Pharmacology I - Anti-Infective (Protein Synthesis) PDF

Pharmacology I Anti-infective (Interfere with Protein Synthesis) Dr. Sana’ AL Aqqad Ph.D. in Clinical Pharmacy & Therapeutics [email protected]  Classification of antibiotics: ❑Antibiotics that Target the Cell wall:...

Pharmacology I Anti-infective (Interfere with Protein Synthesis) Dr. Sana’ AL Aqqad Ph.D. in Clinical Pharmacy & Therapeutics [email protected]  Classification of antibiotics: ❑Antibiotics that Target the Cell wall: ❑Antibiotics that Block Protein ▪ B-Lactam Antibiotics***** Production: ▪ Glycopeptides: Teicoplanin* & ▪ Rifamycins vancomycin* ▪ Aminoglycosides** (gentamycin) ▪ Colistin ▪ Macrolides** (Azithromycin) ▪ Ketolides ▪ Tetracyclines and Glycylcyclines ❑Antibiotics that Target DNA and ▪ Chloramphenicol Replication: ▪ Clindamycin* ▪ Sulfa Drugs ▪ Streptogramins ▪ Quinolones: ciprofloxacin*, ▪ Linezolid levofloxacin* ▪ Nitrofurantoin ▪ Metronidazole** (Flagel)®  Macrolides Macrolide antibiotics follow the old adage: “jack of all trades, master of none’’ ❑ Target ribosomes→ bind to 50S→ suppress protein synthesis & bacterial growth ❑ Active against: some gram+ve/-ve some atypical bacteria some mycobacteria Some spirochetes. But → Not reliably effective against most bacteria in any one group.  Effective against some staphylococci and streptococci & atypical bacteria Not active against: ✓ methicillin-resistant staphylococci (MRSA) ✓ penicillin-resistant streptococci ✓ Enterococci & Enterobacteriaciae (E.Coli, klebsiella) ✓ anaerobic. Most aerobic GM-ve bacilli are resistant But some Neisseria, Bordetella pertussis, Moraxella catarralis, and Haemophilus strains are susceptible. Treat: pharyngitis, otitis media, sinusitis, tonsititis, and bronchitis, especially in PCN-allergic patients. Treat/ part of treat→ atypical pneumonia, usually caused by organisms like Mycoplasma pneumoniae, Legionella pneumonia ❑ Major Clinical Uses TYPES USAGE Erythromycin RTI with streptococci, pneumococci, Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae Azithromycin, ▪ RTI with organisms sensitive to & erythromycin + Haemophilus influenzae, Clarithromycin Moraxella catarrhalis, Mycobacterium Clarithromycin ▪ Used to treat Helicobacter pylori (H. pylor) infections in standard triple therapy protocol ❑ Erythromycin ✓ The oldest of the macrolides (1952) ✓ Short t1/2→ q6hs ✓ Spectrum of activity nearly similar to clarithromycin and azithromycin ✓ Lacks significant activity against H. influenzae→ less useful than the other macrolides in the treatment of respiratory infections. ✓ Can be used to treat bronchitis, pharyngitis, sinusitis, otitis media, and infections in PCN-allergic patients. ✓ Erythromycin is less well tolerated → it is being replaced by newer agents. ❑ Clarithromycin ✓ Twice daily ✓ Has somewhat greater activity (than erythromycin) against: ✓ aerobic GM+ve bacteria ✓ H. influenzae ✓ Azithromycin and clarithromycin have a greater oral bioavailability and achieve higher tissue conc. than erythromycin. ✓ Clarithromycin is the most active against H. pylori. ✓ Used to treat URTI (same as erythromycin) & CAP ❑ Azithromycin ✓ Azicare®, Azimex®, Zitocin® ✓ Once daily (better compliance) ▪ 500 mg PO for 1 day → then 250 mg PO q24h for 4 days; ▪ Capsule, suspension, IV ✓ Somewhat better activity against aerobic gm -ve bacteria and is useful in the treatment of H. influenzae. ✓ Main advantages → taken up in high amounts by tissues and then slowly released over subsequent days. ✓ Uses: similar to clarithromycin (URTI, CAP) ✓ Advantage: No numerous drug interactions seen with erythromycin and clarithromycin. ❑ Macrolides Toxicity ✓ In general, → macrolides are safe drugs, causing several relatively mild adverse reactions. ✓ GI symptoms ✓ Erythromycin is associated with GI symptoms (N,V,D) abdominal pain, ✓ Thrombophlebitis following IV administration. (Azithro.) ✓ Clarithromycin: abnormal taste ✓ Clarithromycin & azithromycin are usually tolerated quite well ✓ QT prolongation ✓ Major drug interactions: Erythromycin then clarithromycin but not azithromycin (little effect) are also capable of inhibiting the cytochrome P-450 system and thereby affecting levels of other drugs. ✓ LFT abnormalities (particularly erythromycin). ✓ Erythromycin also has correlations with hepatotoxicity in pregnant women → use with caution (category B1) ✓ Clarithromycin→ B3 use is not recommended unless needed 15  Clindamycin ▪ Chemically classified as a lincosamide (related to macrolides) ▪ MOA: →very similar to macrolides (bind 50S of ribosome) ▪ Strength: 300mg/600mg IV→ 3-4 times/day ▪ Commonly used today: ▪ IV ▪ Oral (Denacine)® caps. 300 & 150 ▪ topical ▪ vaginal ovules ▪ Oral dose : 150 to 300 mg PO q6–8h ✓ excellent oral bioavailability (90%) ✓ Oral use limited by GI side effects ▪ IV dose: 600 to 900 mg IV q8h. ▪ Available form MOH: 100 mg cap, 300 mg inj ▪ Spectrum like that of erythromycin ✓Active against GM+ve (many strains MRSA)→ gain more importance, Streptococci → even penicillin-resistant ) ✓Not active against aerobic GM-ve (intrinsically resistant ) ▪ Additional activity against most anaerobes, including: ▪ B. fragilis (some stains are resistance) ▪ Clostridium perfringens→ gram –ve anaerobic bacteria ▪ Penetrates well into the bone and abscess cavities. ❑ S.E → major toxicity of clindamycin, which has limited its use ▪ GI symptoms: Nausea, abdominal cramping ▪ Diarrhea (could be bloody diarrhoea )→ Occurrence of (0.01% to 10% of individuals)→pseudomembranous colitis. ▪ metallic / unpleasant taste/loss of appetite ▪ Hypersensitivity ▪ Esophageal ulceration* ▪ Clindamycin should not be injected IV undiluted as a bolus but should be infused over at least 10-60 minutes. * Given in 3 or 4 equal doses *Penetrate the CSF poorly ❑ Used for treatment of: ▪ Topical preparations of the drug are used for the treatment of acne. ▪ Bone and joint infections: osteomyelitis ▪ Aspiration pneumonia ▪ Lung abscesses ▪ Skin and soft tissue infections (by strep, staph. & anaerobes) ▪ Bacterial vaginosis. ▪ Pelvic inflammatory disease PID: 900 mg IV q8h (combination W. genta.) ▪ Intra-abdominal infections ✓→ metronidazole is used more commonly for intra-abdominal infections (clindamycin has less reliable activity against B. fragilis). ▪ Prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease  Aminoglycosides Inhibit protein synth. (ribosomes are the target). Active against gram +ve /-ve bacteria. Often used in combination (synergistic effect) with cell wall–active agents (PCN, & cephalon, vanc.). Streptomycin in 1944→ Neomycin in 1949→ gentamicin in 1963→ tobramycin in 1967→ and amikacin in 1972  Excellent activity against aerobic gram-ve bacteria (unlike vancomycin) ▪ Active to a lesser degree against aerobic gram +ve bacteria. ▪ No activity against anaerobic ▪ Uptake of aminoglycosides is enhanced by antibiotics that inhibit bacterial cell wall synthesis → and tend to be synergistic with cell wall–active antibiotics. ▪ IV/IM ▪ Topical ▪ Eye drops ▪ Oral (poor absorption) ▪ Resistance rare → Some exists gentamicin > tobramicin > amikacin. ▪ Require renal dose adjustment ▪ Close monitoring of Peak & trough ❑ S.E: 1. nephrotoxicity 5-10% (reversible when detected early) 2. ototoxicity. ▪ Risk factors for nephrotoxicity (↑ risk to 50%): ✓ Age (cautiously in older patients) ✓ Preexisting kidney disease (cautiously use in patients with renal failure (dosage adjustments may be necessary) ) ✓ Concomitant nephrotoxins ✓ Sustained trough > 1 mg/dL ✓ Diuretic use (Lasix) ▪ Nephrotoxicity usually observes 4-5 d→ short period teat. Is safe ▪ This risk decreases by the single daily dose ▪ Cross-resistance among aminoglycosides is common ▪ Doses: ▪ Extended-interval dosing: q24 hrs (more convenient) ▪ Traditional dosing → q8hrs reserved for life-threatening infections/ pregnant women/endocarditis/burn > 20 % body ❑ Traditional dosing → q8hrs ▪ Peak and trough conc. should be obtained with 3rd or 4th dose and then every 3 to 4 days, along with regular serum Cr. monitoring. ❑ Extended-interval dosing: q24 hrs (more convenient) ▪ A drug concentration is obtained 6 to 14 hours after the 1st dose ▪ Monitor drug conc. 6 to 14 hours after the dosage at least every week and a serum cr. at least 3 times a week ❑ Gentamicin ▪ Gentamicin is the most used: 20 mg, 80 mg amp. ▪ Traditional dosing→ LD =2 mg/kg IV (2 to 3 mg/kg in the critically ill) ▪ followed by 1.0 to 1.7 mg/kg IV q8h (peak, 4 to 10 mg/mL; trough,