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Abbreviations
CAP
CFU
CLSI
DAEC
EAEC
EHEC
EIEC
EPEC
ESBL
ETEC
GNB
HUS
ICU
IM
LPS
LTCF
MBL
MIC
NNIS
OM
Community-acquired pneumonia
Colony-forming unit
Clinical and Laboratory Standards Institute
Diffusely adherent E. coli
Enteroaggregative E. coli
Enterohemorrhagic E. coli
Enteroinvasive E. coli
Enteropathogenic E. coli
Extended spectrum b-lactamase
Enterotoxigenic E. coli
Gram-negative bacilli
Hemolytic-uremic syndrome
Intensive care unit
Inner membrane
Lipopolysaccharides
Long term care facility
Metallo-carbapenemase
Minimum inhibitory concentration
National nosocomial infections surveillance
Outer membrane
651
652
OMP
PBP
SSTI
STEC
Stx
TMP/SMX
UTI
20.1
20.1.1
Capsule
20.1.2
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20.1.3
20.2
Mechanisms of Resistance
Resistance is a major issue when considering therapy. There are four mechanisms
which may confer resistance in Gram-negative bacteria including Enterobacteriaceae,
(a) Enzymatic modification of the antibiotic like -lactamases and aminoglycoside
modifying enzymes, (b) pump-mediated efflux of antibiotics through the outer
membrane, (c) loss of permeability due to reduced synthesis of porins, and (d) target
modifications as seen in PBPs for -lactams or DNA gyrase and topoisomerase IV,
which confer resistance to quinolones.
20.2.1
b-Lactamases
-lactamases, which are located in the periplasmic space, are the main mechanism
of resistance in Gram-negative bacteria against b-lactam antibiotics. These can be
either chromosomally encoded or plasmid mediated. The latter confer transferability among bacteria, due to their capacity for spreading and posing a challenge for
controlling the dissemination of resistance. -Lactamases are most commonly classified according to two general classifications: the Ambler molecular classification
system and the Bush-Jacoby-Medeiros functional classification system. The former
use sequence-based classification recognizing only four classes designated A to D.
Classes A, C, and D compromise evolutionary distinct groups of serine enzymes,
and class B contains the zinc types. The second classifies b-lactamases by their
substrate preference among penicillin, oxacillin, carbenicillin, cephaloride,
expanded-spectrum cephalosporins, and imipenem and also by their susceptibility
to inhibition by clavulanate. This phenotypic classification faces the problem that
point mutations can greatly alter substrate specificity and inhibitor susceptibility,
changing the group to which an enzyme is assigned [65]. We will review the most
frequent and clinically relevant b-lactamases.
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20.2.1.1
AmpC-Type b-Lactamases
20.2.1.2
ESBLs are derivatives, predominantly, of Amber class A: TEM and SHV type, and
class D: OXA type b-lactamases. Though over the past several years other classes
have been reported, including BES, GES, PER, TLA, VEB, and CTX-M. They have
been found in a wide range of Gram-negative organisms, particularly members of
the Enterobacteriaceae, most commonly in E. coli, K. pneumoniae, and Proteus [8].
The first reported ESBL dates back to 1983, shortly after the introduction of third
generation cephalosporins into clinical practice.
ESBLs arose due to point mutations in TEM-1 and SHV-1 b-lactamases in E. coli
and K. pneumoniae. TEM was named after the Greek patient from whom the first
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655
sample was obtained in 1965 from an E. coli isolate, while SHV denotes a variable
response to sulfhydryl inhibitors [65].
ESBLs confer resistance to penicillins, narrow-spectrum cephalosporins,
oxymino-cephalosporins (third-generation cephalosporins) and aztreonam. Usually
they do not hydrolyze cephamycins (cefoxitin and cefotetan), carbapenems, and
b-lactamase inhibitors. The latter characteristic differentiates these enzymes from
the AmpC-type b-lactamases, which are resistant to b-lactamase inhibitors.
ESBLs can be carried on chromosomes, but typically are plasmid encoded and
often found in association with integrons while conferring the capacity to spread
within both the same and different species.
Plasmids encoding ESBLs may harbor genes that give co-resistance to aminoglycosides, tetracyclines, and trimethoprim/sulfamethoxazole (TMP/SMX); many
ESBL producers are also resistant to quinolones, and in some of these resistant
strains, a plasmid-mediated quinolone resistance determinant defined as qnr, has
been found [35, 64].
Among the risk factors for acquisition of a nosocomial ESBL producers are the
following: prolonged duration of hospital stay, residence in intensive care units
(ICUs), invasive medical devices, prior antibiotic use, renal failure, burns, and
receipt of total parenteral nutrition [66].
Historically ESBLs have been a nosocomial problem, but recent reports show
spread to E. coli in ambulatory patients with CTX-M enzymes as the predominant
enzyme. According to Ben-Ami et al. risk factors for fecal carriage of ESBLproducing Enterobacteriaceae found in 26 out of 246 patients (10.8%) who were
colonized or infected at admission to a hospital were the following: dependent functional state (OR, 4.2; P = .004), current use of antibiotics (OR, 3.4; P = .015), chronic
renal insufficiency (OR, 2.8; P = .03), liver disease (OR, 11.1; P = .02), and use of a
histamine receptor antagonist (OR, 2.8; P = .03) [6].
A recent report by Lewis et al. confirmed CTX-M as the predominant ESBL
isolated in a U.S. Health Care System [44]. Also CTX-M isolates can be hypervirulent [10]; CTX-M-15 for example is not only the dominant ESBL in Europe but has
been found in multi-resistant hypervirulent clones of E. coli, associated with extraintestinal infections [39, 40, 49, 73].
Recognition of ESBLs is critical, since multiple studies have shown that inadequate antibiotic therapy of infections due to organisms of this type is associated
with a high mortality rate; the carbapenems appear to be the agents of choice but
selection of OprD deficient imipenem-resistant P. aeruginosa has been shown to
occur after wide use [76]. Carbapenem resistance can also occur in Enterobacteriaceae
harboring CTX-M when associated with the lack of expression of the OMPK36
porin [55].
Finally, OXA type ESBLs are comparatively rare and have been found mainly in
P. aeruginosa in specimens from Turkey and France [34]. Most OXA-type ESBLs
are relatively resistant to inhibition by clavulanic acid and can hydrolyze carbapenems, so are also classified as carbapenemases, as will be discussed below.
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20.2.1.3
Carbapenemases
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Recently, Endimiani et al. showed the limitations of the current CLSI breakpoints
to detect KPC. In the case of carbapenems, two thirds of imipenem and meropenem
MICs for K. pneumoniae strains with KPC were in the susceptible range, while 95%
of ertapenem MICs were in the resistant range. Hence, the authors recommend that
for K. pneumoniae isolates showing imipenem, meropenem, or doripenem MICs
1 mg/L or ertapenem MICs 2 mg/L, screening for KPC should be done using
PCR or a phenotypic method (i.e., modified Hodge test) [23].
Few studies have measured the clinical impact of these enzymes, so the outcomes are still highly variable and uncertain. One of the studies which tried to
approach it was a city wide surveillance in New York; from 602 K. pneumoniae
studied, 43.5% had ESBLs and 1.5% of those had also KPC, and these KPC producing strains represented a major clonal outbreak at several New York hospitals with
up to 47% mortality rate at 14 days [9, 94, 96].
It is unclear if a common genetic element is responsible for the transmission of
KPC genes around the world. The gene arrangements associated with KPC have
been studied in Klebsiella and P. aeruginosa isolates from Greece, France, and
Colombia. In each case, a unique transposon, Tn4401, was detected [56]. These
studies should be conducted on additional strains from other countries.
20.2.2
Target Modifications
658
These pentapeptides bind to gyrase and topoisomerase IV and protect DNA from
the inhibition by quinolones: qnr genes are now prevalent in different countries and
different species of Enterobacteriaceae including E. coli, K. pneumoniae, E. cloacae, C. freundii, and Salmonella spp., in Asia, Europe, South America and the
United states [13, 63, 68, 81]. Very often, genes for ESBLs are found in the same
plasmid where qnr genes are explaining in part the co-resistance to multiple antibiotic families commonly found in Enterobacteriaceae.
Methylation of ribosomal RNA (rRNA) by 16 S methylases is another mechanism of target modification. Its importance has been well characterized in resistance
against aminoglycosides.
So far, six different enzymes have been classified: RmtA, RmtB, RmtC, RmtD,
ArmA, and NpmA. The NpmA enzyme is the only one that methylates residue
A1408, whereas the others methylate residue G1405 within the aminoacyl site
(A site) of the ribosomal subunit [21].
20.2.3
Efflux Pumps
Efflux pumps have been recognized for many years and are present in every living
cell. There has been growing evidence, indicating their crucial role in resistance to
antimicrobials. While efflux as a mechanism of resistance to antibiotics has been
known for some time, multidrug efflux systems have only recently been identified and
appreciated as significant determinants of resistance. Essentially, these protein components span the outer membrane and actively extrude from the bacteria a vast array
of molecules including metabolites, detergents, organic solvents, as well as antibiotics, using either ATP hydrolysis or an ion-antiport mechanism as its source of energy.
The main goal of this mechanism is to limit the accumulation of toxic components
inside the cell. Efflux pumps can be either drug-specific, which tends to be plasmidencoded and are thus transmissible, or nonspecific, which are normally expressed on
the chromosome. If a pump is overproduced in the latter case, then it may confer
extended cross-resistance to multiple drug class using this single mechanism.
Typically, efflux alone leads to small increases in MIC. However, when multiple
mechanisms come into play simultaneously, susceptibility may change in a dramatic fashion. Recently, a new plasmid-mediated fluoroquinolone efflux pump
called QepA was found in E. coli, showing significant increased levels of resistance
to norfloxacin, ciprofloxacin and enrofloxacin [95].
20.2.4
Porin Loss
Porins are outer membrane channels that work as a filter in a permeability barrier.
Mutational loss retards the access of antibiotics into the bacterial cell. OMPs can be
either specific or nonspecific, allowing the passage of multiple molecules in the latter case.
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Many studies on the structure and regulation of porins in E. coli K-12 are available,
but there is little information concerning clinical isolates of this species. In K. pneumoniae, two major porins, OmpK35 and OmpK36, are produced, but many ESBLproducing K. pneumoniae isolates do not express OmpK35. Loss of both OmpK35 and
OmpK36 in ESBL-producing K. pneumoniae causes resistance to cefoxitin, increased
resistance to expanded-spectrum cephalosporins, and decreased susceptibility to carbapenems, particularly ertapenem. Porin loss also decreases the susceptibility to other
non-b-lactam compounds, such as fluoroquinolones [53].
E. coli grows readily on simple culture media or synthetic media with minimal
nutritional requirements such as glucose or glycerol. E. coli strains are typed according to their antigens: lipopolysaccharide (O), capsule (K) and flagellum (H).
Hundreds of such antigens have been described. However, certain O serogroups
may predominate for various groups of intestinal E. coli infections as well as some
K serogroups predominate for certain extraintestinal infections [61]. Specific pathogenic strains will be discussed later.
20.3.2
Epidemiology
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20.3.3
Clinical Syndromes
20.3.3.1
The majority of E. coli isolates from symptomatic infections of the urinary tract,
bloodstream, cerebrospinal fluid, respiratory tract, and peritonitis can be differentiated from commensal and diarrheagenic strains of E. coli by virtue of their distinctive virulence factor profiles and phylogenetic background. Such strains express
adhesive organelles like type 1 and P pili that allow them to bind and invade host
cells and tissues like the urinary tract [57].
Expression of iron-chelating factors (siderophores) enables extraintestinal E.
coli to steal host iron stores. Deployment of an array of toxins, including hemolysin
and cytotoxic necrotizing factor 1, allows extensive tissue damage facilitating bacterial dissemination as well as releasing host nutrients and disabling immune cells.
These toxins also have the capacity to modulate, in more subtle ways, host signaling
pathways affecting myriad processes, including inflammatory responses, host cell
survival, and cytoskeletal dynamics [91].
Like commensal E. coli (but in contrast to intestinal pathogenic E. coli), extraintestinal pathogenic strains are often found in the normal intestinal flora and do not
cause gastroenteritis in humans.
Urinary Tract Infection (UTI)
The urinary tract is the site most frequently infected by extraintestinal pathogenic
strains. An exceedingly common infection among ambulatory patients, UTI accounts
for 1% of ambulatory care visits in the United States and is second only to lower
respiratory tract infection among infections responsible for hospitalization. UTIs
are divided into a variety of clinical syndromes including uncomplicated cystitis,
pyelonephritis, and catheter-associated UTIs. E. coli is the most common pathogen
for all UTIs, which are the precipitating cause for seven million patient visits per
year with total costs exceeding 1 billion dollars in the United States alone [3].
Uncomplicated cystitis, the most common acute UTI syndrome, presents as dysuria, frequency, and suprapubic pain. In contrast, the appearance of fever or back pain
suggests progression to pyelonephritis. Persistently elevated or increasing fever and
neutrophil counts should prompt evaluation for intrarenal or perinephric abscess or
obstruction. Renal parenchymal damage and loss of renal function during pyelonephritis occur primarily with urinary obstruction. Pregnant women are at unusually high
risk for developing pyelonephritis, which can adversely affect the outcome of pregnancy. Therefore, prenatal screening for and treatment of asymptomatic bacteriuria are
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Bacteremia
E. coli bacteremia arises mainly from primary infection at any extraintestinal site.
In addition, primary E. coli bacteremia can arise from percutaneous intravascular
devices or transrectal prostate biopsy or can result from the increased intestinal
mucosal permeability seen in neonates and in the settings of neutropenia and chemotherapy-induced mucositis, trauma, and burns. Roughly equal proportions of E.
coli bacteremia cases originate in the community and in the hospital. In most studies, E. coli and Staphylococcus aureus are the two most common blood isolates of
clinical significance. E. coli, which is isolated in 1737% of cases, is the gramnegative bacillus most often isolated from the blood in the ambulatory setting and in
most long term care facilities (LTCFs) and hospital settings [5].
Isolation of E. coli from the blood is almost always clinically significant and
typically is accompanied by the sepsis syndrome, severe sepsis (sepsis-induced dysfunction of at least one organ or system), or septic shock. Calculations based on a
conservative estimate for the proportional contribution of E. coli to severe sepsis
(i.e., 17% of all cases) translate into an estimated 40,000 deaths among the affected
patients in the United States in 2001.
The urinary tract is the most common source of E. coli bacteremia, accounting
for one half to two-thirds of episodes. Bacteremia from a urinary tract source is
particularly common in patients with pyelonephritis, urinary tract obstruction, or
instrumentation in the presence of infected urine. The abdomen is the second most
common source, accounting for 25% of episodes. Although biliary obstruction
(stones, tumor) and overt bowel disruption are responsible for many of these cases,
some abdominal sources (e.g., abscesses) are remarkably silent clinically and
require identification via imaging studies (e.g., CT). Therefore, the physician should
be cautious in designating the urinary tract as the source of E. coli bacteremia in the
absence of characteristic signs and symptoms of UTI. Soft tissue, bone, pulmonary,
and intravascular catheter infections are other sources of E. coli bacteremia.
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Pneumonia
E. coli is not usually considered a cause of pneumonia. Enterobacteriaceae account
for only 25% of cases of community-acquired pneumonia (CAP), in part because
these organisms only transiently colonize the oropharynx of a minority of healthy
individuals. However, rates of oral colonization with E. coli and other Gram-negative
bacilli (GNB) increase with the severity of illness and with antibiotic use. Thus,
GNB are a common cause of pneumonia among residents of LTCFs and are an
important cause of hospital-acquired pneumonia, particularly among postoperative
and critically ill patients. Pulmonary infection is usually acquired by aspiration, but
it also occurs via hematogenous spread in which case multifocal nodular infiltrates
can be seen. Tissue necrosis, probably due to cytotoxins produced by GNB, is common. Despite significant institutional variation, E. coli is generally one of the most
commonly isolated GNB in hospital-acquired pneumonia, accounting for 5% of
episodes in U.S.-based studies [30]. Regardless of the host, pneumonia due to
enteric GNB is a serious disease, with high crude and attributable mortality.
Meningitis
E. coli is one of the two leading causes of neonatal meningitis (the other being
group B Streptococcus) and the most common cause among developing countries.
Most of the responsible strains possess the K1 capsular antigen [43]. After the first
month of life, E. coli meningitis is rare. E. coli meningitis after this age usually
implies disruption of the meninges from neurosurgery or after trauma or in the presence of cirrhosis. In patients with cirrhosis, the meninges are thought to be seeded
with E. coli because of the lack of hepatic clearance of portal vein bacteremia.
Skin and Soft Tissue Infections (SSTI)
E. coli contributes frequently to infection of decubitus ulcers and occasionally to
infection of ulcers and wounds of the lower extremity in diabetic patients and other
hosts with neurovascular compromise. In addition, occasionally it causes cellulitis
or infections of burn sites or surgical wounds, especially when the infection originates close to the perineum. Myositis or fasciitis due to E. coli in the thigh should
prompt an evaluation for an abdominal source with contiguous spread.
Endovascular Infection
Despite being one of the most common causes of bacteremia, E. coli rarely seeds
native or prosthetic heart valves. It lacks many of the virulence and adherence factors that allow bacteria to stick to the endothelium and produce disease. When the
organism does seed native valves, it usually does so in the setting of prior valve
disease. E. coli infections of aneurysms and vascular grafts are quite uncommon.
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20.3.3.2
663
Certain strains of E. coli are capable of causing diarrheal disease. At least in the
industrialized world, these strains of E. coli are rarely found in the fecal flora of
healthy persons and instead appear to be always involved in disease. These strains
have evolved a special ability to cause gastroenteric syndromes when ingested in
sufficient quantities by a naive host. There are at least five distinct types of diarrheagenic E. coli: (1) Shiga toxinproducing E. coli/enterohemorrhagic E. coli (EHEC),
(2) enterotoxigenic E. coli (ETEC), (3) enteropathogenic E. coli (EPEC), (4) enteroinvasive E. coli (EIEC), and (5) enteroaggregative E. coli (EAEC). Diffusely adherent E. coli (DAEC) and cytodetaching E. coli have also been described. Transmission
occurs predominantly via contaminated food and water for ETEC, EHEC, EIEC,
and probably EAEC and by person-to-person spread for EPEC (and occasionally
EHEC). Gastric acidity confers some protection against infection; therefore, persons with decreased stomach acid levels are especially susceptible. Humans are the
major reservoir (except for EHEC); host range appears to be dictated by speciesspecific attachment factors. Although there is some overlap, each type possesses a
unique combination of virulence traits that results in a distinctive intestinal pathogenic mechanism. These strains are largely incapable of causing disease outside the
intestinal tract. Except in the case of EHEC and perhaps EAEC, disease due to this
group of pathogens occurs primarily in developing countries.
20.3.4
Antibiotic Considerations
In the past, most E. coli isolates were highly susceptible to a broad range of antibiotic agents; this situation has changed. In general, the frequency of ampicillin resistance precludes its empirical use, even in community-acquired infections. The
prevalence of resistance to first-generation cephalosporins and TMP/SMX is
increasing among community-acquired strains [97]. Until recently, TMP/SMX was
the drug of choice for the treatment of uncomplicated cystitis, but resistance in the
United States increased from 7% in 1990 to 18% in 1998 [78]. Nowadays, this trend
has reached a resistance rate 20% (range, 1345%) [82]. Thus, treatment guidelines switched to alternative agents including fluoroquinolones. Resistance to fluoroquinolones has increased steadily over the last decade all over the world.
In Europe, the trend between 2001 and 2007 is shown in Figs. 20.1 and 20.2. The
prevalence of resistance is higher in settings where fluoroquinolone prophylaxis is
used extensively (e.g., in patients with leukemia, transplant recipients, and patients
with cirrhosis) and among isolates from LTCFs and hospitals [88]. Among quinolone-resistant strains, a significant prevalence of multi-drug resistance has been
well described; in a collaborative study, only 10.8% of fluoroquinolone resistant
strains were found to be resistant only to this class [41].
The prevalence of resistance to third and fourth generation cephalosporins,
monobactams, piperacillin-tazobactam, and the non-amikacin aminoglycosides is
664
legend
No Data
< 1%
15%
510%
1025%
2550%
> 50%
legend
No Data
< 1%
15%
510%
1025%
2550%
> 50%
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legend
No Data
< 1%
15%
510%
1025%
2550%
> 50%
Fig. 20.3 EARRS, proportion of third gen. cephalosporins resistant E. coli in 2007
increasing but is still generally <10% [41]. In Europe, the resistance to third generation
cephalosporins is shown in Fig. 20.3.
Carbapenems and amikacin are the most predictably active agents. Among the
carbapenem class, some prefer to use ertapenem for enterics in order to avoid unnecessary coverage of nonfermenters. Although relevant clinical experience is limited,
tigecycline and polymyxin B or E are highly active in vitro. However, blood and
urine concentrations of tigecycline are lower than those seen in gallbladder and skin
[47, 70], therefore use of this agent should be restricted to its FDA approved indications in skin and intra-abdominal infection. Several reports have described treatment failure in bacteremia and this agent should not be used in that setting [1].
The mainstay of treatment for all diarrheal syndromes is replacement of fluids and
electrolytes. The use of prophylactic antibiotics to prevent travelers diarrhea generally should be discouraged, especially in light of high rates of antimicrobial resistance. However, in selected patients including those in whom an infection would be
lethal, the use of rifaximin, which is non-absorbable and well tolerated, is reasonable. When stools are free of mucus and blood, early patient-initiated treatment of
travelers diarrhea with a quinolone or azithromycin decreases the duration of illness,
and the use of loperamide may halt symptoms within a few hours. Although dysentery caused by EIEC is self-limited, treatment hastens the resolution of symptoms,
particularly in severe cases. Antimicrobial therapy for Shiga Toxin-Producing
Escherichia coli (STEC)/EHEC infection (the presence of which is suggested by
bloody diarrhea without fever) should be avoided, since antibiotics may increase the
incidence of Hemolytic-uremic syndrome (HUS) possibly via increased production/
666
release of shiga-like toxin (Stx). Current in vitro data suggest that antibiotic exposure
increases the risk of HUS in children infected with STEC by inducing expression of
Stx through replication of phages that carry stx genes [38, 67].
Microbiology
20.4.2
Epidemiology
Klebsiella spp., is ubiquitous in nature. They have two common habitats, one being
the environment and the other being the mucosal surfaces of mammals including
humans, which they colonize. In this respect, the genus Klebsiella is like Enterobacter
and Citrobacter. In humans, K. pneumoniae is present as a saprophyte in the
nasopharynx and in the intestinal tract. Reported carriage rates in hospitalized
patients are 77% in stool, 19% in the pharynx and 44% on the hands. They are
amongst the most common causes of a variety of community-acquired and hospitalacquired infections. K. pneumoniae subsp., pneumoniae is the leading cause of disease followed by K. oxytoca. In the United States, it accounts for 38% of all
nosocomial bacterial infections, which is similar to the European statistics. The
NNIS system report (2003) states that among patients in intensive care units in the
United States, 20.6% of all K pneumoniae isolates were non-susceptible to third
generation cephalosporins. This represented a 47% increase compared with resistance rates from 1998 to 2002 [64]. In Europe, the resistance to third generation
cephalosporins is shown in Fig. 20.4.
By the end of the 1990s, carbapenem-resistant K. pneumoniae was isolated harboring the KPC enzymes. Currently, within the Enterobacteriaceae family, K. pneumoniae has the highest rates of carbapenem resistance. These are highly focal causing
outbreaks worldwide and occasionally becoming endemic in some medical centers.
20
667
legend
No Data
< 1%
15%
510%
1025%
2550%
> 50%
Fig. 20.4 EARRS, proportion third gen. cephalosporins resistant K. pneumoniae in 2007
20.4.3
Clinical Syndromes
668
20.4.4
Antibiotic Considerations
20.5
20.5.1
Proteus Species
Microbiology
The genus Proteus consists of motile, aerobic and facultative anaerobic Gram-negative
rods. Proteus is a member of the tribe Proteeae, which includes Morganella and
Providencia. Proteus spp. are identified by the following biochemical characteristics:
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20.5.2
Epidemiology
Members of the Proteus genus are widespread in the environment and are part of the
human gastrointestinal tract commensal flora. Among the genus Proteus, P. mirabilis is by far the most common species identified in clinical specimens. It accounts
for approximately 3% of nosocomial infections in the United States. The most common infections caused by Proteus spp., are UTIs. It causes about 7% of communityacquired UTIs. Additionally, in hospital-acquired UTI, it ranks as a leading organism
after E. coli [60].
20.5.3
Clinical Syndromes
670
foreign bodies in which the bacteria are embedded and from which they emerge to
cause recurrent infections.
P. mirabilis has also been implicated in bacteremia, neonatal meningoencephalitis, meningitis, empyema, osteomyelitis and endocarditis. An unusual case of
transfusion-transmitted P. mirabilis bacteremia was described in a patient transfused with a contaminated unit of platelet concentrate [60].
20.5.4
Antibiotic Considerations
20.6
20.6.1
Enterobacter Species
Microbiology
The major species of the genera are E. cloacae, E. aerogenes and E. agglomerans.
Enterobacter can be readily isolated and separated in the laboratory from other
members of the family. They grow in ordinary agar, ferment glucose, and possess
peritrichous flagella. Some strains are endowed with a capsule. E. cloacae accounts
for more than half of all infections and has been representative of the genera in its
mechanism of resistance, that is, overexpression of AmpC enzymes.
20
20.6.2
671
Epidemiology
20.6.3
Clinical Syndromes
672
20.6.4
Antibiotic Considerations
The propensity to select resistant strains during therapy is an important consideration when treating Enterobacter, since earlier studies have shown how inappropriate treatment can have a negative impact in development of resistance and patient
outcome. Chow and colleagues studied 129 patients with Enterobacter bacteremia
in three tertiary-care university hospitals. Multi-resistance was statistically greater
in Enterobacter when a third-generation cephalosporin had been administered
previously, when compared with other antibiotics (69% and 20%, respectively;
p < 0.001). Furthermore, emergence of resistance during treatment of initially susceptible strains was higher for third-generation cephalosporins as compared to
aminoglycosides (19% vs 1%; p < 0.001). Multi-resistant Enterobacter was associated with a higher mortality when compared with infection due to a sensitive isolate
(32% vs 15%; p < 0.003). The authors concluded that judicious use of third- generation
cephalosporins must be applied and they advised against their use in bacteremia as
monotherapy, regardless of the susceptibility profile [17].
A recent study by Choi and colleagues showed that among AmpC-producing
Enterobacteriaceae, Enterobacter was the main organism capable of selecting resistance to broad-spectrum cephalosporins (8.3%) but overall risk of mortality was low
[16]. Kaye et al. reported in 2001 that 19% of patients with Enterobacter-positive
isolates will develop resistance when treated with broad-spectrum cephalosporins.
The authors report the resistance rate as higher if the Enterobacter is isolated from
blood than from tissue, wounds or urine. Resistance occurred more frequently
among E. aerogenes than E. cloacae (17% vs 9%; p = 0.03); mortality rate due to
multi-resistant Enterobacter was 26% [18, 42].
Paterson et al. reported that approximately 33% of E. cloacae bacterial bloodstream isolates had co-existence of ESBLs and AmpC b-lactamases [64].
Resistance to carbapenems is rare, presumably because two mutations, namely
AmpC derepression and porin loss, are needed in combination to cause full resistance [45]. In the class, ertapenem can be used when P. aeruginosa or A. baumannii
infection have been ruled out.
A report from the SENTRY surveillance system in the USA between 1997 and
2000 showed excellent susceptibility to cefepime and carbapenems (>99%) [36].
Although no statistical differences in clinical improvement, bacteriological eradication and 30-day mortality were found in a study comparing cefepime and carbapenems for the treatment of infections caused by E. aerogenes, treatment failure was
documented in those isolates with higher cefepime MIC [31]. Despite the high susceptibility in many studies, cefepime resistance have been described recently due to
the production of CTX-M enzymes, AmpC b-lactamases hyperproduction and porin
loss [25]. Other antibiotics like aminoglycosides retain good activity but usually are
combined with other agents.
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673
Microbiology
S. marcescens is a motile, aerobic rod that is also easy to differentiate in the microbiology laboratory. Strains of Serratia usually produce extracellular deoxyribonuclease (DNase), lipase and gelatinase. Strains are usually indole and lactose negative.
Some strains are red pigmented. Other members of the genera Serratia include S.
liquefaciens, S. marinorubra, and S. odorifera but S. marcescens accounts for more
than 90% of infections.
20.7.2
Epidemiology
20.7.3
Clinical Syndromes
20.7.4
Antibiotic Considerations
674
20.8
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