Comparison of Species Distribution and Antifungal Resistance in Communit

26 Pages·2010·0.33 MB·English

AAC Accepts, published online ahead of print on 29 November 2010
Antimicrob. Agents Chemother. doi:10.1128/AAC.01079-10
Copyright © 2010, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.
1 AAC01079-10 Version 2
2 Candida Bloodstream Infections: Comparison of Species Distribution and Antifungal Resistance
3 in Community Onset and Nosocomial Isolates in the SENTRY Antimicrobial Surveillance
4 Program (2008-2009)
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6 Short running title: Community onset Candidemia lo
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8 Michael A. Pfaller1,

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9 Gary J. Moet1, tp
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10 Shawn A. Messer1, /a
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11 Ronald N. Jones1,2 .a
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13 Mariana Castanheira1,* rg
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16 1JMI Laboratories, North Liberty, Iowa 52317 USA il 1
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17 2Tufts University School of Medicine, Boston, Massachusetts 02111 USA 2
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20 *Corresponding author: Mariana Castanheira, Ph.D. s
21 JMI Laboratories t
22 345 Beaver Kreek Centre
23 Suite A
24 North Liberty, Iowa 52317 USA
25 Phone: [phone]
26 Fax: [phone]
27 Email: [email protected]
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28 ABSTRACT
29 Community-onset (CO) candidemia, defined as a positive blood culture taken at or within two
30 days of hospital admission, represents a distinct clinical entity associated with substantial
31 morbidity and mortality. Reference MIC results from the SENTRY Antimicrobial Surveillance
32 Program (2008-2009) were analyzed to compare the antifungal resistance patterns and species
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33 distributions from patients with CO and nosocomial bloodstream infections (BSI) in 79 medical o
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34 centers. Among 1,354 episodes of BSI, 494 (36.5%) were classified as CO and 860 (63.5%) as lo
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35 nosocomial in origin. More than 95% of the isolates from both BSI types were contributed by d
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36 Candida albicans (48.4%), C. glabrata (18.2%), C. parapsilosis (17.1%), C. tropicalis (10.6%) f
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37 and C. krusei (2.0%). C. albicans was more common in CO BSI (51.0%) compared to
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38 nosocomial BSI (46.9%), whereas C. parapsilosis and C. krusei, respectively, were more p
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39 common in nosocomial BSIs (18.1 and 2.7%) than in CO BSIs (15.4 and 0.8%). C. glabrata and a
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40 C. tropicalis, respectively, were comparable in both CO (18.4 and 10.5%) and nosocomial (18.1 s
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41 and 10.6%) episodes. Resistance to azoles (fluconazole, posaconazole and voriconazole) and .o
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42 echinocandins (anidulafungin, caspofungin and micafungin) was uncommon (<5%) in CO BSI /
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43 using recently established Clinical and Laboratory Standards Institute breakpoint criteria. A
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44 Resistance to echinocandins (anidulafungin [3.8%], caspofungin [5.1%], micafungin [3.2%]) and il
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45 azoles (fluconazole [7.7%], posaconazole [5.1%], voriconazole [6.4%]) was most prevalent ,
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46 among nosocomial BSI isolates of C. glabrata. CO candidemia is not uncommon and appears to 9

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47 be increasing worldwide due to changing healthcare practices. Although resistance to the y

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48 azoles and echinocandins remains uncommon among CO isolates, we demonstrate the e
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49 emergence of nosocomial occurrences of C. glabrata expressing resistance to both monitored
50 classes of antifungal agents.
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52 Keywords: SENTRY Program, community onset, Candida, resistance
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53 INTRODUCTION
54 Invasive candidiasis (IC; candidemia and other deep-seated infections including
55 disseminated candidiasis, endocarditis, meningitis, and hepatosplenic infection) is now widely
56 recognized as an important public health problem with considerable morbidity, mortality and
57 associated healthcare costs (1, 6, 11, 14, 17, 19, 23, 36, 44). Although much of the literature
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58 concerning IC has focused on nosocomial bloodstream infections (BSI), especially those o
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59 occurring in the intensive care unit (ICU) (3, 12, 13, 25, 27, 49), an increasing incidence of IC lo
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60 overall (35, 50), combined with data from the National Nosocomial Infection System survey, d
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61 which found a decline in the frequency of candidemia among ICU patients in the United States f
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62 (USA) (47), suggest that the burden of IC is shifting from the ICU to other healthcare settings.
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63 Hajjeh et al., (17) have shown that in 1998 through 2000, only 36% of Candida BSIs occurred in p
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64 the ICU, whereas 28% were community-onset (CO), an increase of almost 10% over that a
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65 reported in 1992 and 1994 (19). Subsequently, Sofair et al., (45) determined that 31% of 1,143 s
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66 cases of candidemia were CO infections (occurring ≤2 days after hospital admission). These .o
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67 observations led participants in a recent healthcare associated (HCA) infection summit to /
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68 conclude that clinicians should be aware of the potential for Candida to be a cause of BSI in A
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69 patients presenting to the emergency department (20). il
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70 Recently, Shorr et al., (42) found that CO candidemia represented a distinct clinical ,
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71 entity with substantial morbidity and mortality. Compared with other types (bacterial) of CO 9

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72 BSIs, patients with CO candidemia were more severely ill and likely to have been recently y

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73 discharged from an acute care hospital or admitted from another healthcare facility or nursing e
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74 home (42). Thus candidemia has spread beyond the confines of acute care hospitals and failure
75 to consider CO candidemia in at-risk subjects may have adverse consequences (42).
76 There are now several candidemia surveys that have provided estimates of the
77 frequency of CO compared to nosocomial cases in different geographic locations (1, 6, 10, 11,
78 17, 19, 22, 26, 32, 38, 41, 45, 48); however, very few have examined the distribution of species
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79 in these two settings and none provide data concerning the resistance profiles of CO versus
80 nosocomial isolates to the available systemically active antifungal agents.
81 The SENTRY Antimicrobial Surveillance Program (Antifungal objective), active since
82 1997, has previously reported that 25% of candidemia episodes (1,184) from an international
83 survey in 1997-1999 were non-nosocomial or CO (38). In the present study, we update this
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84 landmark information using the SENTRY Program database from 2008-2009, including o
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85 geographic variation in CO candidemia, species distribution indexed by CO and nosocomial lo
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86 status, and the associated resistance patterns for the contemporary echinocandin and azole d
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87 antifungal agents. f
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88 MATERIALS AND METHODS
89 Organisms and study sites: Between January 2008 and December 2009, a total of 2,085 BSI
90 isolates of Candida spp. from 79 medical centers throughout the world were submitted to JMI
91 Laboratories (North Liberty, Iowa, USA) for identification and reference antifungal susceptibility
92 testing with fluconazole, posaconazole, voriconazole, anidulafungin, caspofungin and
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93 micafungin. The isolates represented consecutive incident cases of patients with candidemia o
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94 treated at hospitals in the Asia-Pacific (16 centers; 51 isolates), European (25 centers; 750 n
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95 isolates), Latin American (10 centers; 348 isolates), and North American (28 centers; 936 d
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96 isolates) regions. CO BSI was defined as an infection detected (positive blood culture) at or f
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97 within two days of hospital admission; whereas nosocomial BSI was defined as an infection not

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98 present on admission and having onset more than two days beyond hospital admission. p
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99 Although some authors divide CO BSI into healthcare associated (HCA) infections (healthcare- a
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100 associated risk factors including recent hospitalization, nursing home, indwelling medical device, s
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101 chemotherapy, dialysis) and community-acquired (CA) infections (no HCA risk factors) (6, 18, .o
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102 24), most studies of CO candidemia do not (17, 42, 45) and the SENTRY Program database /
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103 does not allow for that level of discrimination. Among the more than 2,000 episodes of BSI in A
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104 the present study, the time of candidemia onset (CO versus nosocomial) was provided for 1,354 il
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105 (65%) patient epidsodes. ,
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106 The isolates were identified by standard methods and stored as water suspensions until 1
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107 processed in the study. Before testing, each isolate was passaged on Sabouraud dextrose agar y

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108 (Remel, Lenexa, Kansas, USA) and CHROMagar (Becton Dickinson, Sparks, Maryland, USA) e
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109 to ensure purity and viability.
110 A total of 12 NOS isolates of C. glabrata for which caspofungin MIC values were ≥0.5
111 µg/ml were further characterized for the presence or absence of mutations in the hot spot (HS)
112 regions of fks1 and fks2 as described previously (4, 28, 37).
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113 Antifungal susceptibility testing: All Candida spp. isolates were tested for susceptibility to the
114 echinocandins and triazoles using Clinical and Laboratory Standards Institute (CLSI) broth
115 microdilution methods (7). MIC results for anidulafungin, caspofungin, micafungin and
116 fluconazole were read following 24-h incubation, whereas MIC results for posaconazole and
117 voriconazole were read after 48-h incubation. In all instances the MIC values were determined
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118 visually as the lowest concentration of drug that caused a significant diminution (≥50% o
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119 inhibition) of growth below the control level (7). We used the recently revised CLSI clinical lo
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120 breakpoints (CBP) to identify strains of Candida resistant to the echinocandins and fluconazole d
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121 (33, 34, 37): anidulafungin, caspofungin and micafungin MICs at >0.5 µg/ml were considered f
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122 resistant for C. albicans, C. tropicalis, and C. krusei and MIC values at >4 µg/ml were
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123 considered resistant for C. parapsilosis; anidulafungin and caspofungin MIC values at >0.5 p
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124 µg/ml and micafungin MICs >0.12 µg/ml were declared resistant for C. glabrata; fluconazole a
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125 MIC values of >4 µg/ml were categorized as resistant for C. albicans, C. parapsilosis, and C. s
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126 tropicalis and MICs at >32 µg/ml were considered resistant for C. glabrata. All isolates of C. .o
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127 krusei were considered as resistant to fluconazole. The CLSI resistance breakpoint for /
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128 voriconazole (MIC, >2 µg/ml) was also an indicator of resistance for posaconazole tested A
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129 against all species (8, 39). Quality control was performed by testing CLSI-recommended strains il
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130 C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 (8). ,
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131 RESULTS AND DISCUSSION
132 Frequency of CO candidemia in three geographic regions: Among the 1,354 episodes of
133 candidemia, 494 (36.5%) were CO and 860 (63.5%) were nosocomial (Table 1). The frequency
134 of CO candidemias was considerably higher in North America (50.8%) compared to that
135 observed in Europe (22.4%) and Latin America (28.0%). In each region, however, the frequency
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136 of CO candidemia increased from 2008 to 2009 (data not shown). o
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137 These data may be compared to that of 12 different surveys spanning the last 17 years n
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138 and in several different geographic settings (Table 2). Whereas some of these studies identified d
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139 CA and HCA BSIs, most used the definition for CO defined for the present study, without f
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140 differentiation of CA and HCA. Those who identified CA, HCA and nosocomial BSIs found that

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141 patients presenting with HCA BSI were similar to those with nosocomial infections, whereas p
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142 those with CA infections included patients with intravenous drug use, gastrointestinal disorders a
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143 and diabetes (6). Although the SENTRY program does not collect clinical or risk factore data, s
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144 we assume that the vast majority of the CO BSI patients in this survey have HCA risk factors. .o
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145 Although the variation in the frequency of CO candidemia was considerable (Table 2), /
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146 most of these studies reported that greater than 10% of Candida BSI may be categorized as CO A
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147 with the highest proportions detected in the USA. Within the USA, it is notable that the CO il
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148 candidemia frequency has increased from 16 to 20% in 1992-1993 (19, 48), to 31% in 1998- ,
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149 2000 (45) to 50.8% in the present study. Whereas the later figure seems high, the trend in the 1
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150 U.S. is unmistakable and supports the concerns voiced by Kollef et al (20) and Shorr et al (42). y

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151 As cost containment pressures continue to mount and hospital discharges to secondary e
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152 care facilities (including home care) are expedited, clearly the boundaries between nosocomial
153 and CO infection may no longer be valid (9, 10, 18, 24, 42, 43). In the USA, increasing numbers
154 of patients are being managed in the community with risk-increasing procedures such as
155 chemotherapy, dialysis, parenteral nutrition, parenteral antimicrobial agents, and indwelling
156 catheters (9, 20, 42, 45). Given these considerations, it is interesting that the proportion of CO
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157 candidemia in non-USA locations such as Taiwan (3%), Brazil (9%) and Spain (11%) are
158 considerably lower than in the USA (Table 2), possibly due to a difference in outpatient central
159 venous catheter use and the increasing practice in the USA of the management of various
160 chronic diseases at home rather than in the hospital (1, 17, 45).
161 Species distribution between CO and nosocomial BSI: The 1,354 Candida BSI isolates
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162 included: 655 (48.4%) C. albicans, 247 (18.2%) C. glabrata, 232 (17.1%) C. parapsilosis, 143 o
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163 (10.6%) C. tropicalis, 27 (2.0%) C. krusei, and 50 (3.7%) miscellaneous species including C. nlo
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164 dubliniensis (16 isolates), C. guilliermondii (eight isolates), C. kefyr (six isolates), C. famata d
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165 (three isolates), C. lipolytica (three isolates), C. rugosa (two isolates), C. sake (two isolates), C. f
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166 pelliculosa (two isolates), and one isolate each of C. lambica, C. utilis, C. haemulonii, C.
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167 norvegensis, and C. inconspicua. p
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168 Comparing the frequency of isolation of different species by CO and nosocomial BSI, we a
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169 found only minor differences (Table 3). C. albicans was more common among CO infections, s
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170 while C. parapsilosis and C. krusei were more common among nosocomial candidemias. By .o
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171 comparison most of the other surveys where pathogen distribution was reported showed that C. /
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172 albicans to be more common in nosocomial BSI and C. parapsilosis to be more common in CO A
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173 infections (Table 3). Although it has been speculated that the prominence of C. parapsilosis as a il
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174 cause of candidemia in CO infections may be due to the exogenous introduction of this skin ,
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175 commensal into the bloodstream via long-term vascular catheters, there is little objective 9

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176 evidence to support this hypothesis (6, 45). y

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177 Differences in antifungal agent susceptibilities among isolates from CO versus nosocomial BSIs: e
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178 As shown in Table 4, no resistance to anidulafungin, caspofungin, micafungin, posaconazole or
179 voriconazole was detected among CO isolates of C. albicans, C. parapsilosis, C. tropicalis or C.
180 krusei. In fact, the only resistance to fluconazole detected in these four species was observed in
181 isolates of C. parapsilosis. Among CO isolates of C. glabrata, resistance to anidulafungin,
182 caspofungin and all three triazoles was found in a small number of isolates.
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183 Among the nosocomial isolates of C. albicans, one isolate (patient in Germany) was
184 resistant to all three echinocandins, whereas no resistance to the azoles was detected. None of
185 the nosocomial isolates of C. parapsilosis or C. tropicalis were resistant to the echinocandins;
186 however 5.8% of the nosocomial C. parapsilosis and 3.3% of the nosocomial C. tropicalis were
187 resistant to fluconazole. The finding of resistance to fluconazole but not to the echinocandins
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188 among CO and nosocomial isolates of C. parapsilosis should be noted in light of the o
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189 recommendation of the Infectious Diseases Society of America that infection with this species lo
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190 should be treated with either an azole or amphotericin B (lipid formulation) rather than an d
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191 echinocandin (30). This recommendation may inadvertently result in increased drug pressure on f
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192 C. parapsilosis with a subsequent increase in azole resistance. Thus fluconazole resistance
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193 among C. parapsilosis must be recognized as a possibility and this species should be followed p
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194 closely in the future. Cross resistance between fluconazole and voriconazole was noted in 2.2% a
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195 of C. tropicalis isolates of nosocomial origin. Overall, fluconazole resistance was observed in s
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196 2.6% of CO isolates, but 5.8% of nosocomial isolates. Along these lines it should be noted that .o
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197 C. parapsilosis and C. tropicalis accounted for 29% of all fluconazole resistance in this survey. /
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198 Resistance was infrequent among nosocomial isolates of C. krusei where only two isolates A
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199 resistant to caspofungin were detected. il
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200 Resistance to both azoles and echinocandins was most prominent in C. glabrata ,
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201 isolates, with the highest resistance rates to anidulafungin (3.8%), caspofungin (5.1%), 9

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202 micafungin (3.2%), fluconazole (7.7%), posaconazole (5.1%) and voriconazole (6.4%) found in y

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203 the isolates of nosocomial origin (Table 4). A total of 12 nosocomial isolates of C. glabrata e
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204 (caspofungin MIC, ≥0.5 µg/ml) were selected to be tested for the presence of fks mutations, five
205 were classified as intermediate (MIC, 0.5 µg/ml) and several were classified as resistant (MIC,
206 ≥1 µg/ml) to caspofungin. None of the isolates for which the caspofungin MIC was 0.5 µg/ml
207 contained a fks mutation, while six of the seven resistant isolates were shown to have a
208 mutation in either fks1 or fks2 (Table 5). Of the six isolates shown to have fks mutations, five
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209 were categorized as resistant and one as intermediate to anidulafungin and micafungin (Table
210 5), confirming the utility of the resistant CBP.
211 Other investigators have noted the propensity of C. glabrata to mutate to a multidrug-
212 resistant (MDR) phenotype in vivo in a single patient (5, 21), and have suggested that
213 expression of resistance to echinocandins and other classes of antifungal agents in C. glabrata
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214 is facilitated by the haploid nature of the genome (5, 40). Our observations support the potential o
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215 emergence of an MDR phenotype among nosocomial isolates of C. glabrata with cross nlo
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216 resistance in azole and echinocandin classes. Fear of azole resistance and the generally d
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217 excellent wild-type susceptibility of most species of Candida to the echinocandins has driven the f
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218 use of echinocandins for the treatment of IC (30). The increase of MDR C. glabrata strains has
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219 become a serious concern expressed by several investigators (5, 40, 46) and argues for p
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220 continued close resistance surveillance and the increased application of standardized antifungal a
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221 susceptibility testing. s
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222 The increasing recognition of CO candidemia raises the issue of whether an antifungal .o
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223 therapy should be added to the first-line empirical antimicrobial regimen for patients presenting /
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224 with sepsis (9, 20, 42, 45). It is now evident that a delay in initiating antifungal therapy in the A
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225 critically ill patient is associated with compromised outcomes (an increase in mortality of 8% for il
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226 each hour in which appropriate therapy is delayed), excessive costs of hospitalization, and ,
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227 potentially devastating complications such as endocarditis, endophthalmitis, osteomyelitis, and 9

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228 disseminated candidiasis (2, 15, 16, 23, 29, 31, 42). Shorr et al., (42) has demonstrated that the y

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229 risk-adjusted mortality rate (28.3%), length of stay in hospital (13.7 days) and attributable cost e
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230 ($30,219 per episode) was greater for CO candidemia patients compared with that for patients
231 with CO bacteremia. Ideally the decision to initiate antifungal therapy should be guided by rapid
232 diagnostic markers and/or risk stratification schema in order to maximize benefits and reduce
233 the risk of drug toxicity and resistance development (9, 20). In the absence of such diagnostic
234 aids, it seems reasonable to consider treating high-risk patients with clinical evidence of sepsis
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