Resist%EAncia Enterobact%E9rias Paterson

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Resistance in gram-negative bacteria:Enterobacteriaceae

David L. Paterson, MD, PhDPittsburgh, Pennsylvania

The emergence and spread of resistance in Enterobacteriaceae are complicating the treatment of serious nosocomial infections

and threatening to create species resistant to all currently available agents. Approximately 20% of Klebsiella pneumoniae infections

and 31% of Enterobacter spp infections in intensive care units in the United States now involve strains not susceptible to third-

generation cephalosporins. Such resistance in K pneumoniae to third-generation cephalosporins is typically caused by the acqui-

sition of plasmids containing genes that encode for extended-spectrum b-lactamases (ESBLs), and these plasmids often carry other

resistance genes as well. ESBL-producing K pneumoniae and Escherichia coliare now relatively common in healthcare settings and

often exhibit multidrug resistance. ESBL-producing Enterobacteriaceae have now emerged in the community as well. Salmonella

and other Enterobacteriaceae that cause gastroenteritis may also be ESBL producers, which is of relevance when children require

treatment for invasive infections. Resistance of Enterobacter spp to third-generation cephalosporins is most typically caused by

overproduction of AmpC b-lactamases, and treatment with third-generation cephalosporins may select for AmpC-overproducing

mutants. Some Enterobacter cloacae strains are now ESBL and AmpC producers, conferring resistance to both third- and fourth-

generation cephalosporins. Quinolone resistance in Enterobacteriaceae is usually the result of chromosomal mutations leading

to alterations in target enzymes or drug accumulation. More recently, however, plasmid-mediated quinolone resistance has

been reported in K pneumoniae and E coli, associated with acquisition of the qnr gene. The vast majority of Enterobacteriaceae,

including ESBL producers, remain susceptible to carbapenems, and these agents are considered preferred empiric therapy for

serious Enterobacteriaceae infections. Carbapenem resistance, although rare, appears to be increasing. Particularly troublesome

is the emergence of KPC-type carbapenemases in New York City. Better antibiotic stewardship and infection control are needed

to prevent further spread of ESBLs and other forms of resistance in Enterobacteriaceae throughout the world. (Am J Infect Control

2006;34:S20-8.)

Gram-negative bacteria of the Enterobacteriaceae

family are important causes of urinary tract infections(UTIs), bloodstream infections, hospital- and health-

care-associated pneumonias, and various intra-abdom-

inal infections. Within this family, Escherichia coli is afrequent cause of UTIs, Klebsiella spp and Enterobacterspp are important causes of pneumonia, and all of

the Enterobacteriaceae have been implicated in blood-

stream infections and in peritonitis, cholangitis, and

other intra-abdominal infections. Additionally, organ-

isms such as Salmonella produce gastroenteritis and

subsequently, in some patients, invasive infection.

Emerging resistance in Enterobacteriaceae is a signifi-

cant problem that requires immediate attention. Re-

sistance related to production of extended-spectrum

b-lactamases (ESBLs) is a particular problem in the

handling of Enterobacteriaceae infections, but othermechanisms of resistance are also emerging, leading

to multidrug resistance and threatening to create

panresistant species.

OVERVIEW OF RESISTANCE TRENDS

AND OUTCOMES

Third-generation cephalosporins were originally

developed as b-lactams able to overcome resistance

caused by common b-lactamases. When first intro-

duced, third-generation agents like ceftriaxone, cefo-

taxime, and ceftazidime were stable in the presence

of common b-lactamases. However, within a few years,

hospital-acquired gram-negative bacilli like Klebsiella

pneumoniae and others began producing mutated ver-

sions of these b-lactamases that made them resistant

to third-generation cephalosporins and to the mono-

bactam aztreonam. According to the National Nosoco-

mial Infections Surveillance (NNIS) System report, in

2003, 20.6% of all K pneumoniae isolates from patients

in intensive care units (ICUs) in the United States were

nonsusceptible to third-generation cephalosporins.1

This represented a 47% increase compared with resis-

tance rates for 1998 to 2002. Nonsusceptibility to third-

generation cephalosporins was also observed in 31.1%ofEnterobacter spp and 5.8% ofE coliisolated from pa-

tients in ICUs in 2003. Those rates were approximately

the same as for 1998 to 2002. International studies re-

port even higher rates of nonsusceptible K pneumoniaein hospitals and particularly in ICU settings.2

From the Antibiotic Management Program, University of PittsburghMedical Center, Pittsburgh, PA.

Reprint requests: David L. Paterson, MD, PhD, Suite 3A, Falk MedicalBuilding, 3601 5th Avenue, Pittsburgh, Pennsylvania 15213. E-mail:[email protected].

0196-6553/$32.00

Copyright 2006 by the Association for Professionals in InfectionControl and Epidemiology, Inc. and Elsevier, Inc.

doi:10.1016/j.ajic.2006.05.238

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mailto:[email protected]:[email protected]


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data suggested that an antibiotic MIC of 8 mg/mL was

universally associated with clinical failure and that

high rates of failure were also observed with a MIC of4 mg/mL (Table 2).14 These results are consistent with

those from a variety of observational studies that

show rates of clinical failure .90%, approximately

67%, and,

30% with MICs of 8, 4, and #2 mg/mL, re-spectively.7,15 Whether the susceptibility break points

of Enterobacteriaceae for cephalosporins should be

changed is currently under consideration. The 2005

CLSI guidelines recommend that laboratories report

ESBL-producing isolates as resistant to all penicillins,

cephalosporins, and aztreonam irrespective of in vitro

tests results.16 The presence of inadequately identified

ESBL producers has important implications for both

antibiotic therapy and infection control.

Treatment of ESBL producers

The presence of ESBL-producing Enterobacteriaceae

complicates therapy, especially because these orga-

nisms are often multidrug resistant. When isolates from

a patient indicate an ESBL-producing organism, the

first thing to consider is whether the patient has a

true infection. Patients with positive isolates from urine

or perhaps the respiratory tract may be only colonized,

and clearly, there is no indication for treatment in those

situations. Assuming the patient has a serious infection

due to ESBL-producing Enterobacteriaceae, the choice

of empiric therapy is made difficult by the likelihood

of multidrug resistance and the fact that there are no

data from large, randomized, controlled trials designed

to compare one antibiotic therapy with another for in-

fections caused by ESBL-producing organisms. More-

over, for a variety of reasons, it is unlikely that such astudy will ever be performed. Nonetheless, data from

a number of studies strongly point to carbapenems as

the drugs of choice for empiric treatment of serious in-

fections involving ESBL-producing Enterobacteriaceae.

Subgroup analysis from a randomized, evaluator-

blind trial comparing cefepime with imipenem in

patients with nosocomial pneumonia showed that

100% of patients (10 of 10) receiving imipenem for

pneumonia caused by an ESBL producer experienced

a positive clinical response compared with only 69%

of patients (9 of 13) treated with cefepime.17 Similarly,

Table 1. Selected b-lactamases of gram-negative bacteria

b-Lactamase Examples Substrates

Inhibition by

clavulanate*

Molecular

class

Broad-spectrum TEM-1, TEM-2, SHV-1 Penicillin G, aminopenicillins, carboxypenicillins,

piperacillin, narrow-spectrum cephalosporins

111 A

OXA family Substrates of the broad-spectrum group pluscloxacillin, methicillin, and oxacillin

1

D

Extended-spectrum TEM family, SHV family Substrates of the broad-spectrum group plus

oxyimino-cephalosporins, and monobactam (aztreonam)

1111 A

CTX-M family Substrates of the expanded-spectrum group plus,

for some enzymes, cefepime

1111 A

OXA family Same as for CTX-M family 1 D

Others (PER-1, PER-2, BES-1,

GES/IBC family, SFO-1, TLA-1,

VEB-1, VEB-2)

Same as for TEM family and SHV family 1111 A

AmpC ACC-1, ACT-1, CFE-1, CMY family,

DHA-2, FOX family, LAT family,

MIR-1, MOX-1, MOX-2

Substrates of expanded-spectrum group plus cephamycins 0 C

Carbapenemase IMP family, VIM family, GIM-1, SPM-1

(metallo-b-enzymes)

Substrates of the expanded-spectrum group plus

cephamycins and carbapenems

0 B

KPC-1, KPC-2, KPC-3 Same as for IMP family, VIM family, GIM-1, and SPM-1 111 AOXA-23, OXA-24, OXA-25, OXA-26,

OXA-27, OXA-40, OXA-48

Same as for IMP family, VIM family, GIM-1, and SPM-1 1 D

Adapted from N Engl J Mea.10

*1, 111, and 1111 denote relative sensitivity to inhibition.

Table 2. Outcome of cephalosporin treatment of seriousinfections due to extended-spectrum b-lactamaseproducing organisms

Patients % (n)

MIC (mg/mL)

Experienced failure of

cephalosporin therapy

Died of bacteremia

within 14 days

8 100 (6/6) 33 (2/6)

4 67 (2/3) 0 (0/3)

2 33 (1/3) 0 (0/3)

#1 27 (3/11) 18 (2/11)

Total* 54 (15/28)

MIC, minimum inhibitory concentration.

Adapted from J Clin Microbio.14

*Includes 5 patients with isolates for which MICs were recorded simply as 0.5 to

4 mg/L.

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Nonetheless, the healthcare community needs to be

aware of the potential problem that CA-ESBL producers

may present in the United States in the future, espe-

cially given what has been observed in the United King-

dom and Canada. It suggests that attention be focused

on potential risk factors for community development

of infection with ESBL-producing bacteria. In a Spanishstudy, those risk factors included diabetes mellitus, pre-

vious quinolone use, recurrent UTIs, a previous hospi-

tal admission, and older age in male patients.30 An

Israeli study identified risk factors as previous hospital-

ization within the past 3 months, antibiotic treatment

within the past 3 months, age .60 years, male sex,

K pneumoniae infection, previous use of third-genera-

tion cephalosporins, previous use of second-genera-

tion cephalosporins, previous use of quinolones, and

previous use of penicillin.28 Although both studies

identified previous hospitalization as a risk factor, it

should be noted that cases of infection with an ESBL-producing organism in the community have been

reported in patients without recent hospitalization.

So, cases of true CA-ESBL producers have been docu-

mented. As mentioned previously, ESBL-producing

pathogens may also be involved in gastrointestinal in-

fections acquired in the community. Bacterial species

that have been reported to produce ESBLs leading to

drug-resistant gastroenteritis include Salmonella spp,

Shigella, Vibrio cholerae, and Shiga toxinproducing

E coli.29,32-37 The possible emergence and spread of

Salmonella strains resistant to antibiotics commonly

used as treatment are concerns, because theseinfections can be invasive. Outside the United States,

TEM-, SHV-, and CTX-M-type ESBLs, as well as AmpC

b-lactamases, have been identified in infection-causing

Salmonella.29,32,38 Within the United States, the mecha-nism ofSalmonella resistance to third-generation ceph-

alosporins has been linked to production of AmpC

b-lactamases.39-41 In particular, resistance has been as-

sociated with the plasmid-mediated AmpCb-lactamase

known as CMY-2. Salmonella strains resistant to third-

generation cephalosporins are of concern because (1)

ceftriaxone and, secondarily, quinolones are the drugs

of choice for invasive salmonella disease, and (2) quino-

lones are not indicated for use in children. Fortunately,

ceftriaxone-resistant Salmonella are currently rare in

the United States, but they represent an area that bears

further watching.

ANTIBIOTIC RESISTANCE IN ENTEROBACTERSPECIES

Enterobacter spp are significant causes of nosoco-

mial infection and are intrinsically resistant to amino-

penicillins, cefazolin, and cefoxitin due to production

of constitutive chromosomal AmpC b-lactamases.42

Moreover, b-lactam exposure is capable of inducing

expression of AmpCb-lactamases inEnterobacter spp

with consequent resistance to third-generation cepha-

losporinsand mutations may result in permanent

hyperproduction and persistent resistance. Treatment

of Enterobacter infections with third-generation ceph-

alosporins may select for mutant strains associatedwith hyperproduction of AmpC b-lactamase. The prev-

alence ofEnterobacter spp resistant to third-generation

cephalosporins has increased since the introduction

and common use of these antibiotics. For example, in

1 study, resistance to third-generation cephalosporins

emerged in approximately 20% of patients during

treatment for Enterobacter bacteremia.43 Multidrug-

resistant Enterobacter spp in initial positive blood

cultures were significantly more prevalent (P, .001)

among patients who had previously received third-

generation cephalosporins than among patients who

had previously received other antibiotic treatments,and they were associated with higher mortality rates.43

In summary, third-generation cephalosporins should

be avoided as treatment forserious infection withEnter-

obacter spp because their use in such situations results

in selection of the small number of AmpC-overproduc-

ing mutants present in any collection ofEnterobacterspp isolates and because the typical clinical scenario

is characterized by initial response followed by recur-

rence of infection. In contrast, cefepime is compar-

atively stable to AmpC b-lactamases, and therefore

has been regarded as a suitable option for treatment

ofEnterobacter infections.

42

However, ESBL-producingEnterobacter spp, particularly Enterobacter cloacae,

have been identified in the United States (Table 1),44-46

Europe,47 and Asia.48-50 At our medical center in Pitts-

burgh, approximately 33% of bloodstream isolates havebeen shown to contain E cloacae that produce ESBL

as well as AmpC b-lactamases.51 The MIC of cefepime

may be within that danger zone of 48 mg/mL, where

cephalosporin activity may be compromised. Hence,

not all resistance to later-generation cephalospo-

rins in E cloacae may be the result of hyperpro-

duction of AmpC b-lactamases, and ESBL-producing

strains of E cloacae may be resistant to fourth- as well

as third-generation cephalosporins. The advent of

ESBLs in AmpC-producing E cloacae is certainly some-

thing to be aware of and is potentially clinically

important.

EMERGING QUINOLONE AND CARBAPENEMRESISTANCE

Quinolone resistance

Quinolones are used widely for the treatment of

serious E coliUTIs and may also be used to treat other



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infections caused by other members of the Enterobac-

teriaceae family.52,53 Hence, quinolone resistance in

Enterobacteriaceae may lead to treatment failures

and is a significant concern, as is the recent emergence

of plasmid-mediated resistance to quinolones. Accord-

ing to the 2004 NNIS report, means of 7.3% and 8.2%

ofE coliisolates from US patients in both ICUs and non-ICU areas of hospitals, respectively, and a mean of

3.6% from US outpatients exhibited quinolone resis-

tance.1 Higher rates of quinolone resistance may be

found in ESBL-producing strains of E coli and K pneu-

moniae. For example, 55.8% of infections in the Uni-

versity of Pennsylvania Health System caused by

ESBL-producing E colior K pneumoniae were fluoroqui-

nolone resistant.21 In Shanghai, China, 86.1% of ESBL-

producing E coliand 45.6% of ESBL-producing K pneu-

moniae were reported to be resistant to levofloxacin.54

We studiedK pneumoniae bacteremia from 12 hospitals

in 7 countries and found that overall, 18% of ESBL-pro-ducing isolates were ciprofloxacin resistant and60% of

ciprofloxacin-resistant isolates produced ESBLs.55 Prior

receipt of a quinolone has been shown to be an inde-

pendent risk factor for quinolone resistance.21,55

Quinolone resistance in Enterobacteriaceae is usu-

ally due to alterations in target enzymes (DNA gyrase

and/or topoisomerase IV) or to impaired access to the

target enzymes, occurring either because of changes

in porin expression or because of efflux mecha-

nisms.56 Both of these principal means of resistance

are caused by chromosomal mutations. More recently,

plasmid-mediated quinolone resistance has emergedin K pneumoniae and E coli. The first case of plasmid-

mediated resistance to quinolones in K pneumoniaewas reported in the United States in 1998 and was

from a strain isolated at the University of Alabama in1994.57 The plasmid, pMG252, confers multidrug resis-

tance and was shown to greatly increase quinolone re-

sistance when transferred to strains of K pneumoniaedeficient in outer-membrane porins. The gene asso-

ciated with that resistance has been designated qnr.

Quinolone resistance associated with qnr-containing

plasmids has now emerged in E coliand K pneumoniaestrains.58-60 A recent study in the United States re-

ported that 11.1% ofK pneumoniae strains from 6 states

exhibited plasmid-mediated quinolone resistance asso-

ciated with the qnr gene, although none of the E colistrains examined contained qnr.61 Some of the strains

contained the original pMG252 plasmid, but qnr was

carried on different plasmids for others. The mech-

anism of quinolone resistance associated with qnr-

containing plasmids appears to involve inhibition of

quinolone binding with DNA gyrase.62

The emergence of this new plasmid-mediated

mechanism of quinolone resistance is particularly wor-

risome because it provides a mechanism for the rapid

development and spread of quinolone and multidrug

resistance to important members of the Enterobacteri-

aceae family.

Carbapenem resistance

As mentioned earlier, carbapenems are currentlyconsidered to be the preferred agents for treatment of

serious infections caused by ESBL-producing Entero-

bacteriaceae. Carbapenems are highly stable tob-lacta-

mase hydrolysis, and porin penetration is facilitated

by their general size and structure. Their susceptibility

to most strains of Enterobacteriaceae makes them

generally useful as treatment for multidrug-resistant

organisms. Carbapenem resistance is currently rare

among Enterobacteriaceae, but some worrisome signs

have appeared in recent years.

The expression of AmpC or class A (TEM- or SHV-

type) ESBLs plus loss of outer-membrane proteinshave been associated with carbapenem resistance in

K pneumoniae.63-68 Resistance to carbapenems has

also been reported in K pneumoniaeproducing class

B b-lactamases (metallo-b-lactamases) in various coun-

tries outside the United States, including Brazil,69

Greece,70 China,71 and Singapore.72 A metallo-b-lacta-

maseproducing strain ofE cloacae with reduced sus-

ceptibility to carbapenems has also recently been

observed in Greece.73 Standard susceptibility testing

may categorize metallo-b-lactamaseproducing Enter-

obacteriaceae as susceptible to carbapenems, but an

inoculum effect has been observed, suggesting thatthe susceptibility testing may falsely predict the sus-

ceptibility of particular Enterobacteriaceae to carbape-

nems in the clinical environment.73,74

In the United States, carbapenem resistance has beenobserved in strains ofK pneumoniaeproducing class A

carbapenemases, namely, KPC-1, KPC-2, and KPC-3.75-82

The genes encoding these enzymes are apparently

obtained via plasmid conjugation; the enzymes are ca-

pable of hydrolyzing and inactivating the carbapenems.

KPC-producing strains have generally been shown to

exhibit multidrug resistance that includes piperacillin/

tazobactam, third- and fourth-generation cephalospo-

rins, fluoroquinolones, and aminoglycosides, as well

as carbapenems.82 KPC-1 expression itself was appar-

ently associated with moderate- to high-level carbape-

nem resistance,75 while loss of outer-membrane

proteins appeared to be a required cofactor for high-

level resistance in KPC-2 and KPC-3producing

strains.76,78 In 96 isolates obtained from 10 New York

hospitals, .80% of the KPC-producing organisms be-

longed to a single ribotype.82 This is worrisome because

it suggests that these isolates are not just being selected

by antibiotic use, but rather are being passed from

person to person as a result of breakdown in infection

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control. As with metallo-b-lactamaseproducing Enter-

obacteriaceae, susceptibility testing may falsely indi-

cate the clinical susceptibility of KPC-producing

K pneumoniae due to an inoculum effect.79-81 In vitro

testing suggests that tigecycline and polymyxins

may exhibit the most consistent activity against KPC-

producing strains of K pneumoniae, but this has yet tobe demonstrated clinically.82 KPC-producing strains of

Enterobacter81 and Salmonella spp83 have also been

identified in the United States.

Strains of clinically important Enterobacteriaceae

have now emerged with broader multidrug resistance

than has ever before been observed. As the list of anti-

biotics with potential activity against these strains

continues to shrink, measures that prevent and slow

the spread of multidrug-resistant Enterobacteriaceae

strains throughout the world must be put into action.

SUMMARY

Enterobacteriaceae are significant causes of serious

infections, and many of the most important members

of this family are becoming increasingly resistant to

currently available antibiotics. This is a troubling trend,

and one that requires vigilance and intensified mea-sures to control the further spread of resistance by

these important gram-negative pathogens. Although

improvements in antibiotic stewardship and infection

control are discussed in greater detail by others in

this supplement, it should be emphasized that such im-

provements are necessary if the steady rise in ESBL-producing Enterobacteriaceae and in other forms of

resistance in these species is to be slowed or stopped.

The widespread use of third-generation cephalospo-

rins as the driving force behind the emergence of

ESBL-producing organisms has been shown in many

studies. Because of that risk, third-generation cephalo-

sporins are no longer appropriate as workhorse anti-

biotics in our hospitals, and the restriction of their

use in hospitals and other healthcare facilities has

been shown to reduce the incidence of ESBL-producing

Enterobacteriaceae like K pneumoniae. Quinolones

seem to have replaced third-generation cephalosporins

in hospitals, yet their overuse, particularly in light of

plasmid-mediated quinolone resistance in Enterobac-

teriaceae, may be of concern.

Infection control is the second aspect in restriction

of the emergence and spread of resistant Enterobacte-

riaceae. With regard to ESBL producers, there is ample

evidence of person-to-person spread. Combining re-

ductions in third-generation cephalosporin use with

traditional infection control measuressuch as the

use of gloves, gowns, and hand hygiene in the care

of colonized or infected patientshas been reported

to control the hospital spread of multidrug-resistant

K pneumoniae. Both improvement in antibiotic stew-

ardship and infection control strategies are needed

before it is too latebefore we have to deal with infec-

tions caused by multidrug-resistant Enterobacteriaceae

for which there are no clinically effective drugs.

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