Antibacterial Drugs Flashcards
What are the targets for selective toxicity?
- Cell wall synthesis (Inhibitors of cell wall synthesis)
- Membrane integrity
- Protein synthesis (IPS)
- Nucleic acid synthesis
- Nucleic acid integrity
Beta-lactam antibiotics and vancomycin block
Enzymatic steps outside of the cell or in the periplasmic space
Other ICWS inhibitors act at IC sites
Penicillins
Very selective toxicity (extremely high chemotherapeutic index)
Bactericidal in growing, proliferating cells
Primarily used for gram (+)
Penicillin MOA
- Covalent binding to transpeptidases/penicillin binding proteins
- Inhibition of transpeptidation reaction (Cross-linking of cell wall)
- Activation of murein hydrolases (autolysins)
Penicillin Pharmacokinetics: Absorption
- Many penicillins are acid-sensitive but can be still given orally
- Parenteral penicillins: IV, IM (depo)
- Benzathine penicillin: IM, insoluble, time release, compliance issues
Penicillin Distribution
- Penicillins do not get across the blood-brain barrier, eye, ocular fluid, prostate
- Meningitis may facilitate crossing blood-brain barrier
Penicillin Excretion
- Penicillins excreted by tubular secretion (actively secreted by Organic Acid Secretory System, blocking this with Probenecid extends half-life)
- Exceptions: Nafcillin secreted in bile, Oxa- and Cloxa- in urine and bile
- Penicillins are rapidly cleared (1/2 life 30-60 min)
Time above minimal bacterial concentration (MBC)
relates to efficacy
Cell wall synthesis inhibitors (Penicillin, Cephalosporins, and Vancomycin) exhibit
Time-Dependent Killing (concentration independent). Need extended half life to work effectively.
Pen G and Pen V are primarily useful against
Gram (+)
Staph became rapidly resistant to anti-staphylococcal penicillins b/c
The target of anti-staphylococcal penicillins is beta lactamase (which rapidly mutated)
Anti-staphylococcal penicillins
Nafcillin, Methicillin, Isoxazoyl penicillins (ox-, clox-)
Beta-lactamase resistant
Extended Spectrum penicillins
Ampicillin, Amoxicillin, Ticarcillin, Piperacillin, Mezlocillin
Developed to increase gram (-) activity (broader spectrum)
Can get through lipid membrane
Anti-pseudomonal penicillins
Exclusively for pseudomonal infections!
Adverse effects of penicillins
Ampicillin rash
Hypersensitivity reaction
Resistance to Penicillins
- No cell wall, no activation of murein hydrolases, metabolically inactive
- Inaccessible PBPs
- gram (-)
- Methicillin-resistant Staph. aureus (MRSA) - Beta-lactamase production
- Major mechanism of resistance
- Plasma mediated
- Use beta-lactamase resistant penicillin (Nafcillin, Oxacillin, Cloxacillin)
- Co-administer Beta-lactamase inhibitor (Clauvanic acid, Sulbactam, Tazobactam)
Problems associated with Penicillin use/overuse
Sensitization
Selection for resistant strains (90% of staph are resistant)
Superinfections by resistant organisms (esp. proteus, pseudomonas, serratia, fungi)
Cephalosporins
Structure and function similar to penicillins Less sensitive to beta-lactamases Broader spectrum of activity Poor oral absorption Renal toxicity Cross-reactivity with penicillin More expensive than penicillin Secondary to ICWS: If a penicillin would work, use it
1st generation cephalosporins
only effective against (+) bacteria
Subsequent generation cephalosporins
Greater gram (-) activity
Some with less gram (+) activity (2nd generation)
Less beta-lactamase sensitivity
Cephalosporin resistant (especially 4th generation, Cefepime)
Decreased toxicity
Better distribution to CNS
1st Generation Cephalosporins
Narrow spectrum
Cefazolin
Cephalexin (o)
2nd Generation Cephalosporins
Intermediate spectrum
Cefuroxime (o)
Cefotetan
Ceflacor (o)
3rd Generation Cephalosporins
Broad spectrum
Cefotaxime, Ceftriaxone, Ceftazidime, Cefpoxodime (o)
4th Generation Cephalosporins
Broad spectrum
Cefepime
Cephalosporine adverse effects
Local irritation from injection
Renal toxicity (enhanced by aminoglycosides)
Cefotetan and Cefoperazone can cause Disulfram Effect (Bleeding and platelet disorders, administer vitamin K)
Hypersensitivity: cross-reactivity with penicillin
Monobactum: Aztreonam
Gram (-) activity; inactive against Gram (+) or anaerobes
Beta-lactamase resistant
Crosses blood-brain barrier
No cross-reactivity with penicillin
Carbanepems: :Imipenem
Broad spectrum: Gram (+) and Gram (-) anaerobes
Beta-Lactamase resistant
Pseudomonas develops resistance rapidly, use with aminoglycosides
IV only
Cross blood-brain barrier
Inactivated by renal dipeptidase so co-administer Cilastatin
Low cross-reactivity with penicillin
Meropenem
Dipeptidase-resistant carbapenem
Vancomycin
Inhibits transglycosylation (step before transpeptidation)
Bactericidal for gram +IV for systemic use, oral for C difficile
Systemic: MRSA (synergistic with aminoglycosides)
IV drug cleared through kidney: enhances oto and renal toxicity of aminoglycosides
Red man or neck syndrome: histamine release
Misuse/overuse is problem
Vacomycin-dependent Enterococci
Fosfomycin
Newest ICWS; Gram (+) and (-)
- Inhibits cytoplasmic step in cell wall precursor synthesis
- Active uptake by G6P-transporter
- Oral and parenteral
- Active drug excreted by kidney
- Single dose approved for UTI
- Synergistic with Beta-lactams, aminoglycosides, or fluoroquinolones
Bacitracin
Markedly nephrotoxic Topical antibiotic (OTC only)
Membrane-active drugs: Polymixins
Polymixin B and Polymixin E (Colistin)
Basic peptides (detergents)
Active against gram (-) except Proteus and Neisseria
Topical use due to systemic toxicity (renal)
Salvage therapy for highly resistant strains of Acinetobacter, Pseudomonas, and Enterobacteriae
