Antibiotics and Antibiotic Resistance Flashcards by Jacob Farris

Inhibit bacterial ribosomes (inhibit protein synthesis)

Tetracyclines and Chloramphenicol block tRNA binding
Erythromycin and clindamycin block translocation
Erythromycin and chloramphenicol block peptide bonds.

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Tetracycline types

Tetracycline
Doxycycline
Oxytetracycline
Minocycline

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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.

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Advantage of Tetracyclines

Orally effective, favorable therapeutic index, broad spectrum, penetrates well in most tissues, penetration of human cells to target intracellular parasitic bacteria.

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Disadvantages of tetracyclines

Emerging resistance

Side effects/toxicity.

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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)

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Emerging Resistance to Tetracyclines

Tet-induced transporter protein

Active Efflux.

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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.

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Alternate clinical use of tetracyclines

Syphilis, mycoplasma, ligonella

Treat acne, bronchitis

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Commonly used tetracyclines

Doxycycline

Minocycline

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Chloramphenicol General Properties

Blocks protein synthesis (50s)
Extremely broad spectrum (aerobic/anaerobic gram (+ and -)
Bacteriostatic (few cidal)
Oral, IV; well absorbed, distributed

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Chloramphenicol Side Effects

Bone marrow toxicity (fatal)
“Gray baby” syndrome (elimination)
Multiple Drug Interactions

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Chloramphenicol Clinical Uses

Rarely used in US (previous wide use); common in developing countries.
Alternative to B-lactams for CNS
Many safer replacements.

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Macrolides and Ketolides

Erythromycin - prototype
Azithromycin - Current usage
Clarithromycin - current usage
Ketolides (semi-synthetic derivatives of erythromycin)
Telithromycin (Ketek) newly approved 2004

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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

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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

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Clinical Uses of Macrolides

Few advantages over B-lactams
Used often as alternative to penicillin allergic or uncertain allergic
Safe for children

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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

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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.