• Macrolides
• Lincosamide
• Vancomycin
• Others

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Aminoglycosides forget already?
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Protein Inhibitors
Inhibitors of bacterial protein synthesis
Broad Spectrum
Moderate Spectrum
Narrow Spectrum
Macrolides
Chloramphenicol Tetracyclines
Lincosamides Streptogramins Linezolid
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Chloramphenicol

• Only drug in its class
• PO or IV/IM
• Crosses placental and blood-brain barriers
• Enterohepatic cycling
• Inactivated in liver by glucuronosyl transferase
• Wide spectrum of activity bacteriostatic
• H. influenzae N. meningitidis susceptible
• NOT active against chlamydia

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Chloramphenicol

• Clinical Uses
• Few uses as a systemic drug toxic!
• Severe salmonella infection (back-up)
• Meningitis (b-lactam sensitive patients)
• COMMON USE TOPICAL ANTIMICROBIAL!
• Toxicity
• Few uses as a systemic drug toxic!
• Severe salmonella infections (back-up)
• Meningitis (b-lactam sensitive patients)
• COMMON USE TOPICAL ANTIMICROBIAL!
• Gray baby syndrome (glucuronosyl transferase)
• Cyanosis and cardiovascular collapse!

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Chloramphenicol
Cloramphenicol Inhibits the enzyme peptidyl
transferase
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Chloramphenicol

• Warning Serious blood dyscrasias can occur
  including aplastic anemia leading to leukemia,
  thrombocytopenia, granulocytopenia. Blood
  studies must be conducted before use and
  thereafter during use.
• DO NOT use for trivial infections.
• Indications Serious infection in which other
  agents fail or infections caused by Salmonella
  spp, H. influenza, rickettsea, Bacteriodes
  fragalis.
• Drug of choice for S. typhi acute infections,
  cystic fibrosis regimens
• Monitor serum concentrations
• Renal and hepatic failure
• Used in otic and opthalmic preps
• Take with food if GI upset occurs

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Tetracyclines

• Obtained from Streptomyces and/or by synthetic
  modification
• Activity range and stability similar but not
  exact among all derivatives
• Stereochemically very complex 6 potential
  asymmetric centers
• Amphoteric compounds can behave as either acid
  or base
• Neutral solutions zwitterionic
• Acid solutions - very water soluble but can
  crystallize out of solution in the absence of
  excess acid
• Alkaline solutions lead to degradation
• HCl salts used in oral preps but are very bitter
  - encapsulated
• Epimerization and loss of stereochemistry at C4
  of the A ring (dimethylamino group) occurs very
  easily
• Loss of potency of solutions within about 1 day
• Capable of forming strong chelates with Al2,
  Ca2, Fe2 and Mg2
• Insoluble complexes that are not absorbed - do
  NOT take with milk, antacids that contain metal
  ions, ferric salt supplements (includes multiple
  vitamins) and bicarbonate (ionized therefore
  decreased absorption)
• Affinity for calcium in bone leads to teeth
  staining - important in children lt 8 years old,
  pregnant and breast feeding mothers

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Teeth Staining
Veneered Teeth (top) Stained Bottom
Teeth stained by Tetracyclines
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Tetracyclines

• MOA
• Bind 50s bacterial ribosomal subunit
• Prevents the binding of aminoacyl tRNA to the
  mRNA-ribosomal complex
• Leads to inhibition of bacterial protein
  synthesis
• Binds to mammalian 40s with much lower affinity
• Bacterial cells concentrate tetracyclines by
  active (requires Mg2 and ATP) and passive
  transport
• Resistance mechanisms
• P-glycoprotein (inducible)
• Ribosomal protection
• Inducible cytoplasmic protein protects ribosomes
• Enzymatic oxidation (deactivation)

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Tetracyclines
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Tetracyclines
Release of peptide
Termination
Tetracyclines also block binding of Release
Factor to the A-site
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Tetracyclines

• Spectrum of Activity broadest of any
  antibacterial
• Gram (), Gram (-) including spirochetes,
  mycoplasma, rickettsiae, chlamydiae
• Bacteriostatic A big disadvantage in
  life-threatening infections such as septicemia,
  endocarditis, menigitis,
• Incomplete absorption, enterohepatic
  recirculation and activity against GI bacteria
  lead to superinfections caused by Candida
  albicans (yeast)
• Gram () and Gram (-) organisms commonly
  resistant
• Staphylococcus aureus and Pseudomonas aeruginosa
  superinfections possible with long tern use
• Parenteral use in pregnant or renal failure
  patients results in liver damage

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Tetracyclines

• Clinical Uses Differ due to absorption,
  excretion, distribution
• DOC for
• Mycoplasma pneumoniae (adults) - bronchitis
• Chlamydia
• Rickettsia (Typhus, Rocky Mt. Spotted Fever,
  Ticks Lyme)
• Secondary uses
• Syphilis (Spirochetes)
• URI, LRI (susceptible organisms)
• Chronic bronchitis infection prophylaxis
• Acne
• Selective Uses
• Tetracycline GI ulcers (helicobacter pylori),
  severe acne
• Doxycycline Lyme disease, malaria, amebiasis
• Demeclocycline ADH (Anti-Diuretic Hormone)
  secreting tumors

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Tetracyclines

• Duration of action
• Short acting 6-8 hr. half-life
• Tetracycline, chlortetracycline, oxytetracycline
• Intermediate acting 12 hr. half-life
• Demeclocycline, methacycline
• Long acting 16-18 hr. half-life
• Near complete absorption, slow excretion
• Doxycycline, minocycline
• Allows once-a-day dosing!

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Tetracyclines

• Toxicity
• GI disturbance (mild diarrhea ? sever colitis)
• Bony structures/teeth enamel dysplasia
• Hepatic toxicity necrosis (high dose)
• Renal Toxicity
• May exacerbate existing conditions
• Photosensitivity - demeclocycline
• Vestibular toxicity
• Doxycycline minocycline

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Tetracyclines
Indications URI, UTI, Severe acne, CDC
recommended treatment for sexually transmitted
diseases, brucellosis, Rocky Mountain spotted
fever and other tick fevers including Lyme
disease, other susceptible infections,
topical-conjunctivitis Infections in which the
patient is sensitive (contraindicated) to
penicillins Oral, IV, IM or topical use - discard
parenteral solutions after 12 hours Concentrated
in the liver and renal and biliary excretion
largely unchanged, dosage adjustment needed in
hepatic and renal failure 65 protein bound, 60
excreted unchanged in the urine Best if taken on
a empty stomach with a full glass of water 1 hour
before or 2 hours AFTER meals Indications As
above for TCN, early Lyme disease, sexually
transmitted diseases Oral use only Worst of the
TCNs for photosensitivity 65 to 91 protein
bound, 39 excreted unchanged in the urine
Intermediate Acting
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Tetracyclines
Indications Same as for tetracycline HCl
(susceptible organisms) in UTI, URI, sexually
transmitted diseases and others 40 protein
bound, 70 excreted in the urine unchanged Lowest
lipid solubility of all the TCNs Oral or IM use
only
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Tetracyclines

• Structure Activity Relationships
• Most important are the 6-deoxy compounds
  doxycycline and minocycline
• Greatly increased partition coefficient leads to
  increased oral absorption acid and base
  stability
• Exhibit higher plasma protein binding, higher
  volume of distribution and lower renal clearance
• Minocycline experiences significant
  N-dealkylation by CYP450 enzymes which
  contributes to poor renal excretion and increases
  biliary excretion
• Minocycline seems to avoid resistance that occurs
  to other TCNs due to lower P-glycoprotein
  affinity!

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Acid Stability
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Compare Structures
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Tetracyclines
Indications Sensitive organisms in URI, UTI
including acute gonococcal infections (single
visit 300 mg immediately and 300 mg after 1
hour), syphilis, Chlamydia infections, prevention
of travelers diarrhea at 100 mg /day Oral and
IV use only, DO NOT use SC or IM Stability of
parenteral solutions is a function of diluent 80
to 95 protein bound, 42 excreted unchanged in
the urine with remaining excreted in the bile,
highest lipid solubility of the TCNs May be
taken with food or milk Indications Sensitive
organisms in URI, UTI including syphilis,
Chlamydia infections, sexually transmitted
diseases in patients in which penicillins are
contraindicated, Meningoccal carriers,
Mycobacterium infections 80 protein bound, 16
renally excreted unchanged with remaining
material excreted in the bile May be taken with
food or milk Parenteral solutions are stable at
room temp for 12 hours then discard
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Tetracyclines Topical ONLY
Indications Treatment of acne vulgaris MOA
largely unknown but is known to decrease
inflammation by decreasing the amount of free
fatty acids located in acne lesions - local
effect only Prolonged use can lead to significant
percutaneous absorption so use caution in renal
and hepatic failure External use only - keep out
of eyes, ears and nose
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Photosensitivity

• Some drugs induce photosensitivity in patients
• Doxycycline, minocycline, TMP/SMX, Quinolones
• What is photosensivity?
• What happens chemically?
• What happens physiologically?
• What can be done to protect us?
• Sunscreens
• How do they work?

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Our pal, the color wheel

• What color light is absorbed by something that
  appears blue-green?
• Hint red-orange complementary color
• Wavelength is inversely proportional to energy (E
  hc/l)

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Photon Absorption
Excitation by light causes an electron to move to
a higher energy state!
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Which molecules are most susceptible?

• Conjugated systems aromatic ring systems are
  most likely culprits
• Ring systems can cause the most potential
  damage!
• Why?
• Intercalation!

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Excitation
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Intercalating agents
Side View
Top view
DNA damaged can lead to mutations, cell death
oncogene activation!
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Guanine Reactivity
base labile lesion
O
frank scission
frank scission
- H-
- H
- e-
base labile lesion
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What can we do?

• Sunscreen!
• Absorbs harmful radiation
• UV light!
• PABA
• Silicates/Titanium oxides
• Inorganic compounds capable of absorbing STRONGLY
  in the UV radiation range (l 200 800 nm)

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Macrolides

• First isolated from the soil organism
  actinomycetes with 40 such compounds known to
  date
• Interest today focuses on semi-synthetic agents
• Superior pharmacokinetic properties - enhanced
  acid stability and improved distribution
• Similar chemical/structural characteristics
• A large lactone ring - macrolide with 12, 14 or
  16 members
• A ketone group
• A glycosidically linked amino sugar group used
  to make salts to improved solubility
• MOA Binds selectively to a specific site on the
  50S bacterial ribosomal subunit thereby
  preventing the translocation step of protein
  synthesis
• DOES NOT bind to mammalian ribosomes

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Macrolides
Macrolides prevent the translocation of peptidyl
tRNA from the acceptor site to donor site
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Macrolides

• Resistance mechanisms
• Gram (-) inability of the drug to penetrate cell
  walls
• Gram () Staphylococcus aureus
• Produces an enzyme that methylates a specific
  adenine residue on the 50S ribosomal subunit
• prevents erythromycin or lincomycin binding
• Toxicity
• GI irritation (common)
• Skin rashes
• Eosinophilia (granulocytic phagocyte)
• Inhibits CYP450 watch for drug level increases
• Anticoagulants!

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Macrolides

• Clinical Uses
• Similar to penicillns
• Gram() Gram(-)
• Erythromycin many types!
• Gram() pnemococci staphylococci (b-lactam
  resistant)
• Mycoplasma pneumoniae, Chlamydia, Legionella,
  Ureaplasma, Bordetella pertussis (whooping
  cough)
• Some strains of Hemophilus influenza and Brucella
• Azithromycin as erythromycins
• More active against Hemophilus influenza
• Long half-life (2-4 days)
• Single-dose treatment against Chlamydia
• 4-day course for community-acquired pneumonia
• Clarithromycin
• Treatment of mycobacterium avium (MAC HIV/AIDS)
• Ulcers caused by helicobacter pylori

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Macrolides

• Pharmacokinetics
• Good oral bioavailability
• Distribution to most body tissues
• Azithromycin
• 10 -100x higher conc. in tissues phagocytes
  than plasma
• Absorption impeded by food!
• Elimination
• Rapid 2-5 hours
• Erythromycin biliary excretion
• Clarithromycin hepatic metabolism followed by
  renal excretion
• Slow 2-4 days
• Azithromycin urinary excretion as unchanged
  drug

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Macrolides - Erythromycins
First isolated of the macrolides in 1952 from
Streptomyces erythreus Indications Susceptible
organisms that cause Respiratory infections,
skin and skin structure infections, whooping
cough, Diptheria, erythrasma, intestinal
amebiasis, uncomplicated urethral, endocervicval
or rectal infections, urogenital infections
during pregnancy, nongonococcal urethritis,
primary syphilis, Legionnaires disease,
rheumatic fever, bacterial endocarditis, Listeria
monocytogenes infections Oral use only, CYP3A4
inhibitor, liver excreted, crosses into mother
milk Topical products Erygel, Ake-mycin,
Emgel plus other opthalmic/otic products
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Macrolides - Erythromycins
Best absorbed, most side-effects stearate or
succinate may be preferred
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Macrolides - Erythromycins
Oral use only, prodrug ethylsuccinate ester
hydrolyzed in vivo, absorption is enhanced by
food, somewhat acid-labile
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Macrolides - Erythromycins
Oral use only, acid-labile so film coated tablets
to protect it from stomach acid
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Macrolides - Erythromycins
Injection use only, extremely water soluble and
intended for IV use to achieve high serum
concentrations during life-threatening infections
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Macrolides - Erythromycins
Injection use only, extremely water soluble and
intended for IV use to achieve high serum
concentrations during life-threatening infections
such as Legionnaires disease or when oral
administration of erythromycin is not possible,
solutions are stable for 1 week when refrigerated
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Macrolides
Indications Upper and lower respiratory
infections, mycobacterial infections,
Helicobacter pylori double or triple therapy,
greater potency against a number of organisms
when compared to base (erythromycin) Oral use
only, may be given with or without food, no
dosage adjustment in hepatic failure (is liver
metabolized) but with creatinine clearance of lt
30 dosage adjustment necessary, 70 protein
binding, CYP3A4 inhibitor Markedly improved acid
stability and oral bioavailability, reduced GI
side effects
TOP 200 Drug!
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Macrolides - Other
Indications COPD bacterial infections,
community-acquired pneumonia, genital ulcer
disease, PID, susceptible sexually transmitted
diseases including gonococcal and chlamydial
infection, URI, skin and skin structure
infections, New indication one-dose treatment
for pediatric otitis media IV and oral use only,
DO NOT administer as a bolus or IM Increased acid
stability, increased lipid solubility, food
decreases absorption by 50, 50 plasma protein
bound, largely excreted in the feces as unchanged
drug - extensive enterohepatic recirculation,
DOES NOT inhibit CYP enzymes
TOP 200 Drug!
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Macrolides - Other
Indications Acute bacterial exacerbations of
chronic bronchitis, secondary bacterial infection
of acute bronchitis, community-acquired
pneumonia, pharnygitis/tonsillitis caused by S.
pyogenes, uncomplicated skin and skin structure
infections Hemi-aminal prodrug that is
intestinally absorbed and hydrolyzed in the
plasma, Oral use only, Once a day dosing of 500
mg, administer with food or within 1 hour of
eating do NOT cut, chew or crush tablets due to
susceptibility to stomach acid fecal excretion
via the bile, does NOT inhibit CYP enzymes
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Macrolides - Other
Triacetate ester prodrug! Indications
Diplococcus pneumonia, S. pyogenes URI Oral use
only, Biliary excretion with 20 urinary
excretion, most potent inhibitor of CYP enzymes
among the macrolides May potentiate the
hepatotoxicity of OCs, anti-inflammatory
steroids, theophylline, carbamazepine - due to
epoxide ring acting as an alkylating agent??
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Macrolides - Other
Indications Community Acquired pneumonia
especially Streptococcus pneumonia and others
that are resistant to Erythromycins, acute
exacerbation of chronic bronchitis, acute
sinusitis, tonsilitis/pharyngitis due to Group A
beta-hemolytic streptococci MOA Mechanism of
action specifically designed to overcome
erythromycin resistance within gram-positive
cocci unique in this class! New in late 2001
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Macrolides - Telithromycin

• MOA Designed to overcome erythromycin
  resistance
• Inhibition of peptidyl transferase located on the
  50S subunit of the 30/50 ribosomal complex. This
  leads to inhibition of protein synthesis and
  eventually depletion of ribosomal subunit
  formation similar to Chloramphenicol
• The 3-keto group provides high stability in
  acidic environments and prevents development of
  both erm (methylation) and MLSB (mutation of the
  ribosomal protein) induced resistance
• The butyl imidazolylpyridinyl side chain
• Reduced impact of efflux mechanism of resistance
  (p-glycoprotein)
• Enhances Gram() activity
• Helps to govern intracellular accumulation and
  efflux in phagocytes
• Active against resistant strains of bacteria
  uneffected by erythromycin, azithromycin and
  clarithromycin

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Chloramphenicol
Cloramphenicol Inhibits the enzyme peptidyl
transferase
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Macrolides - Telithromycin

• Pharmacokinetics
• 70 serum protein bound, 90 absorbed orally and
  uneffected by presence or absence of food
• 60 systemic availability due to first pass
  effect metabolism in the liver and GI metabolism
• Excretion 7 biliary/fecal and 13 renal as
  unchanged drug, 37 hepatic metabolism with ½
  non-CYP450 and ½ CYP3A4 mediated
• Multiple elimination pathways limit problems with
  hepatic impaired or renal impaired patients
• Dosage 800 mg qd for 5-10 days (5 days
  typically)
• QT elongation Telithromycin has a macrolide
  structure which is known to have potential
  effects on cardiac repolarization

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Lincosamides
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Lincosamides
Indications Common Gram() infections, some
Gram(-). Very different from Erythromycin
structurally, similar activity. Interestingly,
Lincosamides and erythromycin antagonize each
other No longer in use due to extensive toxicity!
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Lincosamides
Indications Serious infections due to
susceptible strains of bacteria - reserve for use
with the penicillin-allergic patient or when
penicillins are inappropriate. Treatment of
anaerobic infections. Used with primaquine for
PCP (TMP/SMX alternative) Used w/aminoglycoside
or cephalosporin to treat penetrating
wounds. Oral or IV use, food does NOT affect
oral absorption Eliminated at gt90
hepatically Use clindamycin with caution in
renal/hepatic failure - monitor plasma
clindamycin levels DO NOT use for meningitis
does not cross BBB Patient info If diarrhea
occurs notify MD immediately, take each dose with
a full glass of water Cleocin-T topical
cream Cleocin vaginal cream

Also used for prophylaxis of endocarditis during
dental procedures in patients with heart valve
replacements
Can cause fatal colitis discontinue with
diarrhea!
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Bacterial Cell Wall
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Vancomycin

• Produced by Streptococcus orientalis in soil
• Primarily active against Gram() bacteria
• MIC lt 4mg/mL
• Poor oral absorption (IV preferred)
• Used to treat SERIOUS INFECTIONS ONLY!
• Less rapidly bacteriocidal than b-lactams
• Important for management of known
  penicillin-resistant pneumococcal
  staphylococcal infections!

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Vancomycin

• Mechanism of Action
• Inhibits cell wall synthesis
• Prevents synthesis of mucopeptide polymer
• Leads to cell lysis due to osmotic pressure
• Synthesis prevented by vancomycin binding (high
  affinity) to the D-alanine-D-alanine terminus of
  the uridine diphosphate-N-acetylmuramyl peptide
• Prevents crosslinking of peptidoglycan chains
• Inhibits peptidoglycan elongation

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Peptidoglycan Synthesis (Staphylococcus Aureus)
Traspeptidase
M N-acetylmuramic acid G N-acetylglucosamine
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Peptidoglycan Inhibition
1. Fosfomycin 2. Cycloserine 3. Bacitracin 4.
Vancomycin 5. b-Lactams
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Vancomycin Resistance

• Mechanism of Vancomycin Resistance
• Five types VanA, VanB, VanC, VanD and VanE
• Vancomycin induces transcription of genes ?
  Resistance
• controlled via a sensory kinase and response
  regulator
• Transcribed genes translated into altered
  enzymes which are responsible for the synthesis
  of the terminus of the peptidoglycan which will
  be cross linked
• No longer the D-alanine-D-alanine terminus
• VanA, VanB and VanD mutations -
  D-alanine-D-lactate terminus
• VanC and VanE mutations - D-alanine-D-serine
  terminus
• Mutations prevent vancomycin bindinding

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Compare to an Aminoglycoside
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Vancomycin tricyclic glycopeptide
Indications Serious or severe infections not
treatable with other antibiotics including
penicillins and cephalosporins - severe
Staphylococcal, Streptococcal, Diphtheroid
endocarditits, bone infections, skin, repiratory
tract or septicemia Orally it can be given for
bacterial enterocolitis or Pseudomembranous
colitis caused by Clostridium difficili Vancomycin
not active against Gram (-) organisms with the
exception of Neisseria spp. Dosage should be
reduced in renal failure based on creatinine
clearance, 55 protein bound, 15 excreted in the
bile and 75 excreted in the urine by glomerular
filtration
Side effects Hypersensitivity Chills, fever,
rash, extreme flushing (Red-man syndrome)
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Vancomycin Alternatives

• A Streptogramin derivative - polypeptide
  macrocycle

30 70
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Vancomycin Alternatives
Quinupristin/Dolfopristin - Synercid

• Indications Severe vancomycin resistant
  Enterococcus faecium faecalis, complicated skin
  and skin structure infections caused by
  Staphyloccoccus aureus and Streptococcus
  pyogenes. Resistant strains of S. Pneumoniae
• Gram () Cocci
• Fast track approval drug, IV use only, no dosage
  adjustment in renal failure
• 15 renal excretion, use caution in hepatic
  insufficiency, 75 fecal excretion as glutathione
  conjugate, DO NOT dilute with saline containing
  mixtures or other drugs - use D5W (5 Dextrose in
  water) as a diluent
• Inhibitor of CYP3A4 though not metabolized by
  CYP
• MOA Inhibition of both the early and late
  phase of protein synthesis by acting at the
  bacterial ribosome
• Toxicity Infusion related pain (site of
  injection)

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Vancomycin Alternatives
First new structural class of drug to appear in
over 20 years Oxalodinones Upjohn Pharmacia
Indications Severe vancomycin resistant
Enterococcus faecium, complicated skin and skin
structure infections caused by Staphyloccoccus
aureus and Streptococcus pyogenes, nosocomial
pneumonia, community-acquired pneumonia. Other
multiply resistant organisms. MOA Binds unique
site on the 23S bacterial ribosomal RNA of the
50S subunit prevents formation of the 70S
complex responsible for protein synthesis. No
cross-resistance! Oral or IV use, IV use a
separate line, 100 bioavailable orally, 31
protein bound, hepatic metabolism with no CYP
induction, renal excretion of metabolites Patient
info can be taken with or without food, advise
MD if a history of HT do not eat foods high in
tyramine - this drug inhibits MAO, inform MD if
taking pseudoephdrine, phenylpropanolamine or
other decongestants, SSRI, other
antidepressants One case of resistance was
reported shortly after release!
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Other Polypeptide Antibiotics

• Very large peptide chemical structures
• Mainly IV or injectable drugs
• Colistimathane Sodium Coly-Mycin-C
• Indications SERIOUS Gram (-) infections due to
  susceptible strains
• IV or IM
• MOA ???
• Adjust dosage in renal dysfunction
• Polymycin B Sulfate generic only (Polymyxin)
• Indications Bactericidal against most Gram(-)
  bacilli except the Proteus group
• IM/IV intrathecal, ophthalmic/otic use
• IM or intrathecally done only in a hospital
  setting where a MD is available to monitor the
  patient possible neuro and renal toxicity
• MOA increase membrane permeability of bacterial
  cell walls leading to a bactericidal action
• Adjust dosage based on renal function

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Other Polypeptide Antibiotics

• Bacitracin Bac-IM, TopicalBaciguent
• Indications Topical IM treatment of Gram ()
• Limit IM to treatment of infants with pneumonia
  and empyema (puss accumulation) caused by
  susceptible staphylococci
• IM ? renal failure due to tubular and glomerular
  necrosis
• Keep patient hydrated with high urinary output
  (toxicity)
• Monitor renal function prior to treatment daily
  during
• MOA Inhibits cell wall formation
• Interferes with dephosphorylation cycling of the
  lipid carrier that transports peptidoglycan units
  to the growing cell wall
• No cross-resistance with other antimicrobials!

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Peptidoglycan Inhibition
1. Fosfomycin 2. Cycloserine 3. Bacitracin 4.
Vancomycin 5. b-Lactams
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Other Antibiotics
Indications reserve for use in infections not
responding or Contraindicated for other agents S.
aureus or Proteus sp. particularly UTI (Gram
()) MOA interferes with bacterial cell wall
synthesis - bacteriostatic 90 protein bound,
monitor hepatic function and hematologic studies
-discontinue if abnormalities such as jaundice
and/or bleeding
Given in combination therapy too toxic! No
current indications for use.
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Other Antibiotics
Avoid unnecessary use - carcinogenic!!!! Indicatio
ns Anaerobic infections, intra-abdominal
infections, skin and skin structure infections,
gynecological infections, septicemia, CNS
infections, lower respiratory tract infections,
endocarditis, prophylaxis for colorectal surgery,
hepatic coma, Crohns disease, pseudo colitis,
Heliobacter pylori CDC recommended for bacterial
vaginosis (single 2 gram dose), giardiasis
Reduce dosage based on hepatic function, renally
excrete metabolites, avoid alcohol, may cause
metallic taste MOA Binds DNA and prevents
replication Vaginal gel Metro-Gel, Topical use
products also
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Misc. Topical Antibiotics

• Indications Impetigo caused by Staph and Strep
  organisms
• Caused by direct inoculation of group A
  streptococci or Staphylococcus aureus into
  superficial cutaneous abrasions or compromised
  skin.
• It is most commonly seen in children, usually
  located on the face, especially about the nose
  and mouth.
• MOA inhibits the bacterial enzyme isoleucyl
  transfer-RNA synthase

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Misc. Anti-infectives Disinfectants
Indications Cyanide and nitrate poisoning,
urinary tract calculi, genitourinary
antiseptic Bacteriostatic agent Converts
methemoglobin back into hemoglobin Urine and
stool will be a metallic blue-green
color Indications Uncomplicated UTI MOA
Bacteriocidal, inactivates the enzyme
enolpyruvyl transferase Prevents first step of
bacterial cell wall synthesis, reduces adherence
of bacteria to uroepithelial cells Always take
this with water
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Peptidoglycan Inhibition
1. Fosfomycin 2. Cycloserine 3. Bacitracin 4.
Vancomycin 5. b-Lactams
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Sepsis Drugs

• XigrisTM Drotrecogin alfa (activated)-Eli Lilly
• Activated form of Protein C - Recombinant protein
• Human cell culture fermentation
• Glycosylated Serine protease identical to a serum
  produced natural product
• Mechanism of action
• Antithrombotic effect inhibits Factor Va and
  VIIIa
• Indirect profibrinolytic effect inhibits
  plasminogen activator inhibitor-1 (PAI-1)
• Anti-inflammatory effect inhibits inhibits
  tumor necrosis factor, blocks leukocyte adhesion

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Sepsis Drugs

• XigrisTM Drotrecogin alfa (activated)-Eli Lilly
  
• IV infusion for a 96 hour period in a dedicated
  line
• Drug interactions are UNKNOWN at this time
• Contraindications any bleeding including
  stroke, cranial or spinal surgery, head trauma
• Bleeding is the most serious side effect - effect
  prolonged in sepsis patients beyond the normal 2
  hour half-life
• NO known antidote in overdose - immediately stop
  infusion
• How does in infection that lead to sepsis produce
  irreversible organ damage?

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