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Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. Antibiotic Resistance Among Gram-Negative Bacilli in US Intensive Care Units: Implications for Fluoroquinolone Use. JAMA. 2003;289(7):885–888. doi:10.1001/jama.289.7.885
Author Affiliations: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Tex (Dr Neuhauser); Department of Medicine, Rush Medical College, Chicago, Ill (Drs Weinstein and Quinn); Department of Medicine (Drs Weinstein and Quinn) and Department of Emergency Medicine (Dr Rydman), Cook County Hospital, Chicago, Ill; School of Public Health (Dr Rydman) and Department of Pharmacy Practice (Dr Danziger), University of Illinois at Chicago; and Department of Medicine, Louisiana State University School of Medicine, New Orleans (Dr Karam).
Caring for the Critically Ill Patient Section Editor:Deborah J. Cook, MD, Consulting Editor, JAMA.
Context Previous surveillance studies have documented increasing rates of antimicrobial
resistance in US intensive care units (ICUs) in the early 1990s.
Objectives To assess national rates of antimicrobial resistance among gram-negative
aerobic isolates recovered from ICU patients and to compare these rates to
Design and Setting Participating institutions, representing a total of 43 US states plus
the District of Columbia, provided antibiotic susceptibility results for 35 790
nonduplicate gram-negative aerobic isolates recovered from ICU patients between
1994 and 2000.
Main Outcome Measures Each institution tested approximately 100 consecutive gram-negative
aerobic isolates recovered from ICU patients. Organisms were identified to
the species level. Susceptibility tests were performed, and national fluoroquinolone
consumption data were obtained.
Results The activity of most antimicrobial agents against gram-negative aerobic
isolates showed an absolute decrease of 6% or less over the study period.
The overall susceptibility to ciprofloxacin decreased steadily from 86% in
1994 to 76% in 2000 and was significantly associated with increased national
use of fluoroquinolones.
Conclusions This study documents the increasing incidence of ciprofloxacin resistance
among gram-negative bacilli that has occurred coincident with increased use
of fluoroquinolones. More judicious use of fluoroquinolones will be necessary
to limit this downward trend.
Susceptibility data derived from national surveillance can be a barometer
for emerging resistance problems.1,2 Previously,
we published the results of a national intensive care unit (ICU) surveillance
study of aerobic gram-negative bacilli collected between 1990-1993.3 The study revealed a rising incidence of ceftazidime-resistant Klebsiella pneumoniae and Enterobacter species in ICUs. The purpose of the current study was to describe
national rates of antimicrobial resistance in ICUs between 1994-2000.
The surveillance program has been described previously.3 In
brief, each institution agreed to test 100 consecutive gram-negative aerobic
isolates recovered from ICU patients. Organisms were identified to the species
level. Susceptibility tests were performed with a standardized microtiter
minimal inhibitory concentration (MIC) panel (Microscan MKD MIC, Dade International
MicroScan, Sacramento, Calif). Participating laboratories used National Committee
for Clinical Laboratory Standards–recommended validation of MICs with
American Type Culture Collection test strains.3 Piperacillin/tazobactam
and cefepime were added to the panel in 1996 and 1998, respectively. Hospitals
were categorized based on teaching status and bed size. National fluoroquinolone
consumption data were obtained from IMS HEALTH Retail and Provider Perspective
(Plymouth Meeting, Pa) in conjunction with its MIDAS database. The data presented
are from nonduplicate isolates that we evaluated independently of the research
Study variables were subjected to univariate descriptive analysis. Non-normal
data were rank transformed before application of parametric testing when appropriate.
Pearson and Spearman rank order intercorrelational analyses of year of observation
were used to compare resistance rates and fluoroquinolone use. All statistical
analyses were performed using SAS release 8.0 for IBM PC Windows and SAS Version
6.14 for mainframe computers (SAS Institute Inc, Cary, NC).
A total of 35 790 isolates were collected during 1994-2000; 77
to 117 ICUs participated per year, representing 43 states plus the District
of Columbia. Approximately half of the hospitals repeatedly took part in this
program. The majority of institutions were teaching hospitals (85%) and were
intermediate to large sized (200-500 beds [59%]; >500 beds [38%]).
Pseudomonas aeruginosa was the most frequently
isolated organism (23%) followed by Enterobacter species
(14.0%), K pneumoniae (13.6%), and Escherichia coli (11.3%). The remaining 38.1% of isolates included Acinetobacter species (5.8%), Serratia
marcescens (5.4%), Stenotrophomonas maltophilia (4.3%), Proteus mirabilis (3.6%), Citrobacter species (2.9%), and Morganella morganii (0.9%).
Most isolates were cultured from the respiratory tract (51.5%), urine
(16.0%), blood (13.8%), or wounds (11.8%). Pseudomonas aeruginosa was the most frequent isolate from the respiratory tract (31.6%) and
wounds (24.9%); K pneumoniae was the most common
blood isolate (20.8%); and E coli was the most frequent
urine isolate (35.5%).
Antimicrobial agents could be grouped into 3 broad categories based
on overall in vitro activity (Table 1).
While the activity of most agents decreased 6% or less over the study period,
the overall susceptibility to ciprofloxacin decreased steadily from 86% in
1994 to 76% in 2000. Ciprofloxacin maintained excellent in vitro activity
against E coli, but showed reduced activity against
other organisms, especially P aeruginosa. Ciprofloxacin
resistance did not differ significantly in teaching vs nonteaching hospitals
or in hospitals with more than 500 beds vs hospitals with 500 beds or less.
The decline in ciprofloxacin susceptibility was associated significantly with
increasing national use of fluoroquinolones during the study period (Figure 1). Resistance to ciprofloxacin was
associated with cross-resistance to other broad-spectrum antimicrobial agents
We examined susceptibility data for gram-negative bacilli isolated from
ICU patients in 43 states and the District of Columbia. As in 1990-1993,3 amikacin (90%) and imipenem (89%) were the most active
agents. Our findings (Table 1)
suggest that there is an overall chance of 10% or greater that an infecting
gram-negative bacillus in an ICU patient will be resistant to any single agent,
which may help to explain the trend to increased use of multidrug regimens
for initial empirical therapy of suspected nosocomial infection.1-6
Our 1990-1993 data identified the rising incidence of ceftazidime-resistant K pneumoniae and Enterobacter species,
suggesting the widespread presence of plasmid-mediated extended-spectrum β-lactamases
(ESBLs) and of hyperproducers of type 1 chromosomal β-lactamases, respectively.
From 1990-1993 to 1994-2000, there was a further decline in the ceftazidime
susceptibility for K pneumoniae (93% vs 87%) and Enterobacter species (67% vs 63%), similar to the findings
of the most recently published Centers for Disease Control and Prevention
National Nosocomial Infections Surveillance data from 1994-1998.6
The most alarming trend detected in the current study was the decreasing
activity of ciprofloxacin. The overall susceptibility to ciprofloxacin among
aerobic gram-negative bacilli declined from 89% in 1990-19933 to
86% in 1994 to 76% in 2000. The most notable reductions in ciprofloxacin susceptibility
were seen with P aeruginosa (89% in 1990-19933 to 68% in 2000). The declines in activity of ciprofloxacin
correlate with a greater than 2.5-fold increase in use of quinolones (ciprofloxacin,
levofloxacin, ofloxacin)—popular agents for treating community-acquired
pneumonia, urinary tract infections, and skin and soft tissue infections—over
the past 10 years (Figure 1).
Cross-resistance has been observed with the newer fluoroquinolones against
ciprofloxacin-resistant gram-negative bacteria.7 While
there have been suggestions that fluoroquinolone resistance also is related
phenotypically to the presence of ESBLs,8,9 implying
that fluoroquinolone resistance could be driven by cephalosporin use, fluoroquinolone
resistance has not been linked genetically to resistance to other classes
of drugs. However, plasmid-mediated fluoroquinolone resistance has been described
recently,10 and fluoroquinolone use may select
for bacteria with heightened antibiotic efflux capability.11 Thus,
ciprofloxacin resistance may be associated with limited treatment options
for other classes of agents, as observed in our study (Table 2) and other studies.8,12
As with any large national surveillance study, these findings have limitations.
Molecular typing of organisms was not performed; therefore, we cannot exclude
the possibility of epidemics or clonal spread of bacteria. However, the large
number of study sites makes it unlikely that epidemics in an individual ICU
influenced our results. In addition, our analysis did not include or adjust
for potentially important confounders such as case mix, prior antibiotic exposure,
mechanical ventilation, or ICU length of stay. Although actual antibiotic
consumption data for the ICUs under study would allow for a more targeted
correlation of drug exposure and resistance, ecologic population data such
as ours can provide important support for analyses of resistance trends.13 Population-based antibiotic use data may be especially
important for the fluoroquinolones since the extensive use of these agents
in the community setting may affect hospital resistance rates. In fact, fluoroquinolones
are the only class of antibiotics for which resistance has been similar in
the ICU and non-ICU setting.2
In conclusion, our findings add to prior surveillance efforts by (1)
providing a decade-long perspective, (2) presenting results from 35 790
isolates from ICUs nationwide, (3) documenting the rising incidence of antibiotic-resistant
gram-negative bacilli, and (4) comparing these results with fluoroquinolone
use trends. This work expands on other research, including a recent international
study in 5 European countries documenting a high incidence of reduced antibiotic
susceptibility among gram-negative bacteria.14 We
have focused on ciprofloxacin resistance because of the increasingly frequent
use of fluoroquinolones for treatment of urinary tract infections and pneumonia
in the community and hospital setting. Fluoroquinolones that are not affected
by currently circulating resistance mechanisms need to be developed to conserve
this class of agents.15 In the meantime, ongoing
surveillance and more judicious use of fluoroquinolone antibiotics16 will be necessary to limit this downward trend in
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