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Part I
Antimicrobial Chemotherapy
• Be relatively inexpensive
Principles / Definitions
• Spectrum of Activity:
Narrow spectrum - drug is effective against a limited
number of species
• Bacteriostatic
• Bactericidal
• Time dependent killing
• Concentration dependent killing
Principles / Definitions
Altered permeability
Inactivation / destruction of antibiotic
Altered binding site
Novel (new) binding sites
Efflux (pumps) mechanisms
Bypass of metabolic pathways
Antimicrobial Chemotherapy
part II
Synthesis of peptidoglycan
Action of penicillins and
cephalosporines
Action of vancomycin
from Assembling the Peptide Cross-Links in Peptidoglycan
Action of Tetracyclins
Action of macrolids
Action of Aminoglycosides
Action of Aminoglycosides
Amphotercin B - colistin -
Imidazolen - Nystatin -
polymyxins
sulfonamides
sulfonamides
Action of bacterial enzyme
• Without the antibiotic binding to a bacterial
enzyme, the activate site of the enzyme is
able to react with its substrate.
Action of antibiotics on enzyme
• When an antibiotic binds to a bacterial
enzyme, it may alter the activate site of the
enzyme and prevent it from reacting with its
substrate.
Action of oxazolidones
• The oxazolidinones (linezolid) bind to the
50S ribosomal subunit and interfere with its
binding to the initiation complex.
Initiation Complex
Bacterial resistance
• Genetic mutations
• Acquiring resistance from other bacteria
through:
conjugation
Transformation
Transduction
trosposons
• 1. producing enzymes:
• Penicillinase
• Acetylase
• Adenylase
• Phosphorylase
• Chloramphenicol acetyl transferase
• 2. changes in permeability:
• Polymyxines
• Tetracyclins
3.Change in receptors of drug
• PBPs
• 30 S subunite of ribosome
• 50 S subunite of rifosome
• 4. change in metabolisme
• use of folic acid instead of PABA
Antibiotic Classes
• B-lactams
- penicillins / cephalosporins /
- cephamycins / carbapenems
• Glycopeptides
- vancomycin / teicoplanin
- gram positive agents
Structure of -lactam drugs
Penicillins
• Penicillin G / V
- good gram positive (not Staph)
-moderate anaerobic activity
• Anti-staphylococcal penicillins
- Cloxacillin
• Anti-pseudomonal penicillins
- Piperacillin
Cell Wall Active Agents
UDP-L-ala-D-glu-L-lys-D-ala-D-ala
--L-ala-D-glu-L-lys--D-ala-D-ala
pentapeptide--
vancomycin
Cell Wall Active Agents
• B-lactam resistance
1. Production of a B-lactamase (most common)
2. Altered PBP (S.pneumoniae)
3. Novel PBP (MRSA)
4. Altered permeability
• Glycopeptide resistance
- primary concern is Enterococcus / S.aureus
- altered target
- bacteria substitutes D-lac for D-ala
- vancomycin can no longer bind
Cephalosporins
• History
– Discovered in sewage in Sardinia in the
mid 1940s.
– Cephalosporium sp was recovered and
proved a source of cephalosporin.
– Subsequently, four generations of
cephalosporins have emerged.
Cephalosporins
– Activity includes:
• Methicillin susceptible staphylococci
• Streptococci excluding enterococci
• E. coli, Klebsiella sp., and P. mirabilis
• Many anaerobes excluding B. fragilis
Where do you think they should be
used?
• Cefuroxime • Cefoxitin/cefotetan
– Think Haemophilus in – 1st generation plus-
addition to 1st anaerobes
generation specturm – A mixed, non-serious
– A respiratory drug infection surgeon drug
– Think cefazolin/metro
which is what we
would use
Third-Generation Cephalosporins
• Cefotaxime, ceftriaxone (IV)
• Ceftazidime (IV)
– Active against P. aeruginosa.
– Decreased activity against gram positive cocci.
Fourth generation cephalosporins
• Cefepime
– Marginal improvements
– Not available at the QE II
Carbapenems:
What don’t they get?
• Everything except:
• S. aureus
• H. influenzae
• Neisseria sp.
• Bacteroides fragilis
• E. coli and Klebsiella
Lincosamides (clindamycin)
- gram positive, anaerobic activity
• Resistance
Primarily due to aminoglycoside modifying enzymes
Inhibitors of nucleic acid synthesis
• Resistance
- altered permeability (porin channels)
- altered target site
- efflux
Inhibitors of metabolic pathways