Infections Caused by Resistant Gram-Negative Bacteria:

Epidemiology and Management

Keith S. Kaye,1,* and Jason M. Pogue,2
1

Department of Medicine, Detroit Medical Center and Wayne State University, University Health Center, Detroit,
Michigan; 2Department of Pharmacy, Sinai-Grace Hospital, Detroit Medical Center and Wayne State University
School of Medicine, Detroit, Michigan

Infections caused by resistant gram-negative bacteria are becoming increasingly prevalent and now
constitute a serious threat to public health worldwide because they are difficult to treat and are associated with high morbidity and mortality rates. In the United States, there has been a steady increase
since 2000 in rates of extended-spectrum b-lactamaseproducing Enterobacteriaceae, carbapenemresistant Enterobacteriaceae, and multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter
baumannii, particularly among hospitalized patients with intraabdominal infections, urinary tract infections, ventilator-associated pneumonia, and bacteremia. Colonization with resistant gram-negative bacteria is common among residents in long-term care facilities (particularly those residents with an
indwelling device), and these facilities are considered important originating sources of such strains
for hospitals. Antibiotic resistance is associated with a substantial clinical and economic burden,
including increased mortality, greater hospital and antibiotic costs, and longer stays in hospitals and
intensive care units. Control of resistant gram-negative infections requires a comprehensive approach,
including strategies for risk factor identification, detection and identification of resistant organisms,
and implementation of infection-control and prevention strategies. In treating resistant gram-negative
infections, a review of surveillance data and hospital-specific antibiograms, including resistance patterns within local institutions, and consideration of patient characteristics are helpful in guiding the
choice of empiric therapy. Although only a few agents are available with activity against resistant
gram-negative organisms, two recently released b-lactam/b-lactamase inhibitor combinations ceftolozane/tazobactam and ceftazidime/avibactam have promising activity against these organisms. In this
article, we review the epidemiology, risk factors, and antibiotic resistance mechanisms of gram-negative organisms. In addition, an overview of treatment options for patients with these infections is
provided.
KEY WORDS gram-negative bacteria, multidrug resistance, carbapenemase, extended-spectrum b-lactamase,
ceftolozane, avibactam.
(Pharmacotherapy 2015;35(10):949962) doi: 10.1002/phar.1636

A global increase in the number of infections

caused by gram-negative bacteria has occurred
in recent years, with infections caused by these
organisms often more prevalent than gram-posi*Address for correspondence: Keith S. Kaye, Detroit
Medical Center and Wayne State University, University
Health Center, 4201 Saint Antoine, Suite 2B, Box 331,
Detroit, MI 48201; e-mail: KKaye@dmc.org.
2015 Pharmacotherapy Publications, Inc.

tive infections in many settings.1 The growing

risk of antimicrobial resistance among gram-negative bacteria is a worldwide problem due to the
potential for rapid spread of resistance mechanisms and limited treatment options.2 In particular, the development of multidrug-resistant
(MDR) strains, which are resistant to three or
more classes of antimicrobials, or extensively
drug-resistant (XDR) strains, which are resistant
to all but one or two classes of antimicrobials, is

950

PHARMACOTHERAPY Volume 35, Number 10, 2015

a cause of major concern.3 It is estimated that as

many as 2 million patients in the United States
each year develop a bacterial infection (grampositive and/or gram-negative) that is resistant
to antibiotics and that more than 23,000 deaths
are associated with these infections.2 A majority
of these deaths are related to gram-negative
infections, particularly health careacquired
infections caused by extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE),
MDR Acinetobacter baumannii, and MDR Pseudomonas aeruginosa (Table 1).2 The threat of
such infections and the burden they impose
were highlighted recently by an outbreak of carbapenem-resistant Klebsiella pneumoniae (CRKP)
at the U.S. National Institutes of Health (NIH)
Clinical Center. In this outbreak, 18 patients
were colonized, and six deaths were directly
attributable to a K. pneumoniae infection that
occurred despite early implementation of infection-control procedures.4 The rise in antibiotic
resistance is also related, in part, to the widespread use of antimicrobial agents (both appropriate and inappropriate) and to the spread of
resistant strains from person to person or from
nonhuman sources in the environment (e.g.,
food).2
The most important emerging threats associated with antibiotic resistance are the ESCAPE
pathogens (Enterococcus faecium, Staphylococcus
aureus, Clostridium difficile, Acinetobacter species,
P. aeruginosa, and Enterobacteriaceae), which
are organisms that can escape the effects of
antimicrobial agents and cause the majority of
hospital-acquired infections.5 Of note, the last
three represent gram-negative organisms. The
threat of gram-negative bacteria that are resistant
to multiple antibiotics (i.e., MDR and XDR
bacteria) is particularly worrisome,6 because in

Table 1. Minimum Estimates of Morbidity and Mortality

Associated with Health CareAssociated Infections
Caused by Resistant Gram-Negative Bacteria in the United
States2

Resistant Organism
ESBL-producing
Enterobacteriaceae
Carbapenem-resistant
Enterobacteriaceae
MDR Acinetobacter species
MDR Pseudomonas aeruginosa

Estimated
Annual No. of
Cases

Estimated
No. of
Deaths

26,000

1700

9300

610

7300
6700

500
440

ESBL = extended-spectrum b-lactamase; MDR = multidrug-resistant.

addition to becoming resistant to previously

effective antimicrobial agents (such that in some
cases there is no effective treatment option), few
new agents are under development that are
effective against resistant gram-negative bacteria.2 In this review, we discuss the epidemiology
and risk factors of resistant gram-negative infections and evaluate therapeutic regimens for the
management of these infections, highlighting
emerging treatment options.
Overview of Resistant Gram-Negative Infections
Gram-negative bacteria are common causes of
intraabdominal infections (IAIs), urinary tract
infections (UTIs), ventilator-associated pneumonia (VAP), and bacteremia.7 In particular,
Escherichia coli, K. pneumoniae, and P. aeruginosa are important pathogens in the hospital setting, accounting for 27% of all pathogens and
70% of all gram-negative pathogens causing
health careassociated infections in the United
States.7 P. aeruginosa is the most common gramnegative organism causing VAP and the second
most common organism causing catheter-associated UTIs, K. pneumoniae is the most common
gram-negative organism causing central lineassociated bloodstream infections, whereas E. coli
is the most common organism causing UTIs and
the second most common organism causing
health careassociated infections overall.7
Trends in Mechanisms of b-Lactam Resistance
Gram-negative bacteria are highly adaptive
pathogens that develop resistance to antimicrobials through several mechanisms. The production of b-lactamases that hydrolyze the b-lactam
ring is the most common resistance mechanism
for these bacteria against b-lactam antibiotics.
The classification of b-lactamases is based either
on molecular structure (Ambler classification) or
functional similarities (Bush-Jacoby-Medeiros
classification) (Table 2). The major causes of
resistance to third-generation cephalosporins in
Enterobacteriaceae are Ambler class A ESBL
enzymes, including TEM-type (e.g., TEM-3,
TEM-52), SHV-type (SHV-5, SHV-12), and CTXM-type enzymes (CTX-M-1, CTX-M-15).8 In the
United States, among E. coli, ESBLs of the CTXM family have supplanted TEM- and SHV-type
enzymes to become the most common type of
ESBL, with rapid dissemination throughout the
country.9 CTX-M-15 and CTX-M-14 predominate in the United States, with some regional

MANAGEMENT OF RESISTANT GRAM-NEGATIVE BACTERIA Kaye and Pogue

951

Table 2. Summary of b-Lactamases According to Ambler Classification

Ambler
Class

b-Lactamases

Active Site
Agent

Examples

Penicillinases

Serine

Metallo-b-lactamases

Zinc

TEM, SHV, KPC,

CTX-M,
IMP, VIM, NDM

Cephalosporinases

Serine

AmpC

Oxacillinases

Serine

OXA

epidemiology surveys reporting more than 80%

of community-acquired ESBL-producing E. coli
isolates expressing CTX-Mtype ESBLs.9, 10
Although less common, cephalosporin resistance
among E. coli can also result from plasmid-mediated hyperproduction of AmpC b-lactamases.8
Similarly, resistance to cephamycins and cephalosporins among Enterobacter species can also
result from hyperproduction of AmpC b-lactamases.8
The carbapenemases observed among the
Enterobacteriaceae have a broad spectrum of
hydrolytic activity, including activity against
almost all b-lactam antibiotics.11 Types of carbapenemases among the Enterobacteriaceae
include Ambler class A (KPC, NMC, IMI, SME,
GES types), class B (zinc-dependent metallo-blactamases: VIM, IMP, NDM types), and class D
(OXA type) (Table 2).8, 1114 The spread of
CRKP in the United States has largely been driven by the dissemination of Enterobacteriaceae
producing the KPC enzyme, which typically
confers resistance to all b-lactam antibiotics.15
Carbapenemase-encoding genes are usually
located on plasmids or other mobile genetic elements, allowing organisms to acquire genes that
confer resistance to other antimicrobial classes.3
Resistance is spread throughout the various
Enterobacteriaceae genera.
In the case of P. aeruginosa and A. baumannii,
resistance is usually due to either a combination
of different mechanisms, including b-lactamase
production, increased efflux pump activity, and
outer membrane modifications, or to a single
potent resistance mechanism such as carbapenemase production.16 Carbapenem resistance in
A. baumannii, which has emerged as a significant
threat and is resistant to most therapeutic
options, is mediated largely through the production of class D carbapenem-hydrolyzing oxacillinases (including, but not limited to, OXA-23,
OXA-24, OXA-58 cluster, and OXA-51/69 variants).17

Typical Organisms Producing

These b-Lactamases
Escherichia coli, Klebsiella species, Enterobacter species
Klebsiella pneumoniae, E. coli, Klebsiella oxytoca, Enterobacter
species
Enterobacter species, Citrobacter species, Pseudomonas
aeruginosa, Serratia species
K. pneumoniae, E. coli, Citrobacter freundii, Proteus mirabilis,
Acinetobacter baumannii

Epidemiology of Multidrug-Resistant GramNegative Bacteria

Data from the National Healthcare Safety Network (NHSN) in the United States have indicated a steady increase in the prevalence of
MDR K. pneumoniae and E. coli, from 7% in
2000 to 13% in 2008.18 Prevalence rates from
the 2009 to 2010 NHSN database for MDR-resistant strains of K. pneumoniae, E. coli, Enterobacter species, P. aeruginosa, and A. baumannii,
according to infection type, are summarized in
Table 3.7
Prevalence of ESBL-Producing
Enterobacteriaceae
ESBLs are found worldwide in a variety of
genera of Enterobacteriaceae, with more than
1000 types identified.19, 20 Rates of ESBL-producing organisms among members of the Enterobacteriaceae (particularly K. pneumoniae and
E. coli) are of increasing clinical concern.21, 22
Data from the Study for Monitoring Antimicrobial Resistance Trends (SMART), which evaluated antimicrobial susceptibility trends among
gram-negative bacilli isolated from IAIs in North
America during 20052010, revealed that the
proportion of ESBL E. coli increased from 1.7%
in 2005 to 7.3% in 2010.23 Even higher rates of
ESBL-producing E. coli isolated from IAIs were
reported in the SMART program for Asia
(38.3%), Latin America (22.9%), and the Middle
East (18.5%).22
In addition to ESBL-producing E. coli, the
prevalence of ESBL-producing K. pneumoniae
has also risen substantially, and, as a result, in
both of these bacteria have become increasingly
resistant to widely used antimicrobials.21 In the
North American SMART program, the prevalence of ESBL-producing K. pneumoniae among
intraabdominal isolates increased from 3.2% in
2005 to 13.1% in 2010.23 Similarly, high rates

952

PHARMACOTHERAPY Volume 35, Number 10, 2015

Table 3. Rates of Resistance According to Infection Type

and Resistance Type in the United States: National Healthcare Safety Network Data for 200920107
Resistance Rate (%)
Pathogen and Antimicrobial
Resistance
CLABSI CAUTI VAP SSI
Klebsiella pneumoniae and Klebsiella oxytoca
Carbapenem-resistant
12.8
12.5
MDRa
16.8
16.1
Escherichia coli
Carbapenem-resistant
1.9
2.3
MDRa
3.7
2.0
Pseudomonas aeruginosa
Carbapenem-resistant
26.1
21.3
MDRb
15.4
14.0
Enterobacter species
Carbapenem-resistant
4.0
4.6
MDRa
3.7
4.8
Acinetobacter baumannii
Carbapenem-resistant
62.6
74.2
MDRc
67.6
77.6

11.2
13.4

7.9
6.8

3.5
3.3

2.0
1.6

30.2 11.0
17.7 5.3
3.6
1.4

2.4
1.7

61.2 37.3
63.4 43.9

CAUTI = catheter-associated urinary tract infection; CLABSI = central lineassociated bloodstream infection; MDR = multidrug-resistant; SSI = surgical site infection; VAP = ventilator-associated
pneumonia.
a
MDR is defined as intermediate susceptibility or resistance to 1
drug in 3 of 5 of the following classes: extended-spectrum cephalosporins (cefepime, cefotaxime, ceftazidime, ceftriaxone), fluoroquinolones
(ciprofloxacin,
levofloxacin,
moxifloxacin),
aminoglycosides, carbapenems, and piperacillin or piperacillin/tazobactam.
b
MDR is defined as intermediate susceptibility or resistance to 1
drug in 3 of 5 of the following classes: extended-spectrum cephalosporins (cefepime, ceftazidime), fluoroquinolones (ciprofloxacin,
levofloxacin), aminoglycosides, carbapenems, and piperacillin or
piperacillin/tazobactam.
c
MDR is defined as intermediate susceptibility or resistance to 1
drug in 3 of 6 of the following classes: extended-spectrum cephalosporins (cefepime, ceftazidime), fluoroquinolones (ciprofloxacin,
levofloxacin), aminoglycosides, carbapenems, piperacillin or piperacillin/tazobactam, and ampicillin/sulbactam.
Adapted with permission from reference 7.

of ESBL-producing E. coli and K. pneumoniae

among inpatients with UTIs, 6.8% and 10.3%,
respectively, were also reported by the SMART
program in the United States from 2009
2011.24
Prevalence of CRE
Perhaps most ominous is the growing threat
of CRE, as these organisms have become
increasingly recognized as causes of infection in
acute care hospitals in the United States in the
last decade, from 1.2% in 2001 to 4.2% in
2011.25 Prior to 2000, Enterobacteriaceae were
highly susceptible to carbapenems; however,
beginning in the early 2000s, CRE have rapidly
spread throughout the United States, with their
emergence likely due, in part, to the increased
use of carbapenems as empiric and targeted
therapy for infectious diseases caused by b-lac-

tamresistant organisms, notably ESBL-producing Enterobacteriaceae.3, 11 Infections caused by

these organisms have been associated with high
rates of morbidity and mortality, with mortality
rates ranging from 24% to as high as 70%,
depending on the study population and the
treatment used.12 Indeed, although the Centers
for Disease Control and Prevention rates the
hazard level of other resistant gram-negative
organisms (e.g., MDR P. aeruginosa, MDR Acinetobacter species, ESBL-producing Enterobacteriaceae) as serious, the hazard level for CRE is
considered urgent, the highest hazard level.2
Among CRE, CRKP is the most prevalent organism seen in the United States.2, 15 Data from the
NHSN indicate that resistance to carbapenems
among K. pneumoniae isolates has increased
markedly since 2001, and in 20092010, CRKP
was reported in approximately 1113% of bloodstream infections, VAPs, and UTIs, and in
approximately 8% of surgical-site infections
(Table 3).7 Data from The Surveillance Network
(TSN) a centralized database that collects
antimicrobial resistance test results from clinical
laboratories in 217 hospitals across the country
identified that CRE accounted for approximately 4% of bloodstream infections and
approximately 5% of pneumonia cases during
20002009.26
Prevalence of MDR P. aeruginosa and
A. baumannii
Data from TSN indicated that MDR strains of
P. aeruginosa were responsible for 22% of pneumonias and 14.7% of bloodstream infections
between 2000 and 2009.26 TSN data also highlighted that there was a net rise in MDR
P. aeruginosa as a proportion of all cases of
P. aeruginosa infection over this 10-year period,
from 19.2% in 2000 to 21.7% in 2009 for pneumonias, and from 10.7% in 2000 to 13.5% in
2009 for bloodstream infections.26
Although the prevalence of A. baumannii
remained steady over this time period, there was
a progressive decrease in the susceptibility of
this pathogen to most classes of antimicrobial
agents, with about a third of A. baumannii
isolates exhibiting combined resistance to
carbapenems, aminoglycosides, and fluoroquinolones.27 The NHSN data for 20092010
indicated that MDR Acinetobacter species were
found in more than 60% of catheter-associated
UTIs, central lineassociated bloodstream infections, and VAPs caused by this pathogen.7

MANAGEMENT OF RESISTANT GRAM-NEGATIVE BACTERIA Kaye and Pogue

953

Risk Factors for Gram-Negative Resistance

Burden of Resistant Gram-Negative Infections

A number of risk factors for resistant gramnegative infections have been identified. In
particular, prior use of b-lactam antibiotics is
considered to be a particularly important risk
factor. Additional risk factors for ESBLs include
the presence of devices or previous invasive procedures, admission from a long-term care facility, and existing comorbidities.11 Risk factors for
the development of carbapenem-resistant gramnegative bacteremia include the duration of
exposure to carbapenems, the presence of VAP,
and the use of intravascular devices.28 A study
of patients with nosocomial carbapenem-resistant A. baumannii infections showed that prior
hospitalization, longer durations of hospital stay,
an intensive care unit (ICU) stay, prior exposure
to a carbapenem, use of invasive procedures
(e.g., central venous catheterization, urinary
catheterization, mechanical ventilation, total parenteral nutrition), and prior colonization with
A. baumannii were risk factors for the development of these infections.29 For the development
of MDR P. aeruginosa bloodstream infections,
risk factors were found to include advanced age,
prior therapy with quinolones, intravenous drug
abuse, and human immunodeficiency virus
infection.30
Colonization with resistant gram-negative bacteria (e.g., ESBL-producing organisms and CRE)
as well as other MDR organisms is common
among residents in long-term care facilities (particularly long-term acute-care centers [LTACs]
where patients often have indwelling devices)
who are considered reservoirs of resistant gramnegative strains and an important originating
source of such strains for hospitals.3133 Patients
in these types of long-term care facilities are often
colonized with multiple resistant gram-negative
strains,31 among which MDR Enterobacteriaceae
(e.g., K. pneumoniae and E. coli) have emerged as
the most commonly encountered strains.32
Risk factors for MDR gram-negative bacteria
in long-term care settings include prior antibiotic exposure, nonambulatory status, advanced
dementia, and fecal incontinence.34 In an analysis of hospital admissions, exposure to a longterm care facility was strongly associated with
CRE infection (31.6% of all CRE cases
[p<0.001]) and A. baumannii infection (14.9% of
all A. baumannii cases [p<0.001]).33 The elderly,
particularly those in long-term care facilities, are
an important reservoir of MDR gram-negative
bacteria.34, 35

Antibiotic resistance in both gram-negative

and gram-positive infections is associated with a
substantial clinical and economic burden. Gramnegative infections in particular are associated
with an increased severity of illness, greater hospital and antibiotic costs, and longer stays in
hospitals and ICUs.36, 37 Although the total economic burden of resistance is difficult to calculate, it has been estimated that antibiotic
resistance in general is associated with more
than $20 billion in direct health carerelated
costs in the United States, with an additional
$35 billion attributed to lost productivity (2008
U.S. dollars).2 One study found that resistant
gram-negative infections were associated with
significantly higher median hospital costs
($80,500 vs $29,604, p<0.0001), a longer median length of hospital stay (29 vs 13 days,
p<0.0001), a longer median length of ICU stay
(13 vs 1 days, p<0.0001), and increased mortality (23% vs 11%, p<0.0004) compared with
patients infected with sensitive gram-negative
bacterial strains.37 In another study, health care
associated infections with resistant gram-negative pathogens were associated with a 29.3%
(p<0.0001) increase in total hospital costs and a
23.8% (p=0.0003) increase in the length of stay
compared with infections caused by susceptible
strains.38 It has been estimated that ESBLproducing or carbapenemase-producing E. coli
or Klebsiella species infections are associated with
a 3.6-fold increased risk of death and a 1.7-fold
increase in attributable costs as compared with
strains without these resistant mechanisms.39
Poorer clinical outcomes and increased costs
can be due to a number of factors, including a
delay in implementation of appropriate antimicrobial treatment, decreased antimicrobial effectiveness and increased toxicity of second-line
agents, improper dosing leading to excess morbidity and mortality, and/or a need for surgery
or other invasive procedures.39
Infection Control and Antibiotic Stewardship
Control of resistant gram-negative infections
requires a comprehensive approach, including
strategies for risk factor identification, early
detection and identification of resistant organisms, and implementation of infection-control
and prevention strategies. Although the Centers
for Disease Control and Prevention acknowledge
that evidence regarding specific infection control

954

PHARMACOTHERAPY Volume 35, Number 10, 2015

practices for gram-negative organisms is limited,

they have issued guidelines for the control of
infections in acute care facilities where colonization of carbapenem-resistant or carbapenemaseproducing Enterobacteriaceae has been identified. These measures include the use of contact
precautions and implementing Clinical and Laboratory Standards Institute guidelines for the
detection of carbapenemase-producing Klebsiella
species and E. coli, and use of active microbiologic surveillance screening of patients at high
risk for colonization with resistant gram-negative
organisms.40 The European Society of Clinical
Microbiology and Infectious Diseases has also
recognized the growing threat of resistant gramnegative infections and has issued similar guidelines for the management of infection control as
a means of reducing transmission of resistant
gram-negative bacteria.41
The Infectious Diseases Society of America has
developed guidelines for health care institutions
to implement antimicrobial stewardship programs.42 Antibiotic stewardship programs use an
integrative approach designed to improve antimicrobial prescribing and control antimicrobial
resistance. This includes selection of an appropriate antimicrobial agent, dose and route of
administration, and selection of an appropriate
duration of therapy. Appropriate antibiotic stewardship also includes the deescalation and narrowing of antibiotic therapy and selection of the
optimal duration of treatment once the results of
susceptibility testing are known.43 Because combination therapy improves the chances of appropriate empiric therapy, empiric broad-spectrum
combination regimens have been suggested for
use in patients with multiple risk factors for
resistant health careassociated gram-negative
infections.43 The importance of such measures is
underscored by the observation that selection of
appropriate empiric antimicrobial therapy
improves outcomes and shortens hospital stays.43
In a recent study,44 antimicrobial stewardship
coupled with active alerting of positive blood
cultures for gram-negative bacteria was found to
reduce the time to appropriate therapy for
patients with gram-negative bacteremia, reduce
the length of hospital stay, and decrease infection-related mortality compared with patients
with no formalized stewardship intervention.
Importantly, it is critical to couple empiric
broad-spectrum therapy with deescalation and,
when possible, short durations of therapy to
avoid antimicrobial overuse which can promote
increased resistance.

Treatment Regimens for Resistant GramNegative Infections

The choice of appropriate empiric antimicrobial therapy requires knowledge of the local
resistance patterns among the most commonly
isolated pathogens. A review of surveillance data
and hospital-specific antibiograms, including
resistance patterns within the local institutions,
can help in the selection of initial therapy.
Patient characteristics, including underlying
medical conditions, severity of illness, nature of
the infection, previous antibiotic and hospital
exposure, presence of indwelling catheters, and
colonization or a history of infection with antibiotic-resistant organisms, are also helpful in guiding the choice of empiric therapy.43 For patients
with infections caused by ESBL-producing gramnegative bacteria, carbapenems are usually considered first-line therapy.11, 45 A meta-analysis
comparing carbapenems with alternative antibiotics for the treatment of bacteremia caused by
ESBL-producing Enterobacteriaceae found that
carbapenems were associated with lower mortality compared with nonb-lactam/b-lactamase
inhibitor combinations for both definitive (35%
risk reduction) and empiric (50% risk reduction) therapy.46 b-Lactam/b-lactamase inhibitor
combinations that include the classic b-lactamase inhibitors (e.g., sulbactam, clavulanate,
tazobactam) are potential alternatives for these
infections in the setting of in vitro activity, particularly for UTIs; however, well-controlled data
comparing these combinations to carbapenems
are lacking. Cephalosporin monotherapy is generally not recommended for patients with suspected or confirmed ESBL infections, although
the fourth-generation agent cefepime may be an
option for invasive infections caused by ESBLproducing Klebsiella species and E. coli when
the minimum inhibitory concentration (MIC)
for the organism is 2 mg/L; however, as with
b-lactam/b-lactamase inhibitor combinations,
well-controlled data are lacking.47
Treatment of MDR P. aeruginosa should
include appropriate doses of an effective
antipseudomonal agent.11 Options include piperacillin/tazobactam, cefepime or ceftazidime,
aztreonam, group 2 carbapenems (e.g., imipenem, doripenem, meropenem), antipseudomonal
fluoroquinolones (ciprofloxacin, levofloxacin),
aminoglycosides (gentamicin, tobramycin, amikacin), and polymyxins (e.g., colistin).11
Extended-infusion dosing strategies for b-lactams have the ability to produce longer dura-

MANAGEMENT OF RESISTANT GRAM-NEGATIVE BACTERIA Kaye and Pogue

tions of free drug exposure above MIC
(fT > MIC) in isolates with higher MICs and
have resulted in decreased mortality in the treatment of P. aeruginosa infection compared to
intermittent infusions.48 For cefepime, mortality
among patients with P. aeruginosa bacteremia
was significantly lower for patients who received
an extended infusion (3%) compared to patients
who received an intermittent infusion (20%
[p=0.03]).49 Similar outcomes were observed for
patients who received an extended-infusion
piperacillin-tazobactam dosing strategy; the 14day mortality was lower for patients with Acute
Physiology and Chronic Health Evaluation II
scores 17 who received an extended infusion
(12.2%) compared to patients who received
intermittent infusion (31.6% [p=0.04]).48 When
P. aeruginosa is resistant to all other treatment
options, which has been occurring with increasing frequency, clinicians may opt to use
polymyxins due to a lack of alternative options,
despite their high rate of associated nephrotoxicity. Nephrotoxicity rates of 3050% are seen
with both colistin and polymyxin B.50, 51 Other
limitations of the polymyxins include the lack of
a well-defined optimal dosing regimen for colistin and a lack of clinical experience with polymyxin B.12 A comprehensive review of the
polymyxins is beyond the scope of this manuscript but may be found elsewhere.7
CRKP is particularly challenging because it is
the species of CRE most commonly encountered
in the United States and, in many instances, is
resistant to almost all antimicrobial agents.2
Studies evaluating treatment outcomes in
patients with CRE are limited to small single-institution retrospective investigations. Thus, the
lack of randomized controlled trials makes
comparisons of available therapeutic agents difficult.12, 52 Available agents include aminoglycosides, colistin, polymyxin B, minocycline,
tigecycline, fosfomycin, and, in some instances,
carbapenems (Table 4). Although polymyxins
have been considered a last line of defense,
resistance rates among Enterobacteriaceae have
been increasing in some countries, with colistin
monotherapy associated with poor rates of clinical success in patients with invasive infections
caused by CRE.12
Combination therapy with two or more active
drugs (when available), dosed optimally, is associated with increased efficacy in the treatment of
CRE infections.12, 69, 70 A study70 demonstrated
that compared with monotherapy, combination
therapy decreased mortality in patients with

955

bloodstream infections caused by KPC-producing K. pneumoniae (54.3% vs 34.1% mortality

rate for monotherapy vs combination therapy,
p=0.02). Interestingly, the only independent
protective factor against mortality in this analysis was definitive therapy with a triple combination of colistin plus tigecycline plus meropenem
(odds ratio 0.11, 95% confidence interval [CI]
0.020.69, p=0.01). Similar findings were
reported in 205 patients with bloodstream infections caused by KPC-producing K. pneumoniae.69
The 28-day mortality for all causes was 40%
(82/205 patients); however, when patients were
treated with combination regimens that included
a carbapenem, when the carbapenem MIC was
8 lg/ml and thus pharmacodynamically attainable, the mortality rate decreased to 19.4% (6/31
patients). In a combined analysis of 34 studies
(case series and retrospective analyses) evaluating the treatment of invasive infections caused
by CRE, combination therapy with two or more
active drugs (one of which was a carbapenem in
the setting of an MIC 8 lg/ml) was associated
with a significantly lower failure rate compared
with combination therapy with two or more
active drugs not including a carbapenem;
monotherapy with an aminoglycoside, a carbapenem, tigecycline, or colistin; or inappropriate therapy (defined as no therapy with a drug
to which the infecting organism was susceptible).12 Notably, monotherapy with tigecycline or
colistin was associated with failure rates similar
to those for patients receiving inappropriate
therapy. These data suggest that carbapenembased combinations (when pharmacokinetic and
pharmacodynamic targets can be met) that
include another agent with in vitro activity may
be preferred for the treatment of CRE compared
with monotherapy. Conservatively speaking,
although the optimal combination remains
unclear, repeated analyses suggest that combination therapy with two or more active agents,
when pharmacodynamic targets can be met,
should be preferred for invasive CRE infections.
In the treatment of MDR A. baumannii, colistin, polymyxin B, tigecycline, and minocycline
appear to be the most active agents.16, 71 Colistin has in vitro activity against A. baumannii,
including carbapenem-resistant strains; however,
limited pharmacokinetic data make dosage
optimization difficult, and the drug appears to
have a narrow therapeutic window.17 Minocycline has demonstrated activity against some
isolates of MDR A. baumannii, although nonsusceptible isolates are common in some regions.72

FDA-Approved Indications

Uncomplicated urinary tract infection

in women

Infections due to susceptible strains of P.

aeruginosa, Proteus species, E. coli,
Klebsiella-Enterobacter-Serratia species,
Citrobacter species, and Staphylococcus
species

Fosfomycin6164

Aminoglycosidesa
Gentamicin52,6568
Amikacin
Tobramycin

Dosage

Only approved in United States as 3 g for

1 oral dose (i.v. formulation is available
in other countries); optimal dose is unclear
but has ranged from 4 to 24 g/day
Gentamicin or tobramycin 57 mg/kg/day i.v.
Amikacin 15 mg/kg/day i.v.

5 mg/kg/day i.v. of colistin base activity

or 9 million international units i.v.
Polymyxin B 1.25 mg/kg i.v. every 12 hrs

100 mg i.v. followed by 50 mg i.v.

every 12 hrs

2.5 g (ceftazidime 2 g + avibactam 0.5 g)

i.v. every 8 hrs
1.5 g (ceftolozane 1 g + tazobactam 0.5 g)
i.v. every 8 hrs
3 g (ceftolozane 2 g + tazobactam 1 g) is
being studied for nosocomial pneumonia
100200 mg i.v. or p.o. twice daily

FDA
= U.S. Food and Drug Administration; CI = confidence interval; MIC = minimum inhibitory concentration.
a
Information provided is for gentamicin.

Infections due to gram-negative bacteria,

Pseudomonas aeruginosa, Enterobacter
aerogenes, E. coli, and Klebsiella pneumoniae

Infections due to gram-negative bacteria,

including Bartonella bacilliformis,
Brucella species, Klebsiella granulomatis,
Campylobacter fetus, Francisella tularensis,
Vibrio cholerae, Yersinia pestis, Acinetobacter
species, Enterobacter aerogenes, Escherichia
coli, Haemophilus influenzae, Klebsiella
species, Neisseria meningitidis, and Shigella
species (additional gram-positive organisms
and other microorganisms are indicated)
Community-acquired pneumonia,
complicated skin and skin structure
infections,
complicated intraabdominal infections

Complicated intraabdominal infections,

complicated urinary tract infections
Complicated intraabdominal infections,
complicated urinary tract infections

Polymyxins59,60
Colistin (polymyxin E)
Polymyxin B

Tigecycline21,5658

Minocycline55

Ceftolozane-tazobactam54

Ceftazidime-avibactam53

Antimicrobial Agent

Table 4. Current Treatments for Resistant Gram-Negative Infections

Special Considerations

An increase in all-cause mortality was

observed in a meta-analysis of phase III
and IV clinical trials in tigecycline-treated
patients vs comparator (0.6%, 95% CI
0.11.2%).
Achieves suboptimal concentrations in
urine, lungs, and blood; optimal dose is
unclear
Nephrotoxicity is a dose-limiting adverse effect
Optimal dose remains unclear
Loading dose pharmacokinetically warranted
Combination therapy often recommended for
invasive infections
Oral fosfomycin should only be used in the
treatment of cystitis
Rapid development of resistance limits utility
of i.v. formulation as monotherapy
Therapy has been associated with potential
neurotoxicity, ototoxicity, and nephrotoxicity
Dosing methods target a peak concentration
to MIC ratios of 812:1 or high-dose
extended-interval regimens to avoid toxicities
Close monitoring, using 2 time points (peak
and trough concentrations), is necessary to
prevent toxicities

Higher doses can increase serum

concentrations compared with tigecycline

Unknown at this time due to limited data

Unknown at this time due to limited data

956
PHARMACOTHERAPY Volume 35, Number 10, 2015

MANAGEMENT OF RESISTANT GRAM-NEGATIVE BACTERIA Kaye and Pogue

The role of combination therapy in the treatment of extensively drug-resistant A. baumannii
remains unclear, as current data only investigate
the role of colistin-based synergistic combinations and only suggest an improvement in
microbiologic cure with no improvement
demonstrated for clinical cure or mortality.73, 74
Newer Treatment Options
Although the pipeline for new agents for the
treatment of resistant gram-negative bacteria is
limited, there are a few new and emerging treatment options for these difficult-to-treat infections.
Ceftolozane/Tazobactam
Ceftolozane/tazobactam is a combination of a
novel antipseudomonal cephalosporin (ceftolozane) with a b-lactamase inhibitor (tazobactam)
that was approved in December 2014 by the
U.S. Food and Drug Administration (FDA) for
the treatment of complicated UTIs (cUTIs) and
complicated IAIs (cIAIs).75, 76 The antimicrobial
combination has activity against resistant
gram-negative bacteria such as P. aeruginosa
(including MDR and XDR strains) and
Enterobacteriaceae, including ESBL producers.77, 78
Ceftolozane/tazobactam
has
demonstrated
greater activity than currently available cephalosporins, carbapenems, and piperacillin/tazobactam against P. aeruginosa, inhibiting 96.1% of
isolates at an MIC of 4 lg/ml.77 Against MDR
and XDR strains of P. aeruginosa, ceftolozane/tazobactam exhibited good activity, with MICs for
50% and 90% of tested strains (MIC50 and
MIC90, respectively) of 2 and 8 lg/ml, respectively, against MDR strains, and 4 and 16 lg/ml,
respectively, against XDR strains isolated in the
United States from 2011 to 2012.77 Ceftolozane/
tazobactam has also demonstrated greater activity than currently available cephalosporins and
piperacillin/tazobactam against most Enterobacteriaceae,
including
ESBL-producing
strains.75, 77, 79 Ceftolozane/tazobactam is not
active against metallo-b-lactamases (NDM-1,
IMP, VIM) and serine carbapenemases (KPC).
Pharmacokinetic
and
pharmacodynamic
assessments of ceftolozane in an in vivo mouse
thigh infection model indicated that lower mean
percent fT > MIC values are needed for bacteriostasis and bactericidal activity than are commonly needed for other cephalosporins.80 The
percent fT > MIC values for bacteriostasis and
1 log10 bacterial kill of 24.0% and 31.5%,

957

respectively, were recorded for P. aeruginosa, and

26.3% and 31.6%, respectively, for wild-type
Enterobacteriaceae.81 Pharmacodynamic investigation has also been undertaken to identify the
tazobactam exposure necessary to get full inhibition of b-lactamases present in order to restore
ceftolozane activity. Using a translational
approach, another study80 demonstrated that the
%T > threshold concentration needed to restore
bacterial stasis, 1 log10 kill, and 2 log10 kill
were 65.9%, 77.3%, and 90.2%, respectively, of
the dosing interval. Of interest and importance,
the authors were able to relate this threshold to
the ceftolozane MIC in the presence of 4 lg/ml
of tazobactam (the amount used in susceptibility
testing), and they found the threshold concentration to be 0.59 the ceftolozane MIC/4 lg/ml
tazobactam MIC. For example, assuming that the
above listed fT > MIC exposures of ceftolozane
are met, a b-lactamaseproducing Enterobacteriaceae with a ceftolozane/tazobactam MIC of 2/
4 lg/ml would require the tazobactam exposure
to be > 1 lg/ml (which is 0.59 the ceftolozane
MIC) for 77.3% of the dosing interval in order to
achieve a 1 log10 kill.
A phase III clinical trial compared ceftolozane
1 g/tazobactam 0.5 g plus metronidazole 0.5 g
every 8 hours with meropenem 1 g every
8 hours for 414 days in 993 patients with
cIAIs.82 Ceftolozane/tazobactam plus metronidazole demonstrated statistical noninferiority to
meropenem in the primary endpoint. The clinical cure rate in the microbiologic intention-totreat populations at 2432 days after the initiation of therapy was 87.3% (364/417 patients) for
meropenem and 83.0% (323/389 patients) for
the
ceftolozane/tazobactam-based
regimen
(weighted difference 4.2%, 95% CI 8.91 to
0.54). Although ceftolozane/tazobactam is active
against many clinically relevant anaerobic pathogens, including Bacteroides fragilis, it is not universally active against anaerobes in the
gastrointestinal tract, and therefore metronidazole was used in combination with ceftolozane/
tazobactam. In patients with ESBL-producing
Enterobacteriaceae, clinical cure was observed in
23 (95.8%) of 24 patients in the ceftolozane/tazobactam plus metronidazole group and 23
(88.5%) of 26 patients in the meropenem group.
In a phase III multinational, randomized, double-blind trial in 1083 patients with cUTIs or
pyelonephritis, ceftolozane 1 g/tazobactam 0.5 g
intravenously every 8 hours was noninferior
compared with high-dose levofloxacin 750 mg
intravenously once daily, with both given for

958

PHARMACOTHERAPY Volume 35, Number 10, 2015

7 days.83 Ceftolozane/tazobactam provided superior composite cure for the microbiologic modified intention-to-treat population (76.9%) versus
levofloxacin (68.4%) at test-of-cure visit; however, superiority was driven largely by microbiologic cure in patients with levofloxacin-resistant
organsims.
Additional research on the use of ceftolozane/
tazobactam for the treatment of noscomial bacterial pneumonia (either VAP or hospital-acquired
pneumonia) compared to treatment with meropenem is being conducted in an ongoing trial.
In this trial, a dosage of ceftolozane 2 g/tazobactam 1 g intravenously every 8 hours is being
administered to take into account pharmacokinetic differences in critically ill patients as well
as the ~50% penetration of ceftolozane and
tazobactam into the epithelial lining fluid.84
Although results from this clinical trial will not
be available for years, a recent case series of
patients with pneumonia who received the
higher dose was encouraging, as all three
patients had clinical and microbiologic cure.85
Based on its activity against ESBL-producing
Enterobacteriaceae and MDR P. aeruginosa, ceftolozane/tazobactam should be a useful alternative for the treatment of nosocomial infections
caused by resistant gram-negative organisms.
The greatest utility of ceftolozane/tazobactam
appears to be against P. aeruginosa, particularly
isolates resistant to other b-lactam options (including carbapenems). Good penetration in
epithelial lining fluid should make this combination a good choice for the treatment of hospitalacquired pneumonia and VAP.
Ceftazidime/Avibactam
In February 2015, the FDA approved the combination of ceftazidime (2.0 g) and avibactam
(0.5 g) for the treatment of cUTIs and cIAIs
based largely on phase II trial results.86, 87
Ceftazidime/avibactam combines a broad-spectrum
cephalosporin (ceftazidime) and a novel b-lactamase inhibitor (avibactam) to overcome antibiotic resistance and treat the increasing number
of infections resistant to existing therapies.
Avibactam inhibits a broad spectrum of b-lactamases, including class A, class C, and some class
D enzymes, restoring the activity of ceftazidime
against AmpC-hyperproducing, ESBL-producing,
and KPC-producing Enterobacteriaceae.87 However, it does not improve the activity of ceftazidime against metallo-b-lactamases such as
the New Delhi metallo-b-lactamase (NDM-1).87

Although avibactam modestly improves the

activity of ceftazidime (~4-fold decrease in MIC)
against P. aeruginosa, it does not appear to
improve its activity against Acinetobacter
species.87
Coadministration of avibactam and ceftazidime
does not influence the pharmacokinetic profile of
either drug.87 Pharmacodynamic studies have
revealed that avibactam has different binding
characteristics than do other b-lactamase inhibitors. Unlike b-lactamase inhibitors that are
derived from b-lactam substrates and have a high
propensity for hydrolysis, avibactam binds covalently and reversibly with b-lactamases. This
enhanced potency likely explains why avibactam
inhibits a broader range of b-lactamases, including ESBLs, class A carbapenemases (KPC-2), some
class D (OXA) carbapenemases, and chromosomal
and acquired AmpC-type enzymes.88, 89
To date, a limited number of clinical studies
of ceftazidime/avibactam have been published
and additional phase III trials are ongoing to
evaluate the use of this drug for nosocomial
pneumonia (including VAP). In a study of hospitalized patients in 203 patients with cIAIs,
ceftazidime 2.0 g/avibactam 0.5 g plus metronidazole 0.5 g every 8 hours was compared with
monotherapy with meropenem 1.0 g every
8 hours.90 Metronidazole was added to provide
additional activity against anaerobic pathogens
given that ceftazidime/avibactam alone has limited activity against gram-negative anaerobes. A
favorable clinical response was achieved in
91.2% and 93.4% of patients, respectively, in the
ceftazidime/avibactam and meropenem groups
(p=0.60). For those infected with ceftazidime-resistant gram-negative bacilli, favorable microbiologic responses were seen in 25 (96.2%) of 26
patients receiving ceftazidime/avibactam and 16
(94.1%) of 17 patients receiving meropenem.
In the treatment of cUTIs among 137 hospitalized adults, including those with acute
pyelonephritis (63%), ceftazidime 0.5 g/avibactam 0.125 g every 8 hours was compared with
imipenem/cilastatin 0.5 g every 6 hours in a
prospective, investigator-blinded, randomized
trial.91 At test of cure, clinical responses were
seen in 70.4% of patients in the ceftazidime/avibactam group and 71.4% of those receiving imipenem/cilastatin (observed difference
1.1%
[95% CI 27.2% to 25.0%]).91 There was also
no significant difference in efficacy between the
groups when patients were stratified by the diagnosis of acute pyelonephritis versus other
cUTIs.91 Among patients with ceftazidime-resis-

MANAGEMENT OF RESISTANT GRAM-NEGATIVE BACTERIA Kaye and Pogue

tant pathogens (primarily E. coli), favorable
microbiologic response rates were achieved in
85.7% (6/7 patients) and 81.8% (9/11 patients)
of those receiving ceftazidime/avibactam and
imipenem/cilastatin, respectively.
Data presented for FDA approval, evaluating
the efficacy of ceftazidime/avibactam against ceftazidime-resistant pathogens in pooled data from
the phase II trials as well as the ongoing phase
III resistant-pathogen study, have been encouraging. A favorable microbiologic response was
reported in 52 (78.8%) of 66 patients receiving
ceftazidime/avibactam compared to 41 (61.2%)
of 67 patients receiving comparator agents (difference 17.6%, 95% CI 0.529.9%). Clinical
cure rates were similar (87.9% [58/66 patients]
vs 71.6% [48/67 patients]; difference 16.3%,
95% CI 1.328.7%).92
Overall, the addition of avibactam to ceftazidime restores the activity of ceftazidime
against gram-negative bacteria that develop resistance through ESBLs, class A carbapenemases
(KPC), some class D carbapenemases (OXA),
and chromosomal and acquired AmpC-type class
C enzymes. The primary niche for ceftazidime/
avibactam in the treatment of MDR gram-negative bacilli will be for treatment of CRE caused
by class A (KPC) or class D (OXA-48 type) carbapenemases.
Conclusion
Infections caused by gram-negative pathogens
that are resistant to many and, in some cases, all
available antimicrobial agents, are becoming
increasingly common and difficult to treat. For
antibiotics to remain effective for years to come,
physicians must use the available agents responsibly and effectively. The number of therapies
currently available for resistant gram-negative
infections is limited, due, in part, to the emergence and dissemination of carbapenem-resistant
strains. Although there are a few new agents
with promising activity against some resistant
gram-negative organisms (e.g., ceftolozane/tazobactam and ceftazidime/avibactam), the pipeline for new agents on the horizon remains
limited. In order to optimize therapy for patients
while limiting the continued spread of antimicrobial resistance, effective antimicrobial stewardship and best infection control practices are
necessary. Empiric broad-spectrum therapy for
patients at risk of resistant gram-negative infections should be coupled with aggressive de-escalation processes and attempts to minimize the

959

duration of antimicrobial therapy, whenever

possible.
Acknowledgments
Editorial services and assistance with the preparation of this manuscript were provided by The Medicine Group and funded by Forest Laboratories, LLC.
Both authors confirm that they received no payment
for the preparation of this manuscript and developed
the content of this manuscript.

Conflict of Interest
Dr. Keith Kaye serves as a consultant for Cubist Pharmaceuticals, Actavis/Forest Laboratories,
and The Medicines Company. In addition, he
was supported by the National Institute of
Allergy and Infectious Diseases (NIAID); DMID
Protocol Number: 10-0065. Dr. Jason Pogue
serves as a consultant and speaker for Cubist
Pharmaceuticals and as a speaker for Actavis.
References
1. Vincent JL, Rello J, Marshall J, et al. International study of
the prevalence and outcomes of infection in intensive care
units. JAMA 2009;302:23239.
2. Centers for Disease Control and Prevention (CDC). Antibiotic
resistance threats in the United States, 2013. Available from:
http://www.cdc.gov/drugresistance/threat-report-2013/pdf/arthreats-2013-508.pdf. Accessed October 22, 2014.
3. Perez F, Van Duin D. Carbapenem-resistant Enterobacteriaceae: a menace to our most vulnerable patients. Cleve Clin J
Med 2013;80:22533.
4. Snitkin ES, Zelazny AM, Thomas PJ, et al. Tracking a hospital
outbreak of carbapenem-resistant Klebsiella pneumoniae with
whole-genome sequencing. Sci Transl Med 2012;4:148ra16.
5. Peterson LR. Bad bugs, no drugs: no ESCAPE revisited. Clin
Infect Dis 2009;49:9923.
6. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no
drugs: no ESKAPE! An update from the Infectious Diseases
Society of America. Clin Infect Dis 2009;48:112.
7. Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare
Safety Network at the Centers for Disease Control and
Prevention, 20092010. Infect Control Hosp Epidemiol
2013;34:114.
8. Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins
and carbapenems in Gram-negative bacterial pathogens. Int J
Med Microbiol 2010;300:3719.
9. Prabaker K, Weinstein RA. Trends in antimicrobial resistance
in intensive care units in the United States. Curr Opin Crit
Care 2011;17:4729.
10. Doi Y, Park YS, Rivera JI, et al. Community-associated
extended-spectrum beta-lactamase-producing Escherichia coli
infection in the United States. Clin Infect Dis 2013;56:6418.
11. Kanj SS, Kanafani ZA. Current concepts in antimicrobial
therapy against resistant gram-negative organisms: extendedspectrum
beta-lactamase-producing
Enterobacteriaceae,
carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc 2011;86:2509.
12. Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios
PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and
other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev 2012;25:682707.

960

PHARMACOTHERAPY Volume 35, Number 10, 2015

13. Poirel L, Naas T, Nordmann P. Diversity, epidemiology, and

genetics of class D beta-lactamases. Antimicrob Agents Chemother 2010;54:2438.
14. Poirel L, Potron A, Nordmann P. OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother
2012;67:1597606.
15. Centers for Disease Control and Prevention (CDC). Carbapenem-resistant Klebsiella pneumoniae associated with a
long-termcare facility West Virginia, 20092011. MMWR
Morb Mortal Wkly Rep 2011;60:141820.
16. Zavascki AP, Carvalhaes CG, Picao RC, Gales AC. Multidrugresistant Pseudomonas aeruginosa and Acinetobacter baumannii:
resistance mechanisms and implications for therapy. Expert
Rev Anti Infect Ther 2010;8:7193.
17. Pogue JM, Mann T, Barber KE, Kaye KS. Carbapenem-resistant Acinetobacter baumannii: epidemiology, surveillance and
management. Expert Rev Anti Infect Ther 2013;11:38393.
18. Kallen AJ, Srinivasan A. Current epidemiology of multidrugresistant gram-negative bacilli in the United States. Infect Control Hosp Epidemiol 2010;31:S514.
19. Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 2001;14:93351.
20. Dhillon RH, Clark J. ESBLs: a clear and present danger? Crit
Care Res Pract 2012;2012:625170.
21. Falagas ME, Karageorgopoulos DE. Extended-spectrum betalactamase-producing organisms. J Hosp Infect 2009;73:345
54.
22. Hawser SP, Badal RE, Bouchillon SK, et al. Monitoring the
global in vitro activity of ertapenem against Escherichia coli
from intra-abdominal infections: SMART 20022010. Int J
Antimicrob Agents 2013;41:2248.
23. Babinchak T, Badal R, Hoban D, et al. Trends in susceptibility
of selected gram-negative bacilli isolated from intra-abdominal
infections in North America: SMART 20052010. Diagn
Microbiol Infect Dis 2013;76:37981.
24. Bouchillon SK, Badal RE, Hoban DJ, Hawser SP. Antimicrobial susceptibility of inpatient urinary tract isolates of gramnegative bacilli in the United States: results from the study for
monitoring antimicrobial resistance trends (SMART) program:
20092011. Clin Ther 2013;35:8727.
25. Centers for Disease Control and Prevention (CDC). Vital
signs: carbapenem-resistant Enterobacteriaceae. MMWR Morb
Mortal Wkly Rep 2013;62:16570.
26. Zilberberg MD, Shorr AF. Prevalence of multidrug-resistant
Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among specimens from hospitalized patients with
pneumonia and bloodstream infections in the United States
from 2000 to 2009. J Hosp Med 2013;8:55963.
27. Landman D, Bratu S, Kochar S, et al. Evolution of antimicrobial resistance among Pseudomonas aeruginosa, Acinetobacter
baumannii and Klebsiella pneumoniae in Brooklyn, NY. J
Antimicrob Chemother 2007;60:7882.
28. Routsi C, Pratikaki M, Platsouka E, et al. Risk factors for carbapenem-resistant Gram-negative bacteremia in intensive care
unit patients. Intensive Care Med 2013;39:125361.
29. Sheng WH, Liao CH, Lauderdale TL, et al. A multicenter
study of risk factors and outcome of hospitalized patients with
infections due to carbapenem-resistant Acinetobacter baumannii. Int J Infect Dis 2010;14:e7649.
30. Tacconelli E, Tumbarello M, Bertagnolio S, et al. Multidrugresistant Pseudomonas aeruginosa bloodstream infections: analysis of trends in prevalence and epidemiology. Emerg Infect
Dis 2002;8:2201.
31. Dommeti P, Wang L, Flannery EL, Symons K, Mody L. Patterns of ciprofloxacin-resistant gram-negative bacteria colonization in nursing home residents. Infect Control Hosp
Epidemiol 2011;32:17780.
32. Pop-Vicas A, Tacconelli E, Gravenstein S, Lu B, DAgata EM.
Influx of multidrug-resistant, gram-negative bacteria in the
hospital setting and the role of elderly patients with bacterial
bloodstream infection. Infect Control Hosp Epidemiol
2009;30:32531.

33. Marchaim D, Chopra T, Bogan C, et al. The burden of multidrug-resistant organisms on tertiary hospitals posed by
patients with recent stays in long-term acute care facilities.
Am J Infect Control 2012;40:7605.
34. Pop-Vicas A, Mitchell SL, Kandel R, Schreiber R, DAgata
EM. Multidrug-resistant gram-negative bacteria in a long-term
care facility: prevalence and risk factors. J Am Geriatr Soc
2008;56:127680.
35. Denkinger CM, Grant AD, Denkinger M, Gautam S, DAgata
EM. Increased multi-drug resistance among the elderly on
admission to the hospitala 12-year surveillance study. Arch
Gerontol Geriatr 2013;56:22730.
36. Maragakis LL. Recognition and prevention of multidrug-resistant Gram-negative bacteria in the intensive care unit. Crit
Care Med 2010;38:S34551.
37. Evans HL, Lefrak SN, Lyman J, et al. Cost of gram-negative
resistance. Crit Care Med 2007;35:8995.
38. Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA.
Attributable hospital cost and length of stay associated with
health care-associated infections caused by antibiotic-resistant
gram-negative bacteria. Antimicrob Agents Chemother
2010;54:10915.
39. Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and
economic burden of antimicrobial resistance. Expert Rev Anti
Infect Ther 2008;6:75163.
40. Centers for Disease Control and Prevention (CDC). Guidance
for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in acute care facilities. MMWR Morb Mortal Wkly Rep 2009;58:25660.
41. Tacconelli E, Cataldo MA, Dancer SJ, et al. ESCMID guidelines
for the management of the infection control measures to reduce
transmission of multidrug-resistant Gram-negative bacteria in
hospitalized patients. Clin Microbiol Infect 2014;20:155.
42. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an
institutional program to enhance antimicrobial stewardship.
Clin Infect Dis 2007;44:15977.
43. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria.
Clin Microbiol Rev 2012;25:45070.
44. Pogue JM, Mynatt RP, Marchaim D, et al. Automated alerts
coupled with antimicrobial stewardship intervention lead to
decreases in length of stay in patients with gram-negative bacteremia. Infect Control Hosp Epidemiol 2014;35:1328.
45. Pitout JD, Laupland KB. Extended-spectrum beta-lactamaseproducing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis 2008;8:15966.
46. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of
bacteraemia due to Enterobacteriaceae producing extendedspectrum beta-lactamases: a systematic review and meta-analysis. J Antimicrob Chemother 2012;67:2793803.
47. Nguyen HM, Shier KL, Graber CJ. Determining a clinical
framework for use of cefepime and beta-lactam/beta-lactamase
inhibitors in the treatment of infections caused by
extended-spectrum-beta-lactamase-producing
Enterobacteriaceae. J Antimicrob Chemother 2014;69:87180.
48. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications
of an extended-infusion dosing strategy. Clin Infect Dis
2007;44:35763.
49. Bauer KA, West JE, OBrien JM, Goff DA. Extended-infusion
cefepime reduces mortality in patients with Pseudomonas
aeruginosa infections. Antimicrob Agents Chemother
2013;57:290712.
50. Dubrovskaya Y, Prasad N, Lee Y, Esaian D, Figueroa DA,
Tam VH. Risk factors for nephrotoxicity onset associated with
polymyxin B therapy. J Antimicrob Chemother 2015;70:1903
7.
51. Temocin F, Erdinc S, Tulek N, Demirelli M, Bulut C, Ertem
G. Incidence and Risk Factors for Colistin-Associated Nephrotoxicity. Jpn J Infect Dis 2015;68(4):318320.

MANAGEMENT OF RESISTANT GRAM-NEGATIVE BACTERIA Kaye and Pogue

52. van Duin D, Kaye KS, Neuner EA, Bonomo RA. Carbapenemresistant Enterobacteriaceae: a review of treatment and outcomes. Diagn Microbiol Infect Dis 2013;75:11520.
53. Forest Pharmaceuticals Inc. Avycaz (ceftazidime/avibactam)
package insert. Cincinnati, OH; 2015.
54. Cubist Pharmaceuticals. Zerbaxa (ceftolozane/tazobactam)
package insert. Lexington, MA; 2014.
55. The Medicines Company. Minocin (minocycline) package
insert. Parsippany, NJ; 2014.
56. Wyeth Pharmaceuticals Inc. Tygacil (tigecycline) package
insert. Ottawa, ON; 2014.
57. Hoffmann M, DeMaio W, Jordan RA, et al. Metabolism, excretion, and pharmacokinetics of [14C]tigecycline, a first-in-class
glycylcycline antibiotic, after intravenous infusion to healthy
male subjects. Drug Metab Dispos 2007;35:154353.
58. Curcio D. Treatment of recurrent urosepsis with tigecycline: a
pharmacological perspective. J Clin Microbiol 2008;46:18923.
59. Monarch Pharmaceuticals. Coly-Mycin (colistin) package
insert. Bristol, TN; 2006.
60. Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-interval colistin administration in critically ill patients: is this
the right dosing strategy? A preliminary study. Clin Infect Dis
2012;54:17206.
61. Forest Pharmaceuticals Inc. Monurol [package insert]. Saint
Louis, MI; 2007.
62. Schintler MV, Traunmuller F, Metzler J, et al. High fosfomycin concentrations in bone and peripheral soft tissue in
diabetic patients presenting with bacterial foot infection.
J Antimicrob Chemother 2009;64:5748.
63. Matzi V, Lindenmann J, Porubsky C, et al. Extracellular concentrations of fosfomycin in lung tissue of septic patients.
J Antimicrob Chemother 2010;65:9958.
64. Bergan T. Degree of absorption, pharmacokinetics of fosfomycin trometamol and duration of urinary antibacterial
activity. Infection 1990;18(Suppl. 2):S659.
65. Prins JM, Buller HR, Kuijper EJ, Tange RA, Speelman P.
Once-daily gentamicin versus once-daily netilmicin in patients
with serious infectionsa randomized clinical trial. J Antimicrob Chemother 1994;33:82335.
66. Moore RD, Lietman PS, Smith CR. Clinical response to
aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis
1987;155:939.
67. Begg EJ, Barclay ML, Kirkpatrick CJ. The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol
1999;47:2330.
68. Baxter Corp. Gentamine (gentamicin) package insert. Mississauga, ON; 2012.
69. Daikos GL, Tsaousi S, Tzouvelekis LS, et al. Carbapenemaseproducing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role
of carbapenems. Antimicrob Agents Chemother 2014;58:2322
8.
70. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae
carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55:94350.
71. Michalopoulos A, Falagas ME. Treatment of Acinetobacter
infections. Expert Opin Pharmacother 2010;11:77988.
72. Denys GA, Callister SM, Dowzicky MJ. Antimicrobial susceptibility among gram-negative isolates collected in the USA
between 2005 and 2011 as part of the Tigecycline Evaluation
and Surveillance Trial (T.E.S.T.). Ann Clin Microbiol Antimicrob 2013;12:24.
73. Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin
versus colistin plus fosfomycin for treatment of carbapenemresistant Acinetobacter baumannii infections. Antimicrob Agents
Chemother 2014;58:5598601.
74. Durante-Mangoni E, Signoriello G, Andini R, et al. Colistin
and rifampicin compared with colistin alone for the treatment
of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin
Infect Dis 2013;57:34958.

961

75. Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam:

a novel cephalosporin/beta-lactamase inhibitor combination
with activity against multidrug-resistant gram-negative bacilli.
Drugs 2014;74:3151.
76. U.S. Food and Drug Administration. FDA approves new
antibacterial drug Zerbaxa [press release], 2014. Available
from:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427534.htm. Accessed May 15, 2015.
77. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial
activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Hospitals (20112012). Antimicrob
Agents Chemother 2013;57:630510.
78. Juan C, Zamorano L, Perez JL, et al. Activity of a new
antipseudomonal cephalosporin, CXA-101 (FR264205), against
carbapenem-resistant and multidrug-resistant Pseudomonas
aeruginosa clinical strains. Antimicrob Agents Chemother
2010;54:84651.
79. Titelman E, Karlsson IM, Ge Y, Giske CG. In vitro activity of
CXA-101 plus tazobactam (CXA-201) against CTX-M-14- and
CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. Diagn Microbiol Infect Dis 2011;70:13741.
80. Vanscoy B, Mendes RE, McCauley J, et al. Pharmacological
basis of beta-lactamase inhibitor therapeutics: tazobactam in
combination with Ceftolozane. Antimicrob Agents Chemother
2013;57:592430.
81. Craig WA, Andes DR. In vivo activities of ceftolozane, a new
cephalosporin, with and without tazobactam against Pseudomonas
aeruginosa and Enterobacteriaceae, including strains with
extended-spectrum beta-lactamases, in the thighs of neutropenic
mice. Antimicrob Agents Chemother 2013;57:157782.
82. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal
infections in an era of multidrug resistance: results from a randomized, double-blind, Phase 3 Trial (ASPECT-cIAI). Clin
Infect Dis 2015;60:146271.
83. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections,
including pyelonephritis: a randomised, double-blind, phase 3
trial (ASPECT-cUTI). Lancet 2015;385(9981):19491956.
84. Chandorkar G, Huntington JA, Gotfried MH, Rodvold KA,
Umeh O. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J
Antimicrob Chemother 2012;67:24639.
85. Gelfand MS, Cleveland KO. Ceftolozane/tazobactam therapy
of respiratory infections due to multi-drug resistant Pseudomonas aeruginosa. Clin Infect Dis 2015;61(5):853855.
86. U.S. Food and Drug Administration. FDA approves new
antibacterial drug Avycaz [press release], 2015. Available from:
http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm435629.htm. Accessed May 15, 2015.
87. Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime-avibactam: a novel cephalosporin/beta-lactamase inhibitor combination. Drugs 2013;73:15977.
88. Lahiri SD, Mangani S, Durand-Reville T, et al. Structural
insight into potent broad-spectrum inhibition with reversible
recyclization mechanism: avibactam in complex with CTX-M15 and Pseudomonas aeruginosa AmpC beta-lactamases. Antimicrob Agents Chemother 2013;57:2496505.
89. Aktas Z, Kayacan C, Oncul O. In vitro activity of avibactam
(NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing
Klebsiella pneumoniae. Int J Antimicrob Agents 2012;39:869.
90. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam
plus metronidazole versus meropenem in the treatment of
complicated intra-abdominal infections in hospitalized adults:
results of a randomized, double-blind. Phase II trial. J Antimicrob Chemother 2013;68:118392.
91. Vazquez JA, Gonzalez Patzan LD, Stricklin D, et al. Efficacy
and safety of ceftazidime-avibactam versus imipenem-cilastatin
in the treatment of complicated urinary tract infections,

962

PHARMACOTHERAPY Volume 35, Number 10, 2015

including acute pyelonephritis, in hospitalized adults: results

of a prospective, investigator-blinded, randomized study. Curr
Med Res Opin 2012;28:192131.
92. Cerexa Inc. Ceftazidime-Avibactam for injection for treatment
of complicated intra-abdominal infection (used in combination
with metronidazole), complicated urinary tract infection

including acute pyelonephritis, and limited use indication: aerobic gram-negative infections with limited treatment options,
2014. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-Infective
DrugsAdvisoryCommittee/UCM425459.pdf. Accessed March 3,
2015.