US Pharm. 2013;38(12):HS2-HS5.
carbapenem-resistant Enterobacteriaceae (CRE) comprise resistant
gram-negative bacteria with limited treatment options and a high
mortality rate. CRE infection is a growing threat, especially in the
healthcare setting. The Clinical and Laboratory Standards Institute has
defined laboratory indicators to determine the presence of CRE.
Combination regimens including polymyxins, tigecycline, and
aminoglycosides have been reported with limited success. Recommended
prevention strategies are delineated by the CDC and should be
implemented to thwart transmission of CRE. Pharmacists can optimize the
management of patients with CRE infections by understanding the
appropriate treatment and prevention measures for this emerging
For several decades, clinicians have relied on the use of
carbapenem antimicrobials to treat infections caused by resistant
organisms. The development of resistance to broad-spectrum
antimicrobials and the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) in the United States have increased over the past 20 years.
CRE infections pose a serious threat to public health due
to high mortality rates, resistance to commonly used antibiotics,
limited treatment options, and the potential for widespread
dissemination. Mortality rates of 40% to 50% have been reported.1-3
In 2012, the CDC concluded that 4.6% of acute-care hospitals performing
surveillance reported at least one CRE healthcare-associated infection.4 According to the Meropenem Yearly Susceptibility Test Information Collection Program, meropenem-resistant Klebsiella pneumoniae increased from 0.6% in 2004 to 5.6% in 2008.5 Carbapenem resistance has been cited in up to 4.0% of Escherichia coli and 10.8% of K pneumoniae isolates reported to the National Healthcare Safety Network.6
Enterobacteriaceae represent a large family of gram-negative bacteria that includes genera such as Klebsiella, Proteus, Escherichia, and Enterobacter.
The mechanism of resistance was initially reported among
Enterobacteriaceae as overproduction of AmpC beta-lactamases or
extended-spectrum beta-lactamases with porin mutations.7,8
The production of carbapenemases represents another more recent
mechanism for carbapenem resistance among CRE. These enzymes have direct
carbapenem-hydrolyzing activity.9 K pneumoniae
carbapenemase (KPC) enzyme–containing isolates have been found to be
resistant to all beta-lactam agents including penicillins,
cephalosporins, monobactams, and carbapenems.10 In the U.S., the most common carbapenemase is KPC,
an Ambler class A enzyme. Ambler class B metallo-beta-lactamases (MBLs)
have also been identified in the resistance to carbapenems. MBLs among
Enterobacteriaceae are rare in the U.S. and include Verona
integrin-encoded (VIM), imipenemase (IMP), and New Delhi
Risk factors including exposure to antimicrobial therapy
and the healthcare environment are strongly associated with CRE
transmission.11 Fluoroquinolones, which are associated with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, have also been identified as a risk factor for carbapenem-resistant K pneumoniae (CRKP) infection.11-13 Falagas et al identified an association between antipseudomonal penicillins (P = .004), fluoroquinolones (P <.001), carbapenems (P = .01), and glycopeptides (P <.001) and CRKP infection.12 Prior fluoroquinolone and carbapenem use also have been identified as significant independent risk factors for CRKP infection.11 Postacute care facilities may represent reservoirs for the dissemination of CRE.14
Independent risk factors for CRKP carriage also include prolonged
length of stay, sharing a room with a known carrier, increased frequency
of known carriers on the ward, medical-surgical ICU stay, recent
surgical procedures, mechanical ventilation, recent organ or stem cell
transplantation, and central venous catheterization.1,14-16
Symptoms associated with CRE infection vary and correlate
with the infected site. If an infection is present in the lungs or
bladder, patients will present with a cough or urinary symptoms,
respectively. Generalized signs and symptoms of infection are also seen
in those with CRE infection. Most of the CRE infections involve the
urinary tract. However, CRE can lead to infections in the bloodstream or
present as intra-abdominal infections or ventilator-associated
The surveillance definition of CRE according to the
Clinical and Laboratory Standards Institute (CLSI) is Enterobacteriaceae
nonsusceptible to a carbapenem and resistant to all of the following
third-generation cephalosporins that were tested: ceftriaxone,
cefotaxime, and ceftazidime. Recently, new interpretive criteria
(breakpoints) have been implemented to add doripenem and to include
increased ertapenem sensitivity in determining susceptibility to
carbapenems among Enterobacteriaceae (TABLE 1).18,19
An agar diffusion test should be utilized, and ertapenem or meropenem
resistance should be considered resistance to the entire class of
Anderson et al collected a sample of roughly 50 isolates
from 13 different healthcare settings and reported the reference broth
microdilution method as the most sensitive method for identifying
KPC-mediated carbapenem resistance using meropenem, imipenem, and
ertapenem compared to other laboratory methods.10 Ertapenem
was the most specific regardless of which laboratory method was used and
should be used for susceptibility testing when available.10
Although the lowered breakpoints no longer require further testing for
carbapenemases, the CLSI recommends phenotypic testing for carbapenemase
activity using the Modified Hodge Test (MHT) for any isolates producing
carbapenemases that demonstrate decreased susceptibility to carbapenems
in disk diffusion or minimum inhibitory concentration (MIC) testing.21
Clinical diagnosis is based on the presence of infection caused by CRE.
CRE infection may occur in multiple possible sites, including the
bloodstream, respiratory system, and urinary tract.22
Treatment options for CRE infection are limited.
Polymyxins, tigecycline, and aminoglycosides have in vitro activity
against CRE.23,24 Polymyxins possess gram-negative
activity and include polymyxin E (colistimethate) and polymyxin B.
Polymyxins have been used less frequently due to nephrotoxicity and
neurotoxicity safety concerns. However, the emergence of resistance has
directed attention back to the use of this drug class. In vitro studies
of polymyxins demonstrated bactericidal activity against KPC infections,
and synergy in combination with carbapenems, rifampin, or tigecycline
was observed.24-26 The most common combination treatment
regimens used in case reports include polymyxin plus tigecycline,
carbapenem, or aminoglycosides.
In a systematic review by Lee and Burgess, polymyxin
monotherapy was associated with higher rates of treatment failure
compared to polymyxin-based combination therapy (73% vs. 29%, P = .02).27 Reports of resistance to colistin among gram-negative bacteria have been described.28 Lee
et al reported increased polymyxin B MIC values in 3 of 12 patients
treated with polymyxin B monotherapy (1.5 to 32 mcg/mL, 0.75 to 12
mcg/mL, and 0.75 to 1,024 mcg/mL).29 Combination therapy with
polymyxins may be an effective strategy to prevent resistance to
colistin and to successfully treat KPC infections.
Tigecycline, a glycylcycline antimicrobial, has
demonstrated an excellent spectrum of in vitro activity against
KPC-producing organisms. In the SENTRY Antimicrobial Surveillance
Program, tigecycline inhibited 100% of 104 carbapenemase-producing
Enterobacteriaceae isolates collected worldwide.30 Some reports have described tigecycline resistance in Enterobacteriaceae, a treatment-emergent increase in tigecycline MIC, and cases of panresistant K pneumoniae.31-34
Tigecycline is a bacteriostatic agent, and an alternative antimicrobial
should be considered if bactericidal activity is necessary. Urinary and
serum levels of tigecycline are low, and its use for treatment of
urinary tract infections (UTIs) and bloodstream infections as
monotherapy is discouraged. Combination regimens using tigecycline have
been cited in the literature.27
Aminoglycosides, protein synthesis inhibitors, exhibit
concentration-dependent activity and good distribution into urine, bone,
and peritoneal fluid.35 Multivariate analysis showed
aminoglycoside use was independently associated with microbiologic
clearance. In one retrospective cohort study, aminoglycosides had a
higher rate of microbiologic clearance of CRKP in the urine (88%)
compared to polymyxin B (64%, P = .02), tigecycline (43%, P <.001), or the untreated group (36%, P <.001).36
Cross-resistance to aminoglycosides has been noted and is due to the altering enzymes of many CRKP strains.37 The
most frequently used aminoglycoside-based combination treatment
regimens published in case reports included aminoglycosides in
combination with polymyxins, carbapenems, fluoroquinolones, tigecycline,
aztreonam, or tetracyclines. Several cases reported treatment success
with combination therapy including aminoglycosides.27,38,39
The potential risk of nephrotoxicity should be considered, especially with the combination of aminoglycoside and polymyxin.27
Evidence comparing carbapenem monotherapy versus
combination therapy showed higher rates of treatment failure with
monotherapy (60% vs. 26%, P = .03).27
most common treatment regimen used in previous reports was carbapenem
with polymyxin, followed by carbapenem plus aminoglycoside, and
carbapenem with a beta-lactam plus a beta-lactamase inhibitor.27
Bulik and Nicolau evaluated the combination of ertapenem and doripenem
against KPC in both an in vitro chemostat model and an in vivo murine
model.40 Enhanced efficacy of combination therapy in comparison to monotherapy was observed in both models.
The role of double-carbapenem therapy warrants further
investigation. Carbapenem has time-dependent bactericidal activity, but
whether this pharmacodynamic parameter is effective in the presence of
KPCs is debatable.27 Some authors have suggested using
high-dose prolonged-infusion carbapenems in a combination regimen for
organisms with a carbapenem MIC ≤4 mg/L in the treatment of CRE
infections. The recently lowered clinical breakpoints of carbapenems
define susceptibilities to imipenem, meropenem, and doripenem as a MIC
up to 1 mcg/mL and 0.5 mcg/mL for ertapenem.41
Evidence for combination therapy for the treatment of CRE
infections is largely derived from retrospective and observational cases
series. Combination therapy was associated with improved survival in a
retrospective cohort study of patients with KPC-producing K pneumoniae bacteremia (TABLE 2).42
The majority of combination regimens with successful results included a
polymyxin combined with either tigecycline or a carbapenem. In a
multicenter, retrospective cohort study of 125 patients with
bloodstream infections caused by KPC-producing isolates, a significantly
higher 30-day mortality rate was observed among patients treated with
monotherapy versus combination antimicrobial therapy (54.3% vs. 34.1%, P = .02).43 The triple-drug combination of tigecycline, colistin, and meropenem was significantly more common in the survivor group (P
= .009). In one retrospective comparison of 55 patient cases, positive
outcomes were observed in the majority of cases when tigecycline,
aminoglycosides, and polymyxins were used in combination.44
Further clinical studies are needed to establish the effectiveness of
combination treatment and which antimicrobials should be used in
In vitro data suggest rifampin in combination with
polymyxin B and/or doripenem may be a useful therapeutic option for
carbapenem-resistant isolates; however, clinical studies are needed to
elucidate the potential role of this drug in the treatment of CRE
infections.24,45 Of note, fosfomycin, which is currently only
available as oral powder for solution, demonstrates activity against
approximately 50% of CRKP isolates.46,47
of the growing problem of multidrug resistance, reevaluation of the
role of older antimicrobials and the development of new antimicrobials
is needed to address the increasing incidence of CRE infections.
Screening tools are vital in detecting unrecognized CRE colonization.18 Point prevalence surveys generally involve screening all patients in a ward or unit.18
surveillance cultures can be used as part of a comprehensive strategy
to interrupt transmission of CRKP, and they involve patients who might
not be epidemiologically linked to CRE patients but who meet certain
prespecified criteria for being high risk (e.g., patients from long-term
care facilities, patients admitted to the ICU).18,48 A
4.7-fold reduction in the incidence of CRKP infections following
implementation of active surveillance with contact precautions was noted
in a hospital outbreak.48
The CDC recommends eight core measures for control of CRE in acute and long-term care facilities (TABLE 3).18
The use of devices (e.g., central venous and urinary catheters) should
be minimized and reviewed regularly for discontinuation when no longer
necessary. Patients at highest risk for transmission should be housed in
single-patient rooms or cohorted together. Appropriate use of
antimicrobial agents through an antimicrobial stewardship is critical in
controlling multidrug-resistant organisms.18,49
Regional surveys including facility level data such as
facility demographics, overall frequency of CRE detection, and frequency
of CRE cases by timing of detection are often utilized to prevent
transmission from one facility to another. In regions where CRE is
common, the collaboration of healthcare facilities is important to
convey the urgency of the matter and to prioritize CRE prevention. All
acute and long-term care facilities should review current infection
control policies and practices and implement the core measures for CRE
Due to the growing threat of CRE infections in the
healthcare setting, it is important for pharmacists to be familiar with
antimicrobial therapy options, risk factors, and diagnostic indicators.
Prevention strategies should be incorporated at the healthcare system
level. In light of limited data with current treatment options and
growing resistance, development of new antimicrobials is needed.
Pharmacists play a crucial role in providing optimal and appropriate
treatment of patients with CRE infections.
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