Antimicrobial Resistance among Gram-Negative Bacilli Causing Infections in Intensive Care Unit Patients in the United States between 1993 and 2004

Abstract

During the 12-year period from 1993 to 2004, antimicrobial susceptibility profiles of 74,394 gram-negative bacillus isolates
recovered from intensive care unit (ICU) patients in United States hospitals were determined by participating hospitals and
collected in a central location. MICs for 12 different agents were determined using a standardized broth microdilution method.
The 11 organisms most frequently isolated were Pseudomonas aeruginosa (22.2%), Escherichia coli (18.8%), Klebsiella pneumoniae (14.2%), Enterobacter cloacae (9.1%), Acinetobacter spp. (6.2%), Serratia marcescens (5.5%), Enterobacter aerogenes (4.4%), Stenotrophomonas maltophilia (4.3%), Proteus mirabilis (4.0%), Klebsiella oxytoca (2.7%), and Citrobacter freundii (2.0%). Specimen sources included the lower respiratory tract (52.1%), urine (17.3%), and blood (14.2%). Rates of resistance
to many of the antibiotics tested remained stable during the 12-year study period. Carbapenems were the most active drugs
tested against most of the bacterial species. E. coli and P. mirabilis remained susceptible to most of the drugs tested. Mean rates of resistance to 9 of the 12 drugs tested increased with Acinetobacter spp. Rates of resistance to ciprofloxacin increased over the study period for most species. Ceftazidime was the only agent
to which a number of species (Acinetobacter spp., C. freundii, E. aerogenes, K. pneumoniae, P. aeruginosa, and S. marcescens) became more susceptible. The prevalence of multidrug resistance, defined as resistance to at least one extended-spectrum
cephalosporin, one aminoglycoside, and ciprofloxacin, increased substantially among ICU isolates of Acinetobacter spp., P. aeruginosa, K. pneumoniae, and E. cloacae.

Full text

JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 2007, p. 3352–3359 Vol. 45, No. 10
0095-1137/07/$08.00⫹0 doi:10.1128/JCM.01284-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Antimicrobial Resistance among Gram-Negative Bacilli Causing
Infections in Intensive Care Unit Patients in the United States
between 1993 and 2004
䌤
Shawn R. Lockhart,
1
* Murray A. Abramson,
2
Susan E. Beekmann,
1
Gale Gallagher,
2
Stefan Riedel,
1
Daniel J. Diekema,
1
John P. Quinn,
3
and Gary V. Doern
1
University of Iowa Hospital and Clinics, Division of Clinical Microbiology, Iowa City, Iowa
1
; Merck and Co., Inc.,
Merck Research Laboratories, Upper Gwynedd, Pennsylvania
2
; and Cook County Hospital,
Division of Infectious Diseases, Chicago, Illinois
3
Received 26 June 2007/Returned for modification 6 August 2007/Accepted 10 August 2007
During the 12-year period from 1993 to 2004, antimicrobial susceptibility profiles of 74,394 gram-negative
bacillus isolates recovered from intensive care unit (ICU) patients in United States hospitals were determined
by participating hospitals and collected in a central location. MICs for 12 different agents were determined
using a standardized broth microdilution method. The 11 organisms most frequently isolated were Pseudomo-
nas aeruginosa (22.2%), Escherichia coli (18.8%), Klebsiella pneumoniae (14.2%), Enterobacter cloacae (9.1%),
Acinetobacter spp. (6.2%), Serratia marcescens (5.5%), Enterobacter aerogenes (4.4%), Stenotrophomonas malto-
philia (4.3%), Proteus mirabilis (4.0%), Klebsiella oxytoca (2.7%), and Citrobacter freundii (2.0%). Specimen
sources included the lower respiratory tract (52.1%), urine (17.3%), and blood (14.2%). Rates of resistance to
many of the antibiotics tested remained stable during the 12-year study period. Carbapenems were the most
active drugs tested against most of the bacterial species. E. coli and P. mirabilis remained susceptible to most
of the drugs tested. Mean rates of resistance to 9 of the 12 drugs tested increased with Acinetobacter spp. Rates
of resistance to ciprofloxacin increased over the study period for most species. Ceftazidime was the only agent
to which a number of species (Acinetobacter spp., C. freundii,E. aerogenes,K. pneumoniae,P. aeruginosa, and S.
marcescens) became more susceptible. The prevalence of multidrug resistance, defined as resistance to at least
one extended-spectrum cephalosporin, one aminoglycoside, and ciprofloxacin, increased substantially among
ICU isolates of Acinetobacter spp., P. aeruginosa,K. pneumoniae, and E. cloacae.
Gram-negative bacilli (GNB) are a common cause of sepsis,
pneumonia, urinary tract infections, and postsurgical infections
in patients in acute care hospitals (14, 24). Antimicrobial re-
sistance among GNB is increasing worldwide (21). This is a
major public health problem and a cause for both substantial
morbidity and mortality among hospitalized patients. A direct
correlation has been shown between resistance of GNB and
patient mortality, cost of patient care, and length of stay in the
hospital (3, 22, 26, 28). The problem of GNB resistance is of
particular concern in the intensive care unit (ICU) setting.
The most important determinant in the successful manage-
ment of infections in patients in the ICU is prompt institution
of effective empirical antimicrobial therapy; inappropriate em-
pirical therapy affects both patient mortality rates and patient
time spent in the ICU (12, 17). Optimizing empirical therapy
requires knowledge of likely antimicrobial resistance patterns.
With the aim of tracking resistance rates among GNB as the
causes of infection in patients in U.S. ICUs, Merck Research
Laboratories (Merck & Co., Upper Gwynedd, PA) established
a multicenter laboratory-based surveillance program in 1993.
Two previous reports from this investigation were published in
1996 and 2003 (13, 20). The current report describes the in
vitro activity of 12 agents versus more than 74,000 GNB iso-
lates recovered from ICU patients in multiple U.S. hospitals
during the 12-year period from 1993 to 2004.
MATERIALS AND METHODS
Participating centers performed antimicrobial susceptibility testing with 100
consecutive nonduplicate aerobic GNB per study year collected from ICU pa-
tients with infections. Attempts were made to distribute enrolled hospitals evenly
throughout the country according to average population and to represent both
large and small academic institutions and community hospitals. The number of
hospitals enrolled changed from year to year throughout the study. Over the
12-year period of this study, the participating centers numbered between 42
and 99, with an average of 70 per year, and represented 43 states and the
District of Columbia. Careful consideration was give to the hospitals enrolled
to ensure an even geographic distribution and to avoid potential skewing of
the surveillance data.
Only isolates of presumed clinical significance, as determined by the individual
hospitals, were included. Only the first isolate of a particular species per patient
over the entire collection period was acceptable. Organisms were identified using
the conventional methods employed at each hospital. Standardized susceptibility
testing was performed by broth microdilution using commercially prepared mi-
crotiter panels specifically manufactured for this study (Microscan MKD MIC;
Dade International Microscan, Sacramento, CA). This testing was performed in
the clinical microbiology laboratories of participating institutions, and the results
were maintained with a computerized database at Merck Research Laboratories.
Categorization of susceptibility test results as susceptible, intermediate, or resis-
tant was accomplished using the interpretive criteria of the Clinical and Labo-
ratory Standards Institute (CLSI [2]). Antimicrobials tested included ampicillin,
ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-
clavulanate, cefotaxime, ceftriaxone, ceftazidime, cefepime, imipenem, erta-
penem, aztreonam, tobramycin, gentamicin, amikacin, and ciprofloxacin. Quality
control testing was performed at each hospital by using the following quality
* Corresponding author. Mailing address: University of Iowa Hos-
pitals and Clinics, Department of Pathology–6008 BT GH, 200
Hawkins Drive, Iowa City, IA 52242-1009. Phone: (319) 356-2104. Fax:
(319) 356-4916. E-mail: shawn-lockhart@uiowa.edu.
䌤
Published ahead of print on 22 August 2007.
3352

control strains: Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC
25922, and Klebsiella pneumoniae ATCC 700603.
For purposes of analysis, data were grouped into four 3-year blocks: 1993 to
1995, 1996 to 1998, 1999 to 2001, and 2002 to 2004. For each 3-year block, the
MICs at which 50% (MIC
50
) and 90% (MIC
90
) and the percentages of inter-
mediate and resistant values for each major GNB species group were calculated.
Fluoroquinolone usage data in the U.S. (prescriptions per month) were ob-
tained from the IMS Health NSP database for the years 1999 to 2004 and were
expressed as patient days of therapy (PDOT) for each of these years. Fluoro-
quinolone usage levels and fluoroquinolone resistance rates for each year of the
study were compared using SAS version 9.1.3 software.
RESULTS
Organisms characterized. The mean number of isolates
characterized by each hospital per year was 91 (range, 11 to
458). A total of 74,394 isolates were characterized between
1993 and 2004 (Table 1). The organisms most frequently iso-
lated were P. aeruginosa (22.2%), E. coli (18.8%), K. pneu-
moniae (14.2%), Enterobacter cloacae (9.1%), Acinetobacter
spp. (6.2%), Serratia marcescens (5.5%), Enterobacter aerogenes
(4.4%), Stenotrophomonas maltophilia (4.3%), Proteus mirabilis
(4.0%), Klebsiella oxytoca (2.7%) and Citrobacter freundii
(2.0%). These 11 species accounted for 93.4% of the total
number of isolates. The respiratory tract (52.1%), urine
(17.3%), and blood cultures (14.2%) were the sources of ca.
84% of isolates. P. aeruginosa was the organism most fre-
quently isolated in the respiratory tract (26.9%), while E. coli
was most frequently isolated from both urine (42.4%) and
blood (23.9%). Respiratory tract specimens were the most
common sources of isolates for each of the species listed in
Table 1, with the exception of E. coli, for which urine isolates
were predominant.
Antimicrobial susceptibility. The antimicrobials tested and
the percentages of isolates determined to be intermediate and
resistant are listed in Table 2. Because resistance rates re-
mained relatively constant over the 12-year period of this sur-
vey, only results for the most recent 3-year period, 2002 to
2004, are represented in Table 2. Furthermore, data were
provided for 10 of the 11 most frequently isolated species.
Since the CLSI provides limited interpretive breakpoints for S.
maltophilia, this species was not included in Table 2.
Imipenem was consistently the most active agent among
those tested. Eighty-two percent of P. aeruginosa and 88% of
Acinetobacter spp. were susceptible to imipenem. Among the
members of the family Enterobacteriaceae tested, more than
98% were susceptible to imipenem. Ertapenem was also nearly
uniformly active against the Enterobacteriaceae with 95% of
isolates susceptible. Among Acinetobacter spp. isolates, 77.2%
were susceptible to ceftazidime and 71.1% were susceptible to
amikacin. Ceftazidime and amikacin were also among the
agents most active against P. aeruginosa. Ceftazidime, ceftriax-
one, cefepime, piperacillin-tazobactam, imipenem, ertapenem,
aztreonam, tobramycin, and amikacin all remained very active
against E. coli, with mean resistance rates below 5%. Piperacil-
lin (10.5%) and ciprofloxacin (15%) were the least active of the
agents tested versus P. mirabilis.
Ampicillin-sulbactam, in general, had the highest resistance
rates among all of the agents tested. Exceptions included pi-
peracillin, which had higher resistance rates with K. pneumoniae
and K. oxytoca and Acinetobacter spp., which had higher resis-
tance rates to all of the ␤-lactam class antibiotics tested except
ceftazidime, compared to that of ampicillin-sulbactam.
Changes in antimicrobial susceptibility. In general, resis-
tance profiles remained relatively stable over the course of this
study for most organism-antimicrobial combinations. Table 3
lists those combinations for which there was a discernible
change over time. The data in Table 3 were predicated for all
isolates of a species regardless of specimen type. The trends
depicted in Table 3 were also observed when this analysis was
restricted to bloodstream isolates.
As seen in Table 3, resistance rates with Acinetobacter spp.
have increased over the 12-year period of this study, with 9 of
the 12 antibiotics tested (i.e., ampicillin-sulbactam, ceftriax-
one, cefepime, piperacillin, piperacillin-tazobactam, imi-
penem, tobramycin, amikacin, and ciprofloxacin). Interest-
ingly, ceftazidime resistance rates with Acinetobacter spp.
dropped from 23.9% to 14.6% over the study period. There
was also a notable decline in ceftazidime resistance for C.
freundii,E. aerogenes,E. cloacae,K. pneumoniae,P. aeruginosa,
and S. marcescens.
Ciprofloxacin resistance rates increased with several species.
The most dramatic change was observed for Acinetobacter spp.,
for which the percentage of susceptible strains dropped from
61.5% to 35.2% over the period of the study. Decreases in the
percentage of isolates susceptible to ciprofloxacin were also
seen with P. aeruginosa (83.2% to 66.3%), E. coli (98.9% to
82.5%), C. freundii (88% to 73.9%), P. mirabilis (96.4% to
82.9%), E. cloacae (93.5% to 85.9%), and K. pneumoniae (89%
to 81.8%). Although piperacillin susceptibility decreased with
Acinetobacter spp., it increased with both E. aerogenes (65.5%
to 77.9%) and K.pneumoniae (34.3% to 54.3%).
Rates of resistance to tobramycin increased with a number
of species. Over the 12-year study period, tobramycin resis-
tance rates more than doubled with P. aeruginosa,E.coli,C.
freundii, and Acinetobacter spp. Changes in imipenem resis-
tance rates were species dependent. Resistance rates increased
with both P. aeruginosa and Acinetobacter spp. but decreased
with both S. marcescens and P. mirabilis to the extent that both
species were nearly uniformly susceptible during the last study
period. The activity profiles of both aztreonam and piperacil-
lin-tazobactam remained nearly constant during the period of
this survey. Only C. freundii showed an increase in resistance to
ertapenem during the study period.
The trend toward multidrug resistance. Multidrug resis-
tance was monitored for a number of species in the first year
(1993) and the last year (2004) of the study period (Table 4).
Multidrug resistance was defined as resistance to one or more
of the extended-spectrum cephalosporins (ceftazidime, ceftri-
axone, or cefotaxime), one of two aminoglycosides (amikacin
or tobramycin), and ciprofloxacin. There was a greater than
fourfold increase in multidrug resistance rates with Acineto-
bacter spp. during the study period and a more than fivefold
increase in multidrug resistance with P. aeruginosa. Approxi-
mate twofold increases in multidrug resistance rates were seen
with C. freundii,E. cloacae, and K. pneumoniae. Whereas not a
single multidrug-resistant isolate was seen among 724 E. coli
isolates from 1993, 2% of the 800 E. coli isolates from 2004
were multidrug resistant.
Antimicrobial usage data for fluoroquinolones. Annual us-
age levels of fluoroquinolones increased substantially over the
VOL. 45, 2007 ANTIMICROBIAL RESISTANCE AMONG GNB IN THE ICU 3353

TABLE 1. Isolates characterized between 1993 and 2004
Organisms most
frequently isolated
Total no.
isolated
(n⫽74,394)
No. of isolates
1993–1995 1996–1998 1999–2001 2002–2004
Respiratory
tract Urine
Blood-
stream
infection
Other
sources
c
Respiratory
tract Urine
Blood-
stream
infection
Other
sources
Respiratory
tract Urine
Blood-
stream
infection
Other
sources
Respiratory
tract Urine
Blood-
stream
infection
Other
sources
Pseudomonas aeruginosa 16,482 1,887 366 266 488 3,094 569 458 755 3,144 591 528 786 2,287 387 387 489
Escherichia coli 13,961 803 946 415 595 946 1,560 662 792 917 1,799 911 741 684 1,147 546 497
Klebsiella pneumoniae 10,571 996 354 300 350 1,571 506 490 486 1,527 612 642 481 1,121 442 407 286
Enterobacter cloacae 6,779 796 139 232 304 1,162 125 276 406 1,017 183 350 349 783 138 282 237
Acinetobacter spp.
a
4,642 548 62 128 125 927 45 193 157 858 57 212 153 786 57 208 126
Serratia marcescens 4,112 453 60 74 88 910 41 169 132 844 68 192 164 621 54 133 109
Enterobacter aerogenes 3,307 523 77 86 111 726 85 82 141 614 85 102 112 360 58 62 83
Proteus mirabilis 3,011 272 138 68 134 354 269 102 190 326 248 173 176 216 149 91 105
Klebsiella oxytoca 2,018 240 72 44 89 316 70 78 90 294 82 106 87 234 55 88 73
Citrobacter freundii 1,483 153 59 48 100 212 97 47 116 163 97 59 98 83 75 32 44
All other species
b
8,028 966 182 159 320 1,654 250 225 435 1,423 225 284 359 931 171 193 251
a
Includes Acinetobacter baumannii,Acinetobacter spp. nosocomial (NOS), Acinetobacter calcoaceticus,Acinetobacter anitratus,Acinetobacter lwoffii, and Acinetobacter junii.
b
Other species (number of isolates) include Achromobacter group VD (1), Actinobacillus actinomycetemcomitans (1), Actinobacillus ureae (1), Aeromonas caviae (2), Aeromonas hydrophila (79), Aeromonas schubertii
(1), Aeromonas sobria (6), nosocomial (NOS) Aeromonas spp. (13), Agrobacterium tumefaciens (5), Alcaligenes denitrificans (1), Alcaligenes faecalis (27), Alcaligenes odorans (3), NOS Alcaligenes spp. (29), Alcaligenes
xylosoxidans (335), Bacteroides vulgatus (1), Bordetella bronchiseptica (10), Budvicia aquatica (1), Brevundimonas vesicularis (3), Burkholderia cepacia (195), Burkholderia gladioli (3), Burkholderia pickettii (1), NOS
Burkholderia spp. (1), Campylobacter jejuni (1), NOS Capnocytophaga spp. (1), Cedecea davisae (5), NOS Cedecea spp. (3), Chromobacterium violaceum (3), Chryseobacterium gleum (4), Chryseobacterium indologenes (7),
Chryseobacterium meningosepti (15), NOS Chryseobacterium spp. (5), Chryseomonas luteola (7), Citrobacter amalonaticus (96), Citrobacter braakii (34), Citrobacter farmeri (1), Citrobacter indologenes (2), Citrobacter koseri
(734), NOS Citrobacter spp. (71), Citrobacter youngae (7), Citrobacter werkmanii (1), Comamonas acidovorans (13), NOS Comamonas spp. (3), Comamonas testosteroni (1), Edwardsiella tarda (3), Enterobacter amnigenus
(23), Enterobacter asburiae (45), Enterobacter cancerogenus (33), Enterobacter gergoviae (32), Enterobacter hormachei (4), Enterobacter intermedius (12), Enterobacter sakazakii (65), NOS Enterobacter spp. (200), Escherichia
fergusonii (11), Escherichia hermanii (7), NOS Escherichia spp. (2), Escherichia vulneris (3), Flavimonas oryzihabitans (14), Flavobacterium breve (3), Flavobacterium indologenes (18), Flavobacterium meningosepticum (33),
Flavobacterium odoratum (6), NOS Flavobacterium spp. (23), NOS Fusobacterium spp. (1), Haemophilus influenzae (6), Haemophilus parainfluenzae (1), NOS Haemophilus spp. (1), Hafnia alvei (102), Klebsiella
ornithinolytica (27), NOS Klebsiella spp. (65), Klebsiella terrigena (2), Kluyvera ascorbate (8), NOS Kluyvera spp. (9), Leclercia adecarboxylata (6), NOS Leminorella spp. (1), Moraxella catarrhalis (14), Moraxella osloensis
(1), Moraxella phenylpyruvica (1), NOS Moraxella spp. (5), Morganella morganii (744), Ochrobacterium anthropi (6), Pantoea agglomerans (133), NOS Pantoea spp. (2), Pasteurella multocida (12), NOS Pasteurella spp. (1),
Plesiomonas shigelloides (4), Proteus penneri (30), NOS Proteus spp. (14), Proteus vulgaris (191), Providencia alcalifaciens (1), Providencia rettgeri (81), Providencia rustigianii (1), NOS Providencia spp. (3), Providencia stuartii
(319), Pseudomonas alcaligenes (7), Pseudomonas fluorescens (181), Pseudomonas mendocina (8), Pseudomonas paucimobilis (4), Pseudomonas pseudoalcaligenes (1), Pseudomonas putida (48), NOS Pseudomonas spp. (81),
Pseudomonas stutzeri (45), Rahnella aquatilis (3), Ralstonia pickettii (8), NOS Roseomonas spp. (1), Salmonella choleraesuis (3), Salmonella enteritidis (20), Salmonella hadar (1), Salmonella montevideo (1), NOS Salmonella
spp. (46), Salmonella enterica serovar Typhimurium (6), Serratia ficaria (1), Serratia fonticola (23), Serratia liquefaciens (91), Serratia odorans (5), Serratia odorifera (20), Serratia plymuthica (14), Serratia rubidaea (18), NOS
Serratia spp. (54), Shewanella putrefaciens (6), Shigella sonnei (4), NOS Shigella spp. (2), NOS Sphingobacterium spp. (1), Sphingomonas paucimobilis (4), Stenotrophomonas maltophilia (3,217), Vibrio fluvialis (1), Vibrio
vulnificus (3), and Yersinia enterocolitica (4).
c
Including abdomen, abscess, aorta, appendix, aspirate, bile, bone, bowel, biliary, colon, cerebral spinal fluid, drainage, eye, gastrointestinal, graft, gall bladder, kidney, liver, mandible, nasal cavities, mouth, pancreas,
pelvis, perineum, peritoneum, pericardium, spleen, throat, unknown, and wound.
3354 LOCKHART ET AL. J. CLIN.MICROBIOL.

period of this study. For example, in 1999, there were 11,267
PDOT in the U.S.; in 2004, there were 18,898 PDOT. When
fluoroquinolone resistance rates were compared to levels of
fluoroquinolone usage, several statistically significant associa-
tions were elucidated (Table 5). The three strongest associa-
tions were observed with fluoroquinolone resistance in E. coli
and both total fluoroquinolone use and use of levofloxacin and
fluoroquinolone resistance in P. aeruginosa and total fluoro-
TABLE 2. Resistance rates for the 10 most frequently isolated GNB from 2002 to 2004
a
GNB and source
% of isolates (%I/%R)
Ampicillin-
sulbactam Ceftriaxone Ceftazidime Cefepime Piperacillin Piperacillin-
tazobactam Imipenem Ertapenem Aztreonam Tobramycin Amikacin Ciprofloxacin
P. aeruginosa
Respiratory tract 34.9/48.6 6.5/4.6 14.6/13.0 NA/15.9 NA/13.7 3.5/14.9 15.7/18.5 1.8/13.5 6.9/3.5 5.7/27.4
Urine 35.4/48.1 4.1/3.1 16.0/12.9 NA/11.8 NA/14.0 3.1/13.4 17.1/17.3 2.1/17.8 7.8/4.7 2.1/41.9
Bloodstream
infection
42.9/41.3 5.9/5.4 15.3/8.8 NA/18.9 NA/10.9 5.9/14.7 12.4/15.0 1.3/15.8 6.0/3.9 3.1/28.4
All 35.9/48.0 6.3/4.5 14.5/12.5 NA/16.0 NA/13.2 3.8/14.5 15.1/17.8 1.8/13.7 6.9/3.5 4.8/28.9
E. coli
Respiratory tract 13.9/32.3 1.9/5.0 1.3/1.9 0.9/3.5 5.0/35.0 2.9/6.6 0/0 0.3/0.9 0.9/6.0 3.4/8.9 1.5/1.2 0.4/18.6
Urine 12.7/25.9 1.7/3.1 0.9/1.1 0.5/1.8 3.8/33.8 2.3/3.8 0.2/0.3 0.2/1.0 1.0/4.1 2.9/6.0 0.4/0.4 0.2/16.3
Bloodstream
infection
14.1/35.4 2.8/2.9 0.9/1.8 0.4/1.8 5.6/41.9 4.0/3.9 0/0 0.6/0.6 1.8/3.5 3.5/7.1 0.7/1.3 0.2/16.3
All 13.5/30.0 2.1/4.6 1.2/1.6 0.5/2.5 4.3/36.3 2.8/4.8 0.1/0.2 0.4/0.9 1.2/4.6 3.3/7.1 0.7/0.9 0.2/17.3
K. pneumoniae
Respiratory tract 8.2/22.9 4.8/11.7 0.7/4.1 2.1/8.1 19.9/24.9 4.3/11.8 0.7/0.7 0.2/3.5 1.1/15.7 2.2/15.2 5.4/3.4 1.6/16.8
Urine 8.6/21.3 4.3/10.4 1.4/2.9 1.6/6.6 16.2/31.8 5.0/7.5 0.5/0.2 0/2.0 1.1/13.1 2.3/13.6 3.4/2.3 1.1/16.1
Bloodstream
infection
7.6/26.8 4.7/13.8 1.0/4.7 1.5/9.3 13.7/36.7 3.7/13.0 1.5/1.5 0.3/5.2 0.7/16.7 3.9/17.0 5.7/3.7 1.5/18.2
All 8.2/23.6 4.7/11.8 0.8/3.8 1.8/8.1 17.0/28.7 4.0/11.8 1.0/0.7 0.2/3.7 0.9/15.6 2.5/15.1 5.1/3.1 1.4/16.8
E. cloacae
Respiratory tract 19.0/61.6 8.6/26.1 2.6/11.0 4.0/9.3 5.2/31.7 11.6/14.6 0.6/0.4 2.0/2.7 4.7/27.5 2.9/10.6 1.7/1.4 2.2/12.0
Urine 20.3/50.7 8.7/36.2 2.2/12.3 5.8/11.6 10.9/34.8 13.1/20.3 0/0 1.5/2.9 13.0/23.2 2.9/13.8 2.2/2.2 2.9/14.5
Bloodstream
infection
16.7/62.4 10.3/30.1 3.6/13.5 2.8/16.0 6.9/46.0 13.1/17.7 0/0 3.6/0.7 5.0/33.7 2.5/13.1 1.8/2.1 1.4/12.1
All 18.5/62.5 8.9/28.7 2.7/11.7 4.0/10.8 6.1/35.1 12.6/16.2 0.4/0.3 2.3/2.3 5.0/30.1 3.1/11.1 1.6/1.5 1.7/12.4
Acinetobacter spp.
Respiratory tract 7.6/31.6 16.4/53.2 7.4/13.4 13.7/46.6 11.4/50.4 16.9/35.8 6.4/4.8 22.8/60.6 4.6/28.5 5.2/21.9 1.4/61.5
Urine 10.5/29.8 17.5/68.4 10.5/22.8 17.5/54.4 11.1/66.7 26.3/33.3 1.8/8.8 14.0/75.4 3.5/36.8 5.3/31.6 0/74.5
Bloodstream
infection
7.7/39.4 15.4/56.7 10.6/15.9 15.4/51.4 6.1/54.6 17.3/38.9 9.1/4.3 16.4/67.3 3.9/33.3 2.9/26.9 0.5/63.5
All 8.1/33.2 16.2/56.2 8.2/14.6 14.2/49.0 10.9/52.4 17.9/36.9 6.9/5.2 20.7/63.9 5.2/30.3 5.0/23.9 1.0/63.8
S. marcescens
Respiratory tract 12.7/81.0 5.6/4.7 2.1/2.3 1.5/4.4 7.1/9.0 5.3/6.8 0.2/0.5 1.0/1.3 2.1/7.6 4.7/6.4 0.6/0.3 3.7/6.6
Urine 14.8/72.2 7.4/7.4 3.7/3.7 1.9/5.6 9.5/23.8 3.7/5.6 0/1.9 0/3.7 1.9/13.0 9.3/16.7 5.6/3.7 3.7/11.1
Bloodstream
infection
18.8/76.7 6.0/2.3 2.3/0 2.3/2.3 2.5/15.0 6.0/9.0 0/1.5 0.8/0 3.0/7.5 6.8/9.8 1.5/2.3 3.8/1.5
All 14.0/79.6 5.7/4.5 2.2/1.9 1.4/4.0 6.6/10.9 5.5/7.2 0.1/0.7 0.8/1.3 2.5/17.8 5.8/7.1 1.1/0.8 3.7/6.1
E. aerogenes
Respiratory tract 25.6/34.4 13.6/2.8 4.2/3.6 1.1/0.8 9.4/6.8 9.2/2.2 0.6/0 0.6/2.5 7.2/4.7 0.6/0.8 0.6/0.3 0.6/1.9
Urine 20.7/42.0 10.3/6.9 8.6/5.2 0/3.5 11.8/17.7 12.1/5.2 1.7/0 0/1.7 6.9/10.4 0/5.2 0/3.5 3.5/8.6
Bloodstream
infection
19.4/48.4 25.8/1.6 11.3/4.8 0/0 21.1/15.8 17.7/3.2 0/0 0/0 12.9/8.1 1.6/0 0/0 1.6/4.8
All 22.9/38.9 15.6/4.3 5.9/4.6 1.2/1.5 11.3/10.8 11.4/3.4 1.1/0 0.4/2.8 8.4/7.1 0.7/1.8 1.2/0.5 1.1/3.5
P. mirabilis
Respiratory tract 6.0/2.8 6.0/2.8 0.5/0.5 1.4/0.9 1.4/8.1 0.9/0.5 0.5/0 0/0.9 0/2.3 3.2/2.3 0.9/0.5 0.9/13.4
Urine 7.4/8.7 0/0.7 8.6/5.2 1.3/1.3 5.0/15.0 0/1.5 0/0 0/0.7 0/2.7 4.0/3.4 0.7/0 3.4/19.5
Bloodstream
infection
6.7/7.7 1.1/0 0/1.1 0/2.2 0/14.7 1.1/1.1 1.1/0 0/1.1 0/1.1 3.3/4.4 0/0 3.3/12.1
All 7.5/5.3 1.2/0.4 0.5/0.5 0.9/1.4 2.1/10.5 0.7/0.7 0.7/0 0/0.7 0/2.1 3.0/3.6 0.5/0.2 2.1/15.0
K. oxytoca
Respiratory tract 22.2/12.4 3.9/4.3 1.3/0.4 1.3/2.1 41.2/24.7 3.4/6.4 0/0 0/1.3 0.4/7.7 1.3/4.7 0/0.4 0.4/3.9
Urine 21.8/29.1 5.5/14.6 1.8/3.6 1.8/5.5 20.0/40.0 0/18.2 0/0 0/0 1.8/23.6 5.5/12.7 0/0 1.8/10.9
Bloodstream
infection
19.3/25.0 6.8/8.0 0/1.1 1.1/0 10.0/40.0 4.6/10.2 0/0 0/1.1 2.3/13.6 5.7/6.8 2.3/0 2.3/4.6
All 19.8/17.6 4.9/6.0 0.9/1.1 1.1/2.0 32.9/27.0 3.3/8.7 0/0 0/1.1 0.9/11.3 2.9/6.0 0.4/0.4 0.9/6.0
C. freundii
Respiratory tract 10.8/57.8 20.5/30.1 1.2/14.5 2.4/6.0 6.7/36.7 21.7/16.9 0/0 1.2/3.6 9.6/36.1 1.2/27.7 4.8/9.6 7.2/24.21
Urine 13.3/48.0 14.7/28.0 6.7/6.7 4.0/12.0 4.6/22.7 14.7/13.3 0/0 0/4.0 5.3/32.0 1.3/21.3 4.0/4.0 1.3/20.0
Bloodstream
infection
12.5/43.8 12.5/15.6 3.1/15.6 0/0 7.7/46.2 9.4/9.4 0/0 0/3.1 9.4/28.1 6.3/28.1 3.1/0 3.1/18.8
All 12.8/53.4 18.8/25.2 3.9/15.0 2.6/6.8 10.5/37.2 15.4/13.7 0/0 0.4/3.9 9.0/31.6 3.9/23.1 4.7/5.1 4.7/21.4
a
I, intermediate; R, resistant. NA, not available.
VOL. 45, 2007 ANTIMICROBIAL RESISTANCE AMONG GNB IN THE ICU 3355

quinolone use. In general, when levofloxacin was examined
individually, its use was more strongly associated with fluoro-
quinolone resistance than the use of ciprofloxacin, gatifloxacin,
or moxifloxacin.
DISCUSSION
We assessed trends in the development of antimicrobial
resistance among GNB recovered from ICU patients with in-
fections in U.S. hospitals between 1993 and 2004. Surprisingly,
antimicrobial resistance rates remained relatively constant for
the majority of the organism-antimicrobial combinations ex-
amined in this study. In general, carbapenems continue to be
the most active agents versus GNB in U.S. ICUs. For example,
imipenem resistance rates with the Enterobacteriaceae re-
mained at levels of 1% or less throughout the 12-year period of
this survey. These observations are consistent with the results
of other recent surveillance studies from U.S. hospitals (5, 8,
27, 29).
Rhomberg and Jones (27) reported that despite consistent
carbapenem susceptibility rates, “MIC creep” was occurring
with carbapenems versus selected GNB, especially in the New
York City area. Most of this change was thought to be the
result of carbapenemase-producing strains of K. pneumoniae.
With the exception of Acinetobacter spp., imipenem MIC
50
values for the isolates characterized in our study either re-
mained the same between 1993 and 2004 or decreased twofold
(e.g., E. aerogenes,P. aeruginosa, and S. marcescens, for which
TABLE 3. Trends in antimicrobial resistance among various GNB between 1993 and 2004
a
Organism Antimicrobial % of isolates (%I/%R) Trend
b
1993–1995 1996–1998 1999–2001 2002–2004
Pseudomonas aeruginosa Ceftazidime 5.6/9.9 5.6/12 5.2/14.2 6.3/4.5 2
Imipenem 4.5/10.6 3.5/11.1 3.6/13.7 3.8/14.5 1
Tobramycin 0.9/7.8 1.5/9.6 0.4/13.3 1.8/13.7 1
Ciprofloxacin 5.6/11.2 5.7/17.6 5.4/25.1 4.8/28.9 1
Escherichia coli Ampicillin-sulbactam 10/22.9 10.8/26.4 10.3/28.6 13.5/30 1
Ceftriaxone 0.8/1 1.3/2.3 1.6/2.7 2.1/4.6 1
Tobramycin 0.9/1.5 0.1/2.9 1/4.6 3.3/7.1 1
Ciprofloxacin 0.2/0.9 0.4/3.9 0.4/8.3 0.2/17.3 1
Klebsiella pneumoniae Ceftazidime 0.6/12.7 1.4/13.5 1/10.8 0.8/3.8 2
Piperacillin 27.4/38.3 22.3/36.9 22.1/37.4 17/28.7 2
Ciprofloxacin 3.1/7.9 3.4/9.7 1.8/10.5 1.4/16.8 1
Enterobacter cloacae Ceftazidime 3.9/36 4.2/33.8 3.6/30.4 2.7/11.7 2
Ciprofloxacin 2.5/5 2.9/7.6 2.1/10.9 1.7/12.4 1
Acinetobacter spp. Ampicillin-sulbactam 6/18.2 9.3/22 7.5/25.5 8.1/33.2 1
Ceftriaxone 25/30.1 21.3/43 16.3/51.7 16.2/56.2 1
Ceftazidime 10.1/23.9 8.7/36.8 8/45.2 8.2/14.6 2
Cefepime 13.7/31.6 15.5/37.7 14.2/49 1
Piperacillin 18.9/31.4 16.4/40.3 14.8/49.1 10.9/52.4 1
Piperacillin-tazobactam 22.4/18.4 20.1/26.7 17.9/36.9 1
Imipenem 2.1/2 4.4/2.1 6.6/5.6 6.9/5.2 1
Tobramycin 7.8/13 7/24.5 5.8/30.4 5.2/30.3 1
Amikacin 3.7/5.7 3.9/13.4 4.1/19.2 5/23.9 1
Ciprofloxacin 2.6/35.9 3/49.4 1.9/57.1 1/63.8 1
Serratia marcescens Ceftazidime 1.8/8.4 3.5/11.6 2.5/10.7 2.2/1.9 2
Imipenem 2.8/3.6 1.5/1.8 0.7/1.3 0.1/0.7 2
Enterobacter aerogenes Ceftazidime 6.3/23.8 3/24.7 3.5/22.7 5.9/4.6 2
Piperacillin 12.5/22 15.8/17.1 11.5/19.5 11.3/10.8 2
Proteus mirabilis Imipenem 7.7/3.4 2.8/1.2 1.1/1.2 0.7/0 2
Ciprofloxacin 0.3/3.3 2.1/7.8 0.1/13.1 2.1/15 1
Klebsiella oxytoca Cefepime 0.9/3.4 1.9/5.1 1.1/2 2
Citrobacter freundii Ceftazidime 1.9/43.6 1.5/47 3.1/38.9 3.9/15 2
Ertapenem 1.4/1.7 0.4/3.9 1
Tobramycin 2.2/10.8 5.3/12.7 3.4/12.7 3.9/23.1 1
Ciprofloxacin 2.8/9.2 4.7/14.4 3.4/14.9 4.7/21.4 1
a
I, intermediate; R, resistant.
b
Increase (1) or decrease (2) in resistance in the 12-year study period.
TABLE 4. Longitudinal increase in multidrug resistance
Organism
1993 2004
No. of MDR
isolates/total
no. of
isolates
a
%of
MDR
isolates
No. of MDR
isolates/total
no. of
isolates
%of
MDR
isolates
Pseudomonas aeruginosa 13/769 1.7 93/1,004 9.3
Escherichia coli 0/724 0 16/808 2.0
Klebsiella pneumoniae 26/513 5.1 84/633 13.3
Enterobacter cloacae 13/397 3.3 24/406 5.9
Acinetobacter spp. 19/285 6.7 101/338 29.9
Enterobacter aerogenes 6/213 2.8 0/154 0
Proteus mirabilis 1/174 0.6 1/142 0.7
Citrobacter freundii 5/95 5.3 7/63 11.1
a
Multidrug resistances is defined here as being resistant to one or more
extended-generation cephalosporins (ceftazidime, ceftriaxone, or cefotaxime),
one or more aminoglycosides (amikacin or tobramycin), and the fluoroquinolone
ciprofloxacin. MDR, multidrug resistant.
3356 LOCKHART ET AL. J. CLIN.MICROBIOL.

MIC
50
values decreased from ⱖ2␮g/ml in 1993 to 1996 to ⱖ1
␮g/ml in 2001 to 2004). In other words, carbapenem “MIC
creep” was not observed for the current study. Because of the
large number of hospitals involved in this study, our low rates
of carbapenem resistance likely reflect the average rate of
resistance nationwide and would not be influenced by regions,
such as New York City, where carbapenem resistance rates
might be considerably higher.
Amikacin was broadly active against the Enterobacteriaceae
and P. aeruginosa in our study, but 24% of Acinetobacter spp.
were noted to be nonsusceptible. These observations are sim-
ilar to those of Neuhauser et al. (20); however, as opposed to
their study, which reported essentially comparable activity pro-
files for amikacin and imipenem, we noted superior activity
with imipenem versus amikacin for all study isolates except P.
aeruginosa, where the reverse was true.
One of the most important observations from our study was
the consistent downward trend in ciprofloxacin activity versus
GNB from patients in U.S. ICUs over the period from 1993 to
2004. This was noted with 7 of the 10 organisms surveyed. E.
coli went from almost universal susceptibility in 1993 (i.e.,
0.9% resistance) to 17.3% resistance in 2004. Although cipro-
floxacin resistance with E. coli has been reported previously (8,
11, 19, 27), the high resistance rates noted at the end of our
study are truly alarming. This trend was not as apparent in a
previous analysis of the 1994-to-2000 data set (20).
Fluoroquinolone resistance has been observed frequently
for extended-spectrum ␤-lactamase-producing strains of E. coli
and K. pneumoniae (18). Given the manner in which isolates
were characterized in our study, we were are not able to reli-
ably assess extended-spectrum ␤-lactamase production; how-
ever, we observed only a twofold increase in ciprofloxacin
resistance rates for K. pneumoniae isolates between that of the
first 3-year period of this study and the last (i.e., 7.9% to
16.8%). When the data from 2004 alone were analyzed, little
correlation between ciprofloxacin resistance and multidrug re-
sistance was observed for E. coli, i.e., only 16% of ciprofloxa-
cin-resistant isolates were also found to be multidrug resistant.
Among other Enterobacteriaceae species, there was a twofold
increase in ciprofloxacin resistance with C. freundii and E.
cloacae and a fourfold increase with P. mirabilis.Acinetobacter
spp. (64%) and P. aeruginosa (29%) strains exhibited the high-
est levels of ciprofloxacin resistance. These rates are similar to
those reported in the MYSTIC study between 2002 and 2004
from a worldwide collection of isolates (29).
Several studies have linked fluoroquinolone resistance to
fluoroquinolone usage (16, 20). As reported previously, overall
fluoroquinolone usage is strongly linked to the emergence of
fluoroquinolone resistance among GNB, and once established,
resistance rates increase with increased usage. This relation-
ship was also apparent in our study. Of particular interest,
however, was the seemingly disproportionate effect of indi-
vidual fluoroquinolones as drivers of resistance. Specifically,
levofloxacin usage was much more strongly associated with
fluoroquinolone resistance than the usage of ciprofloxacin,
gatifloxacin, or moxifloxacin. With respect to potency versus
GNB, ciprofloxacin is more potent than levofloxacin, and gati-
floxacin and moxifloxacin are less potent still. Intuitively, the
use of less potent agents within an antimicrobial family would
seemingly be more likely to promote resistance than the use of
more potent agents. It may also be that when the potency of
specific agents drops to low enough levels, selective pressure
also diminishes.
The increasing prevalence of multidrug-resistant GNB in
U.S. ICUs is also disturbing. D’Agata previously noted a sub-
stantial increase in multidrug resistance among GNB in one
tertiary care hospital between 1994 and 2000 (4). In that study,
the most common profile was resistance to an aminoglycoside,
an extended-spectrum cephalosporin, and to ciprofloxacin. We
employed the same definition of multidrug resistance and ob-
served a substantial increase in multidrug resistance over the
12-year study period of our survey with C. freundii,E. cloacae,
and K. pneumoniae. While the overall percentage of multidrug-
resistant E. coli isolates in 2004 was small (2%), it represented
a significant increase over that of 1993 when no such isolates
were recovered. This trend toward increasing rates of multi-
drug-resistant GNB has also been observed for several other
studies of more limited scope than ours (9, 15, 23, 25, 31).
We noted a surprising trend toward increasing susceptibility
to ceftazidime with Acinetobacter species, C. freundii,E. aero-
genes,E. cloacae,K. pneumoniae,P. aeruginosa, and S. marc-
escens. We could find no other reports of a similar trend in the
literature. Friedland and colleagues (8) noted that between
1995 and 2000, ceftazidime resistance of Enterobacter spp. had
stabilized and had only slightly increased for K. pneumoniae
and E. coli. Fridkin et al. (7) reported similar results over a
TABLE 5. Fluoroquinolones usage levels between 1999 and 2004 and antimicrobial resistance among GNB between 1999 and 2004
a
Organism
R
2
values for fluoroquinolone resistance compared to that of antimicrobials shown
J01M Levofloxacin Ciprofloxacin Gatifloxacin Moxifloxacin
P. aeruginosa 0.7352 0.6624 0.1806 0.6473 0.1588
E. coli 0.7552 0.7262 0.5846 0.5099 0.6468
K. pneumoniae 0.5544 0.6193 0.6135 0.1816 0.07451
E. cloacae 0.5048 0.5852 0.0968 0.2224 0.0173
Acinetobacter spp. 0.5844 0.6724 0.6602 0.1976 0.6711
S. marcescens 0.1758 0.1212 0.4336 0.2023 0.566
E. aerogenes 0.0914 ⫺0.0338 ⫺0.1401 0.3243 ⫺0.1359
P. mirabilis 0.0556 0.1484 0.0879 ⫺0.1876 0.2782
K. oxytoca ⫺0.0721 ⫺0.1682 ⫺0.0307 0.0415 0.2849
C. freundii 0.4462 0.2455 0.1463 0.6528 0.3016
a
Adjusted linear regression values comparing antimicrobial usage levels of fluoroquinolones in the United States between 1999 and 2004 and rates of antimicrobial
resistance among GNB between 1999 and 2004. J01M, antimicrobial class of fluoroquinolones.
VOL. 45, 2007 ANTIMICROBIAL RESISTANCE AMONG GNB IN THE ICU 3357

shorter time frame (1996 to 1999) in the ICARE surveillance
study. In the NNIS surveillance study (10), ceftazidime resis-
tance of Acinetobacter spp. and of P. aeruginosa was noted to
increase over the same period of time examined in our study.
We are uncertain of the reason for this discrepancy since both
the NNIS study and our investigation were predicated on GNB
isolates from patients in the ICU. One important difference
between these two studies is that the NNIS program is based
on passive reporting of susceptibility test results from partici-
pating laboratories. As a result, the data were generally de-
rived from various different automated susceptibility test sys-
tems which happen to be in place in the routine clinical
microbiology laboratories of participating centers. In contrast,
the data in our study were based on the performance of ref-
erence standard broth microdilution MIC determinations that
had been subjected to rigorous quality controls. If ceftazidime
resistance is indeed becoming less common, it may reflect
diminished usage of this relatively older extended-spectrum
cephalosporin in favor of more recently introduced and more
potent parenteral ␤-lactam agents. Several recent studies have
demonstrated that decreased use of ceftazidime results in de-
creased ceftazidime resistance among GNB in the hospital
setting (1, 6, 30).
Our investigation has certain limitations. Although an at-
tempt was made to restrict testing to GNB of clinical signifi-
cance, in some cases, especially with isolates from the respira-
tory tract and urine specimens, it was impossible to know that
this objective was achieved. We do not believe, however, that
this was a major shortcoming, since resistance rates calculated
from isolates recovered exclusively from blood cultures were
essentially identical to rates derived from isolates from other
sites. Second, patient demographic information, such as age,
gender, primary source of infection, and individual antibiotic
histories, was not available to us, and as a result, no analysis
could be performed that could take these important factors
into account. Third, test isolates were not routinely available to
us for ancillary molecular characterization of either resistance
determinants or clonal relationships. Finally, antimicrobial us-
age data were available only as patient days of therapy based
on prescriptions for the entire country. No regional or individ-
ual hospital data for antimicrobial consumption were available
for analysis. Not withstanding these shortcomings, it is believed
that this study provides a unique, objective, and systematic
view of the scope and magnitude of the problem of antimicro-
bial resistance among GNB in ICU patients today in the
United States. The longitudinal length of this study and the
sheer number of isolates analyzed by a single methodology give
a unique look at the magnitude and scope of the current trend
in drug resistance among GNB. We were able to show that
while drug resistance has become a serious problem with some
antibiotics, especially ciprofloxacin, the rates of resistance to-
ward other antibiotics have remained stable for more than a
decade.
REFERENCES
1. Bamberger, D. M., and S. L. Dahl. 1992. Impact of voluntary vs. enforced
compliance of third-generation cephalosporin use in a teaching hospital.
Arch. Intern. Med. 152:554–557.
2. Clinical and Laboratory Standards Institute. 2006. Performance standards
for antimicrobial susceptibility testing; 16th informational supplement doc-
ument M100–S16. CLSI/NCCLS M100-S15. Clinical and Laboratory Stan-
dards Institute, Wayne, PA.
3. Cosgrove, S. E. 2006. The relationship between antimicrobial resistance and
patient outcomes: mortality, length of hospital stay, and health care costs.
Clin. Infect. Dis. 42(Suppl. 2):S82–S89.
4. D’Agata, E. M. 2004. Rapidly rising prevalence of nosocomial multidrug-
resistant, Gram-negative bacilli: a 9-year surveillance study. Infect. Control
Hosp. Epidemiol. 25:842–846.
5. Diekema, D. J., M. A. Pfaller, R. N. Jones, G. V. Doern, P. L. Winokur, A. C.
Gales, H. S. Sader, K. Kugler, and M. Beach. 1999. Survey of bloodstream
infections due to gram-negative bacilli: frequency of occurrence and antimi-
crobial susceptibility of isolates collected in the United States, Canada, and
Latin America for the SENTRY Antimicrobial Surveillance Program, 1997.
Clin. Infect. Dis. 29:595–607.
6. Empey, K. M., R. P. Rapp, and M. E. Evans. 2002. The effect of an antimi-
crobial formulary change on hospital resistance patterns. Pharmacotherapy
22:81–87.
7. Fridkin, S. K., H. A. Hill, N. V. Volkova, J. R. Edwards, R. M. Lawton, R. P.
Gaynes, J. E. McGowan, Jr., and the Intensive Care Antimicrobial Resis-
tance Epidemiology Project Hospitals. 2002. Temporal changes in preva-
lence of antimicrobial resistance in 23 U.S. hospitals. Emerg. Infect. Dis.
8:697–701.
8. Friedland, I., L. Stinson, M. Ikaiddi, S. Harm, and G. L. Woods. 2003.
Resistance in Enterobacteriaceae: results of a multicenter surveillance study,
1995–2000. Infect. Control Hosp. Epidemiol. 24:607–612.
9. Gales, A. C., R. N. Jones, J. Turnidge, R. Rennie, and R. Ramphal. 2001.
Characterization of Pseudomonas aeruginosa isolates: occurrence rates,
antimicrobial susceptibility patterns, and molecular typing in the global
SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin. Infect. Dis.
32(Suppl. 2):S146–S155.
10. Gaynes, R., J. R. Edwards, and National Nosocomial Infections Surveillance
System. 2005. Overview of nosocomial infections caused by gram-negative
bacilli. Clin. Infect. Dis. 41:848–854.
11. Goettsch, W., W. van Pelt, N. Nagelkerke, M. G. Hendrix, A. G. Buiting, P. L.
Petit, L. J. Sabbe, A. J. van Griethuysen, and A. J. de Neeling. 2000. In-
creasing resistance to fluoroquinolones in Escherichia coli from urinary tract
infections in the Netherlands. J. Antimicrob. Chemother. 46:223–228.
12. Ibrahim, E. H., G. Sherman, S. Ward, V. J. Fraser, and M. H. Kollef. 2000.
The influence of inadequate antimicrobial treatment of bloodstream infec-
tions on patient outcomes in the ICU setting. Chest 118:146–155.
13. Itokazu, G. S., J. P. Quinn, C. Bell-Dixon, F. M. Kahan, and R. A. Weinstein.
1996. Antimicrobial resistance rates among aerobic gram-negative bacilli
recovered from patients in intensive care units: evaluation of a national
postmarketing surveillance program. Clin. Infect. Dis. 23:779–784.
14. Jarvis, W. R., J. R. Edwards, D. H. Culver, J. M. Hughes, T. Horan, T. G.
Emori, S. Banerjee, J. Tolson, T. Henderson, R. P. Gaynes, et al. 1991
Nosocomial infection rates in adult and pediatric intensive care units in the
United States. National Nosocomial Infections Surveillance System. Am. J.
Med. 91:185S–191S.
15. Karlowsky, J. A., M. E. Jones, C. Thornsberry, I. R. Friedland, and D. F.
Sahm. 2003. Trends in antimicrobial susceptibilities among Enterobacteria-
ceae isolated from hospitalized patients in the United States from 1998 to
2001. Antimicrob. Agents Chemother. 47:1672–1680.
16. Kern, W. V., K. Klose, A. S. Jellen-Ritter, M. Oethinger, J. Bohnert, P. Kern,
S. Reuter, H. von Baum, and R. Marre. 2005. Fluoroquinolone resistance of
Escherichia coli at a cancer center: epidemiologic evolution and effects of
discontinuing prophylactic fluoroquinolone use in neutropenic patients with
leukemia. Eur. J. Clin. Microbiol. Infect. Dis. 24:111–118.
17. Kollef, M. H., G. Sherman, S. Ward, and V. J. Fraser. 1999. Inadequate
antimicrobial treatment of infections: a risk factor for hospital mortality
among critically ill patients. Chest 115:462–474.
18. Lautenbach, E., B. L. Strom, W. B. Bilker, J. B. Patel, P. H. Edelstein, and
N. O. Fishman. 2001. Epidemiological investigation of fluoroquinolone re-
sistance in infections due to extended-spectrum beta-lactamase-producing
Escherichia coli and Klebsiella pneumoniae. Clin. Infect. Dis. 33:1288–1294.
19. Livermore, D. M., D. James, M. Reacher, C. Graham, T. Nichols, P.
Stephens, A. P. Johnson, and R. C. George. 2002. Trends in fluoroquinolone
(ciprofloxacin) resistance in Enterobacteriaceae from bacteremias, England
and Wales, 1990–1999. Emerg. Infect. Dis. 8:473–478.
20. Neuhauser, M. M., R. A. Weinstein, R. Rydman, L. H. Danziger, G. Karam,
and J. P. Quinn. 2003. Antibiotic resistance among gram-negative bacilli in
U.S. intensive care units: implications for fluoroquinolone use. JAMA 289:
885–888.
21. NNIS System. 2003. National Nosocomial Infections Surveillance (NNIS)
System report, data summary from January 1992 through June 2003, issued
August 2003. Am. J. Infect. Control 31:481–498.
22. Paladino, J. A., J. L. Sunderlin, C. S. Price, and J. J. Schentag. 2002.
Economic consequences of antimicrobial resistance. Surg. Infect. 3:259–267.
23. Paterson, D. L. 2006. The epidemiological profile of infections with multi-
drug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin. In-
fect. Dis. 43(Suppl. 2):S43–S48.
24. Pfaller, M. A., R. N. Jones, G. V. Doern, and K. Kugler. 1998. Bacterial
pathogens isolated from patients with bloodstream infection: frequencies of
occurrence and antimicrobial susceptibility patterns from the SENTRY an-
3358 LOCKHART ET AL. J. CLIN.MICROBIOL.

timicrobial surveillance program (United States and Canada, 1997). Antimi-
crob. Agents Chemother. 42:1762–1770.
25. Pop-Vicas, A. E., and E. M. D’Agata. 2005. The rising influx of multidrug-
resistant gram-negative bacilli into a tertiary care hospital. Clin. Infect. Dis.
40:1792–1798.
26. Raymond, D. P., S. J. Pelletier, T. D. Crabtree, H. L. Evans, T. L. Pruett, and
R. G. Sawyer. 2003. Impact of antibiotic-resistant Gram-negative bacilli
infections on outcome in hospitalized patients. Crit. Care Med. 31:1035–
1041.
27. Rhomberg, P. R., and R. N. Jones. 2007. Contemporary activity of mero-
penem and comparator broad-spectrum agents: MYSTIC program report
from the United States component (2005). Diagn. Microbiol. Infect. Dis.
57:207–215.
28. Tumbarello, M., T. Spanu, M. Sanguinetti, R. Citton, E. Montuori, F. Leone,
G. Fadda, and R. Cauda. 2006. Bloodstream infections caused by extended-
spectrum-␤-lactamase-producing Klebsiella pneumoniae: risk factors, molec-
ular epidemiology, and clinical outcome. Antimicrob. Agents Chemother.
50:498–504.
29. Unal, S., and J. A. Garcia-Rodriguez. 2005. Activity of meropenem and
comparators against Pseudomonas aeruginosa and Acinetobacter spp. isolated
in the MYSTIC Program, 2002–2004. Diagn. Microbiol. Infect. Dis. 53:265–
271.
30. Urban, C., N. Mariano, N. Rahman, A. M. Queenan, D. Montenegro, K.
Bush, and J. J. Rahal. 2000. Detection of multiresistant ceftazidime-suscep-
tible Klebsiella pneumoniae isolates lacking TEM-26 after class restriction of
cephalosporins. Microb. Drug Resist. 6:297–303.
31. Wisplinghoff, H., M. B. Edmond, M. A. Pfaller, R. N. Jones, R. P. Wenzel,
and H. Seifert. 2000. Nosocomial bloodstream infections caused by Acineto-
bacter species in United States hospitals: clinical features, molecular epide-
miology, and antimicrobial susceptibility. Clin. Infect. Dis. 31:690–697.
VOL. 45, 2007 ANTIMICROBIAL RESISTANCE AMONG GNB IN THE ICU 3359