Antibiotics 2

Front 1

Tetracycline MOA

Back 1

• MOA: Inhibit bacterial protein synthesis by reversibly binding to 30S ribosome (inhibit tRNA attached to the A-site)
• Bacteriostatic
• Broad-spectrum: Against G(+), G(-), anaerobes, rickettsiae, clamydia, vibrio sp., mycoplasma, spirochetesand some protozoa

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Tetracycline MOR

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• Mechanisms of resistance; Ribosome protection (modification); Increased efflux (active transport pump); Impaired influx; Enzymatic inactivation
• Tetracycline-resistant strains may be susceptible to doxycycline, minocycline & tigecycline (poor substrates for the efflux pump that mediate drug resistance)

Front 3

Tetracycline pharmacokinetics and clinical application

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Drug Absorption (oral administration): Doxycycline & minocycline 95-100% absorbed; Factors affecting oral absorption: Food (except for doxycycline & minocycline); Divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; Dairy products & antacid; alkaline pH; Poor oral absorption; IV only; don’t take with food
Drug Distribution:
• Distributed widely to tissues and body fluids (except cerebrospinal fluid)
• Cross the placenta to reach the fetus and are excreted in milk (chelate with calcium Þ bound to and damage growing bones and teeth)
• Inactivated and Metabolized in liver (toxicity higher with liver dysfunction
• Eliminated mainly in urine (except for doxycycline & tigecyclin)
• Good compared to doxy and mino b/c they are long acting (16-18), once daily dosage; tetracycline half life is 36 hours.
• Doxycycline is the preferred oral (once dailydosing possible and absorption not affected by food) and IV agent
• Used to treat acne

Front 4

Tetracycline adverse reactions

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1. GI effects: nausea and vomiting; pseudomembranous colitis (rare but severe); do not use milk or antacids to counter symptoms
2. Damage on teeth and bones (when given to pregnant women or children of young ages): discoloration in the fetal teeth; deformity or growth inhibition of bones
3. liver toxicity
4. kidney toxicity
5. local tissue toxicity: venous thrombosis (IV)
6. photosensitization
7. vestibular reactions: dizziness, vertigo, nausea

Front 5

Aminoglycosides MOA

Back 5

• MOA: Inhibit bacterial protein synthesis by irreversibly binding to 30S ribosome and cause codon misreading of mRNA
• Bactericidal
• Active against G(-) and G(+) bacteria (not anaerobes)
• Rapid ‘concentration-dependent killing’ and great ‘post-antibiotic effect’ (once daily dosage)
• Eliminated by kidney (long t1/2 in renal cortex)

Front 6

Clinical uses for aminoglycosides

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Clinical Uses
• Often combined with a b-lactam antibiotic
for the treatment of serious infections or
infective endocarditis caused by enterococci
(e.g., with penicillin) = SYNERGISTIC EFFECT
Toxicity:
• Significant toxicity (> 5 days of use)
• Ototoxicity (irreversible)
• Nephrotoxicity (reversible)
*** Monitoring serum conc. is essential
“VERY TESTABLE SLIDE”

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Describe briefly the aminoglycosides

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• Streptomycin: Mainly used as a 2nd line agent to treat tuberculosis
• Neomycin: Not safe for systemic use (extremely nephrotoxic); IV is not good; Only used topically or orally
• Kanamycin & paromomycin: Closely related to neomycin, but less toxic; Kana is oral
• Amikacin: Similar to kanamycin, but less toxic; Treat bacteria that are resistant to other aminoglycosides or tuberculosis (2nd line agent)
• Gentamicin: Most often used aminoglycoside
• Tobramycin: Used interchangeaby with gentamicin; Treat infections caused by Pseudomonas aeruginosa
• Netilmicin: Active against some bacteria that are resistant to gentamicin or tobramycin
• Spectinomycin (not really an aminoglycoside): Structurally related to aminoglycosides; Used IM solely to treat drug-resistant gonorrhea in pts who are allergic to penicillin

Front 8

Aminoglycosides MOR

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 Plasmid-encoded aminoglycoside-modifying enzyme (enzymatic modification)
 Altered ribosoma binding sites

Front 9

Macrolides MOA

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MOA: Characterized by the presence of a large macrocyclic lactone ring (macrolide ring) to which deoxy sugars (cladinose or desosamine) are attached
• MOA: Bind to and inhibit 50S ribosomal subunit (inhibit translocation process)
• Effective against G(+) organisms
• Bacteriostatic or bactericidal (at high conc.)
MOR: Active efflux or ¯ cell permeability
• Hydrolyzed by esterases
• Modification of the ribosomal binding site (‘ribosomal protection’)
o Chromosomal mutation
o by inducible or constitutive methylase*
*Constitutive methylase production also confers resistance to clindamycin and streptogramin B (i.e., macrolide-lincosamide-streptogramin resistance, or MLS-type B resistance)

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Macrolide Pharmacokinetics

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 Erythromycin was obtained from Streptomyces erythreus
 Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin
 Erythromycin is destroyed by stomach acid (must be administered with enteric coating)
 Clarithromycin and azithromycin are more stable in stomach acid and are better absorbed
 t1/2:
 Erythromycin: 1.5 hr
 Clarithromycin: 6 hrs
 Azithromycin : 2-4 days (once daily dosing)
Pharmacokinetics: take with empty stomach
 Erythromycin & clarithromycin both inhibit liver cytochrome p450 enzymes (may ­ serum conc. Of theophylline. oral anti-coagulants, cyclosporin, carbamazepine & methylprednisolone)

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Clinical uses of erythromycin

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 The drug of choice for
• Corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma)
• Respiratory, neonatal, ocular, or genital chlamydial infections
• Community-acquired pneumonia (CAP)
• Staphylococcal infections in penicillin-allergic p’ts

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Erythormycin adverse reactions

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GI intolerance (direct stimulation of gut motility)
 Liver toxicity
• Acute cholestatic hepatitis (fever, jaundice, pruritus)

Front 13

Ketolides (Telithromycin)

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• Semisynthetic 14-membered-ring macrolides (differ from erythromycin by substitution of a 3-keto group for the neutral sugar 1-cladinose)
• Many macrolide-resistant pathogens are susceptible to ketolides (once daily dosing)
• Inhibits p450 enzymes ****
• Indicated for treatment of respiratory infections
• Side effects: GI toxicity & severe liver failure

Front 14

MOA and MOR Clindamycin

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MOA: A derivative of lincomycin (belong to lincosamide)
• MOA: Inhibits bacterial protein synthesis by binding to the 23S rRNA* of the 50S subunit
• Broad spectrum (esp active against anaerobes)
MOR: Mutation of the ribosomal site; Modification of the binding site by a constitutively expressed methylase (MLS-type B resistance); Enzymatic inactivation

Front 15

Clinical uses of clindamycin

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• Treat infection caused by bacteroids and other
anaerobes associated with mixed infections
• Recommended for prophylaxis of endocarditis
in p’ts with valvular heart disease who are
undergoing dental procedures
 Major adverse effect Increased risk for diarrhea & colitis due to Clostridium difficile

Front 16

Cloramphenicol MOA and MOR

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• MOA: Binds to 50S ribosome (inhibits the peptidyltransferase reaction)
• Bacteriostatic (broad-spectrum)
o Active against aerobic & anaerobic G(+) & G(-)
• Inactivated in the liver (via conjugation) & excreted in urine
o Dosage adjustment is needed in p’ts with hepatic failure
• Inhibit liver p450 enzymes (potential drug interactions)
• Mechanisms of resistant
o ¯ drug permeable
o Production of plasmid-encoded chloramphenicol acetyltransferase

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Cloramphenicol clinical uses and side effects

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• Used topically in the treatment of eye infections (excellent tissue penetration)
• Alternative agent for treating meningitis in p’ts who are allergic to penicillin
 Major side effects
• Aplastic anemia (irreversible)
• Grey baby syndrome: Newborns lack an effective glucuronic acid conjugation mechanism for the degradation of chloramphenicol; drug accumulation causing hypotension, cyanosis and death.

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Steptogramins MOA

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• Bactericidal
• Quinupristin-dalfopristin (IV)
• Streptogramin B + streptogramin A (30:70)
• MOA: Binds to 50S ribosomal subunit
• Bactericidal
• Active against G(+) cocci (including vancomycin-resistant staphylococci (VRSA) and Enterococcal faecium (VRE)
• Inhibits CYP3A4* enzyme (drug interactions)
• * CYP34A metabolizes warfarin, diazepam, nonnucleoside reverse transcriptase inhibitors and cyclosporine

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Streptomgramins MOR

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 Mechanisms of resistance
• Modification of the quinupristin binding site by a methylase (MLS-B type)
• Enzymatic inactivation of dalfopristin
• Efflux
 Toxicity
• Infusion-related pain & arthralgiamyalgia syndrome (muscle pain)

Front 20

Linezolid MOA and major side effect

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• MOA: inhibits protein synthesis by binding to the 23S rRNA of the 50S subunit (blocks the initiation step of the protein synthesis)
• Bacteriostatic
• Active against many G(+) organisms
• Should be reserved for treatment of infections caused by multidrug-resistant G(+) bacteria (e.g., MRSA)
• Major side effect: hematologic toxicity

Front 21

Time-Dependent Bactericidal Activity

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• Rate and extent of bacterial killing does not increase with increasing drug concentration
• Clinical Goal : Maximize drug exposure (ie, time serum level remains above MIC); 45%-50% of time above minimum inhibitory concentration appears to be adequate for treatment efficacy

Front 22

Concentration-Dependent Bactericidal Activity

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• Rate and extent of bactericidal action increase with increasing drug concentration
-Maximum effect ~10 MIC
• Clinical Goal: Achieve peak or maximum concentration/MIC ratio of >10