ANTIMICROBIAL AGENTS

1. ANTIMICROBIAL AGENTS NAPLEX

2. Selecting Appropriate Antimicrobial Agents • Empiric therapy • Identify the causative organism • Test the sensitivity of the organism to antimicrobial drugs • Identify important host factors: • Site of infection-CNS, bone, prostate, UTI • Susceptibility to toxicity • Patient allergies PG 52

3. Interference with cell wall synthesis • penicillins, cephalosporins • Inhibition of protein synthesis • macrolides, clindamycin, tetracyclines, quinolones • Interference with enzyme unique to bacterial cell • sulfonamides • Interference with the permeability of microbial cell membranes • amphotericin B Mechanisms of Action of Antimicrobial Agents PG 52

4. PABA dihydrofolic acid (DHFA) tetrahydrolfolic acid (THFA) Sulfa Sulfonamides PG 53

5. Mechanism of action : competitive antagonism of PABA in enzyme system essential for bacteria growth. For ophthalmic use, sulfa sodium salt solutions are very alkaline (i.e., pH 10+). The only sodium salt suitable for ophthalmic use is sulfacetamide sodium (solutions have pH of about 7.4). Sulfas are eliminated renally unchanged. Makes them good for UTIs. Sulfas are less soluble in acid urine. This is one cause of crystalluria. Stevens-Johnson syndrome is associated with sulfa use. General considerations - Sulfonamides PG 53

6. General considerations – Sulfonamides (cont’d) Combinations of sulfamethoxazole and trimethoprim (Bactrim, Septra, etc.) are less likely to result in bacterial resistance. Sulfasalazine (Azulfidine) is used in treating inflammatory bowel disease and RA. Watch for sulfa allergy, salicylate allergy, and urine discoloration. - GI side effects, dose is titrated upward slowly, monitor blood counts – dyscrasias If a patient cannot use sulfasalazine because of sulfa sensitivity, use mesalamine products, i.e., Asacol, Pentasa, Rowasa. – various dosage forms Remember that silver sulfadiazine (Silvadene) and mafenide (Sulfamylon) are used topically for treatment of serious burns. PG 53

7. Penicillins PG 54

8. General Considerations – Penicillins Mechanism of action: interfere with bacterial cell-wall synthesis (bactericidal) Note that all penicillins have a beta lactam ring and thiazolidine ring. Possible cross-sensitivity with other beta lactam antimicrobials (e.g., cephalosporins). - percent cross-sensitive ranges from 5-7% PG 54

9. AMino penicillins – AMpicillin, AMoxicillin, bacAMpicillin • NOX penicillins – penicillinase (beta lactamase) resistant penicillins: Nafcillin, OXacillin, clOXacillin (PO), diclOXacillin(PO)----MSSA (vanco alternative) • MEZPCT penicillins – antipseudomonal penicillins: MEZlocillin, Piperacillin, Carbenicillin, Ticarcillin (combo with aminoglycosides, not in the same IV) Therapy problems with penicillins: • Acid Resistance • Beta-lactamase (penicillinase) resistance (combo products; Zosyn, Timentin, Augmentin) • Hypersensitivity Structure Activity Relationships: PG 55

10. Which of the following is an adverse effect associated with use of aminopenicillins? a. polydipsia b. hemolytic anemia c. cholelithiasis d. tardive dyskinesia e. angina

11. Which of the following is an adverse effect associated with use of aminopenicillins? a. polydipsia b. hemolytic anemia c. cholelithiasis d. tardive dyskinesia e. angina

12. Cephalosporins PG 56

13. Contains beta-lactam ring. Therefore, may have cross-sensitivity with penicillins. As you go from 1st generation to 4th generation, you get: • increased gram-negative activity • decreased gram-positive activity • increased resistance to beta-lactamase destruction • increased ability to enter cerebrospinal fluid General considerations PG 56

14. Which of the following antimicrobial agents has effective coverage of streptococcus pneumoniae? I. amoxicillin II. doxycycline III. gentamicin a. I only b. III only c. I and II only d. II and III only e. I, II, and III

15. Which of the following antimicrobial agents has effective coverage of streptococcus pneumoniae? I. amoxicillin II. doxycycline III. gentamicin a. I only b. III only c. I and II only d. II and III only e. I, II, and III Gram + Non-DRSP

16. General considerations (cont’d) First generation (generally start with CEPH): • Good for surgical prophylaxis Second generation (generally start with CEF): • Good for otitis, sinusitis and respiratory tract infections Third generation (generally end with IME or ONE): • Good for meningitis, CAP, gram-negative bacilli, gonorrhea, Proteus, Salmonella, Klebsiella • Cefixime (suprax), cefotaxime (claforan), ceftriaxone (rocephin) Fourth generation (cefepime) Maxipime: • Good antipseudomonal activity PG 57

17. Tetracyclines PG 58

18. Products: • Tetracycline HCI (Achromycin V, Sumycin, Robitet, Panmycin) • Minocycline (Minocin) • Doxycycline (Vibramycin, Doxy 100, Doxychel, Vibra-Tabs) These are bacteriostatic antimicrobials. They interfere with protein synthesis. Broad spectrum antimicrobials. Work against many gram-positive and gram-negative organisms. - also effective against atypical organisms mycoplasma and chlamydia pneumoniae, useful for patients allergic to penicillin b/c gram + coverage General Considerations PG 58

19. General Considerations Not for use in children under age 8. May cause discoloration of developing tooth enamel. Not for pregnant women. May adversely affect fetal development. Most have the potential for causing phototoxicity. Drug interaction with divalent (Mg, Ca, Fe) or trivalent (Al) compounds and tetracyclines may result in complexation and impaired absorption. Do not use together. Broad spectrum activity can lead to thrush or vaginal candidias PG 58

20. Macrolides • General Considerations: • Bacteriostatic – inhibit protein synthesis • May be good for patients who are hypersensitive to beta-lactam antimicrobials. • Good respiratory coverage. • CAP caused by S.pneumo, M.cat, H.flu or atypicals (mycoplasma, legionella, and chlamydia) PG 59

21. Erythromycin • Oral Products • Erythromycin base (E-Mycin, Ery-Tab, PCE, Eryc) • Coating used on most products • Administer on an empty stomach Erythromycin stearate (Erythromycin Stearate, Wyamycin S) • Better absorbed than erythromycin base PG 59

22. Erythromycin (cont’d) • Erythromycin esolate (Ilosone) • Associated with cholestatic hepatitis • Better absorbed than erythromycin base • Erythromycin ethylsuccinate (eryPed, E.E.S.) • Most well absrobed • Available in liquid form • 400 mg of EES = 250 mg of erythromycin base • Parenteral Products • Erythromycin lactobionate • Erythromycin glucepate • Drug Interactions: Mainly due to enzyme inhibition of erythromycin – (3A4) PG 59

23. Clarithromycin (Biaxin) Usually used BID. XL form used once daily. Prodrug: May be given with or without meals Used in combination with a proton pump inhibitor for H. pylori treatment. Metallic taste PG 60

24. Azithromycin (Zithromax) More gram-negative activity than erythromycin or clarithromycin Once-daily dosing, usually for five days after otitis media (e.g., Z-Pack) Available as suspension, tablets, IV Suspension should not be taken with food or antacids. Dirithromycin (Dynabac) Prodrug Once-daily dosing PG 60

25. Lincosamides • General considerations • Watch for pseudomembranous enterocolitis (Clostridium difficile). • Treat clostridium with metronidazole (Flagyl) or oral vancomycin. • Good in gram positive (staph) and gram-negative infections, particularly anaerobes Lincomycin (Lincocin, Lincorex) Morbilliform rash possible; DC drug if it happens Clindamycin (Cleocin) Available in topical form for acne PG 61

26. Which of the following antibiotics has bacteriostatic activity? a. amoxicillin b. ciprofloxacin c. erythromycin d. penicillin e. cephalexin

27. Which of the following antibiotics has bacteriostatic activity? a. amoxicillin (cell wall) b. ciprofloxacin (inhibits DNA gyrase) c. erythromycin (protein synthesis) d. penicillin (cell wall) e. cephalexin (cell wall)

28. Aminoglycosides General Considerations Glycosides – poorly absorbed from the GI tract Bactericidal Good for serious gram-negative pathogens (pseudomonas, proteus, etc.) Frequently administered with extended-action penicillin (IV incompatible) - dosed q8h or q24h (conc. dependant kill) Eliminated by glomerular filtration; Watch for ototoxicity Monitor peaks and troughs – peaks 30 min after infusion, trough 30 minutes before next dose. peak = 4-10ug/ml trough = 0.5-2, adjust dose if CrCl < 60ml/min. hearing test if prolonged therapy PG 61

29. Which of the following antimicrobial agents is available for parenteral use only? I. cefaclor II. tobramycin III. ticarcillin a. I only b. III only c. I and II only d. II and III only e. I, II, and III

30. Which of the following antimicrobial agents is available for parenteral use only? I. cefaclor II. tobramycin III. ticarcillin a. I only b. III only c. I and II only d. II and III only e. I, II, and III

31. Parenteral use Streptomycin sulfate Kanamycin sulfate (Kantrex) Gentamicin sulfate (Garamycin (4mcg-10mcg/ml) Tobramycin sulfate (Nebcin) (4mcg-10mcg/ml) Amikacin sulfate (Amikin) (15mcg-25mcg/ml) Netilmicin sulfate (Netromycin) Reference Peak Range PG 61

32. Which of the following antibiotics requires monitoring of serum levels? a. penicillin b. ceftazidime c. azithromycin d. gentamicin e. cephalexin

33. Which of the following antibiotics requires monitoring of serum levels? a. penicillin b. ceftazidime c. azithromycin d. gentamicin e. cephalexin

34. Oral use Not for systemic action Neomycin sulfate (Mycifradin) - Used for bowel prep prior to surgery , treat diarrhea caused by e.coli, neomycin also binds ammonia, use in patients w/hepatic encephalopathy, watch for absorption interactions Tobramycin (TOBI) –inhaled product for CF patients PG 62

35. Fluoroquinolones General Considerations - Inhibits DNA-Gyrase May cause phototoxicity Not for patients under 18 – affects growth Do not use within 2-4 hours of antacids; iron – also inhibits CYP1A2 (increased levels of theophylline and caffeine) Generally useful for UTI, lower respiratory infections, gonorrhea, prostatitis – older agents have more gram -, less gram + coverage, newer agents have broader gram + [moxifloxacin, gatifloxacin] All end in -oxacin PG 62

36. Names • Second generation • Norfloxacin (Noroxin) – high urine levels - UTIs • Ciprofloxacin (Cipro)- renal elimination: reduce dose • Ofloxacin (Floxin) • Third generation • Levofloxacin (Levaquin) – renal elimination: reduce dose • Sparfloxacin (Zagam) – reports of prolongation of QT interval (D/C) • Gemifloxacin (Factive) – renal elimination: reduce dose, skin rash • Fourth generation • Moxifloxacin (Avelox) – Multi-drug resistant Streptococcus pneumonia (MDRSP) PG 62

37. MISCELLANEOUSANTIMICROBIAL AGENTS Antibacterials Mupirocin (Bactroban) – topical use for impetigo, intranasal for staph Vancomycin (Vancocin) – associated with red man syndrome (must be infused slowly, over min of 30 minutes); reserved for serious/resistant gram + infections (MRSA, enterococcus) – rapid drop in BP accompanied by rash in neck or chest area - Monitoring – 1 hour before and 1 hour after - Peak – 25-40mcg/dl & Trough 5-12mcg/dl Metronidazole (Flagyl) – active against gram-negative organisms and protozoa, (anaerobes) Avoid alcohol. May darken urine. PG 63

38. MISCELLANEOUS ANTIMICROBIAL AGENTS (cont’d) • Carbapenems • broad spectrum; used for resistant gram +/– organisms, pseudomonas, MRSA, enterococcus, anaerobes • similar to penicillins (cross-sensitivity) but b-lactamase resistant • Risk of seizures and renal adjustment • Imipenem/cilastatin (Primaxin) – cilastatin is a renal dipeptidase inhibitor • Meropenem (Merrem)---lacks good pseudomonas coverage • Doripenem (Doribax) • Ertapenem (Invanz) • ----Aztreonam (Azactam)---monobactam, ok with PCN allergy PG 63

39. Which of the following antibiotic is classified as a macrolide? a. telithromycin b. tobramycin c. azithromycin d. doxycycline e. kanamycin

40. Which of the following antibiotic is classified as a macrolide? a. telithromycin b. tobramycin c. azithromycin d. doxycycline e. kanamycin

41. MISCELLANEOUS ANTIMICROBIAL AGENTS (cont’d) VRE and MRSA drugs Quinupristin / dalfopristin (Synercid) – Linezolid (Zyvox) –……oral dosing available Tigecycline (Tygacil) – Chloramphenicol (Chloromycetin) – for typhoid fever; may cause aplastic anemia and gray baby syndrome PG 63-64

42. Pneumonia • Organisms: • Treatment: --Comorbidities: Chronic obstructive pulmonary disease (COPD), diabetes, chronic renal failure, chronic liver failure, heart failure (HF), cancer, asplenia, immunosuppressed

43. Pneumonia • Treatment: --Risk factors for MDR organisms: recent antibiotic therapy (in last 90 days), hospitalized ≥ 5 days,  resistance in environment, nursing home resident, chronic dialysis, home infusion therapy, immunosuppressed

44. Meningitis • Organisms: • Treatment:

45. Urinary Tract Infection • Organisms: • Treatment:

46. STDs • Organisms: • Treatment:

47. Antitubercular Drugs R rifampin I isoniazid P pyrazinamide E ethambutol S streptomycin PG 64

48. Antitubercular Drugs • Isoniazid (Nydrazid, Laniazid) • May cause B6 deficiency – supplement malnourished, alcoholics, kids • Used for prophylaxis or in combo with other drugs for active disease • 6 months of prophylaxis if +PPD; For treatment used in combo with rifampin for at least 6 months • Metabolized by acetylation (slow versus rapid acetylators) • monitor for hepatoxicity • Rifampin (Rifadin, Rimactane) • Potent enzyme inducer (potential drug interactions with many drugs) • Potentially hepatotoxic; • Use may result in discoloration of virtually all body fluids (urine and tears----watch contact lenses) PG 64

49. Antitubercular Drugs (cont.) Ethambutol (Myambutal) – for treatment of MAC and drug-resistant Tb as part of combination therapy - optic neuritis is a rare but serious side effect - monitor with eye exams Pyrazinamide – used in combination therapy; potentially hepatotoxic - may increase uric acid levels Steptomycin- can be used as fourth drug in regimen instead of pyrazinamide PG 65

50. Antimalarials • Quinine sulfate (Quinamm) – also used for muscle cramps; no longer used due to hematologic adverse effects • Doxycycline – tetracycline; possible phototoxicity and binding interactions • Melfoquine HCl (Lariam) – may cause neuropsychiatric adverse effects; once- weekly dosing • Atovaquone/proguanil (Malarone) – newer product; once daily; do not use if renally impaired PG 65