Glycoside Antibiotics

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Glycoside Antibiotics
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Aminoglycosides
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Aminoglycosides
Neomycin 1949 Streptomyces fradiae
Streptomycin 1944 Streptomyces griseus
Gentamicin 1963 Micromonospora purpurea
Kanamycin 1957 Streptomyces kanamyceticus
Tobramycin 1971 Streptomyces tenebrarius
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Mechanism of Action
Bind irreversibly to 30S ribosomal
subunit Distort the A site, causing
codon-anticodon mismatching BACTERICIDAL with a
long post-antibiotic effect Exact lethal
mechanism is not known Electron micrographs
reveal changes in cell wall Treated cells leak
intracellular contents Treated cells are
permeabilized for entry of small
molecules Transported into bacteria by an
energy-dependent accumulation
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Spectrum of Action
Some activity against Gram-positive cocci Good
activity against Gram-negative aerobic
bacteria including Pseudomonas aeruginosa Have
become an important part of therapy regimes if
Pseudomonas is suspected Poor activity
against Gram-negative anaerobes (no transport)
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Uses of Aminoglycosides
Used for serious infections where no other less
toxic drug is available Serious Gram-negative
rod infections Severe pneumonias (e.g.
multi-resistant Klebsiella) Gram-negative
endocarditis Immunocompromised
patients Complicated UTI Suspected
Gram-negative septicaemia Often used in
combination with b-lactams due to synergy
(Enterococcal infections) Pre-operative bowel
sterilization (neomycin metronidazole or
doxycycline) Tuberculosis (streptomycin,
kanamycin or amikacin)
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Side Effects of Aminoglycosides
Allergic reactions (rash, erythema, urticaria,
decreased blood pressure) Nephrotoxicity,
usually mild and reversible impairment of renal
function in 8-26 of patients dose-related
modern studies indicate single high dose may be
better than multiple lower doses Ototoxicity
overall incidence 25, irreversible loss of
hearing AGs enter cells of inner ear damage the
hair cells of the Organ of Corti (auditory branch
of 8th cranial nerve) hearing loss damage
hair cells of Crista Ampullaris (vestibular
branch of 8th cranial nerve) headache,
vertigo, ataxia Auditory damage most often
associated with netilmycinlttobramycinlt
gentamicinlt amikacin Vestibular damage
associated with streptomycin and gentamicin
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Side Effects of Aminoglycosides
Aminoglycoside-induced ototoxicity appears to
have a genetic predisposition in some
individuals A1555G mutation in the mitochondrial
12S ribosomal RNA gene has been shown to be
responsible for this susceptibility in all
familial cases
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Acetylation of Aminoglycosides
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Adenylation of Aminoglycosides
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Phosphorylation of Aminoglycosides
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Resistance to Aminoglycosides
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Resistance to Aminoglycosides
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Structure of Aminoglycoside Kinase (APH(3)-IIIa)
The AG binding site (shown with neomycin) has
similar hydrogen bonding interactions to those
found in the AG binding site on the
ribosome. The van der Waals (hydrophobic)
contacts are different.
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Biosynthesis of Aminoglycosides
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Glycopeptides
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Glycopeptides
Teicoplanin 1986 Actinoplanes teichomyceticus
Vancomycin 1956 Streptomyces orientalis
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Mechanism of Action
Inhibit cell wall biosynthesis by binding to
D-alanyl-D-alanine, preventing incorporation of
precursors into the murein strands. BACTERIOSTATIC
or slowly BACTERICIDAL
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Vancomycin Binding to D-Ala-D-Ala
H N
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Spectrum of Action of Glycopeptides
Gram-positive bacteria only (Not
mycobacteria) Includes methicillin-resistant
staphylococci Vancomycin became the last resort
drug for treatment of MRS in the
1990s Bacteriostatic against enterococci when
used alone Synergistic with aminoglycosides (not
enterococci)
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Adverse Effects of Glycopeptides
Allergic reactions fever, chills, rash, erythema
(Red Man Syndrome), hypotension Ototoxicity
dose dependent (avoided with lt30mg/L) Nephrotoxic
ity (0 7 of patients) Both ototoxicity and
nephrotoxicity are associated with combined use
of Ags Side effects less common with teicoplanin
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Uses of Glycopeptides
Infections due to MRS (pneumonia, endocarditis,
osteomyelitis, soft- tissue abscesses) Severe
staphylococcal infections in beta-lactam allergic
patients Infections in patients being dialyzed
(vancomycin is not cleared by dialysis) Enteroco
ccal infections (decreasing due to
resistance) Antibiotic-induced colitis
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Resistance to Glycopeptides
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Intrinsic Enzyme-mediated Resistance
Many lactobacilli are intrinsically resistant to
vancomycin. They have cell wall
precursors that contain D-alanyl-D-lactate. One
hydrogen bond is missing
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Intrinsic Enzyme-mediated Resistance -2
Sensor
Enzyme-mediated resistance appeared in the
enterococci They have also have cell wall
precursors that contain D-alanyl-D-lactate. There
are several enzymes that destroy the D-Ala-D-Ala
precursor. Induced by the presence of
vancomycin Gene set now present in S. aureus
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Glycopeptide Insensitive Stapylococci
MIC values in the range 4-16 mg/L high enough
to cause problems with clinical
efficacy Obtained through massive thickening of
the cell wall
The additional vancomycin binding sites are
sufficient to prevent the antibiotic from
reaching the cell surface
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Biosynthesis of Glycopeptides
Cross-linking and specific modifications
intoduced by associated enzymes in biosynthetic
cluster
Assembly of peptide backbone by peptide synthase.
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New Glycopeptides
Oritavancin
Status phase III SSTI trial completed. Long
half-life (gt140 h) Overcomes established
resistance in Gram-positive bacteria. Active
against VRSA, elevated MICs against GISA.
Dalbavancin
Status phase III. Overcomes established
resistance in Gram-positive bacteria. Active
against VRSA and GISA (MIC90 2 mg/L).
Telavancin
Status phase III. Overcomes established
resistance in Gram-positive bacteria. Active
against VRSA and GISA (MIC90 2 mg/L).
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Macrolides
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Macrolides14-membered Lactone Ring
Azithromycin 1987
Erythromycin 1951 Actinomyces erythreus
Oleandomycin Streptomyces antibioticus
Telithromycin 2003
Clarithromycin 1988
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Macrolides 16-Membered Lactone Ring
Streptomyces fradiae
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Mechanism of Action
Inhibition of protein synthesis
BACTERIOSTATIC Bind to the 50S
subunit bind to 23S rRNA hairpin 35 in domain
II and peptidyltransferase loop in domain V
Constitutes the polypeptide exit channel of the
peptidyltransferase centre
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Spectrum of Activity
Gram-positive bacteria staphylococci,
streptococci, Corynebacterium
(Erythromycin) Mycobacterium
(Clarithromycin) Gram-negative bacteria
Haemophilus, Legionella, Moraxella,
Bordetella Campylobacter Neisseria Pasteu
rella (Clarithromycin) Anaerobes Bacteroides
(Azithromycin, Clarithromycin) Peptostreptococc
us Clostridium perfringens Propionibacterium
acnes Intra-cellular pathogens Chlamydia,
Mycoplasma Spirochaetes Treponema, Borrelia
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Uses of Macrolides
Respiratory tract infections Mycoplasma
pneumoniae (Erythromycin 1st choice) Chlamydia
trachomatis, C. pneumoniae Whooping cough
(Bordetella) Legionairres Disease (Legionella
pheumophila) Diptheria (Corynebacterium
diptheriae) Penicllin-susceptible Gram-positive
infections (as alternative to PCN) when oral
treatement is indicated for community-acquired
infections
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Adverse Effects of Macrolides
GI disturbance (anorexia, cramps,
diarrhea) Occassional sensitization Hepatotxicit
y impairment in 2-4, may be due to
metabolite cholecystitis jaundice (allergic
reaction) Drug interactions macrolides are
inhibitors of CyP450 (3A4, 1A2) may interact
with warfarin, phenytoin, theophylline,
cyclosporin 1 fatal case attributed to drug
interaction recently created significant
publicity Telithromycin had trouble during
development because of fears over hERG channel
inhbition
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Resistance to Macrolides
Gram-negative bacteria efflux systems and
restricted inlux Acr systems MFS specific
transporters (8 in E. coli) Gram-positive
bacteria efflux systems (mef ABC
transporters) Nucleotide-dependent (msr,
efflux?) methylation system (erm) mutation
of rRNA
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Resistance to Macrolides
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Biosynthesis of Macrolides
Carried out on multi-modular polyketide
synthases. Operate on the same principle as
fatty acid synthase
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Lincosamides
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Lincosamides
Lincomycin Actinomyces roseolus
Clindamycin
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Mechanism of Action Spectrum
Inhibition of protein biosynthesis BACTERIOSTATI
C Bind to 50S ribosome subunit Binding site
spans the peptidyl transferase centre Overlaps
with chloramphenicol and macrolide binding
sites Competes with chloramphenicol And
macrolides
Active against most Gram-positive pathogens (but
not enterococci) and anaerobes, especially
Bacteroides fragilis
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Adverse Effects of Lincosamides
Few serious side effects Diarrhea progressing to
pseudomembranous colitis 20-50 of patients
receiving licomycin 2-20 of patients
receiving clindamycin Results from secondary
(super)infection by Clostridium difficile, which
produce mucotoxin (types A and B) The potent
activity against anaerobes (Bacteroides) clears
the gut of its normal flora and opens the field
for C. difficile
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Single Member Classes
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Oxazolidinone
Zyvox Linezolid Introduced 2000,
discovered 1980s
Mechanism inhibition of protein biosynthesis,
BACTERIOSTATIC Resistance first cases reported
point mutation in 23S rRNA. Indications
Vancomycin-Resistant E. faecium infections,
Nosocomial pneumonia caused by S. aureus
(inc. MRSA)), or Streptococcus pneumoniae
(not PenR). Complicated SSTI caused by
Staphylococcus aureus (inc. MRSA),
Streptococcus pyogenes, or Streptococcus
agalactiae. Community-acquired pneumonia
caused by S. pneumoniae (not PenR) or S.
aureus (not MRSA). Side effects diarrhoea,
headache, nausea. Neuropathy (peripheral, optic)
and thrombocytopenia, especially in
patients with longer courses of therapy.

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Daptomycin
Mechanism impairs integrity of cytoplasmic
membrane, resulting in ion loss
bactericidal Resistance rare clinical
resistance observed in trials and in practice.
Mechanism unknown Indication SSTI,
osteomyelitis. Not approved for pneumonia. Side
effects reversible myopathy of skeletal muscle,
monitoring of CPK may be necessary.
Little clinical experience (approved September,
2003)
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Ramoplanin
Mechanism inhibition of cell wall
biosynthesis, BACTERICIDAL Resistance
not known Status phase III for eradication of
vancomycin-resistant enterococci from the
gastro-intestinal tract phase II trial for the
treatment of Clostridium difficile-associated
diarrhea Side effects not known