Anti-infectives Part I

1. Anti-infectives Part I Anti-infectives include antibiotics and antibacterials, antifungals, antivirals and antiproatozoans.

3. General Principles • Spectrum • Narrow • effective against a FEW bugs • Broad • effective against MANY bugs • Potency • Cidal • only works on actively growing bugs, not mature ones • Static • slows growth till immune system has time to catch up • doesn’t’ work on immunocompromised pts • watch WBC’s

4. Microbial Resistance • Naturally resistant (not our fault) • Acquired resistance (our fault) • Vancomycin Resistant Teracocci (VRE) & MRSA • Selective effect of drug • bug starts off sensitive to drugs then develops resistance • Transfer of genetic material • from one living bug to another (not survival of the fittest) • Destruction of the drug • the bug develops an enzyme that destroys the drug (penicillinace) • Prevent drug from entering bug • bugs develop enzymes that inactivate the drug as it passes the bug’s cell wall • Resistance pumps • bugs develop ability to pump drug back out • Alteration of target site • bug changes its shape of the drugs binding receptor • Development of other metabolic pathways • bug changes its own pathways

5. Treatment of Systemic Infections • Drug selection • Ability of drug to penetrate site • drugs need to be lipid soluble to cross BBB • Culture & Sensitivity • take it first BEFORE starting drug so it doesn’t screw up the lab result • Dose and route • PO • mild to moderate infection unless pt is vomiting • IV/IM • IV for more severe infections but it still stings so monitor site • IM route stings so not used much • Length of tx • PO = 7-10 days • IV = until infection controlled enough to switch to PO

6. Treatment of Systemic Infections • Drug combinations • Emergencies • USE BEST GUESSES FIRST • Mixed infections • May be using more than one antibiotic • Prevention of resistance • Using 2 or more drugs slows down growth of resistance • Drug mechanisms of action • don’t use cidal drug with static drug

7. Adverse Reactions • 5x risk for nosocomial infections • 3x more likely to die • puts you in the hosp longer = incr. risk for more bugs • Antibiotic Induced Diarrhea • CDIF diarrhea • pseudomembranous colitis • Direct tissue toxicity • IV phlebitis • Renal damage aminoglycocides • Neurotoxicity aminoglycocides • Allergic reactions • rash to anaphylactic shock • a rash first sets you up for higher risk of anaphylactic shock d/t 1st exposure • Super-infections • normal body flora destroyed so no defenses against bacteria, yeasts and fungi • local or systemic; annoying or life threatening • Other • diarrhea, vomiting, electrolyte imbalances

8. Miscellaneous • Prevention of infection • prophylactic • esp in bone surgeries • Misuse of antimicrobials

10. 5 Mechanisms of Action • Inhibition of cell wall synthesis • makes cell wall osmotically unstable • cancomycins, penicillins & cephalosporins, carbapenems • Inhibition of protein synthesis • binds to ribosomal subunits • cause pathogen ribosomes to make abnormal or no proteins • cidal or static • aminoglycosides, tetracyclines, streptogramins • ??? erythromycins, chloramphenicol, macrolides, ketolides • Disruption /alteration of membrane permeability • binds to cell walls and makes holes • allows innards to leak out • antifungals • Inhibition of Nucleic Acid (RNA or DNA) synthesis • rifampin (TB), some antiviral’s • Inhibition of specific biochemical (metabolic) pathways • static drugs • sulfa drugs (sulfonamides)

11. Mechanism of Action #1Antibiotics Affecting Bacterial Cell Wall • cidal • beta-lactam • Penicillinstimentinis penicillinase resistant • can cause antibiotic diarrhea • SE: Jarisch-Herxheimer reaction (during syphilis) • IM is irritating so given PO/IV • Cephalosporinsrocephin = one-dose IV for UTI • bone, joint, urinary, soft tissue • Nephrotoxic = Pts w/ decr renal fx may  confusion & seizures • Carbapenems • Monobactamsaztreonam [Azactam]Like penicillin, but no cross sensitivity • unusual taste; numb tongue • Vancomycinfor staph, MRSA, C diff colitis • Ototoxic & Nephrotoxic • Rapid infusion can  “red neck” syndrome. • Resistance noted(VRE) so save this drug as a last resort • Phosphonic acid derivatives fosfomycin [Monurol](granules) for UTI’s. • One dose only for UTI

12. Antibiotics Affecting Bacterial Cell Wall Penicillins • Beta-lactam (4 atom ring gives the cidal effect) antibiotic • Bactericidal – inhibits cell wall synthesis • Only crosses damaged BBB • IM is irritating • IV requires freq doses • kills Gram positive bugs unless it’s extended spectrum • Penicillinase made by bugs to destroy beta-lactam ring of penicillin • Relatively nontoxic bc it works on bugs, not your own body’s cells • GI – including pseudomembranous colitis • Jarisch-Herxheimer reaction • typical during syphilis/spirochete Tx • No need to stop pen, this rxn will go away in about a week • HA, fever, HTN, diaphoresis, chills, myalgia, tachycardia, lethargy

13. Antibiotics Affecting Bacterial Cell Wall Penicillins • Drugs – see book for lists • All generic names end in -cillin • Some penicillins are penicillinase resistant • Timentin • clavulanateadded to an antibiotic makes it –ase resistant • Some have extended spectrum • Cross sensitivity to other beta lactams possible • Allergic to one penicillin means allergic to all • higher chance of being allergic to other beta-lactam antibiotics • i.ecephalosporins

14. Antibiotics Affecting Bacterial Cell Wall Cephalosporins • Also beta-lactam ring & Bactericidal • First generation = Gm+ and some Gm- ; narrow spectrum • Second generation = extended Gm- & some anaerobes; more extended spectrum • Third generation = extended Gm- including pseudomonas • Fourth generation = gets into CSF better. • Possible cross sensitivity to other beta lactams • Relatively nontoxic • USES: bone, joint, urinary, soft tissue • PO/IV • SE: Allergy; NVD c PO; colitis; Decrplts; Renal damage • Pts with decrrenal fx may  confusion & seizures • Drugs – see book. Generic names start w/ ceph- • rocephin = a one-dose IV for UTI

15. Antibiotics Affecting Bacterial Cell Wall Carbapenems • Beta-lactams • but resistant to beta lactamase (same as penicillinase) • Bacteriocidal – make cell wall round & unstable • broad spectrum • IV (parenteral) • dialysis takes it out so give AFTER dialysis • SE: • Seizures • NVD • Colitis • Increased liver fx tests • Allergy – possible cross sensitivity • Drugs – see book. Generic names end w/ -penem

16. Antibiotics Affecting Bacterial Cell Wall Monobactams • aztreonam [Azactam] • Like penicillin, but no cross sensitivity • IM or IV • Action: inhibit cell wall synthesis • SE: • GI; unusual taste; numb tongue • Dec. CBC; • Increased liver fx tests • some CNS effects

18. Antibiotics Affecting Bacterial Cell Wall Vancomycin • Vancocin – mainly for staph, esp MRSA • Also for C diff colitis (antibiotic diarrhea) • Action: inhibits cell wall synthesis – cidal • SE: • Ototoxic • Nephrotoxic • Give IV dose over 1 hour in at least 100cc of fluid • Rapid infusion can  “red neck” syndrome. • Resistance has been noted (VRE) • save this drug as a last resort

19. Antibiotics Affecting Bacterial Cell Wall PhosphonicAcid Derivatives • Action: - inhibits cell synthesis by inactivating enzyme needed for cell wall synthesis • Cidal • SE: • Diarrhea • HA • Drug: fosfomycin [Monurol] – for UTI’s. • comes as Granules • dissolve in water or on applesauce • One dose only for UTI

20. Mechanism of Action #2 Antibiotics Affecting Bacterial Protein Synthesis • Tetracyclines Lyme, rocky mountain spotted fever, typhus, cholera, chlamydia • inactivated by Ca++, Fe, Al, & Zinc • superinfection; photosensitivity; yellow teeth • Macrolidesgeneric =mycin legionnaires, Lyme, syphilis, bubonic plague • Least toxic, static • inactivated by Ca++, Fe, Al, & Zinc • NO grapefruit juice • Aminoglycosides-mycin Tobramycin(inhaler form-Cystic Fibrosis) streptomycin (plague and TB), gentamycin, canamycin, Neomycin • Neurotoxic, Ototoxic & Nephrotoxic (drops GFR) • Monitor Peaks/troughs d/t narrow therapeutic window • Post-antibiotic effect: Drug binds to various tissues so full excretion takes long time. Up to 20 days. • Chloramphenicolgood for CNS infections BUT…Very toxic • Bone marrow suppression (dose related, reversible) • Aplastic (Not making blood cells) anemia (not dose related, irreversible) • Gray baby syndrome (cyanotic, high resp, distended abd, very fatal if not stopped) • Lincosamides Clindamycin • Streptogramins SE: bilirubin levels, joint & muscle pain • Oxazolidinones linezolid [Zyvox]for MRSA & VRE, SE: transient myelosuppression • Ketolides telithromycin [Ketek]Significant post antibiotic effect • static & cidal • NOT beta-lactam

21. Antibiotics Affecting Bacterial Protein Synthesis Tetracyclines • Broad spectrum • Bacteriostaticusually • Lots of resistance • PO usually • drug of choice for lyme, rocky mountain spotted fever, typhus, cholera, clamydia • Problem w/ tetra is Most inactivated by Ca++, Fe, Al, & Zinc • take these supplements at a different type • same with milk, yogurt • SE: GI; superinfection; photosensitivity; skin rashes; • Turns teeth yellow • not for pregnant woman when baby’s teeth are forming • Generic names end in -cycline

22. Antibiotics Affecting Bacterial Protein Synthesis Microlides • Bacteriostatic usually • PO, IV, topical, ophthalmically, • Take PO on empty stomach • legionnaires, Lyme, syphilis, bubonic plague • RTI, soft tissue, etc • Least toxic • SE: GI, HA, dizziness, palpitations • Interactions: MANY, includinggrapefruit juice • Generic names end in -mycin

23. Antibiotics Affecting Bacterial Protein Synthesis Aminoglycosides • BacteriocidalVery effective for Gm- • IM or IV • Monitor Peaks & troughs bc Nephrotoxic so you want to stay w/in the narrow therapeutic window • SE: N/V/D • Drugs: • streptomycin (plague and TB) • gentamycin • canamycin • Neomycin – used PO for bowel preps & liver disease • Tobramycin– comes in inhaler form for Cystic Fibrosis pts. • Post antibiotic effect: Drug binds to various tissues so full excretion takes long time. Up to 20 days.

24. Antibiotics Affecting Bacterial Protein Synthesis Aminoglycosides • Nephrotoxic – Accumulates in renal tubules and drops GFR • Susceptible pts = dehydrated, impaired renal fx, elderly • Ototoxic – Accumulates in sensory cells of the ear (espat high doses) • Susceptible pts = previous hearing/balance disorders, elderly, simultaneous use of other ototoxic drugs • Neurotoxic – Skeletal neuromuscular blockade; Reversed c IV Ca++ • Susceptible pts = medically paralyzed ICU pts • Myasthenia gravis • General anesthetics • Neuromuscular blocking drugs • Caution c babies– Crosses placenta & breast milk. • if crosses placenta baby may be born deaf

25. Antibiotics Affecting Bacterial Protein Synthesis Chloramphenicol • Chloromycetinstructurally different than all others • Bacteriostatic usually (can be cidal) • PO or IV • High CSF concentrations so good for CNS infections BUT: • Very toxic • Bone marrow suppression • dose related, reversible • Aplastic (Not making blood cells) anemia • not dose related, irreversible • Gray baby syndrome • cyanotic, high resp, distended abd, very fatal if not stopped

26. Antibiotics Affecting Bacterial Protein Synthesis Others • lincosamides = clindamycin [Cleocin] • Good for anaerobic bugs • streptogramins(new) • Drugs in this class are synergistic with each other • For VREF & other serious infections • IV • SE: NVD, rash,  bilirubin levels, joint & muscle pain. • Synercid = quinupristin + dalfopristin • synergism together gives 16X the effect of either one • excreted in feces

27. Antibiotics Affecting Bacterial Protein Synthesis Others • oxazolidinones = linezolid [Zyvox] • Bind to bacterial ribosomes • For MRSA & VRE • SE: GI, transient myelosupression, HTN • ketolides = telithromycin [Ketek] • Significant post antibiotic effect • stays a long time in the body • even below therapeutic levels it has an effect • SE: GI, hepatotoxicity, blurred vision • PO

28. Mechanism of Action #3Antibiotics Affecting Membrane Permeability • Binds to cell walls and makes holes • Allows innards to leak out • Antifungals • Polymixin B • Causes cell membrane to leak • Cidal • Usually topical (in neosporin)

29. Antibiotics Affecting Membrane Permeability Miscellaneous Antibacterials • cyclic lipopeptides • Bacitracin– inhibits cell wall synthesis. • Usually topical. • OTC as bacitracin, Neosporin • Daptomycin [Cubicin] • Cidal • Action: depolarizes cell membrane  inhibition of protein, DNA & RNA synthesis • IV only • SE: myopathy

30. Mechanism of Action #4Antibiotics Inhibiting Nucleic Acid synthesis • Fluoroquinolones aka quinolones for TB, some antiviral’s • Prodrug =rifampin(RNA inhibitor) • SE: • Cartilage malformation in fetus & growing child • Tendinitis • GI : NVD, high risk of C diff colitis, • if taken with antacids & sucralfate  dec absorption of antibiotic • Allergic Rxns • Cardiac dysrhythmias, long QT interval • CNS – dizziness, HA, sleep, seizures, hallucinations, confusion • Phototoxicity & Hepatotoxicity • Interactions: • Theophylline and other xanthenes (coffee and chocolate) • cidal • broad spectrum

31. Antibiotics Inhibiting Nucleic Acid synthesis Miscellaneous • Metronidazole [Flagyl] • DNA inhibition in Anaerobic bacteria • protozoa i.e.giardia, h.pylori (ulcers) • Other generic names end in -floxacin • nalidixic Acid [NegGram] • ciprofloxacin [Cipro] – anthrax drug of choice • levofloxacin [Levaquin] – extended spectrum for UTI’s once daily dosing

32. Mechanism of Action #5 Inhibition of specific metabolic pathways • sulfa drugs (sulfonamides) FOR UTI • lots of resistant strains • static • Enters CSF • SE: usually minor • nitrofurantoin [Furadantin, Macrodantin] • DNA inhibitor • Best in acid urine but Turns urine brown or rusty • Static or cidal • phenazopyridine [Pyridium] – azo dye • COMFORT only = to Decrease burning & urgency • Turns urine bright orange • Cranberry juice (& blueberry juice) • Interferes with adherence to bladder wall • Takes 4-8 weeks of 300 ml/day • static drugs • static & cidal

33. Drugs for UTI’s • Sulfonamides – lots of resistant strains • sulphasalazine used for IBD • Bacteriostatic • Action: prevent bacteria from using PABA • PO and IV • Enters CSF • SE: usually minor • Allergy – rash to SJS to anaphylaxis • Cross sensitivity to other sulfa drugs • alergic to one…alergic to all • Crystalluria • poorly soluble in urine(crystallizes in urine) • FORCE FLUIDS to combat this • Bone marrow toxic – aplastic anemia • Hemolytic anemia in pts with G-6PD deficiency • mediteranean descent

34. Drugs for UTI’s • methenamine [Mandelamine] • Cidal • Action: changes to formaldehyde in urine; bugs in urine die • SE: GI • nalidixic Acid [NegGram] – quinolone • nitrofurantoin [Furadantin, Macrodantin] • Best in acid urine for Chronic UTI’s • Static or cidal • Inhibits bacterial protein, DNA, & RNA synthesis • SE: NVA, allergy, pneumonitis, peripheral neuropathy • Turns urine brown or rusty.

35. Drugs for UTI’s • Phenazopyridine [Pyridium ] – azo dye • Antiseptic and anesthetic • Decrease burning & urgency • Turns urine bright orange • Cranberry juice (& blueberry juice) • Interfere c adherence to bladder wall • Takes 4-8 weeks of 300 ml/day

38. Drugs for TB • Long term tx  compliance issues • people stop taking their meds • Drugs are specific for mycobacteria • Use combination of PO drugs • Isoniazid [INH] • Rifampin • rifabutin [Mycobutin] – like rifampin • rifapentine [Priftin] – like rifampin • pyrazinamide [PZA] • ethambutol [Myambutol]

39. Drugs for TB • Preventive tx: if you don’t have active TB • 9 months INH • OR • 2 months of rifampin and PZA • OR • 4 months of rifampin • Standard tx (not for multidrug resistant TB) USES AT LEAST 2 DRUGS • INH + rifampin + PZA + ethambutol x 2 months • Get C & S results first • If sensitive to INH, rifampin & PZA : • Stop ethambutol • Then 4 months of INH + rifampin

40. First Line Drugs for TB • isoniazid [INH]– static or cidal • Jap, Chins, Eskis, and Nat Amsare “rapid acetylators”. • 50% of whites and blacks are “slow acetylators” • Action: may inhibit synthesis of mycolic acids • Used alone for prophylaxis, but not for tx. • SE: • peripheral neuritis - treated c pyridoxine Vit B6 • Optic neuritis • Hepatitis, Mental abnormalities, Seizures • Interactions: • Increased phenytoin levels • Aluminum in antacids  decreases absorption • Steroids  increases steroid effect & deceases INH effect • Disulfram  psychotic episode and coordination problems

41. First Line Drugs for TB • Rifampin • PO or IV • SE: • Flulike syndrome • Rash & urticaria • Epigastric pain, NVAD, abd cramps, flatulence, muscle and joint pains • Inc liver enzymes • Red-orange color to sweat, tears, saliva, urine, feces. • Interactions: • Oral contraceptives, coumadin, etc, etc.

42. First Line Drugs for TB • pyrazinamide [PZA] • Static or cidal • Same action as INH • SE: • Hepaptoxic • High uric acid levels • Rifabutin [Mycobutin] – like rifampin • Rifapentine [Priftin] – like rifampin • Long ½ life so dosed 2x/week

43. First Line Drugs for TB • ethambutol [Myambutol] • Only works for reproducing bugs • SE: • Optic neuritis • Mild allergies – rash, fever

44. Second Line Drugs for TB • Aminosalicylic acid [PAS, Paser] • Can  severe GI problems • Capreomycin [Capastat] – IM only • Cycloserine [Seromycin] – neurotoxic • Ethionamide [Trecator-SC] • For TB & Hansen’s • Streptomycin – IM only