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GENERAL THINGS TO KNOW

ANTIBIOTIC REVIEW DR. MAZIN BARRY, MD, FRCPC, FACP, DTM&H Assistant Professor & Consultant of Medicine Division of Infectious Diseases Faculty of Medicine King Saud University, Riyadh Head of Infection Control King Khalid University Hospital. GENERAL THINGS TO KNOW.

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GENERAL THINGS TO KNOW

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  1. ANTIBIOTIC REVIEWDR. MAZIN BARRY, MD, FRCPC, FACP, DTM&HAssistant Professor & Consultant of MedicineDivision of Infectious DiseasesFaculty of MedicineKing Saud University, RiyadhHead of Infection ControlKing Khalid University Hospital

  2. GENERAL THINGS TO KNOW • General stuff (Disease States, Bugs, Drugs) • Practice - Specific - Local epidemiology (organisms & resistance trends) - Formularies, cost • Patient – specific - Exposure history, risk factors for specific drugs - Allergies, organ dysfunction, interacting medications, weight, height

  3. RESOURCES • BOOKS - Mandell, Douglas, and Bennett’s Priciples and Practice of Infectious Disease - The Sanford Guide to Antimicrobial Therapy. HIV book also available. • ARTICLES - Treatment Guidelines from the Medical Letter “The Choice of Antibacterial Drugs” - Mayo Clinics Proceedings series • PEOPLE - Resident, attending: ID Consultation, Infection Control Personnel; Pharmacy; Micro Lab.

  4. THREE WAYS ANTIBIOTIC USEDProphylaxis, Empiric, Definitive • PROPHYLAXIS - Medical: ~ Exposure to virulent pathogen - HIV, N. meningitis ~ Immunocompromised - HIV with CD4<200, Asplenic, Neutropenic - Procedural (Surgery) Short course recommended / preferred ~ Endocarditis

  5. THREE WAYS ANTIBIOTICS USEDProphylaxis, Empiric, Definitive (2) • Empiric (usually up to 72 hours) - Diagnosis of infection made based on S/S, lab, etc. Likely pathogens suspected but specific pathogen not yet known. - Pick antibiotics based on: = Likely pathogens, local susceptibility trends, and patient-specific factors (allergies, organ dysfunction) - Pearls: = Get cultures on the front end (including special tests) = Start appropriate antibiotics ASAP.

  6. THREE WAYS ANTIBIOTICS USED Prophylaxis, Empiric, Definitive (3) • Definitive - Microbiologic or serologic diagnosis with susceptibilities known or presumed* * syphilis is susceptible to penicillin - Caveats on susceptibility testing:  Interpretation of MIC or KB zone as S, I, or R is bug-drug specific (relative to concentrations of drug in body)  Can’t just pick the one with the lowest MIC - Some results to broad-spectrum agents maybe suppressed (cascaded reporting)  Call the microbiology lab - Additional testing may be needed (KB or E-test)

  7. THREE WAYS ANTIBIOTICS USEDProphylaxis, Empiric, Definitive (4) • Definitive - Use the most effective, least toxic, narrowest spectrum, and most cost effective agent – the “Drug of Choice” (DOC) ~ May actually be a combination of drugs - Ampicillin and Gentamicin for enterococcus endocarditis - Know the alternatives especially for patients with allergy to drug of choice. - Drug, dose, route, interval, and duration is disease state and patient specific.

  8. How Long to Treat? • Not well defined! - Usually less than 14 days! ~ Longer for endocarditis, Osteomyelitis, Prostatitis (& varies by bug & drugs) - Track number of days of therapy in progress note & set endpoint! ~ CoagNegStaph Bacteremia: 5 – 7 days ~ Staph aureus Bacteremia: > 28 days (all IV) Prolonged unnecessary therapy increases risk of resistance, adverse effects, and cost!

  9. Know Your Bugs!Gram - Positive • S. aureus: - 25 – 50% Methicillin Resistant (MRSA) Originally in hospitals; Community Acquired strain now spreading - MSSA DOC: cloxacillin; Cefazolin - CA-MRSA: Vancomycin, Linezolid, Daptomycin ~ If uncomplicated: Trimeth/Sulfa (99%), Clindamycin (70%) • Enterococcus: - DOC: (Ampicillin or Vancomycin) PLUS (Gentamicin or Streptomycin) Nitrofurantoin, Amp or Vanc alone for UTI - VRE, ARE, HLARE varies by hospital

  10. Know Your Bugs!Gram – Positive (2) • S. pneumoniae: -- 20 – 45% have decreased susceptibility to penicillin. ~ = Highest in children (especially daycare, socioeconomic) = Example: Susceptible Intermediate Resistant Penicillin 51% 40% 9% Ceftriaxone 92% 9% (6@MIC 1) 0% Moxifloxacin 98% 2% 0% ~ CNS Infections: = High dose (HD) Ceftriaxone (2g IV Q 12h) + HD Vanco ~ Outside CNS: = Ceftriaxone; Respiratory FQ if at risk for resistance = High dose amoxicillin = +/- Doxycycline, TMP / SMX, Erythromycin

  11. Know Your Bugs!Gram – Negative • E. coli ~ 50% resistant to Ampicillin, Amp / Sulbactam ~ 25% resistant to Trimeth / Sulfa ~ 33% resistant to Ciprofloxacin • P. aeruginosa ~ “Best” Drugs (> 90% susceptible) = Ceftazidime, Cefepime, Piperacillin (with or w/o Tazo) = PLUS an Amikacin for synergy ~ Less effective (80-90% susceptible) = Tobramycin, Gentamicin ~ If C & S verifies susceptibility (65 – 80% susceptible) = Imipenem, Meropenem, Aztreonam, Ciprofloxacin

  12. Know Your Bugs!Gram – Negative (2) • Bad nosocomial Gram – Negative ~ Acinetobacterbaumanii = Doc Colistin* with meropenem (bleaching effect) +/- Amikacin * Alternative is tigecycline ~ Stenotrophomonasmaltophilia(resistant to Imipenem) = DOC Trimethoprin/Sulfamethoxazole (Bactrim) = 10 mg/kg/day of TMP components (2Ds tablets Q12h) • Most ICUs have their own flora & susceptibility patterns. Patients become colonized within 48-72 hrs with these bugs

  13. Know Your Bugs!Other Bacteria • Anaerobes Peptostreptococcus, Clostridium, & Bacteroides - Overall: Amox/Clav, Amp/Sulb, Ticar/Clav, Pip/Tazo, Meropenem, Imipenem, and Tigecycline - Mouth & Lungs: Clindamycin - Abdomen: Metronidazole • Atypical Legionella, Mycoplasma, Chlamydia - Macrolides, Tetracycline, Respiratory fluoroquinolones

  14. Know Your Bugs!By Mechanism of Action • Cell –Wall ~ Penicillin – Binding Proteins (PBP): Beta-Lactams = Penicillins +/- beta-lactamase inhibitors = Cephalosporins = Others (imipenem, aztreonam) ~ Percursor molecules: Vancomycin • Intracellular ~ Ribosomes: Macrolides (5OS), Tetracycline (30S), Aminoglycosides (30S & 50S) ~ DNA gyrase: Quinolones ~ Folate metabolism: Trimethoprim, Sulfa’s

  15. Know Your Bugs! Mechanism of Resistance • Altered target – PBP’s. ~ Absolute Change = no binding = MRSA is resistant to all beta-lactams et al ~ Relative Change =  binding,  MIC = Drug resistant S. pneumoniae • Enzymes destroy – Beta-lactamases ~ Penicillinase: MSSA, H. influenzae, anaerobes = Add beta – lactamase inhibitor or change structure ~ Cephalosporinase: Enterobacter et al ~ Extended Spectrum Beta Lactamase (ESBL): KlebPneumo, E. coli

  16. Penicillins • Penicillin PO, IV & IM = GP (Strep) • Amoxicillin PO, Ampicillin IV = GP (Strep), some GNR (70% H. influenzae) • Cloxacillin PO, IV = GP (MSSA) • Amoxicillin / clavulanate (AUGMENTIN) PO, IV = GP (MSSA, GNR, Anaerobes) • Piperacillin / Tazobactam (Tazocin) IV = GP (MSSA), GNR (> 90% PA), Anaerobes

  17. Cephalosporins & Other Beta-Lactams • Cephalexin PO  Aztreonam Cefazolin IV - Beta-Lactam allergy - GP (MSSA), GNR • Cefuroxime - GNR (80% PA)  Ceftriaxone IV, IM  Imipenem/cilastatin - GP (S. pneumo), Meropenem -GNR - GP (including MSSA) • Ceftazidime IV - 95% GNR - GNR (> 85% PA) - Anaerobes • Cefepime IV - GP (S. pneumo) - GNR (>90% PA) • Ceftaroline IV • GP (MRSA) • GNR (NOT PA, ESBL)

  18. Beta-Lactam Adverse Effects • Allergic / Hypersensitivity in 3 – 10% of pts. = Rash (4-8%) to anaphylaxis (0.01-0.05%, 10-20 minutes) ~ Carbapenems: 5% cross reactive, Cephs 10% ~ Vasculitis, Cytopenias, Fever, Interstitial Nephritis • N/V with PO • Seizures w/ high dose in renal insufficiency • Ceftriaxone: Biliary sludging and bilirubin displacement (don’t use in neonates)

  19. VANCOMYCIN • Exclusively Gram-Positive Spectrum, IV only* • “Last Line of Defense” - Methicillin Resistant Staph - Ampicillin Resistant Enterococcus - Multi-drug Resistant S. pneumonia - 2nd line for C. difficile Colitis (*only indication for PO Vanco) • IV only, Check levels & adjust frequency for renal impairment • Troughs = 10 – 20 (15-20 for pneumonia et al) • Peaks = 20-40 (higher in pneumonia et al) ?Clinical Utility? • 15 – 20 mg/kg/dose (1g) IV Q8 – 12h (Q24h+ for CICr < 60) - Call pharmacy for help with dosing.

  20. QUINOLONES • Ciprofloxacin - GNR (75% PA) • Levofloxacin, Moxifloxacin - GP (S. pneumo), GNR (respiratory; PA 70% w/ Levo) • Cl in pregnancy & children - Rash/photosensitivity, Chelates (PO), CNS side effects, Tendon Rupture QTcprologation, Hypo/Hyperglycemia

  21. AMINOGLYCOSIDES (all IV or IM) • Gentamicin, Tobramycin • GNR (Tobra > Gent vs. P. aeruginosa) • Amikacin, Streptomycin • TB, Multi-drug Resistant GNR • Renal elimination, variable penetration in to tissue CNS < 5%, Lungs 50%, Urine 10 – 100 X • Dosing: - Pick dose based on site/bug and interval per renal function (GFR < 60). - “Once Daily” for select patients only GNR; good renal function). • Nephrotoxicity (non-oliguric) & Ototoxic • Prolonged exposure to elevated levels (troughs >2).

  22. Macrolides & Lincosamides • Erythromycin • GP (Strep) & Atypicals • GI side effects and inhibits CYP450 = drug interactions • Azithromycin IV, PO Clarithromycin PO - GP (Strep), Atypicals & Respiratory GNR; Mycobacterium • Clindamycin (all PO, IV) - GP (GP 75% MRSA), Anaerobes - C. difficilecolitis

  23. Other Antibacterials • Tetracycline PO, Doycyclne PO & IV - GP, GN, Atypicals; Brucella - Binds orally with calcium deposits on teeth, photosensitivity • Trimethoprim / Sulfamethoxazole - GP (98% MSSA & MRSA), 80% GNR - Rash and other ADE’s, Drug interactions with warfarin • Metronidazole - Anaerobes & Protozoa - Reactions with EthOH, Metallic taste, drug interactions with warfarin • Nitrofurantoin - UTI (including VRE) - Contraindicated at GFR < 60

  24. Know your Drugs! • Get an ID consult for: - Linezolid MRSA, VRE lungs; bacterostatic • Daptomycin MRSA, VRE; endocarditis, not lungs • Tigecycline, Colistin PDR Acinetobacterbaumanii

  25. Antiviral • Antivirals - HSV: Acyclovir, Valacyclovir; Famiclovir - CMV: Ganciclovir, Valgancyclovir; Foscarnet - Influenza: Oseltamivir (Tamiflu), Zanamivir; Amantadine

  26. Antifungals • Binds Ergosterol (makes cell walls leak) Amphotericin B - Life – Threatening systemic mycosis • Inhibit cell wall synthesis (Beta 1, 3 D glucan) - Echinocandins (Anidulafungin, Caspofungin, Micafungin) - Candida (including azole R sps.)

  27. Azoles Inhibit Ergosterol Biosynthesis • Fluconazole Candida albicans, Crypto • Itraconazole PO; Histo, Blasto, Aspergillus Voriconazole Aspergillus et al Posiconazole PO Zygomycosis Ketoconazole, Miconazole, & Clotrimazole topical/dermatophytes Isavuconazole : invasive aspergillosis and mucormycosis

  28. Know your Drugs!Pharmacodynamics • Pharmacodynamics (PD) • Bacteriostatic: Inhibit ~ Generally avoid for endocarditis, meningitis, osteomyelitis, and febrile neutropenia ~ Tetracyclines, Macrolides, TMP / SMX, Linezolid • Bacteriocidal: Kill ~ Dose dependent (Peak:MIC > 10) - Aminoglycosides, Quinolones ~ Exposure dependent (T >MIC) - Beta – lactams, vancomycin ~ May require a combination of drugs (e.g., enterococci)

  29. Know your Drugs! • Absorption: IV vs PO - Great PO absorption with fluconazole, fluoroquinolones (watch drug interactions), Metronidazole, TMP/SMX, doxycycline. - IV only: ~ Vancomycin (except for C. difficile) ~ All antipseudomonal agents except ciprofloxacin ~ 3rd and 4th generation cephalosporins (may give IM) ~ Meropenem, Imipenem, ertapenem (IM available) and Aztreonam ~ Aminoglycosides (gentamicin et al) - may give small dose IM

  30. Know Your Drugs! • DISTRIBUTION • CNS Penetration: - Excellent: Metronidazole, chloramphenicol, fluconazole, TB drugs - Adequate with high doses: Ceftriaxone, ceftazidime, ampicillin - Problematic: Vanconmycin, aminoglycosides • Lungs: - Good: quinolones, Macrolides, beta-lactams - Modest: aminoglycosides

  31. Know Your Drugs! • Metabolism / Elimination - Kidneys - Adjust for renal dysfunction (Cl Cr) - May use lower doses for UTI - Liver - Adjust for liver dysfunction (???) - Potential for drug interactions

  32. Dosing in Renal Dysfunction • (140 – Age) X ibw / 72 X S. Cr. - Multiply result by 0.85 if patient female - Round S. Cr. Up (0.8?) if <1 and elderly • Cl Cr <60 adjust interval +/- dose of: - Penicillins (not Nafcillin, Oxacillin) - Cephalosporins (not Ceftriaxone) - Imipenem else 10 X  risk seizures - Aztreonam - Vancomycin - Aminoglycosides

  33. Dosing in Renal Dysfunction • Misc agents - TMP / SMX (and generally avoid) - Fluconazole - Acyclovir - Ganciclovir - Most nucleoside RTI’s • Avoid (nephrotoxic) - Amphotericin B (lipid forms less toxic)

  34. Dosing in Hepatic Dysfunction • Note – also generally don’t need to be adjusted for renal dysfunction. - Ceftriaxone, Nafcillin - Clindamycin, Metronidazole - Macrolides, Tetracyclines - Rifampin, Isoniazid

  35. Drug Interactions! • Drugs cleared by CYP 450 Statins, Cyclosporine, Benzodiazepines, Theophylline, Anticonvulsants, oral hypoglycemic - Levels increase by (Metabolism inhibited by)  Macrolides (Erythromycin)  Azoles (Fluconazole, Itraconazole)  Protease inhibitors  Ciprofloxacin - Levels decreased by (Metabolism induced by)  Rifampicin, rifabutin • Oral Contraceptives - Decreased with rifampin & nafcillin +/- others

  36. Drug Interactions! • Warfarin: - Effect & INR profoundly increased by  trimethoprim/sulfamethoxazole  metronidazole - Significant increase with  fluconazole, +/- Ciprofloxacin - Decreased by  Rifampicin/rifabutin • Multivalent Cations (Ca, Mag, Iron) +/- TF - Decreases absorption of:  Fluroquinolones  Tetracyclines

  37. Adverse EffectsAllergies (NEJM 2006; 354-601-9) • Penicillin Allergy: - Fully cross- reactive with other penicillins- May cross-react with cephalosporins  10% to 1st generation, 1 – 2% to3rd - Not cross reactive with aztreonam. • Sulfa Allergy: - other sulfonamides (including diuretics) - not sulfites, sulfates; +/- sulfones

  38. Adverse EffectsOther • Antibiotics generally safe but…. - Rash: almost any of them - Diarrhea, C. difficile colitis: most of them - Nephrotoxicity: Aminoglycosides, amphotericin - Photosensitivity: fluoroquinolones, tetracyclines - Relatively contraindicates in pregnancy: Aminoglycosides, fluoroquinlones, tetracycline, fluconazole, ribavirin et al..

  39. Preventing the Use of Antibiotics • Verify diagnosis & need for antibiotics - Consider other (non-infections) causes of symptoms - Remember: antibiotics don’t work against viruses • Vaccinate at risk patients - Children, elderly, immunocompromised, healthcare professionals. • WASH YOUR HANDS! - Also stethoscopes

  40. ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC CHARACTERISTICS

  41. ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC CHARACTERISTICS (CONT’D)

  42. ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC CHARACTERISTICS (CONT’D)

  43. ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC CHARACTERISTICS (CONT’D) PBP = penicillin-binding proteins MRSA = methicillin-resistant Staphylococcus aureus PRSP = penicillin-resistant Streptococcus pneumonia PPNG = penicillin-producing Neisseria gonorrhoeae ESBL = extended-spectrum ß-lactamase D-ALA = D-alanine PABA = para-aminobenzoic acid

  44. Acute Otitis Media (AOM) • Dx: bulging TM, or new otorrhea • Pathogen: • No pathogen (4%) • Virus (70%) • Bacteria + virus (66%) • Bacteria (92%) • Strept. Pneumo(49%) • H. Influenzae(29%) • Moraxella catarrhalis(28%)

  45. AOM • Need to know prior antibiotic use and local susceptibilities for S. pneumonia • Amoxocillin, Amoxocillin/clavulinate, cefpodoxime, moxifluxacin (10 days) • Failure to respond in children: tympanocentesis

  46. Malignant Otitis Externa • Sever ear pain, swelling, fever unusual, high ESR • Bony involvement common, can progress to OM of base of skull and TM joint (do CT and treat 6 weeks with surgical debridement) • RF: Elderly, DM, AIDS, chemotherapy • Usually Pseudomonas aeruginosa (95%)  Imipenem or Meropenem  Ceftazidime or Cefepime  Piperacillin (+/- tazobactam) and tobramycin  Ciprofloxacin - PO if mild / early, check susceptibilities

  47. Tonsillitis, pharyngitis • Streptococcus sp. (Group A, C, G) • Viral: EBV, CMV • C. diphtheria • Arcanobacteriumhaemolyticum(rare) • Mycoplasma pneumonia (with cough) • Fusobacteriumnecrophorum • STD: primary HIV, HSV, N. gonorrhea, rarely secondary syphilis

  48. Tonsillitis, pharyngitis • Focus on group A strept. (GAS) (10%) • Decrease symptoms, prevent suppurative complications, decrease contagion, eradicate GAS to prevent acute rheumatic fever • Dx: symptom score above 1 (1 point each for): • History of fever, absence of cough, tender cervical LN, tonsillar exudate • NOT GAS: rhinitis, hoarseness, cough then • Rapid strep Ag test • Rx: Penicillin V 500mh bid for 10 days, cefuroxime if allergic • Can use clindamycin, azithromycin but resistance reported

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