Antibiotics and Antibiotic Resistance Flashcards
Inhibit bacterial ribosomes (inhibit protein synthesis)
Tetracyclines and Chloramphenicol block tRNA binding
Erythromycin and clindamycin block translocation
Erythromycin and chloramphenicol block peptide bonds.
Tetracycline types
Tetracycline
Doxycycline
Oxytetracycline
Minocycline
Properties of Tetracyclines
Naturally occurring, broad spectrum, blocks protein synthesis (30S), bacteriostatic.
Forms complexes with divalent metals (e.g. calcium, magnesium, and iron) harms teeth and bones. Absorbs UV causing sunlight sensitivity and formation of free radicals to cause inflammatory response.
Advantage of Tetracyclines
Orally effective, favorable therapeutic index, broad spectrum, penetrates well in most tissues, penetration of human cells to target intracellular parasitic bacteria.
Disadvantages of tetracyclines
Emerging resistance
Side effects/toxicity.
Side Effects of Tetracyclines
Binding to bone and teeth: serious in pregnancy by discoloring teeth and blunting skeletal growth.
Photosensitivity to the sun
GI upsets
Vertigo
Hepatic and renal toxicity (rare with long course of therapy)
Emerging Resistance to Tetracyclines
Tet-induced transporter protein
Active Efflux.
Clinical Use of Tetracyclines
Safe alternative for beta-lacatam allergies.
Drug of choice for chlamydia/mycoplasma, rickettsial diseases (typhus, rocky mtn spotted fever, Q fever), lyme disease and relapsing Borrelia fevers.
Alternate clinical use of tetracyclines
Syphilis, mycoplasma, ligonella
Treat acne, bronchitis
Commonly used tetracyclines
Doxycycline
Minocycline
Chloramphenicol General Properties
Blocks protein synthesis (50s)
Extremely broad spectrum (aerobic/anaerobic gram (+ and -)
Bacteriostatic (few cidal)
Oral, IV; well absorbed, distributed
Chloramphenicol Side Effects
Bone marrow toxicity (fatal)
“Gray baby” syndrome (elimination)
Multiple Drug Interactions
Chloramphenicol Clinical Uses
Rarely used in US (previous wide use); common in developing countries.
Alternative to B-lactams for CNS
Many safer replacements.
Macrolides and Ketolides
Erythromycin - prototype
Azithromycin - Current usage
Clarithromycin - current usage
Ketolides (semi-synthetic derivatives of erythromycin)
Telithromycin (Ketek) newly approved 2004
Properties of Macrolides/ketolides
Spectrum: Gram + bacteria with Gram -
Blocks protein synthesis (50S ribosome)
Bacteriostatic
Old (erythromycin, E) acid sensitive
New (azithromycin, az) not acid sensitive
Distributes well in tissues (except CNS)
Resistance: Ribosomal methylation and efflux
Side Effects of Macrolides/Ketolides
Few; all relatively safe
Mild G.I. Upset
Erythromycin (E) and Telithromycin (T) interact w/ P450s. Interact w/ theophylline, warfarin, digoxin
Infrequent hepatotoxicity
Clinical Uses of Macrolides
Few advantages over B-lactams
Used often as alternative to penicillin allergic or uncertain allergic
Safe for children
Macrolides Use
Drug of Choice: mycoplasma infections, ligonella, bordetella pertussis, campylobacter jejuni, respiratory strep infections.
Syndromes: Bacterial bronchitis, otitis media, acne
Phrophylaxis: endocarditis, large bowel surgery, oral surgery
Ketolide Use
Developed for special uses: limited resistance, used for resistant gram + stains
Clindamycin (cleocin)
Spectrum: mostly gram + and limited gram -.
Action: blocks protein synthesis (50S binding)
Bacteriostatic
Oral (90% absorbed), IV, and IM
Clindamycin Side Effects
Risk of severe diarrhea, fatal colitis (rare)
Clindamycin Clinical Uses
Limited due to side effects
Topical treatments, acne
Substitute for macrolides (azrithromycin)
Peptide Antibioitics
Polymyxin B (aeorsporin)
Polymyxin E (colistin)
Bacitracin (generic)
Vancomycin (vancocin)
Polymyxin general properties
Charged decapeptides, cation detergents
Gram - bacteria
Act on membrane lipid PE causing membrane lysis
Batericidal
Polymyxin Side Effects
Serious nephrotoxicity, neurotoxicity
Polymyxins Clinical Use
Limited to topical application only (usually in combo with gram + topical)
Cutaneous pseudomonal infections of mucous membranes, eyes, ears.
Bacitracin General Properties
Mixture of polypeptides Block cell wall synthesis (different from B-lactams) Gram + bacteria Bactericidal NOT absorbed by GI tract
Bacitracin Side Effects
Serious Nephrotoxicity
Bacitracin Clinical Uses
Limited to topical application
Used often in combination with polymyxins to offer broad spectrum
Polymyxins = gram -
Bacitracin = gram +
Vancomycin General Properties
Glycopeptide Blocks cell wall synthesis Gram + bacteria Bactericidal IV and oral
Vancomycin Side Effects
Ototoxicity
Nephrotoxicity w/ aminoglycosides
Vancomycin Clinical Uses
Important alternative for resistant gram + strains
Drug of choice for methicillin-resistant S. Aureus (MRSA) and other (MR) strains
Limited but growing resistance
Most prevalent bacterial infection in the world
Mycobacterium tuberculosis exists in 1/3 of the world’s popultion
MTB is a subclass of gram - bugs with high fat outer membrane - not detected by gram stain.
Cell wall distinct from gram +/gram - and high in mycolic acid fatty lipids.
Characteristics of Mycobacteria
Slow growth (24 hr vs 20 minutes double time) Susceptible to develop drug resistance Chronic disease (many years)
Drug Treatment of Mycobacterium Tuberculosis
Isoniazid: blocks fatty acid synthase required for mycolic acid synthesis
Rifampicin: Directly inhibits bacterial RNA polymerase to block mRNA synthesis
Ethambutol: Blocks arabinosyl transferase (required for mycolic acid coupling)
Pyrazinamide: Blocks pyrazinamidase to cause acid build-up and cell death
Treatment of Mycobacterium Tuberculosis
Chronic combination multi-drug therapy is required to overcome resistance.
2 months: isoniazid + rifampicin, ethambutol and pyrazinamide
4 months: Isoniazid + rifampicin
Barriers to Successful treatment of Mycobacterium Tuberculosis
Complexicity (5 drugs/6 months)
Lack of compliance
Cost and Availability
Multiple Side effects (deters compliance)
Results: Emergence of drug-resistant strains
Example Drug-Resistant Bacteria
Methicillin-resistant Staphylococus aureus (MRSA)
Vancomycin-resistant enteroccous (VRE)
Fluoroquinolone-resistant Pseudomonas (FQRP)
Drug-resistant Tuberculosis (DRTB)
Cabapenem-resistant Bacteriaacae (CRE) - NEW!!
Common Mechanisms of Drug Resistance
Spontaneous mutation in target proteins.
Modification of antibiotic binding site on target
Natural enzymes that inactivate agents
Spontaneous changes in membrane permeability (cell wall thickening, upregulation of transporters)
Man-made contributions to resistance
Over-prescription Close quarters health care facilities Day Care Agriculture feedlots (environment) Foreign Exposure
New Techniques
Drugs bind ribosomes to fight resistant bacterial strains
Tigecycline, Quinupristin/Dalfopristin, and Linezolid
Trigecycline
Modified form of minocycline
Blocks protein synthesis at tRNA binding on 30S ribosome.
Bacteritstatic
Good for MRSA and vancomycin resistant strains.
Quinupristin/Dalfopristin
Semisynthetic Derivatives
Blocks protein synthesis at tRNA binding sites on 30S ribosomes (similar to macrolides)
Acts on gram + cocci
Good for MRSA and vancomycin resistant strains.
Linezolid
Oxazolidone Blocks protein synthesis at tRNA formation Bactericidal Minimal side effects Good for resistant strains
Daptomycin (cidectin, cubecin)
Natural cyclic lipopeptide
Membrane ionophore-depolarization
Broadly acting against gram +
Good for MRSA and VRE on the skin.
