Trends in Antifungal Susceptibility of Candida spp. Isolated

Trends in Antifungal Susceptibility of Candida spp. Isolated

Trends in Antifungal Susceptibility of Candida spp. Isolated from Pediatric and Adult Patients
with Blood Stream Infections: SENTRY Antimicrobial Surveillance Program, 1997-2000
Poster #115

M.A. Pfaller1, 3*, D.J. Diekema1, 2, R.N. Jones4, S.A. Messer1, R.J. Hollis1, and the SENTRY Participants Group
Departments of Pathology1, Medicine2 and Epidemiology3, University of Iowa College of Medicine and College of Public Health, Iowa City, Iowa and The JONES Group /JMI Laboratories, North Liberty, Iowa 4

ABSTRACT

MATERIALS AND METHODS - CONTD

RESULTS AND DISCUSSION - CONTD

From 1/1/97 through 12/31/00, 2,047 blood stream infections (BSI) due to Candida spp. were
reported from SENTRY hospitals in the United States (U.S.), Canada, Latin America and
Europe. C. albicans (54%), C. glabrata (16%), C. parapsilosis (15%), and C. tropicalis (10%)
were the most common species. Among the four different age groups ( 1 yr, 2-15 yr, 16-64 yr,
and 65 yr) C. albicans was the most common, causing 60%, 55%, 55% and 50% of
infections, respectively. C. glabrata accounted for 17% - 23% of BSI in the 16-64 yr and 65 yr
age groups versus only 3% of BSI in the two younger age groups. C. parapsilosis (21-24%) and
C. tropicalis (7-10%) were more common than C. glabrata in the 1 yr and 2-15 yr age groups.
Antifungal susceptibility testing using NCCLS microdilution and Etest (amphotericin B) methods
revealed interesting trends in susceptibility across age groups and among the various species.
Isolates of Candida spp. from patients 1 yr were more susceptible to fluconazole,
itraconazole and amphotericin B than isolates from the 65 yr age group. None of the C.
glabrata isolates from the 1 yr age group were resistant to fluconazole compared to 5-9% of
isolates from the 16-64 yr and 65 yr age groups. Isolates of C. tropicalis from patients 1 yr
were more susceptible to flucytosine (MIC90, 0.5 g/ml; 0% resistant) than those isolated from
patients 65 yr (MIC90, 32 g/ml; 11% resistant). The investigational triazoles, posaconazole,
ravuconazole, and voriconazole, were all highly active against all species of Candida from all
age groups. Finally, isolates of C. albicans were more susceptible to amphotericin B (MIC90, 1
g/ml) than were
C. glabrata (MIC90, 4 g/ml) and C. krusei (MIC90, 8 g/ml) suggesting that BSI due to C.
glabrata and C. krusei may require higher doses of amphotericin B. These data demonstrate
differences in the species distribution of pathogens and in antifungal resistance among the
pediatric and adult age groups. Ongoing surveillance will enhance efforts to limit the extent of
antifungal resistance in various age groups.

products (bioMerieux, St. Louis, MO) as recommended by the manufacturer or by conventional methods as
required (22). Isolates were stored as suspensions in water or on agar slants at ambient temperature until
needed.

the NCCLS microdilution method when applied to a subset of 1,142 isolates (Table 5). Notably, 24.4% of C. glabrata
isolates and 47.6% of C. krusei isolates appeared resistant with MICs 2 g/ml when tested by the NCCLS method. As
reported previously, the agreement between Etest and broth microdilution results was excellent, 98.7% within 2 log 2
dilutions (12).

INTRODUCTION
The proliferation of antimicrobial resistance surveillance programs has provided useful information regarding
resistance trends and pathogen distribution among various countries and types of infection (7). Although most
surveillance programs have focused on bacterial pathogens, several have provided information on invasive
candidiasis as well. The population based surveillance study conducted by the Centers for Disease Control
(CDC) (5), the NEMIS Study (2, 9, 16, 19), the SCOPE study (4) and the SENTRY program (3, 11, 13-15) have
all contributed information regarding species distribution and antifungal susceptibilities of blood stream infection
(BSI) isolates of Candida spp. over the decade 1990-2000. Although the CDC and NEMIS studies provided
some information on Candida BSI in both adult and neonatal populations, none of the Candida surveillance
studies have provided information on the distribution of species and antifungal susceptibility profiles of BSI
pathogens stratified according to the age of the patient.
The SENTRY Antifungal Surveillance Program has been active continuously since January 1997 and has
reported antifungal susceptibility and pathogen data for more than 2,000 episodes of Candida BSI in 72 medical
centers internationally (3, 11, 13-15). Participating centers submit isolates representing consecutive episodes of
BSI each month along with limited demographic data including age, sex, medical service and ICU stay. In the
present report, we examine the frequency of pathogen occurrence and antifungal susceptibility profiles of the
various species against both licensed and investigational antifungal agents as they occur in four different age
groups: 1 yr, 2-15 yr, 16-64 yr, and 65 yr. The BSI isolates include all those submitted to the central
monitoring laboratory from North America, Latin American and European SENTRY participants during the fouryear period from 1997-2000.

MATERIALS AND METHODS
Study Design: The SENTRY Program was established in 1997 to monitor the predominant pathogens and
antimicrobial resistance patterns of nosocomial and community acquired infections via a broad network of
sentinel hospitals categorized by geographic location and size (3, 11, 13-15). The present report focuses on BSI
due to Candida spp. from US, Canadian, Latin American, and European sites. BSI due to Candida spp. were
reported from 32 monitored medical centers in the US, 23 in Europe, nine in Latin America, and seven in
Canada over the four-year period from January, 1997 through December, 2000.
Each participant hospital contributed results (organism identification, date of isolation, and hospital location) for
consecutive blood culture isolates (one isolate per patient) of Candida spp. judged to be clinically significant by
local criteria, detected in each calendar month during the study period. All isolates were stored on agar slants
and sent on a regular basis to the University of Iowa College of Medicine (Iowa City, IA) for storage and further
characterization by reference identification and susceptibility testing (8, 22).
Organism Identification: All fungal blood culture isolates were identified at the participating institutions by the
routine method in use at each laboratory. Upon receipt at the monitoring site, the isolates were subcultured onto
potato dextrose agar (Remel, Lenexa, KS) and CHROMagar Candida medium (Hardy Laboratories, Santa
Maria, CA) to ensure viability and purity. Confirmation of species identification was performed with Vitek and API

Susceptibility Testing: Antifungal susceptibility testing of isolates of Candida spp. was performed by the
reference broth microdilution method described by the National Committee for Clinical Laboratory Standards
(NCCLS) (8). Susceptibility of isolates to amphotericin B was determined using Etest (AB BIODISK, Solna,
Sweden) and RPMI 1640 agar with 2% glucose (Remel, Lenexa, KS) as described previously (12). In addition,
a subset of 1142 isolates was also tested against amphotericin B using the NCCLS broth microdilution method.
Standard powders of fluconazole (Pfizer, Inc., New York, NY), voriconazole (Pfizer), ravuconazole (BristolMyers Squibb, Wallingford, CT), posaconazole (Schering-Plough, Kenilworth, NJ), itraconazole (Janssen,
Beerse, Belgium), amphotericin B and flucytosine (Sigma, St. Louis, MO) were obtained from their respective
manufacturers. Following incubation at 35C for 48 h, the MICs of fluconazole, voriconazole, ravuconazole,
posaconazole, itraconazole, and 5FC were read as the lowest concentration at which a prominent decrease in
turbidity relative to the growth control well was observed (8). Amphotericin B MICs determined by Etest were
read after 48 h incubation at 35C and were determined to be at 100% inhibition of growth where the border of
the elliptical inhibition zone intercepted the scale on the strip edge (12). Amphotericin B MICs determined by the
NCCLS method were read at 100% inhibition of growth. Quality Control (QC) was ensured by testing the
NCCLS (8) recommended strains, C. krusei ATCC 6258 and C. parasilosis ATCC 22019.
Interpretive criteria for susceptibility to fluconazole (susceptible, 8 g/ml), itraconazole (susceptible,
0.12 g/ml), and 5FC (susceptible, 4 g/ml) were those published by Rex et al. (17) and the NCCLS (8).
These breakpoints apply to all Candida spp. (including C. glabrata) with the exception of C. krusei which is
considered inherently resistant to fluconazole regardless of the MIC value obtained (8). The investigational
triazoles, posaconazole, voriconazole and ravuconazole, have not been assigned interpretive breakpoints. For
purposes of comparison, and because preliminary pharmacokinetic data indicates that achievable serum levels
for these agents may range from 2 to 6 g/ml depending on the dosing regimen (20), we have employed a
susceptible breakpoint of 1 g/ml for all three agents. Interpretive criteria have not yet been defined for
amphotericin B; however for comparison purposes we have determined the percentage of isolates inhibited by
2 g/ml to be resistant in this surveillance study.

TABLE 1: Species Distribution of Candida Blood Stream Isolates
by Age Group (yr): SENTRY, 1997 - 2000

Species

Frequency of Occurrence of Blood Stream Pathogens: During the four-year study period (January 1997 to
December 2000), a total of 2,047 BSI due to Candida spp. were reported by SENTRY participants. Table 1
compares the frequencies of occurrence of the seven most commonly isolated pathogens during this time
period. These seven species accounted for 99% of all Candida BSI reported from SENTRY study sites. Overall,
the rank order of the top five species was unchanged from year-to-year. These five species (C. albicans,
C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) accounted for 97% of all Candida BSI.

C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
C. guilliermondii
C. lusitaniae
Candida spp.

Comparing the frequency of isolation of different species by age group, we found an identical rank order in the
16-64 yr and 65 yr age groups with C. albicans > C. glabrata > C. parapsilosis > C. tropicalis > C. krusei. The
rank order of species in the 1 yr and 2-15 yr age groups was considerably different from that of the two older
age groups. The infant and pediatric age groups were dominated by C. albicans and C. parapsilosis and very
few infections were due to C. glabrata and C. krusei. Although C. albicans was the most common species in all
age groups, the percentage of BSI due to this species decreased from 60% in the 1 yr group to 50% in the
65 yr group. C. glabrata was the second most common species overall causing 17-23% of BSI in the 16-64 yr
and 65 yr age groups. In contrast, C. glabrata accounted for only 3% of BSI in 1 yr and 2-15 yr age groups
and was surpassed by both C. parapsilosis (21-24%) and C. tropicalis (7-10%).

% of Isolates by Age Group (Yr, No. Tested)
2 - 15
16 - 64
65
Total
(124)
(1028)
(622)
(2047)

60
3
24
7
3
2
1

55
3
21
10
4
2
2
3

55
17
12
11
2
1
1
1

50
23
12
10
2
1
1
1

54
16
15
10
2
1
1
1

Antifungal
Agent

N

C. albicans
(1114)

Fluconazole
Itraconazole
Posaconazole
Ravuconazole
Voriconazole

C. glabrata
(334)

a

Antifungal
Agents
Fluconazole

Age
No
Group(Yr) Tested 0.12
1
273
18
2-15
124
14
16-64
1028
14
65
622
16
Itraconazole
1
273 84b
2-15
124 78b
16-64
1028 70b
65
622 67b
Amphotericin B
1
273
1
2-15
124
1
16-64
1028
0.3
65
622
1
Flucytosine
1
273
60
2-15
124
68
16-64
1028
60
65
622
69

Among the licensed and investigational azoles, fluconazole, posaconazole, ravuconazole, and voriconazole
were all highly active (96-100% susceptible) against C. albicans, C. tropicalis, C. guilliermondii, and C. lusitaniae
regardless of the age group (Table 3). Although fluconazole appeared less active against isolates of C. glabrata
in the 1 yr age group (63% susceptible) compared with those from the 16-64 yr (70% susceptible) and 65
yr (73% susceptible) age groups, there were no highly resistant (MIC, 64 g/ml) isolates in the 1 yr group
compared to 5-9% of isolates from the two older groups. Itraconazole was less active than all of the other azoles
against all species with the exception of C. albicans. Consistent with previous reports (3, 10, 13, 15), all three
investigational triazoles were highly active against all species from all age groups with the exception of C.
glabrata isolates from the 16-64 yr group where 88-90% of isolates were susceptible at 1 g/ml to the three
agents compared to 95-100% of isolates from all other age groups.

0.25
59
48
55
50
97
94
84
83
3
3
2
2
80
80
76
87

Fluconazole susceptible breakpoint, < 8 g/ml (NCCLS, M27-A) b Itraconazole susceptible breakpoint, < 12 g/ml (NCCLS, M27-A) c Flucytosine susceptible breakpoint, < 4 g/ml (NCCLS M27-A) 2 - 15 50/90 %S N 163 0.25/0.5 0.3/0.12 0.03/0.06 0.01/0.03 0.01/0.03 100 95 100 100 100 68 0.25/0.5 0.03/0.12 0.03/0.06 0.01/0.03 0.01/0.03 Fluconazole Itraconazole Posaconazole Ravuconazole Voriconazole 8 8/1/0.25/0.12/0.5/- 63 13 100 100 100 4 2/0.25/0.25/0.12/0.06/- C. parapsilosis (301) Fluconazole Itraconazole Posaconazole Ravuconazole Voriconazole 66 0.5/2 0.12/0.25 0.03/0.12 0.03/0.06 0.03/0.06 100 80 100 100 100 C. tropicalis (209) Fluconazole Itraconazole Posaconazole Ravuconazole Voriconazole 20 0.5/1 0.12/0.25 0.03/0.12 0.03/0.06 0.06/0.12 100 70 100 100 100 99 97 98 98 99 16 - 64 50/90 %S N N Antifungal resistance surveillance programs provide important information, both for the development of empiric antifungal therapy recommendations and for design of programs to control antifungal resistance. The present study demonstrates differences in the spectrum of pathogens and in antifungal susceptibility among the pediatric and adult age groups in the SENTRY Program. > 65
50/90

%S

569 0.25/0.5
0.03/0.12
0.03/0.06
0.01/0.03
0.01/0.03

98
95
99
99
99

314 0.25/0.5
0.03/0.12
0.03/0.06
0.01/0.03
0.01/0.03

99
97
99
99
98

75
100
100
100
100

180

70 142 8/16
8
0.5/2
88
0.5/1
89
0.25/0.5
90
0.12/1

73
6
97
97
95

27 0.5/4
0.12/025
0.06/0.12
0.03/0.06
0.03/0.06

100
63
100
100
100

125 0.5/2
0.12/0.25
0.06/0.12
0.03/0.06
0.03/0.06

13 0.5/2
0.12/0.5
0.03/0.12
0.03/0.12
0.03/0.06

100
62
100
100
100

113

5

16/0.25/0.5/0.25/0.12/-

20
40
100
100
100

23

8/32
0.5/2
0.5/2
0.25/2
0.12/1

100
64
100
100
100

83

96
68
99
97
97

63

0.5/2
0.12/0.5
0.03/0.12
0.03/0.12
0.03/0.12

C. krusei
(39)

Fluconazole
Itraconazole
Posaconazole
Ravuconazole
Voriconazole

C. guilliermondii
(14)

Fluconazole
Itraconazole
Posaconazole
Ravuconazole
Voriconazole

6

2/0.25/0.12/0.25/0.06/-

100
0
100
75
100

2

2/0.12/0.060.03/0.03/-

100
50
100
100
100

5

2/0.25/0.06/0.06/0.06-

100
40
100
100
100

C. lusitaniae
(18)

Fluconazole
Itraconazole
Posaconazole
Ravuconazole
Voriconazole

7

0.25/0.12/0.03/0.03/0.03/-

100
71
100
100
100

2

0.25/0.06/0.03/0.03/0.01/-

100
50
100
100
100

6

0.25/0.12/0.03/0.03/0.01/-

100 3
50
100
100
100

32/64
9
0.5/2
0
0.25/0.5 100
0.25/0.5 95
0.25/1 100

0.5/2
0.12/0.25
0.06/0.12
0.03/0.06
0.03/0.12

100
63
100
100
100

0.5/1
0.12/0.2
0.03/0.25
0.03/0.12
0.03/0.12

100
67
100
100
100

11 32/64
1/2
0.25/0.5
0.5/0.5
0.5/1
1

9
9
100
100
100

>64
4
>8
>8
>8
0.5/0.25/0.03/0.03/0.01/-

0
0
0
0
0
67
33
100
67
100

Most common Candida BSI pathogens by age group
1 yr:
C. albicans (60%), C. parapsilosis (24%)
2-15 yr
C. albicans (55%), C. parapsilosis (21%)
16-64 yr:
C. albicans (55%), C. glabrata (17%)
65 yr:
C. albicans (50%), C. glabrata (23%)
Decreased susceptibility to fluconazole, itraconazole, and amphotericin B was most

prominent among isolates of C. glabrata and C. krusei from all age groups.

The investigational triazoles, posaconazole, ravuconazole, and voriconazole were all

highly active against all species of Candida from all age groups.

Ongoing surveillance is essential and will enhance efforts to limit the extent of resistance

among the various age groups.

ACKNOWLEDGEMENTS
Linda Elliott provided excellent support in the preparation of this manuscript. This study was supported in part by research grants from Bristol-Myers Squibb (SENTRY),
Pfizer Pharmaceuticals, and Schering-Plough Research Institute. We express our appreciation to all SENTRY site participants. Participants contributing data/isolates to
the study included: The Medical Center of Delaware, Wilmington, DE, (L. Steele-Moore); Clarion Health Methodist Hospital, Indianapolis, IN, (G. Denys); Henry Ford
Hospital, Detroit, MI (C. Staley); Summa Health System, Akron, OH (J.R. Dipersio); Good Samaritan Regional Medical Center, Phoenix, AZ (M. Saubolle); Denver
General Hospital, Denver, CO, (M.L. Wilson); University of New Mexico Hospital, Albuquerque, NM, (G.D. Overturf); University of Illinois at Chicago, Chicago, IL, (P.C.
Schreckenberger); University of Iowa Hospitals and Clinics, Iowa City, IA, (R.N. Jones); Creighton University, Omaha, NE, (S. Cavalieri); Froedtert Memorial Lutheran
Hospital-East, Milwaukee, WI, (S. Kehl); Boston VAMC, Boston, MA (S. Brecher); Columbia Presbyterian Medical Center, New York, NY, (P. Della-Latta); Long Island
Jewish Medical Center, New Hyde Park, NY, (H. Isenberg); Strong Memorial Hospital, Rochester, NY, (D. Hardy); Kaiser Regional Laboratory, Berkeley, CA, (J.
Fusco); Sacred Heart Medical Center, Spokane, WA, (M. Hoffmann); University of Washington Medical Center, Seattle, WA, (S. Swanzy); Barnes-Jewish Hospital, St.
Louis, MO, (P.R. Murray); Parkland Health & Hospital System, Dallas, TX, (P. Southern); The University of Texas Medical School, Houston, TX, (A. Wanger);
University of Texas Medical Branch at Galveston, Galveston, TX (B. Reisner); University of Louisville Hospital, Louisville, KY, (J. Snyder); University of Mississippi
Medical Center, Jackson, MS, (J. Humphries); Carolinas Medical Center, Charlotte, NC, (S. Jenkins); University of Virginia Medical Center, Charlottesville, VA, (K.
Hazen); University of Alberta Hospital, Edmonton, Alberta, CAN,( R. Rennie); Health Sciences Centre, Winnipeg, Manitoba, CAN, ( D. Hoban); Queen Elizabeth II
Health Sciences Centre, Halifax, Nova Scotia,CAN, (K. Forward); Ottawa General Hospital, Ottawa, Ontario, CAN, (B. Toye); Royal Victoria Hospital, Montreal,
Quebec, CAN, (H. Robson); Microbiology Laboratory C.E.M.I.C., Buenos Aires, Argentina, (J. Smayvsky); Hospital San Lucas and Olivos Community Hospital, Buenos
Aires, Argentina, (J.M. Casellas/G. Tome); Lamina LTDA, Rio De Janeiro, Brazil, (J.L.M. Sampaio); Unidad De Microbiologia Oriente, Santiago, Chile, (V. Prado);
Hospital Clinico Universidad Catolica, Santiago, Chile, (E. Palavecino); Corp. Para Investig Biologicas, Medellin, Columbia, (J.A. Robledo); Instituto Nacional de la
Nutricion, Mexico City, Mexico, (J.S. Osornio); Laboratorio Medico Santa Luzia, Florianopolis,Brazil; Instituto DE Doencas Infecciosas-IDIPA, Sao Paulo, Brazil, (H.S.
Sader); Centro Medico De Caracas, San Bernadino, Caracas, (M. Guzman); Chru De Lille Hopital Calmette, Lille, Cedex, France (M. Roussel-Delvallez); National
University of Athens Medical School, Athens, Greece (N. Legakis); Sheba Medical Center, Tel-Hashomer, Israel (N. Keller); University Hospital V. de Macarena,
Sevilla, Spain (E.J. Perea); Hospital de Bellvitge, Barcelona, Spain (J. Linares); Hospital Ramon y Cajal, Madrid, Spain (R. Canton); Unite de Bacteriologie, Luasanne,
Switzerland (F. Praplan); Hacettepe Universitaesi Tip Fakultesi, Ankara, Turkey (D. Gur); Universita degli Studi di Genova, Genova, Italy (E. Debbia);Azienda
Policlinico Univ Catania, Catania, Italy (G. Nicoletti); Policlinico Agostino Germelli, Roma, Italy (G. Fadda); Universitat Bonn, Bonn, Germany (K.P. Schaalb); J.-W.Goethe Universitat, Frankfurt, Germany (P. Shah); University Hospital, Linkoping, Sweden (H. Hanberger); Sera & Vaccines Central Research Lab, Warsaw, Poland
(W. Hryniewicz); St. Thomas Hospital, London, United Kingdom (G. French); Univ Libre de bruxelles-Hopital Erasme, Burssels, Belgium (M.J. Struelens); Marmara
Universitesi Tip Fakultesi, Istanbul, Turkey (V. Korten).

REFERENCES

% susceptible at MIC of < 8 g/ml (fluconazole), < 0.12 g/ml (itraconazole) or < 1 g/ml (all other agents) 1. TABLE 4: Antifungal activities of amphotericin B against 1,997 invasive isolates of Candida spp.: SENTRY1997-2000 TABLE 2: Antifungal Activities of Four Licensed Systematic Antifungal Agents Against 2,047 Invasive Isolates of Candida spp. According to Age Group: SENTRY, 1997 - 2000 Difference in Susceptibility Among Age Groups to Both Licensed and Investigational Antifungal Agents: Among the licensed antifungal agents, fluconazole, itraconazole, amphotericin B, and flucytosine, isolates of Candida spp. from patients 1 yr were more susceptible to fluconazole, itraconazole, and amphotericin B than isolates from the 16-64 yr and 65 yr age groups (Table 2). Although flucytosine was uniformly active among all age groups overall (95-98% susceptible), isolates of C. tropicalis from patients 1 yr were more susceptible to this agent (MIC90, 0.5 g/ml; 0% resistant) than those isolates from patients 65 yr (MIC90, 32 g/ml; 11% resistant) (data not shown). <1 50/90 %S Species (N) The predominance of C. albicans and C. parapsilosis as the etiologic agents of fungemia in neonates has been noted previously by Kao et al (5) and Samian et al (19) among others; however, the lack of infections with C. glabrata and C. krusei in this age group is less well appreciated. The increasing importance of C. glabrata in the adult population is well known and the proportion of BSI due to C. glabrata has been noted to be considerably higher in individuals > 60 yrs of
age in some institutions (6, 15). The reasons for these differences are speculative but may relate to the tendency for
neonatologists and pediatricians to use amphotericin B preferentially over fluconazole in the treatment of documented
or suspected candidemia (18) and the pervasive use of fluconazole in the adult hospital population (1). Furthermore,
vertical transmission of C. albicans from mother to infant and horizontal transmission of C. parapsilosis from patient-topatient in the neonatal intensive care unit environment is well documented and may also account for the predominance
of these two species in infants and children (9, 21).

1
(273)

SUMMARY AND CONCLUSIONS

MIC (g/ml) and % susceptible (%(S)a by Age Group (Yr)

It appears that the differences in susceptibility to amphotericin B and the azoles, among the four age groups as shown
in Table 2 may be largely due to differences in species distribution in the younger age groups compared to the older
age groups. The 1 yr and 2-15 yr age groups were dominated by C. albicans and C. parapsilosis both of which were
considerably more susceptible to the tested antifungal agents than C. glabrata. The older age groups, and particularly
the 65 yr group, had relatively fewer infections due to C. albicans and significantly more infections due to C. glabrata
than the younger age groups. The decreased susceptibility of C. glabrata to both the azoles and amphotericin B is
clearly evident in Tables 3 and 4 and likely accounted for the differences in susceptibility among the age groups noted
in Table 2.

RESULTS AND DISCUSSION

The activity of amphotericin B as determined by Etest against the top five species is shown in Table 4. As
expected, amphotericin B was most active against C. albicans (MIC90, 1 g/ml). The activity of amphotericin B
against the other species was significantly less than that observed with C. albicans: C. glabrata (MIC90, 4 g/ml),
C. parapsiolosis (MIC90, 4 g/ml) and C. krusei (MIC90, 8 g/ml). Although the Etest in our hands tended to give
higher amphotericin B MICs for the non-ablicans species than for C. albicans, the same tendency was seen with

TABLE 3: Antifungal activities of fluconazole, itraconazole, and investigational azole
antifungal agents against 2,029 invasive isolates
of Candida spp. according to patient age group: SENTRY 1997-2000

Species
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei

Cumulative % Inhibited at MIC (g/ml)
0.5
1
2
4
8
16
32 64
80 91 95 97 99a 100 100 100
73 85 90 94 95a 97
98 99
a
67 74 81 87 91
95
97 98
64 71 79 86 91a 96
98 99
98 99 100 100 100
98 99 99 99
99
92 97 98 99
99
91 96 99 99
99
28 80 97 99 100
27 72 91 98
99
26 70 91 98
99
20 67 92 99
99
86 95 95 96c
96 97
97 97
c
89 94 98 98
98 99 100 100
c
84 93 95 95
96 98
98 98
92 96 96 97c
97 98
99 99

No.
Tested
1,114
334
301
209
39

Cumulative % Inhibited at (g/ml)a
0.06
0.2
0.6
0.0
0.0
0.0

0.12
0.4
0.9
0.0
0.0
0.0

0.25
2.7
1.8
0.3
0.5
0.0

0.5
38.2
5.7
2.7
8.1
0.0

1
92.1
41.4
44.1
48.8
10.3

2
99.5
83.3
80.9
90.9
43.6

4
100
97.9
97.0
99.5
82.1

2.
3.
4.

8
100
99.7
99.3
100
97.4

16
100
100
100
100
100

32
100
100
100
100
100

Amphotericin B MICs by Etest

5.
6.
7.
8.
9.
10.

a

11.
12.

TABLE 5: In vitro susceptibility of blood stream isolates of Candida spp. to
amphotericin B as determined by Broth Microdilution (BMD) and Etest methodsa
Species (N)
Candida albicans (658)
Candida glabrata (180)
Candia parapsilosis (179)
Candida tropicalis (104)
Candida krusei (21)

a

Test Methods
BMD
Etest
BMD
Etest
BMD
Etest
BMD
Etest
BMD
Etest

Overall agreement between BMD and Etest, 98.7% ( 2 dilutions)

a

Range
0.015-2
0.06-3
0.25-2
0.06-8
0.015-2
0.38-6
0.5-2
0.25-31
1-2
1-8

*Corresponding Author: Michael A. Pfaller, M.D.
Medical Microbiology Division, C606 GH, Department of Pathology
University of Iowa College of Medicine, Iowa City, Iowa 52242
Phone: (319) 384-9566
Fax: (319) 356-4916
Email: [email protected]

MIC (at g/ml)
50%
90%
1
1
0.5
1
1
2
1.5
2
1
1
1.5
3
1
1
2
2
1
2
3
6

% with MIC 2
1.8
1.2
24.4
28.2
9.5
46.6
2.9
6.9
47.6
86.7

13.
14.
15.
16.
17.

18.
19.
20.
21.
22.

Berrouane, Y.F., L.A. Herwaldt, and M.A. Pfaller. 1999. Trends in antifungal use and epidemiology of noscocomial yeast infections in a University hospital.
J. Clin. Microbiol. 37:531-537
Blumberg, H.M., W.R. Jarvis, J.M. Soucie, J.E. Edwards, J.E. Patterson, M.A. Pfaller, M.S. Rangel-Frausto, M.G. Rinaldi, L. Saiman, R.T. Wiblin, R.P. Wenzel,
and the NEMIS Study Group. 2001. Risk factors for candidal blood stream infections in surgical intensive care unit patients: The NEMIS Prospective Multicenter
Study. Clin. Infect. Dis. 33:177-186.
Diekema, D.J., M.A. Pfaller, S.A. Messer, A. Houston, R.J. Hollis, G.V. Doern, R.N. Jones and The SENTRY Participants Group. 1999. In vitro activities of
BMS-207-147 against over 600 contemporary clinical blood stream isolates of Candida species from the SENTRY Antibmicrobial Surveillance Program in North
America and Latin America. Antimicrob. Agents Chemother. 43:2236-2239.
Edmond, M.B., S.E. Wallace, D.K. McClish, M.A. Pfaller, R.N. Jones, and R.P. Wenzel. 1999. Nocsocomial blood stream infections in United States hospitals:
A three-year analysis. Clin. Infect. Dis. 29:239-244.
Kao, A.S., M.E. Brandt, W.R. Pruitt, L.A. Conn, B.A. Perkins, D.S. Stevens, W.S. Baughman, A.L. Reingold, G.A. Rothrock, M.A. Pfaller, R.W. Pinner, and R.A.
Hajjeh. 1999. The epidemiology of candidemia in two United States cities: Results of a population-based active surveillance. Clin. Infect. Dis. 29:1164-1170.
Kauffman, C.A. 2001. Fungal infections in older adults. Clin. Infect. Dis. 33:In Press.
Masterton, R.G. 2000. Surveillance studies: How can they help the management of infection? J. Antimicrob. Chemother. 46:53-58.
National Committee for Clinical Laboratory Standards. 1997. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard
M27-A. National Committee for Clinical Laboratory Standards, Wayne, PA.
Pfaller, M.A., S.A. Messer, A. Houston, M.S. Rangel-Frausto, T. Wiblin, H.M. Blumberg, J.E. Edwards, W. Jarvis, M.A. Martin, H.C. Neu, L. Saiman, J.E.
Patterson, J.C. Dibb, C.M. Roldan, M.G. Rinaldi, and R.P. Wenzel. 1998. National Epidemiology of Mycoses Survey: A multicenter study of strain variation and
antifungal susceptibility among isolates of Candida species. Diagn. Microbiol. Infect. Dis. 31:289-296.
Pfaller, M.A., S.A. Messer, R.J. Hollis, R.N. Jones, G.V. Doern, M.E. Brandt, and R.A. Hajjeh. 1998. In vitro susceptibilities of Candida blood stream isolates to
the new triazole antifungal agents BMS-207147, Sch 56592, and voriconazole. Antimicrob. Agents Chemother. 42:3242-3244.
Pfaller, M.A., R.N. Jones, G.V. Doern, H.S. Sader, R.J. Hollis, and S.A. Messer for the SENTRY Participant Group. 1998. International surveillance of blood
stream infections due to Candida species: Frequency of occurrence and antifungal susceptibilities of isolates collected in1997 in the United States, Canada, and
South America for the SENTRY Program. J. Clin. Microbiol. 36:1886-1889.
Pfaller, M.A., S.A. Messer, and A. Bolmstrom. 1998. Evaluation of Etest for determining in vitro susceptibility of yeast isolates to amphotericin B. Diagn.
Microbiol Infect. Dis. 32:223-227.
Pfaller, M.D., R.N. Jones, G.V. Doern, A.C. Fluit, J. Verhoef, H.S. Sader, S.A. Messer, A. Houston, S. Coffman, and R.J. Hollis for the SENTRY Participant Group
(Europe). 1999. International surveillance of blood stream infections due to Candida species in the European SENTRY Program: Species distribution and
antifungal susceptibility including the investigational triazole and echinocandin agents. Diagn. Microbiol. Infect. Dis. 35:19-25.
Pfaller, M.A., R.N. Jones, G.V. Doern, H.S. Sader, S.A. Messer, A. Houston, S. Coffman, R.J. Hollis, and The SENTRY Participant Group. 2000. Blood stream
infections due to Candida species: SENTRY Antimicrobial Surveillance Program in North America and Latin America. 1997-1998. Antimicrob. Agents Chemother.
44:747-751.
Pfaller, M.A., D.J. Diekema, R.N. Jones, H.S. Sader, A.C. Fluit, R.J. Hollis, and S.A. Messer. 2001. International surveillance of blood stream infections due to
Candida species: Frequency of occurrence and in vitro susceptibility to fluconazole, ravuconazole, and voriconazole among isolates collected from 1997 through
1999 in the SENTRY Antimicrobial Surveillance Program. J. Clin. Microbiol. In Press.
Rangel-Frasuto, M.S., T. Wiblin, H.M. Blumberg, L. Saiman, J. Patterson, M. Rinaldi, M. Pfaller, J.E. Edwards, Jr., W. Jarvis, J. Dawson, and R.P. Wenzel. 1999.
National epidemiology of mycoses survey (NEMIS): Variations in rates of blood stream infections due to Candida species in seven surgical intensive care units
and six neonatal intensive care units. Clin. Infect. Dis. 29:253-258.
Rex, J.H., M.A. Pfaller, J.N. Galgiani, M.S. Bartlett, A. Espinel-Ingroff, M.A. Ghannoum, M. Lancaster, F.C. Odds, M.G. Rinaldi, T.J. Walsh, and A.L. Barry for the
Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. 1997. Development of interpretive breakpoints
for antifungal susceptibility testing: Conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections.
Clin. Infect. Dis. 24:235-247.
Rowen, J.L. and J.M. Tate. 1998. Management of neonatal candidiasis. Neonatal Candidiasis Study Group. Pediatr. Infect. Dis. J. 17:1007-1001.
Saiman, L., E. Ludington, M. Pfaller, S. Rangel-Frausto, R.T. Wiblin, J. Dawson, H.M. Blumberg, J.E. Patterson, M. Rinaldi, J.E. Edwards, R.P. Wenzel, and W.
Jarvis. 2000. Risk factors for candidemia in Neonatal Intensive Care Unit patients. The National Epidemiology of Mycosis Survey study group. Pediatr. Infect.
Dis. J. 19:319-324.
Sheehan, D.J., C.A. Hitchcock, and C.M. Sibley. 1999. Current and emerging azole antifungal agents. Clin. Microbiol. Rev. 12:40-79.
Waggoner-Fountain, L.A., M.W. Walker, R.J. Hollis, M.A. Pfaller, J.E. Ferguson, 2 nd., R.P. Wenzel, and L.G. Donowitz. 1996. Vertical and horizontal transmission
of unique Candida species to premature newborns. Clin. Infec. Dis. 22:803-808.
Warren, N.G., and K.C. Hazen. 1999. Candida, Cryptococcus, and other yeasts of medical importance, p. 1184-1199. In. P.R. Murray, E.J. Baron, M.A. Pfaller,
F.C. Tenover, and R.H. Yolken (ed), Manual of Clinical Microbiology, 7 th ed. ASM Press, Washington, D.C.

A156-03

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