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Epidemiological trends in nosocomial candidemia in intensive care

Epidemiological trends in nosocomial candidemia in intensive care Background: Infection represents a frequent complication among patients in Intensive Care Units (ICUs) and mortality is high. In particular, the incidence of fungal infections, especially due to Candida spp., has been increasing during the last years. Methods: In a retrospective study we studied the etiology of candidemia in critically ill patients over a five-year period (1999–2003) in the ICU of the San Martino University Hospital in Genoa, Italy. Results: In total, 182 episodes of candidaemia were identified, with an average incidence of 2.22 episodes/10 000 patient-days/year (range 1.25–3.06 episodes). Incidence of candidemia increased during the study period from 1.25 in 1999 to 3.06/10 000 patient-days/year in 2003. Overall, 40% of the fungemia episodes (74/182) were due to C.albicans, followed by C. parapsilosis(23%), C.glabrata (15%), C.tropicalis (9%) and other species (13%). Candidemia due to non-albicans species increased and this was apparently correlated with an increasing use of azoles for prophylaxis or empirical treatment. Conclusion: The study demonstrates a shift in the species of Candida causing fungemia in a medical and surgical ICU population during a 5 year period. The knowledge of the local epidemiological trends in Candida species isolated in blood cultures is important to guide therapeutic choices. and European studies [1,2]. Despite the availability of Background Candida is an increasing cause of bloodstream infection effective antifungal therapy, mortality in the last decade (BSI), causing significant mortality and morbidity, espe- remained high, ranging from 36% to 63% [3]. In terms of cially in non-neutropenic critically ill patients. Its overall species of Candida, recently, a shift towards non-albicans incidence raised fivefold in the past ten years and Candida species was reported by some authors especially in hema- spp. is currently between the fourth and the sixth most tological and transplanted patients [4-7]. Some of these common nosocomial bloodstream isolate in American emerging species has been correlated with increased viru- Page 1 of 6 (page number not for citation purposes) BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 lence [8], and sometimes, but not always, with increased oped a clinically and microbiologically documented can- mortality [9]. An increasing role for non-albicans species didemia were identified through a microbiological was also noticed in studies performed among ICU laboratory survey and data were recorded in an electronic patients, although the issue is somewhat controversial data base. The patients chart review was performed in [3,10-12]. order to identify clinically relevant episodes. Candidemia was defined as at least one positive blood culture yielding As shown by the SENTRY antimicrobial surveillance pro- Candida spp. in a patients with fever or other clinical signs gram [1], C. albicans is still the species most frequently iso- of infection. Nosocomial candidemia was defined as a lated in BSI [13,14], while in other groups of patients non- candidemia occurring at least 48 h after admission. Dur- albicans species have surpassed C.albicans as a cause of ing the study period there were no changes in microbio- candidemia. C.parapsilosis and C.tropicalis are isolated logical laboratory techniques. Candida species were more frequently than C.albicans in some European and isolated from blood using BACTEC 860 system (Becton Latin American centres [15]. Dickinson, INC, Sparks, MD). The species were identified using API-32C system (bioMerieux Vitek, Inc, St. Louis, A reduced antifungal susceptibility in non-albicans species MI). Frequencies and descriptives of demographic and and a correlation with routine fluconazole prophylactic clinical characteristics of the patient population were use has been suggested [5,16]. Intrinsic and emerging determined. resistance of non-albicans species to azoles actually repre- sents a major challenge for empirical therapeutic and pro- All patients were evaluable for the inclusion in this study. phylactic strategies [17]. The Chi-square-test or the Fisher Exact-test were used to compare categorical variables. Chi-square-test for trend We have performed a retrospective study of Candida spp. was used to estimate the relationship between albicans BSI in the ICU of the San Martino University Hospital, in and non-albicans isolation rates during the years of study. Genova, Italy, between 1999 and 2003, with the double In order to understand whether or not there was a correla- aim of understanding if any change was detectable in the tion between the distribution of the different Candida spe- distribution of the various Candida species as cause of BSI cies causing BSI and the use of fluconazole, the DDD of over the years and of estimating whether this change, if fluconazole per 1000 patient-days was calculated and existing, was correlated with the use of fluconazole for plotted against the type of isolated Candida on a yearly prophylaxis or therapy. basis. A logistic regression analysis between C. albicans rate and fluconazole usage was then performed.P values < Methods 0.05 were considered significant. The ICU of the San Martino General Hospital in Genova, Italy, is a mid-size medical and surgical unit with 18 beds All the patients consented to participation in the study and about 500 admissions per year. Patients who devel- and publication of the results. Table 1: Patient characteristics of 182 patients with candidemia. Characteristics C.albicans (n= 74) C. non albicans (n= 108) P value Male 41 70 NS Famale 33 38 NS Age (years) mean ± SD Range 58.4 ± 15.4 64.4 ± 11.4 <0.05 Central venous catheterization 65/74 99/108 NS Parenteral nutrition 38/74 64/108 NS Ventilator dependence mean ± SD Range 27.9 ± 23.6 32.6 ± 24.5 NS Apache II score mean ± SD Range 21.8 ± 7.4 25.6 ± 9.8 NS Underline disease Surgery 33/74 40/108 NS Solid tumor 11/74 35/108 <0.05 Solid organ transplant 8/74 10/108 NS Trauma 7/74 9/108 NS Hematological malignancies 6/74 10/108 NS Burn 4/74 3/108 NS Others 5/74 1/108 NS NS = Not significant Page 2 of 6 (page number not for citation purposes) BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 progressively dropped to 24%, with a median percentage year reduction of 13%, while the absolute number and the incidence of C.albicans did not vary during the years 3,50 2000 observed. The change was statistically significant (K = 3,00 24.452; p < 0.0001), although in absence of a rigorous lin- 2,50 ear trend. Non-albicans strains steadily increased through- 2,00 out the study period surpassing C.albicans in the second half of the study and raising from 21% to 67% (P = 0.01) 1,50 (Figure 2). The proportion of non-albicans species went 1,00 from 38% and 21% of total isolates in the years 1999– 0,50 2000 and then to 67%, 73% and 76% in 2001, 2002 and 2003, respectively. Among non-albicans strains, in 2002 0,00 0 Y 1999 Y 2000 Y 2001 Y 2002 Y 2003 Years observed we noted an increase of C.parapsilosis isolation rates, which reached 51% of total, while absence of C.tropicalis was noted in the years 2000–2001. The use of fluconazole for prophylaxis or therapy š■ Figure 1 inciden DDD's of ce of candidemia epis fluconazole × 100 pts/days odes/10 000 patient-days/year; š incidence of candidemia episodes/10 000 patient-days/year; increased four times during the study period. Logistic ■ DDD's of fluconazole × 100 pts/days. regression analysis showed a statistically significant corre- lation between the shift from albicans to non-albicans strains and the yearly fluconazole consumption. As Results shown in figure 3, an increase of 100 fluconazole DDDs In total, 182 episodes of candidaemia were identified, corresponded to a reduction in the isolation of C. albicans with an average incidence of 2.22 episodes/10 000 of 5%. patient-days/year (range 1.25–3.06 episodes), as shown in table 1. Incidence of candidemia increased during the Discussion Our study demonstrates a shift in the species of Candida study period from 1.25 in 1999 to 3.06 episodes/10 000 patient-days/year in 2003 (Figure 1). The demographic causing fungemia in a medical and surgical ICU popula- and clinical characteristics of the patients are summarized tion during a 5 year period. The proportion due to C. albi- in table 1. Patients with Candida non-albicans fungemia cans decreased whereas that due to other species, such as were significantly older. There were no significant differ- C. parapsilosis, C. tropicalis and C.glabrata, increased. Such ences in sex, age, central venous, catheterization, an increase in non-albicans species was also seen in retro- parenteral nutrition, ventilator dependence, Apache II spective reviews of candidemias [4,10,12,15,16]. In con- score and other underline disease. Non-albicans candi- trast to hematologic patients where a decrease in demia are significantly more frequent in patients with C.albicans infection resulted in a significant reduction in solid tumor. Overall, 40% of the episodes (74/182) were the incidence of candidemia [17], in our experience the due to C.albicans, followed by C. parapsilosis(23%), C.gla- overall incidence actually increased (Table 1; Figure 1). brata (15%), C.tropicalis (9%) and other species (13%) Traditionally, C.tropicalis has been the second and C.gla- (Table 2) The percentage of C. albicans which was isolated brata the third or fourth most common Candida species in about 60% of the episodes in the first years of study, recovered from blood [4,8]. In our study C.parapsilosis sur- Table 2: Incidence and distribution of candidemia in the years 1999 – 2003 in S. Martino Hospital ICU expressed in number and percentage of isolates. Polymicrobial infections were excluded. 1999 2000 2001 2002 2003 Total Number of isolates (percentage of species in the year) C.albicans 13 (62) 26 (79) 11 (33) 12 (27) 12 (24) 74 (40) C.parapsilosis 2 (9) 0 4 (12) 23 (51) 13 (26) 42 (23) C. glabrata 0 1 (3) 12 (36) 2 (4) 12 (24) 27 (15) C. tropicalis 5 (24) 0 0 7 (16) 5 (10) 17 (9) Othres (C.kruzei, C.guillermondii, C.lusitanae) 1 (5) 6 (18) 6 (19) 1 (2) 8 (16) 24 (13) Total candidemia 21 33 33 45 50 182 Incidence of candidemia/10 000 patient-days/year 1.25 2 2.05 2.74 3.06 2.22 Incidence of candidemia due to C.albicans/10 000 patient-days/year 0.84 1.58 0.66 0.73 0.73 0.91 Page 3 of 6 (page number not for citation purposes) Incidence of candidemia Fluconazole DDD's x 100 pts/days BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 C. albicans and fluconazole usage 0,9 0,8 0,7 0,6 expected 0,5 observed 0,4 0,3 0,2 0,1 0 500 1000 1500 2000 2500 fluconazole usage (DDD/year) L a Figure 2 lin bicans e plot is represen olates rate tation of s during Candida albicans the study period and Candida non- [DDDs per Figure 3 Cor reducti relation on of using log year] C. albicans istic r isolation r egression between percenta ates and fluconazole use ge Line plot representation of Candida albicans and Candida non- Correlation using logistic regression between percentage albicans isolates rates during the study period. reduction of C. albicans isolation rates and fluconazole use [DDDs per year]. passed the other non-albicans to become the most com- proportion of fungemias due to C. parapsilosis reflect noso- mon species isolated after C.albicans. The high incidence comial acquisition of this species. of C.parapsilosis candidemia has been previously reported in South American hospitals [15,18,19]. The role of C.par- In ICU, the role for the use of fluconazole remains contro- apsilosis as an exogenous acquired pathogen is well known versial, since fluconazole was demonstrated to reduce the and has been associated with parenteral alimentation and incidence of Candida infections in a particular group of intravascular devices [20], commonly used in critical high-risk patient population [26-28]. patients. Though limited by its retrospective nature, our study Several investigators postulated that the widespread use of focuses the attention on predominance of non-C.albicans fluconazole would have selected yeast species intrinsically isolates, usually less susceptible or intrinsically resistant to resistant or less sensitive to fluconazole, such as Candida fluconazole. kruzei, C. glabrata or C. tropicalis [21-23]. Some published reports confirmed this hypothesis, while others did not It is well known that positive blood culture for Candida [2,24,25]. At the San Martino Hospital, the incidence of spp. is a life threatening situation, requiring an empirical infections caused by most non-albicans Candida species antifungal treatment which should started with the appro- changed substantially during the study period. These priate agents as soon as possible. Therefore the knowledge changes occurred in concomitance with a four fold of the local epidemiological trends in Candida species iso- increase in the use of fluconazole. In our ICU, during lated in blood cultures is important to guide therapeutic 2001 and the following years, the usage of fluconazole at choices. dosage of 200–400 mg/day increased because of the changing in prophylactic strategy in high-risk patients, The data we have reported are based on records from the according to the efficacy demonstrated in various reports microbiology laboratory, and thus, have certain inherent [26,27]. A logistic regression analysis showed a statisti- limitations. Our study did not address specific risk factors, cally significant correlation between the shift from albi- which undoubtedly play a role in the selection of species cans to non-albicans strains and the yearly fluconazole causing fungemia. However, this type of study does reveal consumption, as shown in figure 2. However, it be recog- overall long-term trends that should be helpful to physi- nised that other events might have played a role in the cians and antibiotic use committees in establishing guide- selection of different species. For example, in the last 2 lines for the appropriate use of antifungal agents. years of the study, the increased proportion of candi- demias due to C.parapsilosis, a yeast species almost always Competing interests susceptible to fluconazole, is not readily explained by The author(s) declare that they have no competing inter- increased fluconazole use. It is likely that changes in the ests. Page 4 of 6 (page number not for citation purposes) albicans rate BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 8. Kornshian SV, Uwaydah AK, Sobel JD, Crane LR: Fungemia caused Authors' contributions by Candida species and Torulopsis glabrata in the hospitalized MB: Data acquisition, data/statistical analyses, drafting patient: frequency, characteristics and evaluation of factors the manuscript influencing outcome. Rev Infect Dis 1989, 11:379-390. 9. Blot S, Vandewoude K, Hoste E, Poelaert J, Colardyn F: Outcome in critically ill patients with candidal fungaemia: Candida albi- ER: Sample collection, drafting the manuscript, critically cans vs. Candida glabrata. J Hosp Infect 2001, 47:308-13. 10. Hope W, Morton A, Eisen DP: Increase in prevalence of nosoco- revising for medical content mial non-Candida albicans candidaemia and the association of Candida krusei with fluconazole use. J Hosp Infect 2002, AC: Sample collection, critically revising for medical con- 50:56-65. 11. McMullan R, McClurg R, Xu J, Moore JE, Millar BC, Crowe M, Hed- tent derwick S: Trends in the epidemiology of Candida blood- stream infections in Northern Ireland between January 1984 RF: Sample collection, critically revising for medical con- and December 2000. J Infect 2002, 45:25-28. 12. Al-Jasser A, Elkhizzi NA: Distribution of Candida species among tent bloodstream isolates. Saudi Med J 2004, 25:566-69. 13. Yamamura D, Rotstein C, Nicolle LE, Ioannou S: Candidemia at selected Canadian sites: results from the fungal disease reg- MPM: Data acquisition, data analyses istry 1992–1994. CMAJ 1999, 160:493-9. 14. Klingspor L, Tornqvist E, Johansson A, Petrini B, Forsum U, Hedin G: RR: Study design and conception, critically revising for A prospective epidemiological survey of candidemia in Swe- den. Scand J Infect Dis 2004, 36:52-55. medical content 15. Colombo AL, Nucci M, Salomao R: High rate of non-albicans can- didemia in Brazilian tertiary care hospitals. Diagn Microbiol Infect Dis 1999, 34:281-86. FBP: Study design, conception and coordination 16. Luzzati R, Amalfitano G, Lazzarini L, Soldani F, Bellino S, Solbiati M, Danzi MC, Vento S, Todeschini G, Vivenza C, Concia E: Nosocomial CV: Study design, conception and coordination candidemia in non-neutropenic patients at an Italian tertiary care hospital. Eur J Clin Microbiol Infect Dis 2000, 19:602-7. 17. Safdar A, Perlin DS, Armstrong D: Hematogenous infections due All authors contributed to writing of the final manuscript. to Candida parapsilosis: changing trends in fungemic patients at a comprehensive cancer center during the last four decades. Diagn Microbiol Infect Dis 2002, 44:11-6. All authors read and approved the final manuscript 18. Levin AS, Costa SF, Mussi NS, Basso M, Sinto SI, Machado C, Geiger DC, Villares MC, Schreiber AZ, Barone AA, Branchini ML: Candida parapsilosis fungemia associated with implantable and semi- Acknowledgements implantable central venous catheters and the hands of The study was conducted independently of the funding agencies and phar- healthcare workers. Diagn Microbiol Infect Dis 1998, 30:243-9. maceutical companies. 19. Pfaller MA, Jones RN, Doern GV, Sader HS, Hollis RJ, Messer SA: International surveillance of bloodstream infections due to We are grateful to Dr. Mario Cruciani and Prof. Carlo Mengoli for his help- Candida species: frequency of occurrence and antifungal sus- ceptibilities of isolates collected in 1997 in the United States, ful contribution in statistical analyses. Canada, and South America for the SENTRY Program. The SENTRY Participant Group. J Clin Microbiol 1998, 36:1886-9. References 20. Pfaller MA: Epidemiology of candidiasis. J Hosp Infect 1995, 1. Pfaller MA, Diekema DJ, Jones RN, Sader HS, Fluit AC, Hollis RJ, 30(Suppl):329-38. Messer SA, SENTRY Participant Group: International surveillance 21. Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, Vartivarian S: of bloodstream infections due to Candida species: frequency The epidemiology of hematogenous candidiasis caused by of occurrence and in vitro susceptibilities to fluconazole, different Candida species. Clin Infect Dis 1997, 24:1122-8. ravuconazole, and voriconazole of isolates collected from 22. White MH: The contribution of fluconazole to the changing 1997 through 1999 in the SENTRY antimicrobial surveil- epidemiology of invasive Candida infection. Clin Infect Dis 1997, lance program. J Clin Microbiol 2001, 39:3254-9. 24:1129-30. 2. Marchetti O, Bille J, Fluckiger U, Eggimann P, Ruef C, Garbino J, Calan- 23. Berrouane YF, Herwaldt LA, Pfaller MA: Trends in antifungal use dra T, Glauser MP, Tauber MG, Pittet D: Fungal Infection Net- and epidemiology of nosocomial yeast infections in a Univer- work of Switzerland. Epidemiology of candidaemia in Swiss sity Hospital. J Clin Microbiol 1999, 37:531-37. tertiary care Hospitals: secular trends 1991–2000. Clin Infect 24. Malani PN, Bradley SF, Little RS, Kauffman CA: Trends in species Dis 2004, 38:311-20. causing fungaemia in a tertiary care medical centre over 12 3. Vos A, Noble JL, Verduyn-Lunel FM, Foudraine NA, Meis JF: Candi- years. Mycoses 2001, 44:446-9. demia in ICU patients: risk factors for mortality. Infect 1997, 25. Asmundsdottir LR, Erlendsdottir H, Gottfredsson M: Increasing 25:10-13. incidence of Candidemia: results from a 20-year nationwide 4. Nguyen MH, Peacock JE, Morns AJ, Tanner DC, Nguyen ML, Snydman study in Iceland. J Clin Microbiol 2002, 40:3489-92. DR, Wagener MM, Rinaldi MG, Yu VL: The changing face of Can- 26. Pelz RK, Hendrix CW, Swoboda SM, Diener-West M, Merz WG, didemia: emergence of non-Candida albicans species and Hammond J, Lipsett PA: Double-blind placebo-controlled trial antifungal resistance. Am J Med 1996, 100:617-623. of fluconazole to prevent candidal infections in critically ill 5. Rocco TR, Reinsert SE, Simms HH: Effects of fluconazole admin- surgical patients. Ann Surg 2001, 233:542-548. istration in critically ill patients: analysis of bacterial and fun- 27. Eggimann P, Francioli P, Bille J: Fluconazole prophylaxis prevents gal resistance. Arch Surg 2000, 135:160-65. intra-abdominal candidiasis in high-risk surgical patients. Crit 6. Pfaller MA, Jones RN, Doern GV, Sader HS, Messer SA, Houston A, Care Med 1999, 27:1066-72. Coffman S, Hollis RJ: Bloodstream infections due to Candida 28. Shorr AF, Chung K, Jackson WL, Waterman PE, Kollef MH: Flucona- species: SENTRY antimicrobial surveillance program in zole prophylaxis in critically ill surgical patients: a meta-anal- North America and Latin America, 1997–1998. Antimicrob Ag ysis. Crit Care Med 2005, 33:1928-1935. Chemother 2000, 44:747-51. 7. Shelenz S, Grandsen WR: Candidemia in a London teaching Hospital: analysis of 128 cases over a 7 years period. Mycoses 2003, 46:390-6. Page 5 of 6 (page number not for citation purposes) BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2334/6/21/prepub Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." 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Epidemiological trends in nosocomial candidemia in intensive care

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Medicine & Public Health; Infectious Diseases; Parasitology; Medical Microbiology; Tropical Medicine; Internal Medicine
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Abstract

Background: Infection represents a frequent complication among patients in Intensive Care Units (ICUs) and mortality is high. In particular, the incidence of fungal infections, especially due to Candida spp., has been increasing during the last years. Methods: In a retrospective study we studied the etiology of candidemia in critically ill patients over a five-year period (1999–2003) in the ICU of the San Martino University Hospital in Genoa, Italy. Results: In total, 182 episodes of candidaemia were identified, with an average incidence of 2.22 episodes/10 000 patient-days/year (range 1.25–3.06 episodes). Incidence of candidemia increased during the study period from 1.25 in 1999 to 3.06/10 000 patient-days/year in 2003. Overall, 40% of the fungemia episodes (74/182) were due to C.albicans, followed by C. parapsilosis(23%), C.glabrata (15%), C.tropicalis (9%) and other species (13%). Candidemia due to non-albicans species increased and this was apparently correlated with an increasing use of azoles for prophylaxis or empirical treatment. Conclusion: The study demonstrates a shift in the species of Candida causing fungemia in a medical and surgical ICU population during a 5 year period. The knowledge of the local epidemiological trends in Candida species isolated in blood cultures is important to guide therapeutic choices. and European studies [1,2]. Despite the availability of Background Candida is an increasing cause of bloodstream infection effective antifungal therapy, mortality in the last decade (BSI), causing significant mortality and morbidity, espe- remained high, ranging from 36% to 63% [3]. In terms of cially in non-neutropenic critically ill patients. Its overall species of Candida, recently, a shift towards non-albicans incidence raised fivefold in the past ten years and Candida species was reported by some authors especially in hema- spp. is currently between the fourth and the sixth most tological and transplanted patients [4-7]. Some of these common nosocomial bloodstream isolate in American emerging species has been correlated with increased viru- Page 1 of 6 (page number not for citation purposes) BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 lence [8], and sometimes, but not always, with increased oped a clinically and microbiologically documented can- mortality [9]. An increasing role for non-albicans species didemia were identified through a microbiological was also noticed in studies performed among ICU laboratory survey and data were recorded in an electronic patients, although the issue is somewhat controversial data base. The patients chart review was performed in [3,10-12]. order to identify clinically relevant episodes. Candidemia was defined as at least one positive blood culture yielding As shown by the SENTRY antimicrobial surveillance pro- Candida spp. in a patients with fever or other clinical signs gram [1], C. albicans is still the species most frequently iso- of infection. Nosocomial candidemia was defined as a lated in BSI [13,14], while in other groups of patients non- candidemia occurring at least 48 h after admission. Dur- albicans species have surpassed C.albicans as a cause of ing the study period there were no changes in microbio- candidemia. C.parapsilosis and C.tropicalis are isolated logical laboratory techniques. Candida species were more frequently than C.albicans in some European and isolated from blood using BACTEC 860 system (Becton Latin American centres [15]. Dickinson, INC, Sparks, MD). The species were identified using API-32C system (bioMerieux Vitek, Inc, St. Louis, A reduced antifungal susceptibility in non-albicans species MI). Frequencies and descriptives of demographic and and a correlation with routine fluconazole prophylactic clinical characteristics of the patient population were use has been suggested [5,16]. Intrinsic and emerging determined. resistance of non-albicans species to azoles actually repre- sents a major challenge for empirical therapeutic and pro- All patients were evaluable for the inclusion in this study. phylactic strategies [17]. The Chi-square-test or the Fisher Exact-test were used to compare categorical variables. Chi-square-test for trend We have performed a retrospective study of Candida spp. was used to estimate the relationship between albicans BSI in the ICU of the San Martino University Hospital, in and non-albicans isolation rates during the years of study. Genova, Italy, between 1999 and 2003, with the double In order to understand whether or not there was a correla- aim of understanding if any change was detectable in the tion between the distribution of the different Candida spe- distribution of the various Candida species as cause of BSI cies causing BSI and the use of fluconazole, the DDD of over the years and of estimating whether this change, if fluconazole per 1000 patient-days was calculated and existing, was correlated with the use of fluconazole for plotted against the type of isolated Candida on a yearly prophylaxis or therapy. basis. A logistic regression analysis between C. albicans rate and fluconazole usage was then performed.P values < Methods 0.05 were considered significant. The ICU of the San Martino General Hospital in Genova, Italy, is a mid-size medical and surgical unit with 18 beds All the patients consented to participation in the study and about 500 admissions per year. Patients who devel- and publication of the results. Table 1: Patient characteristics of 182 patients with candidemia. Characteristics C.albicans (n= 74) C. non albicans (n= 108) P value Male 41 70 NS Famale 33 38 NS Age (years) mean ± SD Range 58.4 ± 15.4 64.4 ± 11.4 <0.05 Central venous catheterization 65/74 99/108 NS Parenteral nutrition 38/74 64/108 NS Ventilator dependence mean ± SD Range 27.9 ± 23.6 32.6 ± 24.5 NS Apache II score mean ± SD Range 21.8 ± 7.4 25.6 ± 9.8 NS Underline disease Surgery 33/74 40/108 NS Solid tumor 11/74 35/108 <0.05 Solid organ transplant 8/74 10/108 NS Trauma 7/74 9/108 NS Hematological malignancies 6/74 10/108 NS Burn 4/74 3/108 NS Others 5/74 1/108 NS NS = Not significant Page 2 of 6 (page number not for citation purposes) BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 progressively dropped to 24%, with a median percentage year reduction of 13%, while the absolute number and the incidence of C.albicans did not vary during the years 3,50 2000 observed. The change was statistically significant (K = 3,00 24.452; p < 0.0001), although in absence of a rigorous lin- 2,50 ear trend. Non-albicans strains steadily increased through- 2,00 out the study period surpassing C.albicans in the second half of the study and raising from 21% to 67% (P = 0.01) 1,50 (Figure 2). The proportion of non-albicans species went 1,00 from 38% and 21% of total isolates in the years 1999– 0,50 2000 and then to 67%, 73% and 76% in 2001, 2002 and 2003, respectively. Among non-albicans strains, in 2002 0,00 0 Y 1999 Y 2000 Y 2001 Y 2002 Y 2003 Years observed we noted an increase of C.parapsilosis isolation rates, which reached 51% of total, while absence of C.tropicalis was noted in the years 2000–2001. The use of fluconazole for prophylaxis or therapy š■ Figure 1 inciden DDD's of ce of candidemia epis fluconazole × 100 pts/days odes/10 000 patient-days/year; š incidence of candidemia episodes/10 000 patient-days/year; increased four times during the study period. Logistic ■ DDD's of fluconazole × 100 pts/days. regression analysis showed a statistically significant corre- lation between the shift from albicans to non-albicans strains and the yearly fluconazole consumption. As Results shown in figure 3, an increase of 100 fluconazole DDDs In total, 182 episodes of candidaemia were identified, corresponded to a reduction in the isolation of C. albicans with an average incidence of 2.22 episodes/10 000 of 5%. patient-days/year (range 1.25–3.06 episodes), as shown in table 1. Incidence of candidemia increased during the Discussion Our study demonstrates a shift in the species of Candida study period from 1.25 in 1999 to 3.06 episodes/10 000 patient-days/year in 2003 (Figure 1). The demographic causing fungemia in a medical and surgical ICU popula- and clinical characteristics of the patients are summarized tion during a 5 year period. The proportion due to C. albi- in table 1. Patients with Candida non-albicans fungemia cans decreased whereas that due to other species, such as were significantly older. There were no significant differ- C. parapsilosis, C. tropicalis and C.glabrata, increased. Such ences in sex, age, central venous, catheterization, an increase in non-albicans species was also seen in retro- parenteral nutrition, ventilator dependence, Apache II spective reviews of candidemias [4,10,12,15,16]. In con- score and other underline disease. Non-albicans candi- trast to hematologic patients where a decrease in demia are significantly more frequent in patients with C.albicans infection resulted in a significant reduction in solid tumor. Overall, 40% of the episodes (74/182) were the incidence of candidemia [17], in our experience the due to C.albicans, followed by C. parapsilosis(23%), C.gla- overall incidence actually increased (Table 1; Figure 1). brata (15%), C.tropicalis (9%) and other species (13%) Traditionally, C.tropicalis has been the second and C.gla- (Table 2) The percentage of C. albicans which was isolated brata the third or fourth most common Candida species in about 60% of the episodes in the first years of study, recovered from blood [4,8]. In our study C.parapsilosis sur- Table 2: Incidence and distribution of candidemia in the years 1999 – 2003 in S. Martino Hospital ICU expressed in number and percentage of isolates. Polymicrobial infections were excluded. 1999 2000 2001 2002 2003 Total Number of isolates (percentage of species in the year) C.albicans 13 (62) 26 (79) 11 (33) 12 (27) 12 (24) 74 (40) C.parapsilosis 2 (9) 0 4 (12) 23 (51) 13 (26) 42 (23) C. glabrata 0 1 (3) 12 (36) 2 (4) 12 (24) 27 (15) C. tropicalis 5 (24) 0 0 7 (16) 5 (10) 17 (9) Othres (C.kruzei, C.guillermondii, C.lusitanae) 1 (5) 6 (18) 6 (19) 1 (2) 8 (16) 24 (13) Total candidemia 21 33 33 45 50 182 Incidence of candidemia/10 000 patient-days/year 1.25 2 2.05 2.74 3.06 2.22 Incidence of candidemia due to C.albicans/10 000 patient-days/year 0.84 1.58 0.66 0.73 0.73 0.91 Page 3 of 6 (page number not for citation purposes) Incidence of candidemia Fluconazole DDD's x 100 pts/days BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 C. albicans and fluconazole usage 0,9 0,8 0,7 0,6 expected 0,5 observed 0,4 0,3 0,2 0,1 0 500 1000 1500 2000 2500 fluconazole usage (DDD/year) L a Figure 2 lin bicans e plot is represen olates rate tation of s during Candida albicans the study period and Candida non- [DDDs per Figure 3 Cor reducti relation on of using log year] C. albicans istic r isolation r egression between percenta ates and fluconazole use ge Line plot representation of Candida albicans and Candida non- Correlation using logistic regression between percentage albicans isolates rates during the study period. reduction of C. albicans isolation rates and fluconazole use [DDDs per year]. passed the other non-albicans to become the most com- proportion of fungemias due to C. parapsilosis reflect noso- mon species isolated after C.albicans. The high incidence comial acquisition of this species. of C.parapsilosis candidemia has been previously reported in South American hospitals [15,18,19]. The role of C.par- In ICU, the role for the use of fluconazole remains contro- apsilosis as an exogenous acquired pathogen is well known versial, since fluconazole was demonstrated to reduce the and has been associated with parenteral alimentation and incidence of Candida infections in a particular group of intravascular devices [20], commonly used in critical high-risk patient population [26-28]. patients. Though limited by its retrospective nature, our study Several investigators postulated that the widespread use of focuses the attention on predominance of non-C.albicans fluconazole would have selected yeast species intrinsically isolates, usually less susceptible or intrinsically resistant to resistant or less sensitive to fluconazole, such as Candida fluconazole. kruzei, C. glabrata or C. tropicalis [21-23]. Some published reports confirmed this hypothesis, while others did not It is well known that positive blood culture for Candida [2,24,25]. At the San Martino Hospital, the incidence of spp. is a life threatening situation, requiring an empirical infections caused by most non-albicans Candida species antifungal treatment which should started with the appro- changed substantially during the study period. These priate agents as soon as possible. Therefore the knowledge changes occurred in concomitance with a four fold of the local epidemiological trends in Candida species iso- increase in the use of fluconazole. In our ICU, during lated in blood cultures is important to guide therapeutic 2001 and the following years, the usage of fluconazole at choices. dosage of 200–400 mg/day increased because of the changing in prophylactic strategy in high-risk patients, The data we have reported are based on records from the according to the efficacy demonstrated in various reports microbiology laboratory, and thus, have certain inherent [26,27]. A logistic regression analysis showed a statisti- limitations. Our study did not address specific risk factors, cally significant correlation between the shift from albi- which undoubtedly play a role in the selection of species cans to non-albicans strains and the yearly fluconazole causing fungemia. However, this type of study does reveal consumption, as shown in figure 2. However, it be recog- overall long-term trends that should be helpful to physi- nised that other events might have played a role in the cians and antibiotic use committees in establishing guide- selection of different species. For example, in the last 2 lines for the appropriate use of antifungal agents. years of the study, the increased proportion of candi- demias due to C.parapsilosis, a yeast species almost always Competing interests susceptible to fluconazole, is not readily explained by The author(s) declare that they have no competing inter- increased fluconazole use. It is likely that changes in the ests. Page 4 of 6 (page number not for citation purposes) albicans rate BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 8. Kornshian SV, Uwaydah AK, Sobel JD, Crane LR: Fungemia caused Authors' contributions by Candida species and Torulopsis glabrata in the hospitalized MB: Data acquisition, data/statistical analyses, drafting patient: frequency, characteristics and evaluation of factors the manuscript influencing outcome. Rev Infect Dis 1989, 11:379-390. 9. Blot S, Vandewoude K, Hoste E, Poelaert J, Colardyn F: Outcome in critically ill patients with candidal fungaemia: Candida albi- ER: Sample collection, drafting the manuscript, critically cans vs. Candida glabrata. J Hosp Infect 2001, 47:308-13. 10. Hope W, Morton A, Eisen DP: Increase in prevalence of nosoco- revising for medical content mial non-Candida albicans candidaemia and the association of Candida krusei with fluconazole use. J Hosp Infect 2002, AC: Sample collection, critically revising for medical con- 50:56-65. 11. McMullan R, McClurg R, Xu J, Moore JE, Millar BC, Crowe M, Hed- tent derwick S: Trends in the epidemiology of Candida blood- stream infections in Northern Ireland between January 1984 RF: Sample collection, critically revising for medical con- and December 2000. J Infect 2002, 45:25-28. 12. Al-Jasser A, Elkhizzi NA: Distribution of Candida species among tent bloodstream isolates. Saudi Med J 2004, 25:566-69. 13. Yamamura D, Rotstein C, Nicolle LE, Ioannou S: Candidemia at selected Canadian sites: results from the fungal disease reg- MPM: Data acquisition, data analyses istry 1992–1994. CMAJ 1999, 160:493-9. 14. Klingspor L, Tornqvist E, Johansson A, Petrini B, Forsum U, Hedin G: RR: Study design and conception, critically revising for A prospective epidemiological survey of candidemia in Swe- den. Scand J Infect Dis 2004, 36:52-55. medical content 15. Colombo AL, Nucci M, Salomao R: High rate of non-albicans can- didemia in Brazilian tertiary care hospitals. Diagn Microbiol Infect Dis 1999, 34:281-86. FBP: Study design, conception and coordination 16. Luzzati R, Amalfitano G, Lazzarini L, Soldani F, Bellino S, Solbiati M, Danzi MC, Vento S, Todeschini G, Vivenza C, Concia E: Nosocomial CV: Study design, conception and coordination candidemia in non-neutropenic patients at an Italian tertiary care hospital. Eur J Clin Microbiol Infect Dis 2000, 19:602-7. 17. Safdar A, Perlin DS, Armstrong D: Hematogenous infections due All authors contributed to writing of the final manuscript. to Candida parapsilosis: changing trends in fungemic patients at a comprehensive cancer center during the last four decades. Diagn Microbiol Infect Dis 2002, 44:11-6. All authors read and approved the final manuscript 18. 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Shorr AF, Chung K, Jackson WL, Waterman PE, Kollef MH: Flucona- species: SENTRY antimicrobial surveillance program in zole prophylaxis in critically ill surgical patients: a meta-anal- North America and Latin America, 1997–1998. Antimicrob Ag ysis. Crit Care Med 2005, 33:1928-1935. Chemother 2000, 44:747-51. 7. Shelenz S, Grandsen WR: Candidemia in a London teaching Hospital: analysis of 128 cases over a 7 years period. Mycoses 2003, 46:390-6. Page 5 of 6 (page number not for citation purposes) BMC Infectious Diseases 2006, 6:21 http://www.biomedcentral.com/1471-2334/6/21 Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2334/6/21/prepub Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." 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