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Choosing Antibiotics: Before and After the Culture Results

Choosing Antibiotics: Before and After the Culture Results. Gopi Patel, MD August 20, 2010. Picking Antibiotics. What has the patient grown before?. What are the patient’s signs and symptoms?. Prophylaxis. Empiric. Targeted. What is the patient at risk for growing?.

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Choosing Antibiotics: Before and After the Culture Results

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  1. Choosing Antibiotics: Before and After the Culture Results Gopi Patel, MD August 20, 2010

  2. Picking Antibiotics What has the patient grown before? What are the patient’s signs and symptoms? Prophylaxis Empiric Targeted What is the patient at risk for growing? What is the patient growing now?

  3. Antibiotic selection • Risk factors for drug resistance • Recent antimicrobial exposures • Underlying comorbidities • Allergies • Recent interventions • Available and previous culture data • History of MRSA, VRE, Pseudomonas • ESBL-producing GNR • The flora and fauna of the hospital • And perhaps even the unit … • How sick is the patient? • Can always “go big” and narrow as you get more information…

  4. Just to refresh your memory…

  5. Cephalosporins* • * Do NOT cover Enterococcus, Listeria, Legionella, or MRSA

  6. Case 1 • 48 M IVDA admitted with fevers and chills • Fresh track marks on Left arm • Febrile to 39 BP 70/55 HR 112 93%RA • III/VI systolic murmur at LLSB • B/L crackles • Chest X-ray- Congestion B/L • Empiric antibiotics?

  7. As expected • At 14 hours both sets of blood cultures are growing Gram-positive cocci in clusters • Previous history of MRSA • TTE can’t rule out vegetation on mitral valve • TEE refused • Patient grows MRSA • Vancomycin continued

  8. Vancomycin • Discovered in 1956 • Mechanism of action • Inhibits bacterial cell wall synthesis • Binds firmly to D-Ala-D-Ala of the peptidoglycan, preventing elongation and cross-linking • Mechanism of resistance • Altered peptidoglycan binding site • D-Ala-D-Ala is replaced by D-Ala-D-lactate • Thickened cell wall

  9. Toxicity • Nephrotoxicity • Most often in the setting of other nephrotoxic agents and unstable renal function • Hypersensitivity reactions1 • Red man syndrome • Anaphylaxis • Rare reactions • Ototoxicity • Neutropenia and/or thrombocytopenia2 • Linear IgA bullous dermatosis 1 Crit Care. 2003; 7(2) 119-20 2 NEJM. 2007; 356(9) 904-910

  10. Linear IgA Bullous Dermatosis

  11. Dosing

  12. Dosing • Use actual body weight to dose • Round to the nearest 250 mg Use Cockcroft-Gault to calculate Creatinine Clearance NOT MDRD (Given by EDR or SCC) Am J Health-Syst Pharm. 2009;66:82-98

  13. Monitoring • Troughs are most accurate and practical • Obtain trough just prior to the next dose at steady-state (usually after 4th dose) • Levels should be maintained >10 mg/L • Minimum troughs of 15-20 mg/L are recommended for severe or complicated infections (endocarditis, osteomyelitis, meningitis, and pneumonia) 1 Am J Resp Crit Care Med. 2005;171:338. 2 Clin Infect Dis. 2004;39:1267-84. 3 Circulation. 2005; 111:e394-e433.

  14. What if a person can’t “tolerate” Vanco? Anaphylaxis Patient “refuses” drug Can’t get the right levels Ease of dosing

  15. Daptomycin • FDA approved in 2003 • Depolarizes the cell membrane and is rapidly bactericidal against Gram-positives • Approved for the treatment of complicated skin and skin structure infections • S. aureus (including MRSA), GAS, Streptococcus agalactiae, and vanco-susceptible Enterococcus faecalis • Not approved for E. faecium (CLSI breakpoint <4) • Non-inferior to vanco and anti-staph penicillins in S. aureus bacteremia and right-sided endocarditis1 • Jury is out for left-sided endocarditis • NOT indicated for treatment of pneumonia 1 NEJM. 2006; 355(7): 652-65

  16. Dosing • Use actual body weight • For serious, life-threatening infections dosing regimens of 8 to 12 mg/kg have been used1 • Requires 24-hour Antibiotic Approval 1 CID. 2009; 49: 177-80

  17. Toxicity • Rhabdomyolysis and myopathy • Monitor for clinical evidence of myopathy • Check CK/CPK levels every week • Especially if on higher dose or in renal failure • May be at increased risk for toxicity with statins

  18. Microbiologic Failure • Resistance can develop to daptomycin during treatment and may be influenced by exposure to vancomycin • Seen in both S. aureus and Enterococcus spp • NEJM non-inferiority study: 15% of patients in dapto arm with clinical failure • 6/19 (32%) with increased daptomycin MIC • Should not be used if 1° source not removed

  19. What if the patient grew MSSA? • Nafcillin • Nafcillin 2 g IV Q 4 hours • No adjustment • Cefazolin • 2 g IV Q 8 hours for “normal” renal function

  20. S. aureus: its own lecture • Please call an ID consult for MSSA or MRSA bacteremia • High risk for metastatic disease • Future noon conference to follow (10/13/10)

  21. Another refresher …

  22. B-lactam/B-lactamase inhibitors

  23. Case 2 • 57 F transferred from outside hospital after admission for new jaundice and increasing abdominal girth • Diagnosed with “cryptogenic cirrhosis” • Transferred on piperacillin-tazobactam and vancomycin

  24. Case 2 • Patient given vancomycin 1 gram x 1 dose and continued on piperacillin-tazobactam • HD #2 develops worsening encephalopathy • CXR • Blood cultures • U/A and urine culture • Diagnostic paracentesis attempted

  25. Case 2 • Intern calls OSH and finds that patient’s blood cultures there are growing GPC in pairs and chains • Patient on both vanco and pip-tazo at the time the cultures were obtained • Hint: What GPC is not being covered? • Change Antibiotics?

  26. Enterococcus species • Ampicillin-susceptible E. faecalis • Penicillin and ampicillin slowly bactericidal • Ampicillin, piperacillin, penicillin, imipenem • Vancomycin (when susceptible) • 88% of E. faecalis is vanco susceptible at MSH • 20% of E. faecium • Use of aminoglycosides for synergy in the setting of serious infections (e.g., endocarditis)

  27. VRE • FDA approved agents • Linezolid • Quinupristin/Dalfopristin (E. faecium ONLY) • Alternative agents • Daptomycin • Tigecycline

  28. Linezolid • FDA approved in 2000 for complicated skin and skin structure infections, pneumonia, and bloodstream infections • Gram-positive organisms • Nocardia, non-tuberculous mycobacteria, TB • Mechanism of action • Inhibits initiation of protein synthesis by binding 50S ribosome • Oral formulation with 100% bioavailability

  29. Dosing • 600 mg IV/PO every 12 hours • No dose-adjustment for renal insufficiency or liver disease

  30. Toxicity • Safety concerns with prolonged use • Thrombocytopenia and neutropenia • Lactic acidosis • Peripheral neuropathy • Optic neuritis • Serotonin syndrome in combination with SSRIs

  31. Serotonin Syndrome • Described by a triad of symptoms • Mental status change • Autonomic hyperactivity • Fever, hyperreflexia • Neuromuscular abnormalities

  32. Spectrum of Clinical Findings Boyer E and Shannon M. N Engl J Med 2005;352:1112-1120

  33. Linezolid resistance • Rare but has been reported with S. aureus and Enterococcus species

  34. Linezolid- pneumonia • “Intrapulmonary pharmacokinetics” • Require vanco trough ≥ 20 to achieve appropriate alveolar levels? • In 2 RCTs (2001 and 2003) compared vanco v. linezolid for pneumonia and demonstrated no difference in outcomes (aztreonam for GNR coverage) • Controversial subset analysis suggested superiority of linezolid for S. aureus pneumonia

  35. Case 3 • 52 M with HCV cirrhosis admitted with large volume hematemesis • History of SBP on ciprofloxacin prophylaxis • Intubated to maintain airway s/p EGD with banding of varices • Started on ceftriaxone 1 g every 24 hours for SBP prophylaxis • HD #2 febrile to 38.5

  36. Case 3 • Blood cultures sent and diagnostic paracentesis performed • Patient given 1 g of vancomycin and changed from ceftriaxone to cefepime • RBC 1260 WBC 540 90% N • Gram stain: few WBC and no organisms • Blood cultures with GNR at 13 hours in aerobic bottle

  37. Previous culture data • An astute PGY-2 looks back at previous cultures and finds that 8 months earlier the patient grew this in his urine…

  38. URINE CULTURE 01/02/10 >100,000 CFU/mL GRAM NEGATIVE BACILLI Isolate 01 Klebsiella pneumoniae, an ESBL producer CONTACT PRECAUTIONS ANTIBIOTICS Mic SYSTEMIC URINE Aztreonam >16 R Ceftriaxone <8 R* Ceftazidime 16 R Cefotaxime 8 R Cefazolin >16 R* Cefepime <8 R* Ampicillin >16 R* Cefuroxime 16 R* Tetracycline <4 S Ertapenem <2 S Gentamicin <4 S Imipenem <4 S Levofloxacin <2 S Trimethoprim/Sulf<2/38 S

  39. Any changes? A. Continue cefepime B. Change cefepime to levofloxacin C. Change cefepime to imipenem D. Give a dose of gentamicin E. Call ID for a consult because liver is going to ask you to do that anyways

  40. ESBL • Extended-spectrum beta-lactamase (ESBL) producing organisms first described in 1983 • Associated with use of broad spectrum antibiotics • Like ceftriaxone, ceftazidime, pip-tazo • Resistant to penicillins, cephalosporins, and monobactams (aztreonam) • Carbapenems are the drug of choice • Clinical failures associated with alternative agents (like fluoroquinolones) • Increased morbidity and mortality associated with delayed administration of “appropriate” antibiotics

  41. Carbapenems

  42. Carbapenems • Excellent anaerobic coverage • Intrinsic resistance • Enterococcus faecium • MRSA • Stenotrophomonas maltophilia • Burkholderia cepacia (except meropenem) • Penicillin-resistant Streptococcus pneumoniae • Adverse events • Nephrotoxicity • Neurotoxicity

  43. BLOOD CULTURE 08/02/10 GRAM NEGATIVE BACILLI IN AEROBIC BOTTLE AFTER 13 HOURS Isolate 01 Klebsiella pneumoniae, an ESBL producer ANTIBIOTICS Mic SYSTEMIC URINE Aztreonam >16 R Ceftriaxone <8 R* Ceftazidime 16 R Cefotaxime 8 R Cefazolin >16 R* Cefepime <8 R* Ampicillin >16 R* Cefuroxime 16 R* Tetracycline <4 S Ertapenem <2 S Gentamicin <4 S Imipenem <4 S Levofloxacin >2 R Trimethoprim/Sulf<2/38 S

  44. If you ever see this…

  45. BLOOD CULTURE 07/02/10 GRAM NEGATIVE BACILLI IN BOTH BOTTLES AFTER 7 HOURS. Isolate 01 Klebsiella pneumoniae 07/04/10 - This Organism Is Producing a KPC-type Carbapenemase. All Beta-Lactam Antibiotics Should Be Interpreted As Resistant. Susceptibility testing results for Polymyxin B may be used to predict the activity of Colistin (Polymyxin E). - CONTACT PRECAUTIONS ANTIBIOTICS MIC SYSTEMIC URINE Amox/Clavulanate >16/8 R Aztreonam >16 R Ceftriaxone >32 R Ceftazidime >16 R Ciprofloxacin >2 R Cefepime >16 R Amikacin >32 R Ertapenem >4 R Gentamicin <4 S Imipenem >8 R Levofloxacin >4 R Meropenem >8 R Piperacillin/tazo >64 R Trimethoprim/Sulf>2/38 R Tetracycline >4 R Tobramycin >8 R

  46. Call an ID fellow…

  47. Susceptibilities at MSH 2009

  48. Other susceptibilities A. baumannii- 38% susceptible to sulbactam component of amp-sulbactam

  49. Case 4 • 55 F DM, HTN, PVD, ESRD on HD • Admitted with hyperglycemia/HONK • Transferred out of MICU to 9W after stabilized on HD #3 • On HD #5 febrile to 38.7 and lethargic • CXR ordered • Blood cultures sent • U/A and Urine cultures ordered

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