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Transcript
Eur J Clin Microbiol Infect Dis (2007) 26:229–237
DOI 10.1007/s10096-007-0279-3
REVIEW
Antimicrobial therapy for Stenotrophomonas
maltophilia infections
A. C. Nicodemo & J. I. Garcia Paez
Published online: 3 March 2007
# Springer-Verlag 2007
Abstract Stenotrophomonas maltophilia has emerged as
an important nosocomial pathogen capable of causing
respiratory, bloodstream, and urinary infections. The treatment of nosocomial infections by S. maltophilia is difficult,
as this pathogen shows high levels of intrinsic or acquired
resistance to different antimicrobial agents, drastically
reducing the antibiotic options available for treatment.
Intrinsic resistance may be due to reduced outer membrane
permeability or to the multidrug efflux pumps. However,
specific mechanisms of resistance such as aminoglycosidemodifying enzymes or the heterogeneous production of
metallo-β-lactamase have contributed to the multidrugresistant phenotype displayed by this pathogen. Moreover,
the lack of standardized susceptibility tests and their interpretative criteria hinder the choice of an adequate antibiotic
treatment. Recommendations for the treatment of infections
by S. maltophilia are based on in vitro studies, certain
nonrandomized clinical trials, and anecdotal experience.
Trimethoprim-sulfamethoxazole remains the drug of choice,
although in vitro studies indicate that ticarcillin-clavulanic
acid, minocycline, some of the new fluoroquinolones, and
tigecycline may be useful agents. This review describes the
main resistance mechanisms, the in vitro susceptibility
profile, and treatment options for S. maltophilia infections.
A. C. Nicodemo (*) : J. I. G. Paez
Department of Infectious Diseases,
University of São Paulo Medical School,
São Paulo, SP, Brazil
e-mail: [email protected]
A. C. Nicodemo
Rua Barata Ribeiro 414, Conjunto 104,
CEP 01308-000 São Paulo, SP, Brazil
Introduction
Stenotrophomonas maltophilia is a nonfermentative gramnegative bacillus, previously known as Pseudomonas
maltophilia and later as Xanthomonas maltophilia [1–4].
This bacterium is found in various environments such as
water, soil, plants, food, and hospital settings, among others
[5, 6]. The pathogenic factors and virulence associated with
S. maltophilia include the production of proteases and
elastases and the ability to adhere to synthetic materials. S.
maltophilia adheres avidly to medical implants and catheters,
forming a biofilm that renders natural protection against host
immune defenses and different antimicrobial agents [7–10].
The incidence of S. maltophilia isolates provided by
different hospitals ranges from 7.1 to 37.7 cases per 10,000
discharges [6, 11, 12]. Nosocomial S. maltophilia pneumonia is associated with high mortality, particularly when
associated with bacteremia or obstruction. In uncontrolled
clinical trials, mortality rates associated with S. maltophilia
bacteremia range from 21 to 69% [13, 14]. Senol et al. [13]
reported an attributable mortality rate of 26.7% in S.
maltophilia bacteremia. The risk factors for infection by
S. maltophilia include prolonged hospitalization requiring
invasive procedures, previous exposure to broad-spectrum
antibiotics, mechanical ventilation, and severe mucositis
[12, 15–22]. Stenotrophomonas maltophilia is associated
with a broad spectrum of clinical syndromes, including
pneumonia, bloodstream infection, skin infections and
surgical-site-related infections, urinary tract infections,
endocarditis, meningitis, intra-abdominal infections, and
endophthalmitis [6, 23–35].
Patients with cystic fibrosis, a hereditary metabolic
disorder of the exocrine glands that mainly affects the
pancreas, respiratory system, and sweat glands, are commonly colonized by S. maltophilia.
230
Sometimes it is difficult to distinguish between colonization and infection. The differential diagnosis should be based
on the association of factors such as physical examination,
radiograph results, other clinical or image findings, and
laboratory test results, including the microbiological assays.
The treatment of infection caused by S. maltophilia is
controversial and difficult due to genotypic and phenotypic
variability amongst members of S. maltophilia species;
intrinsic resistance mechanisms expressed by S. maltophilia
against most antimicrobial agents; the ability of S. maltophilia
to develop resistance during treatment; poorly standardized
susceptibility tests and their interpretative criteria; and the
difficulty of transferring in vitro findings to clinical practice,
given the lack of randomized clinical trials comparing the
efficacy of antimicrobial agents [6, 36, 37].
Resistance mechanisms
Resistance due to production of beta-lactamases
Beta-lactam resistance is due to the expression of two
inducible β-lactamases, L1 and L2, although not all clinical
S. maltophilia isolates express β-lactamases, even after
induction with a β-lactam agent. L1 metallo-β-lactamase is
a homotetramer of 118 kDa. It is a Zn2+-dependent metalloenzyme that hydrolyzes virtually all classes of β-lactam
agents, including penicillins, cephalosporins, and carbapenems, but not monobactams. Furthermore, the L1 enzyme
is not inhibited by clavulanic acid. L2 serine-β-lactamase is
a cephalosporinase that hydrolyzes aztreonam and is
completely inhibited by clavulanic acid and partially
inhibited by other β-lactamase inhibitors [38–41]. The
expression of such β-lactamases is determined by chromosomal genes, which are highly polymorphic within the
species [42].
In 2000, Avison et al. [43] demonstrated a constitutively
expressed β-lactamase gene from a clinical isolate of S.
maltophilia. Its DNA sequence is almost identical to that of
blaTEM2, and the expressed enzyme is a Bush type 2a
penicillinase with an amino acid sequence identical to that of
TEM-2. This gene was present within a transposon in the
genome of this strain. These findings suggest that this
pathogen can act as a reservoir for mobile β-lactamase genes.
Resistance due to efflux systems
Multidrug resistance efflux pumps have been identified as an
important resistance mechanism in S. maltophilia. The efflux
pump is composed of a membrane fusion protein, an energydependent transporter, and outer membrane proteins (OMPs).
Alonso and Martinez [44] described the cloning and the
characterization of a multidrug efflux pump from S.
Eur J Clin Microbiol Infect Dis (2007) 26:229–237
maltophilia for the first time and named the new system
SmeDEF. In 2001, the same authors [45] showed SmeDEF
expression in 33% of the S. maltophilia strains studied and
a resultant increase in the MICs of tetracyclines, choramphenicol, erythromycin, norfloxacin, and ofloxacin.
Gould and Avison [46] examined a collection of 30
phylogenetically grouped clinical S. maltophilia isolates
from Europe and North, South, and Central America and
compared their resistance profiles to SmeDEF expression
levels. Of 20 spontaneous S. maltophilia drug-resistant
mutants tested, four overexpressed SmeDEF, but only two
carried mutations within the smeT gene, which is the
repressor of the S. maltophilia multidrug SmeDEF efflux
pump. Therefore, mutation in smeT might be responsible
for SmeDEF overproduction in multidrug-resistant strains
of S. maltophilia [47, 48].
In the above-mentioned study of 30 clinical isolates, 6
significantly overexpressed SmeDEF. However, smeT is not
the only gene product that affects SmeDEF expression, and
no general SmeDEF-mediated phenotype can be defined.
Li et al. [49] later described the SmeABC system,
identifying the SmeC as an outer membrane multidrug
efflux protein of S. maltophilia. However, resistance is
dependent only upon the SmeC OMP component of this
multidrug efflux system. The fact that SmeC but not
SmeAB contributes to antimicrobial resistance and can be
expressed independently of these genes suggests that SmeC
also functions as part of an additional as-yet-unidentified
efflux system. Chang et al. [50] have shown that strains
expressing the SmeABC and SmeDEF efflux systems are
resistant to ciprofloxacin and meropenem, respectively.
Aminoglycoside resistance
Current literature suggests that multiple mechanisms may be
involved in aminoglycoside resistance, such as aminoglycoside-modifying enzymes, temperature-dependent resistance
due to outer membrane changes, the efflux-mediated
mechanism, and target modification.
The enzymatic modification of the aminoglycosides is due
to a family of enzymes that includes O-nucleotidyltransferases,
O-phosphotransferases, and N-acetyltransferase. In 1999,
Lambert et al. [51] identified the chromosomal aac(6′)-Iz
gene of S. maltophilia and established that aac(6′)-Iz enzymeproducing strains show higher resistance to gentamicin. Li et
al. [52] have demonstrated that aac(6′)-Iz acetyltransferase
enzyme-expressing strains exhibit reduced susceptibility,
particularly to tobramycin. Recently, Okazaki and Avison
[53] have demonstrated the aph(3′)-IIa determinant of S.
maltophilia, which encodes resistance to the aminoglycosides
class, except for gentamicin.
Changes in the lipopolysaccharide (LPS) structure have
been correlated with changes in resistance to a variety of
Eur J Clin Microbiol Infect Dis (2007) 26:229–237
antimicrobial agents [54]. S. maltophilia exhibits a temperature-dependent variation in susceptibility to several antibiotics, including aminoglycosides and polymyxin B [55].
Temperature-dependent changes in outer membrane fluidity
[56], LPS side-chain length [57], and, possibly, core
phosphate content [58] seem to explain the temperaturedependent variation in aminoglycoside susceptibility, implicating LPS as determinant in the aminoglycoside
resistance in this organism. The ability of S. maltophilia
to alter the size of O-polysaccharide and the phosphate
content of LPS at different temperatures, increasing
resistance to aminoglycosides at 30°C compared to 37°C,
has been shown. McKay et al. [59] cloned a spgM gene
from S. maltophilia that was shown to encode a bifunctional enzyme with both phosphoglucomutase and phosphomanomutase activities. Mutants lacking spgM produced
less LPS than the spgM+ parent strain and tended to have
shorter O-polysaccharide chains. However, spgM mutants
displayed a modest increase in susceptibility to several
antimicrobial agents and were completely avirulent in an
animal infection model. The latter may be related to the
resultant serum susceptibility of spgM mutants, which,
unlike the wild-type parent strain, were rapidly killed by
human serum. This data highlights the contribution made
by LPS to the antimicrobial resistance of S. maltophilia.
Proteins of the small multidrug resistance (SMR) family
have been characterized in some gram-negative bacteria in
which resistance is attributed specifically to aminoglycosides.
Chang et al. [50] detected the smr gene in six S. maltophilia
strains analyzed, although the role of the smr gene in drug
resistance by S. maltophilia requires further study.
The resistance to aminoglycosides can also be due to
target modification (16S rRNA methylation or ribosomal
mutations), which has been documented in some gramnegative pathogens and Mycobacterium spp. [60].
Trimethoprim-sulfamethoxazole resistance
Stenotrophomonas maltophilia resistance mechanisms to
trimethoprim-sulfamethoxazole (SXT) have not been studied thoroughly. Barbolla et al. [61] mentioned the presence
of the sul I gene (plasmid-mediated resistance) in three
clones for which the MICs of SXT were increased.
According to the authors, these findings not only support
the increased spread of class one integrons compared to
other mechanisms, but also reveal the potential limitations
of using SXT therapy in severe infections.
231
biofilms. Stenotrophomonas maltophilia has the ability to
adhere to abiotic surfaces. The positive charge of the cell
surface of the bacterium seems to be an important element that
favors its adhesion to negatively charged surfaces [8]. The
biofilm formation on prosthetic materials such as central
venous catheters, urinary tract catheters, and heart valves,
amongst others, is a biological property of this bacterium.
Biofilms are structured communities of bacterial cells
enclosed in a self-produced expolysaccharide matrix and
adherent to an inert surface. Di Bonaventura et al. [10], in an
in vitro study, characterized the kinetics of S. maltophilia
biofilm formation: bacteria attach rapidly to polystyrene after
2 h of incubation, and then the biofilm formation increases
over time, reaching maximum intensity at 24 h of culture.
The production of extracellular slime or glycocalyx is a
crucial factor in bacterial adherence and in bacterial protection
against host defense mechanisms and antimicrobial agents,
which commonly fail to eradicate the biofilms and consequently, the infection [62]. This highlights the need to remove these
prosthetic devices in order to eradicate the infection.
Susceptibility tests
There are several uncertainties surrounding the in vitro
susceptibility testing of S. maltophilia, which range from the
selection of the antimicrobial agents to be tested, to the best in
vitro methodology to be used, to the accuracy of the in vitro
methods used, to the correlation between the different
methods available [37].
The recommendations established by different professional
societies for susceptibility testing of S. maltophilia vary with
regard to the selection of antimicrobial agents to be tested,
the disk content, the zone diameter interpretative criteria, and
the equivalent MIC breakpoints. The Clinical and Laboratory
Standards Institute (CLSI) recommends the disk diffusion
technique in order to establish the susceptibility of S.
maltophilia, but only to SXT, minocycline, and levofloxacin.
Other agents may be approved for therapy, but according to
the CLSI, their performance has not been sufficiently studied
to establish disk diffusion breakpoints. The MIC interpretative breakpoints are available only for ticarcillin-clavulanic
acid, ceftazidime, minocycline, levofloxacin, SXT, and
chloramphenicol [63]. Therefore, further studies are necessary in order to enhance the in vitro susceptibility testing of
S. maltophilia to different antimicrobial agents.
Treatment
Biofilm formation
Trimethoprim-sulfamethoxazole
Although the biofilm formation is not precisely a “resistance mechanism,” it can increase the resistance to
antimicrobial agents, which typically fail to eradicate
Trimethoprim-sulfamethoxazole should be considered the
empirical choice for clinically suspected S. maltophilia
232
infections and as the treatment of choice for culture-proven
infections by this agent. Susceptibility to this combination
is above 80%, according to the results of studies using
several in vitro methods [12, 14, 37, 64–77]. Sader and
Jones [78], studying 2,076 strains as part of the worldwide
Sentry Antimicrobial Surveillance Program, reported a
resistance rate of 4.7%. Nevertheless, resistance to this
combination is increasing in certain centers.
Ticarcillin-clavulanic acid and aztreonam-clavulanic acid
In general, the β-lactam antibiotics show low activity
against S. maltophilia, owing to the previously mentioned
resistance mechanisms. Rates of resistance of S. maltophilia
to β-lactam agents such as ampicillin, amoxicillin, piperacillin, and aztreonam are invariably high [12, 18, 70–84].
Beta-lactamase inhibitors such as clavulanic acid can
sometimes increase the susceptibility of S. maltophilia to
such agents [82].
The ticarcillin-clavulanic acid combination has been
recommended as a second therapeutic option, mainly in the
treatment of patients who experience adverse effects with
SXT therapy [6]. Several studies have demonstrated susceptibility above 70% to this in vitro drug combination [66–68,
70, 81, 83]. However, Sader and Jones [78], studying 2,076
strains as part of the worldwide Sentry Antimicrobial
Surveillance Program, reported a resistance rate of 54.7%.
Nicodemo et al. [37] reported an in vitro resistance rate of
41%, similar to the rates shown in other studies [79, 85].
Garrison et al. [86], using the pharmacodynamic model to
evaluate the ticarcillin-clavulanic acid combination, have
shown that S. maltophilia strains exhibit partial growth
suppression followed by regrowth, suggesting the need for
controlled studies to establish the true efficacy of this
combination in the treatment of S. maltophilia infections.
The aztreonam-clavulanic acid combination (2:1 and 1:1)
has good in vitro activity, although difficulties with the
interpretation of the diffusion tests in the component ratios
and differences in the pharmacokinetics of these drugs
restrict their use in the treatment of S. maltophilia infections
[72, 82, 84, 85, 87]. Other combinations such as ticarcillinsulbactam, piperacillin-tazobactam, and ampicillin-sulbactam
do not show good activity against this bacterium [12, 19, 75,
80, 82, 83, 85].
Cephalosporins and carbapenems
Cephalosporins in general show low activity against S.
maltophilia, while cefoperazone, ceftazidime, and cefepime
exert some in vitro activity. However, resistance rates are
undesirably high, as reported in various trials [12, 64, 66,
67, 73, 75, 80, 84, 85, 88–90]. The risk of resistance
induction due to β-lactamase production and low β-lactam
Eur J Clin Microbiol Infect Dis (2007) 26:229–237
activity, particularly of the cephalosporins, limits their
empirical use in the treatment of S. maltophilia infections
[12]. Combinations of cephalosporins with β-lactamase
inhibitors, such as ceftazidime-clavulanic acid, cefoperazone-sulbactam, and cefepime-clavulanic acid, are often
mentioned anecdotally, but demonstration of in vitro
effectiveness is scarce [81, 84, 85]. Stenotrophomonas
maltophilia is intrinsically resistant to carbapenems. Howe
et al. [91] have shown that both imipenem and meropenem
are L1 β-lactamase inducers and, thus, are not effective
against in vitro S. maltophilia.
Fluoroquinolones
New fluoroquinolones such as clinafloxacin, levofloxacin,
gatifloxacin, moxifloxacin, and sitafloxacin show superior in
vitro activity compared to earlier quinolones [37, 66, 68, 70,
73, 85, 88, 90, 92–95]. The MIC90 of ciprofloxacin has
increased over the last few years, which can be explained by
ciprofloxacin’s poor Cmax MIC90 ratio [85]. Several studies
have shown the low in vitro activity of this agent against S.
maltophilia strains [19, 64, 71–75, 79, 83, 85, 88–90, 92–
94]. Gesu et al. [92], in an in vitro study comparing the
activities of levofloxacin and ciprofloxacin against clinical
bacterial isolates, evaluated 124 S. maltophilia strains and
verified susceptibility rates of 85.5 and 58.9%, respectively,
to levofloxacin and ciprofloxacin. Valdezate et al. [96]
showed that more than 95% of the S. maltophilia strains
tested were susceptible to the new fluoroquinolones. Clinafloxacin seems to be the most active fluoroquinolone, as
shown by Pankuch et al. [97] and confirmed in further
studies that showed clinafloxacin to be two- to fourfold
superior to levofloxacin, moxifloxacin, trovafloxacin, and
sparfloxacin [70, 93]. Weiss et al. [93], in a comparison of
seven fluoroquinolones, showed that clinafloxacin was the
most active, inhibiting 95% of the 326 strains analyzed,
followed by trovafloxacin (84.3%), moxifloxacin (83.1%),
and sparfloxacin (81.5%).
Gales et al. [68], as part of the worldwide Sentry
Antimicrobial Surveillance Program, demonstrated resistance rates for gatifloxacin of around 2% in Europe and
15% in Canada. Sader and Jones [78] showed low
resistance rates for gatifloxacin (14.1%) and levofloxacin
(6.5%). Cohn and Waites [98], using a time-kill assay,
showed that gatifloxacin had a bactericidal effect against S.
maltophilia isolates, suggesting that gatifloxacin might be
used to treat strains that show in vitro susceptibility.
Biedenbach et al. [94] suggested that gatifloxacin may be
used as a monotherapy or together with a second drug in
the treatment of refractory infections due to S. maltophilia
strains.
Giamarellos-Bourboulis et al. [95] demonstrated the in
vitro bactericidal effect of moxifloxacin against genetically
Eur J Clin Microbiol Infect Dis (2007) 26:229–237
distinct isolates resistant to SXT; nevertheless, monotherapy with moxifloxacin against respiratory tract infections
due to strains for which the MIC is greater than 2 g/l may
select resistant mutants. Ba et al. [99] have shown that
moxifloxacin exhibits greater bactericidal activity than
ciprofloxacin; however, they also verified the selection of
mutants exhibiting resistance to both quinolones. Garrison
et al. [86] detected the appearance of mutants resistant to
both quinolones in a pharmacodynamic model that evaluated ciprofloxacin and levofloxacin. Di Bonaventura et al.
[10] showed that rufloxacin, ofloxacin, and grepafloxacin
exert significant static activity ( p<0.01) in reducing the
biomass and viability of the biofilm produced by S.
maltophilia strains, thus proving useful in the “lock”
therapy of vascular-catheter-related bloodstream infections
by S. maltophilia. More in vivo and in vitro studies are
necessary to establish the true effectiveness of the new
fluoroquinolones, whether used alone or in combination
with other agents.
Aminoglycosides
Aminoglycosides show poor activity against S. maltophilia
strains because of the constitutive production of aminoglycoside-modifying enzymes by S. maltophilia, the temperature-dependent resistance that results from outer
membrane changes, and the expression of efflux pump
systems. Gentamicin, tobramycin, and amikacin show
invariably high levels of resistance [12, 19, 68–70, 72–76,
78, 80, 89, 90, 96].
233
polymyxins interacts with the anionic LPS molecules in
the outer membrane of gram-negative bacteria, thereby
displacing the calcium and magnesium cations that stabilize
the LPS molecules. This process results in an increase in
cell-envelope permeability, leakage of cell contents, and,
consequently, cell death [105, 106]. Moreover, the fattyacid side chain of polymyxins interacts with the LPS
molecules to facilitate further interaction between the
polymyxins and the cell membrane [107].
The use of polymyxins to treat infections by nonfermentative, multiresistant gram-negative bacilli has recently
acquired greater importance. Using MIC determinations,
Gales et al. [90] evaluated 23 S. maltophilia strains and
observed a 73.9% rate of susceptibility to both colistin and
polymyxin B. Nicodemo et al. [37] verified rates of 75.7%
and 77.2% susceptibility to colistin and polymyxin B,
respectively.
The main limitations to the use of polymyxins concern
the scarceness of clinical studies with these drugs and their
toxicity. Susceptibility testing of S. maltophilia is particularly difficult, and MICs and zones for the species are
affected by both temperature and medium. Many isolates
grow better at 30°C, and some isolates grow poorly, or not
at all, at 37°C. The activities of aminoglycosides and
polymyxins against the species are particularly vulnerable
to temperature variation, and isolates often appear falsely
susceptible at 37°C. Isolates should nevertheless be
reported as resistant to these drugs, and to carbapenems,
irrespective of zone diameters [108].
Chloramphenicol and tetracyclines
Synergy
Chloramphenicol shows some in vitro activity against S.
maltophilia isolates, although there are considerable differences in susceptibility profiles (11.5–81.4%). Furthermore,
clinical experience with this drug in the treatment of S.
maltophilia infections is extremely limited [24, 37, 74, 80].
Like the tetracyclines, minocycline shows high in vitro
activity against S. maltophilia strains. Susceptibility of S.
maltophilia to this agent was above 80% in various assays
[73, 75, 79, 90, 96, 100, 101]. Tigecycline, a glycylcycline,
is a compound that has demonstrated good in vitro activity
against S. maltophilia strains [67, 102, 103].
Antimicrobial combinations for the treatment of S.
maltophilia infections remain controversial. It is difficult
to draw a firm conclusion from the published studies due to
the limited number of strains studied, the wide variety of
combinations tested, and the differing methods used. This
also contributes to the difficulty in assessing the clinical
relevance of these in vitro studies. Moreover, although
synergy between drug combinations may be demonstrable,
this effect may not occur in clinically achievable drug
concentrations. Reports of resistance to SXT have fueled
studies of antimicrobial combinations [80].
Zelenitsky et al. [109] found that SXT combined with
other antimicrobial agents such as ceftazidime produced a
net bacterial kill and provided significant benefit over
monotherapy against the few strains studied in a pharmacodynamic in vitro model. Giamarellos-Bourboulis et al. [110],
evaluating colistin-rifampin and colistin-SXT synergies in a
24-h time-kill assay of 24 SXT-resistant strains, found
colistin-rifampin synergy to be 62.5% and colistin-SXT
synergy to be 41.7%. Based on their mechanism of action
Polymyxins
The polymyxins are amphipatic polypeptide antimicrobial
agents. Their basic structure consists of a fatty-acid side
chain attached to a polycationic peptide ring composed of
8–10 amino acids [104]. The polymyxins have a unique
structure and mechanism of action, targeting the bacterial
cell membrane. The polycationic peptide ring of the
234
(see above), the polymyxins would favor the entrance of
rifampin or SXT into the bacterium. Muñoz et al. [111]
found SXT-polymyxin B synergy for SXT-resistant strains,
showing that resistant strains became sensitive to this
combination, which may represent an alternative treatment
for multiresistant strain infections. Traub et al. [77] found a
bactericidal effect when SXT was employed in combination
with rifampicin or polymyxin B. Dawis et al. [112] studied
the gatifloxacin-piperacillin and gatifloxacin-cefepime combinations using the chequerboard method and reported
synergies of 80% and 60%, respectively. However, when
using the time-kill assay, they found no synergy. Visalli et al.
[113], evaluating 20 strains by time-kill assay over 12 h,
verified synergy for the levofloxacin-ceftazidime and levofloxacin-cefoperazone combinations in 7 strains. MuñozBellido et al. [82] studied 32 S. maltophilia strains and
found that the addition of aztreonam to ticarcillin-clavulanic
acid was two- to fourfold more active than aztreonamclavulanic acid, and that both combinations showed good
bactericidal activity. Poulos et al. [114] demonstrated
synergy between SXT and ticarcillin-clavulanic acid by the
chequerboard method and by the time-kill assay in 19
different SXT-resistant strains. Felegie et al. [74], also using
the chequerboard method, reported synergy between SXT and
carbenicillin in 12 of 14 strains analyzed, all sensitive to SXT.
Further in vitro and in vivo studies are necessary to
better evaluate the synergy between different drugs in the
treatment of S. maltophilia infections and the clinical
relevance of in vitro synergy.
Eur J Clin Microbiol Infect Dis (2007) 26:229–237
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Possible alternative approaches
On the basis of in vitro studies only, minocycline, possibly
tigecycline, and some of the new fluoroquinolones such as
moxifloxacin and levofloxacin could be considered alternative options for the treatment of S. maltophilia infections,
mainly in combination therapy [36, 76, 95]. The addition of
another antimicrobial agent should be considered if the
institution has found high rates of resistance to SXT or if
indicated by the severity of the infection.
The choice of monotherapy or combination therapy
remains controversial. Several authors [6, 14, 79, 85, 111]
believe that the bacteriostatic action of most active drugs
and the possibility of resistance development during
treatment warrants consideration of antimicrobial combinations in the treatment of severe infections, especially in
immunocompromised patients.
13.
14.
15.
16.
17.
18.
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