Tetracyclines/Aminoglycosides/Macrolides/Misc.

Question 1

Tetracyclines

Answer 1

• Doxycline
• Minocycline

Question 2

Tetracyclines MOA

Answer 2

• Bacteriostatic, reversibly binds 30 S subunit of bacterial ribosomes, block protein synthesis
• Blocks binding of amino-acyl tRNA
• Passibe diffusion thru outer cell wall
• Drugs actively transported thru bacterial cytoplasmic membrane

Question 3

Tetracyclines Pharmacokinetics

Answer 3

• Incomplete PO

*antacids/dairy products decrease PO absorption

• Wide distribution; some CNS (25%), fetus and milk/nursing (50-60%)
• Excreted primarily unchanged in the urine, accumulates in renal failure

Question 4

Doxycycline Pharmacokinetics

Answer 4

• PO almost complete
• Most widely used tetracyline, long t1/2 (16-18hrs), usually once/day or BID administration
• Excreted mostly by nonrenal mechanisms, via bile > feces as inactive conjugate or chelate, the only tetracycline that does not accumulate in renal insufficiency

Question 5

Doxycline Use

Answer 5

• Activity against Chlamydia trachomatis, anthrax, cholera, Lyme disease, Rocky Mountain Spotted fever (Rickettisiae)
• Doxycycline + Cephalosporin against anaerobic bacteria

Question 6

Minocycline Pharmacokinetics

Answer 6

• Most lipid soluble tetracycline, 100% PO
• Longest t1/2 (16-18hrs.)
• Undergoes significant metabolism, mostly excretion of metabolites in urine and feces
• Especially effective in treatment of acne due to increased penetration of skin

Question 7

Tetracyclines Spectrum

Answer 7

• Gm (+): susceptible species of staph/strep, however other drugs preferred due to bacteriostatic action/increased resistance (altered binding to 30S ribosomal site and inc. efflux of drug)

- B. burgdorferi (Lyme disease)

- Helicobacter pylori (GI ulcers)

- Main indications: Rickettsiae, mycoplasma pneumonia, Chlamydia trachomatis, V. cholera

• Not effective against resistant Gonococci

Question 8

Tetracycline Adverse Effects

Answer 8

• Phototoxicity - reactions in skine exposed to sunlight, esp. demeclocycline>doxycycline
• Skeletel effects - chelates teeth and bones during calcification
• Contraindications: not to be used in children (<8yrs) or during pregnancy
• Hepatotoxicity - esp. in pregnancy

Question 9

Aminoglycosides MOA

Answer 9

• Bacteriocidal, irreversible binding to 30S (and some 50S) to inhibit protein synthesis

*blocks initiation of synthesis

*blocks further translate and elicits premature termination

*incorporation of incorrect amino acid

• Diffuses thru porin channels

*so used for gm (-)

• Most common resistance due to production of microbial enzymes, acetylases, phosphorylases, adenylases; also impaired entry into bacterial cell and altered binding receptor protein on ribosome unit

Question 10

Aminoglycosides

Answer 10

• Gentamicin/Tobramycin
• Netilmicin/Amikacin
• Streptomycin
• Toxicity both time and conc. dependent

Question 11

Aminoglycosides Pharmacokinetics

Answer 11

• Poor PO
• Little if any CNS penetration, high conc. in renal cortex; why they are extremely nephrotoxic
• Post-antibiotic effect that allows for large once/day dosing

*residual cidal effect that last longer tha MIC in plasma

• Must adjust dosage in renal dysfunction proportional to creatinine clearance

Question 12

Aminoglycosides Spectrum

Answer 12

• Gm (+): limited, Staph> Strep; increased resistance, not used alone; used in combo w/Pens/Cephs for serious staph, strep, enterococcal infections>bacteriocidal synergism
• Aerobic gm (-) is primary indication, the big guns, indicated for serious infections. Affects almost all gm(-). Adm w/3rd/4th gen. Pens for Pseudomonas

Question 13

Streptomycin Use

Answer 13

• Generally used in combo w/other drugs; deep IM injections
• W/a Penicillin for enterococcal endocarditis
• Tuberculosis, esp. w/multi-resistant strains, in initial therapy, IM adm

Question 14

Gentamicin/Tobramycin Use

Answer 14

• Gentamicin- most widely used systemic aminoglycoside; less expensive; active against Serratia species and better than Tobramycin when used in combination w/a Penicillin against enterococci; however, streptomycin is preferred w/Pen

- Tobramycin 2-4X more potent against Pseudomonas than Gentamicin; however, it is less effective against enterococci and ineffective against mycobacteria

Question 15

Netilmicin/Amikacin Use

Answer 15

• Netilmicin more resistant to microbial enzymes, used in Gentamicin resistance, otherwise it is comparable to these drugs
• Amikacin exhibits the greatest resistance; used in Gentamicin and Tobramycin resistance; Amikacin less vulnerable to microbial enzymes b/c of protective side chain
• Expensive

Question 16

Aminoglycosides Toxicity

Answer 16

• Ototoxicity- degeneration 8th nerve, contraindicated in pregnancy
• Nephrotoxicity- inc BUN, preteinuria, inc serum creatinine, inabilti to conc. urine, adjust dose to creatinine clearance

Question 17

Aminoglycoside-like Drug

Answer 17

• Spectinomycin

Question 18

Spectinomycin Use

Answer 18

• Structurally related to aminoglycosides
• Only used as alternative to treat gonorrhea in patients allergic to Pens/Cephs or where gonococci are resistant to other drugs (i.e., Fluoroquinolones)
• May also be used during pregnancy

Question 19

Macrolides

Answer 19

• Semi-synthetic derivative: azithromycin, clarithromycin

- Erythromycin

- Clindamycin

Question 20

Macrolides MOA

Answer 20

• Alternate to Pen/Cephs when theres an allergy
• Bacterial resistance when developed to one macrolide becomes common to other macrolides (i.e., alteration of binding site, methylation in gm (+) bacteria 50S ribosome site)

Question 21

Erythromycin MOA

Answer 21

• Macrolide
• Primarily bacteriostatic, binds 50S of bacterial ribosomes, inhibits protein synthesis
• Resistance- change in ribosomal binding site (primary), inc. hydrolysis, dec. drug uptake/efflux pump
• Decomposed by gastric HCL to irritant

Question 22

Erythromycin Spectrum

Answer 22

• Gm (+): alternative to Pens/Cephs for strep and pneumococcal minor throat/ear infections
• GM (-): Legionella pneumophila, Mycoplasma pneumonia, Genital infections: Chlamydia, syphilis, gonorrhea

Question 23

Clarithromycin Use

Answer 23

• Macrolide
• Increased gm (-) activity over other for Leg. pneumophila, C. trachomatis, Mycobacterium avium complex (AIDS); Helicobacter pylori, Borrelia burdorferi

- Inhibits hepatic drug metabolizing enzymes

Question 24

Azithromycin MOA

Answer 24

• Macrolide

- Less GI irritation

• Gm(+) strept activity = ERY; alternates to B-lactams for pharyngitis, sinusitis, community-acquired pneumonia
• Increased gm(-) H. influenzae, N. gonorrhoeae, Chlamyida
• Long t1/2 (2-3days)

Question 25

Clindamycin Spectrum

Answer 25

• Gm(+) and anaerobes, Bacteroides/Clostridium, but not C.difficile

Question 26

Clindamycin Use

Answer 26

• Main use: gm(+) strep and staph infections (e.g., bacterial endocarditis)

Question 27

Clindamycin Adverse Effects

Answer 27

• GI/diarrhea, superinfections, esp. pseudomembranous colitis due to overgrowth of Clostridium difficile within GI tract

Question 28

Linezolid Use

Answer 28

• Blocks early stage of protein synthesis, binds ribosomal RNA of 50S subunit
• Indicated for MRSA, Vancomycin resistant Enterococcus faecium/E. faecalis (VREF), bacteriostatic

Question 29

Chloramphenicol MOA

Answer 29

• Bacteriostatic, binds 50S, inhibits protein synthesis

Question 30

Chloramphenicol Spectrum

Answer 30

• Broad spectrum: gm(+), gm(-), anaerobes

Question 31

Chloramphenicol Adverse Effects

Answer 31

• Good PO, wide dist./CNS, metabolism glucuronidation (usu deficient in infants) “Gray baby syndrome”: depressed breath, CV collapse, cyanosis, abdominal distension, loose green stools, related to inhibition of mitochondria (70S)

- Inhibits CYP450 enzymes, drug interactions

- Bone marrow suppression

- Aplastic anemia; increased risk of leukemia in those who develop this and recover