Michelle A. Barron, MD Associate Professor of Medicine Division of Infectious Diseases University of Colorado Denver Objec&ves Determine who is at risk for invasive candidiasis. Understand whether prophylaxis or pre- emptive therapy with antifungals is useful. Identify new diagnostic tools available for diagnosis of fungal infections. Understand approach to treatment for candiduria and candidemia Clinical Presenta&on 46 yo male with HTN, DM admitted with critical aortic stenosis Underwent AV replacement with a St. Jude valve POD #4, noted to have fever and new infiltrate in RLL Tracheal aspirate obtained Gram stain shows yeast and GNR Culture grows upper respiratory flora Started on empiric broad- spectrum antibiotics Was not tolerating tube feeds, so began TPN via CVC
Can You Predict if the Pa&ent Will Develop Invasive Candidiasis? Candida A High Priority in the ICU: Bloodstream Infec&on Pathogens Pathogen Coagulase-negative Staph Staphylococcus aureus Candida species Enterococcus species Pseudomonas aeruginosa % BSI (n=10,515) 35.9 (1) a 16.8 (2) a 10.1 (3) 9.8 (4) 4.7 (5) Crude Mortality, % 25.7 34.4 47.1 43.0 47.9 a P<.05 for patients in ICU vs non- ICU settings. SCOPE data. Wisplinghoff et al. Clin Infect Dis. 2004;39:309-317. Risk Factors For Systemic Candida Infec&on Colonization by Candida spp. Central venous catheterization Total parenteral nutrition (TPN) Corticosteroid administration Neutropenia Immunosuppression Chemotherapy Cancer (especially hematologic malignancy) Prolonged use of broad spectrum antibiotics Three or more antibiotics ICU stay > 4 days Mechanical ventilation > 48 hours APACHE* II score > 10 Abdominal Surgery Diabetes mellitus *APACHE Acute Physiology and Chronic Health Evaluation
Candida Score (CS) Candida Score 1 point for recent surgery, colonization with Candida at multiple sites, or on TPN Additional 2 points were given if severe sepsis was present Rule validated in a prospective multicenter cohort study in non- neutropenic, critically ill patients admitted for >7 days to the ICU Rate of IC was less than 5% in patients with CS < 3 who did not receive antifungal therapy Patients with a CS >3 had an RR of 5.98 for IC León et al. Crit Care Med. 2006;34:730-737. Leon et al. Crit Care Med. 2009; 37(5):1624-1633 Candida Coloniza&on Index Candida Colonization Index (CCI) Ratio of the number of body sites that yield the same species of Candida divided by the number of sites tested CCI threshold of 0.5 identified patients who developed IC Corrected CCI (CCCI) Semi- quantitative cultures at each body site to account for the density and degree of colonization CCCI >0.4 performed better than CCI at identifying patients at risk for IC Cost of performing multisite cultures seems to have limited its utility Smith et al. Crit Care Med. 2010; 38(8 Suppl):S380- S387. Pittet et al. Ann Surg. 1994; 220(6):751-758. Validated Predic&on Rules for Invasive Candidiasis (IC) Dupont Rule Retrospective review (N=221) Risk factors associated with independent risk of yeast peritonitis Cardiovascular failure Ongoing antimicrobial therapy Female Upper GI tract origin Prospective evaluation (N=51) 1 point assigned to each risk factor Score of 3 was found to have most overall accuracy for yeast isolation Dupont et al. Crit Care Med. 2003;31:752-757.
Validated Predic&on Rules for Invasive Candidiasis (IC) BAMSG Rule - Patients in ICU > 3 days AND 1 Major Risk factor: CVC, receiving antibiotics AND 2 Minor Risk factors: TPN, HD, surgery, pancreatitis, steroids, immunosuppressants Predictive value of the rule Incidence of IC of 10% (RR=4.4) Ostrosky- Zeichner et al. Eur J Clin Microbiol Infect Dis. 2007;26:271-276. If Pa&ent is at Risk for IC, Should You Use Prophylaxis? Impact of Fluconazole Prophylaxis on Candidal Infections Study Favors Fluconazole Eggimann et al Ables et al Pelz et al Garbino et al Odds Ratio (95% CI) % Weight Favors Placebo 0.18 (0.03, 0.98) 13.7 0.67 (0.25, 1.81) 19.2 0.51 (0.23, 1.11) 36.6 0.33 (0.12, 0.88) 30.4 Overall (95% CI) 0.44 (0.27, 0.72).03 1 31.5 Odds Ratio Shorr et al. Crit Care Med. 2005;33:1928-1935. Case Presenta&on On POD #7, started having persistent daily fevers to 39.5 0 C Blood cultures, urine cultures, and tracheal aspirate culture are obtained CXR also obtained Are there other tests you should consider ordering to rule out invasive Candidiasis?
Blood cultures Tradi&onal Diagnosis 57.8% positive with 2 or more organs involved at autopsy 8.3% positive in patients with hepatosplenic candidiasis Negative: 50% Biopsies and other cultures Not always feasible Contaminant vs real? Positive fundoscopic examination Candida endophthalmitis occurs in 3.7-25% of candidemia cases Odabasi et al. Clin Infect Dis. 2004;39:199-205. Ostrosky- Zeichner et al. Clin Infect Dis. 2005;41:654-659. (1 3)- β- D- glucan Assay (BG) BG is a component of the cell wall of most fungi Presence of BG in the serum is indicative of fungal invasion 63% sensitivity and 96% specificity for diagnosis of proven or probable IFI in high risk neutropenic patients Interval between onset of fever as a first sign of IFI and positive BG assay was 0.5 days Twice weekly BG monitoring in 57 patients in SICU 26% of the patients developed IC during ICU stay In patients with proven IC, BG was detected 6 days prior to positive cultures In proven plus probable IC, BG was detected 4 days prior to culture positivity Walsh TJ, et al. Clin Infect Di.s 2008;46:327-360. Odabasi Z, et al. Clin Infect Dis. 2004;39:199-205. Senn L, et al. Clin Infect Dis. 2008;46:878-885. Mohr JF, et al. J Clin Microbiol. 2011; 49(1):58-61. Use of Beta- D- Glucan Assay to Diagnose Candidemia Author Population Sampling Sensitivity, % Specificity, % PPV,% NPV, % Obayashi 1 Febrile patients Single 90 100 59 97 Odabasi 2 AML / MDS Multiple, 2+ 65 96 57 97 Ostrosky- Zeichner 3 Mohr 4 Hospitalized patients ICU patients, surveillance Single 64 92 89 73 Multiple, 2+ 100 63 1. Obayashi et al. Lancet. 1995;345:17-20. 2. Odabasi et al. Clin Infect Dis. 2004;39:199-205. 3. Ostrosky- Zeichner et al. Clin Infect Dis. 2005;41:654-659. 4. Mohr et al. J Clin Microbiol. 2011; 49(1):58-61.
Polymerase Chain Reac&on (PCR) Meta- analysis of studies from 1993-2009 assessing the diagnostic accuracy of direct pcr on blood samples for IC Fifty four studies: 16 case- control studies 36 prospective cohort studies 2 retrospective cohort studies 100% sensitivity and specificity was observed in whole blood samples when case patients had IC and control patients were healthy Specificity >90% was maintained in several analyses using different control groups PCR positivity in patients with proven or probable IC were 85% in this analysis, compared to 38% positivity for blood cultures Avni T, et al. J Clin Microbiol. 2011; 49(2):665-670. Clinical Presenta&on Patient remains febrile and is becoming hypotensive. IVF are administered and pressors are added. Should You Start Empiric Antifungal Therapy? Time- Dependent Mortality: The Justification for Empiric Therapy Delay in treatment is an independent determinant of hospital mortality All patients (N=157) Delay, 33.1% No delay, 11.1% Hospital Mortality, % 35 30 25 20 15 10 5 0 <12 12-24 24-48 >48 Delay in Start of Antifungal Treatment, h Morrell et al. Antimicrob Agents Chemother. 2005;49:3640-3645.
Beta- D- Glucan and Coloniza&on as Triggers for Preemp&ve Therapy Response Rate, % 100 80 60 40 20 Positive for Beta- D- Glucan Negative for Beta- D- Glucan 0 1 2 3 Sites Colonized with Candida sp, n Clinical response rate by number of sites colonized with Candida sp and positive/negative for beta- D- glucan. Takesue et al. World J Surg. 2004;28:625-630. Empiric Therapy: A Failed AVempt 270 ICU patients FLU 800 mg vs placebo Composite end point for success No fever No IFI No d/c due to toxicity No need for other antifungals Patients, % 100 80 60 40 20 0 FLUC PLACEBO Success Failure Schuster et al. Ann Intern Med. 2008;149:83-90. Clinical Presenta&on Patient is stabilized Blood cultures are negative at 48 hours Urine culture with >100k yeast Should You Treat the Candiduria?
Treatment of Candiduria Randomized, blinded study for treatment 316 patients (asymptomatic or minimally symptomatic) Placebo vs. fluconazole (200 mg/d) Efficacy FLU 50% vs. placebo 29% ~ 20% cleared with catheter removal alone Serum creatinine inversely related to eradication 2 weeks post- treatment rates of candiduria same in FLU and placebo group Sobel JD, et al., Clin. Infect. Dis. 30:19-24, 2000 Do not treat asymptomatic candiduria unless risk factors are present Treat Treatment of Candiduria Symptomatic patients Neutropenic patients Low birth- weight infants Patients with urological manipulations/obstruction Treatments Remove hardware (stents and/or Foley) Fluconazole (200-400 mg/d) Lower urinary tract infections: AMB bladder irrigations (rarely useful) 1 Upper urinary tract infections (pyelonephritis): can use azoles and echinocandins 2 1. Drew et al. Clin Infect Dis. 2005;40:1465-1470. 2. Sobel et al. Clin Infect Dis. 2007;44:e46- e49. Clinical Presenta&on Lab calls you 2 days later (96 hours after blood cultures drawn) and tell you that one of the two blood cultures are growing yeast. What do you do with this result?
Approach to Yeast in the Blood Yeast in blood culture Immunocompromised (transplant, BMT, AIDS) Nonimmunocompromised Start lipid polyene and wait for identification (ID) Hemodynamically stable, no previous azoles Hemodynamically unstable, previous azoles Endemic mycosis Candida Start fluconazole, wait for ID and monitor response Start echinocandin or lipid polyene, wait for ID and monitor response Continue lipid polyene until stable, then consider fluconazole or itraconazole as appropriate If good response complete 14 days from first negative culture No response or clearly resistant isolate If good response complete 14 days from first negative culture, may switch to fluconazole or voriconazole if stable and susceptible If no response, switch to another agent from the above classes Ostrosky- Zeichner, Pappas. Crit Care Med. 2006;34:857-863. Catheter Removal No brainer all must be removed! Not so fast: Some catheters are not easy to pull and replace Nucci and Anaissie t examine literature 1 study showed benefit 1 study showed no benefit 2 had marginal benefit If there is evidence of phlebitis or C. parapsilosis there is NO choice (must pull) New biofilm data: Azoles and AMB kill poorly but caspofungin and lipid formulations of AMB kill Candida in biofilms.* t Clin Infect. Dis. 2002; 34:591-599. * Kuhl et al. 2002; Antimicrob Agents Chemother. 46:1773-1780. Ramage et al 42 nd ICAAC, 2002; abstract. M468. Some Important Ques&ons Under what circumstances is fluconazole still first- line therapy? Mild- to- moderate illness, no recent azole exposure When is it appropriate to transition from an IV regimen to step- down therapy with an oral azole? Transition to fluconazole, when appropriate, is encouraged once Candida sp is known and patient is stable Is there a role for combination therapy? Data are limited to patients with endocarditis and CNS disease treated with AMB and 5- flucytosine. Utility of immunotherapy in combination with other agents to be explored (efungumab)
Ques&ons?