1. Antimicrobials: Clinical Considerations Timothy H. Dellit, MD Director, Infection Control and Antimicrobial Management Harborview Medical Center

2. Case 1 60 y o 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 is the clinical concern? What empiric antibiotics should be started?

3. Antimicrobial Considerations 1.Likely organism and susceptibilities 2.Site of infection - SSTI, bacteremia, pneumonia, meningitis, UTI 3.Host factors - Immune deficiencies, age, allergies, renal and hepatic function 4.Antimicrobial factors - Dosage, route, drug interactions, tissue penetration, toxicity, cost 5.Public health considerations - Selection of resistance

4. Bacterial Meningitis Condition PathogenAntimicrobials < 1 month S. agalactiae, E. coliAmpicillin + cefotaxime L. moncytogenesAmpicillin + 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 Staphceftazidime, or meropenem) Clin Infect Dis 2004;29:1267-84

5. 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. Streptococcus pneumoniae

6. Community-Acquired Pneumonia Most common pathogens S. pneumoniae, H. influenzae, Moraxella with concern for C. pneumonia, M. pneumoniae, and Legionella –Outpatient Macrolide or doxycycline Respiratory fluoroquinolone, if recent antimicrobial tx –Inpatient medical ward  -lactam + macrolide vs fluoroquinolone 2002-2003 US Survey revealed 34% non-penicillin 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

7. S. 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

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

9. Fluoroquinolones Concentration-dependent killing (AUC:MIC) Fluoroquinolone targets –DNA gyrase (GyrA and GyrB subunits) separates DNA strands during replication –Topoisomerase IV (ParC and ParE subunits) partitions replicated chromosomal DNA Newer fluoroquinolones (gatifloxacin, gemifloxacin, moxifloxacin) bind equivalently to both enzymes compared to earlier generations such as ciprofloxacin and levofloxacin Moxifloxacin is hepatically eliminated, not for urinary infections Adverse events –GI –CNS –Photosensitivity –Prolonged QTc –Tendonitis/arthropathies –Hyperglycemia or hypoglycemia, particularly elderly with DM

10. S. pneumoniae and Fluoroquinolones Drug MIC 90 AUC Free AUC:MIC Free 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

11. Pseudomonas and Fluoroquinolones DrugDose C max MIC AUC free :MIC Ciprofloxacin400 q12 4.1 0.125 144 400 q8 4.1 0.125 184 Levofloxacin750 q24 12.1 0.5 152 Gatifloxacin400 q12 4.6 1.0 28 Moxifloxacin 400 q24 4.2 2.0 10 IDSA and ATS Guidelines recommend Ciprofloxacin 400mg IV q8hr or Levofloxacin 750 mg qd Am J Respir Crit Care Med 2005;171:388-416

12. 49 y o man with a 1 week h/o viral syndrome with progressive dyspnea, hypoxia, and hypotension. Sputum, pleural fluid, and blood cultures with Gram-positive cocci in clusters. Case 3

13. Case Continued CA-MRSA Pneumonia Clin Infect Dis 2005;40:100-7 Chest 2005;128:2732-8

14. MRSA Resistance to Beta-Lactams Beta-Lactam Modified from David Spach, MD Cell Wall Cell Membrane Alternative Penicillin Binding Protein PBP2a DNA

15. Local MRSA Susceptibilities Clindamycin* Levofloxacin Tetracycline TMP/SMX Vancomycin Harborview UW 65% 15% 24% 6% 93% 97% 95% 98% 100% 100% *D-zone test should be done to look for inducible resistance to clindamycin 8% at HMC and 13% at UWMC

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

17. Concerns with Vancomycin Association between increasing MIC and clinical failure, particularly prolonged bacteremia –Breakpoint lowered to < 2 mcg/ml Monitoring of serum levels –No clear relationship between level and efficacy or toxicity –Routine monitoring not necessary Changing renal function or renal insufficiency –Peak levels should not be measured as vancomycin is not “concentration-dependent” and peak level predictably 15-20 mcg/ml above trough –Trough of 15-20 mcg/ml 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

18. Vancomycin-Resistant Staphylococcus aureus Intermediate resistance (VISA or GISA) first documented in Japan 1996, US in 1997 –Increased cell wall thickness limiting glycopeptide access to site of cell wall synthesis Vancomycin-resistant S. aureus (VRSA or GRSA) isolated in June 2002 –Contained vanA resistance gene identical to vanA gene in patient’s vancomycin-resistant Enterococcus faecalis

19. Adapted from David Spach, MD Daptomycin: Mechanism of Action  Aztreonam (Azactam) 1. Ca 2+ -Dependent Binding to Cell Membrane 2. Depolarizes Membrane & K + Efflux

20. Daptomycin Novel lipopeptide class causing depolarization of the bacterial membrane Active against MSSA, MRSA, VRSA, coag-neg Staph, S. pyogenes, S. pneumoniae, E. faecium, and E. faecalis including VRE Initially approved for complicated skin and soft tissue infections at 4 mg/kg/d IV Subsequently FDA approved for S. aureus bacteremia and right-sided endocarditis at 6 mg/kg/d IV (N Engl J Med 2006;355:653-65) –6/19 with microbiologic failure developed resistance with increasing MIC Not active in lung due to surfactant Monitor CK for myositis

21. Reduced Susceptibility to Vancomycin Associated with Reduced Susceptibility to Daptomycin in S. aureus No. (%) of Isolates VancomycinDaptomycinDaptomycin MIC, mcg/mlMIC 2 mcg/ml < 2 812 (97) 30 (3) 4 11 (20) 43 (80) 8-16 1 (7) 15 (93) > 32* 5 (100) 0 (0) * vanA mediated resistance Clin Infect Dis 2006;42:1652-3

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

23. Linezolid 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% Possible survival benefit in MRSA pneumonia? Adverse events: –GI (nausea and vomiting) –Marrow suppression (thrombocytopenia, anemia, leukopenia) –Serotonin syndrome (weak monoamine oxidase inhibitor) –Lactic acidosis –Optic neuritis, peripheral neuropathy, Bell’s palsy –Inhibition of mitochondrial protein synthesis Linezolid-resistant VRE and MRSA reported due to mutation in 23S rRNA

24. Case 4 34 y o man h/o HIV with CD4 100 presents with 1 month h/o cough, fever, night sweats, and weight loss. CXR with right upper lobe cavitary lesion and sputum with 4+ AFB. Mycobacterium tuberculosis

25. Case 4 Questions Why do we use 4 drug to treat TB? (isoniazid, rifampin, pyrazinamide, ethambutol, plus B6) –Rate of spontaneous mutations Rifampin: 1 in 10 8 INH: 1 in 10 6 Cavitary disease with 10 9 organisms –INH resistance 10% in King County What should we start first, TB meds, HIV meds, or all at the same time? What are the potential drug interactions and how do they impact our therapy?

26. Antiretrovirals and P450 Protease inhibitors may induce or inhibit –Ritonavir potent inhibitor of P450 CYP3A4 Low dose ritonavir boosting (standard PI dosing) Simplified regimens with decreased toxicity Non-nucleoside RT inhibitors –Efavirenz and nevirapine are inducers –Substrate of CYP2B6 G516T polymorphism 3% Caucasians, 20% African-Americans Higher drug levels, delayed clearance Higher CNS adverse events Clin Infect Dis 2006;42:408-10

27. Tuberculosis, HIV, and P450 Rifampin and protease inhibitors –Rifampin induces PI metabolism Reduces (Fos)amprenavir 82%, lopinavir/ritonavir 75% –PI inhibits rifampin metabolism Increased toxicity –Generally cannot use rifampin in combination –Dose-reduced rifabutin (150 mg qod with lopinavir/rit) Rifampin and efavirenz –Rifampin decreases efavirenz by 26% –Increase efavirenz from 600mg to 800 mg qhs http://depts.washington.edu/madclin/

28. Case 5 30 y o patient is admitted to the psychiatry service with suicidal depression. Two days after admission it is noted that the patient has fever, chills, cough, and myalgias that began 4 days ago. A nasal wash is positive for influenza B. Which of the following is true? A. The patient should be treated with amantadine B. The exposed staff should receive amantadine prophylaxis if they were not vaccinated C. The patient and exposed staff should receive oseltamivir for treatment and prophylaxis, respectively D. Although the development of amantadine resistance during therapy is common, resistance has not been reported for oseltamivir

29. Antivirals for Influenza Adamantanes –Amantadine and rimantadine –Target M2 ion channel, interfering with viral uncoating –Only active against influenza A High rate of resistance (91%) among H3N2 during 2005- 2006 influenza season Neurominidase inhibitors –Oseltamivir and zanamivir –Development of oseltamivir resistance during therapy (N Engl J Med 2005;353:25:2667-72) –Unknown dose or duration for avian influenza –Stockpile and limited supply

30. Clinical Antimicrobial Principles Considerations when selecting antimicrobials –Likely organism and susceptibility patterns –Site of infection –Host factors –Antimicrobial factors –Emergence of resistance Understanding antimicrobial pharmocokinetics/dynamics and resistance mechanisms can help guide appropriate usage Knowledge of local susceptibility patterns is essential Paucity of new drugs in the pipeline