1. 1 Catheter-Related Bloodstream Infection Guidance Revisited Janice Pohlman, M.D. FDA AIDAC Presentation October 14, 2004

2. 2 CRBSI Background US estimates: 200,000 - 400,000 episodes annually Attributable mortality range: 12-25% in prospective studies Epidemiology: CNS, S. aureus, (C. albicans, enterococci, Gram negative rods) Paucity of randomized clinical trial data in the study of CRBSI

3. 3 CRBSI Guidance Document AIDAC Discussion 1999* (1) Issues: –lack of pathognomonic signs and symptoms of CRBSI clinical criteria of fever is nonspecific catheter exit inflammation is not sensitive –heterogeneity of patient population, catheter types, virulence of causative pathogens *http://www.fda.gov/ohrms/dockets/ac/acmenu.htm

4. 4 CRBSI Guidance Document AIDAC Discussion 1999 (2) Issues continued: –establishing the definition of catheter-related BSI microbiologic diagnosis clinical diagnosis of exclusion: bacteremia in patient with a catheter and no other focus of infection –use of microbiologic criteria to identify the catheter as the source of BSI (what is the appropriate threshold for a positive result?)

5. 5 CRBSI Guidance Document AIDAC Discussion 1999 (3) Issues continued: –defining the magnitude of antimicrobial treatment effect (versus catheter removal) for organisms of low virulence that colonize the skin –ramifications of adjunctive catheter removal after randomization and initiation of therapy –use of clinical or microbiologic endpoints to define treatment efficacy

6. 6 CRBSI Industry Experience (1) Pharmaceutical industry experience with a CRBSI Phase 2 trial* 75/2639 (2.8%) of screened patients identified primarily by positive blood cultures were ultimately enrolled in the trial –30% did not meet the microbiologic criteria for diagnosis (cultures not obtained versus culture data not suggestive) –20% excluded on the basis of prior antimicrobial therapy *http://www.fda.gov/cder/drug/antimicrobial/

7. 7 CRBSI Industry Experience (2) The number of patients meeting the microbiologic criteria for the definition of CRBSI may relate to the method of screening. –Phase 2 trial for the treatment of CRBSI using an approved drug: 23/39 (59%) enrolled had evidence of Gram positive bacteremia or infection* –Other pharmaceutical industry experience: 25% of patients identified by clinical criteria and/or local evidence of catheter- related infection met minimal microbiologic criteria (blood + catheter exit site cultures) for the diagnosis of CRBSI –Prospective studies of patients with clinically suspected CRBSI have yielded approximately 10-15% of subjects with microbiologic evidence of CRBSI *Raad I, et al. Eur J Clin Microbiol Infect Dis 1999;18:199-202.

8. 8 Guidelines for the Management of Intravascular Catheter-Related Infections* Evidence based recommendations Data to support most recommendations is based on small clinical trials and not randomized controlled clinical trials Guidelines assume you already have effective therapy and are useful for clinical practice, but are not designed to assess efficacy of new antimicrobial therapies * Mermel, et al. Clin Infect Dis 2001:32:1249-72.

9. 9 CRBSI Diagnostics (1) Catheter Maintained: –quantitative blood cultures –differential time to positivity Under investigation: –acridine orange leucocyte cytospin –endoluminal brush

10. 10 CRBSI Diagnostics (2) Differential time to positivity –early studies indicated utility primarily in immunocompromised patients with long-term or tunneled catheters –recent published study indicated utility in patients with both short- and long-term catheters (short- term defined as < 30 days)* diagnosis of CRBSI based on semiquantitative catheter tip and/or quantitative cultures) sensitivity was lower in short-term catheters and specificity was lower in long-term catheters *Raad I, et al. Ann Intern Med 2004;140:18-25.

11. 11 CRBSI Diagnostics (3) Catheter Maintained (continued): Problems associated with catheter-maintained diagnostics: –inability to aspirate blood back for culture –which lumen of the catheter should be cultured –establishment of appropriate threshold for positive result Problems associated in particular with quantitative blood cultures: –not available in many institutions –long turn-around time (48-72 hours)

12. 12 CRBSI Diagnostics (4) Catheter removal required –quantitative or semi-quantitative catheter tip or segment cultures Problems associated with catheter segment diagnostics: –needless removal of uninfected catheters –retrospective diagnosis of CRBSI –establishment of appropriate threshold for positive result –potential inhibitory effect of antimicrobial impregnated catheters on subsequent catheter cultures

13. 13 CRBSI Diagnostics (5) Do we need the catheter culture data? General consensus of the 1999 AIDAC was yes, particularly where the predominant pathogen is also the most frequent blood culture contaminant Alternative definitions have been proposed: –probable or suspected CRBSI positive peripheral blood culture (second positive independent blood culture for organisms associated with skin contamination - CNS) no other secondary source of infection identified catheter cultures not done or no catheter versus peripheral blood differential was demonstrated

14. 14 Current CRBSI Guidance Document (1) Microbiologic criteria for diagnosis: Concordant growth of the same organism from peripheral blood and one of the following: –quantitative catheter blood culture (C:P ratio of 3:1 to 5:1) –quantitative catheter segment (  10 3 CFU) or semiquantitative catheter segment (>5 CFU) regardless of pathogen –culture of inner catheter hub (  10 3 CFU for skin colonizers, any growth for other pathogens) –culture of catheter entry site exudate (regardless of pathogen) –culture of infusate (regardless of pathogen)

15. 15 Current CRBSI Guidance Document (2) Concordance requires growth of the same species, with the same antibiogram; PFGE is strongly recommended for skin colonizers The modified intent-to-treat population (all randomized who meet the clinical and microbiologic criteria) is the co-primary population for a non- inferiority efficacy analysis Outcome of cure is defined as resolution of entry signs and symptoms and negative blood cultures at test-of-cure visit

16. 16 CRBSI Future Options (1) Maintain the Current Guidance PROS systematic approach to study of treatment efficacy maintains current level of diagnostic specificity not organism specific and may provide data on CRBSI due to a variety of organisms CONS difficult enrollment adjunctive catheter removal post-randomization and initiation of therapy is problematic antimicrobial treatment effect in infections due to low virulence pathogens is not known positive PBC with catheter site culture raises issue regarding specificity of diagnosis

17. 17 CRBSI Future Options (1) Maintain the Current Guidance Does the committee have any advice or suggestions for facilitation of clinical trials of CRBSI?

18. 18 CRBSI Future Options (2) Major Modification of the Guidance PROS increase number of patients eligible for inclusion and evaluability CONS decrease the specificity of diagnosis, thereby decreasing the scientific rigor of the study

19. 19 CRBSI Future Options (3) Consider CRBSI within the Context of a PBSA Indication PROS study of virulent pathogen where antimicrobial treatment effect is better defined catheters are more likely to be removed may increase available population for study CONS limits variety of organisms studied lack of consensus on duration of treatment for uncomplicated cases differentiating uncomplicated cases that become complicated (persistent fever or + BC) from treatment failure in drug efficacy trial need for additional diagnostic test