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Therapy and outcome of Candida glabrata versus Candida albicans bloodstream infection
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Diagnostic Microbiology and Infectious Disease 60 (2008) 273 – 277 www.elsevier.com/locate/diagmicrobio
Therapy and outcome of Candida glabrata versus Candida albicans bloodstream infection☆ Michael J. Klevay a , Erika J. Ernst b , Jesse L. Hollanbaugh b , Joshua G. Miller b , Michael A. Pfaller c , Daniel J. Diekema a,c,⁎ a
Department of Medicine, University of Iowa, Iowa City, IA 52242, USA b College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA c Department of Pathology, University of Iowa, Iowa City, IA 52242, USA Received 8 August 2007; accepted 9 October 2007
Abstract Candida glabrata is a common cause of bloodstream infection (BSI) and exhibits reduced susceptibility to antifungal agents. Those with C. glabrata BSI may therefore be at increased risk for a delay in receiving appropriate therapy and poor treatment outcome. We compared treatment and outcome of patients with C. glabrata to controls with Candida albicans BSI. Each patient with C. glabrata BSI from July 1997 through December 2004 was matched with a control patient infected with C. albicans. Appropriateness of therapy was defined using current guidelines, and the mortality end point was 30 days following the initial positive blood culture. Overall, 78% of patients received appropriate therapy (39/54 [72%] for C. glabrata versus 45/54 [83%] for C. albicans, P = 0.2). Crude 30-day mortality was high for both groups (41% for C. glabrata versus 44% for C. albicans, P = 0.7). There was no trend in mortality according to time of therapy initiation, but mortality was lower for those who received appropriate therapy (35% versus 71% for inappropriate therapy, P = 0.002). Twelve percent of patients received no antifungal therapy and contributed disproportionately to overall crude mortality. Strategies to decrease the incidence of untreated candidemia may favorably impact outcome. © 2008 Elsevier Inc. All rights reserved. Keywords: Candida glabrata; Bloodstream infection; Antifungal therapy
Candida spp. have emerged as the 4th most common cause of nosocomial bloodstream infection (BSI) (Wisplinghoff et al., 2004). Despite the introduction of multiple systemic antifungal agents with activity against Candida, these infections continue to be associated with high attributable mortality rates (Gudlaugsson et al., 2003; Pfaller and Diekema, 2007). Morrell et al. (2005) recently reported that it is common for the initiation of antifungal therapy to be delayed, and that a delay in therapy beyond 12 h after culture is associated with higher mortality. Garey et al. (2006) have shown that mortality increases incrementally with each day of a delay in ☆ Preliminary results of this study were presented in abstract form at Focus on Fungal Infections 17, San Diego, CA, March 2007, and the Infectious Diseases Society of America 45th Annual Meeting, San Diego, CA, October 2007. ⁎ Corresponding author. Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Tel.: +1-319384-5626; fax: +1-319-356-4916. E-mail address: [email protected] (D.J. Diekema).
0732-8893/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2007.10.001
therapy for candidemia in patients treated with fluconazole. Candida glabrata has emerged as the 2nd most common cause of candidemia in US hospitals (Pfaller and Diekema, 2007; Trick et al., 2002) and is less susceptible to fluconazole and the other azoles, as well as amphotericin, than is Candida albicans (Pfaller and Diekema, 2007; Pfaller et al., 2004). For this reason, patients with C. glabrata BSI may be at higher risk for receipt of inappropriate therapy or adverse outcome compared with those with C. albicans BSI. The purpose of this study is to describe how the appropriateness of antifungal therapy and outcome for C. glabrata BSI compare to infection with C. albicans. 1. Methods 1.1. Setting The University of Iowa Hospitals and Clinics (UIHC), Iowa City, IA, is a 680-bed teaching hospital providing tertiary care for the State of Iowa. The UIHC is a level 1
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trauma center, has 128 intensive care unit beds, and supports active bone marrow transplant and solid organ transplant programs. The UIHC institutional review board approved this study.
The mortality end point was defined at 30 days following the 1st positive blood culture for Candida spp.
1.2. Study design
We compared categoric variables between case and control groups with the χ2 or Fisher's exact test as appropriate and compared continuous variables with a paired t test. α was set at 0.05, and all P values were 2 tailed. We performed statistical analyses using SPSS version 13.0 for Windows (Chicago, IL).
A matched retrospective cohort study was performed. All cases of C. glabrata BSI between July 1997 and December 2004 were identified from a database maintained in the Clinical Microbiology Laboratory at UIHC. C. glabrata BSI was defined as at least 1 positive blood culture for C. glabrata during the study period. Patients with C. albicans BSI were selected from the database and matched to cases 1:1 by the closest date of hospital admission. Data on antifungal therapy and outcomes were collected by retrospective chart review. 1.3. Microbiologic methods Candida spp. were identified using Vitek and API products or conventional methods, as required, and antifungal susceptibility testing was performed with the reference broth microdilution method in accordance with Clinical and Laboratory Standards (CLSI) standards (NCCLS, 2002). Interpretive criteria for fluconazole susceptibility were those published by the CLSI (NCCLS, 2004). Candida parapsilosis strain ATCC 22019 and Candida krusei strain ATCC 6258 were tested with each run for quality control. 1.4. Definitions We defined appropriate therapy for candidemia as the use of a systemic antifungal drug active in vitro against the patient's Candida isolate. The antifungal agent and dose must have been consistent with Infectious Diseases Society of America (IDSA) guidelines with adjustments for weight, renal, or hepatic dysfunction. To be in strict accordance with IDSA guidelines, we must continue therapy for at least 14 days following the last positive blood culture (Pappas et al., 2004). However, consistent with other investigators (Morgan et al., 2005), we accepted a minimum of 7 days of an active antifungal agent at correct doses to meet our criteria for appropriate therapy. If a patient died while receiving otherwise appropriate antifungal therapy, he or she was considered to have received an appropriate course of therapy. The time to initiation of therapy was reported as the number of days following the blood culture after which any antifungal drug was started, with day = 0 representing the initiation of therapy on the day that the culture was drawn, day = 1 representing therapy starting on the day after the culture was drawn, and so on. Untreated candidemia was defined as lack of antifungal therapy during the hospitalization of a patient with a positive blood culture for Candida spp. Reasons for absence of therapy for candidemia were determined from review of the medical record.
1.5. Statistical analyses
2. Results Fifty-five patients had C. glabrata BSI identified during the study period. Due to difficulty in matching 1 study patient with a C. albicans-infected control patient, this patient was excluded, leaving 54 patients in the C. glabrata group and 54 patients in the C. albicans group. Patients with C. albicans infection were matched to C. glabrata patients within 6 months of hospital admission date in 47 of 54 pairs (87%) and within 1 year in all cases. Seven of the C. glabrata patients had polymicrobial BSI episodes with other Candida spp. (C. albicans [6] and C. parapsilosis [1]), and 1 C. albicans patient also had Candida lusitaniae isolated from blood. The patients we categorized as having received inappropriate therapy received either no therapy during the hospital stay, fluconazole therapy for a fluconazoleresistant C. glabrata isolate, an antifungal at a dose lower than recommended by IDSA guidelines, or a duration of therapy shorter than 7 days after documented clearance of the bloodstream. The 30-day mortality and the proportion of patients in each group who met the 7- and 14-day appropriate therapy criteria are found in Table 1. Mortality did not differ by species, with 22/54 (41%) patients with C. glabrata dead at 30 days, compared with 24/54 (44%) C. albicans patients (P = 0.7). There were also no differences in appropriateness of therapy according to species: 33/54 patients (61%) with C. glabrata versus 34/54 patients (63%) with C. albicans BSI (P = 0.8) received appropriate therapy for 14 days, and 39/54 patients (72%) with C. glabrata versus 45/54 (83%) with C. albicans BSI (P = 0.2) received appropriate therapy for at least 7 days.
Table 1 Appropriateness of therapy and 30-day mortality of C. glabrata versus C. albicans BSI C. glabrata C. albicans Total Total patients (n) Appropriate therapy: 14-day duration Appropriate therapy: 7-day duration 30-day mortality (%)
54 33 (61%) 39 (72%) 41
54 34 (63%) 45 (83%) 44
108 67 (62%) 84 (78%) 43
P N 0.05 for all comparisons between C. glabrata and C. albicans infection.
M.J. Klevay et al. / Diagnostic Microbiology and Infectious Disease 60 (2008) 273–277
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Table 2 Empiric therapy choices for patients with C. albicans and C. glabrata BSI Regimen
C. albicans (n, %)
C. glabrata (n, %)
Fluconazole ≤400 mg/day Fluconazole 800/400 Fluconazole 800 mg/day Caspofungin Amphotericin Othera No treatment
26 2 6 0 13 2 5
9 (17) 1 (2) 12 (22) 9 (17) 14 (26) 0 (0) 8 (15)
a
(48) (4) (11) (0) (24) (4) (9)
1 treated with voriconazole, 1 treated with amphotericin + fluconazole.
Table 2 lists the number of patients with C. albicans and C. glabrata infection receiving various empiric antifungal therapy choices. Although empiric therapy choices were most often made prior to species identification, patients infected with C. glabrata were much more likely to receive empiric therapy with an echinocandin or a higher dose of fluconazole than were patients with C. albicans BSI. Consequently, rates of appropriate therapy did not differ according to species. When all 108 candidemic patients were analyzed together, crude mortality at 30 days after onset of candidemia was 35% among the 84 patients in the 7 days of appropriate therapy group versus 71% among the 24 patients not receiving appropriate therapy (P = 0.002). Among the 24 patients not receiving appropriate therapy as defined in this study, 13 received no antifungal therapy (representing over half of all patients not receiving appropriate therapy and 12% of all candidemic patients). The 30-day crude mortality among patients receiving no therapy was 85%. Mortality according to the timing of initiation of antifungal therapy is illustrated in Fig. 1. There was no trend in mortality seen with timing of therapy (P = 0.3 for trend), but as outlined above, the mortality was significantly higher among those patients who received no antifungal therapy. Fig. 2 illustrates the relationship between time to initiation of therapy and mortality according to species. Notably, patients infected with C. glabrata were not more likely to receive delayed antifungal treatment than were
Fig. 2. Thirty-day mortality according to time to initiation of antifungal therapy, by Candida spp. (P = 0.3 for C. albicans; P = 0.06 for C. glabrata).
those with C. albicans. Five of the untreated patients died within 24 h of culture, 3 more died within the 1st week, and another 3 died within 2 weeks of culture. The results of analyses of mortality according to timing of initiation of therapy were unchanged when patients who died within 72 h of culture (and their matches) were excluded from the analysis (data not shown). Only 35% of the C. glabrata isolates were susceptible to fluconazole, 50% were susceptible and dose dependent, and 15% were resistant. All but 1 of the C. albicans isolates was fluconazole susceptible, and this was susceptible and dose dependent. There were several reasons evident in medical records for the failure to administer antifungal therapy in 13 patients: 1) death prior to blood culture turning positive (n = 5), 2) removal of the central venous catheter felt to be adequate therapy (n = 2), 3) resolution of fever prior to blood culture positivity felt to be an indication for withholding antifungal therapy (n = 1), 4) repeat blood cultures negative, positive culture felt to be contaminant (n = 1), 5) withdrawal of aggressive care and removal of life support (n = 1), 6) decision to await identification of yeast prior to starting therapy, and patient died prior to yeast identification (n = 1), and 7) no clear reason given (n = 2, in each case the blood culture result was called to the patient care area but was not mentioned in physician progress notes). Untreated patients occurred throughout the study period. 3. Discussion
Fig. 1. Thirty-day mortality according to time to initiation of antifungal therapy (P = 0.3).
C. glabrata has emerged as an important nosocomial pathogen in the United States (Pfaller et al., 2003; Trick et al., 2002). The reduced susceptibility of C. glabrata to azoles and amphotericin B poses a challenge to choice of appropriate empiric antifungal therapy for patients with candidemia prior to the availability of species identification or antifungal susceptibility test results. We postulated that patients with C. glabrata BSI might be less likely than those with C. albicans BSI to receive appropriate
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therapy or perhaps to have a longer delay to initiation of appropriate therapy. We did not detect a difference in receipt of appropriate antifungal therapy dependent on Candida spp., in that patients infected with C. glabrata were as likely to receive appropriate antifungal therapy as those infected with C. albicans. This demonstrates physicians' familiarity with the variable fluconazole susceptibility patterns of C. glabrata. Empiric therapy, once yeast was identified, appeared to be guided by the microbiology of previous Candida colonization and prior azole exposure, leading to more patients with C. glabrata being started on an echinocandin or high-dose fluconazole therapy. The identification of other species-specific risk factors among Candida may provide clinicians with additional guidance in choosing empiric antifungal therapy. In our study, patients receiving at least 7 days of appropriate antifungal therapy following bloodstream clearance had a lower mortality at 30 days compared to those that did not. This is consistent with the findings of Almirante et al. (2005) who found a decrease in mortality in candidemic patients receiving at least 5 days of any antifungal. Likewise, Morgan et al. (2005) found lower attributable mortality rates in candidemic patients receiving at least 7 days of antifungal therapy than in those who received inadequate therapy. Delays in antifungal therapy until blood cultures are positive for yeast are common. In a recent single center cohort of 157 candidemic patients, 134 patients did not receive empiric antifungal therapy prior to culture positivity. In the 9 patients who were initiated on therapy within 12 h of culture, mortality was significantly lower than in those initiated on therapy after 12 h (Morrell et al., 2005). Garey et al. (2006) reported 192 candidemic patients from 4 centers and found an incremental increase in mortality for each day of delay in initiation of fluconazole. Timing to initiation of therapy in our study did not demonstrate this incremental increase in mortality, which may be a reflection of the severity of illness at the time of candidemia in these patients. The absence of antifungal therapy had more of an impact on mortality than did timing of therapy, as demonstrated by the 85% mortality in untreated patients. Over the past 2 decades, treatment of all episodes of candidemia has been recommended, and formal guidelines for therapy were 1st published in 2000. Although rarely, Candida BSI clears with removal of an infected central venous catheter without antifungal therapy, it is difficult to predict who will develop complications of hematogenous seeding of Candida. The morbidity and risk of these sequelae outweigh the risk of antifungal therapy, especially with the development of multiple newer antifungal agents with improved side effect profiles compared to amphotericin B deoxycholate (Edwards et al., 1997). In most instances of untreated candidemia that have been reported, patients have either died by the time yeast is identified in blood cultures, or palliative care has been instituted (Macphail et al., 2002; Malani et al., 2005). This was consistent with our findings, but, in addition, we found that other reasons for lack of
therapy included either the physician attributing the positive blood culture to contamination, the removal of an infected central venous catheter was thought to be sufficient, the patient appeared clinically improved without therapy, or physicians were awaiting identification of the yeast prior to treating the infection. Though these cases may represent a minority of candidemic patients, there appears to be an opportunity for educating physicians that isolation of Candida from blood cultures never should be considered a contaminant and that catheter removal without antifungal therapy is a gamble with high risk of failure. In the case of clinical improvement without therapy, this raises concerns that the patient will have hematogenously seeded a distant site and therefore is at risk for developing complications of candidemia. Lastly, most cases of yeast isolated from the blood of hospitalized patients will represent Candida (Lecciones et al., 1992); therefore, empiric therapy should be initiated once this result becomes available. Methods to reduce the number of untreated patients may also include preemptive or earlier empiric therapy (OstroskyZeichner and Pappas, 2006). Piarroux et al. (2004) reported results of a successful preemptive strategy in surgical intensive care unit patients at a single center with the use of a Candida colonization index. Patients with a corrected colonization index of ≥0.4 (number of surveillance cultures of gastric and tracheal aspirates, urine, and oropharyngeal and rectal swabs with heavy growth of Candida per number of cultures obtained) received preemptive therapy with fulldose fluconazole and had a lower incidence of invasive Candida infection compared to a retrospective cohort of controls (3.8% versus 7%, P = 0.03). The incidence of surgical intensive care unit (SICU)-acquired Candida infection decreased to 0.0% from 2.2% in controls (P b 0.001). The generalizability of these results and the costeffectiveness of such an approach are yet to be determined. In summary, we found that patients infected with C. glabrata were as likely to receive appropriate antifungal therapy as patients with C. albicans, and that receiving 7 days of appropriate therapy was associated with lower 30-day mortality. Lack of antifungal therapy had a more significant impact on mortality than timing of initiation of therapy, and strategies to decrease the incidence of untreated candidemia may improve outcome. Further work to develop improved rapid diagnostics and new approaches to preemptive or early empiric therapy are needed. Acknowledgments This study was supported in part by a research grant from Merck. References Almirante B, Rodriguez D, Park BJ, Cuenca-Estrella M, Planes AM, Almela M, Mensa J, Sanchez F, Ayats J, Gimenez M, Saballs P, Fridkin SK, Morgan J, Rodriguez-Tudela JL, Warnock DW, Pahissa A, Barcelona
M.J. Klevay et al. / Diagnostic Microbiology and Infectious Disease 60 (2008) 273–277 Candidemia Project Study Group (2005) Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, Barcelona, Spain, from 2002 to 2003. J Clin Microbiol 43:1829–1835. Edwards JE, Bodey GP, Bowden RA, Büchner T, de Pauw BE, Filler SG, Ghannoum MA, Glauser M, Herbrecht R, Kauffman CA, Kohno S, Martino P, Meunier F, Mori T, Pfaller MA, Rex JH, Rogers TR, Rubin RH, Solomkin J, Viscoli C, Walsh TJ, White M (1997) International conference for the development of a consensus on the management and prevention of severe candidal infections. Clin Infect Dis 25:43–59. Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, Bearden DT (2006) Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 43: 25–31. Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, Herwaldt L, Pfaller M, Diekema D (2003) Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 37:1172–1177. Lecciones JA, Lee JW, Navarro EE, Witebsky FG, Marshall D, Steinberg SM, Pizzo PA, Walsh TJ (1992) Vascular catheter-associated fungemia in patients with cancer: analysis of 155 episodes. Clin Infect Dis 14: 875–883. Macphail GLP, Taylor GD, Buchanan-Chell M, Ross C, Wilson S, Kureishi A (2002) Epidemiology, treatment and outcome of candidemia: a fiveyear review at three Canadian hospitals. Mycoses 45:141–145. Malani A, Hmoud J, Chiu L, Carver PL, Bielaczyc A, Kauffman CA (2005) Candida glabrata fungemia: experience in a tertiary care center. Clin Infect Dis 41:975–981. Morgan J, Meltzer MI, Plikaytis BD, Sofair AN, Huie-White S, Wilcox S, Harrison LH, Seaberg EC, Hajjeh RA, Teutsch SM (2005) Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol 26:540–547. Morrell M, Fraser VJ, Kollef MH (2005) Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 49:3640–3645.
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National Committee for Clinical Laboratory Standards (2002) Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard, M27-A2. 2nd ed. Wayne, PA: National Committee for Clinical Laboratory Standards; 2002. National Committee for Clinical Laboratory Standards (2004) Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts: Approved Guideline, M44-A. Wayne, PA: National Committee for Clinical Laboratory Standards; 2004. Ostrosky-Zeichner L, Pappas PG (2006) Invasive candidiasis in the intensive care unit. Crit Care Med 34:857–863. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, Edwards JE (2004) Guidelines for treatment of candidiasis. Clin Infect Dis 38: 161–189. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163. Pfaller MA, Messer SA, Boyken L, Tendolkar S, Hollis RJ, Diekema DJ (2003) Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location. J Clin Microbiol 41:2176–2179. Pfaller MA, Messer SA, Boyken L, Tendolkar S, Hollis RJ, Diekema DJ (2004) Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to seven systemically active antifungal agents: a global assessment from the ARTEMIS Antifungal Surveillance Program conducted in 2001 and 2002. J Clin Microbiol 42:3142–3146. Piarroux R, Grenouillet F, Balvay P, Tran V, Blasco G, Millon L, Boillot A (2004) Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med 32:2443–2449. Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP, National Nosocomial Infections Surveillance System Hospitals (2002) Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989–1999. Clin Infect Dis 35: 622–630. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309–317.
Diagnostic Microbiology and Infectious Disease 60 (2008) 273 – 277 www.elsevier.com/locate/diagmicrobio
Therapy and outcome of Candida glabrata versus Candida albicans bloodstream infection☆ Michael J. Klevay a , Erika J. Ernst b , Jesse L. Hollanbaugh b , Joshua G. Miller b , Michael A. Pfaller c , Daniel J. Diekema a,c,⁎ a
Department of Medicine, University of Iowa, Iowa City, IA 52242, USA b College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA c Department of Pathology, University of Iowa, Iowa City, IA 52242, USA Received 8 August 2007; accepted 9 October 2007
Abstract Candida glabrata is a common cause of bloodstream infection (BSI) and exhibits reduced susceptibility to antifungal agents. Those with C. glabrata BSI may therefore be at increased risk for a delay in receiving appropriate therapy and poor treatment outcome. We compared treatment and outcome of patients with C. glabrata to controls with Candida albicans BSI. Each patient with C. glabrata BSI from July 1997 through December 2004 was matched with a control patient infected with C. albicans. Appropriateness of therapy was defined using current guidelines, and the mortality end point was 30 days following the initial positive blood culture. Overall, 78% of patients received appropriate therapy (39/54 [72%] for C. glabrata versus 45/54 [83%] for C. albicans, P = 0.2). Crude 30-day mortality was high for both groups (41% for C. glabrata versus 44% for C. albicans, P = 0.7). There was no trend in mortality according to time of therapy initiation, but mortality was lower for those who received appropriate therapy (35% versus 71% for inappropriate therapy, P = 0.002). Twelve percent of patients received no antifungal therapy and contributed disproportionately to overall crude mortality. Strategies to decrease the incidence of untreated candidemia may favorably impact outcome. © 2008 Elsevier Inc. All rights reserved. Keywords: Candida glabrata; Bloodstream infection; Antifungal therapy
Candida spp. have emerged as the 4th most common cause of nosocomial bloodstream infection (BSI) (Wisplinghoff et al., 2004). Despite the introduction of multiple systemic antifungal agents with activity against Candida, these infections continue to be associated with high attributable mortality rates (Gudlaugsson et al., 2003; Pfaller and Diekema, 2007). Morrell et al. (2005) recently reported that it is common for the initiation of antifungal therapy to be delayed, and that a delay in therapy beyond 12 h after culture is associated with higher mortality. Garey et al. (2006) have shown that mortality increases incrementally with each day of a delay in ☆ Preliminary results of this study were presented in abstract form at Focus on Fungal Infections 17, San Diego, CA, March 2007, and the Infectious Diseases Society of America 45th Annual Meeting, San Diego, CA, October 2007. ⁎ Corresponding author. Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Tel.: +1-319384-5626; fax: +1-319-356-4916. E-mail address: [email protected] (D.J. Diekema).
0732-8893/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2007.10.001
therapy for candidemia in patients treated with fluconazole. Candida glabrata has emerged as the 2nd most common cause of candidemia in US hospitals (Pfaller and Diekema, 2007; Trick et al., 2002) and is less susceptible to fluconazole and the other azoles, as well as amphotericin, than is Candida albicans (Pfaller and Diekema, 2007; Pfaller et al., 2004). For this reason, patients with C. glabrata BSI may be at higher risk for receipt of inappropriate therapy or adverse outcome compared with those with C. albicans BSI. The purpose of this study is to describe how the appropriateness of antifungal therapy and outcome for C. glabrata BSI compare to infection with C. albicans. 1. Methods 1.1. Setting The University of Iowa Hospitals and Clinics (UIHC), Iowa City, IA, is a 680-bed teaching hospital providing tertiary care for the State of Iowa. The UIHC is a level 1
274
M.J. Klevay et al. / Diagnostic Microbiology and Infectious Disease 60 (2008) 273–277
trauma center, has 128 intensive care unit beds, and supports active bone marrow transplant and solid organ transplant programs. The UIHC institutional review board approved this study.
The mortality end point was defined at 30 days following the 1st positive blood culture for Candida spp.
1.2. Study design
We compared categoric variables between case and control groups with the χ2 or Fisher's exact test as appropriate and compared continuous variables with a paired t test. α was set at 0.05, and all P values were 2 tailed. We performed statistical analyses using SPSS version 13.0 for Windows (Chicago, IL).
A matched retrospective cohort study was performed. All cases of C. glabrata BSI between July 1997 and December 2004 were identified from a database maintained in the Clinical Microbiology Laboratory at UIHC. C. glabrata BSI was defined as at least 1 positive blood culture for C. glabrata during the study period. Patients with C. albicans BSI were selected from the database and matched to cases 1:1 by the closest date of hospital admission. Data on antifungal therapy and outcomes were collected by retrospective chart review. 1.3. Microbiologic methods Candida spp. were identified using Vitek and API products or conventional methods, as required, and antifungal susceptibility testing was performed with the reference broth microdilution method in accordance with Clinical and Laboratory Standards (CLSI) standards (NCCLS, 2002). Interpretive criteria for fluconazole susceptibility were those published by the CLSI (NCCLS, 2004). Candida parapsilosis strain ATCC 22019 and Candida krusei strain ATCC 6258 were tested with each run for quality control. 1.4. Definitions We defined appropriate therapy for candidemia as the use of a systemic antifungal drug active in vitro against the patient's Candida isolate. The antifungal agent and dose must have been consistent with Infectious Diseases Society of America (IDSA) guidelines with adjustments for weight, renal, or hepatic dysfunction. To be in strict accordance with IDSA guidelines, we must continue therapy for at least 14 days following the last positive blood culture (Pappas et al., 2004). However, consistent with other investigators (Morgan et al., 2005), we accepted a minimum of 7 days of an active antifungal agent at correct doses to meet our criteria for appropriate therapy. If a patient died while receiving otherwise appropriate antifungal therapy, he or she was considered to have received an appropriate course of therapy. The time to initiation of therapy was reported as the number of days following the blood culture after which any antifungal drug was started, with day = 0 representing the initiation of therapy on the day that the culture was drawn, day = 1 representing therapy starting on the day after the culture was drawn, and so on. Untreated candidemia was defined as lack of antifungal therapy during the hospitalization of a patient with a positive blood culture for Candida spp. Reasons for absence of therapy for candidemia were determined from review of the medical record.
1.5. Statistical analyses
2. Results Fifty-five patients had C. glabrata BSI identified during the study period. Due to difficulty in matching 1 study patient with a C. albicans-infected control patient, this patient was excluded, leaving 54 patients in the C. glabrata group and 54 patients in the C. albicans group. Patients with C. albicans infection were matched to C. glabrata patients within 6 months of hospital admission date in 47 of 54 pairs (87%) and within 1 year in all cases. Seven of the C. glabrata patients had polymicrobial BSI episodes with other Candida spp. (C. albicans [6] and C. parapsilosis [1]), and 1 C. albicans patient also had Candida lusitaniae isolated from blood. The patients we categorized as having received inappropriate therapy received either no therapy during the hospital stay, fluconazole therapy for a fluconazoleresistant C. glabrata isolate, an antifungal at a dose lower than recommended by IDSA guidelines, or a duration of therapy shorter than 7 days after documented clearance of the bloodstream. The 30-day mortality and the proportion of patients in each group who met the 7- and 14-day appropriate therapy criteria are found in Table 1. Mortality did not differ by species, with 22/54 (41%) patients with C. glabrata dead at 30 days, compared with 24/54 (44%) C. albicans patients (P = 0.7). There were also no differences in appropriateness of therapy according to species: 33/54 patients (61%) with C. glabrata versus 34/54 patients (63%) with C. albicans BSI (P = 0.8) received appropriate therapy for 14 days, and 39/54 patients (72%) with C. glabrata versus 45/54 (83%) with C. albicans BSI (P = 0.2) received appropriate therapy for at least 7 days.
Table 1 Appropriateness of therapy and 30-day mortality of C. glabrata versus C. albicans BSI C. glabrata C. albicans Total Total patients (n) Appropriate therapy: 14-day duration Appropriate therapy: 7-day duration 30-day mortality (%)
54 33 (61%) 39 (72%) 41
54 34 (63%) 45 (83%) 44
108 67 (62%) 84 (78%) 43
P N 0.05 for all comparisons between C. glabrata and C. albicans infection.
M.J. Klevay et al. / Diagnostic Microbiology and Infectious Disease 60 (2008) 273–277
275
Table 2 Empiric therapy choices for patients with C. albicans and C. glabrata BSI Regimen
C. albicans (n, %)
C. glabrata (n, %)
Fluconazole ≤400 mg/day Fluconazole 800/400 Fluconazole 800 mg/day Caspofungin Amphotericin Othera No treatment
26 2 6 0 13 2 5
9 (17) 1 (2) 12 (22) 9 (17) 14 (26) 0 (0) 8 (15)
a
(48) (4) (11) (0) (24) (4) (9)
1 treated with voriconazole, 1 treated with amphotericin + fluconazole.
Table 2 lists the number of patients with C. albicans and C. glabrata infection receiving various empiric antifungal therapy choices. Although empiric therapy choices were most often made prior to species identification, patients infected with C. glabrata were much more likely to receive empiric therapy with an echinocandin or a higher dose of fluconazole than were patients with C. albicans BSI. Consequently, rates of appropriate therapy did not differ according to species. When all 108 candidemic patients were analyzed together, crude mortality at 30 days after onset of candidemia was 35% among the 84 patients in the 7 days of appropriate therapy group versus 71% among the 24 patients not receiving appropriate therapy (P = 0.002). Among the 24 patients not receiving appropriate therapy as defined in this study, 13 received no antifungal therapy (representing over half of all patients not receiving appropriate therapy and 12% of all candidemic patients). The 30-day crude mortality among patients receiving no therapy was 85%. Mortality according to the timing of initiation of antifungal therapy is illustrated in Fig. 1. There was no trend in mortality seen with timing of therapy (P = 0.3 for trend), but as outlined above, the mortality was significantly higher among those patients who received no antifungal therapy. Fig. 2 illustrates the relationship between time to initiation of therapy and mortality according to species. Notably, patients infected with C. glabrata were not more likely to receive delayed antifungal treatment than were
Fig. 2. Thirty-day mortality according to time to initiation of antifungal therapy, by Candida spp. (P = 0.3 for C. albicans; P = 0.06 for C. glabrata).
those with C. albicans. Five of the untreated patients died within 24 h of culture, 3 more died within the 1st week, and another 3 died within 2 weeks of culture. The results of analyses of mortality according to timing of initiation of therapy were unchanged when patients who died within 72 h of culture (and their matches) were excluded from the analysis (data not shown). Only 35% of the C. glabrata isolates were susceptible to fluconazole, 50% were susceptible and dose dependent, and 15% were resistant. All but 1 of the C. albicans isolates was fluconazole susceptible, and this was susceptible and dose dependent. There were several reasons evident in medical records for the failure to administer antifungal therapy in 13 patients: 1) death prior to blood culture turning positive (n = 5), 2) removal of the central venous catheter felt to be adequate therapy (n = 2), 3) resolution of fever prior to blood culture positivity felt to be an indication for withholding antifungal therapy (n = 1), 4) repeat blood cultures negative, positive culture felt to be contaminant (n = 1), 5) withdrawal of aggressive care and removal of life support (n = 1), 6) decision to await identification of yeast prior to starting therapy, and patient died prior to yeast identification (n = 1), and 7) no clear reason given (n = 2, in each case the blood culture result was called to the patient care area but was not mentioned in physician progress notes). Untreated patients occurred throughout the study period. 3. Discussion
Fig. 1. Thirty-day mortality according to time to initiation of antifungal therapy (P = 0.3).
C. glabrata has emerged as an important nosocomial pathogen in the United States (Pfaller et al., 2003; Trick et al., 2002). The reduced susceptibility of C. glabrata to azoles and amphotericin B poses a challenge to choice of appropriate empiric antifungal therapy for patients with candidemia prior to the availability of species identification or antifungal susceptibility test results. We postulated that patients with C. glabrata BSI might be less likely than those with C. albicans BSI to receive appropriate
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therapy or perhaps to have a longer delay to initiation of appropriate therapy. We did not detect a difference in receipt of appropriate antifungal therapy dependent on Candida spp., in that patients infected with C. glabrata were as likely to receive appropriate antifungal therapy as those infected with C. albicans. This demonstrates physicians' familiarity with the variable fluconazole susceptibility patterns of C. glabrata. Empiric therapy, once yeast was identified, appeared to be guided by the microbiology of previous Candida colonization and prior azole exposure, leading to more patients with C. glabrata being started on an echinocandin or high-dose fluconazole therapy. The identification of other species-specific risk factors among Candida may provide clinicians with additional guidance in choosing empiric antifungal therapy. In our study, patients receiving at least 7 days of appropriate antifungal therapy following bloodstream clearance had a lower mortality at 30 days compared to those that did not. This is consistent with the findings of Almirante et al. (2005) who found a decrease in mortality in candidemic patients receiving at least 5 days of any antifungal. Likewise, Morgan et al. (2005) found lower attributable mortality rates in candidemic patients receiving at least 7 days of antifungal therapy than in those who received inadequate therapy. Delays in antifungal therapy until blood cultures are positive for yeast are common. In a recent single center cohort of 157 candidemic patients, 134 patients did not receive empiric antifungal therapy prior to culture positivity. In the 9 patients who were initiated on therapy within 12 h of culture, mortality was significantly lower than in those initiated on therapy after 12 h (Morrell et al., 2005). Garey et al. (2006) reported 192 candidemic patients from 4 centers and found an incremental increase in mortality for each day of delay in initiation of fluconazole. Timing to initiation of therapy in our study did not demonstrate this incremental increase in mortality, which may be a reflection of the severity of illness at the time of candidemia in these patients. The absence of antifungal therapy had more of an impact on mortality than did timing of therapy, as demonstrated by the 85% mortality in untreated patients. Over the past 2 decades, treatment of all episodes of candidemia has been recommended, and formal guidelines for therapy were 1st published in 2000. Although rarely, Candida BSI clears with removal of an infected central venous catheter without antifungal therapy, it is difficult to predict who will develop complications of hematogenous seeding of Candida. The morbidity and risk of these sequelae outweigh the risk of antifungal therapy, especially with the development of multiple newer antifungal agents with improved side effect profiles compared to amphotericin B deoxycholate (Edwards et al., 1997). In most instances of untreated candidemia that have been reported, patients have either died by the time yeast is identified in blood cultures, or palliative care has been instituted (Macphail et al., 2002; Malani et al., 2005). This was consistent with our findings, but, in addition, we found that other reasons for lack of
therapy included either the physician attributing the positive blood culture to contamination, the removal of an infected central venous catheter was thought to be sufficient, the patient appeared clinically improved without therapy, or physicians were awaiting identification of the yeast prior to treating the infection. Though these cases may represent a minority of candidemic patients, there appears to be an opportunity for educating physicians that isolation of Candida from blood cultures never should be considered a contaminant and that catheter removal without antifungal therapy is a gamble with high risk of failure. In the case of clinical improvement without therapy, this raises concerns that the patient will have hematogenously seeded a distant site and therefore is at risk for developing complications of candidemia. Lastly, most cases of yeast isolated from the blood of hospitalized patients will represent Candida (Lecciones et al., 1992); therefore, empiric therapy should be initiated once this result becomes available. Methods to reduce the number of untreated patients may also include preemptive or earlier empiric therapy (OstroskyZeichner and Pappas, 2006). Piarroux et al. (2004) reported results of a successful preemptive strategy in surgical intensive care unit patients at a single center with the use of a Candida colonization index. Patients with a corrected colonization index of ≥0.4 (number of surveillance cultures of gastric and tracheal aspirates, urine, and oropharyngeal and rectal swabs with heavy growth of Candida per number of cultures obtained) received preemptive therapy with fulldose fluconazole and had a lower incidence of invasive Candida infection compared to a retrospective cohort of controls (3.8% versus 7%, P = 0.03). The incidence of surgical intensive care unit (SICU)-acquired Candida infection decreased to 0.0% from 2.2% in controls (P b 0.001). The generalizability of these results and the costeffectiveness of such an approach are yet to be determined. In summary, we found that patients infected with C. glabrata were as likely to receive appropriate antifungal therapy as patients with C. albicans, and that receiving 7 days of appropriate therapy was associated with lower 30-day mortality. Lack of antifungal therapy had a more significant impact on mortality than timing of initiation of therapy, and strategies to decrease the incidence of untreated candidemia may improve outcome. Further work to develop improved rapid diagnostics and new approaches to preemptive or early empiric therapy are needed. Acknowledgments This study was supported in part by a research grant from Merck. References Almirante B, Rodriguez D, Park BJ, Cuenca-Estrella M, Planes AM, Almela M, Mensa J, Sanchez F, Ayats J, Gimenez M, Saballs P, Fridkin SK, Morgan J, Rodriguez-Tudela JL, Warnock DW, Pahissa A, Barcelona
M.J. Klevay et al. / Diagnostic Microbiology and Infectious Disease 60 (2008) 273–277 Candidemia Project Study Group (2005) Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, Barcelona, Spain, from 2002 to 2003. J Clin Microbiol 43:1829–1835. Edwards JE, Bodey GP, Bowden RA, Büchner T, de Pauw BE, Filler SG, Ghannoum MA, Glauser M, Herbrecht R, Kauffman CA, Kohno S, Martino P, Meunier F, Mori T, Pfaller MA, Rex JH, Rogers TR, Rubin RH, Solomkin J, Viscoli C, Walsh TJ, White M (1997) International conference for the development of a consensus on the management and prevention of severe candidal infections. Clin Infect Dis 25:43–59. Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, Bearden DT (2006) Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 43: 25–31. Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, Herwaldt L, Pfaller M, Diekema D (2003) Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 37:1172–1177. Lecciones JA, Lee JW, Navarro EE, Witebsky FG, Marshall D, Steinberg SM, Pizzo PA, Walsh TJ (1992) Vascular catheter-associated fungemia in patients with cancer: analysis of 155 episodes. Clin Infect Dis 14: 875–883. Macphail GLP, Taylor GD, Buchanan-Chell M, Ross C, Wilson S, Kureishi A (2002) Epidemiology, treatment and outcome of candidemia: a fiveyear review at three Canadian hospitals. Mycoses 45:141–145. Malani A, Hmoud J, Chiu L, Carver PL, Bielaczyc A, Kauffman CA (2005) Candida glabrata fungemia: experience in a tertiary care center. Clin Infect Dis 41:975–981. Morgan J, Meltzer MI, Plikaytis BD, Sofair AN, Huie-White S, Wilcox S, Harrison LH, Seaberg EC, Hajjeh RA, Teutsch SM (2005) Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol 26:540–547. Morrell M, Fraser VJ, Kollef MH (2005) Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 49:3640–3645.
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National Committee for Clinical Laboratory Standards (2002) Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard, M27-A2. 2nd ed. Wayne, PA: National Committee for Clinical Laboratory Standards; 2002. National Committee for Clinical Laboratory Standards (2004) Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts: Approved Guideline, M44-A. Wayne, PA: National Committee for Clinical Laboratory Standards; 2004. Ostrosky-Zeichner L, Pappas PG (2006) Invasive candidiasis in the intensive care unit. Crit Care Med 34:857–863. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, Edwards JE (2004) Guidelines for treatment of candidiasis. Clin Infect Dis 38: 161–189. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163. Pfaller MA, Messer SA, Boyken L, Tendolkar S, Hollis RJ, Diekema DJ (2003) Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location. J Clin Microbiol 41:2176–2179. Pfaller MA, Messer SA, Boyken L, Tendolkar S, Hollis RJ, Diekema DJ (2004) Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to seven systemically active antifungal agents: a global assessment from the ARTEMIS Antifungal Surveillance Program conducted in 2001 and 2002. J Clin Microbiol 42:3142–3146. Piarroux R, Grenouillet F, Balvay P, Tran V, Blasco G, Millon L, Boillot A (2004) Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med 32:2443–2449. Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP, National Nosocomial Infections Surveillance System Hospitals (2002) Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989–1999. Clin Infect Dis 35: 622–630. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309–317.