INFECTIOUS DISEASE BASICS Selected Topics

1. INFECTIOUS DISEASE BASICS +(Selected Topics) Stuart Johnson, MD Associate Professor Loyola University Medical Center and the Hines VA Hospital

2. Case#1 A 70 yr-old-man admitted to the CCU 4 days previously for a �troponin leak� now has a temperature of 38.50C. Your response: A. Start Zosyn B. Start vancomycin C. Start Zosyn & vancomycin D. Obtain blood & urine cultures, get CXR E. A & D F. B & D G. All of the above

3. Fever ? Antibiotics Infectious fevers Non-infectious fevers Unintended consequences of antibiotics

4. Fever  Noninfectious etiologies:ETOH/Drug withdrawal Fat emboliPost-op fever (<48H) Transplant rejectionPost transfusion fever DVT / PEDrug fever Gout/pseudogoutIntracranial infarct/bleed HematomaAdrenal insufficiency CirrhosisAMI GI bleedPancreatitis Adrenal insufficiencyIschemic bowel IV contrastNeoplastic fever Decubitus ulcershyperthyroidism

5. Case#1, Cont. Urine culture: + 30,000 col/mL S. aureus (R- amp, S- oxa, S- tmp/smz) Urinalysis: Nit +, LE +, 2-5 WBC/hpf, 2-5 RBC/hpf Your response: A. Start tmp/smz B. Change foley catheter C. Renal ultrasound D. Obtain more blood cultures E. All of the above

6. S. aureus in Urine S. aureus is an uncommon etiology of primary UTI When cultured from urine > Think Bacteremia

7. Case#1, Cont. Exam: L arm PICC line, site is clean, not red CXR: Clear lung fields Blood cultures: 1 of 2 sets + GPCs in clusters ID: S. aureus (R- amp, S- oxa, S- tmp/smz) Your response: A. Obtain more blood cultures (through PICC line and peripherally) B. Start oxacillin 2 gm iv Q 4 h C. Pull PICC line D. Wait for clinical response & follow up blood culture results before removing PICC line E. A, B & C F. A, B & D

8. S. aureus Bacteremia?S. epidermidis* Bacteremia * or, other coagulase-negative staphylococci

9. Case#1, Cont. PICC line is removed 3 days later, patient is still febrile and blood cultures are still positive (GPCs, ID pending) Patient complains of low back pain and incontinence Your response: A. Change oxacillin to vancomycin B. Cardiac echo (TEE) C. MRI of spine D. Tagged WBC scan

10. Fever, Back Pain, Lower Extremity Neurologic Findings = Spinal epidural abscess until proven otherwise = True infectious disease emergency

11. Intravenous Catheters Factors pointing towards catheter as source: bacteremia or fungemia in immunocompetent patient w/o underlying diseases no identifiable local infection presence of device at onset of fever inflammation or pus at exit site or along tunnel multiple blood cultures for organisms usually considered as contaminants (CNS, Bacillus sp, Corynebacterium, Candida sp.)

12. Intravascular Catheters, Cont. To pull or not to pull�. Patient is in shock Patient manifests embolic phenomenon DIC ARDS Clinical evidence of vascular compromise (arterial) Re-insert at a different site If positive blood cultures persist consider suppurative phlebitis, SBE, embolic infection

13. ICU-Acquired Pneumonia Diagnosis may be difficult Abnormal CXR may represent: CHF Atelectasis ARDS Patient may be intubated and sedated no cough colonized respiratory secretions difficult to separate pneumonia from tracheitis or tracheobronchitis, abscess

14. ICU-Acquired Pneumonia, Cont. Empiric therapy Length of hospital stay <2 days consider community-acquired agents Respiratory flouroquinolone (e.g., moxifloxacin) Ceph3 + azithromycin >2 days consider additional hospital-acquired organisms monobactam (imipenem or meropenem) AP PCN (Pip or Zosyn) + aminoglycoside Ceph 3/4 + aminoglycoside + clindamycin

15. ICU-Acquired Sinusitis Almost never the cause of FUO (MY RULE) Most common risk factor is NT or NG tube Evaluation only undertaken after more likely etiologies ruled out 60% gram negative (P. aeruginosa most common) 30% gram positive (S. aureus most common) 5-10% fungi Presentation:cough, purulent nasal discharge +/- headache, periorbital edema, facial pain, tooth pain, earache, sore throat, foul breath, wheezing, fever

16. Case#2 A 70 yr-old-woman admitted to the ward with multiple watery stools, fever. Was hospitalized 2 weeks ago for pneumonia, developed diarrhea then which responded to oral metronidazole Your response: A. Start oral metronidazole B. Start oral metronidazole at a higher dose C. Start oral vancomycin D. Send stool for C. difficile toxin E. Put patient in contact isolation if toxin assay is + F. Put patient in conatct isolation right away G. A, D & F

19. Major Risk Factors forClostridium difficile-associated Diarrhea (CDAD) Antibiotic exposure Hospitalization/ Institutionalization

20. Initial (Incorrect) Hypothesis

21. Rate of CDAD in Patients Colonized and Non-colonized with CD from 4 Prospective Studies

22. Revised Hypothesis

23. Case#3 A 70 yr-old-man admitted to the ward 4 days ago with pneumonia now has watery stools, fever. C. difficile toxin immunoassay is negative x 2 (specimens obtained on separate days) Your response: A. Send stool for O & P and enteric culture B. Request flexible sigmoidoscopy exam C. Start loperamide D. Send stool for third C. difficile toxin assay E. Start oral metronidazole

24. Fatal Case of Pseudomembranous Colitis (PMC), August 1999

25. Toxin A-,B+ Clostridium difficile Variants

26. Four Toxin EIA Tests vs. Cytotoxin & Culture

27. Diagnostic Testing Summary

29. CDAD in Eastern Quebec1991 to 2003

30. Multi-Hospital Regional CDAD Outbreak, Montreal 2003-4

31. Emergence of an Epidemic Strain ofC. difficile in the US, 2000-3

32. Acute care hospitals with CDAD outbreaks between 2001 and 2004

33. Toxin Variations in the Epidemic Strain

34. Possible Virulence Factors: Epidemic Strain Hypothesis Slide 10 Polymorphisms and deletions in tcdC variants that have been identified in toxinotype III strains (tcdC may downregulate production of toxins A and B) may result in a decreased ability to regulate toxin production, causing dramatically increased amounts of toxins A and B to be observed. This association requires further verification.1-3 Spigaglia P, et al. Molecular analysis of the pathogenicity locus and polymorphism in the putative negative regulator of toxin production (TcdC) among Clostridium difficile clinical isolates. J Clin Microbiol. 2002;40:3470-3475. Rupnik M, et al. Revised nomenclature of Clostridium difficile toxins and associated genes. J Med Microbiol. 2005;54:113-117. McDonald LC, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-2441.Slide 10 Polymorphisms and deletions in tcdC variants that have been identified in toxinotype III strains (tcdC may downregulate production of toxins A and B) may result in a decreased ability to regulate toxin production, causing dramatically increased amounts of toxins A and B to be observed. This association requires further verification.1-3 Spigaglia P, et al. Molecular analysis of the pathogenicity locus and polymorphism in the putative negative regulator of toxin production (TcdC) among Clostridium difficile clinical isolates. J Clin Microbiol. 2002;40:3470-3475. Rupnik M, et al. Revised nomenclature of Clostridium difficile toxins and associated genes. J Med Microbiol. 2005;54:113-117. McDonald LC, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-2441.

36. Outbreak Strains are NOT New: Comparison of Historic and Epidemic REA �BI� types

37. Fluoroquinolone Resistance in Epidemic Strains and Controls However, high-level fluroquinolone resistance, particularly gatifloxacin and moxifloxacin resistance was seen in all of the current epidemic strain isolates and was more prevalent than in non-epidemic strains in the same hospitals were the outbreaks occurred. In addition, we were able to identify this strain in our C. difficile isolate collection from patients dating back to the early 1980�s. This strain was not recognized as causing outbreaks and the isolates were all susceptible to gati and moxiHowever, high-level fluroquinolone resistance, particularly gatifloxacin and moxifloxacin resistance was seen in all of the current epidemic strain isolates and was more prevalent than in non-epidemic strains in the same hospitals were the outbreaks occurred. In addition, we were able to identify this strain in our C. difficile isolate collection from patients dating back to the early 1980�s. This strain was not recognized as causing outbreaks and the isolates were all susceptible to gati and moxi

38. Summary

39. States with the Epidemic Strain of C. difficile Confirmed by CDC and Hines VA labs (N=27),Updated 3/30/2007

40. Severe C. difficile Diarrhea CaseLUMC, March 2005

42. Prospective, Randomized Treatment Trials of CDAD Agent Cure Rate* Relapse Rate Time to Resolution Metronidazole 94 - 95% 5 - 16% 2.4 - 3.2 days Vancomycin 94 - 100% 15 - 16% 2.6 - 3.1 days *Successful treatment of the initial episode of C. difficile-associated disease. Slide 22 This table gives a summary of cure rate (defined as successful treatment of the initial episode C. difficile-associated disease), relapse rates, and time to resolution for metronidazole and vancomycin. The cure rate for metronidazole ranges from 94% to 95%, and the relapse rate ranges from 5% to 16%. The cure rate for vancomycin is from 94% to 100%, and the relapse rate varies from 15% to 16%.1 Johnson SJ, Gerding DN. Summary of prospective randomized treatment trials of CDAD. In Antimicrobial Therapy & Vaccines. 2nd edition. Yu V, et al., eds. New York: Apple Trees Productions; 2002. Slide 22 This table gives a summary of cure rate (defined as successful treatment of the initial episode C. difficile-associated disease), relapse rates, and time to resolution for metronidazole and vancomycin. The cure rate for metronidazole ranges from 94% to 95%, and the relapse rate ranges from 5% to 16%. The cure rate for vancomycin is from 94% to 100%, and the relapse rate varies from 15% to 16%.1 Johnson SJ, Gerding DN. Summary of prospective randomized treatment trials of CDAD. In Antimicrobial Therapy & Vaccines. 2nd edition. Yu V, et al., eds. New York: Apple Trees Productions; 2002.

43. Recent Observational Reports of CDAD Response to Metronidazole Rx Slide 22 This table gives a summary of cure rate (defined as successful treatment of the initial episode C. difficile-associated disease), relapse rates, and time to resolution for metronidazole and vancomycin. The cure rate for metronidazole ranges from 94% to 95%, and the relapse rate ranges from 5% to 16%. The cure rate for vancomycin is from 94% to 100%, and the relapse rate varies from 15% to 16%.1 Johnson SJ, Gerding DN. Summary of prospective randomized treatment trials of CDAD. In Antimicrobial Therapy & Vaccines. 2nd edition. Yu V, et al., eds. New York: Apple Trees Productions; 2002. Slide 22 This table gives a summary of cure rate (defined as successful treatment of the initial episode C. difficile-associated disease), relapse rates, and time to resolution for metronidazole and vancomycin. The cure rate for metronidazole ranges from 94% to 95%, and the relapse rate ranges from 5% to 16%. The cure rate for vancomycin is from 94% to 100%, and the relapse rate varies from 15% to 16%.1 Johnson SJ, Gerding DN. Summary of prospective randomized treatment trials of CDAD. In Antimicrobial Therapy & Vaccines. 2nd edition. Yu V, et al., eds. New York: Apple Trees Productions; 2002.

44. Response Time for Treatment of C. difficile Infection with Metronidazole or Vancomycin

45. Oral Vancomycin vs Metronidazole in Severe CDAD Prospective, randomized, double-blind, placebo-controlled trial Vancomycin 125 mg PO QID x 10 days vs Metronidazole 250 mg PO QID x 10 days Patients stratified by disease severity Severe disease defined as admission to an ICU, presence of pseudomembranes on endoscopy, or ? 2 of the following Age > 60 years Temperature > 101?F Albumin level < 2.5 mg/dL White blood cell count > 15,000 cell/mm3 Slide 45 Zar et al.1 recently published the results of a prospective, randomized, double-blind, placebo-controlled trial of 125 mg of oral vancomycin compared with 250 mg of oral metronidazole 4 times a day for 10 days in the treatment of C. difficile-associated diarrhea. Patients were stratified by disease severity. Severe disease was defined as an admission to the intensive care unit, the presence of pseudomembranes on endoscopy, or at least two of the following: age > 60 years, a temperature > 101?F, an albumin level < 2.5 mg/dL, or a white blood cell count > 15,000 cell/mm3. Zar FA, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:August 1 [Epub ahead of print].Slide 45 Zar et al.1 recently published the results of a prospective, randomized, double-blind, placebo-controlled trial of 125 mg of oral vancomycin compared with 250 mg of oral metronidazole 4 times a day for 10 days in the treatment of C. difficile-associated diarrhea. Patients were stratified by disease severity. Severe disease was defined as an admission to the intensive care unit, the presence of pseudomembranes on endoscopy, or at least two of the following: age > 60 years, a temperature > 101?F, an albumin level < 2.5 mg/dL, or a white blood cell count > 15,000 cell/mm3. Zar FA, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:August 1 [Epub ahead of print].

46. Oral Vancomycin vs Metronidazole in CDAD 172 patients enrolled and 150 completed the trial Slide 46 In the study by Zar et al.,1 172 patients were enrolled and 150 completed the trial. Of these 150 patients, 81 had mild disease and 69 had severe disease. Among those with mild disease, treatment with vancomycin resulted in a clinical cure in 98% of patients and with metronidazole in 90% of patients (P=0.36). Among those with severe disease, treatment with vancomycin resulted in a clinical cure in 97% of patients and with metronidazole in 76% of patients (P=0.02). The findings of these authors suggest that vancomycin and metronidazole are equally effective for the treatment of mild CDAD and that vancomycin is superior in the treatment of severe disease. Zar FA, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:August 1 [Epub ahead of print]. Slide 46 In the study by Zar et al.,1 172 patients were enrolled and 150 completed the trial. Of these 150 patients, 81 had mild disease and 69 had severe disease. Among those with mild disease, treatment with vancomycin resulted in a clinical cure in 98% of patients and with metronidazole in 90% of patients (P=0.36). Among those with severe disease, treatment with vancomycin resulted in a clinical cure in 97% of patients and with metronidazole in 76% of patients (P=0.02). The findings of these authors suggest that vancomycin and metronidazole are equally effective for the treatment of mild CDAD and that vancomycin is superior in the treatment of severe disease. Zar FA, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:August 1 [Epub ahead of print].

47. Recurrent C. difficile Diarrhea Occurs ~20% Risk of subsequent episode in patients who already have had a recurrence: 45% Pathophysiology: Reinfection with the original strain or a new strain* Failure to mount antibody response Antibiotic resistance not a factor in relapse � *Johnson S, et al JID 1989;159:340

48. Multiple Recurrent C. difficile DiarrheaTreatment Options: Vancomycin regimens Tapering or pulsed Combined with Rifampin Metronidazole not recommended risk of neurotoxicity Saccharomyces boulardii IVIG Fecal Transplantation

49. Multiple CDAD Recurrences (Fecal Transplantation) Preparation of donor specimen: Fresh (< 6 hr) ~30 g or ~ 2 cm3 vol Add 50 mL 0.9NS and homogenize with blender Filter suspension with paper coffee filter Refilter Aas J, et al. Clin Infect Dis 2003:36:580-5

50. Rifaximin (Xifaxin)

51. �Rifaximin chaser� following Standard Therapeutic Cocktail for breaking the Cycle of Multiple CDAD Recurrences Protocol: Rifaximin 400 twice daily for 2 weeks administered immediately after completing a suppressive course of vancomycin and before recurrence of symptoms 7 of 8 patients with multiple CDAD recurrences (4-8 episodes/ pt.) had no further diarrhea recurrence 1 patient had a symptomatic recurrence 10 days after stopping rifaximin, but responded to a second course of rifaximin without subsequent recurrence.

53. Conclusions

54. Infection Control Measures for Clostridium difficile Glove use Johnson S, et al. Am J Med. 1990;88:137 Hand hygiene* Untested, but likely effective Private Room/Isolation Untested, but likely effective Environmental cleaning with bleach Mayfield JL et al. Clin Infect Dis 2000;31:995 Antibiotic restriction Clindamycin Pear SM, et al. Ann Intern Med 1994;120:272 Cephalosporin Settle, et al. Aliment Pharm Ther 1998;12:1217 *CDC recommends hand washing with soap & water in setting of a CDAD outbreak