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Antibiotic Review by Dr. Mazin Barry: General Guidelines & Clinical Pearls

Gain valuable insights on antibiotic use - from prophylaxis to definitive treatment - covering disease states, bugs, drugs, and local epidemiology. Explore resources, including books, articles, and expert advice. Understand the three ways antibiotics are utilized and how to choose the most effective treatment. Learn about common pathogens and treatment options for Gram-positive and Gram-negative bacteria. Stay informed on evolving resistance patterns. Discover best practices for antibiotic therapy duration and considerations in clinical settings.

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Antibiotic Review by Dr. Mazin Barry: General Guidelines & Clinical Pearls

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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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