门诊病人抗生素应用（英文ppt）antibioticsin

Antibiotics in Outpatient Practice N. Buttar MD Antibiotics in Outpatients Different Groups Penicillin Cephalosporin Quinolones Sulfa Tetracycline Macrolides Miscellaneous -Lactam Antibiotics -Lactam antibiotics Name is due to beta-lactam ring in their chemical structure Include: - Penicillin - Cephalosporins and related compounds - Imipenem - Aztreonam They are bactericidal They inhibit key enzymes in bacterial cell wall synthesis They activate cell wall autolytic enzymes causing lysis of bacteria. Well absorbed orally. Resistance to -lactam antibiotics Increasing at significant rate. Common problem in primary care. Major mechanism of resistance is production of beta-lactamase enzyme. -Lactam antibiotics -lactamase activity is present in: Gram positive -Staphylococcus aureus -Staphylococcus epidermidis Gram negative - H. Influenzae - Neisseria gonorrhea - Moraxella catarrhalis - E. coli - Proteus - Serratia - Pseudomonas - Klebsiella - Anaerobic- Bacteroides species -Lactam antibiotics can be divided into classes based on their antimicrobial spectrum Penicillin Natural Penicillin Penicillinase resistant Amino penicillin Beta-lactam, beta-lactamase inhibitor combinations Antipseudomonal Penicillin Oral Cephalosporins 1st generation 2nd generation 3rd generation Penicillin 1940s-first became commercially available. Resistance noted shortly after introduction. Still widely used and new derivatives are being developed. Natural Penicillin Penicillin VK Potassium salt of phenoxymethyl. Well absorbed orally. Peak level achieved within 60 minutes Indications: -Gram positive infections of throat, respiratory tract, and soft tissue -Drug of choice for group A streptococcal pharyngitis -Active against anaerobes, so commonly used for oral and dental infections. Penicillinase Resistant Penicillin Have side chain that inhibits penicillinase. Were developed because of resistance of Staphylococcus to natural penicillin. Active against Staphylococcus and Streptococcus. Not active against gram negative and MRSA. Primary indication for soft tissue and skin infections. Should be taken two hours before meals. - Cloxacillin (Tegopen). - Dicloxacillin (Dynapen). Amino-Penicillin Amoxicillin Ampicillin Bacampicillin (Spectrobid) First penicillins discovered to be active against gram negative rods like E. coli and H. Influenzae. Amino-Penicillin Same coverage like Pen VK plus: - Listeria monocytogenes - Enterococcus - Proteus mirabilus - E coli - H. flu Amino-Penicillin Amoxicillin is more completely absorbed than Ampicillin. Serum levels are twice as high. Small amount is left in GI tract, so less diarrhea. However, more complete absorption makes it less effective for Shigella enteritis. Both have same antibacterial spectrum. Bacampicillin is more expensive and no advantage. Amino-Penicillin Primarily used for: Otitis media Sinusitis Bronchitis Urinary tract infection esp. Enterococcus Bacterial diarrhea Salmonella infection Shigella infection. H. Influenzae and E. Coli are increasingly becoming resistant. -lactam, -lactamase inhibitors Only combinations available orally is: Amoxicillin clavulanic acid Provides increased coverage of -lactamase producing strain of : Staphylococcus -aureus,saprophyticus and epidermidis Haemophilus influenzae N. gonorrhea M. catarrhalis Proteus and Klebsiella Bacteroides species Little activity against : Pseudomonas MRSA -lactam, -lactamase inhibitors Excellent drug for treating infection due to human and animal bites. May be first choice for -lactamase producing organisms: - Otitis media - Sinusitis - Bronchitis - UTI - Skin and soft tissue infections -lactam, -lactamase inhibitors Common Side Effects GI disturbance, diarrhea -Can be decreased by taking drug with food or water Rash Candida Anti-Pseudomonal Penicillin Carbenicillin (Geocillin) only oral preparation Excellent oral absorption However, it is metabolized so rapidly, serum levels remain low, which limits clinical usefulness. Cephalosporins Structurally, they have -lactam ring and thiazolidine ring. Produced from Cephalosporium acremonium in 1962. Brotzu noted clearing of microorganisms from sea water near a sewage outlet. Divided into generations depending upon their spectrum of activity. First Generation n Cefadroxil (Duricef) n Cephalexin (Keflex) n Cephadine (Velosef) Well-absorbed even in presence of fat. High urinary concentration. Decrease dosage in renal failure. Duricef is once daily but expensive. First Generation Coverage Streptococcus Methicillin sensitive Staphylococcus aureus E. Coli Klebsiella Proteus mirabilis Effective in Tx of skin and soft tissue infection Preferred to anti-staph Penicillin (Cloxacillin) due to less GI side effects and better taste. 2nd line agents for UTI (after Sulfa and Quinolones) Not effective agent against Pseudomonas and Enterococcus. Safe in pregnancy. Not effective against H. Influenzae M. catarrhalis Other gram negative -lactamase organisms Role of these agents for bronchitis, otitis media, sinusitis and pneumonia is not clear. Second Generation n Cefaclor (Ceclor) n Cefprozil (Cefzil) n Cefuroxine axetil (Ceftin) n Loracabef (Lorabid) is Carbacephem but very similar to 2nd generation Second Generation They have improved activity against common -lactamase producing respiratory pathogens such as: Methicillin sensitive S. aureus H. Influenzae N. Caterrhalis E. Coli Klebsiella Proteus mirabilis Due to wide spread use, resistance has increased More expensive than 1st generation Second Generation Indicated second line in : Otitis media Bronchitis Sinusitis Ceftin is only 2nd generation ceph approved for UTI. Ceclor may cause serum sickness esp in kids and have highest H. flu resistance. Absorption with food: - Ceclor Decreased - Cefzil - No effect - Ceftin - Increased Third Generation Cefdinir (Omnicef) Cefixine (Suprax) Cefpodoxine (Vantin) Ceftibuten (Cedax) Third Generation Better resistance to plasmid mediated -lactamase activity. So they have expanded coverage of gram negative as compared to 1st and 2nd generation Convenient dosage-once or twice daily Expensive Third Generation They have variable loss of efficacy against gram positive coverage especially - Streptococcus pneumoniae and - Staphylococcus species This limits their usefulness in otitis media and respiratory infections Poor staph coverage limits use for skin and soft tissue infections Omnicef and Vantin have better coverage for staphylococcus and streptococcus pneumoniae They are most useful oral 3rd generation antibiotics. Cedax has poor S. pneumoniae coverage, so not clinically useful. Dosage and Cost Drug Pediatric dose Adult dose Cost mg/kg/day mg Pen VK 25-50 250-500 QID $ 2 Cloxacillin 50-100 250-500 QID $15 Dicloxacillin 12.5-100 250-500 QID $20 Amoxicillin 40-90 250-500 TID $8 or 875 BID Ampicillin 50-100 250-500 QID $ 6 Augmentin 45 250-500 TID $ 80-120 or 875 BID Duricef 30 500-1000 BID $50-80 Dosage and Cost Drug Pediatric dose Adult dose Cost mg/kg/day mg Keflex 25-50 250-500 QID $ 20-30 Velocef 25-50 250-500 QID $ 30 Ceclor 20-40 250-500 TID $ 60 Cefzil 15-30 250-500 BID $ 70 Ceftin 20-30 125-500 BID $ 40-50 Lorabid 15-30 200-400 BID $ 65 Omnicef 14 300 BID or 600 QD $ 60 Suprax 8 200BID or 400 QD $ 75 Vantin 10 100-400 BID $ 60 Cedax 9 400 QD $ 80 Macrolides Azithromycin Clarithromycin Telithromycin Erythromycin Mechanisms of Action Bacteriostatic They bind to 50 S subunits of bacterial ribosomes ,leading to inhibition of protein synthesis. Structure Clarithromycin has same 14 membered lactone ring as erythromycin, only difference is, at position 6 a methoxy group replaces hydroxyl group. Azithromycin has 15 membered ring and a methyl substituted nitrogen replacing the 9 A carboxyl group. That is why it is referred to as azalide rather than macrolide. Telithromycin 1st member of Ketolide group Especially designed to target macrolide resistant respiratory tract pathogens It has keto group substituted for L- at C3 and N- substituted carbanate at C11/C12 This enables it to bind more tightly to ribosomal RNA which increases to potency and decrease resistance Resistance Two main mechanisms Alternates in ribosomal proteins Alternates in macrolide efflux pump These are responsible for gram positive cocci (strep and staph) resistance Complete cross resistance between, E, A and C for gram positive cocci by alternating in ribosomal protein synthesis Resistance to telithromycin by this mechanism is not yet common So this is active against most erythromycin resistant respiratory pathogens However, resistance can occur due to efflux pump mechanism Macrolides Incidence of macrolide resistance to streptococcus pneumoniae: 1995 10.6% 1999 20.6% 2004 30% Azithromycin, Clarithromycin, and Telithromycin have enhanced gram negative activity compared to erythromycin. So erythromycin resistant gram negative may be sensitive to newer drugs. Spectrum of Activity Azithromycin, clarithromycin, telithromycin Erythromycin sensitive s. pneumoniae H. Influenzae Moraxella catarrhalis Atypicals - Legionella pneumoniae - Chlamydia - Mycoplasm Telithromycin also active against erythromycin resistant s. pneumoniae Macrolides Gram Negative E. coli Salmonella Yersinia entercolitica Shigella Campylobacter jejuni Vibrio chlerae N. Gonorrhea H. Pylori Clarithromycin, azithromycin primary agent to treat mycobacterium avium complex infection in HIV patients Pharmacokinetics Clarithromycin, azithromycin, and telithromycin have improved oral absorption, longer half life and better tissue and intracellular penetration than erythromycin Only azitromycin available as inject able formulation. Clarithromycin, azithromycin, and telithromycin are stable at gastric pH so better bioavailability than erythromycin and enteric coating not required. Macrolides Serum concentrations with azithromycin are much lower than clarithromycin. Extended release azithromycin has a higher peak serum concentration and more systemic exposure than standard regimen. Biaxin XL has slow gastric absorption and should be taken with food. Food does not affect rate or extend absorption of telithromycin. Excretion Azithromycin is excreted in bile and in feces, with very little appearing in urine. Clarithromycin is metabolized in the liver using cytochrome P450 enzyme system. 30% is excreted unchanged in urine. Telithromycin- multiple routes in elimination, 7% feces, 13% urine, rest is metabolized by CYP450 and new CYP450 half way. Special Populations Renal Azithromycin does not need dosage adjustment. Clarithromycin- Patients with creatinine clearance below 30mm/Hg ,decrease dose by 50% or dosing interval should be doubled. Telithromycin does not require adjustment in mild to moderate renal failure. Special Populations Pregnancy: Erythromycin (category B) is safest because of many years of clinical experience Azithromycin (category B) has more experience than clithromycin and telithromycin (category C) Adverse Reactions Erythromycin Gastrointestinal QT prolongation and sudden death Clarithromycin is associated with QT prolongation Telithromycin can prolong QT interval So avoid in: -Bradycardia -Congenital prolongation of QT syndrome -Patient taking 1A and III anti-arrhythmia, quinidine, procainamide, dofetilide Azithromyxin has minimal affect on Qt interval and has not been linked to torasdes. -minor interaction with CTTP3A4 system. Adverse Reactions Others: Severe reactions are rare like: Anaphylaxis Stevens-Johnson syndrome Pseudo membranous colitis Cholestatic hepatitis Due to long half life, severe reactions from azithromycin can persist for many days. GI Symptoms -Nausea, diarrhea, abdominal pain in 2-5% of patients on azithromycin and clarithromycin. and 12% on telithromycin. -Dysgeusia is frequent with clarithromycin and telithromycin -Clarithromycin liquid is better tasting. Pricing and Dosage Pack (Zithromax) 1 g (3): $80.12 Suspension (reconstituted) (Zithromax) 100 mg/5 mL (15): $38.70 200 mg/5 mL (15): $37.61 200 mg/5 mL (22.5): $37.61 200 mg/5 mL (30): $37.61 Tablets (Zithromax) 500 mg (30): $451.45 600 mg (6): $121.45 Tablets (Zithromax Tri-Pak) 500 mg (3): $47.91 Tablets (Zithromax Z-Pak) 250 mg (6): $50.76 Pricing and Dosage Tablet, 24-hour (Biaxin XL) 500 mg (20): $96.85 Tablet, 24-hour (Biaxin XL Pac) 500 mg (14): $74.13 Tablets (Biaxin) 250 mg (20): $95.95 500 mg (20): $88.67 Pricing and Dosage Suspension (E.E.S. 200) 200 mg/5 mL (200): $12.91 Suspension (E.E.S. 400) 400 mg/5 mL (100): $12.82 Suspension (Erythromycin Ethylsuccinate) 200 mg/5 mL (200): $9.04 400 mg/5 mL (100): $10.91 Suspension (reconstituted) (E.E.S. Granules) 200 mg/5 mL (100): $12.62 200 mg/5 mL (200): $20.83 Tablet, EC (Ery-Tab) 333 mg (30): $10.91 500 mg (20): $8.69 Tablet, EC (PCE) 333 mg (30): $63.17 500 mg (20): $55.39 Tablets (E.E.S. 400) 400 mg (40): $12.64 Tablets (Erythrocin Stearate) 250 mg (30): $7.56 500 mg (20): $9.92 Tablets (Erythromycin Base) 500 mg (40): $11.39 Tablets (Erythromycin Ethylsuccinate) 400 mg (40): $11.38 Pricing and Dosage Tablets (Ketek) 400 mg (60): $299.99 Quinolones General Nalidixic acid and cinoxacin and oxoline are original quinolones Oxoline is no longer available. Addition of fluoride to original quinolones yielded new clan of drug known as flouroquinolones. They have a broader antimicrobial spectrum and improved pharmacokinetics. Quinolones General: They have excellent safety and tolerability. They have become popular alternatives to penicillin and cephalosporins in various injections. Originally approved for urinary tract infections. But enhanced activity has extended their use. Quinolones General : Flouroquinolones are broad spectrum antibiotics. They have activity against gram negative especially Pseudomonas aeruginosa. They are well absorbed orally. Tissue and fluid (bile, stool, urine, prostate, respiratory tract, bone, muscle) can often exceeds serum concentrations, so very effective for certain infectoins like pneumonia. 100% bioavailability and equal to IV route. So switch to oral in hospital as soon as possible. Quinolones General: They penetrate cerebral spinal fluid in presence of inflamed meninges but experience is scant. Well tolerated and has few side effects. But can have serous adverse effects . Side Effects Nausea and vomiting in 3-6% of patients Headaches, confusion, dizziness Photo toxicity-more common with Sparfloxacin (Zagam) and Lomefloxacin (Maxaquin) Hepatotoxicity- Trovan Cardio toxicity-Sparfloxacin QT interval prolongation-Grepafloxacin, Sparfloxacin Avoid in tricyclic antidepressants-Maxifloxacin, Phenothiazines and class I anti-arrhythmias Cartilage damage in young in animal studies. In one study no arthropathies in 1000 children treated with Ciprofloxacin, but do not use in less than 18 years old. Bacterial resistance has been seen. Antimicrobial activity Introduced in 1980. First generation was widely used because of only oral antibiotic available to cover serious infections like gram negative organisms, i.e. Pseudomonas Six new flouroquinolones have been introduced in last ten years Levaquin 1977 Sparfloxacin-1999 Tequin and Avelox 2000 In 1999 Grepafloxacin was withdrawn due to torsades de pointes Class Agent Antibacterial Indications spectrum 1st Generation Nalidixic acid Gram - ve Uncomplicated UTI (Negram) not pseudomonas 2nd Generation Norfloxacin gram including Uncomplicated and (Noroxin) pseudomonas some complicated UTI Lomefloxacin gram + (including S STD (Maxaquin) aureus, not S. Prostatitis pneumoniae Skin and soft tissue Enoxacin some atypicals Diarrhea and (Penetrex) typhoid fever Most commonly Anthrax used avail as Ciprofloxacin (Cipro) oral and IV Ofloxacin (Floxacin) Class Agent Antibacterial Indications spectrum 3rd Generation Levofloxacin Same as 2nd Same as 2nd (Levaquin) generation and generation and Sparfloxacin expanded gram + acute (Zagam) coverage and exacerbations Gatifloxacin resistant of COPD (Tequin) pneumococcal Moxifloxacin Expanded activity (Avelox) against atypicals Less active against Pseudomonas than Cipro 4th Generation Trovafloxacin Same as 3rd Same as 3rd (Trovan) generation and generation anaerobic coverage excluding UTI, pyelonephritis +Intraabdominal infections, pelvic infections, Nosocomial pneumonia FDA Approved Use Uncomplicated UTI Nalidixic acid and Cinobac, Noroxin, Maxaquin, Penetrex, Floxin, Cipro, Levaquin Complicated UTI Noroxin, Maxaquin, Pentrex, Cipro, Levaquin Skin and Soft Tissue Cipro, Levaquin, Floxin Infections Urethral and Cipro, Noroxin, Penetrex, Floxin Cervical gonococcal FDA Approved Use STD, Chlamydia Ofloxacin and gonococcal Bone and joint Infections (gram -) Ciprofloxacin Infectious diarrhea Thyphoid fever Prostatitis Norfloxacin, Ofloxacin COPD/CAP Levaquin, Zagam, Maxaquin Acute sinusitis Cipro, Levaquin, Avelox Quinolones: Compared with Cipro, newer agents have enhanced gram + coverage with minimal decrease in gram -ve coverage, especially S. pneumoniae Cipro is most potent anti-pseudomonas flouroquinalone Levaquin has enhanced activity against S. pneumoniae, S. aureus, Enterococcal Mycoplasm and Chlamydia Quinolones: Most of flouroqui