Role of Ertapenem

in the Era of
Antimicrobial Resistance
Predictive Factors for Multidrug-Resistant Organisms
Yehuda Carmeli
Tel Aviv Medical Center, Israel; Beth Israel Deaconess Medical Center
Harvard Medical School, Boston, Massachusetts, USA

The occurrence of organisms

resistant to single or multiple
antimicrobial agents represents
an important and expanding
clinical problem throughout the
world. Antimicrobial resistance
can not only restrict practitioners
in their use of some therapeutic
agents but can also contribute
to treatment failures. Thus, it is
important for all health care
professionals to be alert to the
diversity, prevalence, microbial
characteristics, and appropriate
treatment of resistant organisms
in their particular clinical setting.
Figure 1. Proportion of fluoroquinolone-resistant E. coli isolates reported by countries participating
in EARSS in 2004. Reproduced with permission from the EARSS Annual Report 2004.1

This article reviews the scope of the growing
antimicrobial resistance problem, identifies those
patients who might be at particular risk of
developing infections of resistant organisms,
summarizes a risk stratification procedure to
serve as a guide to the judicious use of
antibiotics, and suggests when to prescribe
carbapenems, such as ertapenem, to treat
patients with confirmed or suspected resistant
organisms.
Increasing Occurrence of Resistant
Organisms Throughout the World
Numerous epidemiological studies in various
countries and clinical settings illustrate the
increasing frequency of occurrence of resistant
organisms. According to the European
Antimicrobial Resistance Surveillance System
(EARSS), a network of national surveillance centers
that monitor antimicrobial resistance in 31
countries, fluoroquinolone-resistant Escherichia coli
isolates are widespread across Europe and have
increased from 9% in 2001 to 14% in 2004.1 In
southern European countries such as Italy, Spain,
and Portugal, the proportion of fluoroquinolone-
resistant isolates of E. coli rates is as high as 25%
to 50% (Fig. 1).1 Increasing rates of quinolone-
resistant E. coli in blood isolates have also been
reported in the US and England over the period
1995 to 2002 (Fig. 2).2 These statistics are
particularly important given that E. coli represents
the most frequent gram-negative rod organism
identified in blood cultures.
The National Nosocomial Infections Surveillance
System (NNIS) has also reported a similar
increasing trend in the resistance of Klebsiella
pneumoniae to third generation cephalosporins
in patients with hospital-onset infections over
the period 1989 to 2003.3 This trend applies to
both intensive care unit (ICU) patients as well
as nonintensive care patients. Of particular
concern is the dramatic rise in the percent of
resistance of K. pneumoniae in the ICU setting
in 2003.
 antibiotics including piperacillin-tazobactam, ciprofloxacin,
levofloxicin, ampicillin, and gentamicin are very low (Fig. 3).
Quinolone-resistant E. coli blood isolates In fact, taking a break-point of 80%, only the carbapenems
represent reliable therapy for ESBL producers.
12
% ciprofloxacin resistant

Collectively, these data indicate a dramatic change in the

10
8 cephalosporins, aminoglycosides, quinolones, and
6 trimethoprim-sulfamethoxazole (TMP/SMX) are now
4
2 drug resistance rather than single-drug resistance.
0
1995 1996 1997 1998 1999 2000 2001
England US
Figure 2. Increasing frequency of quinolone-resistant E. coli in blood isolates in
England (1995–2001) and the US (1997–2002). Adapted from Livermore DM et al2
and Biedenback DJ et al.4
In a recent review, Turner described a high incidence of
expanded-spectrum beta-lactamases (ESBLs) mainly in E.
coli, K. pneumoniae, and Proteus mirabilis.5 The incidence of
ESBL-producing K. pneumoniae varied by geographic
region, with the highest rate in eastern Europe and South
America (>50% of isolates) and the lowest rate in North
America and northern Europe (12.3% and 16.7%,
respectively). ESBLs are particularly clinically relevant since
they render all penicillins and cephalosporins ineffective. In
addition, ESBL-producing organisms frequently possess
resistance to other classes of antibiotics, such as
aminoglycosides, fluoroquinolones, and piperacillin-
tazobactam. This assertion is illustrated by the findings of a
9-year survival study (1994 to 2002) showing a rapidly rising
prevalence of the proportion of nosocomial multidrug
resistance (3 or more antibiotic classes) to gram-negative
bacilli (Pseudomonas aeruginosa, Enterobacter spp, E. coli,
Klebsiella spp, and Proteus spp).6 Susceptibilities of isolates
of ESBLs-producing E. coli and Klebsiella spp. to a variety of
Susceptibilities of 1030 ESBL-
producing E. coli & Klebsiella spp.
100
90
80
% Susceptibility
paradigm of antibiotic therapy. Resistance to penicillins,
coexisting in organisms isolated from patients, and, as a
result, emphasis should be placed on managing multiple-
2002
Choice of Antibiotic in Gram-Negative
Sepsis Impacts Clinical Outcome
In light of the increased occurrence of MDR, the appropriate
choice of antimicrobial therapy is critical to help avert
treatment failures. A recent literature review by Bochud and
colleagues indicates that early and appropriate antibiotic
therapy (defined as use of at least one antibiotic active in
vitro against causative pathogen) markedly improves the
outcome of patients with both gram-negative and gram-
positive bacteremia and severe sepsis or septic shock
(Fig. 4).8 For example, in patients with gram-negative
bacteremia and sepsis, appropriate antibiotic therapy was
associated with an overall mortality rate half that observed in
patients receiving inappropriate therapy (28% vs. 49%,
p<0.001). The mortality rate is even higher in patients with
ESBL-producing bacteremia, with death occurring in
approximately 30% to 80% of patients.
Who Is at Risk for Resistant Gram-Negative
Infections?
Changes in our health care system have markedly impacted
how patients with bloodstream infections are managed, with
a shift in the care of sick individuals from hospitals to the
community. Outpatients tend to be older, sicker, and receive
more intravenous therapies at home. In addition, more
patients are being treated in nursing homes and long-term
care facilities. As a result, resistant organisms are spreading
from the hospital setting into the community. This has
resulted in an erosion of the traditional classification of
infections as either community-acquired or hospital-acquired
(nosocomial).
As a result, a new classification system for acquisition of

70 bacteremia has evolved and includes 3 broad categories:

60
50 1) Nosocomial infections (those which occur after 72
40 hours in hospital and usually result from the use of
30 invasive devices and procedures)
20
10 2) Health-care–associated infections (similar to
0 nosocomial in many patient characteristics)
m

in

cin

cin

n
zo

ici
ac
ne

ne

ne

Ta

xa

ika

am
lox
pe

ipe

pe

p-

flo

3) True community-acquired infections

Am

nt
ta

ro

Pi

of
Im

vo
Er

Ge
Me

pr

Le
Ci

To help physicians differentiate between patients with

resistant organisms and those without, it is appropriate to
Figure 3. Susceptibilities of 1030 ESBL-producing E. coli and Klebsiella spp. to review the following prediction rules.
various antibiotic regimens. Adapted from Colodner R et al.7

2

Adequacy of therapy in GNR sepsis
Underlying Mortality with Mortality without
disease appropriate therapy appropriate therapy
combined data (range) combined data (range)
Rapidly 84% 85%
fatal (80%–86%) (71%–100%)
Ultimately 42% 67%
fatal (39%–45%) (63%–72%)
Nonfatal 10% 29%
(0%–13%) (23%–31%)
Total 28% 49%
(22%–32%) (47%–51%)
Figure 4. Impact of the appropriateness of antibiotic therapy on the
mortality of gram-negative bacteremia. Adapted from Bochud PY et al.8
GNR = gram-negative rods; NS = not significant
Prediction Rule 1
Health-care–associated gram-negative rod infections
are likely to be caused by resistant Enterobacteriaceae
and are unlikely to be caused by nonfermenters unless
invasive procedures have been performed.
Fluoroquinolone use is significantly associated with
the occurrence of fluoroquinolone-resistant
Enterobacteriaceae. According to a pooled analysis
of 10 case-controlled studies, recent fluoroquinolone
exposure among patients with Enterobacteriaceae
infections resulted in an 18.7-times higher risk of
developing fluoroquinolone-resistant infections
compared with individuals not exposed to
fluoroquinolone.9
Prediction Rule 2
Infections occurring after exposure to an antibiotic
agent suggest the development of resistance to this
agent and an increased likelihood of resistance to all
co-selected agents.
Co-selection of multidrug resistance (MDR) is
suggested by the presence of resistance to penicillin,
cephalosporins, aminoglycosides, trimethoprim-
sulfamethoxazole, or quinolones.
In light of these prediction rules, a system of risk
stratification for the development of resistant
organisms can be developed that is based on an
assessment of the degree of contact between
patients and the health care system, prior antibiotic
treatment, and patient characteristics (Fig. 5).
Resistant pathogens should not be suspected if
the patient has had no contact with the health care
system, no recent antibiotic treatment, and if the
patient is young with few comorbid conditions.
The presence of resistant Enterobaceriaceae (but
not nonfermenters/non-Pseudomonas) should be
considered if the patient has had contact with the
health care system (e.g., recent hospital admission,
nursing home, dialysis) but has not had any invasive
procedures, or if the patient has received recent
p Value therapy with antibiotics. The presence of
Pseudomonas should be suspected if the patient
has been in hospital or ICU for an extended period
(e.g., >5 days) and/or has developed an infection
NS
after undergoing invasive procedures, or if the patient
has specific comorbid conditions that put the patient
<0.001 at higher risk for Pseudomonas infections (e.g.,
cystic fibrosis, advanced Acquired Immunodeficiency
Syndrome [AIDS]).
<0.001
Multidrug Resistance and the
<0.001
New Era of Carbapenem Use
Due to the increasing occurrence of MDR, an era of
high carbapenem use is evolving. MDR is common
among gram-negative rod organisms, mostly among
ESBL producers. For infections suspected to be
caused by ESBL producers, carbapenems are the
most reliable empiric therapy and are also more
effective than other classes of directed therapy.
Ertapenem—Pharmacologically
Different from Other Carbapenems
Three basic groups of carbapenems can be
distinguished on the basis of their spectrum of
activity10
•Group 1 (e.g., ertapenem) exhibits broad coverage
against gram-positive, gram-negative, and
anaerobes, but limited activity against
nonfermentative gram-negative bacilli
•Group 2 (e.g., imipenem, meropenem) also
possesses a broad spectrum of activity as well as
activity against P. aeruginosa and Acinetobacter
baumannii
•Group 3 (none currently licensed) with activity
against methicillin-resistant staphylococci
Risk Stratification
A. Contact with the health care system
(1) no contact
(2) contact with health care (e.g., recent admission, nursing
home, dialysis) without invasive procedures
(3) long hospitalization and/or invasive procedures
B. Antibiotic treatment
(1) no treatment
(2) recent treatment
C. Patient characteristics
(1) young, few comorbid conditions
(2) old or multiple comorbidities
(3) cystic fibrosis, structural lung disease, advanced
AIDS, neutropenia, other severe immunodeficiency
Figure 5. Risk stratification based on an assessment of the degree of
contact between patients and the health care system, prior antibiotic
treatment, and patient characteristics.
3
 Intra-Abdominal Surgery with INVANZ™
Ertapenem pharmacokinetics Study (OASIS-1), OASIS-2, and
1000
Plasma ertapenem concentration (mg/L) Efficacy, Safety, and Tolerability of
Total Intravenous Ertapenem vs. Piperacillin-
100 MIC90 Organism Tazobactam in the Treatment of
Free mg/L
Complicated Intra-abdominal Infections
16.0 Pseudomonas aeruginosa,
10 enterococci, MRSA in Hospitalized Patients (STITCH).

1 1.0 Anaerobes Acquisition of Imipenem-

0.1
0.01
0 4
Hours after 1 g intravenous dose of ertapenem
Figure 6. Plasma ertapenem levels after intravenous administration in relation to the
MIC90 for various classes of bacterial pathogens. Reproduced with permission from
Friedland I et al.12
Ertapenem, a Group 1 carbapenem, is sufficiently
pharmacologically different from other carbapenems that the
class cannot be considered homogenous. Ertapenem
possesses a benzoate side change that changes the overall
electrical charge of the molecule. As a result of this charge,
ertapenem is highly protein bound in plasma, resulting in a
slow rate of clearance and a prolonged half-life, and is
selectively active against Enterobacteriaceae but not
nonfermentive gram-negative aerobes.11
Ertapenem Plasma Levels Exceed MIC90
for Susceptible Bacteria Throughout
Dosing Interval
A comparison of the plasma ertapenem levels after
intravenous administration and the MIC90 for various
classes of bacterial pathogens is a useful way to visualize
the spectrum of clinical antimicrobial activity over the
dosing interval. MIC90 values were based on isolates
from patients with moderate-to-severe compli-
cated intraabdominal, complicated skin/skin-
structure, acute pelvic, or complicated urinary
0.25 MSSA, pneumococci Resistant Pseudomonas
0.12 Group A streptococci
Rarely Seen After Ertapenem
0.03 Enterobacteriaceae
Therapy
8 12 16 20 24 During therapy with broad-spectrum
antimicrobial agents, bowel
colonization with resistant bacteria
can often develop through genetic
mutation or induction, through exogenous acquisition, or
by selective pressure on organisms already present but
undetectable. This can result in an important reservoir for
the spread of resistant organisms. By examining the
effects of antibiotics on the bowel flora acquisition and
susceptibility patterns from treated patients, early insight
into emerging resistance can be obtained.
Three international, prospective, comparative trials—
OASIS-1, OASIS-2, and STITCH—assessed the impact
of three different antimicrobial regimens frequently
employed to treat intraabdominal infections on the
susceptibility pattern of bowel flora at the end of
treatment.13,14 Patients were randomized to receive
ertapenem or piperacillin-tazobactam (OASIS-1 and
STITCH) or ceftriaxone plus metronidazole (OASIS-2).
Acquisition rates for P. aeruginosa resistance to
imipenem or piperacillin-tazobactam as well as
Enterobacteriaceae resistance to study drug and
vancomycin-resistant Enterococcus faecalis or
Enterococcus faecium were determined in rectal swabs
Effect of Ertapenem on GI carriage
of Imipenem-Resistant Pseudomonas
% patients resistant isolates % patients resistant isolates

% patients resistant isolates

tract infections or community- acquired pneu- 10 10

monia. The MIC90 for all Enterobacteriaceae, 8 8
streptococci, methicllin-susceptible 6 6
ct in-
am
ba ill

Staphylococcus aureus (MSSA). Haemophilus

az e/
ole

4 4
m
zo ac
e

nid on
ne
lin

Ta iper
m

tro iax
pe
ne

se
e

influenzae, Moraxella catarrhalis, and anaer-

obes was ≤1 µg/mL. This level was below the
P
lin

lin

lin

2 2
Me eftr
Ba

ta
pe

Er
se

se

se
ta

C
Ba

Ba

Ba
Er

0 0
0 0 1.3 1.3 0 1 0 0
free drug concentration for at least 8 hours and OASIS-1 OASIS-2
below the mean plasma concentration following 10
a 1 g intravenous infusion of ertapenem for at 8
least 24 hours, i.e., the entire recommended 6
dosing interval (Fig. 6).12
m

4
ne

ct in-
pe

am
ba ill
ta

zo ac
e
e

Er

2
lin
lin

These data also suggest that ertapenem has little

Ta iper
se
se

P
Ba
Ba

0
propensity to confer a selective pressure for 0 1.6 0 0

development of imipenem-resistant STITCH

Pseudomonas since these organisms are not
covered by ertapenem. This assertion is illustrated
by the recent findings of three studies: Optimizing
Figure 7. GI carriage of imipenem-resistant Pseudomonas after treatment with ertapenem,
piperacillin-tazobactam, or ceftriaxone plus metronidazole in the OASIS-1, OASIS-2, and STITCH tri-
als. Adapted from DiNubile MJ et al.13, 14

4
taken at baseline and at end of Enterobacteriaceae
n-
illi m
therapy. In each trial, the ac acta

% patients resistant isolates

% patients resistant isolates

r
pe b
14 Pi azo 14
percentage of patients with 12 T
12
imipenem-resistant 10 10
8 8 n-
Pseudomonas was zero at illi m
6 6 ac ta
baseline and increased very ne
m
per bac m
4 e
lin
e pe 4 e Pi azo e ne
lin tr a lin T lin pe
2 se se 2 se se ta
little (<2%) after treatment with Ba Ba
E
Ba Ba Er
0 0.6 12.2 0.6 1.3
0 0 1.9 0 0.6
ertapenem, piperacillin-
Piperacillin/tazobactam resistance Ertapenem resistance
tazobactam, or ceftriaxone OASIS- I
e/ le
plus metronidazole (Fig. 7). on zo
ax da
tf ri roni

% patients resistant isolates

% patients resistant isolates
These studies also showed 18 Ce et
M 18
that treatment with ertapenem 16 16
14 14
did not select for piperacillin- 12 12
10 10
e
tazobactam or ceftrioxone 8
e se
lin
m
8 /
ne ole
6 lin Ba ne 6 xo daz m
resistance, as illustrated by se pe e ia i e ne
4 Ba ta 4 lin ftr on lin pe
2 Er 2 se Ce etr se ta
data from OASIS-1 and Ba M Ba Er
0 0
2.6 17.1 4.6 1.5 0 0.5 0.5 0.5
OASIS-2 (Fig. 8). Ceftriaxone resistance Ertapenem resistance
OASIS-2
Figure 8. Effect of ertapenem on piperacillin-tazobactam or ceftriaxone resistance in the OASIS-1
and OASIS-2 trials. Adapted from DiNubile MJ et al.13

Summary
Resistance of gram-negative rods to commonly used antimicrobial agents occurs frequently on
hospital admission and often involves MDR, requiring individualized treatment decisions. As a guide
to the judicious use of antibiotics, a risk stratification procedure should be employed, based on an
assessment of the degree of contact between patients and the health care system, prior antibiotic
treatment, and patient characteristics.
Carbapenems represent an important class to treat MDR gram-negative rods, and should be
used sparingly in patients with infections not suspected of being MDR. Ertapenem is appropriate
for patients with confirmed or suspected extended-spectrum cephalosporin-resistant
Enterobacteriaceae and when nonfermenters are not the likely pathogens. Ertapenem is also
appropriate as directed therapy, mostly for ESBL producers. Imipenem and meropenem should be
used in patients with confirmed or suspected resistant Pseudomonas spp. and Acinetobacter spp.

REFERENCES
1. European Antimicrobial Resistance Surveillance System 8. Bochud PY, Bonten M, Marchetti O, Calandra T.
Annual Report 2004. ISBN 90-6960-131-1, 1–136. 2004. Antimicrobial therapy for patients with severe sepsis and
Bilthoven, The Netherlands, EARSS. septic shock: An evidence-based review. Crit Care Med
2. Livermore DM, Nichols T, Lamagni TL et al. Ciprofloxacin- 2004;32:S495–S512.
resistant Escherichia coli from bacteraemias in England; 9. Bolon MK, Wright SB, Gold HS, Carmeli Y. The magnitude
increasingly prevalent and mostly from men. J Antimicro of the association between fluoroquinolone use and
Chemother 2003;52:1040–1042. quinolone-resistant Escherichia coli and Klebsiella
3. National Nosocomial Infections Surveillance (NNIS) System pneumoniae may be lower than previously reported.
Report, data summary from January 1992 through June Antimicrob Agents Chemother 2004;48:1934–1940.
2004, issued October 2004. Am J Infect Control 10. Shah PM, Isaacs RD. Ertapenem, the first of a new group of
2004;32:470–485. carbapenems. J Antimicrob Chemother 2003;52:538–542.
4. Biedenbach DJ, Moet GJ, Jones RN. Occurrence and 11. Nix DE, Majumdar AK, DiNubile MJ. Pharmacokinetics and
antimicrobial resistance pattern comparisons among pharmacodynamics of ertapenem: An overview for clinicians.
bloodstream infection isolates from the SENTRY J Antimicrob Chemother 2004;53 Suppl 2:ii23–ii28.
Antimicrobial Surveillance Program (1997–2002). Diagn 12. Friedland I, Mixson LA, Majumdar A et al. In vitro activity of
Microbiol Infect Dis 2004;50:59–69. ertapenem against common clinical isolates in relation to
5. Turner PJ. Extended-spectrum beta-lactamases. Clin Infect human pharmacokinetics. J Chemother 2002;14:483–491.
Dis 2005;41 Suppl S273–S275. 13. DiNubile MJ, Friedland I, Chan CY et al. Bowel colonization
6. D'Agata EM. Rapidly rising prevalence of nosocomial with resistant gram-negative bacilli after antimicrobial therapy
multidrug-resistant, gram-negative bacilli: A 9-year of intra-abdominal infections: Observations from two
surveillance study. Infect Control Hosp Epidemiol randomized comparative clinical trials of ertapenem therapy.
2004;25:842–846. Eur J Clin Microbiol Infect Dis 2005;24:443–449.
7. Colodner R, Keller N, Samra Z et al. First National 14. DiNubile MJ, Chow JW, Satishchandran V et al. Acquisition
Surveillance of In-Vitro Susceptibility of Extended-Spectrum of resistant bowel flora during a double-blind randomized
Beta-Lactamase Producing E. coli and Klebsiella spp. in clinical trial of ertapenem versus piperacillin-tazobactam
Israel. (abstract). Presented at 45th Interscience Conference therapy for intraabdominal infections. Antimicrob Agents
on Antimicrobial Agents and Chemotherapy (ICAAC), Chemother 2005;49:3217–3221.
Washington, DC, USA, December 16–19, 2005.

5
 How Can We Limit the Occurrence of Resistant Organisms
in the Hospital Setting?
Debra Goff
Associate Professor, Infectious Diseases Specialist
The Ohio State University Medical Center, Columbus, Ohio, USA
The increasing prevalence of ESBL-producing organisms,
the limited success of screening for ESBL-producing
organisms in microbiological laboratories, and the increase
in mortality, morbidity, and costs associated with the
occurrence of resistant organisms have created a need to
limit the occurrence of resistant organisms, especially in the
hospital setting. Currently, the best approach to limit or
prevent resistance includes the elimination of the
unnecessary use of broad-spectrum antibiotics and the
implementation of good infection control practices.1
There are several evidence-based properties of antibiotics
that might best minimize resistance in hospitalized patients:
• The antibiotic should not be a strong selector for
development of resistance
• It should possess no activity against Pseudomonas
aeruginosa unless coverage of this pathogen is
necessary
• It should be given for as short a duration of time as
studies would suggest is efficacious
• It should be administered within the context of a mixing
approach to achieve heterogeneity
Assessing Unintended Consequences of
Broad-Spectrum Antibiotic Therapy
Treatment of serious infections with antibiotics should be
assessed not only in terms of clinical and bacterial efficacy
but also in terms of the potential ecological adverse effects.
The ecological adverse effects of antibiotic therapy is
referred to as collateral damage2 and includes the selection
of drug-resistant organisms and the unwanted
development of colonization or infection with multidrug-
resistant organisms. For example, use of cephalosporins
has been linked to the development of vancomycin-
resistant enterococci, ESBL-producing Klebsiella
pneumoniae, beta-lactam–resistant Acinetobacter spp.,
and Clostridium difficile. Similarly, quinolone use has been
linked to infection with methicillin-resistant S. aureus and
increasing quinolone resistance in gram-negative bacilli
(e.g., P. aeruginosa).
When selecting an antibiotic for sustained use in hospital,
it is important to strike a balance between clinical and
bacterial efficacy and collateral damage. One way to
assess the risk of collateral damage from antibiotics is
through antimicrobial surveillance in the form of yearly
antibiograms. This allows detection of any shifts in antimi-
6
crobial susceptibility so that appropriate changes can be
made to prescribing and infection control practices.
Use of Antibiograms to Improve Antibiotic
Prescribing at a University Hospital
Antimicrobial surveillance data from the Medical Intensive
Care Unit (MICU) at The Ohio State University Medical
Center (OSUMC) indicate that the incidence of multidrug-
resistant K. pneumoniae increased by more than 100%
from 4% in 2002 to 9% in 2003, with over 50% of ESBL
infections being community acquired. Patients with ESBL
-producing K. pneumoniae were located in many different
areas of the hospital and not just in the MICU.3
Based on a review of yearly antibiograms, it was noted
that the only class of antibiotics that had susceptibilities
over 70% to ESBL-producing K. pneumoniae was imipen-
em. These findings necessitated a careful assessment of
hospital-wide prescribing practices to avoid limiting
physicians from using imipenem for all community-
acquired infections.
Our prescribing dilemma was resolved with the introduc-
tion of ertapenem. Ertapenem was added to the hospital
formulary on May 27, 2003 because it provides an effec-
tive antibiotic for ESBL-producing pathogens without
resorting to imipenem, and is an alternative to ampicillin/
sulbactam or other antibiotics for postoperative surgical
patients. However, ertapenem is not used for empiric
therapy of nosocomial infections and does not cover
P. aeruginosa, Acinetobacter spp., or Enterococcus spp.
To assist residents in choosing appropriate antibiotic ther-
apy at our hospital, a simple schematic was developed to
illustrate the effects of various antibiotic agents on collat-
eral damage (Fig. 9). The goal is to preserve the activity of
imipenem and piperacillin-tazobactam against P. aerugi-
nosa through effective utilization of other antimicrobial
agents if coverage against P. aeruginosa is not required.
Ertapenem Does Not Appear to Negatively
Impact Susceptibility of Imipenem or Other
Gram-Negative Antimicrobials
With the addition of ertapenem to the OSUMC hospital
formulary, it was important to monitor the effect of
ertapenem on the susceptibility of gram-negative
aerobes to other formulary antibiotics including, for
example, imipenem, piperacillin-tazobactam, cefepime,
ampicillin/sulbactam, ciprofloxacin, and tobramycin.
Ertapenem was
effective against all Targeted Empiric Coverage
ESBL-producing
organisms and was
primarily prescribed by

age
surgeons for mixed Ertapenem

Dam
nonpseudomonal,
intraabdominal

ral
Ampicillin/sulbactam

late
infections, and
skin/skin-structure

Col
infections. Hospital
Piperacillin/tazobactam
antibiograms before
and after ertapenem
addition showed that Imipenem
ertapenem did not
negatively effect
es

nos s
ativ nas

L’s t
pos es

ESBistan

ugi ona
itiv

a
gram-negative
es

m- rob
neg mo

aerudom
Res
Gra Anae

susceptibilities to
m- udo

Pse
Gra -Pse

imipenem or other
gram-negative agents.4
n
No

In fact, the incidence

of ESBL-producing Empiric Coverage
K. pneumoniae at
OSUMC has
Figure 9. Schematic used by residents at The Ohio State University Medical Center depicting the effects of vari-
decreased from ous antibiotic agents on collateral damage.
9% to 5%.

Summary
A variety of surveillance data indicate that antimicrobial resistance is increasing, particularly
with respect to ESBL-producing K. pneumoniae, and Escherichia coli. Unit-specific
antibiograms are essential to identify trends in resistance problems and make
recommendations as to appropriate antibiotic therapy. The addition of ertapenem at
Ohio State University Medical Center did not decrease the susceptibility of imipenem or
other gram-negative antibiotics, and, in fact, the incidence of ESBL-producing K.
pneumoniae has decreased.

REFERENCES
1. Livermore DM. Multiple mechanisms of antimicrobial resistance
in Pseudomonas aeruginosa: Our worst nightmare? Clin Infect
Dis 2002;34:634–640.
2. Paterson DL. Collateral damage from cephalosporin or
quinolone antibiotic therapy. Clin Infect Dis 2004;38(Suppl
4):S341–S345.
3. Potoski BA, Goff DA, Sierawski SJ. Clinical outcomes and
microbiologic analysis of patients with extended-spectrum
beta-lactamase producing Klebsiella pneumoniae (ESBL-KP).
Abstract #565 presented at the 40th Annual Meeting of the
Infectious Diseases Society of America (IDSA), October 24–27,
2002, Chicago, Illinois, USA.
4. Goff DA. Ertapenem: Effect on gram-negative pathogens 19
months after formulary addition. Presented at ICAAC,
Washington, DC, USA, 2005, abstract C1 93A.

7
Role of Ertapenem
in the Era of
Antimicrobial Resistance

Key Points
• Antimicrobial surveillance data reveal an increasing worldwide occurrence
of resistant organisms, including those resistant to multiple antibiotics

• Changes in our health care system have resulted in these resistant

organisms spreading from the hospital setting into the community

• A risk stratification system, based on an assessment of patient

characteristics and exposure to the health care system and prior
antibiotics, should be employed to identify patients likely to have resistant
organisms

• Antibiotic selection should be based on clinical and bacterial efficacy as

well as the potential for adverse ecological effects, such as the selection
of drug-resistant organisms and the unwanted colonization or infection
with organisms possessing multidrug resistance (MDR)

• The evolution of MDR has resulted in an era of high carbapenen use.

For infections suspected to be caused by ESBL producers,
carbapenems such as ertapenem are the most reliable and effective
empiric therapy

• Ertapenem is appropriate for patients with confirmed or suspected

extended-spectrum cephalosporin-resistant Enterobacteriaceae and
when nonfermenters are not the likely pathogens

• Acquisition of imipenem-resistant Pseudomonas is rarely seen after

ertapenem therapy, according to recent bowel colonization studies

• The addition of ertapenem to the formulary at a major US medical center

did not negatively impact the susceptibility of gram-negative aerobes to
other formulary antibiotics, including imipenem, piperacillin-tazobactam,
cefepime, ampicillin/sulbactam, ciprofloxacin, and tobramycin

This publication is provided as a service to the medical profession and represents the opinions of the authors, not necessarily those of Merck & Co., Inc.
or its affiliates. Due to individual countries’ regulatory requirements, indications and uses of products may vary. Before prescribing any products, please
consult the local prescribing information available from the manufacturer.

Copyright © 2006 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 5-08 IVZ 2005-W-226361-NL