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Nosocomial infections are an important source of morbidity and mortality in hospitalized patients. In the intensive care unit (ICU), infections from Candida species are increasingly common and candidemia and is now the fourth leading cause of bloodstream infection in the surgical ICU (1-4). In spite of their common occurrence many as 50% of invasive candidiasis cases go undiagnosed until autopsy (5). Undoubtedly this is due to the difficulty in recognition of patients who are likely to have fungal infections, and most importantly the lack of consensus about what factors constitute a definite, probable and possible fungal infection.
Risk factors that are associated with fungal infection in the surgical ICU patients are many and include: severity of illness, invasive devices or procedures, broad spectrum antibiotics, parenteral nutrition, immunosuppression, ICU length of stay and fungal colonization (1, 6, 7, 8). A simplified scoring system using 2.5 of a cut-off for identifying patients who would warrant prophylaxis has been proposed but not yet verified (8).
This score is obtained by awarding a single point for: the use of parenteral nutrition, broad spectrum antibi- otics, multi-focal colonization with fungus, and being a surgical patient. Two points are awarded if severe sepsis is present. Thus, the combination of severe sepsis and any other factor would suggest antifungal pro- phylaxis is warranted, or the combination of any of the other two additional factors. The validity of this scor- ing system should be examined in multi-institutional trials.
Defining the appropriate surgical ICU patient who will benefit from antifungal prophylaxis is controver- sial (6, 7, 8). First, consensus on the definition of prophylaxis vs. pre-emptive treatment must be recognized.
Prophylaxis is defined as the use of an agent to prevent infection prior to known colonization, whereas pre- emptive therapy is the introduction of an agent to patients with well-established risk factors, including a known degree of colonization with Candida spp. (11, 12). These subtle differences in definitions contribute to the ongoing confusion and controversy in this area. In some institutions, antifungal prophylaxis is per- formed without generalized consensus regarding the evidence from randomized clinical trials of prophylax- is. Some authors use the term targeted prophylaxis to replace the use of the term preemptive therapy.
In order to use appropriate targeted prophylaxis or preemptive therapy, the selection of patients with risk factors and or diagnostic tests should enrich the patient population whereby and expected infection rate of In recent years rapid diagnostic techniques have become available in the form of improved high-resolu- tion computed tomography (HRCT) scanning, and non-culture based methods such as detection of circulating fungal antigens and nucleic acid amplification techniques.
HRCT is very useful in patients with suspected Aspergillus and can identify patients with early disease on average 5 days before the disease would have been diagnoses. The negative predictive value of a chest At the present time, auxiliary serologic tests such as of fungal wall elements (mannan) , D-arabinitol (cell membrane metabolite), enolase (cell cytoplasm) or PCR assays are of somewhat limited value in non-neu- tropenic patients, or in patients where Aspergillus is not suspected (6, 9). These tests have mixed sensitivities and specificity. However, recently the results of the 1,3 beta glucan measurement for the diagnosis of inva- sive fungal infection was completed at six centers (10). At a cutoff of 60 pg/mL, the sensitivity and specificity of the assay were 69.9% and 87.1%, respectively, with a positive predictive value (PPV) of 83.8% and a nega- tive predictive value (NPV) of 75.1%. At a cutoff value of 80 pg/mL, the sensitivity and specificity were 64.4% and 92.4%, respectively, with a PPV of 89% and an NPV of 73%. Of the 107 patients with proven candidiasis, 81.3% had positive results at a cutoff value of 60 pg/mL, and 77.6% had positive results at a cutoff value of 80 pg/mL. Of the 10 patients with aspergillosis, 80% had positive results at cutoff values of 60 and 80 pg/mL.
Patients with more unusual fungal pathogens had a similar reasonable PPV and NPV.
Galactomannan, a component of the Aspergillus cell wall, is released during invasive disease and may be detected in cerebrospinal fluid, bronchial fluid, urine, pericardial fluid and blood, where the level of antigen- emia corresponds to the degree of tissue invasion and clinical outcome. Maertens and colleagues have recently suggested that use of this test with two consecutive values of an optical density of greater than or equal to 0.5 can be used as a screening tool to identify those patients who should have a HRCT and bron- choscopy for suspected invasive fungal infection (13). These authors however note that while invasive infec- tions with Aspergillus were identified, other invasive fungal infections were only identified by standard tech- niques. In addition the patient population was hematological malignancies, and not surgical or ICU patients, thus the use of these tests is promising but not widely supported.
When considering a prophylaxis regimen, several criteria must be considered to determine the viability of the practice. The overall incidence and severity of fungal disease must be frequent and/or fungal infec- tions must have a substantial and measurable increase in morbidity and mortality of the patient population.
The prophylactic regimen must have high tolerability, be cost-effective and be confined to use in the appro- priate high risk patients. Several published clinical trials have evaluated the use of antifungal prophylaxis (amphotericin, nystatin, ketoconazole and fluconazole) in selected critically ill and surgical patients (Table 1) (14-26). Finally, because of the small size of many of the trials, several meta-analysis and a cost-effective analysis have been performed in the last several years (27-32). In general these studies demonstrate that anti- fungal prophylaxis does reduce the incidence of invasive fungal infections (28-32). However, there is no signifi- cant known decrease in the risk of death, and the cost of prophylaxis, the possibility of adverse drug reac- tions, and the possible acquisition of resistance must all be weighted against the benefit in high risk patient 1. 1. Blumberg HM, Jarvis WR, Soucie JM, et al. Risk factors for candidal bloodstream infections in surgi- cal intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis 2001; 33: 177-86 2. Trick WE, Fridkin SK, Edwards JR, et al. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999. Clin Infect Dis 2002; 35: 627-30 3. Beck-Sagué CM, Jarvis WM, the National Nosocomial Infections Surveillance System. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. J Infect Dis 1993; 167: 4. Centers for Disease Control. National Nosocomial Infections Surveillance(NNIS) System Report, data summary from January 1992 through June 2003, issued August 2003. Am J Infect Control 2003; 31: 481- 5. Solomkin JS, Flohr AB, Quie PG, Simmons RL. The role of Candida in intraperitoneal infections.
6. Lipsett PA. Surgical critical care: fungal infections in surgical patients. Crit Care Med 2006; 34(9 Suppl): 7. Ostrosky- Zeichner L and Pappas P. Invasive candidiasis in the intensive care unit. Crit Care Med. 2006; 8. Leon C, Ruiz_Santana S, Saavedra P et al. A bedside scoring systtem (’Candida score”) for early antifun- gal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 2006; 34: 9. Eggimann P, Garbino J, Pittet D. Epidemiology of Candida species infections in critically ill non- immunosuppressed patients. Lancet Infect Dis 2003; 3: 685-702 10. Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter clinical evaluation of the (1-->3) beta- D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005; 41: 654-9.
11. Lipsett PA. Clinical trials of antifungal prophylaxis among patients in surgical intensive care units: con- cepts and considerations. Clin Infect Dis 2004; 39 Suppl 4: S193-9. 12. Pittet D, Monod M, Suter PM, Frenk E, Auckenthaler R. Candida colonization and subsequent infec- tions in critically ill surgical patients. Ann Surg 1994; 220(6): 751-8. 13. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and Computed Tomography-Based Preemptive Antifungal Therapy in Neutropenic Patients at High Risk for Invasive Fungal Infection: A Prospective Feasibility Study. Clinical INfectious Diseases 2005; 41-1242-50. 14 Singhal S, Ellis RW, Jones SG, Miller SJ, Fisher NC, Hastings JG, et al. Targeted prophylaxis with amphotericin B lipid complex in liver transplantation. Liver Transpl 2000; 6(5): 588-95. 15. Shah T, Lai WK, Gow P, Leeming J, Mutimer D. Low-dose amphotericin for prevention of serious fungal infection following liver transplantation. Transpl Infect Dis 2005; 7(3-4): 126-32. 16. Savino JA, Agarwal N, Wry P, Policastro A, Cerabona T, Austria L. Routine prophylactic antifungal agents (clotrimazole, ketoconazole, and nystatin) in nontransplant/nonburned critically ill surgical and trauma patients. J Trauma 1994; 36(1): 20-5; discussion 25-6. 17. Slotman GJ, Burchard KW. Ketoconazole prevents Candida sepsis in critically ill surgical patients. Arch 18. Normand S, Francois B, Darde ML, Bouteille B, Bonnivard M, Preux PM, et al. Oral nystatin prophylax- is of Candida spp. colonization in ventilated critically ill patients. Intensive Care Med 2005; 31(11): 1508- 19. Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant recipients. A random- ized, double-blind, placebo-controlled trial. Ann Intern Med 1999; 131(10): 729-37. 20. Ables AZ BN, Valainis GT, et al. Fluconazole prophylaxis of severe candida infection in trauma and post- surgical patients: a prospective, double blind, randomized, placebo-controlled trial. Infect Dis Clin Pract 21. Eggimann P, Francioli P, Bille J, Schneider R, Wu MM, Chapuis G, et al. Fluconazole prophylaxis pre- vents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med 1999; 27(6): 1066-72. 22. Garbino J, Lew DP, Romand JA, Hugonnet S, Auckenthaler R, Pittet D. Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: a randomized, double-blind, placebo-con- trolled trial in patients treated by selective digestive decontamination. Intensive Care Med 2002; 28(12): 23. Pelz RK, Hendrix CW, Swoboda SM, Diener-West M, Merz WG, Hammond J, et al. Double-blind place- bo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg 24. Jacobs S, Price Evans DA, Tariq M, Al Omar NF. Fluconazole improves survival in septic shock: a ran- domized double-blind prospective study. Crit Care Med 2003; 31(7): 1938-46. 25. Sharpe MD, Ghent C, Grant D et al. Efficacy and Safety of Itraconazole Prophylaxis for Fungal Infections After Orthotopic Liver Transplantation: A Prospective, Randomized, Double-Blind Study.
26. Piarroux R, Grenouillet F, Balvay P, Tran V, Blasco G, Millon L, et al. Assessment of preemptive treat- ment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med 2004; 32(12): 2443-9. 27. Golan Y, Wolf MP, Pauker SG et al. Empiricial Anti-Candida Therapy among Selected Patients in the Intensive Care Unit: A Cost-Effectiveness Analysis. Ann Intern Med. 2005; 143: 857-869 28. Cruciani M, de Lalla F, Mengoli C. Prophylaxis of Candida infections in adult trauma and surgical inten- sive care patients: a systematic review and meta-analysis. Intensive Care Med 2005; 31(11): 1479-87. 29. Shorr AF, Chung K, Jackson WL, Waterman PE, Kollef MH. Fluconazole prophylaxis in critically ill sur- gical patients: a meta-analysis. Crit Care Med 2005; 33(9): 1928-35; quiz 1936 30. Playford EG, Webster AC, Sorrell TC, Craig JC. Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: systematic review and meta-analysis of randomized clinical trials. J Antimicrob Chemother 2006; 57(4): 628-38. 31. Playford EG, Webster , A. C. , Sorrel, l T. C. , Craig, J. C. Antifungal agents for preventing fungal infec- tions in non-neutropenic critically ill patients. Cochrane Database of Systematic Reviews 2006; 1: 1-42. 32. Vardakas KZ, Samonis G, Michalopoulos A, Soteriades ES, Falagas ME. Antifungal prophylaxis with azoles in high-risk, surgical intensive care unit patients: a meta-analysis of randomized, placebo-con- trolled trials. Crit Care Med 2006; 34(4): 1216-24. Infection
Prophylaxis
Inter vention
Population
Outcomes
Definitions
vs. Preemptive
(infection)
(mortality)
Prevention of IFI: histological evidence of tis- Prophylaxis No patients had of Candida from >3 normally non-sterile sites (throat, rec-tum, urine, sputum) Prevention of IFI: histological evidence of tis- Prophylaxis AmB: 2 episodes Prevention of Positive culture of sterile site Prevention of Positive culture of sterile site Presence of Candida spp. in tra- Prophylaxis Placebo 25% vs. no evidence of bacterial/viral causeSuperficial FI: fungal UTI, thrush, skin lesions and time to in- tonitis caused by Candida spp.; plete resolution of tra-abdominal > 1 blood culture positive for Candida infec- Candida spp.; urine culture Development Candidemia: > 1 positive blood Prophylaxis Severe infec- of severe Can- culture + histologically docu- Overall inci-dence: Placebo 16% vs. Flucona-zole 5.8%; RR 0.35; 95% CI 0.11-0.94 Definite: histologic/microbiolo- Prophylaxis Proven IFI: Presumed: positive blood cul-ture or single sterile site (not Prevention of Proven IFI=definite or pre- Current Appointments:
The Johns Hopkins University School of Medicine The Johns Hopkins University School of Nursing Assistant Professor of Anesthesiology and Critical Care Medicine The Johns Hopkins University School of Medicine Undergraduate Education:
Graduate Education:
Medical Education:
Post Graduate Training:
The John Hopkins Hospital, Baltimore, Maryland Faculty Advanced Training Specialty Certificate, Gastrointestinal Surgery Professional Experience:
The John Hopkins Hospital, Baltimore, Maryland Instructor, Johns Hopkins University School of Medicine Francis Scott Key Hospital/ Bayview Medical Center 1990 - present Active Staff - Department of Surgery The Johns Hopkins Hospital, Baltimore, Maryland Assistant Professor, Department of Surgery, Johns Hopkins University School of Medicine Baltimore Veterans Administration Hospital Assistant Professor, Department of Anesthesiology and The Johns Hopkins Hospital, Baltimore, Maryland 1994 - present Fellowship Director, Surgical Critical Care The Johns Hopkins Hospital, Baltimore, Maryland The Johns Hopkins University School of Nursing The Johns Hopkins University School of Medicine 1995 - present Assistant Professor of Anesthesiology, Critical Care Medicine The Johns Hopkins University School of Medicine The Johns Hopkins Hospital, Baltimore, Maryland The Johns Hopkins University School of Medicine Program Director, General Surgery Residency Program The Johns Hopkins University School of Medicine Student Assessment and Program Evaluation Subcommittee The Johns Hopkins University School of Medicine

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