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Principles of Treating Infectious Illnesses in Critical Care: Focus on Antibiotic Resistance and Choice. “We shall now discuss in a little more detail the struggle for existence.” C Darwin 1859. Slide Sub-Title. Discussion Topics. Using antibiotics wisely Impact on microbial resistance

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  1. Principles of Treating Infectious Illnesses in Critical Care: Focus on Antibiotic Resistance and Choice “We shall now discuss in a little more detail the struggle for existence.” C Darwin 1859 Slide Sub-Title Resident ICU Course

  2. Discussion Topics • Using antibiotics wisely • Impact on microbial resistance • Impact on patient outcomes • Choosing initial antibiotics and tailoring when data become available • Using pharmacology and pharmacodynamics to optimize bacterial killing • Applying clinically relevant specific antibiotic information Resident ICU Course

  3. Post-Antibiotic Era Mortality: What the Future Holds? Resident ICU Course

  4. Clinical Relevance of ResistanceAnn Intern Med 2001; 134:298 • Increased morbidity/mortality 60-80,000 deaths • Increased hospitalization • Transmission to others • Influences antibiotic choices • Direct/indirect costs 2 million pts suffer nosocomial infections/yr; 50-60% involve resistant pathogens • Cost = <$30 billion/yr at $24K per case Resident ICU Course

  5. Mechanisms of Bacterial Resistance to Antibiotics Resident ICU Course

  6. Resident ICU Course

  7. The Pharmacology of Infectious Diseases Involves Many Factors HOST BUG DRUG Nicolau DP Am J Man Care 1998:4(10 Suppl) S525-30 Resident ICU Course

  8. Selection of Antimicrobial Therapy:Host Factors • Allergies, age, pregnancy, hepatic and renal function, concomitant drug therapy, immunocompentence, and co-morbidities • Site of infection • Must cover common pathogens for specific infectious diagnosis until culture results return • Must consider temporal relationships • Organisms differ with early vs late onset hospital-acquired pneumonia • Organisms may reflect selective pressure if antibiotics previously administered (Antimicrobial history taking is extremely important!) Resident ICU Course

  9. Selection of Antimicrobial Therapy: Drug Factors • Variable antibiotic tissue penetration • Protected sites: pulmonary secretions, the central nervous system, eye, prostate, abscess, bone • Drug clearance: many are renally cleared • Exceptions: the macrolides, amphotericin, caspofungin, voriconazole, clindamycin, tetracyclines, moxifloxacin, linezolid, ceftriaxone, and the antistaphylococcal penicillins • Bioavailability • Good absorption for most quinolones, linezolid, cotrimoxazole, metronidazole, fluconazole, voriconazole, clindamycin, cephalexin, doxycycline, minocycline • Toxicity profile • Cost truths: generic cheaper than brand name and oral/enteral cheaper than parenteral, BUT: antimicrobial costs represent a small fraction of infection treatment Resident ICU Course

  10. Selection of Antimicrobial Therapy:Pathogen Factors • Susceptibility patterns • Vary from institution to institution and even among nursing units • Change quickly if resistant clone becomes established and spreads • Antibiograms are available from the laboratory at most hospitals and updated regularly, and are essential to choose appropriate empirical therapy • Using MIC (minimum inhibitory concentration) data • Requires knowledge of achievable drug concentrations at the site of infection • Comparisons within a class of antibiotics can be helpful; example = Tobramycin with an MIC of <1mcg/ml for P aeruginosa is preferred over gentamicin with MIC of 4 for that organism Resident ICU Course

  11. Correct Initial Choice of Abx Offers Survival Benefit Rello et al Infection-Related Mortality Initial Appropriate Therapy Ibrahim et alInfection-Related Mortality Initial Inappropriate Therapy Kollef et al Crude Mortality Luna et alCrude Mortality 0 20 40 60 80 100 Mortality (%) Kollef MH, et al. Chest. 1998;113:412-420; Ibrahim EH, et al. Chest. 2000;118:146-155 Luna CM, et al. Chest. 1997;111:676-685; Rello J, et al. Am J Respir Crit Care Med. 1997;156:196-200.

  12. Targeted Approach to Antimicrobial Treatment When microbiologic data are known, narrow antibiotic coverage Kollef M. Why appropriate antimicrobial selection is important: Focus on outcomes. In: Owens RC Jr, Ambrose PG, Nightingale CH., eds. Antimicrobial Optimization: Concepts and Strategies in Clinical Practice. New York:Marcel Dekker Publishers, 2005:41-64. Resident ICU Course

  13. Treatment Duration?Refer to Guidelines Cited on Slide 23 for More Complete Information • Uncomplicated UTIs • Depends on antibiotic (Single dose: gatifloxacin; 3 days: ciprofloxacin, TMP/SMX; 7 days: nitrofurantoin, oral cephalosporins) • Endocarditis (4- 6 weeks) • Osteomyelitis (4-6 weeks) • Catheter-related infections? Depends on organism • S. epidermidis and line removed: 5-7 days, line not removed, 10-14 days • S. aureus: 14 days +/- TEE Resident ICU Course

  14. Treatment Duration?Refer to Guidelines Cited on Slide 23 for More Complete Information • Pneumonia • Hospital/healthcare-associated with good clinical response: 8 days (unless etiologic pathogen is P. aeruginosa, ~10-14 days) • Assumes active therapy administered initially Resident ICU Course

  15. Antibiotic regimen 8 days 15 days 8vs 15 Day Treatment of VAPNo difference in outcome except if P. aeruginosa involved P=0.65 Probability of survival No. at risk 197 187 172 158 151 148 147 204 194 179 167 157 151 147 Days after Bronchoscopy JAMA 2003 290:2588

  16. Treatment Duration of Community-Associated Pneumonia : No Consensus • Guidelines • IDSA (2000)—treat Streptococcus pneumoniae until afebrile 72 hours; gram negative bacteria, Staphylococcus aureus, “atypicals” = 2 weeks • Canadian IDS/TS (2000) = 1–2 weeks • ATS (2001)—standard is 7–14 days, but with new agents, may shorten duration (ie, 5–7 days for outpatients) • BTS (2001)—subject to clinical judgment (7–21 days) • Evidence • “The precise duration of treatment … is not supported by robust evidence”–BTS • “Not aware of controlled trials”–IDSA Bartlett JG, et al. Clin Infect Dis. 2000;31:347-382. Mandell LA, et al. Clin Infect Dis. 2000;31:383-421. British Thoracic Society. Thorax. 2001;56 (Suppl 4): iv1-iv64. American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-1754. Resident ICU Course

  17. Treatment Duration?Refer to Guidelines Cited on Slide 23 for More Complete Information • Meningitis (Tunkel et al. Clin Infect Dis 2004;39:1267-84) • Neisseria meningitidis (7days) • Haemophilus influenzae (7 days) • Streptococcus pneumoniae (10-14 days) • Streptococcus agalactiae (14-21 days) • Aerobic gram negative bacilli (21 days) • Listeria monocytogenes (21 days) Resident ICU Course

  18. When is Combination Therapy Considered Appropriate? • Initial empirical “coverage” of multi-drug resistant pathogens until culture results are available (increases chances of initial active therapy) • Enterococcus (endocarditis, meningitis?) • P. aeruginosa (non-urinary tract = controversial; limit aminoglycoside component of combination after 5-7 days in responding patients) • S. aureus, S. epidermidis (Prosthetic device infections, endocarditis)-Rifampin/gentamicin+ vancomycin (if MRSA or MRSE) or antistaphylococcal penicillin • Mycobacterial infections • HIV Resident ICU Course

  19. Recently Published Guidelines: • Hospital/healthcare/ventilator pneumonia Am J Respir CCM 2005; 171:388 • Bacterial Meningitis IDSA: Tunkel, CID, 2004;39:1267-84. • Complicated intra-abdominal infections IDSA: Solomkin, CID, 2003;37;997-1005. • Guidelines for treatment of Candidiasis IDSA: Pappas, CID, 2004;38:16-89. • Prevention of IV catheter infections IDSA: O’Grady, CID, 2002, 35:1281-307. • Management of IV Catheter Related Infections IDSA: Mermel, CID 2001;32:1249-72. • Updated community acquired pneumonia IDSA: Mandell, CID, 2003, 37:1405-33. • Treatment of tuberculosis ATS et al.: 2003, AJRCC • Empiric therapy of suspected Gm+ in Surgery Solomkin, 2004, AJS; 187:134-45. • Use of Antimicrobials in Neutropenic Patients IDSA: Hughes, CID, 2002;34:730-51. • Guide to Development of Practice Guidelines IDSA: CID, 2001;32:851-54. Resident ICU Course

  20. Antibiotic Pharmacology and the Pharmacodynamics of Bacterial Killing Resident ICU Course

  21. Bacterial Targets for Antibiotics Resident ICU Course

  22. Pharmacodynamics of BacterialKilling Concentration-dependent (greater bacterial kill at higher concentrations) vs. Concentration-independent Resident ICU Course

  23. Beta-lactams Vancomycin Clindamycin Macrolides Concentration MIC T>MIC Time (hours) The Pharmacodynamics of Bacterial KillingConcentration-Independent: Optimal kill defined by time over the minimum inhibitory concentration (T>MIC) Resident ICU Course

  24. Meropenem 500 mg Administered as a 3 h Infusion Extends the Time Over the MIC vs a 0.5 h infusion 100.0 Rapid Infusion (30 min) Extended Infusion (3 h) 10.0 Concentration(mcg/mL) 1.0 MIC Additional T>MIC gained 0.1 0 2 4 6 8 Time (h) Dandekar PK et al. Pharmacotherapy. 2003;23:988-991.

  25. Dosing Adjustments in Renal Disease? • Yes • Almost all cephalosporins and most other beta-lactams (penicillins, aztreonam, carbapenems) • Most quinolones • Vancomycin • Cotrimethoxazole • Daptomycin • Fluconazole • No • Doxycycline • Erythromycin, azithromycin • Linezolid • Clindamycin • Metronidazole • Oxacillin, nafcillin, dicloxacillin • Ceftriaxone • Caspofungin • Voriconazole PO • Amphotericin b • Avoid use altogether • Tetracycline • Nitrofurantoin (CrCl <40) • Voriconazole IV (CrCl<50) • Aminoglycosides (if possible) Resident ICU Course

  26. Selected Review of Specific Agents Resident ICU Course

  27. Penicillin • Mechanism of activity • Interferes with cell wall synthesis • Adverse reactions • CNS toxicity—encephalopathy and seizures with high doses and renal dysfunction • Allergic reactions • Treatment of choice for susceptible enterococcal and streptococcal pathogens as well as Treponema pallidum (syphilis) Resident ICU Course

  28. Resistant (MICs >2) Intermediate (MICs 0.12-1) Penicillin Resistance with Streptococcus pneumoniae in the United States 40 35 30 25 20 Percent 15 10 5 0 1979-87 1988-89 1990-91 1992-93 1994-95 1997-98 1999-00 2001-02 2002-03 5589 487 524 799 1527 1601 1531 1940 1828 35 15 17 19 30 34 33 45 44 1980’s 1990’s 2000’s

  29. Antistaphylococcal Penicillins • Agents • Nafcillin, oxacillin • Mechanism of action • Interferes with cell wall synthesis • Active against penicillinase producing, methicillin susceptible S. aureus (MSSA) • preferred over vancomycin (faster killing, better outcomes, see following slide) • Side effect profile as per the penicillins • Role in therapy: directed therapy against MSSA • Current rate of MRSA = 40-50% Resident ICU Course

  30. Oxacillin Bactericidal Activity Resident ICU Course

  31. Broad-Spectrum Penicillins • Ampicillin, piperacillin, with and without beta-lactamase inhibitors • Interferes with cell wall synthesis • Adds additional gram negative activity and with beta-lactamase inhibitor adds anaerobic and antistaphylococcal activity • Adjust dosing for renal dysfunction Resident ICU Course

  32. Are there any beta-lactams that can be used in a true beta-lactam allergic patient? • Aztreonam active against gram negative enterics, but remember, NO activity against gram positive nor anaerobic organismsWhat is the rate of cross-reactivity in patients with history of anaphylaxis to penicillin? • Cephalosporins (2-18%) Opportunity for x-reaction decreases as generations increase • Carbapenems (50%) Imipenem, meropenem, ertapenem Resident ICU Course

  33. Cephalosporins • Prototypical agents • First generation: cefazolin • Second generation: limited utility • Third generation: ceftazidime, ceftriaxone • Fourth generation: cefepime • Mech of action: interferes with cell wall synthesis • Microbiologic activity dependent on generation and specific agent (see next slides) • None are effective against enterococci nor listeria monocytogenes • Toxicity • Seizures, bone marrow depression Resident ICU Course

  34. Cephalosporin Specifics • First gen: cefazolin • Good activity against gram positive organisms, and commonly effective against E. coli, P. mirabilis, K. pneumoniae—NO CNS PENETRATION • Second gen: cefuroxime and cefoxitin • Limited utility: cefoxitin for GI surgery prophylaxis • Third gen: ceftriaxone • Good activity against gram positives and gram negative enterics, not for P. aeruginosa • Adequate CNS concentrations achieved • Third gen: ceftazidime • Little activity against gram positive organisms, good activity against enterics and P. aeruginosa Resident ICU Course

  35. Cephalosporin Specifics • Fourth gen: cefepime • Good activity against gram positive and gram negative organisms including P. aeruginosa • Does not induce beta-lactamase production • Good CNS penetration Resident ICU Course

  36. Carbapenems • Prototypical agents: imipenem/cilastatin, meropenem, ertapenem • Mech action • Interferes with cell wall synthesis • Spectrum of activity • Gram positive, gram negative, and anaerobic organisms • Not active against methicillin resistant S. aureus and epidermidis, S. maltophilia • Commonly results in candida overgrowth • Side effect profile • Nausea and vomiting with rapid administration • Seizures (imipenem > meropenem = ertapenem) • Risk factors: underlying CNS pathology and decreased renal function Resident ICU Course

  37. Quinolones • Prototypical agents (available both IV and PO) • Ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin • Mech of action: interferes with bacterial DNA replication • Spectrum of activity • Pneumococcus: moxi = gati > levo • Gram negative enterics: all • P. aeruginosa: cipro = levo 750mg > moxi, gati • Resistance in P. aeruginosa to all quinolones sharply increasing! • Adverse events • Mania, tremor, seizures, QTc prolongation (gati, moxi, levo), hypo- hyperglycemia (gati > levo, moxi, cipro) • Drug interactions • Oral formulations with concurrent GI ingestion of bi and trivalent cations • Enzyme inhibition by ciprofloxacin with warfarin and theophylline • Concurrent use of agents with prolong QTc with moxifloxacin, gati, levo • Avoid gatifloxacin in diabetics, particularly if on type II sulfonylureas Resident ICU Course

  38. Alarming Increase in Rate of Quinolone Resistance in P. aerugniosa Fluoroquinolone-resistant Pseudomonas aeruginosa Non-Intensive Care Unit Patients Intensive Care Unit Patients Source: National Nosocomial Infections Surveillance (NNIS) System

  39. Important Reduction in GI Tract Quinolone Absorption with Bi and Tri-Valent Cations Resident ICU Course

  40. Vancomycin (also formerly known as Mississippi Mud)Name derived from the word “Vanquish” Resident ICU Course

  41. Vancomycin • Mech of action • Interferes with cell wall synthesis • Spectrum of activity • All common gram positive pathogens except • Enterococcus faecium (VRE) • Enteral formulation effective against Clostridium difficile (after failing metronidazole) • Not active against gram negative organisms Resident ICU Course

  42. Vancomycin • Toxicity • Ototoxicity? Rare, if at all • Nephrotoxicity? Only when combined with aminoglycosides • Red man syndrome: local histamine release • Slow infusion, pretreat with antihistamines • Bone marrow depression after long-term use • Dosing: 10-20mg/kg at an interval determined by CrCl initially and subsequently by trough determinations • Target trough serum levels = 5-15 mg/dL for line infections and 15-20 mg/dL for pulmonary, CNS or deep seated infections (ie endocarditis, osteomyelitis) Resident ICU Course

  43. Linezolid (Zyvox) • Novel class; oxazolidinone • Inhibits protein synthesis • Activity: virtually all gram positive organisms • Resistance already seen (during long term use and in patients with indwelling prosthetic devices) • Favorable pharmacokinetics; IV = po (600mg every 12 hours) • Bone marrow depression (usually >2wks tx), GI Resident ICU Course

  44. Linezolid • Potential roles in therapy • Infections caused by vancomycin-resistant enterococci • Infections caused by staphylococci in patients who cannot tolerate beta-lactam agents or vancomycin • Use in patients who have failed initial treatment for staphylococci infections? • As a vancomycin alternative in patients receiving concurrent aminoglycosides • As an enteral dosing formulation alternative for parenteral vancomycin treatment for MRSA infections Resident ICU Course

  45. Lipopeptides Daptomycin(Cubicin) MOA:disruption of plasma membrane function Pharmacology: • Dosing Form:IV only • Regimens:4 mg/kg q24h(FDA approved for MRSA, MSSA skin soft tissue infections) & 6 mg/kg q24h (under investigation for Enterococci, endocarditis) • Highly protein bound • Concentration-dependent killing • Side Effects:myopathy, check CKs Microbiology: • Activity against VRE, MRSA, VISA, PRSP Baltz RH. Biotechnology of Antibiotics. 1997. Tally FP, DeBruin M. J Antimicrob Chemother 2000;46:523-26.

  46. Rifampin • Benefits: • Most potent anti-staphylococcal agent (only used adjunctively) • IV & PO • QD dosing • Inexpensive PO (IV $$$$$$) DNA mRNA THFA Ribosomes 50 50 New Protein DFHA • Disadvantages: • RESISTANCE Develops rapidly, CANNOT be used as a single agent • Drug Interactions: MANY!! Substrate of: CYP2A6, 2C9, 3A4 INDUCES: CYP1A2, 2A6, 2C9, 2C19, 3A4 30 30 mRNA Owens RC Jr. Treatment guidelines for MRSA in the elderly. Omnicare Formulary Guide. 2004.

  47. Rifampin Rash, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis • Monitor: • CBC • Chemistry (Scr, BUN) • LFTs hepatitis Interstitial nephritis Thrombocytopenia

  48. Aminoglycosides • Prototypical agents • Gentamicin, tobramycin, amikacin • Mech of action • Inhibition of protein synthesis, concentration dependent activity on bacterial kill • Spectrum of activity • Enterobacteriaceae, P. aeruginosa, Acinetobacter spp, enterococci (synergy only) • Adjunctive agents, not optimal as single agents except for UTIs • Toxicity • Ototoxicity, nephrotoxicity • Risk factors: pre-existing renal dysfunction, duration of therapy >5 days, age, use of other nephrotoxins • Dosing • Conventional: gentamicin/tobramycin (1-2mg/kg), amikacin (7.5mg/kg) at an interval determined by CrCl • Extended interval: gentamicin/tobramycin (5-7mg/kg), amikacin (15-20mg/kg) every 24 hours or longer depending on CrCl • Not for pregnant patients, those on renal replacement therapy or end stage renal disease, cystic fibrosis, or burns >20% body surface Resident ICU Course

  49. Once-daily regimen Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens Optimizes Concentration-dependant Effect on Bacterial Kill 14 12 Conventional (three-times daily regimen) 10 Concentration (mg/L) 8 6 4 2 0 0 24 4 8 12 16 20 Time (hours) Nicolau et al. Antimicrob Agents Chemother 1995;39:650–655

  50. Metronidazole • Mech of action: complex---toxic to bacterial DNA • Microbial activity • Anaerobes • Initial treatment of choice for C. difficile • 100% bioavailable: IV = oral dose • Toxicity minimal • Neurotoxic at high doses • No dose adjustments in renal disease Resident ICU Course

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