Pathogens Resistant to Antimicrobial Agents-epidemiology,Molecular Mechanisms and Clinical Management

Infect Dis Clin N Am 18 (2004) 467–511

Pathogens resistant to antimicrobialagents: epidemiology, molecular

mechanisms, and clinical management

Keith S. Kaye, MD, MPHa,*, John J. Engemann, MDa,Henry S. Fraimow, MDb, Elias Abrutyn, MDc

aDepartment of Medicine, Duke University Medical Center,

Box 3152, Durham, NC 27710, USAbDepartment of Medicine, University of Medicine and Dentistry of New Jersey,

401 Haddon Avenue, Room 274, Camden, NJ 08103, USAcDepartment of Medicine, Drexel University College of Medicine, 245 North 15th Street,

Mailstop 441, Philadelphia, PA 19102–1192, USA

This article reviews the molecular mechanisms by which resistance traitsare conferred and disseminated. The focus then shifts to the molecularepidemiology and clinical management of certain multidrug-resistantbacteria.

Mechanisms of resistance

It is important to distinguish the several ways in which an organism maydemonstrate resistance. Intrinsic resistance to an antimicrobial agentcharacterizes resistance that is an inherent attribute of a particular species;all organisms of the species may lack the appropriate drug-susceptible targetor possess natural barriers that prevent the agent from reaching the target.Some examples are the natural resistance of gram-negative bacteria tovancomycin because the drug cannot penetrate the gram-negative outermembrane, or the intrinsic resistance of the penicillin binding proteins (PBP)of enterococci to the effects 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: [email protected] (K.S. Kaye).

0891-5520/04/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.idc.2004.04.003

mailto:[email protected]

468 K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467–511

Acquired resistance, the primary focus of this article, reflects a truechange in the genetic composition of a bacterium so that a drug that oncewas effective is no longer active, resulting in clinical resistance. Sometimesgenetic change results in diminished activity, but not complete loss of drugeffectiveness.

The major strategies used by bacteria to avoid the actions of antimicro-bial agents are outlined in Table 1. These include limiting the intracellularconcentration of the antimicrobial agent by decreased influx or increasedefflux, or neutralization of the antimicrobial agent by enzymes thatreversibly or irreversibly inactivate the drug; alteration of the target so thatthe agent no longer interferes with it; and elimination of the targetaltogether by the creation of new metabolic pathways [1]. Bacteria mayuse one or multiple mechanisms against a single agent or class of agents ora single change may result in resistance to several different agents or evenmultiple unrelated drug classes.

Gram-positive and gram-negative bacteria possess different structuralcharacteristics and these differences can influence the mechanisms forprimary resistance. The targets of most antimicrobial agents are locatedeither in the cell wall, cytoplasmic membrane, or within the cytoplasm. Ingram-negative bacteria, the outer membrane may provide an additional

Table 1

General mechanisms of resistance to antimicrobial agents

Resistance mechanism Specific examples References

Diminished intracellular drug concentration

Decreased outer

membrane permeability

b-Lactams (eg, OmpF, OprD) [3]

Decreased cytoplasmic

membrane transport

Quinolones (eg, OmpF);

aminoglycosides

(decreased energy)

[1,4]

Increased efflux Tetracyclines; (eg, tetA);

quinolones (eg, norA);

macrolides (eg, mefA);

multiple drugs (eg, mexAB-OprF)

[3,289,290]

Drug inactivation

(reversible or irreversible)

b-Lactams (b-lactamases);

aminoglycosides (modifying

enzymes); chloramphenicol

(inactivating enzymes)

[1,4,162]

Target modification Quinolones (gyrase modifications);

rifampin (DNA polymerase

binding); b-lactams (penicillin

binding protein changes);

macrolides (rRNA methylation);

linezolid (23srRNA modifications);

[6,7,83]

Target bypass Glycopeptides (vanA, vanB);

trimethoprim (thymidine-deficient

strains)

[8]

469K.S. Kaye et al / Infect Dis Clin N Am 18 (2004) 467–511

intrinsic barrier that prevents drugs from reaching these targets. Modifica-tions in outer membrane permeability by both alterations in porin proteinchannels and by up-regulation of intrinsic multidrug efflux pumps maycomprise a component of the mechanisms contributing to resistance inmany gram-negative organisms. In addition, inactivating enzymes releasedacross the cytoplasmic membrane can function more efficiently within theconfines of the periplasmic space.

The mechanisms by which intracellular concentrations of drugs arelimited include decreased permeability through the outer membrane,decreased uptake through the cytoplasmic membrane, and active effluxback out across the cytoplasmic membrane and the outer membrane.Acquired outer membrane permeability changes in gram-negative organismspreviously attributed solely to alterations in outer membrane porin proteinsare now also understood to be related to the up-regulation of complexmultidrug efflux pumps whose expression is linked to that of outermembrane proteins, such as the MexAB-OprM system of Pseudomonasaeruginosa [2,3]. These efflux systems are widely distributed among gram-negative pathogens, such as P aeruginosa and Enterobacteriaceae, and maybe an important component of resistance to b-lactams, but usually result inhigh-level resistance only when also associated with b-lactamase production[2,3]. Imipenem resistance in P aeruginosa can be mediated by alteration ofa specific porin OprD that is used preferentially by this agent [2,3].Decreased outer membrane permeability through porin changes and effluxalso may play a role in resistance to fluoroquinolones and aminoglycosides.Resistance mediated by decreased uptake across the metabolically activecytoplasmic membrane is best demonstrated by small-colony aminoglyco-side-resistant mutants of staphylococci, but this mechanism is less importantthan other mechanisms of aminoglycoside resistance [4]. Active antimicro-bial efflux systems play a role in resistance to many different agents,including macrolides, tetracyclines, quinolones, chloramphenicol, and b-lactams.

Inactivating enzymes remain the predominant mechanism of resistance toseveral major classes of antimicrobial agents. Resistance to b-lactams ismediated by awide variety of b-lactamases that hydrolytically inactivate thesedrugs. b-Lactamases can be either plasmid or chromosomally mediated, andtheir expression can be constitutive or induced. Unlike those of gram-positives, b-lactamases of gram-negative organisms are confined to theperiplasmic space, which may explain some of the differences in theirphenotypic expression and ease of laboratory detection. Of particularimportance in the hospital setting are the class I chromosomal b-lactamasesof organisms, such as Enterobacter cloacae, that are produced in high levelsafter exposure to an inducing b-lactam agent (particularly to third-generationcephalosporins), and the extended spectrum b-lactamases, mediating re-sistance to third-generation cephalosporins and aztreonam [5]. Anothermajor class of inactivating enzymes is the family of aminoglycoside-modifying


enzymes. These enzymes are widely distributed in both gram-positive andgram-negative bacteria, and usually are plasmid-mediated [4]. Resistance tochloramphenicol and macrolides also can be mediated by modifying orinactivating enzymes [6].

Target modifications are widely used by bacteria to develop resistance toa wide variety of antimicrobial agents [7]. Some of these alterations mayrequire as little as a single mutational event at a critical gene sequence in theprimary target to create a new, functional target with reduced affinity for theantimicrobial agent. Such changes account for the relative ease of selectionof rifampin-resistant mutants of staphylococci and streptococci by changesin DNA polymerase or the selection of high-level streptomycin-resistantmutants with altered ribosomes. Although some target modifications can bedirectly selected, others, such as development of resistance to semisyntheticpenicillins in staphylococci, require acquisition of novel exogenous DNA.Modification of PBP is the primary determinant of penicillin resistance inStreptococcus pneumoniae, Neisseria meningitidis, and Enterococcus faecium.Modification of the genes encoding DNA gyrases and topoisomerases is themajor mechanism of resistance to quinolones, and target modification isimportant in resistance to macrolides, tetracyclines, rifampin, and mupir-ocin [7].

Some bacteria have gone beyond simple target modification and haveacquired novel systems in which the antimicrobial target is no longernecessary for survival of the organism. This is achieved by creation of newmetabolic pathways to bypass the primary target. Perhaps the mostelaborate examples of this are the vanA and vanB clusters that mediateresistance to glycopeptides in enterococci [8]. Target bypass also is the majormechanism of acquired resistance to folate antagonists.

Mechanisms of dissemination of resistance genes

In addition to the complex strategies used to express resistance toantimicrobial agents, bacteria also can avail themselves of a variety ofefficient mechanisms for the transfer of resistance genes to other organismsand to other species [6,9,10]. The bacterial genome consists of chromosomalDNA, which encodes for general cellular characteristics and metabolic andrepair pathways, and smaller circular DNA elements or plasmids that mayencode for supplemental bacterial activities, such as virulence factors andresistance genes, and for genes essential to the independent mobilization andtransmission of the plasmid elements. Most resistance genes are plasmid-mediated, but plasmid-mediated traits can interchange with chromosomalelements. Transfer of genetic material from a plasmid to the chromosomecan occur by simple recombinational events, but the process is greatlyfacilitated by means of transposons. Transposons are small, mobile DNAelements capable of mediating transfer of DNA by removing and inserting


themselves into host chromosomal and plasmid DNA. Many resistancegenes, 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. Multipleresistance transposons can then be clustered together on even largercomposite transposable elements capable of simultaneously transferringmultiple unrelated resistance genes [10].

Resistance determinants carried on the chromosome are transmittedvertically by clonal dissemination. Resistance determinants on plasmids canalso be transferred vertically, although plasmids may be lost from thebacterial population if they no longer confer a particular selectiveadvantage. Plasmids also are capable of horizontal transfer by conjugation,although the efficiency of plasmid transfer both within and between speciescan vary tremendously. Plasmid transfer between gram-positive and gram-negative bacteria, once thought to be an unlikely event, can occur both inthe laboratory and in the gastrointestinal tract of gnotobiotic mice,suggesting that such transfer events between even distantly related organ-isms may be important in nature [9].

Conjugative transposons of gram-positive bacteria are capable of directlymediating gene transfer without plasmids. Transformation, direct incorpo-ration of free DNA by bacterial cells, may also be important for theevolution of resistance in Neisseria and streptococcal species [7,10].

Specific pathogens

Resistant gram-positive cocci

Multidrug-resistant enterococciEnterococcus spp is the third most common organism associated with

hospital-acquired infection [11]. Enterococci are common causes of noso-comial urinary tract infections, surgical site infections, and bloodstreaminfections [12]. Enterococcus faecalis, and the more penicillin-resistant Efaecium, are the two major enterococcal pathogens.

Enterococci are a normal part of human gastrointestinal flora (up to 107

organisms per gram of stool) [13]. These organisms are hardy and survive onthe hands of hospital personnel and on fomites in the hospital environment.Resistant strains may become established and persist as part of a patient’s orhealth care worker’s gastrointestinal flora. Fecal concentrations of entero-cocci may increase in those given antibiotics active against intestinal floraother than enterococci [14,15].

Enterococci are naturally tolerant to penicillins, and resistant tocephalosporins, clindamycin, and achievable serum levels of aminoglyco-sides. Cephalosporin resistance is caused by poor affinity of cephalosporinsfor enterococcal PBPs. Natural low-level aminoglycoside resistance isattributed to the inability of aminoglycosides to penetrate the enterococcal


cell wall, but activity is enhanced in the presence of cell wall–active drugs,such as ampicillin or vancomycin [16]. Enterococci are usually intrinsicallytolerant, or lysis resistant, to the effects of penicillins and glycopeptidesalone. Until the emergence of drug-resistant isolates, bactericidal therapywas reliably achieved with synergistic combinations of cell wall–active drugsplus aminoglycosides.

Enterococci demonstrate several types of penicillin resistance. Penicillinresistance in E faecalis is mediated by b-lactamase production and has beenreported from a few nosocomial outbreaks both within and outside of theUnited States [17,18], but infections with such strains are still veryuncommon. Chromosomal high-level penicillin resistance is a species-specific characteristic of E faecium, but is occasionally found in otherspecies [19,20]. Low-level penicillin-resistant E faecium are found in normalfecal flora, but high-level resistant strains are likely to be nosocomiallyacquired [21]. Ampicillin resistance to an intermediate level (mean inhibitoryconcentration [MICs] of 16–64 lg/mL) seems to be attributable toalterations in PBPs, and in most cases is associated with the overexpressionof PBP5, a PBP with low affinity for penicillins [22]. High-level penicillin-resistant E faecium are also resistant to imipenem and b-lactam–b-lactamaseinhibitors and are often glycopeptide-resistant [23,24].

High-level gentamicin resistance, mediated by a bifunctional inactivatingenzyme, first appeared in 1978 and rapidly spread worldwide. As many as60% 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 otheraminoglycosides in clinical use in the United States, with the possible excep-tion of streptomycin. Importantly, highly resistant strains do not demon-strate synergistic killing of enterococci when aminoglycosides are combinedwith penicillin or vancomycin [26]. Most high-level gentamicin resistance iscarried on transposons and is plasmid mediated [26]. Detection of high-levelgentamicin resistance requires either special susceptibility wells or screeningplates 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 significantly increasedover the past several years [11]. VRE are established throughout the UnitedStates and Europe, but are less frequently isolated in Asia and LatinAmerica [27]. The prevalence of VRE remains low in true community-acquired isolates in the United States, but is notably higher in Europe. VREhave been isolated from sewage and various animal sources in Europe, andin one study from the feces of 12% of nonhospitalized individuals [28,29].The previous use of glycopeptide-containing animal feed may explain theincreased prevalence in some European communities. The increase inglycopeptide resistance in the United States followed the marked increasein vancomycin usage in many hospitals, as methicillin-resistant Staphylo-


coccus aureus (MRSA) strains became established in the 1980s. Most VREseem to have been acquired nosocomially or institutionally, and spread ofepidemic strains both within and between institutions is well documented[30]. From 1989 to 2002, the proportion of enterococcal isolates from ICUsthat were resistant to vancomycin increased from 0.3% in 1989 to 23.9% in1998, and further increased to 27.5% in 2002 [11]. Some risk factors forVRE colonization or infection include the exposure to antibiotics, such asbroad-spectrum cephalosporins, fluoroquinolones, vancomycin, and anti-anaerobic drugs; longer length of hospital and ICU stays; intrahospitaltransfer between patient floors; 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 thebacterial cell. They interfere with cell wall synthesis by tightly binding tothe D-alalanine–D-alanine terminal dipeptide on the peptidoglycan pre-cursor, sterically blocking the subsequent transglycosylation and trans-peptidation reactions. The vancomycin-resistance mechanisms involvea complex series of reactions that ultimately result in the building of thecell wall by bypassing the D-alanine–D-alanine–containing pentapeptideintermediate structure, thereby eliminating the glycopeptide target [33].

Vancomycin-resistant enterococci initially were characterized phenotyp-ically as vanA, vanB, and vanC strains based on levels of resistance tovancomycin, cross-resistance to teicoplanin, and the inducible or constitu-tive nature of resistance [34]. The genotype and molecular basis for eachresistance type have now been characterized (Table 2). The vanA cluster hasbeen identified predominantly in E faecium and E faecalis but has also beenfound in other enterococci, streptococci, Oerskovia, and Bacillus, and mostrecently has been found in S aureus [35–39], and there is evidence for in vivo

Table 2

Glycopeptide-resistant enterococci

Genotype

Vancomycin

MIC (lg/mL)

Teicoplanin

MIC (lg/mL) Expression

Typical

location

vanA 64–1024 16 Inducible Plasmida

vanB 4–1024 1b Induciblec Chromosomed

vanCe 2–32 1 Constitutive

and inducible

Chromosome

vanD 64–256 4–32 Constitutive

and induciblefChromosome

vanE 16 0.5 Inducible Chromosome

vanG 16 0.5 Inducible Chromosome

a Strains with vanA on the chromosome have been described.b Teicoplanin-resistant strains have emerged with MIC � 16.c Constitutively expressing strains have been described.d Plasmids containing vanB have been described.e Species-specific variants vanC-1, vanC-2, and vanC-3 have been described.f Both have been described.


transfer of vanA resistance plasmids [40,41]. vanB is found almost exclu-sively in E faecium and E faecalis. vanC1, C2, C3, D, E, and G are rarelyfound in enterococci causing human infection [42–44].

Resistance to linezolid has recently been reported [45] and is mediated bythe G2576U or similar mutations of the 23S ribosome [46].

Management of infections caused by resistant enterococci. b-Lactamase-producing E faecalis strains can still be treated with either imipenem or withb-lactam-b-lactamase inhibitor combinations [17]. Ampicillin-resistant Efaecium strains are generally resistant to all penicillins and imipenem. Forstrains with MICs of up to 64 lg/mL, theoretically very high doses ofampicillin or amoxicillin can be used depending on the site of infection. Forserious infections caused by ampicillin-resistant E faecium, however,vancomycin is the agent of choice, provided that the strain is not alsovancomycin-resistant.

The major implication of high-level aminoglycoside resistance to bothgentamicin 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 wall–active agent alone, whereas cure ratesare as high as 70% to 80% when a bactericidal combination can be used[47]. In animal models, some studies have demonstrated a benefit ofcontinuous-infusion ampicillin therapy [47]. When bactericidal therapycannot be achieved, valve replacement may become necessary for cure.Teicoplanin monotherapy seems to be more active in animal models thanvancomycin monotherapy, but this agent is not available in the UnitedStates [47]. Need for bactericidal therapy is less clear for infections otherthan endocarditis. Aminoglycoside therapy should be discontinued whenhigh-level resistance is identified.

Vancomycin-resistant enterococci currently pose the greatest clinicalchallenge. Most strains of vancomycin-resistant E faecalis retain suscepti-bility to ampicillin and penicillin, and these agents can still be used fortherapy. Vancomycin-resistant E faecium isolates are usually highly resistantto ampicillin and may also have high-level aminoglycoside resistance. Thecombination of penicillin plus vancomycin plus gentamicin has beeninvestigated [48]. Teicoplanin has been used to treat infections caused byvanB strains, but resistance has been noted [49].

Linezolid, an antimicrobial agent in the oxazolidinone class, quinupris-tin-dalfopristin, a parenteral streptogramin combination antibiotic (bothapproved by the Food and Drug Administration in 2000), and daptomy-cin, a novel lipopeptide (approved in 2003), have activity against entero-cocci. Linezolid has excellent in vitro activity against E faecium and Efaecalis and has been effective in treating infections caused by VRE [50].Quinupristin-dalfopristin demonstrates bacteriostatic activity against mostvancomycin-resistant E faecium but has no activity against E faecalis [51].Daptomycin has excellent in vitro activity against vancomycin-susceptible


and vancomycin-resistant E faecium and E faecalis [52]. This topic isdiscussed in more detail elsewhere in this issue.

Other potentially useful agents in the treatment of infections caused byVRE include the tetracyclines, chloramphenicol, newer fluoroquinolones,and rifampin. Many strains are susceptible to chloramphenicol and sometetracycline-resistant strains may remain susceptible to minocycline [53,54].A number of antimicrobial drug combinations have been studied in animalmodels, such as b-lactam–b-lactam, b-lactam–glycopeptide, and b-lactam–fluoroquinolone regimens, but limitations exist for each combination [48].Promising therapeutic agents that are under development or are being testedin 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 toinfection control measures to limit the spread of these isolates in the hospitalsetting [59]. These issues are addressed in the Centers for Disease Controland Prevention (CDC) guidelines for preventing the spread of vancomycinresistance and consist of education; prompt laboratory detection andreporting; appropriate isolation and screening for colonized contacts; andmost importantly, restriction of vancomycin use [60].

Multidrug-resistant Staphylococcus aureusSince 1996, there have been several reports of infections caused by

MRSA with intermediate susceptibility (MIC 8–16 lg/mL) to vancomycin(vancomycin intermediate susceptibility S aureus [VISA]) [61]. There arenow three reports of unique S aureus strains in the United States fullyresistant (MIC > 16 lg/mL) to vancomycin (vancomycin-resistant S aureus[VRSA]) [39,62,291]. Because S aureus is one of the most common causes ofcommunity-acquired and nosocomial infections in the world [63] andbecause most MRSA also are resistant to multiple other agents, theevolution and dissemination of glycopeptide resistance in S aureus isextremely troublesome. In addition, the spread of MRSA from nosocomialto health care–associated settings [64] and the emergence of community-acquired MRSA [65] are concerning developments.

Epidemiology and characteristics of resistance. Staphylococcus aureus is themost common pathogen isolated from nosocomial infection sites in theUnited States and is the most commonly isolated organism from hospital-acquired pneumonia, surgical site infections, and nosocomial infection sitesoverall (18%, 20%, and 19%, respectively) [12]. S aureus is also a frequentcause of bloodstream infections, skin and soft tissue infections, catheter-associated infections, and endocarditis [66,67]. The percentage of S aureusisolates 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 hasbeen a nosocomial pathogen. MRSA has now been identified, however, as


an important pathogen among patients in the outpatient setting who are atincreased risk of staphylococcal colonization and also among patients whohave direct or even indirect exposure to a hospital environment (ie, healthcare-associated MRSA) [64,69]. The occurrence of true community-acquiredMRSA infections in otherwise healthy individuals without risk factors isincreasing in incidence in many areas, particularly in pediatric populations[65].

Methicillin-resistant S aureus has been implicated relatively frequently inhospital outbreaks [70]. Risk factors for nosocomial bacteremia caused byMRSA are the presence of severe, systemic diseases; presence of indwellingcentral venous catheters; increased length of stay in the hospital; and priorantimicrobial exposure [71–73]. Risk factors for health care-associatedbacteremia caused by MRSA include recent hospitalization or receipt ofantimicrobial agents, presence of an indwelling urinary catheter, andresidence in a nursing home [74].

Methicillin resistance in staphylococci is most commonly mediated by themecA gene, which encodes for a single additional PBP, PBP2a, with lowaffinity for all b-lactams [1,7]. This mechanism accounts for methicillinresistance in over 98% of resistant isolates [75]. Strains with mecA-mediatedmethicillin resistance are classically referred to as MRSA. The mecA gene iswidely distributed in both coagulase-positive and coagulase-negative staph-ylococci, is carried on a transposon, and seems to integrate into a single site inthe staphylococcal chromosome along with an additional 30 kilobase ofDNA, the mec locus [76]. In most strains, this includes a regulatory locus,mecR1-mecl, and may include additional insertion elements that are potentialintegration sites for unrelated resistance determinants. Expression of mecAcan be either constitutive or inducible. Expression of resistance also depends,in part, on other chromosomal genes, which are part of cellular peptidoglycanmetabolism and can regulate the degree of resistance without altering levels ofPBP2a. This process is reviewed in detail elsewhere [77]. Interestingly,compared with nosocomial stains, community strains ofMRSA have distinct,smaller mecA loci and possess unique exotoxin gene profiles [65].

Independent risk factors for infections caused by VISA include priorinfection caused by MRSA and antecedent vancomycin use within 3 monthsbefore VISA infection [78]. Most patients in the United States with VISAinfections received repeated, prolonged exposures to vancomycin and receiveddialysis at the time of infection [78]. The mechanisms conferring glycopeptideresistance in VISA seem to involve cell wall thickening with reduced levels ofpeptidoglycan cross-linking and do not seem to require the acquisition of newDNA. It is postulated that reduced levels of peptidoglycan cross-linking leadto an increase in the presence of free D-alanyl–D-alanine side chains. Theseside chains can bind vancomycin outside the cell membrane and preventvancomycin from reaching its cell membrane targets [79,80].

There have been three reports of clinical isolates of VRSA [39,62,291]. Inthese isolates, vancomycin resistance was conferred by the vanA resistance


cluster, which also mediates glycopeptide resistance in some enterococcalspecies [41]. Before isolation of VRSA, co-infection with MRSA and VREwas documented in one patient, suggesting that the vanA gene wastransferred from the VRE strain to the MRSA isolate, as has occurred invitro [39,41].

Methicillin-resistant S aureus isolates containing mecA are resistant to allb-lactam antibiotics. Most nosocomial and health care–associated isolatesfrequently carry multiple other resistance determinants. Many of theseresistance determinants are clustered on transferable chromosomal elementsor plasmids, whereas others are chromosomal in origin [81]. The plasmid-mediated traits include aminoglycoside-modifying enzymes, tetracyclineefflux genes, and macrolide-methylating enzymes, and resistance determi-nants for trimethoprim-sulfamethoxazole. Quinolone resistance is mediatedprimarily by alterations in DNA topoisomerases, but also by the staphy-lococcal norA gene by way of active efflux [7,82]. Resistance to macrolide,lincosamide, and streptogramin antibiotics may be conferred by modifica-tions of target sites, active efflux, and by inactivating enzymes [67,75].Gentamicin resistance also can occur by selection of small-colony, mem-brane energy-deficient mutants. Linezolid resistance occurs by modificationof the 23s ribosome of S aureus [83]. In contrast to nosocomial isolates, mostcommunity-acquired MRSA strains are susceptible to multiple classes ofantibiotics other than b-lactams, including trimethoprim-sulfamethoxazole,clindamycin, aminoglycosides, tetracyclines, and fluoroquinolones [65].

Management of infections caused by multidrug-resistant Staphylococcusaureus. The major reservoir for MRSA in most colonized patients is thenares. Unlike VRE, there is evidence to suggest that colonization can beeradicated from a significant proportion of carriers [84]. Several treatmentregimens have been used, including topical, oral, and combined topical andoral regimens. In studies with long-term follow-up, relapse rates are high,particularly in patients who have chronically colonized sites in addition tothe nares. The major topical agents used include bacitracin and mupirocin.Mupirocin has eliminated nasal and hand colonization in both hospitalpersonnel and colonized patients in long-term care facilities and dialysisunits, and has been used in the preoperative setting to prevent surgical siteinfections caused by S aureus, but increased resistance to this agent is nowbeing seen [85], and a recent controlled trial showed no effect of mupirocinon the prevention of nosocomial S aureus infections [292].

For treatment of community-acquired MRSA infections, clindamycin isoften effective, but should be restricted to erythromycin-susceptible isolates(ie, to those strains with macrolide resistance mediated by efflux and not bymethylating enzymes) [86–88]. Other options include trimethoprim-sulfa-methoxazole, fluoroquinolones, tetracycline, and linezolid [86,87]. Vanco-mycin is also an option, but this must be given by the intravenous route,which complicates outpatient therapy.


The current treatment of choice for nosocomial and health care–associated MRSA infections is intravenous vancomycin. Vancomycin isa less active antistaphylococcal agent than a b-lactam against methicillin-susceptible strains. This may account for the relatively slow response ofsome MRSA infections to treatment [89]. Gentamicin is synergistic withvancomycin in vitro against many MRSA strains; this combination has beenused for bacteremia and endovascular infections. Rifampin plus vancomycinmay be either additive or antagonistic in vitro. This combination may beparticularly useful in the cerebrospinal fluid (CSF) and with infection offoreign bodies. Rifampin resistance emerges quickly when the drug is usedalone [7]. Clindamycin, trimethoprim-sulfamethoxazole, and fluroquino-lones (the latter often in combination with rifampin) have been used forMRSA infections caused by susceptible strains [90]. Resistance to olderquinolones is now common among MRSA, occurring in as many as 90% ofisolates in some hospitals [91]. Quinolone regimens, particularly when usedas a single agent, should be used with caution because resistance can emergeduring therapy. Many strains are tetracycline susceptible, but the use ofmost tetracyclines is limited by the emergence of resistance during therapy.Minocycline has excellent in vitro activity, even against tetracycline-resistantMRSA isolates, and has been used extensively in Japan for MRSAinfections, including endocarditis [92]; however, increasing resistance tominocycline in MRSA has been described. Fusidic acid, which is notavailable in the United States, also has some activity against MRSA whenused in combination with other drugs [84].

For the treatment of infections caused by VISA and VRSA, most strainsremain susceptible to some older agents, doxycycline, minocycline, rifampin,and trimethoprim-sulfamethoxazole [62,78]. For treatment of infectionscaused by VISA, vancomycin may still be an option, particularly if used incombination with another active agent, such as rifampin or an aminoglyco-side, but treatment failures can still occur. Because teicoplanin is in-trinsically less active against S aureus than vancomycin, it is unlikely tobe effective in treatment of VISA or VRSA [93,94]. Other combinationtreatment regimens for MRSA and VISA infection that have been usedsuccessfully with only limited clinical experience or have demonstrated invitro or in vivo synergy include ampicillin-sulbactam and arbekacin [95],and vancomycin and other b-lactam antibiotics [96,97]. There is no clinicalexperience in humans, however, with these combinations for the treatmentof VISA infections.

Linezolid has good in vitro activity against both methicillin-susceptibleand methicillin-resistant S aureus strains [52,98]. Linezolid has been shownto be effective in the treatment of skin and soft tissue infection andnosocomial pneumonia caused by MRSA. Quinupristin-dalfopristin hasexcellent activity against S aureus [52,98]. The combination of vancomycinand quinupristin-dalfopristin has been reported to be effective in thetreatment of patients who failed therapy with vancomycin alone [99]. Other


therapeutic agents with which there is limited clinical experience includedaptomycin, a recently approved agent that has excellent bactericidalactivity against multidrug-resistant S aureus [52,98]; some of the newerfluoroquinolones, such as gemifloxacin, moxifloxacin, and trovafloxacin[100–102]; and agents under development including evernimicin (SCH27,899), an oligosaccharide [103], novel glycopeptides including oritavancin(LY333328) and dalbavancin (BI397) [57,104], and agents belonging to theglycylcycline antimicrobial drug class [105]. Novel cephalosporins activeeven against staphylococci carrying the mecA gene are also entering clinicaltrials.

The CDC has published guidelines regarding the prevention and controlof infections caused by VISA and VRSA [106]. These guidelines focus on thejudicious use of vancomycin, the use of effective laboratory screeningmethods, and obtaining investigational antimicrobial drugs when clinicallyappropriate.

Penicillin and multidrug-resistant pneumococciInfections caused by S pneumoniae are a major cause of morbidity and

mortality worldwide. In the United States, pneumococcal disease accountsfor approximately 3000 cases of meningitis, 500,000 cases of pneumonia,and 7 million cases of otitis media yearly [107]. The incidence of invasivepneumococcal disease was 23.2 cases per 100,000 in the United States in1998 [108]. Penicillin-resistant pneumococci from sites other than CSF areeither intermediately resistant, with MICs of 1 to 2 lg/mL, or highly resis-tant, with MICs of 4 lg/mL or greater; breakpoints for isolates from theCSF are one dilution lower (CSF breakpoints: susceptible 0.5 lg/mL, inter-mediate 1 lg/mL, resistant 2 lg/mL).

Epidemiology and characteristics of resistance. In a recent study, 34.2% ofpneumococci isolated in the United States were not fully susceptible topenicillin, and 21.5% of isolates had high-level resistance [109]. High ratesof resistance have been reported in other countries [110]. Interestingly, mostresistant isolates worldwide belong to a limited number of serotypes. Ina recent study of American isolates, 89% of resistant strains were serotypes6B, 23F, 14, 9V, or 19F [111].

Molecular analyses have demonstrated clonal dissemination of resistantisolates worldwide. These observations support in vitro data characterizingpenicillin resistance as being stable, and having the ability to persist andspread in the absence of antibiotic selective pressure. Molecular studies alsosuggest that resistant isolates arose independently. Together, these obser-vations suggest that low-level penicillin resistance probably evolved in-dependently under selective antibiotic pressure in a limited number ofpneumococcal serotypes, and subsequent evolution to high-level resistancemay have occurred by recombination events. Well-adapted, high-levelresistant strains probably disseminated widely by clonal spread. Risk factors


for the acquisition of penicillin-resistant strains include prior hospitalizationand other institutionalization, increased length of hospital stay, attendancein child care centers, frequent otitis media infections, having had a recentepisode of pneumonia, and prior antibiotic exposure [112–114].

Penicillin-resistance in S pneumoniae is caused by changes in the genesthat encode for the five high-molecular-weight PBPs of the organism[112,115]. These changes result in PBPs with reduced affinity for b-lactamagents. PBP profiles of the most highly resistant strains generally show morePBP alterations than do those of low-level resistant strains [115]. In additionto clonal dissemination of resistant strains, resistance can spread byhomologous recombinational events among PBP genes of different strains[7]. Such events can occur between different pneumococcal species andbetween pneumococci and closely related viridans streptococcal species.Oral streptococci have been postulated to be the major reservoir for thenovel DNA required to create the genetic sequences demonstrated by someof the altered pneumococcal PBP genes [7]. Along with altered PBP,penicillin-resistant pneumococci also demonstrate altered peptidoglycanstructures. Penicillin tolerance may be found in strains with reducedpenicillin susceptibility that fail to lyse at penicillin concentrations farabove the MIC; however, the clinical significance of this observationremains unclear [116].

The PBP changes in penicillin-resistant strains also result in diminishedsusceptibility to other b-lactam agents [117], but the levels of resistance todifferent agents vary greatly. Penicillin-resistant strains are uniformlyresistant to penicillin derivatives, such as ampicillin and the ureidopenicillins(eg, amoxicillin, ampicillin, piperacillin, and ticarcillin), and generally areresistant to first- and second-generation cephalosporins. Certain third-generation agents, particularly cefotaxime and ceftriaxone, are ofteneffective, in part because of their high level of activity and in part becausethe tissue levels attained by these agents are high [118,119]. A source ofconcern is the observation that strains resistant to high concentrations ofcefotaxime and ceftriaxone (MIC � 2 lg/mL) are becoming increasinglycommon (14.4% of all strains reported in one recent study were ceftriaxone-resistant) [109]. Infections caused by these resistant strains have beenassociated with clinical failure, particularly in cases of pneumococcalmeningitis [118].

Penicillin-resistant strains are frequently also resistant to other non–b-lactam antimicrobial agents and are often multidrug resistant. Resistance toerythromycin, tetracycline, trimethoprim-sulfamethoxazole, and chloram-phenicol is most common [109]. Macrolide resistance in S pneumoniae ismost 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 efflux pumps(mefA, mefE) resulting in variable-level resistance to macrolides alone (Mphenotype). The increase in macrolide resistance from 10.6% to 20.4%


among invasive isolates in the United States from 1995 to 1999 was almostentirely caused by an increase in M phenotype strains [120]. The clinicalimplications of M-type resistance for use of newer macrolides and azalidesremains controversial, but these isolates can be treated with clindamycin[121]. Chloramphenicol and rifampin resistance is common in South Africanisolates, but rare in the United States [110,118]. Although vancomycin-tolerant pneumococcal isolates have recently been isolated [122], no strainsfully resistant to vancomycin have been reported. Although the olderfluoroquinolones (eg, ciprofloxacin) lack reliable activity against pneumo-cocci, newer fluoroquinolones, such as levofloxacin, gatifloxacin, moxiflox-acin, gemifloxacin, and garenoxacin, inhibit most strains at achievable levels[123].

Fluoroquinolone resistance has developed during therapy, especially inpatients with prior fluoroquinolone exposures, leading to clinical failure[124]. Resistance to the newer formulations in the United States, however,remains uncommon (\1%) [123]. The mechanism of decreased susceptibil-ity to the newer fluoroquinolones is primarily caused by mutations in theparC gene of topoisomerase IV and the gyrA gene of DNA gyrase [125].

Management of infections caused by penicillin-resistant pneumococci. Noevidence indicates that penicillin-resistant strains are more virulent thanother pneumococcal isolates, but the outcome of serious infections causedby resistant strains may be worse because of delays in initiation of effectivetreatment [118,126].

The most challenging management issues concern the treatment ofmeningitis caused by resistant pneumococci. Although third-generationcephalosporins are active against many intermediately and highly penicillin-resistant strains, treatment failures have been reported in patients withisolates having MICs to ceftriaxone or cefotaxime of 2 lg/mL [126].Vancomycin, the preferred agent in the treatment of meningitis caused bycephalosporin-resistant pneumococci, remains active against all pneumo-coccal isolates, but penetration into the CSF is unreliable. In one un-controlled series, 4 of 11 patients failed to improve on vancomycinmonotherapy [127]. The combination of vancomycin plus ceftriaxone isoften used as empiric therapy until the results of susceptibility tests areknown. Interestingly, in animal models, in the absence of steroids, thecombination of vancomycin and ceftriaxone appeared more effective thaneither agent alone [128], raising the possibility that the combination mightbe effective treatment for patients with penicillin-resistant pneumococcalmeningitis; 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 cefotaximebut is rifampin susceptible, combination therapy with vancomycin plusrifampin might be effective [128]. In these circumstances, vancomycin levelsshould be maximized to ensure adequate central nervous system penetration.


Carbapenems traditionally have had excellent in vitro activity againstmost pneumococci [130]. Imipenem has been used successfully for resistantpneumococcal meningitis, but this agent has a relatively high incidence ofinducing seizures, particularly in the presence of other brain abnormalities[130]. Meropenem has a lower incidence of seizure induction but clinicalexperience is limited [131]. Among isolates with decreased susceptibility topenicillin, carbapenems may have reduced activity, potentially limiting theirtherapeutic role [132,133]. Another treatment option is chloramphenicol,but treatment failures have been described [134].

Steroid therapy can reduce antimicrobial penetration into the CSF bydecreasing inflammation. In animal models, steroid therapy has beenassociated with failure of cephalosporin or vancomycin monotherapy. Thecombination of ceftriaxone and rifampin remained effective, however, evenwhen given concomitantly with steroids [118]. In addition, a recent trialdemonstrated that dexamethasone decreased mortality in adults with acutebacterial meningitis [135]. All patients with resistant pneumococcal menin-gitis should undergo early repeat lumbar puncture to document sterilizationof the CSF.

For pneumonia, bacteremia, and other invasive nonmeningeal infectionsthere are several therapeutic options including penicillins and cephalospo-rins. Blood and tissue levels of these b-lactams are much higher than thoseachieved in the CSF. In series of patients with community-acquiredpneumococcal infections, overall response rates for patients with susceptibleand penicillin-resistant isolates were identical, even when penicillin orampicillin was used [118]. The breakpoints for susceptibility to third-generation cephalosporins for nonmeningeal sites are higher than those forCSF isolates. Vancomycin may be considered for highly resistant organisms,unless the infecting organism is susceptible to third-generation cephalospo-rins, in which case the cephalosporins are preferred. The newer fluoroqui-nolones (eg, levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin), andfor susceptible strains, the macrolides, tetracycline, clindamycin, chloram-phenicol, and trimethoprim-sulfamethoxazole, are acceptable alternativesfor treating infections outside the CSF [118,136]. Telithromycin, a ketolideantimicrobial agent recently approved for the treatment of respiratoryinfections, has good in vitro activity against pneumococcal isolates withreduced susceptibility to penicillin [109]. Telithromycin has reduced activity,however, among strains of pneumococci that exhibit high rates of macrolideresistance [137]. Guidelines for the treatment of community-acquiredpneumonia, including bacteremic pneumococcal pneumonia, were recentlypublished [136].

One other important clinical dilemma is the effective treatment of otitismedia caused by resistant pneumococci. Initial therapy frequently is empiricand the antibiotic administered should have activity against Haemophilusinfluenzae. The CDC consensus group recommends amoxicillin in doses of80–90 mg/kg/d as the agent of choice for otitis media in children [138]. These


doses result in middle ear levels that inhibit resistant pneumococci. Amoxi-cillin-clavulanic acidmay also be used. This agentmay be given using the usualdose (eg, 40 mg/kg/d) but an additional dose of amoxicillin (40 mg/kg/d)should be added. Alternatively, the reformulated version of amoxicillin-clavulanic acid (Augmentin ES-600) that contains additional amoxicillin canbe given in divided doses of 90mg/kg/d (based on the amoxicillin component).

Linezolid, quinupristin-dalfopristin, and daptomycin are emerging astreatment options, but clinical experience is limited [52,139]. Evernimicin (anovel oligosaccharide) [140] also had good activity in vitro against resistantS pneumoniae.

To limit the dissemination of resistant pneumococcal strains, health careprofessionals should adhere to the CDC recommendations regardingadministration of the pneumococcal polysaccharide and protein-polysac-charide conjugate vaccines [107,141,142].

Resistant gram-negative microorganisms

Escherichia coli and Klebsiella spp resistant to broad-spectrumcephalosporins

Escherichia coli and Klebsiella are common hospital pathogens. E coli isthe most common gram-negative pathogen associated with nosocomialinfections and is the most common organism isolated in cases of hospital-acquired urinary tract infections (representing 12% and 24% of pathogensisolated from infection sites, respectively) [12]. Klebsiella pneumoniae is alsocommon, representing 5% of nosocomial infection site isolates and 8% ofhospital-acquired urinary tract infections and pneumonia isolates [12].Resistance of these organisms to broad-spectrum cephalosporins is largelymediated by extended-spectrum b-lactamases (ESBLs), designated Bush-Jacoby-Medeiros group 2be. These enzymes confer resistance to oxyimino-b-lactam antibiotics. Most ESBLs are derivatives of TEM and SHV, whichhave undergone amino acid substitutions at the active site of the enzyme.These enzymes are often plasmid-borne. Depending on the location of thesubstitution, susceptibility of cefotaxime, ceftazidime, and aztreonam to theb-lactamase can be variably diminished. ESBLs are most commonlyexpressed in K pneumoniae, Klebsiella oxytoca, and E coli, although theyhave been detected in other organisms including Salmonella spp, Paeruginosa, Proteus mirabilis, and other Enterobacteriaceae [143–147].Plasmids producing ESBLs often carry resistance to other antibiotics. Therole of ESBLs in hospital and nursing home outbreaks, and their ability tobe transferred to other bacterial species by transfer of plasmid DNA, makeseffective control and treatment of ESBLs a growing challenge.

Epidemiology and mechanisms of resistance. Extended-spectrum b-lacta-mases were first discovered in Europe in 1983 and soon after in the UnitedStates. Since then their prevalence has increased. By 1990, 14% of all


K pneumoniae isolated from French hospitals were ESBL producers, withrates approaching 50% in some hospitals [148]. In some American hospitalsthe rate is as high as 40% [149]. As reported by the CDC, in 2002, the rate ofceftazidime-resistant K pneumoniae reached 14%, and ceftazidime-resistantE coli reached 6.3% in American ICUs [11]. Teaching hospitals have a higherprevalence of resistance [150].

Extended-spectrum b-lactamases–producing organisms are generallynosocomial, although nursing home outbreaks have been reported [151].Outbreaks can occur through either clonal spread of a specific plasmid-carrying strain, or through transfer of a particular plasmid to a variety ofbacterial strains, or even to different bacterial genera [151,152]. Resistantorganisms can pass from patient to patient on the hands of health careproviders [153]. Risk factors for acquisition of ESBLs are generally similarto those reported for other hospital-acquired organisms and includeemergency abdominal surgery, mechanical ventilation, the presence ofpercutaneous devices, tracheostomy, longer length of hospital stay, andincreased patient morbidity [150,151,154]. Of particular interest are thoserisk factors associated with antimicrobial drugs. Exposure to antibiotics ingeneral, and particularly to ceftazidime and aztreonam, has been associatedwith an increased prevalence of ESBL-producing organisms [155,156]. Otherstudies, however, have found no association between third-generationcephalosporin use and ESBL emergence [151,157]. Exposure to trimetho-prim-sulfamethoxazole has also been associated with acquisition of ESBLs[151]. Restriction of cephalosporin use has been associated with control ofhospital outbreaks [158,159].

More than 70 ESBLs have been described, with greater than 100 in theTEM class, over 40 in the SHV family, over 30 in the CTX-M class, and 15in the OXA family. A website maintains an up-to-date, complete listing ofall identified ESBLs: http://www.lahey.org/studies/inc_webt.asp [160]. EachESBL has unique amino acid substitutions at active sites of the enzyme,affecting its isoelectric point and affecting the enzyme’s affinity for andhydrolytic activity of oxyimino-b-lactams [150]. Different substitutions havevariable effects on the activities of the b-lactamases. Most ESBLs haveincreased activity against ceftazidime and aztreonam and diminishedactivity against cefotaxime, although the opposite may be true in somecases. For example, in SHV and TEM b-lactamases, a serine substitution forglycine at amino acid 238 causes decreased hydrolytic activity againstceftazidime but increases activity against cefotaxime [150]. CTX-M–typeESBLs, however, generally have more activity against cefotaxime thanceftazidime [161]. Multiple b-lactamases conferring resistance to differentclasses of b-lactam antibiotics can be found within a single bacterial strain.The diversity of cephalosporin susceptibility profiles manifested by differentESBL enzymes makes detection of some ESBL-producing strains a majorchallenge for the clinical laboratory. These enzymes are not capable ofhydrolyzing cephamycins and carbapenems [162].

http://www.lahey.org/studies/inc_webt.asp


Another mechanism facilitating b-lactamase activity involves loss ofporin channels in the outer cellular membrane and up-regulation of effluxpumps, decreasing antibiotic concentrations in the periplasmic space andfacilitating hydrolysis by b-lactamases. This often results in increasedresistance to cephalosporins, cephamycins, and b-lactam inhibitors[150,163,164]. Plasmids producing ESBLs often carry resistance to otherantibiotics, including aminoglycosides, tetracyclines, chloramphenicol, tri-methoprim, and sulfonamides [150].

Escherichia coli and Klebsiella possess other mechanisms of b-lactamantibiotic resistance, unrelated to ESBL production. Resistance to extended-spectrum cephalosporins, cephamycins, oxyimino-b-lactams, and b-lactaminhibitors in E coli and K pneumoniae can be mediated by plasmid-mediatedb-lactamases similar to those chromosomal AmpC enzymes produced insuch species as E cloacae and Serratia marcescens [165,166]. Additionalporin mutations can result in carbapenem resistance [150]. Carbapenemresistance in K pneumoniae can also be modulated by plasmid-mediatedmetallo-b-lactamase production [150] and by the production of plasmid-mediated class A carbapenem-hydrolyzing enzymes [167]. Resistance to b-lactam–b-lactamase inhibitor antibiotics can occur by alterations in porinchannels; TEM and SHV hyperproduction; by the production of inhibitor-resistant 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 toquinolones and aminoglycosides, leaving few alternatives for treatment[168,169]. Alterations in DNA gyrase (topoisomerase II, and to a lesserextent toperisomerase IV), porin channel mutations, and efflux mechanismscan confer quinolone resistance [82]. Enzymatic modifications can lead toaminoglycoside resistance [67].

Implementation of effective laboratory screening methods for the de-tection of ESBLs is a critical factor in the control of hospital outbreaks andis necessary for accurate surveillance. These methods are discussed in moredetail elsewhere in this issue.

Management of infections caused by Escherichia coli and Klebsiella sppresistant to broad-spectrum cephalosporins. Treatment of infections causedby organisms expressing ESBLs is a growing challenge. Even when theseorganisms display in vitro susceptibility to third-generation cephalosporins,treatment failures often occur, limiting the effectiveness of these antibioticsin vivo [150,156]. Cephamycins, such as cefoxitin, are a treatment option,but plasmid-mediated AmpC b-lactamase production and porin channelmutations may limit their clinical utility [150]. Ceftibuten, an oral oxyimino-b-lactam that binds less tightly to ESBLs than other cephalosporins, hasreasonable in vitro activity [170], but clinical experience with this antibioticis limited. Cefepime, a fourth-generation cephalosporin, inhibits 90% to100% of ESBL-carrying organisms in vitro [171,172], but it is still subject to


hydrolysis and inoculum effects [150,172]. Compared with ceftazidime-susceptible organisms, ceftazidime-resistant K pneumoniae are moreresistant to other classes of antibiotics [168,173]. In one study, ESBL-producing isolates were resistant to gentamicin and ciprofloxacin in 67%and 45% of cases, respectively, compared with rates of 3.6% and 2% forceftazidime-susceptible organisms [173]. For susceptible isolates, amino-glycosides, quinolones, and trimethoprim-sulfamethoxazole remain effectivetreatment options. Carbapenems, including imipenem, meropenem, andertapenem, are effective in the treatment of bacteria containing ESBLs, withsusceptibility rates ranging from 93% to 100% [156,172–174]. Mutationsleading to ESBL formation may increase in vitro susceptibility to b-lactam–b-lactam inhibitor antibiotics. These antimicrobial drugs possess good invitro activity against some ESBL-expressing organisms [175,176] and havebeen shown to protect against ESBL acquisition [177]. For the treatment ofinfections caused by ESBL-producing organisms, however, these agentsshould be used with caution. Even in the presence of in vitro susceptibility,clinical failures may occur [178].

Pseudomonas and other gram-negative rods producing AmpCAnother important mechanism of resistance in gram-negative organisms

is the production of inducible chromosomal b-lactamases, most notablyAmpC (Bush-Jacoby-Medeiros group 1). The presence of these chromo-somal enzymes is a species-specific characteristic of some Enterobacter,Serratia, Pseudomonas, Citrobacter, and indole-positive Proteus species[179]. These organisms are virulent nosocomial pathogens that can presentfulminantly, and because of effective resistance mechanisms, they are oftendifficult to treat effectively. The appearance of plasmid-mediated b-lactamases similar to AmpC in K pneumoniae and E coli raises concernsregarding the potential for widespread dissemination of this resistancemechanism [165,166].

Epidemiology and mechanisms of resistance. Pseudomonas aeruginosa isa common nosocomial pathogen. It has been associated with 9% of allhospital-acquired infection isolates, and is the most common cause ofnosocomial gram-negative pneumonia, representing 17% of isolates. Enter-obacter spp are also common pathogens, representing 6% of all hospital-acquired isolates and 11% of pneumonia isolates [12]. In ICUs, theseorganisms are the most common cause of gram-negative bacteremia(accounting for �9% of all bloodstream pathogens); gram-negativenosocomial pneumonia (�28% of all pathogens); and gram-negativeurinary tract infections (�17%) [66].

The production of AmpC is regulated through complex interactionsamong chromosomal bacterial genes. These interactions are influenced bychanges in the cytoplasmic concentrations of intermediates of mureinpeptidoglycan synthesis and degradation [180,181]. AmpC is usually not


produced at high levels initially, but exposure to particular b-lactamantibiotics, including cephalosporins, cephamycins, monobactams, andextended-spectrum penicillins, can cause a transient increase or inductionof AmpC production [180–182]. Certain genetic mutations lead to consti-tutive cephalosporinase production [181]. In both of these cases, the increasein AmpC production is regulated by changes in the homeostatic levels ofintermediate products of murein synthesis [180,181]. This topic is covered ingreater detail elsewhere [162,180–182].

Although resistance of these organisms to b-lactam antibiotics isprimarily conferred by AmpC production, the relative impermeability ofthe outer cellular membrane and structural alterations of the outermembrane often also contribute to b-lactam resistance [67]. Cefepime,a fourth-generation cephalosporin, has a lower affinity for b-lactamasesthan third-generation cephalosporins, penetrates the outer membrane moreeffectively, and exhibits increased affinity for some essential PBP [183].Cefepime often exhibits greater activity against AmpC-producing organismsthan other cephalosporins [184,185].

Resistance to classes of antibiotics other than b-lactams is also prevalentamong these organisms. In P aeruginosa (and also in Enterobacter spp andother chromosomal AmpC-producing organisms) carbapenem resistancecan occur by mutational loss of a porin channel, and by acquired zinc b-lactamases (also called metallo-b-lactamases), IMP and VIM [186–189].These metallo-b-lactamases can also rapidly hydrolyze cephalosporins andpenicillins (but not aztreonam), and can be encoded by integrins, raisingconcerns regarding horizontal spread of this resistance trait [186–188]. Insome instances, multidrug efflux systems may contribute to the expressionof carbapenem resistance [190]. Independent risk factors for acquisition ofimipenem-resistant P aeruginosa include an ICU stay; increased duration ofhospitalization; and exposure to imipenem, piperacillin-tazobactam, andaminoglycosides [191]. Aminoglycoside resistance can be conferred byenzymatic modification and by cell wall impermeability. Quinolone re-sistance is often modulated by antibiotic efflux systems and by alterations inDNA gyrase [188].

Management of infections caused by Pseudomonas and other enteric gram-negative rods producing AmpC. In 2002, rates of ceftazidime resistance of32% and 30% for Enterobacter spp and P aeruginosa were reported inAmerican ICUs. Compared with resistance rates from 1997 to 2001, the rateof ceftazidime resistance for P aeruginosa increased by 22% [11]. Althoughisolates may initially test as ‘‘susceptible’’ to third-generation cephalospo-rins, resistance can emerge during treatment with these antibiotics, dependingon the site of infection and the magnitude of inoculum of organisms present.In one study, 19% of bloodstream E cloacae isolates developed resistance tothird-generation cephalosporins once exposed to these agents [192]. AmpCis not susceptible to b-lactamase inhibitors. Cefepime, a fourth-generation


cephalosporin, is a much weaker inducer of AmpC production than third-generation cephalosporins, and has good activity against P aeruginosa[185,193]. In recent studies, greater than 80% of Pseudomonas isolates weresensitive to this antibiotic, as were more than 99% of other AmpC-producing Enterobacteriaceae discussed previously [184,185]. The carbape-nems are another effective treatment option. In recent studies, 86% ofPseudomonas isolates and more than 98% of Enterobacter isolates remainedsensitive [193,194]. P aeruginosa resistance to imipenem is emerging,however, in certain regions of the United States [195]. Quinolones andaminoglycosides are often effective, although resistance is also emerging tothose classes [196]. In cases of multidrug-resistant P aeruginosa infection,intravenous colistin is a therapeutic option, although renal toxicity is oftena limiting factor [197,198]. Aerosolized colistin is sometimes used for thetreatment of pulmonary infections because of multidrug-resistant P aerugi-nosa [199]. When treating organisms that have the ability to produce AmpC(particularly Enterobacter spp), cephalosporins and extended-spectrumpenicillins should be used in combination with another class of antimicro-bial drugs or should be avoided altogether. Because of the high prevalenceof antibiotic resistance and because of the potential for emergence ofresistance, deep-seated Pseudomonas infections should be treated with twoactive agents that demonstrate additive or synergistic activity, such as a b-lactam in combination with either an aminoglycoside or fluoroquinolone,during the initial stages of therapy. After clinical improvement is noted, andthe burden of infection is decreased, de-escalation to a single antibiotic isoften appropriate.

Stenotrophomonas maltophiliaStenotrophomonas maltophilia (formerly Xanthomonas maltophilia) is an

aerobic gram-negative rod that causes bacteremia, respiratory tract infec-tion, 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) withbroad activity against penicillins, carbapenems, cephalosporins, and b-lactam inhibitors [162,202]. L2 is a cephalosporinase (Bush-Jacoby-Me-deiros class 2e) active against cephalosporins and monobactams. A TEM-2b-lactamase encoded on a Tn-1 like transposon was also recently clonedfrom an S maltophilia isolate [203]. Decreased membrane permeabilitysecondary to porin mutations often leads to quinolone resistance [204].Aminoglycosides generally are not active against S maltophilia, probablybecause of inactivating enzymes and alterations in the cell surface [202].Overexpression of the multidrug efflux pump SmeDEF in S maltophilia maycontribute to decreased susceptibility to tetracyclines, erythromycin, quino-lones, and chloramphenicol [205].

Trimethoprim-sulfamethoxazole, a bacteriostatic agent, is the treatmentof choice for infections caused by S maltophilia. Ticarcillin-clavulanate is the


only b-lactam–b-lactam inhibitor combination antibiotic that is reliablyeffective and may be used in patients who are intolerant of or infected withan isolate resistant to trimethoprim-sulfamethoxazole [202]. Resistance toboth of these agents is increasing; recent studies reported that 5% of Smaltophilia in the United States and 10% of isolates in Europe were resistantto trimethoprim-sulfamethoxazole [206]. Ceftazidime does not possessreliable activity and should not be used empirically [206]. Cefepime hasgreater activity than ceftazidime (88.7% versus 35.3% of Americanbloodstream isolates susceptible in one study) [207]. Resistance to imipenemapproaches 100% [207]. Among the available fluoroquinolones, gatiflox-acin, levofloxacin, moxifloxacin, and trovafloxacin have better in vitroactivity than ciprofloxacin [206,208]. In one study, 93% of isolates weresusceptible to gatifloxacin [206]. Minocycline has good in vitro activity [208],but clinical experience is limited. Use of antibiotic combinations, includingtrimethoprim-sulfamethoxazole plus ticarcillin-clavulanate or a third-gen-eration cephalosporin, and trimethoprim-sulfamethoxazole plus minocy-cline plus ticarcillin-clavulanate is being explored for the treatment ofserious S maltophilia infections [209–211]. Although aztreonam is usuallyinactive against S maltophilia, one study demonstrated synergistic activity invitro when combined with ticarcillin-clavulanate [211].

Acinetobacter sppAcinetobacter 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-spectrumantimicrobial agents are particularly susceptible to invasive Acinetobacterinfection [212–215]. Acinetobacter is an important cause of nosocomialbloodstream infection and can cause soft tissue infection, urinary tractinfection, abdominal infection, meningitis, and endocarditis [216,217].Hospital outbreaks occur, and often are related to contaminated respiratoryequipment [212].

Resistance mechanisms to b-lactam antibiotics in Acinetobacter are notclearly understood, but resistance is common. Resistance frequently seems tobe related to b-lactamase production, but other mechanisms have beenidentified. TEM-l and CARB enzymes seem to confer resistance to penicillinsand some narrow-spectrum cephalosporins, whereas chromosomally pro-duced cephalosporinases and plasmid-mediated ESBLs are thought tomodulate resistance to broader-spectrum cephalosporins [162,218]. Carba-penem resistance is conferred by multiple different mechanisms includingcarbapenemase production of the IMP and VIM-type, production of OXA-type b-lactamases, reduced cellular uptake, target mutations, and alterationsin the PBP [186,219–221]. Aminoglycoside resistance is mediated by amino-glycoside-modifying enzymes, and quinolone resistance by mutationalchanges of topoisomerase IV [222,223].


Carbapenems are themost reliable therapeutic agents for infections causedby Acinetobacter, but resistance has begun to emerge in multiple geographicareas. Recent studies have reported rates of carbapenem resistance inAcineto-bacter baumani, themore resistantAcinetobacter species, as high as 11% [224].A 1999 study reported meropenem resistance at greater than 50% in all iso-lates of A baumani recovered from 15 hospitals in Brooklyn, New York [195].b-Lactam–b-lactamase inhibitor combination antibiotics have good in vitroactivity againstAcinetobacter lwoffi (�15% are resistant) but are less effectiveagainstA baumani (20%–30% are resistant to piperacillin-tazobactam) [224].Ampicillin-sulbactam may be active against strains of Acinetobacter resistantto all other b-lactam agents, perhaps because of the unique antimicrobialactivity of the sulbactam component against some acinetobacters. Ceftazi-dime and cefepime have modest activity, but approximately 35% of A lwoffiandA baumani strains are resistant [224]. Aminoglycoside resistance occurs inapproximately 20% to 30% of A baumani isolates [215]. Resistance toquinolones is variable, precluding use of these drugs empirically before theresults of susceptibility tests are known. In one study, approximately 80% ofisolates tested were found to be ciprofloxacin-resistant [225]. Colistin isa therapeutic option for strains resistant to all other antibiotics [197].

Salmonella sppSalmonellae are gram-negative bacilli that are important human patho-

gens. Salmonella typhi and Salmonella paratyphi colonize only humans anddisease is acquired through close contact with infected individuals or carriers.Infection with S typhi or S paratyphi can cause typhoid fever, a serioussystemic illness. Nontyphoidal species, such as Salmonella enteritidis andSalmonella enterica, are food-borne pathogens that can asymptomaticallycolonize the human intestine or cause clinical illnesses, such as gastroenteritisand bacteremia. Resistance to antimicrobial agents used to treat typhoidaland nontyphoidal species has emerged and disseminated rapidly.

Resistance to chloramphenicol in S typhi emerged in the 1970s, andseveral major outbreaks have been caused by chloramphenicol-resistantstrains [226,227]. Resistance to chloramphenicol is often mediated by a self-transferable plasmid (IncHI) that also mediates resistance to sulfonamides,tetracycline, amoxicillin, trimethoprim-sulfamethoxazole, and streptomycin[226,227]. Resistance to the fluoroquinolones is an emerging problem,particularly in Asia, and is usually mediated by chromosomal pointmutations in the gyrA gene. Resistance to nalidixic acid may predict clinicalfailure of quinolone therapy, even among isolates with in vitro quinolonesusceptibility [227–229]. Resistance to third-generation cephalosporins (eg,ceftriaxone and cefotaxime) has occurred sporadically [230].

The quinolones, such as ciprofloxacin, are considered the drugs of choicefor empiric treatment of typhoid fever, except in areas of the world wherequinolone resistance is common (eg, Asia) [227]. Resistance to nalidixic acidwas reported among 23% of S typhi isolates identified through the National


Antimicrobial Resistance Monitoring System in 2000 [229]. Resistance tociprofloxacin 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 wasreported in 26% of all S typhi isolates [231]. Other potential oral alternativesfor treatment of S typhi infections include amoxicillin, trimethoprim-sulfamethoxazole, cefixime, azithromycin, and chloramphenicol, as long asthese agents possess in vitro activity against a given strain [227]. Third-generation cephalosporins, such as ceftriaxone and cefotaxime, remainactive but require intravenous administration.

Resistance among nontyphoidal strains of salmonellae emerged in the1990s and spread rapidly. Emergence of multiresistance to ampicillin,chloramphenicol, and trimethoprim-sulfamethoxazole is caused in part bythewidespread dissemination ofSalmonella typhimuriumdefinitive phage type104 (DT 104). This strain contains chromosomal determinants that mediateresistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole,streptomycin, and tetracycline [232,233]. Resistance to fluoroquinolones hasalso emerged among nontyphoidal salmonellae in the United Kingdom(includingDT104), and in theUnited States resistance to the fluoroquinolonesis often mediated by gyrA mutations [234]. Resistance to broad-spectrumcephalosporins is conferred by plasmid-mediated AmpC-type cephalospo-rinase production [235] and sometimes by ESBL production [236]. Resistanceto 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 indicatedexcept if there is extraintestinal disease or a high risk of extraintestinaldisease [239]. Despite the emergence of resistant strains, the fluoroquino-lones remain reliable agents for the treatment of most invasive infectionscaused by nontyphoidal salmonellae. In 1999, approximately 8% of BritishS typhimurium and S enteritidis isolates tested were quinolone resistant[240]. In the United States, quinolone resistance is much less common, butoutbreaks caused by quinolone-resistant strains have occurred, includingone in a nursing home from 1996 to 2000 [241]. For isolates that aresusceptible to trimethoprim-sulfamethoxazole or ampicillin, these agents aregood therapeutic options. Multidrug-resistant S typhimurium DT104 nowaccounts for approximately 9% of Salmonella isolates and approximately30% of S typhimurium isolates in the United States, however, limiting theefficacy of these agents [233,242]. Broad-spectrum cephalosporins, such asceftriaxone and cefotaxime, have remained active against most nonty-phoidal salmonella isolates, although strains resistant to these agents havebeen isolated sporadically in the United States [243,244].

Campylobacter jejuniCampylobacter spp are fastidious, curved, motile gram-negative bacilli

and are the leading bacterial food-borne cause of diarrhea and a common


cause of travelers’ diarrhea [245,246]. An estimated 2.1 to 2.4 million casesof campylobacteriosis occur annually in the United States [247]. Indeveloping countries, Campylobacter is one of the most frequently isolatedbacterial pathogens in infants with diarrhea [248]. Fifty percent to 70% ofall Campylobacter infections in humans are likely related to consumption ofcontaminated poultry [248,249].

Campylobacter jejuni is responsible for more than 90% of human cases ofcampylobacteriosis [249]. C jejuni usually causes self-limited watery orbloody diarrhea associated with fever and abdominal pain, and rarely causesbacteremia, septic arthritis, endocarditis, and osteomyelitis [248,249].Noteworthy potential postinfectious complications of Campylobacter in-clude Guillain-Barre syndrome and reactive arthritis [249].

Fluoroquinolone resistance was first noted in the early 1990s in Asia andEurope, which coincided with the addition of enrofloxacin to animal feed[249,250]. In Spain, quinolone resistance increased from 1% during theperiod 1985 to 1987 to 81% 10 years later [251]. Thailand experienceda similar increase during the 1990s (0% in 1990 to 84% in 1995) [252]. Ratesof fluoroquinolone resistance among Campylobacter are lower in the UnitedStates, but agricultural use of fluoroquinolones again coincided withincreased resistance. In one American study, resistance increased from1.3% in 1992 to 10.2% in 1998 [253]. Imported isolates can contributesignificantly to local resistance patterns [253,254].

Resistance to the macrolides remains low (\5% in most regions)[255,256]. Most isolates are susceptible to aminoglycosides, chloramphen-icol, clindamycin, nitrofurantoin, and imipenem [249]. A point mutation atcodon 86 in the gyrA DNA gyrase gene is the most common mutationconferring quinolone resistance [257]. Mutations in the parC gene occur lessfrequently [250], but the presence of mutations in both regions confers high-level quinolone resistance [250]. Multidrug efflux pumps may also have a rolein the development of quinolone resistance [258]. Erythromycin resistance inCampylobacter is caused by ribosomal alterations [250].

For patients with uncomplicated Campylobacter infection, supportivecare with administration of fluids is typically all that is required. Antimicro-bials are recommended for pregnant or immunocompromised patients andthose with invasive or severe illness (eg, high fevers or symptoms for greaterthan 1 week) [239]. Fluoroquinolones remain a therapeutic option for manyisolates, but because of increasing resistance, treatment with a macrolide,particularly erythromycin, is recommended [239].

Neisseria meningitidisNeisseria meningitidis, a gram-negative diplococcus, is an important

cause of septicemia and pyogenic meningitis. Persons with asplenia (func-tional or anatomic), cirrhosis, deficiency of properdin or terminal comple-ment components, and possibly persons infected with HIV are predisposedto invasive meningococcal infection [259]. Additional risk factors for


infection include low socioeconomic status, African American race, expo-sure to tobacco smoke, and the presence of concurrent viral infection of theupper respiratory tract. New military recruits and students living indormitories are also at increased risk for invasive infection [260].

Resistance of N meningitidis to antimicrobial drugs was not an issue untilthe 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 chromo-somal gene encoding dihydropteroate synthase [262]; these chromosomalalterations can be transferred between N meningitidis serogroups and toother Neisseria spp [262]. Meningococcal strains with MICs to penicillinranging from 0.1 to 1 lg/mL are considered to have intermediate resistanceto penicillin [261]. The predominant mechanism of reduced penicillinsusceptibility is a change in PBP2 and PBP3. Alterations in PBP2 lead todecreased affinity to penicillin, and increased MICs [261]. High-levelresistance to penicillin can also be caused by the production of a plasmid-mediated penicillinase, but this resistance mechanism occurs infrequently[261,263]. Chloramphenicol resistance is caused by the production ofchloramphenicol acetyltransferase. Horizontal transfer of genetic materialbetween strains of N meningitidis likely plays an important role in thedissemination of chloramphenicol resistance [264]. Resistance to rifampin isoften mediated by point mutations in the rpo B gene leading to alterations inthe RNA polymerase. In addition, resistance can be mediated by alterationsin membrane permeability [261].

A recent French study reported that between 1999 and 2002, approxi-mately 30% of invasive N meningitidis had reduced susceptibility topenicillin and that absolute penicillin resistance was also increasing [265].A recent American study reported similar rates of isolates with decreasedsusceptibility to penicillin (�30%) [266], although a CDC-based activepopulation-based surveillance study identified only 3% of clinical isolates tobe of intermediate resistance, a proportion unchanged since 1991 [263].Rates of resistance to sulfa drugs (ie, trimethoprim-sulfamethoxazole andsulfadiazine) were approximately 40% in recent American studies [263,266].High-level chloramphenicol resistance has been described in Southeast Asiaand in Europe [267]. Resistance to rifampin was reported in 3% of isolatesin one recent report [263].

Despite reports of increasing antibiotic resistance, multiple therapeuticoptions are available. Penicillin remains an excellent choice for therapy ofconfirmed meningococcal infections [259,261,263]. There is no evidence thatintermediate level resistance affects outcome when high-dose penicillin isused and high-level penicillin resistance is rare. The clinical consequences ofchloramphenicol resistance are not yet clearly understood, but resistance tothis agent is of concern in developing countries where chloramphenicol isstill used to treat meningococcal meningitis [267]. The third-generation


cephalosporins (ceftriaxone and cefotaxime) and the new quinolones remainhighly active and are excellent therapeutic choices [268].

Neisseria gonorrhoeaeNeisseria gonorrhoeae is a gram-negative diplococcus, typically acquired

sexually or perinatally. Gonorrhea is the second most common reportableinfectious disease in the United States, causing an estimated 650,000infections per year [269]. In addition to urethritis and cervicitis, Ngonorrhoeae can cause disseminated infection and is the most commoncause of nontraumatic arthritis in young adults [270]. Reported rates ofgonorrhea 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 substanceabuse [272].

Antimicrobial resistance has been a concern with N gonorrhoeae since the1940s when resistance to sulfonamides was first noted; this was followed bypenicillin resistance in the 1950s, tetracycline resistance in the 1980s, andfluoroquinolone resistance in the 1990s [273,274].

High-level penicillin resistance (MIC � 16 lg/mL) in N gonorrhoeae ismost often mediated by penicillinase production [275]. Penicillin resistancecaused by production of a plasmid-encoded TEM-1–type b-lactamase wasfirst detected in N gonorrhoeae in 1976 and has now disseminated worldwide[274,276]. In the United States, the percentage of penicillinase-producing Ngonorrhoeae 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 ina 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 efflux pump; and penB, which decreasesantibiotic permeability across the cell membrane through a porin genemutation [275,278]. Chromosomally mediated resistance to penicillin waspresent in 2.1% of isolates in a recent American survey [277].

Resistance to tetracycline occurs through chromosomally mediatedchanges in cell membrane porins or by ribosomal protection by theplasmid-mediated tetM resistance gene [275,279]. Additional chromosomalmutations lead to resistance to spectinomycin [280]. Macrolide resistancecan occur through efflux pumps, erm methylases, and changes in the 23Sribosome [281].

Fluoroquinolone-resistant N gonorrhoeae (MIC � 1 lg/mL) has dissem-inated to many countries [282–284] and is widespread in certain parts ofAsia. In a recent study, greater than 35% of N gonorrhoeae isolates in thePhilippines and Vietnam were quinolone resistant [285]. There have alsobeen alarming increases in quinolone resistance reported recently in Englandand Wales [283]. The overall prevalence of quinolone-resistant gonococci inthe United States was 2.2% in 2002, but most of these strains were reported


from California and Hawaii (20% of isolates tested in Honolulu in 2001were resistant) [273,277]. Decreased susceptibility to fluoroquinolones iscaused by mutations in the parC gene of topoisomerase IV and gyrA ofDNA gyrase [286,287].

The CDC currently recommends third-generation cephalosporins (eg,ceftriaxone), which are still highly active, for first-line therapy of gonococcalinfection [288]. Cefixime is the only nonquinolone oral agent recommendedfor the treatment of gonorrhea, but is no longer being marketed in theUnited States [288]. Fluoroquinolones (eg, ciprofloxacin, ofloxacin, orlevofloxacin) remain an excellent oral therapeutic option for most isolatesbut should not be used empirically in patients acquiring infection in areaswhere the prevalence of quinolone-resistant gonorrhea is greater than 1%(eg, Asia, Hawaii, California) [288]. For patients who cannot receivea cephalosporin and who are at risk for quinolone-resistant N gonorrhoeae,spectinomycin is a therapeutic option [288]. Susceptibility testing shouldalways be performed for patients who fail therapy for gonorrhea. Patientswith gonorrhea in whom co-infection with chlamydia cannot be ruled outshould also be treated for chlamydia [288].

Summary

The emergence of resistance to antimicrobial agents continues to evolvesubstantially, influencing the evaluation and treatment of infections innosocomial and health care–associated settings and in the community.Bacteria use several strategies to avoid the effects of antimicrobial agents,and have evolved highly efficient means for clonal spread and for thedissemination of resistance traits. Control of antibiotic-resistant pathogensprovides a major challenge for the medical and public health communitiesand for society. Control of the emergence of resistant pathogens requiresadherence to infection control guidelines, such as those issued by the CDC(http://www.cdc.gov/ncidod/hip/Guide/guide.htm), and physicians, pa-tients, and health care consumers must all understand the need forjudicious 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