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KSU NUR 7755 FALL 2010 D. GODWIN

ANTIBIOTIC OVERVIEW. KSU NUR 7755 FALL 2010 D. GODWIN. How to choose…. PROPER DIAGNOSIS LIKELY PATHOGEN HOST CHARACTERISTICS (immune status, infx site, body organ function) DRUG OPTIONS: Drug ’ s expected activity aga pathogen DRUG SELECTION. DIAGNOSIS: H&P.

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KSU NUR 7755 FALL 2010 D. GODWIN

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  1. ANTIBIOTIC OVERVIEW KSU NUR 7755 FALL 2010 D. GODWIN

  2. How to choose… • PROPER DIAGNOSIS • LIKELY PATHOGEN • HOST CHARACTERISTICS (immune status, infx site, body organ function) • DRUG OPTIONS: • Drug’s expected activity aga pathogen • DRUG SELECTION

  3. DIAGNOSIS: H&P • Hx: Onset? Progression? Local/general sx?APQRST? Predisposing Factors: • exposure to virus/bacteria/allergen/ Mycobacteria? Virus? Chlamydia? Mycoplasma? • Food, travel … • PE: • VS: tachycardia/ tachypnea/ FEVER • Fever:Diff: autoimmune d/o, malignancy • Lack of fever: ?nsaid , steroid?, immunosuppressed? (<105 not harmful,?helpful) • Drug induced fever: varies w/ drug use; hypersensitiviy reaction, antigen-antibody complex-> macrophages-> release interleukin 1 • (b-lactams, antconvulsants, allopurinol, nitrofurantoin, sulfonamides, phenothiazines, methyldopa, hydralazine

  4. DIAGNOSIS cont HEENT: TMs, pharynx, nodes Chest: heart sounds, lung sounds Abd/GU: tender? Rebound? Tense? Swelling? Skin: erythema, tenderness, d/c PAIN: location, quality etc Neuro: gait? Speech? Affect?

  5. DIAGNOSIS: Lab Identify pathogen: Source: • Throat swab: • NP swab: • Sputum: • Wound/Lesion culture: • Urine Culture: • Lab/ Radiology test: • CBC • ESR • CXR

  6. CELL LINE bands T-cells B-cells Natural killer cells Hi: bact Allergy parasite Hi: viral

  7. LIKELY PATHOGEN: LAB • usu Leukocytosis b/c incr. granulocytes (neuts, bands, eos), lymphs to destroy microbes • Bacterial: incr granulocytes often w/ bands (left shift) • Low WBC: poor response to bact infx.. poor prognosis • Lymphocytosis: usu viral, TB, fungal • Mono: TB, lymphoma • Eos: allergy, parasites

  8. LIKELY PATHOGEN: LAB UA: ua, cx,? wbcs, nitrites?, LE? Sputum: epithelials? Leukocytes? CSF: cells? Protein? glucose? joint fluid: culture? Blood cultures :2 sets (aerobic/anaerobic) 1hr apart Result… is it: Pathogen? Contaminant? Nl flora? (esp/ w/skin, pharynx, nose, ears, eyes, throat perineum)

  9. Likely Respiratory Pathogens Atypicals: Chlamydia Mycoplasma Legionella G+: Strep pneumoniae Strep pyogenes Staph aureus G-: Moraxella Catarrhalis Hemophilus influenza Klebsiella Pseudomonas Consider likely organism when choosing antibiotic.

  10. Likely Pathogen: Acute Sinusitis Children Adults • S. pneumoniae35-42% 20-43% (40% Pcn resistant) • H. influenzae21-28% 22-35% • (30% to 40%beta -lactamase producing thus amoxicillin resistant.) • M. catarrhalis21-28% 2-10% • (75% beta -lactamase producing thus amoxicillin resistant.) • Strep. species 3-7% 3-9% • Anaerobes 3-7% 0-9% • Staph. aureus 0-8% Chronic sinusitis: • Pseudomonas aeruginosa • Group A streptococcus • Staphylococcus aureus • anaerobes

  11. AOM Likely Pathogens: S.pneumo, H.Flu, M.Cat NL AOM

  12. Like pathogen: S. Pyogenes ?mono ?gonorrhea Strep throat

  13. Likely pathogen? Strep pneumo H.flu S.aureus m.cat Pseudomonas Klebsiella Mycoplasma Chlamydia Legionella Influenza virus adenovirus Lobar pneumonia

  14. Likely pathogen: Skin & Soft Tissue Common organisms: Mrsa 15% Mssa 31% S. aureus 46% G+, aerobic Other 17.3% Pseudomonas aeruginosis G-, aerobic 10.8% Enterococci (faecalis) G+, aerobic 8.2% E.Coli G-, anaerobic 7% Enterobacter G-, aerobic 5.9% Klebsiella G-, aerobic 5.1%

  15. Likely pathogen: Strep pyogenes Scarlet Fever Rash

  16. Likely Pathogen: S. aureus Deep folliculitis: Carbuncle(group of infected hair follicles)

  17. Likely Pathogen: Staph or Strep Lymphangitis (w/cellulitis)

  18. Likely Pathogens: GU • Escherichia coli: 85% • Staphylococcus saprophyticus: 4.4% Women >50yr: • Klebsiella pneumonia 4.3% • Enterococcus species • Proteus mirabilis 3.7% • Pseudomonas and other gram-negative rods

  19. LIKELY PATHOGEN: Local antibiograms

  20. National G- antibiogram 2007, SE US Org. lev cipro amp roc ceftin septra • Klebsiella 88 85 0 88 79 85 • E coli 71 71 45 95 90 73 • Proteus 62 61 90 90 97 68 • Pseudomonas 62 61 - - - -

  21. s.pneumo antibiogram: central ga. 2009 Mic %S %I %R • Levo 1 97 0 3 • Rocephin 1 96 1 3 • Amox/clav8 80 14 6 • Ceftin 8 96 1 3 • Omnicef 8 68.8 4.3 26.9 • Septra 4 61 9 28 • Clinda 73 3 22 • Pcn 4 60 20 20

  22. Susceptibility of Isolates Percentage of Strains Susceptible Agent S. pneumoniae H. influenzae M. catarrhalis • Amox/clav 94 98 100 • Amoxicillin 80 77 70 • Rocephin 96 100 94 • Omnicef 100 85 • Ceftin 97 83 50 • Erythro 54 0 100 • Azithromycin 2 100 • Tetra 69 25 96 • Clindamycin 78 0 0 • Levo 97 100 100 • TMP/SMX 70 78 19

  23. HOST CHARACTERISTICS: Allergies: reaction vs allergy Current Meds: AGE: pathogens differ in age groups Organ function/ maturity by age >65: decline in nephrons: increase side effects Pregnancy: drug teratogenicity Liver function: Renal function: EX: amoxil w/ nl RF: t1/2 0.7-1.2 hr w/ decreased RF: t1/2 7-21 hr

  24. Antibiotic DRUG OPTIONS SULFA: Septra, Bactrim (TMP/SMX) TETRACYCLINES: doxycycline MACROLIDES: Erythromycin Clarithromycin (Biaxin) Azithromycin (Zithromax) KETALIDE: Telithromycin (Ketek) QUINOLONES: Levofloxacin (Levaquin) Ciprofloxacin (Cipro) Moxifloxacin (Avelox) Gemifloxacin (Factive) OTHER:Macrobid, Flagyl PENICILLINS: Amoxicillin, PenV Augmentin, BiCillin CEFALOSPORINS: 1stgen: Cephalexin (Keflex) 2nd gen: cefuroxime (Ceftin) cefprozil (Cefzil) cefaclor (Ceclor) cefadroxil (Duricef) 3rd gen: cefdinir (Omnicef) cefpodoxime (Vantin) cefixime (Suprax) ceftibuten (Cedax) ceftriaxone (Rocephin)

  25. PCN hx 1928 Sir Alexander Fleming observed Penicillium mold destroyed colonies of S.aureus 1940 Europe needed mass quantities for war 1941 attempts at mass production 3/14/1942: 1st pt treated for streptococcal septicemia w/ U.S.-made PCN. 1/2 total supply produced at the time used on that one patient. 6/1942 only enough U.S. PCN avail. to treat ten pts 1943:PCN:most effective antibact. agent to date 1944PCN mass-produced... available to treat Allied soldiers wounded on D-Day • Price dropped: • 1940:nearly priceless • 1943: $20/dose • 1946: $0.5/dose

  26. PCN PCN actively excreted: 80% rapidly cleared w/i 3-4h --> thus required frequent dosing. Early PCN era: drug so scarce and so valued, it was isolated from urine and reused Research needed to slow PCN excretion. Look for molecule to compete w/ PCN for the transporter responsible for excretion . Thus: probenecid -->competitively inhibits PCN excretion, increasing PCN concentration, prolonging activity. Eventually, mass-production techniques and semi-synthetic PCN resolved the supply issues.

  27. PCN hx cont. • 1947:resistant Staph. aureusappears • 1955 Tetracycline :most prescribed broad spectrum anbx in US • 1957Nystatin patented, cure fungal infxs • 1981 SmithKline Beecham patented semisynthetic antibiotic “Amoxicillin” • 1998 sold as Amoxicillin, Amoxil, Trimox.

  28. PCN iterations… Narrow spectrum of activity Then ..semisynthetic penicillins, w/improved bioavailability, spectrum, stability, tolerance • 1st: ampicillin: broad spectrum Then .. beta-lactamase-resistant PCNs (flucloxacillin, dicloxacillin,methicillin). Then…anti-pseudomonal PCNs (carbenicillin, ticarcillin, piperacillin, (good Gram-neg activity). Other beta lactams: carbapenemscephalosporins,

  29. Organisms.. • Ampicillin: • G+ • some G- (proteus, Ecoli, Hflu) • Augmentin: • addition: G+:MRSA • extended g-: Hflu, Mcat, klebsiella • Cephs: • 1st gen: G+, some G- • 2nd: better G- (Hflu, Mcat) • 3rd: broad G-, Pseudomonas, less G+ • 4th: improved resistance to B-lactamases

  30. Mode of action: bactericidal PCN interfere w/cell wall PCNs bind to PBPs which form the bonds between crosslinks in peptidoglycan inhibit synthesis of peptidoglycan layer (mesh-like layer outside the plasma membrane) Penicillin-binding proteins (PBPs). Peptidoglycan layer is important for cell wall integrity, especially in Gram+ organisms thicker in Gram(+)bacteria (20-80nanometers) vs Gram(-) bacteria (7-8nanometers)

  31. resistance to β-lactams anbx Bacteria alter their PBP proteins. Thus..β-Lactam anbxs cannot bind as effectively to altered PBPs IE:MRSA and PCN-resistant S. pneumo Increase Dose of BL ADD: clavulanic acid …inactivates penicillinase Gm(-) bacteria produce Beta Lactamases….Enzymes that break open the antibiotic’s β-lactam ring Broad spectrum B-lactamases Extended spectrum b- lactamases, (ESBL) Penicillinase Cephalosporinases Mycoplasma has no cell wall--inherently resistant to B -lactams

  32. Beta lactams b/c “Beta lactam ring” Ampicillin • Amoxicillin Penicillin Augmentin

  33. PCNs Narrow-spectrum (β-lactamase resistant) methicillin oxacillin nafcillin cloxacillin dicloxacillin flucloxacillin • Narrow-spectrum • (β-lactamase sensitive) • benzathine PCN • benzylPCN (PCN G) • phenoxymethylpcn (PCN V) • procaine PCN

  34. Broader spectrum PCNs: Extended-spectrum temocillin Azlocillin Carbenicillin Ticarcillin Mezlocillin Piperacillin Moderate-spectrumAmoxicillinAmpicillin Broad-spectrumamoxicillin+clavulanic acid (Augmentin)

  35. Cephalosporins • 2nd generation • Moderate spectrum with anti-Haemophilus activity • Cefaclor (Ceclor) • Cefuroxime (Ceftin) • Cefprozil (Cefzil) • 2nd generation cephamycins • Moderate spectrum with anti-anaerobic activity. • Cefotetan IM/IV • Cefoxitin (Mefoxin) 1st generation Moderate spectrum Cephalexin(Keflex) Cefazolin (Ancef) Cefadroxil (Duricef)

  36. Cephs • 4th generation • Broad spectrum w/ enhanced activity against Gram (+) bacteria and β-lactamase stability. • -cefepime (Maxipime) 3rd generation Broad spectrumCeftriaxone(Rocephin)Cefotaxime( Claforan)Cefpodoxime (Vantin)Ceftibuten (Cedax)Cefdinir (Omnicef) Broad spectrum w/ anti-Pseudomonas activity. Ceftazidime(Fortaz)

  37. Other beta lactams • Monobactams • Unlike other β-lactams, the monobactam contains a nucleus with no fused ring attached. Thus, there is less probability of cross-sensitivity reactions. • aztreonam (Azactam) • tigemonam • nocardicin A • tabtoxinine-β-lactam Carbapenems & Penem Broadest spectrum of β-lactam anbxs imipenem (with cilastatin meropenem ertapenem faropenem doripenem

  38. SIDE EFFECTS INFREQUENT: Fever Vomiting Erythema Dermatitis Angioedema Seizures Pseudomembranous colitis COMMON: Diarrhea/Nausea Rash/ Urticaria Neurotoxicity Superinfection (candidiasis)

  39. PCN misc • No renal adjustment:(non-renal clearance) • Nafcillin • Oxacillin • Cloxacillin • Dicloxacillin • Renal adjustment: Ampicillin • Usually ok w/ preg, lactation, coumadin

  40. Macrolides erythromycin “macrolide lactone ring” azithromycin Clarithromycin

  41. Macrolide:MOA “protein synthesis inhibitors” Ribosomes, the site of protein synthesis, are a major target for antibiotics. The bacterial ribosome subunit“50S” contains “peptidyltransferase” The “peptidyltransferase” forms peptide links between amino acids Macrolide antibiotics inhibit the “peptidyltransferase” by binding at the peptidyl transferase cavity This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. protein

  42. MOA • Macrolides accumulate w/i WBCs, and are transported to site of infection. • Telithromycin: highest tissueconcentration then azithro, clarithro, and erythro • Azithro:high levels in sputum,lung, • neutrophil: (10-100x plasma) • Clarithro: lung (levels 6-8x plasma ). The clinical significance of better tissue penetration not known. Organisms: Atypical: Mycoplasma, Legionella, Chlamydia ?S. pneumo ?Hflu

  43. resistance Acquired resistance • altered macrolide binding sites on bacterial ribosome • active macrolide efflux pump

  44. Azithro metab Clarithro metab • T 1/2 11-14 hrs. • W/Mult doses: T1/2: 68hrs • Elimination: bile,feces • Urine: 6% unchanged • No renal adjustment • rapid first-pass hepatic metabolism. • clarithromycin T1/2 5hr metabolite T1/2 7hr • XR:slower abs; • take w/ food • routes of elimination: urinary / biliary • Renal adjustment 50% • Bioavailability: 50% clarithromycin best macro.

  45. quinolones Syntheticbroad-spectrum bactericidal anbx “Fluoroquinolone”: fluorineatom attached to the central ring system cipro levofloxacin quinolone

  46. Quinolones: MOA Inhibits two bacterial topoisomerases. (1)DNA gyrase: enzyme that unwinds double stranded DNA so it can duplicate(Gm- bacteria) (2)TopoisomeraseIV: untangles daughter chromosomes (Gm+ bacteria) • Quinolonesbind these enzymes thus prevent bacterial DNA from unwinding and duplicating. • But…Resistance develops:Mutation of DNA gyrase or topoisomerase IVEfflux

  47. Quinolones… Bacterial cidal • Quinolones enter cells thru pores in bact. cell walls -> thus effective to treat intracellular pathogens such as Legionella pneumophila , Mycoplasma pneumoniae • Effective against… • Atypicals • G+, G- • Not anaerobes

  48. U.S. Boxed Warning: 1st gen: attempt to create a synthetic chloroquine (WWII malaria drug) 1962:“nalidixic acid” for UTI 1972:M/S d/o reported Incr. risk tendonitis & tendon rupture Esp. > 60yo; steroid use; organ transplant 1981:Rheumatic disease reported w/norfloxacin 1996:Warning label requested re: tendon rupture 2005:2nd petition seeking black box warning FDA responded.. “no decision yet” 2006:3rd petition 2008:FDA requested boxed warning regarding spontaneous tendon ruptures

  49. Interactions Increase quinolone toxicity: Theophylline, NSAIDS,corticosteroids Reduced quinolone absorption: cations (ie: Al or Mg-containing antacids, Ca, Fe, Zn Interactions w/ : Sucralfate, Probenecid, Cimetidine, Warfarin, antiviral agents, Phenytoin, Cyclosporine, Rifampin, Pyrazinamide, Cycloserine CYP1A2 inhibitor (esp cipro) : increased level antidepressants (ie: amitriptyline, imipramine), clonazapine, Olanzapine, caffeine, Ropivacaine, Theophylline, Zolmitriptan SE: tendon rupture, QT prolongation

  50. 2nd-generation: ciprofloxacin Cipro ofloxacin(opth. only) REMOVED FROM CLINICAL USE: enoxacin fleroxacin UNAVAILABLE US: lomefloxacin nadifloxacin rufloxacin pefloxacin RESTRICTED USE: norfloxacin Quinolone generations 1st-generation: REMOVED FROM CLINICAL USE: cinoxacin GENOTOXIC flumequine nalidixic acid UNAVAILABLE US: oxolinic acid piromidic acid pipemidic acid rosoxacin(Restricted use)

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