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Antibiotic Basics

Antibiotic Basics. Steven Bradley, MD Harborview Chief Medical Resident Inpatient Services. Antimicrobial Considerations. Likely organism and susceptibilities Site of infection - SSTI, bacteremia, pneumonia, meningitis, UTI Host factors - Immune deficiencies, age, allergies, renal and

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Antibiotic Basics

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  1. Antibiotic Basics Steven Bradley, MD Harborview Chief Medical Resident Inpatient Services

  2. Antimicrobial Considerations • Likely organism and susceptibilities • Site of infection - SSTI, bacteremia, pneumonia, meningitis, UTI • Host factors - Immune deficiencies, age, allergies, renal and hepatic function • Antimicrobial factors - Dosage, route, drug interactions, tissue penetration, toxicity, cost • Public health considerations - Selection of resistance

  3. Antimicrobial Case 1 20 yo woman presents with 3 days of fever, sore throat, and cervical adenopathy. Rapid strep test is positive. What is the preferred therapy? • Azithromycin for 5 days • Penicillin V for 10 days • Levofloxacin 500 mg for 10 days • Vancomycin 1 gm BID for 7 days

  4. Antimicrobials: Site of Action Protein Synthesis 50S Ribosome- Macrolides/Ketolides- Clindamycin- Chloramphenicol- Quinupristin-Dalfopristin 30S Ribosome- Aminoglycosides- Tetracyclines - Glycylcyclines 70S Initiation Complex- Linezolid Cell Wall- Beta-Lactams - Glycopeptides Cell Membrane- Daptomycin - Polymixin DNA Inhibitor - Fluoroquinolone- TMP-SMX- Metronidazole Adapted from David Spach, MD

  5. Bacteria: Cell Wall Synthesis Cell Wall Synthesis Penicillin Binding Proteins Penicillin Binding Protein DNA Cell Wall Cell Membrane Adapted from David Spach,MD

  6. Beta-lactam Antimicrobials • Penicillins • Cephalosporins • Carbapenems • Monobactams

  7. Site of β-lactamase Activity O R1 C NH HC H2C C C N C COOH S CH3 CH3 O β-lactamase

  8. Beta-Lactam: Mechanism of Action Cell Wall Synthesis Beta-Lactam DNA Cell Membrane Cell Wall Penicillin Binding Proteins Adapted from David Spach, MD

  9. Penicillins • Penicillin G and penicillin V • Streptococcus pyogenes • Pharyngitis, syphilis • Aminopenicillins • Ampicillin and amoxicillin • H. influenzae, Enterococcus, Listeria • Acute otitis media, acute bacterial sinusitis • Penicillinase-resistant penicillins • Methicillin, nafcillin, oxacillin, dicloxacillin • Staphylococcus aureus (MSSA), Streptococcus • No gram-negative activity • SSTI, osteomyelitis, septic arthritis

  10. Extended-spectrum Penicillins • Carboxypenicillins (Ticarcillin) • Gram-negative coverage including Pseudomonas • Ureidopenicillins (Piperacillin) • Gram-negative coverage including Pseudomonas • Penicillin β-lactamase inhibitor combinations • Amox-clav, amp-sulb, ticar-clav, pip-tazo • Increase Staphylococcus and anaerobic coverage

  11. Cephalosporins • First Generation • Cefazolin, cephalexin • Second Generation • Cefuroxime • Cefamycins: cefoxitin, cefotetan • Third Generation • Ceftriaxone, ceftazidime • Fourth Generation • Cefepime Increasing Gram-negative Coverage Increasing Gram-positive Coverage

  12. Carbapenems • Imipenem/cilastin, meropenem • Broad spectrum of activity including Pseudomonas • Meropenem less likely to provoke seizures • Ertapenem • Not active against Pseudomonas, Acinetobacter, and Enterococcus faecalis • Most reliable activity against ESBL and ampC containing organisms

  13. Monobactams • Aztreonam • Activity restricted to aerobic gram-negative bacteria including most Pseudomonas • Does not display cross-reactive hypersensitivity reactions in patients with penicillin allergies

  14. Beta-Lactam Allergy • 10-20% of those reporting PCN allergy are truly allergic when assessed by skin testing • Positive predictive value of 14% • Potential cross-reactivity with cephalosporins (8%) and carbapenems, but not monobactams • Skin test for major (benzylpenicilloyl polylysine) and minor determinants • Positive skin test: 41-67% risk of significant allergy • Negative skin test: 1-4% risk, none life threatening • Desensitization when no other options

  15. Antimicrobial Case 1 20 yo woman presents with 3 days of fever, sore throat, and cervical adenopathy. Rapid strep test is positive. What is the preferred therapy? • Azithromycin for 5 days • Penicillin V for 10 days • Levofloxacin 500 mg for 10 days • Vancomycin 1 gm BID for 7 days

  16. Antimicrobial Case 2 45 y o woman presents with 3 day history of acute onset of fever 39 C, chills, cough productive of green phlegm, SOB, and right-sided chest pain. CXR demonstrates RLL infiltrate.

  17. Community-Acquired Pneumonia • Most common pathogens S. pneumoniae, H. influenzae, Moraxella with concern for C. pneumonia, M. pneumoniae, and Legionella • 2002-2003 US Survey revealed 34% non-susceptible (16% intermediate, 18% resistant) • WA 2003: 16% intermediate, 7% resistant • S. pneumoniae do not produce beta-lactamase • Alteration in penicillin binding protein with decreased affinity for beta-lactam • Beta-lactamase inhibitors (clavulanate or sulbactam) will not improve efficacy

  18. Streptococcus pneumoniae Resistance AntimicrobialPercent Resistant Macrolide 29% TMP/SMX 32% Tetracyclines 16% Fluoroquinolones* 2.3% *21.9% of S. pneumoniae isolates in 2002-2003 had fluoroquinolone mutations in parC and/or gyrA compared to 4.7% in 1997-1998. Clin Infect Dis 2005;41:139-48

  19. Community-Acquired Pneumonia • Outpatient • Macrolide or doxycycline • Respiratory fluoroquinolone, if recent antimicrobial tx • Inpatient medical ward • -lactam + macrolide vs. fluoroquinolone • Retrospective analysis of 14,000 Medicare patients found lower mortality with cephalosporin + macrolide or fluoroquinolone compared to cephalosporin alone (Arch Intern Med 1999;159:2562-72) • Lower in-hospital mortality among patients with bacteremic pneumococcal pneumonia treated with -lactam + macrolide compared to -lactam alone (Clin Infect Dis 2003;36:389-95) Clin Infect Dis 2003;37:1405-33.

  20. Fluoroquinolone: Mechanism of Action Fluoroquinolone DNA Topoisomerase IV DNA Gyrase DNA Cell Wall Cell Membrane Adapted from David Spach, MD

  21. Fluoroquinolones • Concentration-dependent killing (AUC:MIC) • Moxifloxacin is hepatically eliminated, not for urinary infections • Adverse events • GI • CNS • Photosensitivity • Prolonged QTc • Tendonitis/arthropathies • Hyperglycemia or hypoglycemia, particularly elderly with DM

  22. S. pneumoniae and Fluoroquinolones Drug MIC90 AUCFree AUC:MICFree Ciprofloxacin (750 bid) 1.0 28 28 Levofloxacin (500 qd)1.0 34 34 Levofloxacin (750 qd)1.0 70 70 Gatifloxacin (400 qd) 0.25 26 106 Gemifloxacin (320 qd) 0.03 140-280 Moxifloxacin (400 qd)0.12 24 200 Cutoff criterion of AUC:MIC >33.7 for gram-positives? Clin Infect Dis 2005;41:S127-35

  23. High-dose, Short-course Levofloxacin for CAP • Attempt to increase AUC:MIC ratio while decreasing overall drug exposure • Multi-center, randomized, double-blind study comparing 750 mg qd x 5 days vs. 500 mg qd x 10 days in the treatment of CAP • Found equivalent clinical and microbiological outcomes Clin Infect Dis 2003;37:752-60

  24. The patient decompensated and required intubation. He became afebrile after 48 hours. They remained intubated at 96 hours and developed a new fever and infiltrate on CXR. What infection are you concerned for? What pathogens need to be considered in this setting? What antibiotic choices are appropriate? Case Modified

  25. Nosocomial Pneumonia/Ventilator Associated Pneumonia • Common pathogens include coliforms, Staph and Pseudomonas aeruginosa • Coverage should now cover broadly for gram positives, gram negatives, and Pseudomonas • Anti-pseudomonal penicillin (pip/tazo) or fluoroquinolone • MRSA coverage (vanco) • Eight day therapy equivalent to 14 day

  26. Pseudomonas and Fluoroquinolones Drug Dose Cmax MIC AUCfree:MIC Ciprofloxacin 400 q12 4.1 0.125 144 400 q8 4.1 0.125 184 Levofloxacin 750 q24 12.1 0.5 152 Gatifloxacin 400 q12 4.6 1.0 28 Moxifloxacin 400 q24 4.2 2.0 10 New IDSA and ATS Guidelines for HAP/VAP recommend Ciprofloxacin 400mg IV q8hr or Levofloxacin 750 mg qd Am J Respir Crit Care Med 2005;171:388-416

  27. Antimicrobial Case 6 20 y o woman presents with 2 day h/o dysuria, urgency, and frequency. UA with >50 WBC/hpf, +leukocyte esterase Cystitis treatment options: Amoxicillin, 40-50% resistance among E. coli Nitrofurantoin x 7 days -cystitis only, does not achieve adequate blood levels TMP-SMX x 3 days, though increasing resistance -culture selection bias reflecting hospital setting -85% predicted clinical cure rate with 30% resistance Fluoroquinolone, ? if >10-20% resistance to TMP-SMX Clin Infect Dis 1999;29:745-58

  28. Antimicrobial Case #3 • What if this patient was 75 and had a chronic foley catheter?

  29. Complicated UTI • In the setting of obstruction (BPH), reflux, catheter • Similar pathogen profile • Enterobacteriaceae (E.coli), enterococci • Nosocomial bugs • Treat for extended period (2 weeks) and remove obstruction if possible • Beware of asymptomatic bacteruria • Treatment leads to resistance

  30. Antimicrobial Case 5 35 y o man with a history of methamphetamine use presents to clinic with a right biceps abscess.

  31. Previous “Standard of Care” • If abscess appreciated, I&D performed without culturing • Depending on severity of SSTI, either admitted for IV beta-lactam (cefazolin or nafcillin), or discharged empirically on cephelexin without concern for resistant organisms • This approach is no longer appropriate

  32. Proportion of S. aureus Nosocomial Infections Resistant to Oxacillin (MRSA) Among Intensive Care Unit Patients, 1989-2003* *Source: NNIS System, data for 2003 are incomplete

  33. Community-Associated MRSA • Clinical manifestations • Predominantly skin and soft tissue (JAMA 2003;290:2976-2984) • Necrotizing fasciitis (N Engl J Med 2005;352:1445-53) • Necrotizing pneumonia (Clin Infect Dis 2005;40:100-7) • Different from HA-MRSA • Panton-Valentine Leukocidin exotoxin associated with tissue necrosis and leukocyte destruction (JAMA 2003;290:2976-2984)

  34. Increased Rates of MRSA Healthcare contact Surgery Dialysis Indwelling devices IDDM HIV Long-term care facilities IDU (Clin Infect Dis 2002;34:425-33) Correction facilities (Clin Infect Dis 2003;37:1384-8) MSM (Clin Infect Dis 2005;40:1529-34) Native Americans, Pacific Islanders Other close contact Athletic (N Engl J Med 2005;352:468-75) Nasal Carriage of S. aureus • 20-40% of people colonized with S. aureus • 20% persistent, 60% intermittent, 20% never

  35. Antimicrobial Susceptibility Patterns CA-MRSA HC-MRSA Clindamycin 83 21 Erythromycin 44 9 Fluoroquinolone 79 16 Rifampin 96 94 Tetracycline 92 92 TMP/SMX 95 90 Vancomycin 100 100 JAMA 2003;290:2976-2984

  36. Vancomycin Linezolid Daptomycin Quinupristin/dalfopristin Tigecycline TMP-SMX Minocycline/Doxy Clindamycin Fluoroquinolone Linezolid Treatment Options for MRSA Infections Intravenous*Oral* *with or without rifampin, however NEVER use rifampin monotherapy due to rapid emergence of resistance

  37. TMP/SMX MechanismThe Folic Acid Pathway Sulfonamides Trimethroprim PABA // DihydrofolicAcid // TetrahydrofolicAcid Tetrahydropteroic acid synthetase Dihydrofolate reductase Purines Adverse Events: -Hypersensitivity reaction -Marrow suppression -Hemolysis (G6PD deficiency) -Displace bilirubin from albumin DNA

  38. Oxazolidinone: Mechanism of Action 50S Ribosome Oxazolidinone 30S Ribosome 50S fMet-tRNA 30S 70 S Initiation Complex DNA Modified from David Spach, MD

  39. Linezolid • Oxazolidinone • Active against MSSA, MRSA, VRSA, coag-neg Staph, S. pyogenes, S. pneumoniae, E. faecalis, E. faecium including VRE, as well as some Nocardia and mycobacteria • Oral bioavailability 100% • Adverse events: • GI (nausea and vomiting) • marrow suppression (thrombocytopenia, anemia, leukopenia) • serotonin syndrome (weak monoamine oxidase inhibitor) • lactic acidosis • optic neuritis • Linezolid-resistant VRE and MRSA reported due to mutation in 23S rRNA

  40. Concerns with Vancomycin • Association between increasing MIC and clinical failure, particularly prolonged bacteremia • Monitoring of serum levels • No clear relationship between level, efficacy and toxicity • Routine monitoring not necessary • Changing renal function or renal insufficiency • Peak levels should not be measured as vancomycin is not “concentration-dependent” • Trough of 15-20 mg/L in endocarditis, osteomyelitis, and VAP though clinical data is limited Clin Infect Dis 2006;42:S51-7 Am J Respir Crit Care Med 2005;171:388-416

  41. MRSA Nosocomial Pneumonia • Retrospective analysis of a prospective, randomized, double-blind study • Vancomycin +/- aztreonam vs. linezolid +/- aztreonam • Survival benefit with linezolid in the sub-set of patients with MRSA pneumonia • Vancomycin group with higher rates of bacteremia and co-morbidities (cardiac, diabetes, renal) • Role of toxin inhibition with linezolid or clindamycin? • Awaiting prospective confirmation Chest 2003;124:1789-1797 Chest 2005;128:2732-2738

  42. Antimicrobial Case X 60 yo male admitted to the hospital with one day history of fever, headache, photophobia, and neck stiffness. CSF reveals WBC 542 with neutrophil predominance, protein 90, and glucose 30. What empiric antibiotics should be started?

  43. Bacterial Meningitis Condition Pathogen Antimicrobials < 1 month S. agalactiae, E. coli Ampicillin + cefotaxime L. moncytogenes Ampicillin +aminoglycoside 2-50 years S. pneumoniae, Vanco + ceftriaxone N. meningitidis > 50 years S. pneumoniae, Vanco + ceftriaxone+ amp N. meningitidis, L. monocytogenes Post-neuro- Gram-neg (Pseudomonas), Vanco + (cefepime, Surgery S. aureus, Coag-neg Staph ceftazidime, or meropenem) Clin Infect Dis 2004;29:1267-84

  44. Antimicrobial Case 4 70 y o woman with bronchitis treated with moxifloxacin who develops fever, abdominal pain, and profuse, watery, maloderous diarrhea. WBC 24K.

  45. Clostridium difficile • Colonization • 3% healthy adults • 20-40% of hospitalized patients • Unintended consequence of antimicrobial therapy • Perturbation of competing flora • Cephalosporins, clindamycin, and fluoroquinolones • Recent reports of increasing frequency and severity • Epidemic strain with 18-bp tcdC deletion and binary toxin • Metronidazole or oral vancomycin • 90% vs. 88% response rates (Lancet 1983;2:1043-6) • ?Increasing recurrence and failure with metronidazole Clin Infect Dis 2005;40:1586-90 N Engl J Med 2005;353:2433-41 Clin Infect Dis 2005;40:1591-7 N Engl J Med 2005;353:2442-9

  46. Metronidazole • Reduced metabolites damage bacterial DNA • Active against anaerobic gram-negative bacilli and most Clostridium • Favored in management of C. difficile • Absorbed well with good CSF penetration (used in CNS abscess as opposed to clindamycin which has poor CSF penetration) • Adverse events: • Nausea, metallic taste • Disulfiram-like reaction

  47. Antimicrobial Case 7 42 y o sexually active man presents with 3 day h/o dysuria and purulent urethral discharge. Increasing fluoroquinolone resistance IM ceftriaxone or PO cefpodoxime 15% co-infection with Chlamydia -azithromycin or doxycycline Neisseria gonorrheae

  48. Bad Bugs, No Drugs • Gram-positive bacteria • MRSA and VRE • Emergence of vancomycin-resistant S. aureus and linezolid-resistant Enterococcus • Gram-negative bacteria • Pan-resistant Acinetobacter and Pseudomonas • Colistin/Polymixin E • nephrotoxicity 20-30% • neurotoxicity 7% • Extended-spectrum β-lactamase organisms Clin Infect Dis 2006;42:657-68

  49. Antimicrobial Principles • Judicious use of antimicrobial therapy to optimize clinical outcomes while minimizing unintended consequences • Toxicity, drug-drug interactions • Emergence of resistance • C. difficile • Understanding antimicrobial pharmocokinetics/dynamics and resistance mechanisms can help guide appropriate usage • Knowledge of local susceptibility patterns is essential • Development of antimicrobial resistance is directly related to antimicrobial usage • Paucity of new drugs in the pipeline

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