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  • The potential for drug interactions must always be considered Most of the newer agents have low affinity for the hepatic cytochrome P450 system or are excreted renally There are reports that polyvalent cations can reduce the oral bioavailability of quinolones anywhere from 10-50%, especially when given concomitantly This is a problem especially in patients on multiple medications such as the elderly or ICU patients QT prolongation? Check patient profiles!
  • Antibacterial resistance in several important groups of microbial pathogens appears to be correlated with the use of fluoroquinolones. This is true for several clinically important gram-negative bacilli. Therefore, infection with a gram-negative bacillus in patients who have received fluoroquinolone treatment in the past is more likely to be with a resistant organism, including resistant P aeruginosa . 1 Further support for this pattern comes from a recent hospital program that restricted quinolone use, particularly levofloxacin. 2 After a lag of 5 months, the monthly percentage of levofloxacin-resistant P aeruginosa decreased significantly by 0.77% ( P <0.005), declining from 43.8% in January 2001 to 37.7% by March 2004. A drop in gentamicin-and cefepime-resistance was also associated with decreased quinolone use. 2 Prior quinolone use also increases the likelihood of infection with ESBL-producing strains. Case-control studies have identified ESBL-producing K pneumoniae and E coli in nursing home patients who were previously treated with quinolones. 3 In addition, nosocomial Acinetobacter infections in the ICU have been associated with prior quinolone use. 4 References: 1. Paterson DL. “Collateral damage” from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis. 2004;38(suppl 4):S341–S345. 2. Paterson DL; Lopez-Lozano J, Potoski B, Capitano B, Monnet DL. Effects of reduction of quinolone use on antibiotic susceptibility in Pseudomonas aeruginosa. Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30, 2004;Washington DC. Abstract 401968. 3. Wiener J, Quinn J, Bradford P, et al. Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA. 1999;281:517–523. 4. Villers D, Espaze E, Coste-Burel M, et al. Nosocomial Acinetobacter baumannii infections: microbiological and clinical epidemiology. Ann Intern Med. 1998;129:182–189.
  • Data from a study by Neuhauser et al, illustrated in this slide, show that the increasing resistance rates for P aeruginosa and other key gram-negative bacilli from 1994 to 2000 correlated with fluoroquinolone use. The percentage of susceptible P aeruginosa strains declined dramatically, from 89% in 1990 through 19 93 to 68% in 2000. This decline in activity was associated with a significant increase in total fluoroquinolone use over that same time period. 1 Reference: 1. Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. Antibiotic resistance among gram- negative bacilli in US intensive care units: implications for fluoroquinolone use. JAMA . 2003;289:885 – 888.
  • antibiotics

    1. 1. Antibiotics at SFGH Clinical Pearls & Treatment Recommendations dr shabeel pn
    2. 2. Important Contacts and Info <ul><li>ID Fellow Pager 443-BUGS (ext 4114) </li></ul><ul><ul><li>Page for ID consults (and approval of restricted antimicrobials-weekends only) </li></ul></ul><ul><li>ID Pharmacist Pager 443-IDRX (ext 5574) </li></ul><ul><ul><li>Page for antibiotic questions and approval of restricted antimicrobials (weekdays only) </li></ul></ul><ul><li>UCSF/SFGH/VASF ID Website </li></ul><ul><ul><li>WWW.UCSF.EDU/IDMP </li></ul></ul><ul><ul><li>Empiric treatment, Antibiotic Dosing, ID References </li></ul></ul>
    3. 3. Overview <ul><li>Beta-lactams </li></ul><ul><ul><li>Penicillins </li></ul></ul><ul><ul><li>Cephalosporins </li></ul></ul><ul><ul><li>Carbapenems </li></ul></ul><ul><ul><li>Monobactams </li></ul></ul><ul><li>Fluoroquinolones </li></ul><ul><ul><li>Ciprofloxacin, Levofloxacin, etc. </li></ul></ul><ul><li>Glycopeptides </li></ul><ul><ul><li>Vancomycin </li></ul></ul><ul><li>Pneumonia </li></ul><ul><ul><li>CAP </li></ul></ul><ul><ul><li>HAP/VAP </li></ul></ul><ul><li>S. aureus infections </li></ul><ul><ul><li>Bacteremia and Endocarditis </li></ul></ul><ul><ul><li>Skin and soft tissue infections </li></ul></ul><ul><ul><li>Osteomyelitis </li></ul></ul>
    4. 4. Beta-lactam antibiotics
    5. 5. Beta-lactams: Overview <ul><li>Mechanism of action: inhibit transpeptidases (PBPs) responsible for cell wall synthesis </li></ul><ul><li>Time-dependent, bactericidal activity versus most pathogens </li></ul><ul><li>Spectrum of activity determined by: </li></ul><ul><ul><li>Affinity for target PBPs </li></ul></ul><ul><ul><li>Ability to penetrate through porins in the gram-negative cell wall </li></ul></ul><ul><ul><li>Stability to beta-lactamase degradation (carbapenems>cephalosporins>>>penicillins) </li></ul></ul>
    6. 6. Penicillin generations <ul><ul><li>Natural and anti-staphylococcal penicillins </li></ul></ul><ul><ul><ul><li>penicillin G & V, nafcillin, oxacillin </li></ul></ul></ul><ul><ul><ul><li>limited spectrum, mostly Gram-positive </li></ul></ul></ul><ul><ul><li>Aminopenicillins </li></ul></ul><ul><ul><ul><li>ampicillin, amoxicillin </li></ul></ul></ul><ul><ul><ul><li>broader spectrum, some enteric Gram-negatives </li></ul></ul></ul><ul><ul><li>Carboxypenicillins </li></ul></ul><ul><ul><ul><li>carbenicillin, ticarcillin </li></ul></ul></ul><ul><ul><ul><li>Activity against nosocomial Gram-negatives </li></ul></ul></ul><ul><ul><li>Ureidopenicillins </li></ul></ul><ul><ul><ul><li>piperacillin, mezlocillin </li></ul></ul></ul><ul><ul><ul><li>Improved activity versus Pseudomonas </li></ul></ul></ul>
    7. 7. Natural Penicillins <ul><li>Penicillin G & V- use limited due to acquired resistance in S. aureus however they are active against: </li></ul><ul><ul><li>Beta-hemolytic streptococcus including Group A strep </li></ul></ul><ul><ul><li>S. pneumoniae & Viridans Strep (resistance effects empiric treatment of meningitis and endocarditis) </li></ul></ul><ul><ul><li>Meningococcus </li></ul></ul><ul><ul><li>Anaeobes: Clostridium , Peptostreptococcus , Actinomyces </li></ul></ul><ul><ul><li>T.pallidum </li></ul></ul>
    8. 8. Commonly used penicillins <ul><li>Anti-staphylococcal penicillins </li></ul><ul><ul><li>Nafcillin, Oxacillin, Dicloxacillin </li></ul></ul><ul><ul><li>Used almost exclusively for the treatment of MSSA and other sensitive staphylococci </li></ul></ul><ul><li>Aminopenicillins (Amoxicillin, Ampicillin) </li></ul><ul><ul><li>Active vs. streptococcal species (but not Staph!) </li></ul></ul><ul><ul><li>More active than PCN against S. pneumoniae , Enterococcus, Listeria </li></ul></ul><ul><ul><li>Active against non-beta-lactamase producing Haemophilus spp, Neisseria spp, E. coli, Proteus mirabilis </li></ul></ul>
    9. 9. Penicillin/Beta-lactamase inhibitor combinations (BLIs) <ul><li>Ampicillin/ sulbactam Unasyn ® </li></ul><ul><li>Amoxicillin/ clavulanic acid Augmentin® </li></ul><ul><li>Ticarcillin/ clavulanic acid Timentin ® </li></ul><ul><li>Piperacillin/ tazobactam Zosyn ® </li></ul><ul><li>Addition of BLI results in reliable activity vs: S. aureus (MSSA) , H. influenzae, Proteus spp., E. coli, Klebsiella spp, & B. fragilis </li></ul><ul><li>Timentin and Zosyn are also active against many nosocomial Gram-negatives incl. Pseudomonas </li></ul>
    10. 10. Penicillins: Places in therapy <ul><li>Penicillin – pharyngitis, necrotizing fasciitis, endocarditis, meningococcemia, syphillis </li></ul><ul><li>Nafcillin – documented infections caused by MSSA such as endocarditis </li></ul><ul><li>Amp/Amoxicillin – upper and lower respiratory tract infections, otitis media </li></ul><ul><ul><li>Plus sulbactam or clavulanate: Intraabdominal and pelvic infections </li></ul></ul><ul><li>Pip/tazo (Zosyn ®) – most of the above plus nosocomial infections (pneumonia and sepsis) </li></ul>
    11. 11. 1st Generation Cephalosporins <ul><li>Cefazolin/Cephalexin </li></ul><ul><li>Gram-negative activity </li></ul><ul><ul><li>P roteus mirabilis </li></ul></ul><ul><ul><li>E . coli </li></ul></ul><ul><ul><li>K lebsiella spp esp. K.pneumoniae </li></ul></ul><ul><li>Gram-positive activity </li></ul><ul><ul><li>S. aureus (MSSA)- most active cephalosporins! </li></ul></ul><ul><ul><li>Group A, B, C, G streptococcus </li></ul></ul><ul><ul><li>Weaker activity versus S. pneumoniae </li></ul></ul><ul><ul><li>No activity versus enterococci </li></ul></ul>
    12. 12. 2 nd generation Cephalosporins <ul><li>Gram-negative activity –Cefoxitin/Cefuroxime </li></ul><ul><ul><li>H .influenzae </li></ul></ul><ul><ul><li>N eisseria gonorrhea </li></ul></ul><ul><ul><li>P roteus spp </li></ul></ul><ul><ul><li>E .coli [incl 1st Gen -R isolates] </li></ul></ul><ul><ul><li>K lebsiella spp [incl 1st Gen - R isolates] </li></ul></ul><ul><ul><li>Cefoxitin & Cefotetan have activity versus gram-negative anaerobes ( B. fragilis ) </li></ul></ul><ul><li>Gram-positive activity </li></ul><ul><ul><li>Moderate activity against MSSA </li></ul></ul><ul><ul><li>Increased activity versus S. pneumoniae </li></ul></ul>
    13. 13. 3 rd generation cephalosporins <ul><li>Gram-negative activity – Ceftriaxone/Cefotaxime </li></ul><ul><ul><li>H .influenzae </li></ul></ul><ul><ul><li>N eisseria gonorrhea </li></ul></ul><ul><ul><li>P roteus spp </li></ul></ul><ul><ul><li>E .coli [incl 2nd Gen Ceph -R isolates] </li></ul></ul><ul><ul><li>K lebsiella [incl 2nd Gen Ceph -R isolates] </li></ul></ul><ul><ul><li>S higella, Salmonella </li></ul></ul><ul><li>Gram-positive activity </li></ul><ul><ul><li>Most active cephalosporins against pneumococcus </li></ul></ul><ul><ul><ul><li>Good CNS penetration compared to 1 st & 2 nd gen. CPHs </li></ul></ul></ul><ul><ul><li>Moderate activity versus MSSA </li></ul></ul>
    14. 14. Third-generation Cephalosporins: Problem Gram-negative Pathogens <ul><li>C itrobacter </li></ul><ul><li>A cinetobacter </li></ul><ul><li>P seudomonas </li></ul><ul><li>E nterobacter </li></ul><ul><li>S erratia </li></ul><ul><li>Extended Spectrum β -lactamase (ESBL) producing E.coli and Klebsiella </li></ul>
    15. 15. 4th Generation Cephalosporin Cefepime (Maxipime) <ul><li>Gram-negative activity: </li></ul><ul><ul><li>H .influenzae </li></ul></ul><ul><ul><li>E nterobacter </li></ul></ul><ul><ul><li>N .gonorrhea </li></ul></ul><ul><ul><li>P roteus & Pseudomonas </li></ul></ul><ul><ul><li>E .coli* </li></ul></ul><ul><ul><li>C itrobacter </li></ul></ul><ul><ul><li>K lebsiella* </li></ul></ul><ul><ul><li>S erratia </li></ul></ul><ul><li>Gram-positive activity </li></ul><ul><ul><li>Comparable to ceftriaxone </li></ul></ul><ul><ul><li>MSSA </li></ul></ul><ul><ul><li>S. pneumomiae </li></ul></ul>*Cefepime is not reliably active versus ESBL-producing E.coli and Klebsiella
    16. 16. Extended spectrum β -lactmases (ESBLs) <ul><li>Most ESBLs are derived from the common β -lactamases found in E. coli and Klebsiella </li></ul><ul><ul><li>A single point mutation in the active site of the enzyme results in ↑ affinity for 3 rd and 4 th generation cephalosporins and aztreonam </li></ul></ul><ul><ul><li>Confers clinical resistance to all cephalosporins and aztreonam </li></ul></ul><ul><li>Nationallly 5%–15% of Klebsiella & E. coli isolates produce ESBLs </li></ul><ul><ul><li>SFGH: ~ 5% produce ESBLs </li></ul></ul><ul><ul><li>LHH: 25% of E. coli are ESBL producers! </li></ul></ul>
    17. 17. ESBLs cont. <ul><li>Many ESBL producers are multi-drug resistant (FQs, AGs, TMP/SMX) </li></ul><ul><ul><li>At SFGH > 90% of ESBL producers are also resistant to fluoroquinolones </li></ul></ul><ul><li>Biggest risk factor is recent exposure to 3 rd /4 th generation cephalosporins or fluoroquinolones </li></ul><ul><li>Carbapenems are poor substrates and remain active, drugs of choice for serious infections caused by ESBL-producers </li></ul>
    18. 18. Cephalosporin places in therapy <ul><li>1st generation (cefazolin, cephalexin) </li></ul><ul><ul><li>skin & soft tissue infections?, UTIs </li></ul></ul><ul><li>2nd generation </li></ul><ul><ul><li>URIs (cefuroxime), PID (cefoxitin) </li></ul></ul><ul><li>3rd generation (ceftriaxone) </li></ul><ul><ul><li>pyelonephritis, CAP, SBP, meningitis </li></ul></ul><ul><li>4th generation (cefepime) </li></ul><ul><ul><li>nosocomial infections including pneumonia, sepsis, febrile neutropenia </li></ul></ul>
    19. 19. Cephalosporin allergic potential <ul><li>Document the nature of the penicillin allergy </li></ul><ul><ul><li>Type I IgE-mediated immediate hypersensitivity reaction such as hives, angioedema, anaphylaxis </li></ul></ul><ul><ul><li>If truly IgE mediated, cross-reactivity for penicillin and cephalosporins is estimated to be ~5% </li></ul></ul><ul><ul><li>VERSUS </li></ul></ul><ul><ul><li>Maculopapular or morbilliform rashes most common </li></ul></ul><ul><ul><li>Ampicillin rash- often not a true allergy, often associated with concurrent allopurinol use or viral illness [EBV ] </li></ul></ul><ul><li>Cephalosporins may be safely prescribed unless the penicillin allergy is suspicious for Type I reaction </li></ul>
    20. 20. Carbapenems <ul><li>Imipenem, Meropenem, & Doripenem </li></ul><ul><ul><li>Very broad spectrum, cover practically all gram-negative pathogens including ESBL producers </li></ul></ul><ul><ul><li>Good activity against Strep & MSSA; marginal enterococcus activity </li></ul></ul><ul><ul><li>Excellent coverage of anaerobes </li></ul></ul><ul><ul><li>Reserved for serious nosocomial infections especially in patient with prior exposure to broad spectrum antibiotics </li></ul></ul><ul><li>Ertapenem </li></ul><ul><ul><li>Similar to other penems except that is lacks activity against Pseudomonas & Acinetobacter </li></ul></ul>
    21. 21. Ertapenem <ul><li>Added to SFGH formulary in 2006 </li></ul><ul><li>Primary indication is for intraabdominal infections as a single, once-daily drug </li></ul><ul><ul><li>Does not require ID approval for this indication </li></ul></ul><ul><li>Is useful in treating infections caused by ESBL-producing E.coli & Klebsiella </li></ul><ul><li>For intraabdominal infections instead of ceftriaxone or a FQ plus metronidazole: Ertapenem 1 gram IV daily </li></ul>
    22. 22. Fluoroquinolones <ul><li>Synthetic, broad-spectrum antibiotics </li></ul><ul><ul><li>Gram-positive, Gram-negative, “Atypicals” </li></ul></ul><ul><ul><li>Newer agents: anaerobes and mycobacteria </li></ul></ul><ul><li>Inhibit DNA gyrase and/or topoisomerase IV </li></ul><ul><li>Concentration-dependent, bactericidal activity </li></ul><ul><li>Generally well tolerated, however significant toxicities have resulted in several products being withdrawn from the market </li></ul>
    23. 23. Fluoroquinolones Spectrum of Activity: Gram-positive <ul><li>Strong* Moderate Weak </li></ul><ul><li>Levofloxacin Ciprofloxacin # Norfloxacin </li></ul><ul><li>Moxifloxacin Ofloxacin </li></ul><ul><li>Gemifloxacin </li></ul><ul><li>* These drugs are considered “respiratory” quinolones given there potent activity versus S. pneumoniae </li></ul><ul><li># Ciprofloxacin may also be considered “strong” for S. aureus </li></ul>
    24. 24. Fluoroquinolones Spectrum of Activity: Gram-negative *covers Pseudomonas aeuruginosa Norfloxacin <ul><ul><li>Moxifloxacin </li></ul></ul><ul><ul><li>Gemifloxacin </li></ul></ul><ul><ul><li>Ofloxacin </li></ul></ul><ul><ul><li>CiprofloxacinLevofloxacin </li></ul></ul>Weak Moderate Strong
    25. 25. Quinolones: other pathogens <ul><li>“ Atypical” coverage </li></ul><ul><ul><li>Predictably active vs Mycoplasma & Legionella </li></ul></ul><ul><ul><li>Newer agents (not ciprofloxacin) reliably inhibit chlamydia </li></ul></ul><ul><li>Anaerobes ( B. fragilis ) </li></ul><ul><ul><li>Moxifloxacin has improved activity </li></ul></ul><ul><li>M. tuberculosis & atypical mycobacteria </li></ul><ul><ul><li>Newer drugs (moxi, levo) have good activity </li></ul></ul>
    26. 26. FQ Pharmacokinetics <ul><li>Well absorbed from the GI tract allowing oral administration to most patients – including hospitalized patients </li></ul><ul><li>Mixed route of elimination, depending upon agent. Levofloxacin most dependent upon renal elimination. </li></ul>
    27. 27. FQ Drug Interactions <ul><li>Do not administer concomitant mulitvalent cations – chelation forms an inactive complex </li></ul><ul><li>Reduction in bioavailability </li></ul><ul><ul><li>Mg ++ , Ca ++ , Fe +++ , Al +++ </li></ul></ul><ul><ul><li>Sucralfate (Carafate  ) – Al +++ </li></ul></ul><ul><ul><li>Tube Feedings !!!! </li></ul></ul><ul><li>Admin FQ 2 hrs before/4hrs after </li></ul><ul><li>Drug interaction: warfarin </li></ul>
    28. 28. Quinolone agents: place in therapy <ul><li>UTIs including pyelonephirits </li></ul><ul><li>Bacterial gastroenteritis </li></ul><ul><li>Community-acquired pneumonia </li></ul><ul><li>Nosocomial pneumonia </li></ul><ul><ul><li>Oral treatment of P. aeruginosa </li></ul></ul><ul><li>Chronic Osteomyelitis </li></ul><ul><li>X STDs (no longer CDC recommended for treatment of gonorrhea) </li></ul>
    29. 29. Fluoroquinolone Use and Resistance in Gram-Negative Pathogens <ul><li>Prior use of quinolones is related to: </li></ul><ul><ul><li>Increased risk of infection with ESBL producing strains of Klebsiella and E coli 2 </li></ul></ul><ul><ul><li>Increased risk of infection with quinolone-resistant strains P. aeruginosa 1 </li></ul></ul><ul><ul><li>Nosocomial Acinetobacter infections 3 </li></ul></ul>1. Paterson DL. Clin Infect Dis. 2004;38(suppl 4):S341 –S 345. 2. Wiener J et al. JAMA. 1999;281:517 –5 23. 3. Villers D et al. Ann Intern Med. 1998;129:182 – 189.
    30. 30. Gram-Negative Bacilli Resistance Associated With Fluoroquinolone Use Adapted from Neuhauser MM et al. JAMA. 2003;289:885–888; copyright (2003), with permission from American Medical Association, all rights reserved. 0 5 10 15 20 25 30 35 1994 1995 1996 1997 1998 1999 2000 0 50,000 100,000 150,000 200,000 250,000 Strains resistant to ciprofloxacin, % Fluoroquinolone use, kg P aeruginosa All gram-negative bacilli Fluoroquinolone use
    31. 31. 2006 SFGH Inpatient Susceptibilities (Gram-negative pathogens) N/A 89 86 96 95 Pip/Tazo 79 69 55 33 N/A Acinetobacter baumanii N/A 84 80 N/A N/A Pseudomonas aeruginosa 80 94 92 74 N/A Enterobacter cloacae 85 97 97 92 92 Klebsiella pneumoniae 64 80 94 92 84 Escherichia coli SMX/TMP Cipro/Levo Cefepime Ceftriax Kefzol Organism
    32. 32. Anti-pseudomonal antibiotics <ul><li>Beta-lactams </li></ul><ul><ul><li>Cefepime </li></ul></ul><ul><ul><li>Piperacillin/tazobactam </li></ul></ul><ul><ul><li>Imipenem </li></ul></ul><ul><ul><li>Meropenem </li></ul></ul><ul><ul><li>Aztreonam </li></ul></ul><ul><ul><li>Ceftazidime </li></ul></ul><ul><ul><li>Ticarcillin/clavulanate </li></ul></ul><ul><li>Fluoroquinolones </li></ul><ul><ul><li>Ciprofloxacin (PO) (IV) </li></ul></ul><ul><ul><li>Levofloxacin (PO) (IV) </li></ul></ul><ul><li>Aminoglycosides </li></ul><ul><ul><li>Gentamicin </li></ul></ul><ul><ul><li>Tobramycin </li></ul></ul>Green - formulary item, no restrictions Yellow - formulary but requires ID approval Red - non-formulary item
    33. 33. Comparative Antibiotics (SFGH 1 Day Therapy) <ul><li>Ceftriaxone 1 gm q24h $4 </li></ul><ul><li>Ciprofloxacin (IV) 400 mg q12h $6 </li></ul><ul><li>Levofloxacin (IV) 750 mg q24h $14 </li></ul><ul><li>Cefepime 2 gm q12h $38 </li></ul><ul><li>Ertapenem 1 gm q24h $43 </li></ul><ul><li>Zosyn ® 4.5 gm q8h $58 </li></ul><ul><li>Ciprofloxacin (po) 500 mg q12h $0.10 </li></ul><ul><li>Levofloxacin (po) 750 mg q24h $4 </li></ul>
    34. 34. Treatment of Community-Acquired PNA <ul><li>Ward patients </li></ul><ul><ul><li>Ceftriaxone 1 gram Q24h + Doxycycline 100 mg po BID then transition to oral doxycycline +/- amoxicillin 1gram po bid (NOT levofloxacin!) for ~7 days OR </li></ul></ul><ul><ul><li>Levofloxacin 750 mg IV/PO q24h for 5 days </li></ul></ul><ul><li>Patients requiring ICU admission </li></ul><ul><ul><li>Ceftriaxone + Azithromycin 500 mg IV q24h (azithro x5 days only) +/- Vancomycin </li></ul></ul>
    35. 35. HAP or VAP Suspected (All Disease Severity) Late Onset or Risk Factors for Multi-drug Resistant (MDR) Pathogens No Yes Limited Spectrum Antibiotic Therapy Empiric Antibiotic Therapy for HAP Broad Spectrum Antibiotic Therapy For MDR Pathogens
    36. 36. Empiric Antibiotics for HAP Assess Risk Factors For Drug Resistant Pathogens <ul><li>Prior Antibiotic Therapy (past 90 days) </li></ul><ul><li>Prior Hospitalization (90 days) </li></ul><ul><li>Chronic care, Nursing home, dialysis </li></ul><ul><li>Immunosuppressive disease or therapy </li></ul><ul><li>Late on-set VAP </li></ul>
    37. 37. HAP/VAP: Empiric regimens <ul><li>Early-onset infection and/or limited risk factors for infection with resistant organisms </li></ul><ul><li>Vancomycin + Ceftriaxone OR </li></ul><ul><li>Vancomycin + Levofloxacin </li></ul><ul><li>These regimens limit exposure to broad-spectrum antibiotics, preserving susceptibility for later in the hospital course </li></ul><ul><li>Course of therapy is generally 1 week! </li></ul>
    38. 38. HAP/VAP: Empiric regimens <ul><li>Late onset, risk factors for drug resistant organisms present, or patient unstable </li></ul><ul><li>Vancomycin </li></ul><ul><li>+ </li></ul><ul><li>Cefepime </li></ul><ul><li>OR </li></ul><ul><li>Meropenem – if previous exposure to cefepime and/or patient is hemodynamically unstable </li></ul><ul><li>(Addition of a second Gram-negative drug [quinolone or aminoglycoside] is not routinely recommended at SFGH) </li></ul><ul><li>Treatment course is still generally 1 week! </li></ul>
    39. 39. “Aspiration” Pneumonia <ul><li>Aspiration pneumonia (not lung abscess) </li></ul><ul><ul><li>Ceftriaxone & Levofloxacin have reasonable coverage of oral anaerobes- ok to use alone for the treatment of “aspiration” pneumonia </li></ul></ul><ul><ul><li>No need to add Clindamycin or Metronidazole ! </li></ul></ul><ul><li>Aspiration in nosocomial setting </li></ul><ul><ul><li>Just treat as if it was a nosocomial pneumonia per the previous slide, no need to give directed anaerobic therapy </li></ul></ul>Marik. Aspiration pneumonitis and pneumonia. NEJM. 2001;344:665-71
    40. 40. SFGH & MRSA: Overview <ul><li>60% of all Staph aureus isolates at SFGH are methicillin-resistant </li></ul><ul><li>80% of the MRSA isolates are the community-acquired USA300 strain (CA-MRSA) </li></ul><ul><li>For serious infections vancomycin is generally the treatment of choice (for now?) </li></ul><ul><li>Oral treatment options for include: </li></ul><ul><ul><li>TMP/SMX 99% are susceptible </li></ul></ul><ul><ul><li>Doxycycline 83% are susceptible </li></ul></ul><ul><ul><li>Clindamycin 82% are susceptible </li></ul></ul><ul><ul><li>Linezolid 100% are susceptible ($120/day-requires ID approval!) </li></ul></ul>
    41. 41. PubMed Community-MRSA Articles
    42. 42. MRSA in San Francisco Hospitals
    43. 43. Current FDA-Approved Drug Treatments for MRSA infections <ul><li>Linezolid (IV,PO) </li></ul><ul><li>Vancomycin (IV) </li></ul><ul><li>Daptomycin (IV) </li></ul><ul><li>Vancomycin (IV) </li></ul><ul><li>Linezolid (IV, PO) </li></ul><ul><li>Vancomycin (IV) </li></ul><ul><li>Daptomycin (IV) </li></ul><ul><li>Tigecycline (IV) </li></ul>cSSSI=complicated skin and skin structure infection Nosocomial Pneumonia cSSSI Bacteremia inc R-sided endocarditis
    44. 44. Vancomycin: Overview <ul><li>Glycopeptide antibiotic </li></ul><ul><ul><li>Bactericidal against most pathogens (?) </li></ul></ul><ul><ul><li>Inhibits cell wall synthesis by binding to terminal D-ala-D-ala dipeptide of peptidoglycan precursor </li></ul></ul><ul><li>Spectrum of activity: Most Gram-positives </li></ul><ul><ul><li>Staphlyococci: MSSA & MRSA, Coag-negative staph </li></ul></ul><ul><ul><li>Streptococcus spp </li></ul></ul><ul><ul><li>Enterococcus faecalis </li></ul></ul>
    45. 45. Vancomcyin Kinetics/Dosing <ul><li>Vancomycin dosing </li></ul><ul><ul><li>Based on total body weight and renal function </li></ul></ul><ul><ul><li>Half life of 6 hrs in pts w/normal renal function </li></ul></ul><ul><ul><li>Anuric patients t 1/2 = 7 days </li></ul></ul><ul><li>Dosing Examples </li></ul><ul><ul><li>30 mg/kg/day in 2 (or 3) doses for patients with normal renal function </li></ul></ul><ul><ul><li>70 kg; ClCr= 80ml/min Vanco 1 gram q12h </li></ul></ul><ul><ul><li>100 kg; ClCr= 80ml/min Vanco 1 gram q8h (or 1.5 q12) </li></ul></ul>
    46. 46. Vancomycin Monitoring <ul><li>DO NOT order vancomycin peaks </li></ul><ul><li>Vancomycin troughs levels </li></ul><ul><ul><li>Routine monitoring not recommended </li></ul></ul><ul><ul><li>Monitor in serious infections (endocarditis, meninigitis osteomyelitis, etc.), renal failure, obese, elderly </li></ul></ul><ul><ul><li>Once an adequate trough is obtained do not reorder unless there is a significant change in renal function </li></ul></ul><ul><ul><li>Target trough for most infections is 10-20 mcg/ml (15-20 for CNS infections, VAP, osteomyelitis) </li></ul></ul>
    47. 47. Vancomycin: Adverse Effects <ul><li>“ Red man” syndrome - pruritis, erythematous rash involving face & neck </li></ul><ul><ul><li>Secondary to release of histamine </li></ul></ul><ul><ul><li>Mange by slowing infusion, antihistamines </li></ul></ul><ul><li>Neutropenia & Thrombocytopenia with prolonged courses </li></ul><ul><li>Current formulation is not thought to be ototoxic or nephrotoxic by itself, however it may potentiate the effects of other nephro or ototoxic drugs </li></ul>
    48. 48. Vancomycin for MRSA: Common Problems <ul><li>Slow bacterial killing compared to beta-lactams </li></ul><ul><li>Poor tissue penetration, particularly into lung and bone </li></ul><ul><li>Heterogeneous resistance with vancomycin MICs within the susceptible range (MIC > 1 mcg/ml) </li></ul><ul><li>Clinical translation: </li></ul><ul><ul><li>Prolonged bacteremia </li></ul></ul><ul><ul><li>High rates of clinical failure (especially for pneumonia and osteomyelitis) </li></ul></ul>
    49. 49. Relationship of MIC to Vancomycin Treatment Failures in MRSA Infections MIC, minimal inhibitory concentration. Moise-Broder PA et al. Clin Infect Dis. 2004;38;1700-1705 . 22% 27% 51% Failure Rate (%) 31% MIC ( μ g/mL)
    50. 50. S. aureus bacteremia <ul><li>All S. aureus bacteremia should be managed in consultation with the Infectious Diseases Service </li></ul><ul><ul><li>High rates of endovascular infection and metastatic disease! </li></ul></ul><ul><li>Vancomycin should be started empirically </li></ul><ul><ul><li>If MSSA transition to nafcillin or cefazolin </li></ul></ul><ul><li>Uncomplicated bacteremia should be treated with a minimum of 14 days of IV therapy </li></ul><ul><li>Complicated bacteremia generally requires 4 to 6 weeks of IV therapy (+/- oral consolidation therapy for osteo and/or hardware infections) </li></ul>
    51. 51. Purulent skin and soft tissue infection caused by MRSA Tice, Honolulu
    52. 52. Empiric Treatment of Skin and Soft-Tissue Infections (SSTI) : Oral Treatment Options <ul><li>Abscess with & without surrounding cellulitis </li></ul><ul><ul><li>Incision and drainage, no antibiotics if adequate I&D and patient has no signs of systemic infection </li></ul></ul><ul><ul><li>If antibiotics are needed cover for CA-MRSA with Clindamycin, TMP/SMX, or Doxycycline </li></ul></ul><ul><li>Cellulitis without purulent drainage </li></ul><ul><ul><li>Cover CA-MRSA and Group A Strep </li></ul></ul><ul><ul><ul><li>Clindamycin alone OR </li></ul></ul></ul><ul><ul><ul><li>TMP/SMX or Doxycycline plus Amoxicillin </li></ul></ul></ul>
    53. 53. MRSA Osteomyelitis <ul><li>Rate of failure with six-weeks of IV vancomycin monotherapy was 46% in recent SFGH study </li></ul><ul><li>Ortho/ID guidelines to address high failure rate </li></ul><ul><ul><li>6 weeks of IV therapy; usually vancomycin + oral rifampin </li></ul></ul><ul><ul><li>Followed by 2 to 3 months of oral combination therapy based on sensitivities </li></ul></ul><ul><ul><li>Please get an ID consult when prolonged IV antibiotics are planned for osteomyelitis </li></ul></ul>
    54. 54. Final Thoughts <ul><li>When in doubt ask for help </li></ul><ul><li>Less is (generally) more </li></ul><ul><ul><li>Empirical antibiotics should be based on likely pathogens and clinical situation </li></ul></ul><ul><ul><li>Narrow antibiotics to culture confirmed pathogens </li></ul></ul><ul><ul><li>Treat for the shortest effective duration </li></ul></ul><ul><li>Respect the Staph! </li></ul>
    55. 55. Contact Information <ul><li>Dan Deck, Pharm.D. </li></ul><ul><ul><li>Extension: 5574 </li></ul></ul><ul><ul><li>Pager: 443-4379 </li></ul></ul><ul><ul><li>Email: </li></ul></ul>