Pathogens Resistant To Antimicrobial Agents-Epidemiology, Molecular Mechanisms and Clinical Management

Infect Dis Clin N Am 18 (2004) 467511
Pathogens resistant to antimicrobial

agents: epidemiology, molecular
mechanisms, and clinical management
Keith S. Kaye, MD, MPHa,*, John J. Engemann, MDa,
Henry S. Fraimow, MDb, Elias Abrutyn, MDc
a
Department of Medicine, Duke University Medical Center,

Box 3152, Durham, NC 27710, USA
b
Department of Medicine, University of Medicine and Dentistry of New Jersey,
401 Haddon Avenue, Room 274, Camden, NJ 08103, USA
c
Department of Medicine, Drexel University College of Medicine, 245 North 15th Street,
Mailstop 441, Philadelphia, PA 191021192, USA
This article reviews the molecular mechanisms by which resistance traits

are conferred and disseminated. The focus then shifts to the molecular
epidemiology and clinical management of certain multidrug-resistant
bacteria.
Mechanisms of resistance
It is important to distinguish the several ways in which an organism may
demonstrate resistance. Intrinsic resistance to an antimicrobial agent
characterizes resistance that is an inherent attribute of a particular species;
all organisms of the species may lack the appropriate drug-susceptible target
or possess natural barriers that prevent the agent from reaching the target.
Some examples are the natural resistance of gram-negative bacteria to
vancomycin because the drug cannot penetrate the gram-negative outer
membrane, or the intrinsic resistance of the penicillin binding proteins (PBP)
of enterococci to the eects of the cephalosporins.
Dr. Kaye was supported by a T. Franklin Williams Young Investigator Award from the
Infectious Diseases Society of America, the Association of Subspecialty Professors, John A.
Hartford Foundation, and Elan Pharmaceuticals. Dr. Abrutyn was supported in part by
a grant from the Tenet Healthcare Foundation.
* Corresponding author.
E-mail address: kaye0001@mc.duke.edu (K.S. Kaye).
0891-5520/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.idc.2004.04.003
468
K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511
Acquired resistance, the primary focus of this article, reects a true

change in the genetic composition of a bacterium so that a drug that once
was eective is no longer active, resulting in clinical resistance. Sometimes
genetic change results in diminished activity, but not complete loss of drug
eectiveness.
The major strategies used by bacteria to avoid the actions of antimicrobial agents are outlined in Table 1. These include limiting the intracellular
concentration of the antimicrobial agent by decreased inux or increased
eux, or neutralization of the antimicrobial agent by enzymes that
reversibly or irreversibly inactivate the drug; alteration of the target so that
the agent no longer interferes with it; and elimination of the target
altogether by the creation of new metabolic pathways [1]. Bacteria may
use one or multiple mechanisms against a single agent or class of agents or
a single change may result in resistance to several dierent agents or even
multiple unrelated drug classes.
Gram-positive and gram-negative bacteria possess dierent structural
characteristics and these dierences can inuence the mechanisms for
primary resistance. The targets of most antimicrobial agents are located
either in the cell wall, cytoplasmic membrane, or within the cytoplasm. In
gram-negative bacteria, the outer membrane may provide an additional
Table 1
General mechanisms of resistance to antimicrobial agents
Resistance mechanism
Specic examples
Diminished intracellular drug concentration

Decreased outer
b-Lactams (eg, OmpF, OprD)
membrane permeability
Decreased cytoplasmic
Quinolones (eg, OmpF);
membrane transport
aminoglycosides
(decreased energy)
Increased eux
Tetracyclines; (eg, tetA);
quinolones (eg, norA);
macrolides (eg, mefA);
multiple drugs (eg, mexAB-OprF)
Drug inactivation
b-Lactams (b-lactamases);
(reversible or irreversible)
aminoglycosides (modifying
enzymes); chloramphenicol
(inactivating enzymes)
Target modication
Quinolones (gyrase modications);
rifampin (DNA polymerase
binding); b-lactams (penicillin
binding protein changes);
macrolides (rRNA methylation);
linezolid (23srRNA modications);
Target bypass
Glycopeptides (vanA, vanB);
trimethoprim (thymidine-decient
strains)
References
[3]
[1,4]
[3,289,290]
[1,4,162]
[6,7,83]
[8]
469
intrinsic barrier that prevents drugs from reaching these targets. Modications in outer membrane permeability by both alterations in porin protein
channels and by up-regulation of intrinsic multidrug eux pumps may
comprise a component of the mechanisms contributing to resistance in
many gram-negative organisms. In addition, inactivating enzymes released
across the cytoplasmic membrane can function more eciently within the
connes of the periplasmic space.
The mechanisms by which intracellular concentrations of drugs are
limited include decreased permeability through the outer membrane,
decreased uptake through the cytoplasmic membrane, and active eux
back out across the cytoplasmic membrane and the outer membrane.
Acquired outer membrane permeability changes in gram-negative organisms
previously attributed solely to alterations in outer membrane porin proteins
are now also understood to be related to the up-regulation of complex
multidrug eux pumps whose expression is linked to that of outer
membrane proteins, such as the MexAB-OprM system of Pseudomonas
aeruginosa [2,3]. These eux systems are widely distributed among gramnegative pathogens, such as P aeruginosa and Enterobacteriaceae, and may
be an important component of resistance to b-lactams, but usually result in
high-level resistance only when also associated with b-lactamase production
[2,3]. Imipenem resistance in P aeruginosa can be mediated by alteration of
a specic porin OprD that is used preferentially by this agent [2,3].
Decreased outer membrane permeability through porin changes and eux
also may play a role in resistance to uoroquinolones and aminoglycosides.
Resistance mediated by decreased uptake across the metabolically active
cytoplasmic membrane is best demonstrated by small-colony aminoglycoside-resistant mutants of staphylococci, but this mechanism is less important
than other mechanisms of aminoglycoside resistance [4]. Active antimicrobial eux systems play a role in resistance to many dierent agents,
including macrolides, tetracyclines, quinolones, chloramphenicol, and blactams.
Inactivating enzymes remain the predominant mechanism of resistance to
several major classes of antimicrobial agents. Resistance to b-lactams is
mediated by a wide variety of b-lactamases that hydrolytically inactivate these
drugs. b-Lactamases can be either plasmid or chromosomally mediated, and
their expression can be constitutive or induced. Unlike those of grampositives, b-lactamases of gram-negative organisms are conned to the
periplasmic space, which may explain some of the dierences in their
phenotypic expression and ease of laboratory detection. Of particular
importance in the hospital setting are the class I chromosomal b-lactamases
of organisms, such as Enterobacter cloacae, that are produced in high levels
after exposure to an inducing b-lactam agent (particularly to third-generation
cephalosporins), and the extended spectrum b-lactamases, mediating resistance to third-generation cephalosporins and aztreonam [5]. Another
major class of inactivating enzymes is the family of aminoglycoside-modifying
470
enzymes. These enzymes are widely distributed in both gram-positive and

gram-negative bacteria, and usually are plasmid-mediated [4]. Resistance to
chloramphenicol and macrolides also can be mediated by modifying or
inactivating enzymes [6].
Target modications are widely used by bacteria to develop resistance to
a wide variety of antimicrobial agents [7]. Some of these alterations may
require as little as a single mutational event at a critical gene sequence in the
primary target to create a new, functional target with reduced anity for the
antimicrobial agent. Such changes account for the relative ease of selection
of rifampin-resistant mutants of staphylococci and streptococci by changes
in DNA polymerase or the selection of high-level streptomycin-resistant
mutants with altered ribosomes. Although some target modications can be
directly selected, others, such as development of resistance to semisynthetic
penicillins in staphylococci, require acquisition of novel exogenous DNA.
Modication of PBP is the primary determinant of penicillin resistance in
Streptococcus pneumoniae, Neisseria meningitidis, and Enterococcus faecium.
Modication of the genes encoding DNA gyrases and topoisomerases is the
major mechanism of resistance to quinolones, and target modication is
important in resistance to macrolides, tetracyclines, rifampin, and mupirocin [7].
Some bacteria have gone beyond simple target modication and have
acquired novel systems in which the antimicrobial target is no longer
necessary for survival of the organism. This is achieved by creation of new
metabolic pathways to bypass the primary target. Perhaps the most
elaborate examples of this are the vanA and vanB clusters that mediate
resistance to glycopeptides in enterococci [8]. Target bypass also is the major
mechanism of acquired resistance to folate antagonists.
Mechanisms of dissemination of resistance genes

In addition to the complex strategies used to express resistance to
antimicrobial agents, bacteria also can avail themselves of a variety of
ecient mechanisms for the transfer of resistance genes to other organisms
and to other species [6,9,10]. The bacterial genome consists of chromosomal
DNA, which encodes for general cellular characteristics and metabolic and
repair pathways, and smaller circular DNA elements or plasmids that may
encode for supplemental bacterial activities, such as virulence factors and
resistance genes, and for genes essential to the independent mobilization and
transmission of the plasmid elements. Most resistance genes are plasmidmediated, but plasmid-mediated traits can interchange with chromosomal
elements. Transfer of genetic material from a plasmid to the chromosome
can occur by simple recombinational events, but the process is greatly
facilitated by means of transposons. Transposons are small, mobile DNA
elements capable of mediating transfer of DNA by removing and inserting
471
themselves into host chromosomal and plasmid DNA. Many resistance

genes, such as plasmid-mediated b-lactamases, tetracycline-resistance genes,
and aminoglycoside-modifying enzymes, are organized on transposons,
which may have a broader host range than their parent plasmids. Multiple
resistance transposons can then be clustered together on even larger
composite transposable elements capable of simultaneously transferring
multiple unrelated resistance genes [10].
Resistance determinants carried on the chromosome are transmitted
vertically by clonal dissemination. Resistance determinants on plasmids can
also be transferred vertically, although plasmids may be lost from the
bacterial population if they no longer confer a particular selective
advantage. Plasmids also are capable of horizontal transfer by conjugation,
although the eciency of plasmid transfer both within and between species
can vary tremendously. Plasmid transfer between gram-positive and gramnegative bacteria, once thought to be an unlikely event, can occur both in
the laboratory and in the gastrointestinal tract of gnotobiotic mice,
suggesting that such transfer events between even distantly related organisms may be important in nature [9].
Conjugative transposons of gram-positive bacteria are capable of directly
mediating gene transfer without plasmids. Transformation, direct incorporation of free DNA by bacterial cells, may also be important for the
evolution of resistance in Neisseria and streptococcal species [7,10].
Specic pathogens
Resistant gram-positive cocci
Multidrug-resistant enterococci
Enterococcus spp is the third most common organism associated with
hospital-acquired infection [11]. Enterococci are common causes of nosocomial urinary tract infections, surgical site infections, and bloodstream
infections [12]. Enterococcus faecalis, and the more penicillin-resistant E
faecium, are the two major enterococcal pathogens.
Enterococci are a normal part of human gastrointestinal ora (up to 107
organisms per gram of stool) [13]. These organisms are hardy and survive on
the hands of hospital personnel and on fomites in the hospital environment.
Resistant strains may become established and persist as part of a patients or
health care workers gastrointestinal ora. Fecal concentrations of enterococci may increase in those given antibiotics active against intestinal ora
other than enterococci [14,15].
Enterococci are naturally tolerant to penicillins, and resistant to
cephalosporins, clindamycin, and achievable serum levels of aminoglycosides. Cephalosporin resistance is caused by poor anity of cephalosporins
for enterococcal PBPs. Natural low-level aminoglycoside resistance is
attributed to the inability of aminoglycosides to penetrate the enterococcal
472
cell wall, but activity is enhanced in the presence of cell wallactive drugs,
such as ampicillin or vancomycin [16]. Enterococci are usually intrinsically
tolerant, or lysis resistant, to the eects of penicillins and glycopeptides
alone. Until the emergence of drug-resistant isolates, bactericidal therapy
was reliably achieved with synergistic combinations of cell wallactive drugs
plus aminoglycosides.
Enterococci demonstrate several types of penicillin resistance. Penicillin
resistance in E faecalis is mediated by b-lactamase production and has been
reported from a few nosocomial outbreaks both within and outside of the
United States [17,18], but infections with such strains are still very
uncommon. Chromosomal high-level penicillin resistance is a speciesspecic characteristic of E faecium, but is occasionally found in other
species [19,20]. Low-level penicillin-resistant E faecium are found in normal
fecal ora, but high-level resistant strains are likely to be nosocomially
acquired [21]. Ampicillin resistance to an intermediate level (mean inhibitory
concentration [MICs] of 1664 lg/mL) seems to be attributable to
alterations in PBPs, and in most cases is associated with the overexpression
of PBP5, a PBP with low anity for penicillins [22]. High-level penicillinresistant E faecium are also resistant to imipenem and b-lactamb-lactamase
inhibitors and are often glycopeptide-resistant [23,24].
High-level gentamicin resistance, mediated by a bifunctional inactivating
enzyme, rst appeared in 1978 and rapidly spread worldwide. As many as
60% of enterococci from some hospitals are high-level gentamicin-resistant,
but resistance remains strongly associated with nosocomial acquisition [25].
High-level gentamicin-resistant enterococci are highly resistant to all other
aminoglycosides in clinical use in the United States, with the possible exception of streptomycin. Importantly, highly resistant strains do not demonstrate synergistic killing of enterococci when aminoglycosides are combined
with penicillin or vancomycin [26]. Most high-level gentamicin resistance is
carried on transposons and is plasmid mediated [26]. Detection of high-level
gentamicin resistance requires either special susceptibility wells or screening
plates with high concentrations of gentamicin or streptomycin (eg, 500 lg/
mL). This topic is discussed in more detail elsewhere in this issue.
Vancomycin-resistant enterococci (VRE) have signicantly increased
over the past several years [11]. VRE are established throughout the United
States and Europe, but are less frequently isolated in Asia and Latin
America [27]. The prevalence of VRE remains low in true communityacquired isolates in the United States, but is notably higher in Europe. VRE
have been isolated from sewage and various animal sources in Europe, and
in one study from the feces of 12% of nonhospitalized individuals [28,29].
The previous use of glycopeptide-containing animal feed may explain the
increased prevalence in some European communities. The increase in
glycopeptide resistance in the United States followed the marked increase
in vancomycin usage in many hospitals, as methicillin-resistant Staphylo-
473
coccus aureus (MRSA) strains became established in the 1980s. Most VRE
seem to have been acquired nosocomially or institutionally, and spread of
epidemic strains both within and between institutions is well documented
[30]. From 1989 to 2002, the proportion of enterococcal isolates from ICUs
that were resistant to vancomycin increased from 0.3% in 1989 to 23.9% in
1998, and further increased to 27.5% in 2002 [11]. Some risk factors for
VRE colonization or infection include the exposure to antibiotics, such as
broad-spectrum cephalosporins, uoroquinolones, vancomycin, and antianaerobic drugs; longer length of hospital and ICU stays; intrahospital
transfer between patient oors; use of enteral tube feedings or sucralfate;
and liver transplant requiring surgical re-exploration [31,32].
Glycopeptides are large, complex molecules that do not enter the
bacterial cell. They interfere with cell wall synthesis by tightly binding to
the D-alalanineD-alanine terminal dipeptide on the peptidoglycan precursor, sterically blocking the subsequent transglycosylation and transpeptidation reactions. The vancomycin-resistance mechanisms involve
a complex series of reactions that ultimately result in the building of the
cell wall by bypassing the D-alanineD-alaninecontaining pentapeptide
intermediate structure, thereby eliminating the glycopeptide target [33].
Vancomycin-resistant enterococci initially were characterized phenotypically as vanA, vanB, and vanC strains based on levels of resistance to
vancomycin, cross-resistance to teicoplanin, and the inducible or constitutive nature of resistance [34]. The genotype and molecular basis for each
resistance type have now been characterized (Table 2). The vanA cluster has
been identied predominantly in E faecium and E faecalis but has also been
found in other enterococci, streptococci, Oerskovia, and Bacillus, and most
recently has been found in S aureus [3539], and there is evidence for in vivo
Table 2
Glycopeptide-resistant enterococci
Genotype
Vancomycin
MIC (lg/mL)
Teicoplanin
MIC (lg/mL)
vanA
vanB
vanCe
641024
41024
232
16
1b
1
vanD
64256
432
vanE
vanG
16
16
0.5
0.5
a
b
c
d
e
f
Expression
Inducible
Induciblec
Constitutive
and inducible
Constitutive
and induciblef
Inducible
Inducible
Strains with vanA on the chromosome have been described.

Teicoplanin-resistant strains have emerged with MIC 16.
Constitutively expressing strains have been described.
Plasmids containing vanB have been described.
Species-specic variants vanC-1, vanC-2, and vanC-3 have been described.
Both have been described.
Typical
location
Plasmida
Chromosomed
Chromosome
Chromosome
Chromosome
Chromosome
474
transfer of vanA resistance plasmids [40,41]. vanB is found almost exclusively in E faecium and E faecalis. vanC1, C2, C3, D, E, and G are rarely
found in enterococci causing human infection [4244].
Resistance to linezolid has recently been reported [45] and is mediated by
the G2576U or similar mutations of the 23S ribosome [46].
Management of infections caused by resistant enterococci. b-Lactamaseproducing E faecalis strains can still be treated with either imipenem or with
b-lactam-b-lactamase inhibitor combinations [17]. Ampicillin-resistant E
faecium strains are generally resistant to all penicillins and imipenem. For
strains with MICs of up to 64 lg/mL, theoretically very high doses of
ampicillin or amoxicillin can be used depending on the site of infection. For
serious infections caused by ampicillin-resistant E faecium, however,
vancomycin is the agent of choice, provided that the strain is not also
vancomycin-resistant.
The major implication of high-level aminoglycoside resistance to both
gentamicin and streptomycin is the inability to achieve bactericidal therapy,
which is a major issue in the treatment of endocarditis. Approximately 40%
of patients are cured using a cell wallactive agent alone, whereas cure rates
are as high as 70% to 80% when a bactericidal combination can be used
[47]. In animal models, some studies have demonstrated a benet of
continuous-infusion ampicillin therapy [47]. When bactericidal therapy
cannot be achieved, valve replacement may become necessary for cure.
Teicoplanin monotherapy seems to be more active in animal models than
vancomycin monotherapy, but this agent is not available in the United
States [47]. Need for bactericidal therapy is less clear for infections other
than endocarditis. Aminoglycoside therapy should be discontinued when
high-level resistance is identied.
Vancomycin-resistant enterococci currently pose the greatest clinical
challenge. Most strains of vancomycin-resistant E faecalis retain susceptibility to ampicillin and penicillin, and these agents can still be used for
therapy. Vancomycin-resistant E faecium isolates are usually highly resistant
to ampicillin and may also have high-level aminoglycoside resistance. The
combination of penicillin plus vancomycin plus gentamicin has been
investigated [48]. Teicoplanin has been used to treat infections caused by
vanB strains, but resistance has been noted [49].
Linezolid, an antimicrobial agent in the oxazolidinone class, quinupristin-dalfopristin, a parenteral streptogramin combination antibiotic (both
approved by the Food and Drug Administration in 2000), and daptomycin, a novel lipopeptide (approved in 2003), have activity against enterococci. Linezolid has excellent in vitro activity against E faecium and E
faecalis and has been eective in treating infections caused by VRE [50].
Quinupristin-dalfopristin demonstrates bacteriostatic activity against most
vancomycin-resistant E faecium but has no activity against E faecalis [51].
Daptomycin has excellent in vitro activity against vancomycin-susceptible
475
and vancomycin-resistant E faecium and E faecalis [52]. This topic is

discussed in more detail elsewhere in this issue.
Other potentially useful agents in the treatment of infections caused by
VRE include the tetracyclines, chloramphenicol, newer uoroquinolones,
and rifampin. Many strains are susceptible to chloramphenicol and some
tetracycline-resistant strains may remain susceptible to minocycline [53,54].
A number of antimicrobial drug combinations have been studied in animal
models, such as b-lactamb-lactam, b-lactamglycopeptide, and b-lactam
uoroquinolone regimens, but limitations exist for each combination [48].
Promising therapeutic agents that are under development or are being tested
in clinical trials include evernimicin (SCH 27899, an oligosaccharide) [55];
newer glycopeptides, such as oritavancin (LY333328) [56] and dalbavancin
(BI397) [57]; and tigecycline, a glycylcycline agent [58].
Of critical importance in the management of VRE is strict adherence to
infection control measures to limit the spread of these isolates in the hospital
setting [59]. These issues are addressed in the Centers for Disease Control
and Prevention (CDC) guidelines for preventing the spread of vancomycin
resistance and consist of education; prompt laboratory detection and
reporting; appropriate isolation and screening for colonized contacts; and
most importantly, restriction of vancomycin use [60].
Multidrug-resistant Staphylococcus aureus
Since 1996, there have been several reports of infections caused by
MRSA with intermediate susceptibility (MIC 816 lg/mL) to vancomycin
(vancomycin intermediate susceptibility S aureus [VISA]) [61]. There are
now three reports of unique S aureus strains in the United States fully
resistant (MIC > 16 lg/mL) to vancomycin (vancomycin-resistant S aureus
[VRSA]) [39,62,291]. Because S aureus is one of the most common causes of
community-acquired and nosocomial infections in the world [63] and
because most MRSA also are resistant to multiple other agents, the
evolution and dissemination of glycopeptide resistance in S aureus is
extremely troublesome. In addition, the spread of MRSA from nosocomial
to health careassociated settings [64] and the emergence of communityacquired MRSA [65] are concerning developments.
Epidemiology and characteristics of resistance. Staphylococcus aureus is the
most common pathogen isolated from nosocomial infection sites in the
United States and is the most commonly isolated organism from hospitalacquired pneumonia, surgical site infections, and nosocomial infection sites
overall (18%, 20%, and 19%, respectively) [12]. S aureus is also a frequent
cause of bloodstream infections, skin and soft tissue infections, catheterassociated infections, and endocarditis [66,67]. The percentage of S aureus
isolates resistant to methicillin in American ICUs has increased from 30%
to 40% in the mid-1990s to 57.1% in 2002 [11,68]. Traditionally, MRSA has
been a nosocomial pathogen. MRSA has now been identied, however, as
476
an important pathogen among patients in the outpatient setting who are at

increased risk of staphylococcal colonization and also among patients who
have direct or even indirect exposure to a hospital environment (ie, health
care-associated MRSA) [64,69]. The occurrence of true community-acquired
MRSA infections in otherwise healthy individuals without risk factors is
increasing in incidence in many areas, particularly in pediatric populations
[65].
Methicillin-resistant S aureus has been implicated relatively frequently in
hospital outbreaks [70]. Risk factors for nosocomial bacteremia caused by
MRSA are the presence of severe, systemic diseases; presence of indwelling
central venous catheters; increased length of stay in the hospital; and prior
antimicrobial exposure [7173]. Risk factors for health care-associated
bacteremia caused by MRSA include recent hospitalization or receipt of
antimicrobial agents, presence of an indwelling urinary catheter, and
residence in a nursing home [74].
Methicillin resistance in staphylococci is most commonly mediated by the
mecA gene, which encodes for a single additional PBP, PBP2a, with low
anity for all b-lactams [1,7]. This mechanism accounts for methicillin
resistance in over 98% of resistant isolates [75]. Strains with mecA-mediated
methicillin resistance are classically referred to as MRSA. The mecA gene is
widely distributed in both coagulase-positive and coagulase-negative staphylococci, is carried on a transposon, and seems to integrate into a single site in
the staphylococcal chromosome along with an additional 30 kilobase of
DNA, the mec locus [76]. In most strains, this includes a regulatory locus,
mecR1-mecl, and may include additional insertion elements that are potential
integration sites for unrelated resistance determinants. Expression of mecA
can be either constitutive or inducible. Expression of resistance also depends,
in part, on other chromosomal genes, which are part of cellular peptidoglycan
metabolism and can regulate the degree of resistance without altering levels of
PBP2a. This process is reviewed in detail elsewhere [77]. Interestingly,
compared with nosocomial stains, community strains of MRSA have distinct,
smaller mecA loci and possess unique exotoxin gene proles [65].
Independent risk factors for infections caused by VISA include prior
infection caused by MRSA and antecedent vancomycin use within 3 months
before VISA infection [78]. Most patients in the United States with VISA
infections received repeated, prolonged exposures to vancomycin and received
dialysis at the time of infection [78]. The mechanisms conferring glycopeptide
resistance in VISA seem to involve cell wall thickening with reduced levels of
peptidoglycan cross-linking and do not seem to require the acquisition of new
DNA. It is postulated that reduced levels of peptidoglycan cross-linking lead
to an increase in the presence of free D-alanylD-alanine side chains. These
side chains can bind vancomycin outside the cell membrane and prevent
vancomycin from reaching its cell membrane targets [79,80].
There have been three reports of clinical isolates of VRSA [39,62,291]. In
these isolates, vancomycin resistance was conferred by the vanA resistance
477
cluster, which also mediates glycopeptide resistance in some enterococcal

species [41]. Before isolation of VRSA, co-infection with MRSA and VRE
was documented in one patient, suggesting that the vanA gene was
transferred from the VRE strain to the MRSA isolate, as has occurred in
vitro [39,41].
Methicillin-resistant S aureus isolates containing mecA are resistant to all
b-lactam antibiotics. Most nosocomial and health careassociated isolates
frequently carry multiple other resistance determinants. Many of these
resistance determinants are clustered on transferable chromosomal elements
or plasmids, whereas others are chromosomal in origin [81]. The plasmidmediated traits include aminoglycoside-modifying enzymes, tetracycline
eux genes, and macrolide-methylating enzymes, and resistance determinants for trimethoprim-sulfamethoxazole. Quinolone resistance is mediated
primarily by alterations in DNA topoisomerases, but also by the staphylococcal norA gene by way of active eux [7,82]. Resistance to macrolide,
lincosamide, and streptogramin antibiotics may be conferred by modications of target sites, active eux, and by inactivating enzymes [67,75].
Gentamicin resistance also can occur by selection of small-colony, membrane energy-decient mutants. Linezolid resistance occurs by modication
of the 23s ribosome of S aureus [83]. In contrast to nosocomial isolates, most
community-acquired MRSA strains are susceptible to multiple classes of
antibiotics other than b-lactams, including trimethoprim-sulfamethoxazole,
clindamycin, aminoglycosides, tetracyclines, and uoroquinolones [65].
Management of infections caused by multidrug-resistant Staphylococcus
aureus. The major reservoir for MRSA in most colonized patients is the
nares. Unlike VRE, there is evidence to suggest that colonization can be
eradicated from a signicant proportion of carriers [84]. Several treatment
regimens have been used, including topical, oral, and combined topical and
oral regimens. In studies with long-term follow-up, relapse rates are high,
particularly in patients who have chronically colonized sites in addition to
the nares. The major topical agents used include bacitracin and mupirocin.
Mupirocin has eliminated nasal and hand colonization in both hospital
personnel and colonized patients in long-term care facilities and dialysis
units, and has been used in the preoperative setting to prevent surgical site
infections caused by S aureus, but increased resistance to this agent is now
being seen [85], and a recent controlled trial showed no eect of mupirocin
on the prevention of nosocomial S aureus infections [292].
For treatment of community-acquired MRSA infections, clindamycin is
often eective, but should be restricted to erythromycin-susceptible isolates
(ie, to those strains with macrolide resistance mediated by eux and not by
methylating enzymes) [8688]. Other options include trimethoprim-sulfamethoxazole, uoroquinolones, tetracycline, and linezolid [86,87]. Vancomycin is also an option, but this must be given by the intravenous route,
which complicates outpatient therapy.
478
The current treatment of choice for nosocomial and health care

associated MRSA infections is intravenous vancomycin. Vancomycin is
a less active antistaphylococcal agent than a b-lactam against methicillinsusceptible strains. This may account for the relatively slow response of
some MRSA infections to treatment [89]. Gentamicin is synergistic with
vancomycin in vitro against many MRSA strains; this combination has been
used for bacteremia and endovascular infections. Rifampin plus vancomycin
may be either additive or antagonistic in vitro. This combination may be
particularly useful in the cerebrospinal uid (CSF) and with infection of
foreign bodies. Rifampin resistance emerges quickly when the drug is used
alone [7]. Clindamycin, trimethoprim-sulfamethoxazole, and uroquinolones (the latter often in combination with rifampin) have been used for
MRSA infections caused by susceptible strains [90]. Resistance to older
quinolones is now common among MRSA, occurring in as many as 90% of
isolates in some hospitals [91]. Quinolone regimens, particularly when used
as a single agent, should be used with caution because resistance can emerge
during therapy. Many strains are tetracycline susceptible, but the use of
most tetracyclines is limited by the emergence of resistance during therapy.
Minocycline has excellent in vitro activity, even against tetracycline-resistant
MRSA isolates, and has been used extensively in Japan for MRSA
infections, including endocarditis [92]; however, increasing resistance to
minocycline in MRSA has been described. Fusidic acid, which is not
available in the United States, also has some activity against MRSA when
used in combination with other drugs [84].
For the treatment of infections caused by VISA and VRSA, most strains
remain susceptible to some older agents, doxycycline, minocycline, rifampin,
and trimethoprim-sulfamethoxazole [62,78]. For treatment of infections
caused by VISA, vancomycin may still be an option, particularly if used in
combination with another active agent, such as rifampin or an aminoglycoside, but treatment failures can still occur. Because teicoplanin is intrinsically less active against S aureus than vancomycin, it is unlikely to
be eective in treatment of VISA or VRSA [93,94]. Other combination
treatment regimens for MRSA and VISA infection that have been used
successfully with only limited clinical experience or have demonstrated in
vitro or in vivo synergy include ampicillin-sulbactam and arbekacin [95],
and vancomycin and other b-lactam antibiotics [96,97]. There is no clinical
experience in humans, however, with these combinations for the treatment
of VISA infections.
Linezolid has good in vitro activity against both methicillin-susceptible
and methicillin-resistant S aureus strains [52,98]. Linezolid has been shown
to be eective in the treatment of skin and soft tissue infection and
nosocomial pneumonia caused by MRSA. Quinupristin-dalfopristin has
excellent activity against S aureus [52,98]. The combination of vancomycin
and quinupristin-dalfopristin has been reported to be eective in the
treatment of patients who failed therapy with vancomycin alone [99]. Other
479
therapeutic agents with which there is limited clinical experience include

daptomycin, a recently approved agent that has excellent bactericidal
activity against multidrug-resistant S aureus [52,98]; some of the newer
uoroquinolones, such as gemioxacin, moxioxacin, and trovaoxacin
[100102]; and agents under development including evernimicin (SCH
27,899), an oligosaccharide [103], novel glycopeptides including oritavancin
(LY333328) and dalbavancin (BI397) [57,104], and agents belonging to the
glycylcycline antimicrobial drug class [105]. Novel cephalosporins active
even against staphylococci carrying the mecA gene are also entering clinical
trials.
The CDC has published guidelines regarding the prevention and control
of infections caused by VISA and VRSA [106]. These guidelines focus on the
judicious use of vancomycin, the use of eective laboratory screening
methods, and obtaining investigational antimicrobial drugs when clinically
appropriate.
Penicillin and multidrug-resistant pneumococci
Infections caused by S pneumoniae are a major cause of morbidity and
mortality worldwide. In the United States, pneumococcal disease accounts
for approximately 3000 cases of meningitis, 500,000 cases of pneumonia,
and 7 million cases of otitis media yearly [107]. The incidence of invasive
pneumococcal disease was 23.2 cases per 100,000 in the United States in
1998 [108]. Penicillin-resistant pneumococci from sites other than CSF are
either intermediately resistant, with MICs of 1 to 2 lg/mL, or highly resistant, with MICs of 4 lg/mL or greater; breakpoints for isolates from the
CSF are one dilution lower (CSF breakpoints: susceptible 0.5 lg/mL, intermediate 1 lg/mL, resistant 2 lg/mL).
Epidemiology and characteristics of resistance. In a recent study, 34.2% of
pneumococci isolated in the United States were not fully susceptible to
penicillin, and 21.5% of isolates had high-level resistance [109]. High rates
of resistance have been reported in other countries [110]. Interestingly, most
resistant isolates worldwide belong to a limited number of serotypes. In
a recent study of American isolates, 89% of resistant strains were serotypes
6B, 23F, 14, 9V, or 19F [111].
Molecular analyses have demonstrated clonal dissemination of resistant
isolates worldwide. These observations support in vitro data characterizing
penicillin resistance as being stable, and having the ability to persist and
spread in the absence of antibiotic selective pressure. Molecular studies also
suggest that resistant isolates arose independently. Together, these observations suggest that low-level penicillin resistance probably evolved independently under selective antibiotic pressure in a limited number of
pneumococcal serotypes, and subsequent evolution to high-level resistance
may have occurred by recombination events. Well-adapted, high-level
resistant strains probably disseminated widely by clonal spread. Risk factors
480
for the acquisition of penicillin-resistant strains include prior hospitalization

and other institutionalization, increased length of hospital stay, attendance
in child care centers, frequent otitis media infections, having had a recent
episode of pneumonia, and prior antibiotic exposure [112114].
Penicillin-resistance in S pneumoniae is caused by changes in the genes
that encode for the ve high-molecular-weight PBPs of the organism
[112,115]. These changes result in PBPs with reduced anity for b-lactam
agents. PBP proles of the most highly resistant strains generally show more
PBP alterations than do those of low-level resistant strains [115]. In addition
to clonal dissemination of resistant strains, resistance can spread by
homologous recombinational events among PBP genes of dierent strains
[7]. Such events can occur between dierent pneumococcal species and
between pneumococci and closely related viridans streptococcal species.
Oral streptococci have been postulated to be the major reservoir for the
novel DNA required to create the genetic sequences demonstrated by some
of the altered pneumococcal PBP genes [7]. Along with altered PBP,
penicillin-resistant pneumococci also demonstrate altered peptidoglycan
structures. Penicillin tolerance may be found in strains with reduced
penicillin susceptibility that fail to lyse at penicillin concentrations far
above the MIC; however, the clinical signicance of this observation
remains unclear [116].
The PBP changes in penicillin-resistant strains also result in diminished
susceptibility to other b-lactam agents [117], but the levels of resistance to
dierent agents vary greatly. Penicillin-resistant strains are uniformly
resistant to penicillin derivatives, such as ampicillin and the ureidopenicillins
(eg, amoxicillin, ampicillin, piperacillin, and ticarcillin), and generally are
resistant to rst- and second-generation cephalosporins. Certain thirdgeneration agents, particularly cefotaxime and ceftriaxone, are often
eective, in part because of their high level of activity and in part because
the tissue levels attained by these agents are high [118,119]. A source of
concern is the observation that strains resistant to high concentrations of
cefotaxime and ceftriaxone (MIC 2 lg/mL) are becoming increasingly
common (14.4% of all strains reported in one recent study were ceftriaxoneresistant) [109]. Infections caused by these resistant strains have been
associated with clinical failure, particularly in cases of pneumococcal
meningitis [118].
Penicillin-resistant strains are frequently also resistant to other nonblactam antimicrobial agents and are often multidrug resistant. Resistance to
erythromycin, tetracycline, trimethoprim-sulfamethoxazole, and chloramphenicol is most common [109]. Macrolide resistance in S pneumoniae is
most commonly caused by either ribosomal methylation (ermA, ermB)
resulting in inducible cross-resistance to lincomycins and streptogramins
(macrolide, lincosamide, and streptogramin b phenotype) or to eux pumps
(mefA, mefE) resulting in variable-level resistance to macrolides alone (M
phenotype). The increase in macrolide resistance from 10.6% to 20.4%
481
among invasive isolates in the United States from 1995 to 1999 was almost
entirely caused by an increase in M phenotype strains [120]. The clinical
implications of M-type resistance for use of newer macrolides and azalides
remains controversial, but these isolates can be treated with clindamycin
[121]. Chloramphenicol and rifampin resistance is common in South African
isolates, but rare in the United States [110,118]. Although vancomycintolerant pneumococcal isolates have recently been isolated [122], no strains
fully resistant to vancomycin have been reported. Although the older
uoroquinolones (eg, ciprooxacin) lack reliable activity against pneumococci, newer uoroquinolones, such as levooxacin, gatioxacin, moxioxacin, gemioxacin, and garenoxacin, inhibit most strains at achievable levels
[123].
Fluoroquinolone resistance has developed during therapy, especially in
patients with prior uoroquinolone exposures, leading to clinical failure
[124]. Resistance to the newer formulations in the United States, however,
remains uncommon (\1%) [123]. The mechanism of decreased susceptibility to the newer uoroquinolones is primarily caused by mutations in the
parC gene of topoisomerase IV and the gyrA gene of DNA gyrase [125].
Management of infections caused by penicillin-resistant pneumococci. No
evidence indicates that penicillin-resistant strains are more virulent than
other pneumococcal isolates, but the outcome of serious infections caused
by resistant strains may be worse because of delays in initiation of eective
treatment [118,126].
The most challenging management issues concern the treatment of
meningitis caused by resistant pneumococci. Although third-generation
cephalosporins are active against many intermediately and highly penicillinresistant strains, treatment failures have been reported in patients with
isolates having MICs to ceftriaxone or cefotaxime of 2 lg/mL [126].
Vancomycin, the preferred agent in the treatment of meningitis caused by
cephalosporin-resistant pneumococci, remains active against all pneumococcal isolates, but penetration into the CSF is unreliable. In one uncontrolled series, 4 of 11 patients failed to improve on vancomycin
monotherapy [127]. The combination of vancomycin plus ceftriaxone is
often used as empiric therapy until the results of susceptibility tests are
known. Interestingly, in animal models, in the absence of steroids, the
combination of vancomycin and ceftriaxone appeared more eective than
either agent alone [128], raising the possibility that the combination might
be eective treatment for patients with penicillin-resistant pneumococcal
meningitis; however, supporting clinical data are sparse [129].
Rifampin should never be used alone to treat pneumococcal meningitis,
but if the infecting organism is highly resistant to ceftriaxone and cefotaxime
but is rifampin susceptible, combination therapy with vancomycin plus
rifampin might be eective [128]. In these circumstances, vancomycin levels
should be maximized to ensure adequate central nervous system penetration.
482
Carbapenems traditionally have had excellent in vitro activity against

most pneumococci [130]. Imipenem has been used successfully for resistant
pneumococcal meningitis, but this agent has a relatively high incidence of
inducing seizures, particularly in the presence of other brain abnormalities
[130]. Meropenem has a lower incidence of seizure induction but clinical
experience is limited [131]. Among isolates with decreased susceptibility to
penicillin, carbapenems may have reduced activity, potentially limiting their
therapeutic role [132,133]. Another treatment option is chloramphenicol,
but treatment failures have been described [134].
Steroid therapy can reduce antimicrobial penetration into the CSF by
decreasing inammation. In animal models, steroid therapy has been
associated with failure of cephalosporin or vancomycin monotherapy. The
combination of ceftriaxone and rifampin remained eective, however, even
when given concomitantly with steroids [118]. In addition, a recent trial
demonstrated that dexamethasone decreased mortality in adults with acute
bacterial meningitis [135]. All patients with resistant pneumococcal meningitis should undergo early repeat lumbar puncture to document sterilization
of the CSF.
For pneumonia, bacteremia, and other invasive nonmeningeal infections
there are several therapeutic options including penicillins and cephalosporins. Blood and tissue levels of these b-lactams are much higher than those
achieved in the CSF. In series of patients with community-acquired
pneumococcal infections, overall response rates for patients with susceptible
and penicillin-resistant isolates were identical, even when penicillin or
ampicillin was used [118]. The breakpoints for susceptibility to thirdgeneration cephalosporins for nonmeningeal sites are higher than those for
CSF isolates. Vancomycin may be considered for highly resistant organisms,
unless the infecting organism is susceptible to third-generation cephalosporins, in which case the cephalosporins are preferred. The newer uoroquinolones (eg, levooxacin, moxioxacin, gatioxacin, and gemioxacin), and
for susceptible strains, the macrolides, tetracycline, clindamycin, chloramphenicol, and trimethoprim-sulfamethoxazole, are acceptable alternatives
for treating infections outside the CSF [118,136]. Telithromycin, a ketolide
antimicrobial agent recently approved for the treatment of respiratory
infections, has good in vitro activity against pneumococcal isolates with
reduced susceptibility to penicillin [109]. Telithromycin has reduced activity,
however, among strains of pneumococci that exhibit high rates of macrolide
resistance [137]. Guidelines for the treatment of community-acquired
pneumonia, including bacteremic pneumococcal pneumonia, were recently
published [136].
One other important clinical dilemma is the eective treatment of otitis
media caused by resistant pneumococci. Initial therapy frequently is empiric
and the antibiotic administered should have activity against Haemophilus
inuenzae. The CDC consensus group recommends amoxicillin in doses of
8090 mg/kg/d as the agent of choice for otitis media in children [138]. These
483
doses result in middle ear levels that inhibit resistant pneumococci. Amoxicillin-clavulanic acid may also be used. This agent may be given using the usual
dose (eg, 40 mg/kg/d) but an additional dose of amoxicillin (40 mg/kg/d)
should be added. Alternatively, the reformulated version of amoxicillinclavulanic acid (Augmentin ES-600) that contains additional amoxicillin can
be given in divided doses of 90 mg/kg/d (based on the amoxicillin component).
Linezolid, quinupristin-dalfopristin, and daptomycin are emerging as
treatment options, but clinical experience is limited [52,139]. Evernimicin (a
novel oligosaccharide) [140] also had good activity in vitro against resistant
S pneumoniae.
To limit the dissemination of resistant pneumococcal strains, health care
professionals should adhere to the CDC recommendations regarding
administration of the pneumococcal polysaccharide and protein-polysaccharide conjugate vaccines [107,141,142].
Resistant gram-negative microorganisms
Escherichia coli and Klebsiella spp resistant to broad-spectrum
cephalosporins
Escherichia coli and Klebsiella are common hospital pathogens. E coli is
the most common gram-negative pathogen associated with nosocomial
infections and is the most common organism isolated in cases of hospitalacquired urinary tract infections (representing 12% and 24% of pathogens
isolated from infection sites, respectively) [12]. Klebsiella pneumoniae is also
common, representing 5% of nosocomial infection site isolates and 8% of
hospital-acquired urinary tract infections and pneumonia isolates [12].
Resistance of these organisms to broad-spectrum cephalosporins is largely
mediated by extended-spectrum b-lactamases (ESBLs), designated BushJacoby-Medeiros group 2be. These enzymes confer resistance to oxyiminob-lactam antibiotics. Most ESBLs are derivatives of TEM and SHV, which
have undergone amino acid substitutions at the active site of the enzyme.
These enzymes are often plasmid-borne. Depending on the location of the
substitution, susceptibility of cefotaxime, ceftazidime, and aztreonam to the
b-lactamase can be variably diminished. ESBLs are most commonly
expressed in K pneumoniae, Klebsiella oxytoca, and E coli, although they
have been detected in other organisms including Salmonella spp, P
aeruginosa, Proteus mirabilis, and other Enterobacteriaceae [143147].
Plasmids producing ESBLs often carry resistance to other antibiotics. The
role of ESBLs in hospital and nursing home outbreaks, and their ability to
be transferred to other bacterial species by transfer of plasmid DNA, makes
eective control and treatment of ESBLs a growing challenge.
Epidemiology and mechanisms of resistance. Extended-spectrum b-lactamases were rst discovered in Europe in 1983 and soon after in the United
States. Since then their prevalence has increased. By 1990, 14% of all
484
K pneumoniae isolated from French hospitals were ESBL producers, with

rates approaching 50% in some hospitals [148]. In some American hospitals
the rate is as high as 40% [149]. As reported by the CDC, in 2002, the rate of
ceftazidime-resistant K pneumoniae reached 14%, and ceftazidime-resistant
E coli reached 6.3% in American ICUs [11]. Teaching hospitals have a higher
prevalence of resistance [150].
Extended-spectrum b-lactamasesproducing organisms are generally
nosocomial, although nursing home outbreaks have been reported [151].
Outbreaks can occur through either clonal spread of a specic plasmidcarrying strain, or through transfer of a particular plasmid to a variety of
bacterial strains, or even to dierent bacterial genera [151,152]. Resistant
organisms can pass from patient to patient on the hands of health care
providers [153]. Risk factors for acquisition of ESBLs are generally similar
to those reported for other hospital-acquired organisms and include
emergency abdominal surgery, mechanical ventilation, the presence of
percutaneous devices, tracheostomy, longer length of hospital stay, and
increased patient morbidity [150,151,154]. Of particular interest are those
risk factors associated with antimicrobial drugs. Exposure to antibiotics in
general, and particularly to ceftazidime and aztreonam, has been associated
with an increased prevalence of ESBL-producing organisms [155,156]. Other
studies, however, have found no association between third-generation
cephalosporin use and ESBL emergence [151,157]. Exposure to trimethoprim-sulfamethoxazole has also been associated with acquisition of ESBLs
[151]. Restriction of cephalosporin use has been associated with control of
hospital outbreaks [158,159].
More than 70 ESBLs have been described, with greater than 100 in the
TEM class, over 40 in the SHV family, over 30 in the CTX-M class, and 15
in the OXA family. A website maintains an up-to-date, complete listing of
all identied ESBLs: http://www.lahey.org/studies/inc_webt.asp [160]. Each
ESBL has unique amino acid substitutions at active sites of the enzyme,
aecting its isoelectric point and aecting the enzymes anity for and
hydrolytic activity of oxyimino-b-lactams [150]. Dierent substitutions have
variable eects on the activities of the b-lactamases. Most ESBLs have
increased activity against ceftazidime and aztreonam and diminished
activity against cefotaxime, although the opposite may be true in some
cases. For example, in SHV and TEM b-lactamases, a serine substitution for
glycine at amino acid 238 causes decreased hydrolytic activity against
ceftazidime but increases activity against cefotaxime [150]. CTX-Mtype
ESBLs, however, generally have more activity against cefotaxime than
ceftazidime [161]. Multiple b-lactamases conferring resistance to dierent
classes of b-lactam antibiotics can be found within a single bacterial strain.
The diversity of cephalosporin susceptibility proles manifested by dierent
ESBL enzymes makes detection of some ESBL-producing strains a major
challenge for the clinical laboratory. These enzymes are not capable of
hydrolyzing cephamycins and carbapenems [162].
485
Another mechanism facilitating b-lactamase activity involves loss of

porin channels in the outer cellular membrane and up-regulation of eux
pumps, decreasing antibiotic concentrations in the periplasmic space and
facilitating hydrolysis by b-lactamases. This often results in increased
resistance to cephalosporins, cephamycins, and b-lactam inhibitors
[150,163,164]. Plasmids producing ESBLs often carry resistance to other
antibiotics, including aminoglycosides, tetracyclines, chloramphenicol, trimethoprim, and sulfonamides [150].
Escherichia coli and Klebsiella possess other mechanisms of b-lactam
antibiotic resistance, unrelated to ESBL production. Resistance to extendedspectrum cephalosporins, cephamycins, oxyimino-b-lactams, and b-lactam
inhibitors in E coli and K pneumoniae can be mediated by plasmid-mediated
b-lactamases similar to those chromosomal AmpC enzymes produced in
such species as E cloacae and Serratia marcescens [165,166]. Additional
porin mutations can result in carbapenem resistance [150]. Carbapenem
resistance in K pneumoniae can also be modulated by plasmid-mediated
metallo-b-lactamase production [150] and by the production of plasmidmediated class A carbapenem-hydrolyzing enzymes [167]. Resistance to blactamb-lactamase inhibitor antibiotics can occur by alterations in porin
channels; TEM and SHV hyperproduction; by the production of inhibitorresistant TEM enzymes (Bush-Jacoby-Medeiros Group 2br); and in E coli,
by chromosomal cephalosporinase AmpC production [150,162,165].
b-Lactam-resistant Klebsiella and E coli strains are often resistant to
quinolones and aminoglycosides, leaving few alternatives for treatment
[168,169]. Alterations in DNA gyrase (topoisomerase II, and to a lesser
extent toperisomerase IV), porin channel mutations, and eux mechanisms
can confer quinolone resistance [82]. Enzymatic modications can lead to
aminoglycoside resistance [67].
Implementation of eective laboratory screening methods for the detection of ESBLs is a critical factor in the control of hospital outbreaks and
is necessary for accurate surveillance. These methods are discussed in more
detail elsewhere in this issue.
Management of infections caused by Escherichia coli and Klebsiella spp
resistant to broad-spectrum cephalosporins. Treatment of infections caused
by organisms expressing ESBLs is a growing challenge. Even when these
organisms display in vitro susceptibility to third-generation cephalosporins,
treatment failures often occur, limiting the eectiveness of these antibiotics
in vivo [150,156]. Cephamycins, such as cefoxitin, are a treatment option,
but plasmid-mediated AmpC b-lactamase production and porin channel
mutations may limit their clinical utility [150]. Ceftibuten, an oral oxyiminob-lactam that binds less tightly to ESBLs than other cephalosporins, has
reasonable in vitro activity [170], but clinical experience with this antibiotic
is limited. Cefepime, a fourth-generation cephalosporin, inhibits 90% to
100% of ESBL-carrying organisms in vitro [171,172], but it is still subject to
486
hydrolysis and inoculum eects [150,172]. Compared with ceftazidimesusceptible organisms, ceftazidime-resistant K pneumoniae are more
resistant to other classes of antibiotics [168,173]. In one study, ESBLproducing isolates were resistant to gentamicin and ciprooxacin in 67%
and 45% of cases, respectively, compared with rates of 3.6% and 2% for
ceftazidime-susceptible organisms [173]. For susceptible isolates, aminoglycosides, quinolones, and trimethoprim-sulfamethoxazole remain eective
treatment options. Carbapenems, including imipenem, meropenem, and
ertapenem, are eective in the treatment of bacteria containing ESBLs, with
susceptibility rates ranging from 93% to 100% [156,172174]. Mutations
leading to ESBL formation may increase in vitro susceptibility to b-lactam
b-lactam inhibitor antibiotics. These antimicrobial drugs possess good in
vitro activity against some ESBL-expressing organisms [175,176] and have
been shown to protect against ESBL acquisition [177]. For the treatment of
infections caused by ESBL-producing organisms, however, these agents
should be used with caution. Even in the presence of in vitro susceptibility,
clinical failures may occur [178].
Pseudomonas and other gram-negative rods producing AmpC
Another important mechanism of resistance in gram-negative organisms
is the production of inducible chromosomal b-lactamases, most notably
AmpC (Bush-Jacoby-Medeiros group 1). The presence of these chromosomal enzymes is a species-specic characteristic of some Enterobacter,
Serratia, Pseudomonas, Citrobacter, and indole-positive Proteus species
[179]. These organisms are virulent nosocomial pathogens that can present
fulminantly, and because of eective resistance mechanisms, they are often
dicult to treat eectively. The appearance of plasmid-mediated blactamases similar to AmpC in K pneumoniae and E coli raises concerns
regarding the potential for widespread dissemination of this resistance
mechanism [165,166].
Epidemiology and mechanisms of resistance. Pseudomonas aeruginosa is
a common nosocomial pathogen. It has been associated with 9% of all
hospital-acquired infection isolates, and is the most common cause of
nosocomial gram-negative pneumonia, representing 17% of isolates. Enterobacter spp are also common pathogens, representing 6% of all hospitalacquired isolates and 11% of pneumonia isolates [12]. In ICUs, these
organisms are the most common cause of gram-negative bacteremia
(accounting for 9% of all bloodstream pathogens); gram-negative
nosocomial pneumonia (28% of all pathogens); and gram-negative
urinary tract infections (17%) [66].
The production of AmpC is regulated through complex interactions
among chromosomal bacterial genes. These interactions are inuenced by
changes in the cytoplasmic concentrations of intermediates of murein
peptidoglycan synthesis and degradation [180,181]. AmpC is usually not
487
produced at high levels initially, but exposure to particular b-lactam

antibiotics, including cephalosporins, cephamycins, monobactams, and
extended-spectrum penicillins, can cause a transient increase or induction
of AmpC production [180182]. Certain genetic mutations lead to constitutive cephalosporinase production [181]. In both of these cases, the increase
in AmpC production is regulated by changes in the homeostatic levels of
intermediate products of murein synthesis [180,181]. This topic is covered in
greater detail elsewhere [162,180182].
Although resistance of these organisms to b-lactam antibiotics is
primarily conferred by AmpC production, the relative impermeability of
the outer cellular membrane and structural alterations of the outer
membrane often also contribute to b-lactam resistance [67]. Cefepime,
a fourth-generation cephalosporin, has a lower anity for b-lactamases
than third-generation cephalosporins, penetrates the outer membrane more
eectively, and exhibits increased anity for some essential PBP [183].
Cefepime often exhibits greater activity against AmpC-producing organisms
than other cephalosporins [184,185].
Resistance to classes of antibiotics other than b-lactams is also prevalent
among these organisms. In P aeruginosa (and also in Enterobacter spp and
other chromosomal AmpC-producing organisms) carbapenem resistance
can occur by mutational loss of a porin channel, and by acquired zinc blactamases (also called metallo-b-lactamases), IMP and VIM [186189].
These metallo-b-lactamases can also rapidly hydrolyze cephalosporins and
penicillins (but not aztreonam), and can be encoded by integrins, raising
concerns regarding horizontal spread of this resistance trait [186188]. In
some instances, multidrug eux systems may contribute to the expression
of carbapenem resistance [190]. Independent risk factors for acquisition of
imipenem-resistant P aeruginosa include an ICU stay; increased duration of
hospitalization; and exposure to imipenem, piperacillin-tazobactam, and
aminoglycosides [191]. Aminoglycoside resistance can be conferred by
enzymatic modication and by cell wall impermeability. Quinolone resistance is often modulated by antibiotic eux systems and by alterations in
DNA gyrase [188].
Management of infections caused by Pseudomonas and other enteric gramnegative rods producing AmpC. In 2002, rates of ceftazidime resistance of
32% and 30% for Enterobacter spp and P aeruginosa were reported in
American ICUs. Compared with resistance rates from 1997 to 2001, the rate
of ceftazidime resistance for P aeruginosa increased by 22% [11]. Although
isolates may initially test as susceptible to third-generation cephalosporins, resistance can emerge during treatment with these antibiotics, depending
on the site of infection and the magnitude of inoculum of organisms present.
In one study, 19% of bloodstream E cloacae isolates developed resistance to
third-generation cephalosporins once exposed to these agents [192]. AmpC
is not susceptible to b-lactamase inhibitors. Cefepime, a fourth-generation
488
cephalosporin, is a much weaker inducer of AmpC production than thirdgeneration cephalosporins, and has good activity against P aeruginosa
[185,193]. In recent studies, greater than 80% of Pseudomonas isolates were
sensitive to this antibiotic, as were more than 99% of other AmpCproducing Enterobacteriaceae discussed previously [184,185]. The carbapenems are another eective treatment option. In recent studies, 86% of
Pseudomonas isolates and more than 98% of Enterobacter isolates remained
sensitive [193,194]. P aeruginosa resistance to imipenem is emerging,
however, in certain regions of the United States [195]. Quinolones and
aminoglycosides are often eective, although resistance is also emerging to
those classes [196]. In cases of multidrug-resistant P aeruginosa infection,
intravenous colistin is a therapeutic option, although renal toxicity is often
a limiting factor [197,198]. Aerosolized colistin is sometimes used for the
treatment of pulmonary infections because of multidrug-resistant P aeruginosa [199]. When treating organisms that have the ability to produce AmpC
(particularly Enterobacter spp), cephalosporins and extended-spectrum
penicillins should be used in combination with another class of antimicrobial drugs or should be avoided altogether. Because of the high prevalence
of antibiotic resistance and because of the potential for emergence of
resistance, deep-seated Pseudomonas infections should be treated with two
active agents that demonstrate additive or synergistic activity, such as a blactam in combination with either an aminoglycoside or uoroquinolone,
during the initial stages of therapy. After clinical improvement is noted, and
the burden of infection is decreased, de-escalation to a single antibiotic is
often appropriate.
Stenotrophomonas maltophilia
Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia) is an
aerobic gram-negative rod that causes bacteremia, respiratory tract infection, skin and soft tissue infection, and endocarditis [200,201]. The inducible,
chromosomal enzymes L1 and L2 confer resistance to b-lactam antibiotics.
L1 is a Bush-Jacoby-Medeiros class 3 enzyme (or metallo-b-lactamase) with
broad activity against penicillins, carbapenems, cephalosporins, and blactam inhibitors [162,202]. L2 is a cephalosporinase (Bush-Jacoby-Medeiros class 2e) active against cephalosporins and monobactams. A TEM-2
b-lactamase encoded on a Tn-1 like transposon was also recently cloned
from an S maltophilia isolate [203]. Decreased membrane permeability
secondary to porin mutations often leads to quinolone resistance [204].
Aminoglycosides generally are not active against S maltophilia, probably
because of inactivating enzymes and alterations in the cell surface [202].
Overexpression of the multidrug eux pump SmeDEF in S maltophilia may
contribute to decreased susceptibility to tetracyclines, erythromycin, quinolones, and chloramphenicol [205].
Trimethoprim-sulfamethoxazole, a bacteriostatic agent, is the treatment
of choice for infections caused by S maltophilia. Ticarcillin-clavulanate is the
489
only b-lactamb-lactam inhibitor combination antibiotic that is reliably

eective and may be used in patients who are intolerant of or infected with
an isolate resistant to trimethoprim-sulfamethoxazole [202]. Resistance to
both of these agents is increasing; recent studies reported that 5% of S
maltophilia in the United States and 10% of isolates in Europe were resistant
to trimethoprim-sulfamethoxazole [206]. Ceftazidime does not possess
reliable activity and should not be used empirically [206]. Cefepime has
greater activity than ceftazidime (88.7% versus 35.3% of American
bloodstream isolates susceptible in one study) [207]. Resistance to imipenem
approaches 100% [207]. Among the available uoroquinolones, gatioxacin, levooxacin, moxioxacin, and trovaoxacin have better in vitro
activity than ciprooxacin [206,208]. In one study, 93% of isolates were
susceptible to gatioxacin [206]. Minocycline has good in vitro activity [208],
but clinical experience is limited. Use of antibiotic combinations, including
trimethoprim-sulfamethoxazole plus ticarcillin-clavulanate or a third-generation cephalosporin, and trimethoprim-sulfamethoxazole plus minocycline plus ticarcillin-clavulanate is being explored for the treatment of
serious S maltophilia infections [209211]. Although aztreonam is usually
inactive against S maltophilia, one study demonstrated synergistic activity in
vitro when combined with ticarcillin-clavulanate [211].
Acinetobacter spp
Acinetobacter is a gram-negative coccobacillus that has emerged as an
important nosocomial pathogen. Patients with impaired host defenses,
patients in the ICU, patients with respiratory failure, central venous lines,
and other invasive devices, and patients who have received broad-spectrum
antimicrobial agents are particularly susceptible to invasive Acinetobacter
infection [212215]. Acinetobacter is an important cause of nosocomial
bloodstream infection and can cause soft tissue infection, urinary tract
infection, abdominal infection, meningitis, and endocarditis [216,217].
Hospital outbreaks occur, and often are related to contaminated respiratory
equipment [212].
Resistance mechanisms to b-lactam antibiotics in Acinetobacter are not
clearly understood, but resistance is common. Resistance frequently seems to
be related to b-lactamase production, but other mechanisms have been
identied. TEM-l and CARB enzymes seem to confer resistance to penicillins
and some narrow-spectrum cephalosporins, whereas chromosomally produced cephalosporinases and plasmid-mediated ESBLs are thought to
modulate resistance to broader-spectrum cephalosporins [162,218]. Carbapenem resistance is conferred by multiple dierent mechanisms including
carbapenemase production of the IMP and VIM-type, production of OXAtype b-lactamases, reduced cellular uptake, target mutations, and alterations
in the PBP [186,219221]. Aminoglycoside resistance is mediated by aminoglycoside-modifying enzymes, and quinolone resistance by mutational
changes of topoisomerase IV [222,223].
490
Carbapenems are the most reliable therapeutic agents for infections caused
by Acinetobacter, but resistance has begun to emerge in multiple geographic
areas. Recent studies have reported rates of carbapenem resistance in Acinetobacter baumani, the more resistant Acinetobacter species, as high as 11% [224].
A 1999 study reported meropenem resistance at greater than 50% in all isolates of A baumani recovered from 15 hospitals in Brooklyn, New York [195].
b-Lactamb-lactamase inhibitor combination antibiotics have good in vitro
activity against Acinetobacter lwo (15% are resistant) but are less eective
against A baumani (20%30% are resistant to piperacillin-tazobactam) [224].
Ampicillin-sulbactam may be active against strains of Acinetobacter resistant
to all other b-lactam agents, perhaps because of the unique antimicrobial
activity of the sulbactam component against some acinetobacters. Ceftazidime and cefepime have modest activity, but approximately 35% of A lwo
and A baumani strains are resistant [224]. Aminoglycoside resistance occurs in
approximately 20% to 30% of A baumani isolates [215]. Resistance to
quinolones is variable, precluding use of these drugs empirically before the
results of susceptibility tests are known. In one study, approximately 80% of
isolates tested were found to be ciprooxacin-resistant [225]. Colistin is
a therapeutic option for strains resistant to all other antibiotics [197].
Salmonella spp
Salmonellae are gram-negative bacilli that are important human pathogens. Salmonella typhi and Salmonella paratyphi colonize only humans and
disease is acquired through close contact with infected individuals or carriers.
Infection with S typhi or S paratyphi can cause typhoid fever, a serious
systemic illness. Nontyphoidal species, such as Salmonella enteritidis and
Salmonella enterica, are food-borne pathogens that can asymptomatically
colonize the human intestine or cause clinical illnesses, such as gastroenteritis
and bacteremia. Resistance to antimicrobial agents used to treat typhoidal
and nontyphoidal species has emerged and disseminated rapidly.
Resistance to chloramphenicol in S typhi emerged in the 1970s, and
several major outbreaks have been caused by chloramphenicol-resistant
strains [226,227]. Resistance to chloramphenicol is often mediated by a selftransferable plasmid (IncHI) that also mediates resistance to sulfonamides,
tetracycline, amoxicillin, trimethoprim-sulfamethoxazole, and streptomycin
[226,227]. Resistance to the uoroquinolones is an emerging problem,
particularly in Asia, and is usually mediated by chromosomal point
mutations in the gyrA gene. Resistance to nalidixic acid may predict clinical
failure of quinolone therapy, even among isolates with in vitro quinolone
susceptibility [227229]. Resistance to third-generation cephalosporins (eg,
ceftriaxone and cefotaxime) has occurred sporadically [230].
The quinolones, such as ciprooxacin, are considered the drugs of choice
for empiric treatment of typhoid fever, except in areas of the world where
quinolone resistance is common (eg, Asia) [227]. Resistance to nalidixic acid
was reported among 23% of S typhi isolates identied through the National
491
Antimicrobial Resistance Monitoring System in 2000 [229]. Resistance to

ciprooxacin is infrequent in the United States [229], but was found in 23%
of S typhi isolates in the United Kingdom in 1999 [231]. In that study,
multidrug resistance to chloramphenicol, ampicillin, and trimethoprim was
reported in 26% of all S typhi isolates [231]. Other potential oral alternatives
for treatment of S typhi infections include amoxicillin, trimethoprimsulfamethoxazole, cexime, azithromycin, and chloramphenicol, as long as
these agents possess in vitro activity against a given strain [227]. Thirdgeneration cephalosporins, such as ceftriaxone and cefotaxime, remain
active but require intravenous administration.
Resistance among nontyphoidal strains of salmonellae emerged in the
1990s and spread rapidly. Emergence of multiresistance to ampicillin,
chloramphenicol, and trimethoprim-sulfamethoxazole is caused in part by
the widespread dissemination of Salmonella typhimurium denitive phage type
104 (DT 104). This strain contains chromosomal determinants that mediate
resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole,
streptomycin, and tetracycline [232,233]. Resistance to uoroquinolones has
also emerged among nontyphoidal salmonellae in the United Kingdom
(including DT104), and in the United States resistance to the uoroquinolones
is often mediated by gyrA mutations [234]. Resistance to broad-spectrum
cephalosporins is conferred by plasmid-mediated AmpC-type cephalosporinase production [235] and sometimes by ESBL production [236]. Resistance
to the carbapenems has been reported and is mediated by porin loss,
cephalosporinase production, and carbapenemase production [237,238].
Treatment of nontyphoidal salmonellosis is generally not indicated
except if there is extraintestinal disease or a high risk of extraintestinal
disease [239]. Despite the emergence of resistant strains, the uoroquinolones remain reliable agents for the treatment of most invasive infections
caused by nontyphoidal salmonellae. In 1999, approximately 8% of British
S typhimurium and S enteritidis isolates tested were quinolone resistant
[240]. In the United States, quinolone resistance is much less common, but
outbreaks caused by quinolone-resistant strains have occurred, including
one in a nursing home from 1996 to 2000 [241]. For isolates that are
susceptible to trimethoprim-sulfamethoxazole or ampicillin, these agents are
good therapeutic options. Multidrug-resistant S typhimurium DT104 now
accounts for approximately 9% of Salmonella isolates and approximately
30% of S typhimurium isolates in the United States, however, limiting the
ecacy of these agents [233,242]. Broad-spectrum cephalosporins, such as
ceftriaxone and cefotaxime, have remained active against most nontyphoidal salmonella isolates, although strains resistant to these agents have
been isolated sporadically in the United States [243,244].
Campylobacter jejuni
Campylobacter spp are fastidious, curved, motile gram-negative bacilli
and are the leading bacterial food-borne cause of diarrhea and a common
492
cause of travelers diarrhea [245,246]. An estimated 2.1 to 2.4 million cases

of campylobacteriosis occur annually in the United States [247]. In
developing countries, Campylobacter is one of the most frequently isolated
bacterial pathogens in infants with diarrhea [248]. Fifty percent to 70% of
all Campylobacter infections in humans are likely related to consumption of
contaminated poultry [248,249].
Campylobacter jejuni is responsible for more than 90% of human cases of
campylobacteriosis [249]. C jejuni usually causes self-limited watery or
bloody diarrhea associated with fever and abdominal pain, and rarely causes
bacteremia, septic arthritis, endocarditis, and osteomyelitis [248,249].
Noteworthy potential postinfectious complications of Campylobacter include Guillain-Barre syndrome and reactive arthritis [249].
Fluoroquinolone resistance was rst noted in the early 1990s in Asia and
Europe, which coincided with the addition of enrooxacin to animal feed
[249,250]. In Spain, quinolone resistance increased from 1% during the
period 1985 to 1987 to 81% 10 years later [251]. Thailand experienced
a similar increase during the 1990s (0% in 1990 to 84% in 1995) [252]. Rates
of uoroquinolone resistance among Campylobacter are lower in the United
States, but agricultural use of uoroquinolones again coincided with
increased resistance. In one American study, resistance increased from
1.3% in 1992 to 10.2% in 1998 [253]. Imported isolates can contribute
signicantly to local resistance patterns [253,254].
Resistance to the macrolides remains low (\5% in most regions)
[255,256]. Most isolates are susceptible to aminoglycosides, chloramphenicol, clindamycin, nitrofurantoin, and imipenem [249]. A point mutation at
codon 86 in the gyrA DNA gyrase gene is the most common mutation
conferring quinolone resistance [257]. Mutations in the parC gene occur less
frequently [250], but the presence of mutations in both regions confers highlevel quinolone resistance [250]. Multidrug eux pumps may also have a role
in the development of quinolone resistance [258]. Erythromycin resistance in
Campylobacter is caused by ribosomal alterations [250].
For patients with uncomplicated Campylobacter infection, supportive
care with administration of uids is typically all that is required. Antimicrobials are recommended for pregnant or immunocompromised patients and
those with invasive or severe illness (eg, high fevers or symptoms for greater
than 1 week) [239]. Fluoroquinolones remain a therapeutic option for many
isolates, but because of increasing resistance, treatment with a macrolide,
particularly erythromycin, is recommended [239].
Neisseria meningitidis
Neisseria meningitidis, a gram-negative diplococcus, is an important
cause of septicemia and pyogenic meningitis. Persons with asplenia (functional or anatomic), cirrhosis, deciency of properdin or terminal complement components, and possibly persons infected with HIV are predisposed
to invasive meningococcal infection [259]. Additional risk factors for
493
infection include low socioeconomic status, African American race, exposure to tobacco smoke, and the presence of concurrent viral infection of the
upper respiratory tract. New military recruits and students living in
dormitories are also at increased risk for invasive infection [260].
Resistance of N meningitidis to antimicrobial drugs was not an issue until
the emergence of sulfonamide resistance in the 1950s [261]. More recently,
resistances to penicillin, chloramphenicol, and rifampin have been described
[261].
Sulfonamide resistance is mediated by genetic alterations in the chromosomal gene encoding dihydropteroate synthase [262]; these chromosomal
alterations can be transferred between N meningitidis serogroups and to
other Neisseria spp [262]. Meningococcal strains with MICs to penicillin
ranging from 0.1 to 1 lg/mL are considered to have intermediate resistance
to penicillin [261]. The predominant mechanism of reduced penicillin
susceptibility is a change in PBP2 and PBP3. Alterations in PBP2 lead to
decreased anity to penicillin, and increased MICs [261]. High-level
resistance to penicillin can also be caused by the production of a plasmidmediated penicillinase, but this resistance mechanism occurs infrequently
[261,263]. Chloramphenicol resistance is caused by the production of
chloramphenicol acetyltransferase. Horizontal transfer of genetic material
between strains of N meningitidis likely plays an important role in the
dissemination of chloramphenicol resistance [264]. Resistance to rifampin is
often mediated by point mutations in the rpo B gene leading to alterations in
the RNA polymerase. In addition, resistance can be mediated by alterations
in membrane permeability [261].
A recent French study reported that between 1999 and 2002, approximately 30% of invasive N meningitidis had reduced susceptibility to
penicillin and that absolute penicillin resistance was also increasing [265].
A recent American study reported similar rates of isolates with decreased
susceptibility to penicillin (30%) [266], although a CDC-based active
population-based surveillance study identied only 3% of clinical isolates to
be of intermediate resistance, a proportion unchanged since 1991 [263].
Rates of resistance to sulfa drugs (ie, trimethoprim-sulfamethoxazole and
sulfadiazine) were approximately 40% in recent American studies [263,266].
High-level chloramphenicol resistance has been described in Southeast Asia
and in Europe [267]. Resistance to rifampin was reported in 3% of isolates
in one recent report [263].
Despite reports of increasing antibiotic resistance, multiple therapeutic
options are available. Penicillin remains an excellent choice for therapy of
conrmed meningococcal infections [259,261,263]. There is no evidence that
intermediate level resistance aects outcome when high-dose penicillin is
used and high-level penicillin resistance is rare. The clinical consequences of
chloramphenicol resistance are not yet clearly understood, but resistance to
this agent is of concern in developing countries where chloramphenicol is
still used to treat meningococcal meningitis [267]. The third-generation
494
cephalosporins (ceftriaxone and cefotaxime) and the new quinolones remain

highly active and are excellent therapeutic choices [268].
Neisseria gonorrhoeae
Neisseria gonorrhoeae is a gram-negative diplococcus, typically acquired
sexually or perinatally. Gonorrhea is the second most common reportable
infectious disease in the United States, causing an estimated 650,000
infections per year [269]. In addition to urethritis and cervicitis, N
gonorrhoeae can cause disseminated infection and is the most common
cause of nontraumatic arthritis in young adults [270]. Reported rates of
gonorrhea in the United States decreased by 71.3% between 1981 and 1996
[271]. Risk factors for infection with N gonorrhoeae include prior infection,
multiple sexual partners, African American race, young age, and substance
abuse [272].
Antimicrobial resistance has been a concern with N gonorrhoeae since the
1940s when resistance to sulfonamides was rst noted; this was followed by
penicillin resistance in the 1950s, tetracycline resistance in the 1980s, and
uoroquinolone resistance in the 1990s [273,274].
High-level penicillin resistance (MIC 16 lg/mL) in N gonorrhoeae is
most often mediated by penicillinase production [275]. Penicillin resistance
caused by production of a plasmid-encoded TEM-1type b-lactamase was
rst detected in N gonorrhoeae in 1976 and has now disseminated worldwide
[274,276]. In the United States, the percentage of penicillinase-producing N
gonorrhoeae peaked in 1991 at 11% but declined to 1.2% in 2002 [277].
Multiple chromosomal mutations can mediate lower-level penicillin
(MIC > 2 lg/mL) resistance. Resistance genes typically accumulate in
a stepwise fashion, leading to gradually increasing penicillin MICs [275].
These resistance genes include penA, which encodes an altered PBP 2; mtr,
which increases expression of an eux pump; and penB, which decreases
antibiotic permeability across the cell membrane through a porin gene
mutation [275,278]. Chromosomally mediated resistance to penicillin was
present in 2.1% of isolates in a recent American survey [277].
Resistance to tetracycline occurs through chromosomally mediated
changes in cell membrane porins or by ribosomal protection by the
plasmid-mediated tetM resistance gene [275,279]. Additional chromosomal
mutations lead to resistance to spectinomycin [280]. Macrolide resistance
can occur through eux pumps, erm methylases, and changes in the 23S
ribosome [281].
Fluoroquinolone-resistant N gonorrhoeae (MIC 1 lg/mL) has disseminated to many countries [282284] and is widespread in certain parts of
Asia. In a recent study, greater than 35% of N gonorrhoeae isolates in the
Philippines and Vietnam were quinolone resistant [285]. There have also
been alarming increases in quinolone resistance reported recently in England
and Wales [283]. The overall prevalence of quinolone-resistant gonococci in
the United States was 2.2% in 2002, but most of these strains were reported
495
from California and Hawaii (20% of isolates tested in Honolulu in 2001

were resistant) [273,277]. Decreased susceptibility to uoroquinolones is
caused by mutations in the parC gene of topoisomerase IV and gyrA of
DNA gyrase [286,287].
The CDC currently recommends third-generation cephalosporins (eg,
ceftriaxone), which are still highly active, for rst-line therapy of gonococcal
infection [288]. Cexime is the only nonquinolone oral agent recommended
for the treatment of gonorrhea, but is no longer being marketed in the
United States [288]. Fluoroquinolones (eg, ciprooxacin, ooxacin, or
levooxacin) remain an excellent oral therapeutic option for most isolates
but should not be used empirically in patients acquiring infection in areas
where the prevalence of quinolone-resistant gonorrhea is greater than 1%
(eg, Asia, Hawaii, California) [288]. For patients who cannot receive
a cephalosporin and who are at risk for quinolone-resistant N gonorrhoeae,
spectinomycin is a therapeutic option [288]. Susceptibility testing should
always be performed for patients who fail therapy for gonorrhea. Patients
with gonorrhea in whom co-infection with chlamydia cannot be ruled out
should also be treated for chlamydia [288].
Summary
The emergence of resistance to antimicrobial agents continues to evolve
substantially, inuencing the evaluation and treatment of infections in
nosocomial and health careassociated settings and in the community.
Bacteria use several strategies to avoid the eects of antimicrobial agents,
and have evolved highly ecient means for clonal spread and for the
dissemination of resistance traits. Control of antibiotic-resistant pathogens
provides a major challenge for the medical and public health communities
and for society. Control of the emergence of resistant pathogens requires
adherence to infection control guidelines, such as those issued by the CDC
(http://www.cdc.gov/ncidod/hip/Guide/guide.htm), and physicians, patients, and health care consumers must all understand the need for
judicious use of antibiotics (http://www.cdc.gov/drugresistance/healthcare/
default.htm).
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Pathogens Resistant To Antimicrobial Agents-Epidemiology, Molecular Mechanisms and Clinical Management

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Infect Dis Clin N Am 18 (2004) 467511

Pathogens resistant to antimicrobial

Department of Medicine, Duke University Medical Center,

This article reviews the molecular mechanisms by which resistance traits

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

Acquired resistance, the primary focus of this article, reects a true

Diminished intracellular drug concentration

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

enzymes. These enzymes are widely distributed in both gram-positive and

Mechanisms of dissemination of resistance genes

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

themselves into host chromosomal and plasmid DNA. Many resistance

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

Strains with vanA on the chromosome have been described.

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

and vancomycin-resistant E faecium and E faecalis [52]. This topic is

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

an important pathogen among patients in the outpatient setting who are at

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

cluster, which also mediates glycopeptide resistance in some enterococcal

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

The current treatment of choice for nosocomial and health care

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

therapeutic agents with which there is limited clinical experience include

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

for the acquisition of penicillin-resistant strains include prior hospitalization

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

Carbapenems traditionally have had excellent in vitro activity against

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K pneumoniae isolated from French hospitals were ESBL producers, with

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

Another mechanism facilitating b-lactamase activity involves loss of

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

produced at high levels initially, but exposure to particular b-lactam

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

only b-lactamb-lactam inhibitor combination antibiotic that is reliably

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

Antimicrobial Resistance Monitoring System in 2000 [229]. Resistance to

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

cause of travelers diarrhea [245,246]. An estimated 2.1 to 2.4 million cases

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

cephalosporins (ceftriaxone and cefotaxime) and the new quinolones remain

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

from California and Hawaii (20% of isolates tested in Honolulu in 2001

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

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[100] Hoogkamp-Korstanje JA. In-vitro activities of ciprooxacin, levooxacin, lomeoxacin,

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K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511

K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467511