James J. Rahal, Carl Urban, David Horn, Katherine Freeman, Sorana Segal-Maurer, James Maurer, Noriel Mariano, Sheila Marks, Janice M. Burns, Dana Dominick, Mimi Lim. Class Restriction of Cephalosporin Use to Control Total Cephalosporin Resistance in Nosocomial Klebsiella. JAMA. 1998;280(14):1233–1237. doi:10.1001/jama.280.14.1233
From the Infectious Disease Section, Department of Medicine (Drs Rahal, Urban, and Segal-Maurer and Mr Mariano), and the Departments of Surgery (Dr Maurer), Nursing (Mss Marks, Burns, and Lim), and Pharmacy (Ms Dominick), New York Hospital Medical Center of Queens and Cornell University Medical College, and the Department of Biostatistics (Dr Freeman), Montefiore Medical Center and Albert Einstein College of Medicine, New York; and Merck & Co Inc, West Point, Pa (Dr Horn).
Context.— Resistance to most or all cephalosporin antibiotics in Klebsiella species has developed in many European and North American
hospitals during the past 2 decades.
Objective.— To determine if restriction of use of the cephalosporin class of antibiotics
would reduce the incidence of patient infection or colonization by cephalosporin-resistant Klebsiella.
Design.— A before-after comparative 2-year trial.
Setting.— A 500-bed, university-affiliated community hospital in Queens, NY.
Patients.— All adult medical and surgical hospital inpatients.
Intervention.— A new antibiotic guideline excluded the use of cephalosporins except
for pediatric infection, single-dose surgical prophylaxis, acute bacterial
meningitis, spontaneous bacterial peritonitis, and outpatient gonococcal infection.
All other cephalosporin use required prior approval by the infectious disease
Main Outcome Measure.— Incidence of patient infection or colonization by ceftazidime-resistant Klebsiella during 1995 (control period) compared with 1996
Results.— An 80.1% reduction in hospital-wide cephalosporin use occurred in 1996
compared with 1995. This was accompanied by a 44.0% reduction in the incidence
of ceftazidime-resistant Klebsiella infection and
colonization throughout the medical center (P<.01),
a 70.9% reduction within all intensive care units (P<.001),
and an 87.5% reduction within the surgical intensive care unit (P<.001). A concomitant 68.7% increase in the incidence of imipenem-resistant Pseudomonas aeruginosa occurred throughout the medical
center (P<.01). All such isolates except one were
susceptible to other antibiotics.
Conclusion.— Extensive cephalosporin class restriction significantly reduced nosocomial,
plasmid-mediated, cephalosporin-resistant Klebsiella
infection and colonization. This occurred at the price of increased imipenem
resistance in P aeruginosa, which remained susceptible
to other agents. Thus, an overall reduction in multiply-resistant pathogens
was achieved within 1 year.
ANTIBIOTIC RESISTANCE among nosocomial pathogens has been an evolving
process since the development of penicillin-resistant Staphylococcus
aureus more than 40 years ago.1 During
the past decade, resistance in gram-negative bacilli to cephalosporin antibiotics
has accelerated because of the appearance of plasmid-mediated extended spectrum β-lactamases
(ESBLs) inKlebsiella, Escherichia
coli, and Proteus mirabilis.2,3
More recently, cephamycin resistance in ESBL-producing Klebsiella has occurred because of decreased antibiotic uptake and/or
acquisition of a novel ESBL.4,5
Thus, most clinicians have relied on imipenem, piperacillin-tazobactam, ciprofloxacin,
or amikacin for effective treatment of serious infection due to multiresistant Klebsiella.6,7
At our institution an outbreak of ESBL-producing Klebsiella infection occurred in 1990 despite an antibiotic restriction
program that required prior approval of all third-generation cephalosporins
and imipenem.8 From 1991 to 1995 the hospital
prevalence of ESBL-producing Klebsiella gradually
increased from 5 to 10 isolates to 10 to 20 isolates per month. Also, in 1995,
cephamycin resistance emerged in approximately 30% to 40% of ESBL-producing Klebsiella.5 This ominous
development created a unique situation in which all cephalosporin/cephamycin
derivatives became ineffective against an increasing proportion of Klebsiella isolates.
There is almost universal agreement that increasing antimicrobial resistance
is related to selective pressure exerted by the use of these agents.9,10 Withdrawal of such pressure has been
suggested frequently as a method by which specific resistance may be reversed.10,11 In addition, in vitro propagation
of ESBL-producing Klebsiella in the absence of antibiotics
has resulted in reversion to cephalosporin susceptibility.12
The purpose of this study was to test the clinical corollary of this
phenomenon, specifically, that hospital-wide restriction of use of a specific
class of antimicrobial agents (cephalosporins/cephamycins) would result in
significant reduction of resistance to the restricted class. Following our
prior restriction of only late-generation cephalosporins, increased imipenem
use was accompanied by the emergence of imipenem-resistant Acinetobacter.13 After control of this
outbreak, imipenem resistance was limited to Pseudomonas
aeruginosa. Thus, a secondary purpose of this study was to determine
whether class restriction of cephalosporins would further increase both the
use of imipenem and resistance to this agent in P aeruginosa.
The study plan included the following objectives: (1) to restrict the
hospital use of parenteral and oral cephalosporins, with 5 specific exceptions,
between January 1, 1996, and December 31, 1996, and to compare the incidence
of colonizing and infecting isolates of ceftazidime-resistant Klebsiella with that recorded by identical surveillance methods from
January 1, 1995, to December 31, 1995; (2) to compare the incidence of colonizing
and infecting isolates of imipenem-resistant P aeruginosa during the same periods; (3) to compare parenteral cephalosporin and
imipenem-cilastatin sodium use during 1995 and 1996 by examination of pharmacy
case records; (4) to make the above comparisons using surveillance and antibiotic
use data from the entire hospital, individual intensive care units, and combined
intensive care units.
Surveillance of multiresistant pathogens in our 500-bed medical center
has been conducted for purposes of infection control since 1989. Following
our initial identification of ceftazidime-resistant Klebsiella and imipenem-resistant Acinetobacter in the
years 1989 and 1990, we conducted surveillance of all ceftazidime- or imipenem-resistant
isolates of E coli, Klebsiella, Enterobacter, Acinetobacter, and P aeruginosa.8
For purposes of this study, identical surveillance methods were conducted
in 1995 prior to hospital-wide cephalosporin restriction and in 1996 after
such restriction had been implemented. Infection control practitioners reviewed
daily susceptibility data from the clinical microbiology laboratory on all
of the above species. Cultures were obtained according to clinical indications.
All ceftazidime- or imipenem-resistant isolates were recorded according to
body site and hospital location. One isolate was recorded per body site per
patient. The number of patients harboring ceftazidime- or imipenem-resistant
isolates of each species was recorded, as well as the number of patients harboring
each species, regardless of antibiotic susceptibility. From these data, the
proportion of ceftazidime and imipenem resistance within each species was
calculated monthly. Also, the incidence of ceftazidime or imipenem resistance
for each species was defined by a ratio equal to the total number of colonized
and infected patients (patient-related isolates) divided by the average daily
census (patient-days/days per month). Incidence ratios were determined for
the total hospital, individual intensive care units, and combined intensive
care units. Colonization or infection by each isolate was determined by criteria
of the Centers for Disease Control and Prevention, Atlanta, Ga.14
Ceftazidime- or imipenem-resistant isolates from patients admitted from nursing
homes or other community sources were recorded but were not included in the
calculation of nosocomial incidence unless recovery of the isolate occurred
72 hours or more after admission. Isolates recovered within 72 hours of admission
from a nursing home were defined as nursing home associated.
All patients from whom ceftazidime-resistant Klebsiella (or other gram-negative bacilli) were recovered were cared for with
standard contact precautions. Those in intensive care units were placed in
a cohort. This policy remained constant during both study years.
Antibiotic therapy was prescribed by the house staff and attending physicians
with consultative advice by the hospital's infectious disease section. During
1995, approval by the infectious disease fellows or attending physicians was
required for the use of late-generation cephalosporins (ceftazidime, ceftriaxone,
cefotaxime) and imipenem-cilastatin beyond a single dose for immediate therapy.
Approval was obtained by telephone or formal consultation with suggestions
for alternative therapy, as indicated. In 1996, the hospital's pharmacy and
therapeutics committee adopted an antibiotic utilization guideline, which
required such approval for all-hospital cephalosporin use (parenteral and
oral) with the exceptions of pediatric infection and use of ceftriaxone for
treatment of meningitis or presumed gonococcal infection, cefotaxime for presumed
spontaneous bacterial peritonitis, and cefazolin for surgical prophylaxis.
Treatment with imipenem required the same approval with the exception of use
in the medical, surgical, and cardiac intensive care units. In these units,
imipenem use was allowed for 72 hours. Continued administration then required
approval. The following parenteral antibacterial agents were available without
prior approval: ampicillin-sulbactam, piperacillin-tazobactam, trimethoprim-sulfamethoxazole,
doxycycline, ofloxacin, gentamicin, tobramycin, amikacin, oxacillin sodium,
erythromycin, clindamycin, and vancomycin hydrochloride. Ciprofloxacin was
available without prior approval in intensive care units only. Available oral
antibiotics were penicillin, ampicillin, amoxicillin, amoxicillin–clavulanate
potassium, erythromycin, clarithromycin, clindamycin, dicloxacillin sodium,
doxycycline, ofloxacin, ciprofloxacin, and trimethoprim-sulfamethoxazole.
All physicians annually received a summary of the hospital's antibiotic
susceptibility patterns. For this study, the rationale for new guidelines
was reinforced with presentations by members of the infectious disease section
at conferences and grand rounds.
The use of cephalosporins and imipenem throughout the hospital and in
individual intensive care units in 1995 and 1996 was recorded after examining
all noncomputerized pharmacy patient records and by retrieving computerized
data from the remaining portion of patient records.
The incidence ratios for ceftazidime-resistant Klebsiella and imipenem-resistant P aeruginosa were
computed monthly during 1995 and 1996. Differences between the 2 years with
regard to the ratios were tested in 2 ways. The first was to consider the
2 years as independent samples (unpaired) and to perform a distribution-free
analysis (Wilcoxon rank sum test) since sample sizes were small and ratios
were typically not normally distributed. The second method, which accounted
for possible seasonal variations, involved pairing the ratios by corresponding
months and testing their differences for significance using a Wilcoxon signed
Monthly data describing use of all cephalosporins, individual cephalosporins,
and imipenem-cilastatin were analyzed in the same manner.
Table 1 demonstrates statistically
significant reductions in hospital cephalosporin use, accompanied by a similarly
significant increase in imipenem use in 1996 as compared with 1995. The average
daily census for the hospital in 1995 and 1996 remained essentially constant
(376 and 368, respectively). The use of all cephalosporins decreased by 80.1%,
while the use of ceftazidime and cefotetan decreased by 72.5% and 95.7%, respectively.
A 140.6% increase in imipenem-cilastatin use occurred in 1996. The majority
of this increase was in the intensive care units.
Table 2 provides the geographic
source of all patient-related resistant isolates of both species in 1995 and
1996, including (1) those isolated from nosocomial sources, (2) those isolated
within 72 hours of admission from a nursing home, (3) those isolated from
outpatients, (4) those isolated from patients seen in the emergency department,
and (5) those isolated from patients in an affiliated nursing home but not
admitted to the hospital.
Among hospitalized patients, the proportion of ceftazidime-resistant Klebsiella that was nursing home associated, rather than
nosocomial, rose from 15.3% in 1995 to 27.0% in 1996, despite fewer total
isolates in 1996. This was not true for the nursing home–associated
proportion of imipenem-resistant P aeruginosa, which
declined from 14.1% in 1995 to 11.0% in 1996.
The proportion of all Klebsiella patient isolates
that were ceftazidime resistant declined from 19.6% in 1995 to 14.2% in 1996.
The proportion of all P aeruginosa patient isolates
that were imipenem resistant rose from 8.9% in 1995 to 16.7% in 1996.
The absolute number of patient-related ceftazidime-resistant Klebsiella isolates decreased hospital-wide from 150 in 1995 to 84
in 1996, a 44.0% reduction (Table 3).
The greatest reductions occurred in all intensive care units combined, from
55 to 16 isolates (70.9% reduction) and particularly in the surgical intensive
care unit, from 40 to 5 isolates (87.5% reduction). The highest monthly incidence
in 1996 occurred in January, suggesting a lag period prior to the effect of
cephalosporin restriction. The changes in incidence, when related to average
daily census, were statistically significant hospital-wide and in the intensive
care units by unpaired (P<.01 and P<.05, respectively) and paired (P<.001
to P<.01) analyses. Changes in the medical and
cardiac intensive care units were not statistically significant. The hospital-wide
incidence of infection due to ceftazidime-resistant Klebsiella declined from 0.75 to 0.48 per 1000 patient-days, a 36% reduction.
Eight ceftazidime-resistant Klebsiella isolates were
resistant to imipenem and all other antibiotics (except polymyxin B sulfate)
in 1995 and none in 1996.
Imipenem-ResistantP aeruginosa. The absolute number of patient-related imipenem-resistant P aeruginosa isolates increased hospital-wide from 67 in 1995 to 113
in 1996, a 68.7% increase (Table 4).
The greatest increase occurred in all intensive care units combined, from
20 to 35 isolates (75.0% increase). The changes in incidence when related
to average daily census were statistically significant hospital-wide (P<.01) and in all intensive care units (P<.01). Among individual intensive care units, only the cardiac
care unit demonstrated a significant increase in incidence by unpaired analysis
(P<.05). The hospital-wide incidence of infection
due to imipenem-resistant P aeruginosa rose from
0.35 to 0.55 per 1000 patient-days, an increase of 57%. All isolates except
1 remained susceptible to an alternative agent.
Anatomic Source and Nosocomial Distribution of Ceftazidime-ResistantKlebsiellaand Imipenem-ResistantP aeruginosa. The decrease in nosocomial ceftazidime-resistant Klebsiella during 1996 occurred primarily in the number of patient-related
sputum isolates which were reduced by more than two thirds (Table 5). The number of pulmonary infections were reduced proportionately.
A two-thirds increase in imipenem-resistant P aeruginosa occurred predominantly among sputum isolates with a proportionate
increase in pulmonary infections. Blood isolates of ceftazidime-resistant Klebsiella were reduced by half in 1996, while those of
imipenem-resistant P aeruginosa remained at a low
Previous attempts to reduce ESBL-mediated resistance to cephalosporins
in Klebsiella by antibiotic control have focused
on restriction of ceftazidime or all third-generation cephalosporins. Reduction
of resistance by such restriction plus infection control measures, or infection
control alone, has been described.15,16
Other studies have failed to demonstrate any such reduction or have yielded
mild-to-moderate declines in resistance by restriction of third-generation
cephalosporins, with or without concomitant changes in infection control policies.17- 20 At
our institution, approval by an infectious disease physician was required
for use of all late-generation cephalosporins (ceftazidime, cefotaxime, ceftriaxone)
and imipenem from 1988 through 1995. Nevertheless, the prevalence of ceftazidime-resistant Klebsiella increased steadily in association with newly
superimposed cephamycin (cefotetan) and imipenem resistance. Thus, we chose
to test the concept of total antibiotic class restriction, which resulted
in an 80.1% reduction of all cephalosporin use in 1996 and a 44% decline in
the incidence of ceftazidime-resistant Klebsiella
compared with 1995. The greatest reduction, by 87.5%, occurred in the surgical
intensive care unit. This was associated with a shift in the predominant site
of ceftazidime-resistant Klebsiella from sputum of
patients in intensive care units to the urine of those in general medical
and surgical units. The incidence of pulmonary infection and colonization
by ceftazidime-resistant Klebsiella in the intensive
care units declined in 1996, while such urinary infection and colonization
in general medical and surgical units persisted. Concomitantly, the proportion
of hospitalized patients colonized or infected with nursing home–associated
ceftazidime-resistant Klebsiella increased almost
2-fold in 1996. Thus, although the incidence of ceftazidime-resistant Klebsiella was reduced significantly hospital-wide, it
persisted primarily in the urine of less acutely ill patients, often as hospital-acquired
colonizing organisms in those admitted from nursing homes.
Interestingly, the highest incidence of ceftazidime-resistant Klebsiella in 1996 occurred in the first month of that
year. By comparing calendar years 1995 and 1996, we did not estimate a lag
period between change in cephalosporin use and a subsequent change in resistance.
Thus, omission of a lag period may have diminished the true effect of cephalosporin
restriction in 1996. In a similar study by Ma et al,20
conducted in the late 1970s, intensive cephalosporin restriction resulted
in a 46% reduction of cephalothin-resistance among Klebsiella isolates but only after a 1-year lag. In our study the reduction in
ceftazidime resistance after 1 month of cephalosporin restriction may have
been because of the simultaneously increased use of imipenem, particularly
in intensive care units. Similarly, a reduction in the prevalence of ceftazidime-resistant Klebsiella was noted by Rice et al7
within 1 year after restriction of ceftazidime and introduction of piperacillin-tazobactam.7 In our institution, prior failure of third-generation
cephalosporin restriction alone may have been due to the continued use of
cefotetan, a cephamycin that selected for a novel ESBL among ceftazidime-resistant
strains of Klebsiella.5
Whether restriction of only third-generation cephalosporins and cephamycins
would have yielded the same results as total class withdrawal remains to be
Despite the complexity of factors that influence the incidence of antibiotic
resistance, the results of this study suggest that class restriction of use
of cephalosporins was the major determinant in the hospital-wide reduction
of ceftazidime-resistant Klebsiella in 1996. Methods
of infection control, detection of ceftazidime-resistant isolates, and exclusion
of multiple isolates from the same patient source remained constant during
1995 and 1996. However, new antibiotic guidelines may have increased awareness
of cephalosporin resistance sufficiently to alter personnel behavior and affect
outcome. Further, the efficacy of antibiotic restriction is influenced by
the activity of substituted agents and by the prevalent mechanisms of resistance.
Dissemination of resistance genes by bacterial conjugation and plasmid or
transposon transfer, as in ceftazidime-resistant Klebsiella, leads rapidly to large polyclonal populations of resistant organisms,
which may escape the most stringent infection control efforts. Since many
resistant genes may be transferred on the same plasmid, clinical use of any
of several antibiotics may place selective pressure which favors survival
of that plasmid. Thus, antibiotic class restriction alone is unlikely to eliminate
plasmid-mediated antimicrobial resistance. Antibiotic restriction and infection
control play complementary roles in preventing both the selection and spread
of resistant bacterial pathogens. Our ongoing molecular epidemiologic studies
by pulsed-field gel electrophoresis have demonstrated multiple clusters (defined
by 75%-90% genetic similarity) among ceftazidime-resistant Klebsiella. This finding suggests that nosocomial transmission may
be responsible for a persistent, but lower, incidence of ceftazidime resistance
following cephalosporin class restriction.
The reduction in cephalosporin resistance among our nosocomial Klebsiella isolates was accompanied by an increased incidence
of imipenem-resistant P aeruginosa. Unlike our earlier
experience with increased use of imipenem, imipenem-resistant Acinetobacter did not appear during 1996.15
Imipenem resistance in P aeruginosa among North American
isolates is due primarily to an alteration in outer membrane permeability,
possibly combined with slow hydrolysis by class I β-lactamases.21 Both mechanisms are chromosomal rather than plasmid
mediated. Permeability alterations may result in selective resistance to carbapenems
or multidrug resistance. However, all of our imipenem-resistant P aeruginosa isolates, with 1 exception, remained susceptible to other β-lactam
agents, quinolones, or aminoglycosides. In contrast, our ceftazidime-resistant Klebsiella strains were frequently resistant to all antibiotics
except imipenem, and those strains that developed imipenem resistance were
not susceptible to any commonly used agent.5
Thus, the decrease in ceftazidime-resistant Klebsiella
that occurred in 1996 represented an overall reduction in nosocomial multiresistant
Because nosocomial antimicrobial resistance patterns vary widely among
institutions, antibiotic use policies must be adjusted in response to specific
situations. Class restriction of cephalosporins, if adopted, need not be permanent
but may lead to rotation of antibiotic classes in response to evolving resistance
patterns. A recent position paper by the Society for Healthcare Epidemiology
of America, Mount Royal, NJ, and Infectious Diseases Society of America, Alexandria,
Va, has proposed methods to "interdict the dissemination of resistant strains."22 Implementation of these methods requires multidisciplinary
collaboration to define and monitor resistance; identify mechanisms; characterize
resistant organisms phenotypically and genotypically; maintain control of
selected antibiotics; educate medical personnel to achieve cooperation; establish
stable infection control methods; and measure outcomes. Strong administrative
and medical staff support are essential to such a collaboration. Our study
demonstrates that application of these elements to a program of extensive
antimicrobial class restriction can yield positive results but not without
the potential development of new and possibly unexpected resistance patterns.
Further refinement of such methods and the addition of novel microbiologic,
epidemiologic, pharmacologic, and clinical techniques will be necessary to
address the continuing challenge of antimicrobial resistance.