International Journal of Antimicrobial Agents 29 Suppl.

3 (2007) S33–S41
www.ischemo.org

Non-fermentative Gram-negative bacteria

D.A. Enoch*, C.I. Birkett, H.A. Ludlam
Clinical Microbiology & Public Health Laboratory, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QW, UK

Abstract
Over the past decade, non-fermenting Gram-negative bacteria have emerged as important opportunistic pathogens in the increasing
population of patients who are immunocompromised by their disease or medical treatment. These bacteria are assisted by their ubiquitous
distribution in the environment and have a propensity for multiple, intrinsic or acquired drug resistance. The infections that they cause now
pose significant problems in terms of treatment and infection control, whilst the commonly observed rapid emergence of bacterial resistance
to new antimicrobial compounds raises concerns regarding the clinical lifespan of these agents. Studies are urgently required to assess
whether combination therapy can improve the long-term utility of new drugs in the treatment of patients infected with non-fermenters.
© 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Keywords: Non-fermenters; Pseudomonas aeruginosa; Stenotrophomonas maltophilia; Burkholderia cepacia; Acinetobacter baumannii

1. Introduction The European Antimicrobial Resistance Surveillance Sys-

Non-fermenting Gram-negative bacteria (“non-fermenters”)
are widespread in the environment and are an increasing
cause of serious infections in hospital practice, primarily
affecting the expanding population of patients immuno-
compromised by disease or by medical and surgical
treatments. Many species are notable for their resistance
to multiple antibiotics and the facility with which they
may acquire further resistances. Acquisition of resistance
may also promote their proliferation in hospitals, leading
to significant antibiotic treatment and infection control
challenges. There is a pressing need for novel antimicrobials
to address the problem caused by these organisms.
Non-fermenters comprise numerous species belonging
to many genera. This review will focus on the four
species most often causing significant problems in hospital
practice, namely Pseudomonas aeruginosa, Acinetobacter
baumannii, Stenotrophomonas maltophilia and members of
the Burkholderia cepacia complex, discussing the in vitro
activity of the drugs available to treat infections caused by
these organisms.
Surveillance programmes demonstrate the increasing
problem of antimicrobial resistance globally. The SEN-
TRY Program was established in 1997 to measure the
predominant pathogens and their antimicrobial resistance
patterns over a broad network of sentinel hospitals
in the USA, Canada, South America and Europe [1].
* Corresponding author. D.A. Enoch.
Tel.: +44 1223 257 035; fax: +44 1223 242 775.
E-mail: david.enoch@addenbrookes.nhs.uk (D.A. Enoch).
tem (EARSS) provides data on the prevalence and
spread of resistance for seven major invasive bacte-
ria, including P. aeruginosa (but not A. baumannii,
B. cepacia complex and S. maltophilia), in Europe
(http://www.earss.rivm.nl/), illustrating the wide geograph-
ical variation in antimicrobial resistance. The British
Society for Antimicrobial Chemotherapy (BSAC) Resis-
tance Surveillance Programme (http://www.bsacsurv.org)
provides local data for the UK and Irish Republic. In
this paper, we review recent data from these programmes
and other literature for P. aeruginosa, A. baumannii,
S. maltophilia and B. cepacia complex.
2. The organisms
2.1. Pseudomonas aeruginosa
Pseudomonas aeruginosa is widely distributed in the
environment. It is a leading cause of nosocomial infections,
being responsible for 10% of all hospital-acquired infec-
tions (HAIs) [2]. Infection is usually opportunistic and as-
sociated with invasive devices, mechanical ventilation, burn
wounds or surgery. Cross-infection from other colonised
patients occurs and is encouraged by suppression of hospital
patients’ normal flora with broad-spectrum antibiotics to
which this organism is widely resistant. The organism also
has a propensity to colonise and infect the lungs of cystic
fibrosis (CF) patients and is virtually ineradicable in this
setting.
Pseudomonas aeruginosa has an impressive armamen-
tarium of virulence factors, allowing it to combat host

0924-8579/$ – see front matter © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
S34 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41

defences. These include the flagellum, pili, alginate produc-

tion, mucoid phenotypes in CF, lipopolysaccharide, type III
secretion factors, secreted proteases, oxidative factors and
toxins [3]. Quorum sensing may regulate expression of viru-
lence factors [4]. The emergence and gradual dissemination
of metallo-b-lactamases, with their ability to hydrolyze all
b-lactams except aztreonam, has further compromised the
activity of many agents traditionally used for the treatment
of P. aeruginosa infections [5], although it remains more
common for pan-resistance to arise by accumulation of
successive mutations affecting efflux, impermeability and
AmpC b-lactamase expression.
Susceptibility testing gives variable results for isolates
recovered from samples in patients with CF, and its role in
EARSS 2005 Report: http://www.rivm.nl/earss/Images/EARSS%202005_tcm61-34899.pdf
antibiotic choice has been questioned as patients commonly
Fig. 2. Proportion of invasive Pseudomonas aeruginosa isolates resistant
improve despite receiving apparently inappropriate ther- to carbapenems in 2005, from the European Antimicrobial Resistance
apy [6]. Outside this setting, laboratory-detected resistance Surveillance System (EARSS) (http://www.earss.rivm.nl). Carbapenem
is believed to be significant. resistance is high all over Europe, with only Norway and The Netherlands
reporting proportions of <5%. Reproduced with permission from
EARSS.
2.1.1. Trends in isolation and resistance
2002 (n=171) 2003 (n=185) 2004 (n=207) 2005 (n=197)
In the SENTRY Program, the numbers of isolates of 20.0
P. aeruginosa reported are increasing, although distinct 18.0
differences exist by geographic region and site of infection. 16.0
SENTRY data reported that multidrug-resistant (resistant
14.0
to piperacillin, ceftazidime, imipenem and gentamicin)
12.0
% resistance

P. aeruginosa bloodstream isolates were most prevalent

10.0
in Latin America (12.0−17.6%; average 15.0%), fol-
8.0
lowed by Europe (5.1−14.2%; average 9.3%) and North
6.0
America (1.6−2.5%; average 2.1%) between 1997 and
2001 [1] (Fig. 1). Multidrug resistance in bloodstream 4.0

infections saw a steady increase between 1997 and 2001, 2.0

with resistance even to the carbapenems widespread in 0.0

Ceftazidime Gentamicin Imipenem Ciprofloxacin
Europe (Fig. 2). The UK situation is better: the BSAC
Fig. 3. British Society for Antimicrobial Chemotherapy bacteraemia
bacteraemia survey reported relatively stable or declining surveillance data for Pseudomonas aeruginosa from 2002–2005 [7] for
rates of resistance among P. aeruginosa isolates between the UK and Republic of Ireland.
2002 and 2005, except possibly to ciprofloxacin (Fig. 3).
North American surveillance studies report a rise in
aminoglycoside [8], carbapenem [9] and fluoroquinolone [8]
Europe (1152) Latin America (608) North America (1550) resistance. By 2005, US studies reported ceftazidime and
20.0
imipenem MIC50 values (minimum inhibitory concentration
17.6 for 50% of the organisms) ranging from <1 mg/L to
16.0
14.3 14.2 14.5 >32 mg/L [10,11] and from 0.06 mg/L to 16 mg/L [10],
% MDR Resistance

15.0
12.0 respectively, with this great diversity perhaps reflecting
10.1 10.4
10.0
9.5 different patient groups or the effects of local outbreak
strains with more or less resistance. In CF, MIC50 values
5.1 for ceftazidime and imipenem ranged from 0.25 mg/L to
5.0
2.5
1.6 2.1 2.0 2.0 >512 mg/L and 0.5 mg/L to >512 mg/L, respectively [12].
0.0
Reported rates of multidrug-resistant P. aeruginosa from the
1997 1998 1999 2000 2001 SENTRY Program varied from 1.1% to 31.2% according to
Fig. 1. SENTRY Program data for multidrug-resistant (MDR) Pseu- geographic location [13].
domonas aeruginosa from bloodstream isolates (1997–2001). Adapted
from ref. [1]. Whilst multidrug resistance remained relatively stable 2.2. Acinetobacter baumannii
between 1997 and 2001 in North America, it increased from 12.0 to 17.6%
of P. aeruginosa isolates in Latin America over the same time period and Acinetobacter baumannii is also widely distributed in the
more than doubled in Europe. environment. It is generally non-pathogenic in healthy
 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41 S35

Cumulative no. hospitals affected

individuals, except possibly as an agent of wound infection 80

in military casualties from the Middle East [14,15]. Over the 70

last decade it has become an increasing cause of serious 60
opportunistic infection, particularly ventilator-associated 50
pneumonia and invasion of burns wounds, in susceptible 40
patients in Intensive Care Units (ICUs). Virulence factors 30
are limited, consistent with the organism’s limited invasive 20
potential. It produces no cytotoxins and its lipopolysaccha-
10
ride is of uncertain endotoxigenic potential. Its enhanced
0
survival is due to a combination of bacteriocin production,

Q3

Q3
Q4

Q4

Q2
0

4
Q2
Q3
Q4

Q2

Q4

Q2

Q2
Q3

Q3
Q4
the presence of a capsule and prolonged viability under

200

200
200

200

dry conditions [16]. The population structure is highly
clonal, with single strains commonly affecting multiple
patients in a unit or hospital. Indeed, a few lineages
of A. baumannii have achieved “epidemic” status as
nosocomial pathogens, spreading to cause outbreaks of
infections in many hospitals and countries [17]. Many of
these outbreaks have involved strains that were multidrug
resistant, including to carbapenems and amikacin, with
colistin and tigecycline sometimes representing the only
remaining therapeutic options [17,18].
2.2.1. Trends in isolation and resistance
BSAC surveillance data illustrate resistance trends in
A. baumannii for bacteraemias only since 2001 [7]. In
2005, >30% of bacteraemia isolates were resistant to
gentamicin and piperacillin/tazobactam [7] (Fig. 4). Many
isolates from non-bacteraemic sources are even more
resistant [19,20]. Similar trends have been reported in other
countries [21]. A recent study from Greece reported >94%
resistance to ceftazidime, amikacin, piperacillin/tazobactam
and imipenem, whilst colistin MICs ranged from 0.25 mg/L
to >1024 mg/L and those of tigecycline from 0.12 mg/L
to 4 mg/L [22]. In the USA, ceftazidime and amikacin
MICs range from <0.06 mg/L to 128 mg/L and <0.5 mg/L
to >64 mg/L, respectively. Several mechanisms for car-
bapenem resistance have been described, namely class D
2002 (n=28) 2003 (n=38)
45.0
40.0
35.0
30.0
% resistance
200
S.E. clone OXA-23 clone 1 OXA-23 clone 2
Fig. 5. Carbapenem-resistant Acinetobacter clones in the UK (2000–2004).
Reproduced from ref. [23]. These data illustrate the rise of carbapenem-
resistant clones in the UK over a 5-year period between 2000 and 2005.
There was no evidence of widely disseminated clones at the beginning in
2000, whereas by 2004 the SE clone and the OXA-23 clone affected ca.
40 hospitals in the UK.
OXA-type carbapenemases and class B metalloenzymes
(IMP or VIM family), whilst PER extended-spectrum
enzymes cause resistance to third-generation cephalosporins
in many isolates in Turkey [24].
Multidrug-resistant isolates of A. baumannii have in-
creased significantly in the UK since 2002, becoming most
prevalent in hospitals in London and southeast England [19,
20]. Pulsed-field gel electrophoresis has shown that many of
these isolates belong to three clones that possess the non-
metallo OXA-23 or -51 carbapenemases as the predominant
mechanism for their carbapenem resistance. All three
exhibit resistance to b-lactams (including carbapenems),
fluoroquinolones and many aminoglycosides, although they
vary in susceptibility to amikacin. The most prevalent
clones, each recorded from ca. 40 hospitals, are the SE
clone and the OXA-23 clone l; their spread since 2000 is
illustrated in Fig. 5 [23].
Risk factors for acquisition of multidrug-resistant A. bau-
mannii include presence on an ICU or burns unit, large
hospital size (>500 beds) [25] and previous exposure to
2004 (n=41) 2005 (n=43) antibiotics [25,26], notably carbapenems [27]. Immunosup-
pression, emergency admission, respiratory failure or me-
chanical ventilation, invasive procedures, urinary catheteri-
sation and recent surgery are further risk factors [25–27].
Attributable mortality is hard to define, since A. bauman-
nii tends only to cause infection in very vulnerable patients

25.0
and its properties may be clone-specific; nevertheless, rates
20.0
up to 20% [28] and >61% [29] have been claimed in
15.0
bacteraemia. Its capacity to acquire resistance to multiple
10.0 antimicrobial agents has made this organism a significant
5.0 challenge in many healthcare institutions.
0.0
Gentamicin Pip/tazo Imipenem Ciprofloxacin 2.3. Burkholderia cepacia complex
Fig. 4. British Society for Antimicrobial Chemotherapy bacteraemia
Members of B. cepacia complex are well recognised,
surveillance data for Acinetobacter baumannii from 2002–2005 [7]. The
data show increasing rates of resistance, with levels reaching over 30% for if uncommon, nosocomial pathogens. They are more
gentamicin, piperacillin/tazobactam (Pip/tazo) and ciprofloxacin and over important in CF, where the spread of epidemic strains
5% for imipenem by 2005. has presented significant infection control problems, both
S36 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41
in hospital units and among the CF community as a
whole [30].
A number of potential virulence factors have been
identified, although not all of these have been proven to
affect the pathogenesis of human disease [31]. They in-
clude intrinsic antimicrobial resistances (e.g. to polymyxins
and aminoglycosides), the ability to form biofilms, pili,
the cenocepacia (pathogenicity) island [32], production of
exopolysaccharide, haemolysin, melanin and extracellular
proteases, flagella, lipopolysaccharide, siderophore produc-
tion, type III secretion factors and the ability to invade and
survive inside respiratory cells and macrophages.
Burkholderia multivorans (genomovar II) and Burkholde-
ria cenocepacia (genomovar III) account for the majority
of infecting strains in Europe and the USA, and iso-
lation of B. cepacia complex isolates from respiratory
CF samples is accepted as a poor prognostic marker [33].
A fulminant pneumonic and septicaemic process called
“cepacia syndrome” may occur in 10% of colonised
CF patients, more commonly with B. cenocepacia than
B. multivorans [32]. Patients with B. cenocepacia had a
shorter survival than patients with P. aeruginosa (P = 0.01)
in a recent study but there was no difference in survival
between P. aeruginosa and B. multivorans [32]. Some
centres decline lung transplantation to patients colonised
with B. cepacia complex [34].
Burkholderia pseudomallei is prevalent in Southeast Asia
and the Northern Territory of Australia both as a soil
organism and as a primary pathogen, often in patients with
underlying diabetes mellitus. It is associated with 30−40%
mortality in septicaemic disease, even when treated with
appropriate antibiotics, although with much lower mortality
rates for pulmonary disease. Tigecycline has an MIC90
of 2 mg/L [35] and may be an alternative therapy to
ceftazidime for melioidosis, although clinical trials are
needed to support this hypothesis.
2.3.1. Trends in isolation and resistance
A recent review of HAIs related to contaminated substances
reported B. cepacia to be a significant contaminant of
substances other than blood products [36]. SENTRY data
reported B. cepacia to comprise 7.7% of “uncommonly
isolated” non-enteric Gram-negative bacilli between 1997
and 2003 [11]. In the USA, resistance ranges from 9.3% for
co-trimoxazole to 48% for imipenem [11]. Among patients
with CF, resistance to imipenem was >84% in Europe
and the USA [12,37]. MIC50 values for piperacillin ranged
from 4 mg/L [38] to 256 mg/L [12] for multidrug-resistant
CF isolates.
2.4. Stenotrophomonas maltophilia
Independent risk factors for infection with S. maltophilia
include chronic obstructive pulmonary disease, neutropenia,
the presence of a central venous catheter, prolonged
hospitalisation and previous therapy with broad-spectrum
antibiotics [39]. Nosocomial transmission of S. maltophilia
is rare and most infections are with unique strains.
Stenotrophomonas maltophilia is associated with signif-
icant morbidity and mortality in immunocompromised
patients [39]. Putative, but poorly understood, virulence
factors include a range of exoenzymes such as DNase,
RNase, fibrinolysin, lipases, hyaluronidase, protease and
elastase, the ability to survive and then multiply in medical
solutions and the ability to adhere to prosthetic materials.
Bacteraemias related to central venous catheters and
nosocomial pneumonia are the two most common man-
ifestations of true infection due to S. maltophilia, al-
though most isolates originating from the respiratory tract
represent colonisation rather than infection. Recovery of
the organism from this site, or from urinary catheters,
should not ordinarily prompt antibiotic treatment. In rare
cases, S. maltophilia is associated with skin and soft-tissue
infections, endocarditis, meningitis, urinary tract infections,
intra-abdominal infections and ophthalmological syndromes
related to applied or implanted foreign materials.
Mortality rates of 10−60% in patients with bacteraemia
due to S. maltophilia have been reported [40,41], although
attributable mortality is again hard to define in the types
of patient sufficiently ill to be affected by this species.
The majority of isolates remain sensitive to co-trimoxazole,
although toxicity or intolerance remains the major problem
in some patients, for whom ticarcillin/clavulanic acid may
be considered as an alternative. Fluoroquinolones may be
useful as adjuncts to co-trimoxazole or ticarcillin/clavulanic
acid therapy [42].
2.4.1. Trends in isolation and resistance
The number of isolates of S. maltophilia reported are
increasing worldwide, although reports tend to be from
individual institutions and associated with the introduction
of carbapenem use [43]. This increase may reflect a change
in patient types rather than a change in epidemiology.
Among ‘uncommonly isolated’ non-enteric Gram-nega-
tive bacilli, recent SENTRY data report S. maltophilia
to comprise 59.2%, with a roughly even distribution
between respiratory and blood isolates (49% and 41%,
respectively) [11]. Distinct differences exist in the frequency
by geographic region and site of infection [43].
Co-trimoxazole resistance varies widely. Betriu et al. [44,
45] reported that
2% of Spanish isolates of S. maltophilia
were resistant, whereas an Italian study reported 80.9%
resistance [46]. The highest levels of resistance are seen in
CF isolates, with 84% resistance to co-trimoxazole, 50%
to ticarcillin/clavulanic acid, 74% to colistin and 11% to
doxycycline [47]. A recent surveillance study reported that
>40% of pneumonia isolates from the USA are resistant
to b-lactams and ciprofloxacin [48]. A further problem –
and caution – when reading surveillance data is that the
MICs of b-lactams vary with the medium [49]; those of
aminoglycosides vary with the test temperature [49].
 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41
3. Antibiotics for treatment of infections due to
non-fermentative Gram-negative bacteria
3.1. Aminoglycosides
Aminoglycosides are a long-established component of
therapy for infections due to non-fermenters, although they
should be seen as adjuncts rather than as sole agents [50].
Against P. aeruginosa they are generally combined with
b-lactams, although the evidence for synergy is weak except
with penicillins. Bacterial resistance may occur owing
to reduced drug uptake, increased efflux pump activity
and enzymatic inactivation. This topic has been reviewed
elsewhere [51]. They have no in vitro activity against
S. maltophilia and B. cepacia. Tobramycin is inherently the
most active of the group against P. aeruginosa, where most
resistance to aminoglycosides in general is mutational due
to impermeability or efflux [51]. Pseudomonas aeruginosa
isolates with the highest MICs were most commonly from
CF patients, with tobramycin MIC50 and MIC90 values of
8 mg/L and 64 mg/L for mucoid isolates and 16 mg/L and
256 mg/L for non-mucoid isolates, respectively [12].
3.2. Co-trimoxazole
The combination of trimethoprim and sulphamethoxazole
is active in vitro against many isolates of B. cepacia and
S. maltophilia, but not P. aeruginosa. Acquired resistance
is common in A. baumannii. Co-trimoxazole is the
treatment of choice for infections with S. maltophilia [52]
and significant morbidity may occur in patients with
co-trimoxazole-resistant S. maltophilia bacteraemia [53].
Despite the Committee for Safety of Medicines in the UK
advising against its general use, co-trimoxazole remains
the standard therapy for these infections, and trimethoprim
therapy alone is not active.
3.3. Colistin
The polymyxins are a group of five chemically differ-
ent bactericidal antibiotics (polymyxins A to E). Only
polymyxin B and polymyxin E (colistin) have been used in
clinical practice. Resistance may develop through mutation
and occurs of a result of alterations of the outer membrane.
Colistin has a wide spectrum of activity against Gram-
negative organisms, including A. baumannii, P. aeruginosa
and S. maltophilia, but is inactive against B. cepacia
owing to its unusual lipopolysaccharide structure. Although
resistance to polymyxin B has recently been reported in
P. aeruginosa isolates from the USA and elsewhere [54], it
remains rare and is almost exclusive to CF isolates. Recent
clinical reports and reviews of experience with colistin
are encouraging, with side effects observed less often than
expected from historical data [55–60].
S37
3.4. Penicillins with activity against non-fermenters
A number of semisynthetic penicillins, including ticarcillin
and piperacillin, have activity against non-fermenters. These
agents can be used in combination with the b-lactamase
inhibitors clavulanic acid, tazobactam or sulbactam, al-
though these do not inhibit all b-lactamases of these
species. Moreover, most resistance in P. aeruginosa is
due to non-b-lactamase mechanisms, principally efflux, and
b-lactamase inhibitors have no effect on this mechanism.
Resistance rates are typically highest in isolates from
CF patients [12] and in outbreaks of carbapenem-resistant
P. aeruginosa and A. baumannii [61]. Temocillin is used for
the treatment of B. cepacia in CF, but otherwise has little
activity against non-fermenters [62].
3.5. Cephalosporins
The cephalosporin with most potent activity against non-
fermenters is ceftazidime [63]. Its spectrum of activity
includes P. aeruginosa, S. maltophilia, A. baumannii,
B. cepacia and B. pseudomallei, for which it is standard
therapy. Resistance occurs via a variety of mechanisms,
including hydrolysis by b-lactamases and efflux (e.g. by
upregulation of MexAB–OprM in P. aeruginosa) [64].
3.6. Carbapenems
Carbapenems are b-lactams with exceptionally broad an-
tibacterial spectra. Meropenem and imipenem/cilastatin are
active against non-fermenters. Ertapenem has no activity
against these organisms and will not be discussed here [65].
Resistance in Gram-negative organisms usually results from
a combination of impaired drug entry, efflux and the
presence of a b-lactamase. Diminished permeability is
often a result of loss of the outer membrane proteins
through which carbapenems enter the periplasmic space
and is a well known mechanism for P. aeruginosa
where loss of OprD is associated with resistance [66].
Multidrug efflux systems (e.g. MexAB–OprM) are present
in P. aeruginosa and can excrete meropenem as well
as penicillins, fluoroquinolones and cephalosporins [66],
although it is important to note that imipenem escapes this
type of mechanism [67]. Stenotrophomonas maltophilia is
intrinsically resistant to carbapenems owing to production
of inducible zinc-metalloenzyme (L-1 enzyme) with car-
bapenemase activity [68]. Meropenem is one of the most
active agents versus B. cepacia and some would regard it
as the agent of choice.
Doripenem is currently undergoing six phase III trials
for a variety of conditions including complicated urinary
tract infection, pneumonia and complicated intra-abdominal
infections. It has similar activity to meropenem and
imipenem against carbapenemase-negative A. baumannii
strains, but no carbapenem retains activity against strains
with expression of OXA or metallo-carbapenemases [69].
S38 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41

Table 1
Potency of tigecycline against non-fermentative Gram-negative bacteria (adapted from refs. [38,77])

Organism MIC a (mg/L) % Susceptible b % Resistant b

Range MIC50 MIC90

Pseudomonas aeruginosa (n = 1121) [77] 0.12 to >32 8 16 5.1 77.2

Acinetobacter spp. (n = 326) [77] 0.06−8 0.5 2 94.5 0.9
Burkholderia cepacia (n = 21) [38] 0.25−32 1 16 67.0 29.0
Stenotrophomonas maltophilia (n = 203) [77] 0.12−8 1 2 93.1 3.0
a MIC, minimum inhibitory concentration (MIC50/ 90 , MIC for 50% and 90% of the organisms, respectively).
b The tigecycline susceptible breakpoint was defined as
2 mg/L and the resistance breakpoint as 8 mg/L for comparison purposes
only [78]; these values are now accepted by the US Food and Drug Administration (FDA) but are one doubling dilution higher than
the values adopted for Enterobacteriaceae by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)/European
Medicines Agency (EMEA), who presently have no values specific for non-fermenters.

It is unlikely that doripenem will prove to be superior to
meropenem, but this requires additional clinical studies.
3.7. Fluoroquinolones
In general, ciprofloxacin remains the most potent agent in
this class against non-fermenters and is particularly valued
and widely used. It is the only oral agent with activity
against P. aeruginosa. Fluoroquinolones have been widely
used for the treatment of a wide variety of infections.
Perhaps predictably, their use is increasingly compromised
by the widespread emergence of bacterial resistance [70].
For the treatment of S. maltophilia, there is some clinical
evidence that addition of moxifloxacin (more active than
ciprofloxacin against this species) to co-trimoxazole may be
therapeutically advantageous [42]. Resistance mechanisms
have recently been reviewed elsewhere [70] and mostly
entail reduction in permeability, upregulation of efflux (also
affecting b-lactams) and mutation of DNA gyrase and
topoisomerase IV genes.
3.8. Tigecycline
Tigecycline is a glycylcycline, a semisynthetic derivative
of minocycline with a 9-t-butylglycylamido substitution.
Glycylcyclines act by binding to the bacterial 30S ribosomal
subunit, blocking entry of the aminoacyl-tRNA molecules
into the acceptor site of the ribosome, and are mostly
considered to be bacteriostatic. The main determinants of
acquired resistance to tetracyclines, namely active efflux
and ribosomal protection, are overcome by steric hindrance
from the large R-group at position 9. Tigecycline has in
vitro activity against a number of Gram-negative species,
including A. baumannii (including many carbapenem-
resistant isolates) and S. maltophilia. It lacks useful
activity against P. aeruginosa. Tigecycline is able to
evade Tet-type efflux pumps (responsible for plasmid-
mediated tetracycline resistance) but is susceptible to the
chromosomal resistance–nodulation–cell division (RND)
family of multidrug efflux pumps, including MexXY–OprM
of P. aeruginosa [71], which explains the intrinsic resistance
of this species, and the AcrAB pump found in Proteus
mirabilis [72]. Published resistance rates for tigecycline
range from 58.5% to 97% for P. aeruginosa [38,73], 0%
to 6% A. baumannii [74,75], 0% to 29% for B. cepacia
complex [38,76] and 0% to 3.5% for S. maltophilia [45,48].
Table 1 [38,77] lists the MICs of tigecycline.
3.9. Combination therapy
The potential benefits of combination antibiotic therapy
are well recognised. They include a broadened and more
reliable spectrum of activity, enhanced antibacterial activity
due to any synergistic or additive effect allowing lower
doses of toxic agents to be given, and prevention of the
emergence of resistance. Enhanced in vitro activity has
been noted for a number of antimicrobial combinations
tested against A. baumannii. These include polymyxin B,
imipenem and rifampicin [79], polymyxin B, rifampicin
and sulbactam [80] and colistin and rifampicin [81]. There
have been reports of some centres using tigecycline and
nebulised colistin against Acinetobacter pneumonia [82],
although studies are needed to evaluate this combination
formally. Enhanced in vitro activity has also been noted
for a number of antimicrobial combinations used against
P. aeruginosa, and b-lactam/aminoglycoside combinations
remain the standard of care for severe infections. In
vitro synergy was demonstrated with the combination
of cephalosporins and fluoroquinolones [83], colistin and
ceftazidime [84] and a macrolide plus tobramycin [85]. Syn-
ergy was also demonstrated in vitro with the combination
of macrolides with ceftazidime (for B. cepacia) and co-
trimoxazole (for S. maltophilia) for infecting organisms
from patients with CF [85]. Conversely, no enhanced in
vitro antibacterial activity against P. aeruginosa was found
with combinations of ciprofloxacin and colistin [84].
There are few clinical studies of combinations of
antimicrobial agents for the treatment of multidrug-
resistant non-fermenters. Colistin was combined with a
carbapenem in 19 of 25 patients, amikacin in 8 of
25 patients, tobramycin (3), cefepime (3), quinolone (2),
ampicillin/sulbactam (3) and aztreonam (1 patient) in a
 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41
retrospective non-controlled observational study of 25 crit-
ically ill patients with infection due to multidrug-resistant
P. aeruginosa or A. baumannii [86]. End-of-treatment
mortality was 21%. Ten patients with carbapenem-resistant
A. baumannii were treated with a combination of imipenem
and rifampicin in a recent prospective study [87]. Three
patients died, two because of therapeutic failure, and seven
responded. High-level rifampicin resistance developed in
7 of 10 patients. The authors suggested this combination
should not be used for the treatment of severe infection with
these organisms.
4. Conclusions
Pseudomonas aeruginosa, A. baumannii, S. maltophilia and
members of the B. cepacia complex are an increasingly
recognised cause of infection and are increasingly difficult
to treat.
Glycylcyclines demonstrate useful in vitro activity against
many non-fermenters except P. aeruginosa, but clinical
trials are needed to determine their role in the treatment
of infections due to these organisms. Of particular concern
are early reports of the development of resistance and
treatment failure in two patients with carbapenem-resistant
A. baumannii bacteraemia being treated with tigecycline
for other conditions [88]. The two patients had received
9 days and 16 days of treatment with tigecycline when
bacteraemias were detected. The MICs were 4 mg/L and
16 mg/L, respectively, but these fell to 1 mg/L and 4 mg/L
after addition of phenyl-arginine-b-naphthylamide, a pump
inhibitor, suggesting efflux as the mechanism of resistance.
Noting a mean peak serum concentration of only 0.63 mg/L,
the authors suggest that tigecycline should not be used
to treat bloodstream infections caused by organisms with
MICs >1 mg/L [88], which corresponds with the European
Medicines Agency (EMEA)/European Committee on Anti-
microbial Susceptibility Testing (EUCAST) breakpoint.
There are currently no other drugs, besides doripenem,
in phase II or III trials for the treatment of multidrug-
resistant non-fermenters. Novel efflux pump inhibitors have
not yet entered human clinical trials, although they appear
promising [89]. Therefore, currently available antibiotics
require judicious and prudent use, following evidence-
based trial data whenever possible. The role of combining
these antibiotics in combating the development of further
antibiotic resistance and delivering superior clinical efficacy
requires more rigorous evaluation than in the past.
Acknowledgements
Editorial assistance during the preparation of this manuscript
was provided by Magus Strategic Communications Ltd.
S39
Role of funding source
The supplement has been funded by an unrestricted
educational grant from Wyeth UK. Wyeth UK have had no
input into the content or editorial.
References
[1] Jones RN. Global epidemiology of antimicrobial resistance among
community-acquired and nosocomial pathogens: a five-year summary
from the SENTRY Antimicrobial Surveillance Program (1997–2001).
Semin Respir Crit Care Med 2003;24:121−34.
[2] Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y.
Multidrug-resistant Pseudomonas aeruginosa: risk factors and
clinical impact. Antimicrob Agents Chemother 2006;50:43−8.
[3] Pier GB, Ramphal R. Pseudomonas aeruginosa. In: Mandell GL,
Bennett JE, Dolin R, editors. Principles and practice of infectious
diseases. Philadelphia, PA: Churchill Livingstone; 2005. p. 216.
[4] Heurlier K, Denervaud V, Haas D. Impact of quorum sensing on fitness
of Pseudomonas aeruginosa. Int J Med Microbiol 2006;296:93–102.
[5] Walsh TR. The emergence and implications of metallo-beta-
lactamases in Gram-negative bacteria. Clin Microbiol Infect
2005;11(Suppl. 6):2−9.
[6] Foweraker JE, Laughton CR, Brown DF, Bilton D. Phenotypic
variability of Pseudomonas aeruginosa in sputa from patients with
acute infective exacerbation of cystic fibrosis and its impact on
the validity of antimicrobial susceptibility testing. J Antimicrob
Chemother 2005;55:921−7.
[7] British Society for Antimicrobial Chemotherapy. Resistance Surveil-
lance Website: Bacteraemia. BSAC; 2006. http://www.bsacsurv.org/
[accessed 30 January 2007].
[8] Mutnick AH, Rhomberg PR, Sader HS, Jones RN. Antimicrobial
usage and resistance trend relationships from the MYSTIC
Programme in North America (1999–2001). J Antimicrob Chemother
2004;53:290−6.
[9] Lautenbach E, Weiner MG, Nachamkin I, Bilker WB, Sheridan A,
Fishman NO. Imipenem resistance among Pseudomonas aeruginosa
isolates: risk factors for infection and impact of resistance on clinical
and economic outcomes. Infect Control Hosp Epidemiol 2006;27:
893–900.
[10] Bouchillon SK, Hoban DJ, Johnson BM, Johnson JL, Hsiung A,
Dowzicky MJ. In vitro activity of tigecycline against 3989 Gram-
negative and Gram-positive clinical isolates from the United States
Tigecycline Evaluation and Surveillance Trial (TEST Program; 2004).
Diagn Microbiol Infect Dis 2005;52:173−9.
[11] Sader HS, Jones RN. Antimicrobial susceptibility of uncommonly
isolated non-enteric Gram-negative bacilli. Int J Antimicrob Agents
2005;25:95–109.
[12] Chen Y, Garber E, Zhao Q, et al. In vitro activity of doripenem
(S-4661) against multidrug-resistant gram-negative bacilli isolated
from patients with cystic fibrosis. Antimicrob Agents Chemother
2005;49:2510−1.
[13] Gales AC, Jones RN, Turnidge J, Rennie R, Ramphal R.
Characterization of Pseudomonas aeruginosa isolates: occurrence
rates, antimicrobial susceptibility patterns, and molecular typing in
the global SENTRY Antimicrobial Surveillance Program, 1997–1999.
Clin Infect Dis 2001;32(Suppl. 2):S146−55.
[14] Jones A, Morgan D, Walsh A, et al. Importation of multidrug-resistant
Acinetobacter spp. infections with casualties from Iraq. Lancet Infect
Dis 2006;6:317−8.
[15] Davis KA, Moran KA, McAllister CK, Gray PJ. Multidrug-resistant
Acinetobacter extremity infections in soldiers. Emerg Infect Dis 2005;
11:1218−24.
[16] Wendt C, Dietze B, Dietz E, Ruden H. Survival of Acinetobacter
baumannii on dry surfaces. J Clin Microbiol 1997;35:1394−7.
S40 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41
[17] Coelho JM, Turton JF, Kaufmann ME, et al. Occurrence of
carbapenem-resistant Acinetobacter baumannii clones at multiple
hospitals in London and Southeast England. J Clin Microbiol
2006;44:3623−7.
[18] Bogaerts P, Naas T, Wybo I, et al. Outbreak of infection
by carbapenem-resistant Acinetobacter baumannii producing the
carbapenemase OXA-58 in Belgium. J Clin Microbiol 2006;44:
4189−92.
[19] Turton JF, Kaufmann ME, Warner M, et al. A prevalent, multiresistant
clone of Acinetobacter baumannii in Southeast England. J Hosp Infect
2004;58:170−9.
[20] Manuel RJ, Shin GY, Farrag N, Holliman R. Endemic carbapenem-
resistant Acinetobacter baumannii in a London hospital. J Antimicrob
Chemother 2003;52:141−2.
[21] Van Looveren M, Goossens H. Antimicrobial resistance of
Acinetobacter spp. in Europe. Clin Microbiol Infect 2004;10:684–
704.
[22] Souli M, Kontopidou FV, Koratzanis E, et al. In vitro activity of
tigecycline against multiple-drug-resistant, including pan-resistant,
gram-negative and gram-positive clinical isolates from Greek
hospitals. Antimicrob Agents Chemother 2006;50:3166−9.
[23] Livermore DM, Woodford N, The beta-lactamase threat
in Enterobacteriaceae, Pseudomonas and Acinetobacter. Trends
Microbiol 2006;14:413−20.
[24] Urban C, Segal-Maurer S, Rahal JJ. Considerations in control
and treatment of nosocomial infections due to multidrug-resistant
Acinetobacter baumannii. Clin Infect Dis 2003;36:1268−74.
[25] Cisneros JM, Rodriguez-Bano J, Fernandez-Cuenca F, et al. Risk-
factors for the acquisition of imipenem-resistant Acinetobacter
baumannii in Spain: a nationwide study. Clin Microbiol Infect
2005;11:874−9.
[26] Garcia-Garmendia JL, Ortiz-Leyba C, Garnacho-Montero J, et al.
Risk factors for Acinetobacter baumannii nosocomial bacteremia in
critically ill patients: a cohort study. Clin Infect Dis 2001;33:939−46.
[27] del Mar Tomas M, Cartelle M, Pertega S, et al. Hospital outbreak
caused by a carbapenem-resistant strain of Acinetobacter baumannii:
patient prognosis and risk-factors for colonisation and infection. Clin
Microbiol Infect 2005;11:540−6.
[28] Chen HP, Chen TL, Lai CH, et al. Predictors of mortality in
Acinetobacter baumannii bacteremia. J Microbiol Immunol Infect
2005;38:127−36.
[29] Robenshtok E, Paul M, Leibovici L, et al. The significance of
Acinetobacter baumannii bacteraemia compared with Klebsiella
pneumoniae bacteraemia: risk factors and outcomes. J Hosp Infect
2006;64:282−7.
[30] Festini F, Buzzetti R, Bassi C, et al. Isolation measures for prevention
of infection with respiratory pathogens in cystic fibrosis: a systematic
review. J Hosp Infect 2006;64:1−6.
[31] Mahenthiralingam E, Urban TA, Goldberg JB. The multifarious,
multireplicon Burkholderia cepacia complex. Nat Rev Microbiol
2005;3:144−56.
[32] Jones AM, Dodd ME, Govan JR, et al. Burkholderia cenocepacia
and Burkholderia multivorans: influence on survival in cystic fibrosis.
Thorax 2004;59:948−51.
[33] De Soyza A, Archer L, Wardle J, et al. Pulmonary transplantation
for cystic fibrosis: pre-transplant recipient characteristics in patients
dying of peri-operative sepsis. J Heart Lung Transplant 2003;22:
764−9.
[34] LiPuma JJ. Burkholderia cepacia complex: a contraindication to lung
transplantation in cystic fibrosis? Transpl Infect Dis 2001;3:149−60.
[35] Thamlikitkul V, Trakulsomboon S. In vitro activity of tigecycline
against Burkholderia pseudomallei and Burkholderia thailandensis.
Antimicrob Agents Chemother 2006;50:1555−7.
[36] Vonberg RP, Gastmeier P. Hospital-acquired infections related to
contaminated substances. J Hosp Infect 2007;65:15−23.
[37] Bonacorsi S, Fitoussi F, Lhopital S, Bingen E. Comparative in
vitro activities of meropenem, imipenem, temocillin, piperacillin,
and ceftazidime in combination with tobramycin, rifampin, or
ciprofloxacin against Burkholderia cepacia isolates from patients with
cystic fibrosis. Antimicrob Agents Chemother 1999;43:213−7.
[38] Cheng NC, Hsueh PR, Liu YC, et al. In vitro activities of
tigecycline, ertapenem, isepamicin, and other antimicrobial agents
against clinically isolated organisms in Taiwan. Microb Drug Resist
2005;11:330−41.
[39] Nseir S, Di Pompeo C, Brisson H, et al. Intensive care unit-acquired
Stenotrophomonas maltophilia: incidence, risk factors, and outcome.
Crit Care 2006;10:R143.
[40] Friedman ND, Korman TM, Fairley CK, Franklin JC, Spelman DW.
Bacteraemia due to Stenotrophomonas maltophilia: an analysis of 45
episodes. J Infect 2002;45:47−53.
[41] Pathmanathan A, Waterer GW. Significance of positive
Stenotrophomonas maltophilia culture in acute respiratory tract
infection. Eur Respir J 2005;25:911−4.
[42] British Society for Antimicrobial Chemotherapy. Stenotrophomonas
maltophilia guideline. BSAC; 2005. http://www.bsac.org.uk/content_
display.cfm?cit_id=258 [accessed 7 February 2007].
[43] Meyer E, Schwab F, Gastmeier P, Ruden H, Daschner FD. Is
the prevalence of Stenotrophomonas maltophilia isolation and
nosocomial infection increasing in intensive care units? Eur J Clin
Microbiol Infect Dis 2006;25:711−4.
[44] Betriu C, Rodriguez-Avial I, Sanchez BA, Gomez M, Alvarez J,
Picazo JJ. In vitro activities of tigecycline (GAR-936) against recently
isolated clinical bacteria in Spain. Antimicrob Agents Chemother
2002;46:892−5.
[45] Betriu C, Rodriguez-Avial I, Sanchez BA, Gomez M, Picazo JJ.
Comparative in vitro activities of tigecycline (GAR-936) and
other antimicrobial agents against Stenotrophomonas maltophilia. J
Antimicrob Chemother 2002;50:758−9.
[46] Bonfiglio G, Cascone C, Azzarelli C, Cafiso V, Marchetti F,
Stefani S. Levofloxacin in vitro activity and time-kill evaluation
of Stenotrophomonas maltophilia clinical isolates. J Antimicrob
Chemother 2000;45:115−7.
[47] San Gabriel P, Zhou J, Tabibi S, Chen Y, Trauzzi M, Saiman L.
Antimicrobial susceptibility and synergy studies of Stenotrophomonas
maltophilia isolates from patients with cystic fibrosis. Antimicrob
Agents Chemother 2004;48:168−71.
[48] Fritsche TR, Sader HS, Stilwell MG, Dowzicky MJ, Jones RN.
Antimicrobial activity of tigecycline tested against organisms causing
community-acquired respiratory tract infection and nosocomial
pneumonia. Diagn Microbiol Infect Dis 2005;52:187−93.
[49] King A. Recommendations for susceptibility tests on fastidious
organisms and those requiring special handling. J Antimicrob
Chemother 2001;48(Suppl. 1):77−80. Erratum: 2002;49:1050.
[50] Edson RS, Terrell CL. The aminoglycosides. Mayo Clin Proc 1999;
74:519−28.
[51] Poole K. Aminoglycoside resistance in Pseudomonas aeruginosa.
Antimicrob Agents Chemother 2005;49:479−87.
[52] Valdezate S, Vindel A, Loza E, Baquero F, Canton R. Antimicrobial
susceptibilities of unique Stenotrophomonas maltophilia clinical
strains. Antimicrob Agents Chemother 2001;45:1581−4.
[53] Tsiodras S, Pittet D, Carmeli Y, Eliopoulos G, Boucher H, Harbarth S.
Clinical implications of Stenotrophomonas maltophilia resistant to
trimethoprim–sulfamethoxazole: a study of 69 patients at 2 university
hospitals. Scand J Infect Dis 2000;32:651−6.
[54] Landman D, Bratu S, Alam M, Quale J. Citywide emergence
of Pseudomonas aeruginosa strains with reduced susceptibility to
polymyxin B. J Antimicrob Chemother 2005;55:954−7.
[55] Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ, et al.
Treatment of multidrug-resistant Acinetobacter baumannii ventilator-
associated pneumonia (VAP) with intravenous colistin: a comparison
with imipenem-susceptible VAP. Clin Infect Dis 2003;36:1111−8.
 D.A. Enoch et al. / International Journal of Antimicrobial Agents 29 Suppl. 3 (2007) S33–S41
[56] Levin AS, Barone AA, Penco J, et al. Intravenous colistin as therapy
for nosocomial infections caused by multidrug-resistant Pseudomonas
aeruginosa and Acinetobacter baumannii. Clin Infect Dis 1999;28:
1008−11.
[57] Linden PK, Kusne S, Coley K, Fontes P, Kramer DJ, Paterson D.
Use of parenteral colistin for the treatment of serious infection due
to antimicrobial-resistant Pseudomonas aeruginosa. Clin Infect Dis
2003;37:e154−60.
[58] Markou N, Apostolakos H, Koumoudiou C, et al. Intravenous colistin
in the treatment of sepsis from multiresistant Gram-negative bacilli
in critically ill patients. Crit Care 2003;7:R78−83.
[59] Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S,
Falagas ME. Colistin treatment in patients with ICU-acquired
infections caused by multiresistant Gram-negative bacteria: the
renaissance of an old antibiotic. Clin Microbiol Infect 2005;11:
115−21.
[60] Reina R, Estenssoro E, Saenz G, et al. Safety and efficacy of colistin
in Acinetobacter and Pseudomonas infections: a prospective cohort
study. Intensive Care Med 2005;31:1058−65.
[61] Jones RN, Deshpande LM, Bell JM, et al. Evaluation of
the contemporary occurrence rates of metallo-beta-lactamases in
multidrug-resistant Gram-negative bacilli in Japan: report from the
SENTRY Antimicrobial Surveillance Program (1998–2002). Diagn
Microbiol Infect Dis 2004;49:289−94.
[62] Lekkas A, Gyi KM, Hodson ME. Temocillin in the treatment of
Burkholderia cepacia infection in cystic fibrosis. J Cyst Fibros 2006;
5:121−4.
[63] Andes DR, Craig WA. Cephalosporins. In: Mandell GL, Bennett
JE, Dolin R, editors. Principles and practice of infectious diseases.
Philadelphia, PA: Churchill Livingstone; 2005. p. 20−1.
[64] Li XZ, Nikaido H, Poole K. Role of mexA–mexB–oprM in antibiotic
efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother
1995;39:1948−53.
[65] Livermore DM, Sefton AM, Scott GM. Properties and potential of
ertapenem. J Antimicrob Chemother 2003;52:331−44.
[66] Kohler T, Michea-Hamzehpour M, Epp SF, Pechere JC. Carbapenem
activities against Pseudomonas aeruginosa: respective contributions
of OprD and efflux systems. Antimicrob Agents Chemother 1999;
43:424−7.
[67] Mushtaq S, Ge Y, Livermore DM. Comparative activities
of doripenem versus isolates, mutants, and transconjugants of
Enterobacteriaceae and Acinetobacter spp. with characterized beta-
lactamases. Antimicrob Agents Chemother 2004;48:1313−9.
[68] Howe RA, Wilson MP, Walsh TR, Millar MR. Susceptibility testing
of Stenotrophomonas maltophilia to carbapenems. J Antimicrob
Chemother 1997;40:13−7.
[69] Jones RN, Huynh HK, Biedenbach DJ. Activities of doripenem
(S-4661) against drug-resistant clinical pathogens. Antimicrob Agents
Chemother 2004;48:3136−40.
[70] Ruiz J. Mechanisms of resistance to quinolones: target alterations,
decreased accumulation and DNA gyrase protection. J Antimicrob
Chemother 2003;51:1109−17.
[71] Dean CR, Visalli MA, Projan SJ, Sum PE, Bradford PA. Efflux-
mediated resistance to tigecycline (GAR-936) in Pseudomonas
aeruginosa PA01. Antimicrob Agents Chemother 2003;47:972−8.
[72] Visalli MA, Murphy E, Projan SJ, Bradford PA. AcrAB multidrug
efflux pump is associated with reduced levels of susceptibility
to tigecycline (GAR-936) in Proteus mirabilis. Antimicrob Agents
Chemother 2003;47:665−9.
[73] Fritsche TR, Sader HS, Stilwell MG, Dowzicky MJ, Jones RN.
Potency and spectrum of tigecycline tested against an international
collection of bacterial pathogens associated with skin and soft tissue
infections (2000–2004). Diagn Microbiol Infect Dis 2005;52:195–
201.
S41
[74] Pachon-Ibanez ME, Jimenez-Mejias ME, Pichardo C, Llanos AC,
Pachon J. Activity of tigecycline (GAR-936) against Acinetobacter
baumannii strains, including those resistant to imipenem. Antimicrob
Agents Chemother 2004;48:4479−81.
[75] Seifert H, Stefanik D, Wisplinghoff H. Comparative in vitro
activities of tigecycline and 11 other antimicrobial agents against
215 epidemiologically defined multidrug-resistant Acinetobacter
baumannii isolates. J Antimicrob Chemother 2006;58:1099–100.
[76] Milatovic D, Schmitz FJ, Verhoef J, Fluit AC. Activities of
the glycylcycline tigecycline (GAR-936) against 1,924 recent
European clinical bacterial isolates. Antimicrob Agents Chemother
2003;47:400−4.
[77] Sader HS, Jones RN, Stilwell MG, Dowzicky MJ, Fritsche TR.
Tigecycline activity tested against 26,474 bloodstream infection
isolates: a collection from 6 continents. Diagn Microbiol Infect Dis
2005;52:181−6.
[78] Jones RN. Disk diffusion susceptibility test development for the
new glycylcycline, GAR-936. Diagn Microbiol Infect Dis 1999;35:
249−52.
[79] Yoon J, Urban C, Terzian C, Mariano N, Rahal JJ. In vitro double and
triple synergistic activities of polymyxin B, imipenem, and rifampin
against multidrug-resistant Acinetobacter baumannii. Antimicrob
Agents Chemother 2004;48:753−7.
[80] Tascini C, Menichetti F, Bozza S, Del Favero A, Bistoni F. Evaluation
of the activities of two-drug combinations of rifampicin, polymyxin
B and ampicillin/sulbactam against Acinetobacter baumannii. J
Antimicrob Chemother 1998;42:270−1.
[81] Hogg GM, Barr JG, Webb CH. In-vitro activity of the combination
of colistin and rifampicin against multidrug-resistant strains of
Acinetobacter baumannii. J Antimicrob Chemother 1998;41:494−5.
[82] Taccone FS, Rodriguez-Villalobos H, De Backer D, et al. Successful
treatment of septic shock due to pan-resistant Acinetobacter
baumannii using combined antimicrobial therapy including
tigecycline. Eur J Clin Microbiol Infect Dis 2006;25:257−60.
[83] Fish DN, Choi MK, Jung R. Synergic activity of cephalosporins plus
fluoroquinolones against Pseudomonas aeruginosa with resistance to
one or both drugs. J Antimicrob Chemother 2002;50:1045−9.
[84] Gunderson BW, Ibrahim KH, Hovde LB, Fromm TL, Reed MD,
Rotschafer JC. Synergistic activity of colistin and ceftazidime
against multiantibiotic-resistant Pseudomonas aeruginosa in an
in vitro pharmacodynamic model. Antimicrob Agents Chemother
2003;47:905−9.
[85] Saiman L, Chen Y, Gabriel PS, Knirsch C. Synergistic activities of
macrolide antibiotics against Pseudomonas aeruginosa, Burkholderia
cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxi-
dans isolated from patients with cystic fibrosis. Antimicrob Agents
Chemother 2002;46:1105−7.
[86] Sobieszczyk ME, Furuya EY, Hay CM, et al. Combination therapy
with polymyxin B for the treatment of multidrug-resistant Gram-
negative respiratory tract infections. J Antimicrob Chemother 2004;
54:566−9.
[87] Saballs M, Pujol M, Tubau F, et al. Rifampicin/imipenem combination
in the treatment of carbapenem-resistant Acinetobacter baumannii
infections. J Antimicrob Chemother 2006;58:697–700.
[88] Peleg AY, Potoski BA, Rea R, et al. Acinetobacter baumannii
bloodstream infection while receiving tigecycline: a cautionary report.
J Antimicrob Chemother 2007;59:128−31.
[89] Talbot GH, Bradley J, Edwards Jr JE, Gilbert D, Scheld M, Bartlett JG.
Bad bugs need drugs: an update on the development pipeline from
the Antimicrobial Availability Task Force of the Infectious Diseases
Society of America. Clin Infect Dis 2006;42:657−68.