Presentation on theme: "Invasive Fungal Infections in Critically Ill Patients"— Presentation transcript:
1 Invasive Fungal Infections in Critically Ill Patients Abhay Dhand M.D.Director, Transplant Infectious DiseasesWestchester Medical Center, Valhalla NY
2 Invasive Fungal Infections in Critically Ill Patients Objectives:1. To understand the epidemiology and risk factors for invasive fungal infections in critically ill patients. 2. To familiarize with various investigative modalities for diagnosis of invasive fungal infections. 3. To understand the available anti-fungal therapies and their optimal use in patients in ICU setting. 4. To learn important drug interactions between anti-fungal therapies and commonly used drugs in ICU setting.
3 Incidence of Fatal Invasive Mycoses in USA CandidiasisAspergillosisMc Neil et al 2001 Clin Infect Dis 33;641
4 Focus on Candidiasis Invasive Candida infections: 4th most common nosocomial bloodstream infection in the USA with mortality approaching 40% in line related candidemia*Slide 4Pathogen No. of Isolates Incidence (%)Serious fungal infections are on the rise as shown by the increase of life-threatening infections due to invasive Candida.1,2Per a 1983 nationwide survey of medical and surgical patients in the United States, the 9th most common cause of nosocomial bloodstream infections was the Candida species.3In a 3-year (1995–1998) surveillance study of 49 hospitals across the United States, the high incidence of Candida infections places it as the 4th leading cause of nosocomial bloodstream infections.4In this study, only coagulase-negative staphylococci, Staphylococcus aureus, and enterococci have higher rates of incidence.4Coagulase-negative staphylococciStaphylococcus aureusEnterococciCandida species*In a 3-year (1995–1998) surveillance study of 49 hospitals in the United States.Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244; Andriole VT J Antimicrob Chemother 1999;44:151–162; Uzun O, Anaissie EJ Ann Oncol 2000;11:1517–1521.References1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162.2. Uzun O, Anaissie EJ. Predictors of outcome in cancer patients with candidemia. Ann Oncol 2000;11:1517–1521.3. Centers for Disease Control and Prevention. Nosocomial infection surveillance, Morb Mortal Wkly Rep 1984;33(2SS):9SS–21SS.4. Edmond MB, Wallace SE, McClish DK et al. Nosocomial bloodstream infections in United States hospitals: A three-year analysis. Clin Infect Dis 1999;29:239–244.
5 Species of Candida Most Commonly Isolated in Bloodstream Infections C. glabrata16%C. albicans54%C. parapsilosis15%C. tropicalis8%C. krusei2%other Candida spp 5%Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747–751.Species of Candida Most Commonly Isolated in Bloodstream InfectionsIn an international surveillance study :Since then increase in Candida spp. with higher incidence of fluconazole resistance.Snydman DR Chest 123(Suppl 5):500S-503S). Garbino J. et al Medicine;81:Slide 5Data above are taken from 634 bloodstream isolates of Candida species reported in 34 medical centers over a two-year period (1997–1998)122 centers in the United States and 12 from Latin America/Canada1This report was part of the SENTRY Antimicrobial Surveillance Program1It shows that by far the most common species is C. albicans, accounting for 54% of reported incidence of Candida infections. C. glabrata accounts for 16%, C. parapsilosis for 15%, C. tropicalis for 8%, C. krusei for 2%, and other Candida species are noted as 5%.1Reference1. Pfaller MA, Jones RN, Doern GV et al and The SENTRY Participant Group. Bloodstream infections due to Candida species: SENTRY antimicrobial surveillance Program in North America and Latin America, 1997– Antimicrob Agents Chemother 2000;44:747–751.
6 Invasive Candidiasis in the ICU Common in the ICU(9.8/1000 admissions)With high morbidity(increased LOS ~22 days)& mortality (~ 30-40%)Difficult to diagnose (cultures positive in only ~ 50%).We can define ICU risk factors for candidiasis and target the population at highest risk with empiric Rx.Recent increase in Candida spp. resistant to fluconazole.Eur J Clin Microbiol Infect Dis. 2004:23;
7 Risk for Invasive Mycosis Non-Neutropenic patients: related to barrier breakdown, change in colonization.Acute renal failure (RR 4.2)Parenteral nutrition with intralipid (RR 3.6)Prior surgery specially GI (RR 7.3)Indwelling central line ? Triple lumen (RR 5.4)Broad spectrum antibioticsDiabetesBurnsMechanical VentilationSlide 7The high incidence of invasive fungal infections has arisen primarily as a consequence of advanced medical treatment technologies, especially in gravely ill patients.1,2Fungal invasion is prevalent1,2When patients are immunosuppressed (e.g., neutropenic patients or solid-organ transplant recipients)When there is disruption of the gastrointestinal tract (e.g., surgery, trauma, or chemotherapy)If there is disruption of anatomical barriers (e.g., catheterization or mechanical ventilation)In circumstances in which normal microflora are disturbed (e.g., through use of broad-spectrum antibiotics)Awareness of risk factors for invasive fungal infection is key to identifying potential patient candidates for antifungal therapy.1,2The multicenter National Epidemiology of Mycosis Survey (NEMIS) was the largest prospective study designed to determine risk factors for developing candidal bloodstream infections (CBSIs) among patients in surgical and neonatal intensive care units.1Previous studies evaluating risk factors had several limitations, including the utilization of data from a single institution over a long time period, and not being prospective in design. In addition, few were focused on surgical intensive care unit populations.1In NEMIS, independently associated risk factors for CBSIs included acute renal failure, parenteral nutrition, and prior surgery. Neutropenia was not an independent risk factor.1Adapted from Blumberg HM et al, and the NEMIS Study Group Clin Infect Dis 2001;33:177–186; Garber G Drugs 2001; 61(suppl 1):1–12.References1. Blumberg HM, Jarvis WR, Soucie JM et al and the NEMIS Study Group. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: The NEMIS prospective multicenter study. Clin Infect Dis 2001;33:177–186.2. Garber G. An overview of fungal infections. Drugs 2001;61(suppl 1):1–12.
8 Risk for Invasive Mycosis Neutropenic patients:risks related to non- neutropenic patientsplusimmune cell suppression and underlying malignancy.SteroidsSevere immunosuppression: BMT or SOTAdapted from Blumberg HM et al, and the NEMIS Study Group Clin Infect Dis 2001;33:177–186; Garber G Drugs 2001; 61(suppl 1):1–12.
9 Major Risk Factors: Candidiasis Prior antibiotic use,Central venous catheters,Total parenteral nutrition,Major surgery (abdominal) within one week,Steroids, Immunosuppression.Intensive care unit length of stay: the rate of infections rising rapidly after 7-10 daysDimopoulos G, et al. Candidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study. Eur J Clin Microbiol Infect Dis. 2007
10 Candidemia in Non-neutropenic ICU Patients Risk Factors for Non-albicans Candida Spp. Nationwide Australian prospective cohort study.Patients with ICU-acquired candidemia over 3 yr.C albicans 62%, C glabrata 18%, C parasilopsis 8%, C tropicalis 6%, C krusei 4%, Other Candida spp. 2%Independent risk factors for non-albicans candida or potentially fluconazole-resistant species:Age (OR 1.3),Recent GI surgery (OR 2.9),Prior exposure to systemic antifungal agents (OR 4.6) especially fluconazole (OR 5.7).EG Playford et al. Crit. Care Med. 2008; 36(7):
11 Malignancy, Diabetes, Renal disease, Steroids, TPN, Burns Risk Factor SelectionMalignancy, Diabetes, Renal disease, Steroids, TPN, BurnsFeverAntibioticsSelection of Candida and ColonizationInstrumentionCVCGI surgerySkin or mucosal damageInfection: Invasive Candidiasis
12 Pathogens Responsible for Invasive Fungal Infections in HSCT and SOT Recipients* Based on data on 886 invasive fungal infections; % of infections were caused by Candida or Aspergillus spp29%42%Candida sppAspergillus sppIn a pooled analysis of hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients who were diagnosed with an invasive fungal infection (IFI), 71% of the infections were caused by either Aspergillus or Candida spp; these 2 fungal pathogens were the greatest concerns in these patient populations.These data were obtained from the TRANSNET database of patients undergoing HSCT or SOT procedures at 25 centers in the United States from March 2001 to December 2003.During this time period, at least 1 IFI occurred in 2.4% (224/9314) of HSCT recipients and 2.1% (207/9937) of SOT recipients.Prevalence of pathogens responsible for IFIs in patients following HSCT or SOT: Aspergillus spp 29%, Candida spp 42%, and other fungi 29%. The numbers in the original paper do not add up to 100%.If asked about other fungi, please provide the following information:Other fungi consisted of other moulds (14%), Cryptococcus spp (4%), endemic fungi (3%), and Pneumocystis jirovecii (2%).Remind the audience that posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections only.ReferencePappas PG, Alexander B, Marr K, et al. Invasive fungal infections (IFIs) in hematopoietic stem cell (HSCTs) and organ transplant recipients (OTRs): overview of the TRANSNET database. In: Program and Abstracts of the 42nd Annual Meeting of the Infectious Diseases Society of America. Alexandria, VA: Infectious Diseases Society of America; Abstract 671.Other fungi*Pooled data from infections in HSCT and SOT recipients.HSCT indicates hematopoietic stem cell transplant;SOT, solid organ transplant.Pappas PG, et al. In: Program and Abstracts of the42nd Annual Meeting of the Infectious DiseasesSociety of America Abstract 671.12
13 Candidiasis in SOT Recipients Analysis of data from 19,237 HSCT and SOT recipients from centers in the United States from 2001 to 2003SOT recipientsIncidence of invasive candidiasis, %2.6This was a study of 19,237 hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients from 25 US transplant centers (TRANSNET) conducted from March 2001 to December 2003.Invasive Candida infections developed in 2.6% of SOT recipients during the study period.Based on pooled data for both patient populations, overall mortality in patients with invasive candidiasis was 40%.Based on pooled data for both patient populations, investigator-determined mortality attributable to invasive candidiasis was 24%.ReferenceAndes D, Safdar N, Hadley S, et al. Epidemiology of invasive Candida infections in solid and hematologic transplantation: prospective surveillance results from the TRANSNET database. Abstract presented at: 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract M-1014.Based on pooled data for both patient populations, the investigator-determined mortality attributable to invasive candidiasis was 24% ( overall mortality of 40%)HSCT indicates hematopoietic stem cell transplant;SOT, solid organ transplant.Andes D, et al. ICAAC Abstract M-1014.13
14 Invasive Candida Infections Reported in Various Transplant Types* 6050423840Prevalence, %30The prevalence of an invasive Candida infection varies based on the type of transplant. Eighty percent of invasive Candida infections occur in liver and kidney transplant recipients.This was a study of 19,237 hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients from 25 US transplant centers (TRANSNET) conducted from March 2001 to December 2003.Invasive Candida infections developed in 2.6% of SOT recipients during the study period.Overall mortality in patients with invasive candidiasis was 40% for both populations of transplant recipients. Investigator-determined mortality attributable to invasive candidiasis was 24% for both populations of transplant recipients.ReferenceAndes D, Safdar N, Hadley S, et al. Epidemiology of invasive Candida infections in solid and hematologic transplantation: prospective surveillance results from the TRANSNET database. Abstract presented at: 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract M-1014.201712810LiverKidneyPancreasLungHeart*Numbers reflect data collected by TRANSNET from 2001 to 2004.Andes D, et al. ICAAC Abstract M-1014.14
15 Invasive Mycosis Candidiasis Aspergillosis MICU or SICU Oncology SOT or BMTCandidiasisAspergillosisMICU/SICU: invasive candidiasis fourth leading cause of bloodstream infections with increased cost, morbidity and mortality.Transplantation units: invasive aspergillosis one of the leading causes of infectious complications with an 80% mortality.MICU/SICU: invasive candidiasis fourth leading cause of bloodstream infections with increased cost, morbidity and mortality..Loss of Barrier immunityLoss of barrierpluscellular immunityDecreasing immunity
16 Aspergillosis in SOT Recipients Analysis of interim data from 4110 SOT procedures from 19 centers in the United States from March 2001 to December 2002Transplant type, n (%)Incidence*Mortality†Heart3 (0.8)2 (66.7)Kidney3 (0.1)Liver3 (0.3)1 (33.3)Lung10 (3.5)2 (20.0)Other1 (0.4)Although the incidence of invasive aspergillosis in this patient population is low, mortality rates were high. It is important to note that the cause of death was not necessarily attributable to invasive aspergillosis.These interim results of a prospective multicenter surveillance program were collected from the TRANSNET database from 4110 solid organ transplant procedures at 19 centers in the United States over a 22-month period from March 2001 to December 2002.It is important to note that the incidence of fungal infections were calculated from data limited to the 12 months following transplantation. In addition, patients may have received antifungal treatment, both of these circumstances may have contributed to the low incidence of invasive aspergillosis found in this study.ReferenceMorgan J, Wannemuehler KA, Marr KA, et al. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol. 2005;43(suppl 1):S49-S58.*Weighted aggregate incidence after 12 months.†Three months after diagnosis of aspergillosis.SOT indicates solid organ transplant.Morgan J, et al. Med Mycol. 2005;43(suppl 1):S49-S58.16
17 Lung/Lung and Heart Transplant Aspergillosis Is Associated With a High Rate of Mortality in Many Patient Populations1008060Case-fatality Rate, %*4020High rates of mortality are associated with aspergillosis regardless of the patient population.In this study, data recovered from a review of the medical literature were examined systemically and pooled to investigate case-fatality rates attributable to aspergillosis.From 1995 through 1999, 222 randomized, controlled clinical trials, case-control studies, cohort studies, and case series were identified.Of these 222 studies, the 50 conducted in Europe, North America, and Japan reported original data on ≥10 cases of Aspergillus infection and were not duplicated elsewhere.The results of the data analysis highlight the high rate of mortality associated with aspergillosis. In most patient categories, mortality exceeded 50%.Bone marrow and hematopoietic stem cell transplant recipients had especially high mortality rates.ReferenceLin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32:Leukemia/ LymphomaBone Marrow/ HSCTKidney TransplantLung/Lung and Heart TransplantLiver TransplantAIDS/ HIV*Determined from 1941 patients from 50 studies published between 1995 and 1999.HSCT indicates hematopoietic stem cell transplant.Lin SJ, et al. Clin Infect Dis. 2001;32:17
18 Zygomycosis Vulnerable populations 56% mortality Malignancy Bone marrow transplantationSolid organ transplantationCorticosteroid exposureGvHDCMV reactivityNeutropeniaUncontrolled Diabetes mellitusInitial presentation with sinusitisOccurrence as breakthrough prior Voriconazole prophylaxis56% mortalityothers…Fusarium sp.Penicillium sp.Trichosporon sp.Marr, CID 2002Steinbach, J Infect 2004Roden, et al. Clin Inf Dis 2005;41:Kontoyiannis et al. JID, 2005; 191:Siwek et al. CID 2004; 39:
19 Laboratory Diagnosis: Candida Microbiology methods:Recovery of Candida species from sterile sites (ex. blood, peritoneal fluid) is diagnostic of IC and recovery from multiple non-sterile sites is highly suggestive of IC in the at-risk patient.Blood culture is positive in less than 50% of patients with autopsy proven IC.Molecular methods:early identification ex PNA FISHSerological methods:early diagnosis ex. 1,3 beta D glucan assay.Histopatholgic methods.
20 Clinical Diagnosis: Candida The clinical manifestations of IC are nonspecific, but may include:Fever and progressive sepsis with multi-organ failure despite antibiotics.Invasive candidiasis (IC) related cutaneous lesions.Macronodular rash frequently confused with drug allergies. A biopsy of the deeper layers of skin particularly the vascularized areas and the dermis is important.Ophthalmic lesions (Candida endophthalmitis).A fundoscopic evaluation for the presence of Candida endophthalmitis should be performed in patients with candidemia.IC-related cutaneous lesions: These lesions have been described in cancer patients and heroin addictsAbout 15% of neutropenic patients with IC will have a characteristic macronodular rash; the rash may be isolated to the extremities or abdomen or may cover the entire body, and is frequently confused with drug allergies, which is why a biopsy of the deeper layers of skin (particularly the vascularized areas and the dermis) is important. A significant percentage of patients with candidemia have 1 or more retinal lesions that may represent Candida endophthalmitis.[A fundoscopic evaluation for the presence of Candida endophthalmitis (typically with C albicans) should be performed. Endophthalmitis is a common complication of hematogenous candidiasis in the nonneutropenic patient and can be the initial manifestation of IC (Figure 5). Reports of the frequency of ocular involvement by Candida species vary widely (3% to 78%),[ ] depending on the patient population (very rare in neutropenic patients), the diagnostic criteria used, the study design (prospective vs retrospective), and the physician performing the examination (best performed by an ophthalmologist). Fundoscopic examination should be repeated in critically ill patients with candidemia because ocular involvement can develop within 2 weeks after diagnosis
21 Serological Methods ? early aid in empiric therapy decision making Plasma beta-D-glucan, a cell wall constituent of fungi, was measured before starting antifungal therapy empirically on postoperative patients, colonized with candida & having risk factors for candida infection.47% of those with positive test responded to Rx but 9% of those negative responded (p<.01) (OR= 13).Number of sites colonized with candida also predicted response. Colonization at ≥ 3 sites vs. 1 site (p=0.03) (OR=7.57).In postoperative patients colonized with candida, & with fever despite antibiotics a beta-D-glucan assay was useful for deciding whether to start empiric therapy.Takesue Y et al. World J Surg. 2004; 28(6):
22 “I don’t want you to make the wrong mistake” —Yogi Berra TREATMENT“I don’t want you to make the wrong mistake” —Yogi Berra
23 Candidemia: Who do we treat? Answer: Essentially everybodyEven a single +BC can be relevantConcerned about hematogenous seedingSpread to the eyeCan cause blindnessLesions are common!26-29% rate
24 Catheter Exchange? Yes! Lots of consistent data Without catheter removal, 82% had persistent infectionLecciones, Clin Infect Dis 1992;14:Shortened duration of fungemia from 5.6 to 2.6 daysP < (Rex, Clin Infect Dis 1995;21: )Reduced mortality: 41% to 21%P < (Nguyen, Arch Intern Med 1995;155: )Especially true for C. parapsilosisVery strong link with cathetersKojic, Clin Microbiol Rev 2004;17:
25 Candiduria Asymptomatic candiduria High risk for dissemination No treatment unless high-risk dissemination (AIII).Focus on elimination of predisposing factors. (BIII).High risk for disseminationUrologic manipulations (BIII)Use short course fluconazole or even amphotericin BNeutropenic patients and low birth weight infantsTreat as for invasive candidiasis.Consider imaging kidneys/collecting system (BIII)
26 Can we wait for the blood culture results in candidemia? Retrospective cohort analysis 1/ /2004: N=157 patients with candidemia.Delay in empiric Rx of candidemia till after blood cultures turn positive resulted in higher mortality.Start of anti-fungal Rx >12 hrs of drawing a blood culture that turns positive had AOR= 2.09 for mortality, p=0.018.134/157 had therapy after cultures turn positive.Morrel M et al Antimicrob Agents Chemother. 49(9):3640-5
27 Mortality vs. number of days to 27Mortality vs. number of days toinitiate fluconazole after culture doneMultivariate model independentrisk factors for hospital mortality17%DaysVariableOdds RatioP ValueTime to start fluconazole1.500.014APACHE II1.13<0.001Up to 70% patients did not receiveantifungals within 24 hours + bloodCultureDifficulties in diagnosing a fungal infection may lead to delays in treatment.However, delays in antifungal treatment have been associated with poor outcomes. This has been shown in a number of studies for IFIs caused by Candida spp.In a 4-center study of 230 patients with candidemia, mortality increased each day that treatment with fluconazole was delayed1Delayed time to start of fluconazole treatment was determined to be a significant risk factor for mortalityThese data demonstrate the patient outcomes vary by time, with better outcomes more likely to occur early. Prophylaxis is the earliest possible stage in the continuum of IFI-management strategies.Please note: Posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infectionsReferences:1. Garey KW et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis. 2006;43:25.Garey KW et al. Clin Infect Dis. 2006;43:25.
28 Therapy of IC in the ICUA definitive diagnosis of IC may be delayed when the clinical and laboratory tools readily available to clinicians are used to assess patients for Candida infection.A delay in diagnosis will unfortunately result in a delay in initiation of antifungal therapy, which is associated with increased mortality*.Therefore, in the patient with suspected Candida infection, treatment may need to be initiated on the basis of individual patient factors before a definitive diagnosis is made.*Morrel M et al Antimicrob Agents Chemother. 49(9):*Garey K et al Clin Infect Dis. 43:
29 Aspergillus species are found in : AspergillosisAspergillus species are found in :SoilAir; spores may be inhaledWater / storage tanks in hospitals etcFoodCompost and decaying vegetationFire proofing materialsBedding, pillowsVentilation and air conditioning systemsComputer fansAspergillus sporesObjective: Aspergillus spores are widespread and are readily inhaled.
30 Development of Aspergillosis INHALATIONEnvironmental exposureConstructionCOLONIZATIONPulse steroidOKT3/Antilymphocyte therapyAntibiotic useOrgan failureRe-transplantationThrombocytopeniaINFECTIONDISSEMINATION
31 Invasive aspergillosis in solid-organ transplantation: diagnosis Radiology: chest X-ray and CT: no halo signMicrobiologyRespiratory secretions: BAL/biopsyDirect microscopycultureSerological surveillanceELISA for galactomannanPCRErgin et al. Transplant International 2003; 16:
32 Strategies for dealing with systemic fungal infectious disease
33 Optimal antifungal management? TreatmentProphylaxisRemoteEmpiricalPossiblePre-emptiveProbable diseaseSpecificProven41403938Temperature (°C)37Galactomannan+PCR36Culture+Tissue+-771421283542495663-140.1110Days after transplantGranulocytesDisease likelihood
34 Site of Action of Selected Anti-fungal Agents Cell membranePolyenes AmB (sterols)Azoles Fluconazole (CYP450)Slide 34Cell wallEchinocandins Caspofungin (Glucan synthesis inhibitors)Currently available antifungal agents can be classified by their site of action in fungal cells,1 which can have important implications for both efficacy and tolerability. Available agents include the polyenes, nucleoside analogs, and the azoles.1 These agents are not ideal because amphotericin B treatment is associated with severe side effects, and nucleoside analogs and azole possess a fungistatic rather than fungicial action.2 These classes are limited by lack of selective toxicity for fungal cells, that is, their therapeutic target is not exclusive to the fungal cell.2 For this reason, new antifungals—glucan synthesis inhibitors, also called echinocandins—that target the cell wall (not found in mammalian cells) are an important focus of current research which have the potential to provide a superior efficacy and safety profile versus current agents.2-5Adapted from Andriole VT J Antimicrob Chemother 1999;44:151–162; Graybill JR et al Antimicrob Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Expert Opin Invest Drugs 2001;10(8):1545–1558.References1. Andriole VT. Current and future antifungal therapy: New targets for antifungal agents. J Antimicrob Chemother 1999;44:151–162.2. Debono M, Gordee RS. Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol 1994;48: 471–497.3. Graybill JR, Najvar LK, Luther MF et al. Treatment of murine disseminated candidiasis with L-743,872. Antimicrob Agents Chemother 1997;41(8):1775–1777.4. Marco F, Pfaller MA, Messer SA et al. Activity of MK-0991 (L-743,872), a new echinocandin, compared with those of LY and four other antifungal agents tested against blood stream isolates of Candida spp. Diagn Microbiol Infect Dis 1998;31:33–37.5. Groll AH, Walsh TJ. Caspofungin: Pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Invest Drugs 2001;10(8):1545–1558.