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review article
mechanisms of disease
classification of b -lactamases
Understanding the new enzymes requires a brief review of b-lactamase classification.
Hundreds of b-lactamases have been described and have been given a bewildering va-
riety of names (see Glossary). Fortunately, the enzymes can be classified on the basis of
their primary structure into four molecular classes (A through D),9 or on the basis of
their substrate spectrum and responses to inhibitors into a larger number of functional
groups.10 Class A and class C b-lactamases are the most common and have a serine
residue at the active site, as do class D b-lactamases. Class B comprises the metallo-
b-lactamases. Twenty years ago, plasmids mediating resistance to b-lactam antibiotics
in Escherichia coli and other Enterobacteriaceae most often carried genes encoding class A
enzymes such as TEM-1 or SHV-1 or class D enzymes such as OXA-1.11 Class B and C en-
zymes had a broader spectrum of activity but were almost always encoded by chromo-
somal genes and hence were confined to particular bacterial species.
Glossary
AmpC b-lactamase: This type of broad-spectrum enzyme, usually encoded on the bacterial chromosome, is active on
cephamycins as well as oxyimino-b-lactams.
b-Lactamb-lactamase inhibitor combinations: Clavulanic acid, sulbactam, and tazobactam are inhibitory b-lactams
that bind to and block the action of class A, and to a lesser extent, class D b-lactamases. The inhibitors are available
in combinations with otherwise b-lactamasesusceptible antibiotics, such as ticarcillinclavulanic acid, ampicillin
sulbactam, and piperacillintazobactam.
Carbapenems: Compounds with a fused b-lactam system in which the sulfur atom of the five-member ring is replaced by
carbon. Examples include imipenem, meropenem, and ertapenem.
Cephamycins: Cephalosporins with a 7a-methoxy side chain that blocks hydrolysis by class A and class D b-lactamases.
Examples include cefoxitin, cefotetan, and cefmetazole.
Extended-spectrum b-lactamase (ESBL): This name was originally coined to reflect the expanded substrate spectrum of
enzymes derived from narrower-spectrum TEM, SHV, or OXA b-lactamases. The term now also refers to b-lacta-
mases, such as those in the CTX-M family, with a similar phenotype but a separate heritage.
Inhibitor-resistant b-lactamase: Enzyme variants in the TEM family (and, less often, the SHV family) with reduced sen-
sitivity to clavulanic acid, sulbactam, and tazobactam inhibitors as a result of amino acid substitutions.
Inoculum effect: Increased resistance with increasing numbers of test bacteria. One possible mechanism is increased
hydrolysis with larger inocula of b-lactamaseproducing organisms.
Integron: A unit of DNA containing a gene for a site-specific integrase (intI) and a recombination site (attI), into which
gene cassettes made up of an antibiotic-resistance gene linked to a 59-base element (or attC site) can be integrated.
A strong promoter adjacent to the attI site ensures that the integrated genes will be efficiently expressed. Integrons
can be part of a transposon or a defective transposon and thus have an additional potential for mobility.
Monobactam: A monocyclic b-lactam. The single commercially available example is aztreonam, which has an oxyimino
side chain and is therefore also an oxyimino-b-lactam.
Oxyimino-b-lactams: b-Lactams with an oxyiminoside chain designed to block the action of b-lactamase. Sometimes
referred to as third-generation cephalosporins, they include cefotaxime, ceftriaxone, ceftazidime, and cefepime
(a fourth-generation derivative).
Plasmid: An extrachromosomal segment of DNA, usually circular, varying in size from a few kilobases to a 10th or more
of the size of the bacterial chromosome. Plasmids larger than 20 kb are often conjugative and can promote their
transfer between bacterial hosts. Resistance plasmids carry resistance genes, often organized into integrons or car-
ried on transposons. Other plasmids carry metabolic genes or act as sex factors to promote transfer of the bacterial
chromosome.
SHV, TEM, OXA, IMP, VIM, and KPC: b-Lactamase families with members (denoted by numerals, as in SHV-1) that are
related by a few amino acid substitutions. b-Lactamase nomenclature is not standardized. SHV denotes a variable
response to sulfhydryl inhibitors; TEM was named after the patient (Temoneira) from whom the first sample was ob-
tained; CTX-M, OXA, and IMP reflect an ability to hydrolyze cefotaxime, oxacillin, and imipenem, respectively; VIM
denotes Verona integron-encoded metallo-b-lactamase; and KPC is derived from Klebsiella pneumoniae carbapene-
mase. The origin of names for other b-lactamases is just as variable and arcane.
Transposon: A mobile unit of DNA that can jump, or transpose, from one DNA molecule to another for example, from
a plasmid to a chromosome or from a plasmid to a plasmid, usually without site specificity. In class I transposons, a
pair of insertion sequences (segments of DNA that can replicate and insert more or less randomly at other sites)
flank a resistance gene. In class II transposons, terminal inverted-repeat segments enclose the genes for a trans-
posase (tnpA), a resolvase (tnpR), and one or more antibiotic-resistance genes. Some transposons are conjugative.
configuration of the active site of the enzyme, allow- shv-type esbl s (class a)
ing access to oxyimino-b-lactams (Fig. 1).14,18 SHV-1 shares 68 percent of its amino acids with
Opening the active site to b-lactam substrates TEM-1 and has a similar overall structure (Fig. 1).22
also typically enhances the susceptibility of the en- As with TEM, SHV-type ESBLs have one or more
zyme to b-lactamase inhibitors, such as clavulanic amino acid substitutions around the active site.
acid. Amino acid substitutions distinct from those More than 50 varieties of SHV are currently recog-
leading to the ESBL phenotype can confer resistance nized on the basis of unique combinations of amino
to inhibitors, but the combination of inhibitor resis- acid replacements.20 SHV-type ESBLs currently pre-
tance and an extended spectrum of activity seems to dominate in surveys of resistant clinical isolates in
be, with rare exceptions,19 incompatible. More than Europe and America.21,23 SHV-5 and SHV-12 are
130 TEM enzymes are currently recognized, and among the most common members of this family.21
their variety provides a useful way to follow the
spread of individual resistance genes.20 TEM-10, ctx-mtype esbl s (class a)
TEM-12, and TEM-26 are among the most common The most common group of ESBLs not belonging
in North and South America.21 to the TEM or SHV families was termed CTX-M to
Inhibition by Molecular
b-Lactamase Examples Substrates Clavulanic Acid* Class
Broad-spectrum TEM-1, TEM-2, SHV-1 Benzylpenicillin (penicillin G), amino- +++ A
penicillins (amoxicillin and ampi-
cillin), carboxypenicillins (carbeni-
cillin and ticarcillin), ureidopenicillin
(piperacillin), narrow-spectrum
cephalosporins (cefazolin, cepha-
lothin, cefamandole, cefuroxime,
and others)
OXA family Substrates of the broad-spectrum + D
group plus cloxacillin, methicillin,
and oxacillin
Expanded-spectrum TEM family and SHV Substrates of the broad-spectrum ++++ A
family group plus oxyimino-cephalo-
sporins (cefotaxime, cefpodoxime,
ceftazidime, and ceftriaxone) and
monobactam (aztreonam)
Others (BES-1, GES/IBC Same as for TEM family and SHV ++++ A
family, PER-1, PER-2, family
SFO-1, TLA-1, VEB-1,
and VEB-2)
CTX-M family Substrates of the expanded-spectrum ++++ A
group plus, for some enzymes,
cefepime
OXA family Same as for CTX-M family + D
AmpC ACC-1, ACT-1, CFE-1, Substrates of expanded-spectrum 0 C
CMY family, DHA-1, group plus cephamycins (ce-
DHA-2, FOX family, fotetan, cefoxitin, and others)
LAT family, MIR-1,
MOX-1, and MOX-2
Carbapenemase IMP family, VIM family, Substrates of the expanded-spec- 0 B
GIM-1, and SPM-1 trum group plus cephamycins
and carbapenems (ertapenem,
imipenem, and meropenem)
KPC-1, KPC-2, and KPC-3 Same as for IMP family, VIM family, +++ A
GIM-1, and SPM-1
OXA-23, OXA-24, OXA- Same as for IMP family, VIM family, + D
25, OXA-26, OXA-27, GIM-1, and SPM-1
OXA-40, and OXA-48
highlight their greater activity against cefotaxime from Southeast Asia; and GES-1, GES-2, and IBC-2
than against ceftazidime. More than 40 CTX-M en- in isolates from South Africa, France, and Greece.24
zymes are currently known.6 Belying their name, PER-1 is also common in multiresistant acinetobac-
some hydrolyze ceftazidime more rapidly than they ter species in Korea and Turkey.25 Some of these
do cefotaxime. CTX-M-14, CTX-M-3, and CTX-M-2 enzymes are found in Enterobacteriaceae as well,
are the most widespread.6 whereas other uncommon ESBLs (such as BES-1,
IBC-1, SFO-1, and TLA-1) have been found only in
other class a esbl s Enterobacteriaceae.26-29
Other class A ESBLs are uncommon and have been
found mainly in Pseudomonas aeruginosa and at a lim- oxa-type esbl s (class d)
ited number of geographic sites: PER-1 in isolates in Twelve ESBLs derived from OXA-10, OXA-1, or
Turkey, France, and Italy; VEB-1 and VEB-2 in strains OXA-2 by amino acid substitutions are currently
mid-mediated KPC enzymes, are effective carba- to multiple patients, so that in hospital outbreaks
penemases as well. Finally, some OXA-type b-lac- one type of ESBL often predominates. Particular
tamases have carbapenemase activity, augmented TEM-type ESBL varieties seem to have a fixed geo-
in clinical isolates by additional resistance mecha- graphic distribution, whereas at least some SHV
nisms, such as impermeability or efflux.8,34 types have been found all over the world, suggest-
ing that they have a multifocal origin. For example,
factors influencing TEM-3 is common in France and has been reported
b -lactamase expression in a few other European countries but has not been
reported in the United States, whereas SHV-5 and
As if the variety of enzymes were not enough, fur- SHV-12 have been detected worldwide.
ther complications arise because expression of re- The genes encoding the TEM-1 and TEM-2
sistance is affected by additional factors. The same b-lactamases are carried by transposons, as are the
enzyme may express different resistance pheno- genes encoding some TEM-type ESBLs (Fig. 2).44
types, depending on the bacterial host and the test The gene encoding SHV-1 is found on the chromo-
conditions. For ESBLs of the TEM and SHV fami- some of most strains of K. pneumoniae.45-47 SHV
lies, the expanded spectrum is accompanied by a genes also occur on transmissible plasmids; for
loss of intrinsic hydrolytic activity.35,36 This loss can example, one has been found on a 7.5-kb block of
be compensated for by an increase in gene dosage DNA apparently captured from the klebsiella chro-
(through gene duplication or carriage on a multi- mosome.48 Genes encoding the remaining types of
copy plasmid) or the presence of a promoter with b-lactamase are often found incorporated into in-
increased activity (through a mutation or insertion- tegrons (Fig. 2) but have their origin elsewhere. For
sequence substitution). example, the genes for CTX-Mtype enzymes are
In some organisms (P. aeruginosa in particular), found on the chromosome of kluyvera, a genus of
an active efflux system can reduce the intracellular rarely pathogenic commensal organisms. Rather
accumulation of antibiotic and allow an enzyme than evolving from a progenitor with a more limit-
with only limited hydrolytic capacity to inactivate the ed spectrum of activity, the CTX-M group appears
drug before it can reach its target; in other organ- to have emerged in multiple places by plasmid ac-
isms, this effect is achieved by diminished expres- quisition of b-lactamase genes from such a wide-
sion of an outer-membrane porin required for spread environmental reservoir.6
b-lactam uptake. In Klebsiella pneumoniae, decreased Integrons are also involved in the acquisition of
expression of outer-membrane porins often accom- AmpC-type b-lactamases by plasmids. Many of
panies ESBL production and may allow a TEM- or these plasmid-mediated enzymes can be related to
SHV-type ESBL to express resistance to cefepime or chromosomal AmpC enzymes of particular species:
allow an AmpC b-lactamase to express resistance thus, ACC-1 is related to the enzyme produced by
to imipenem.37,38 Hafnia alvei; ACT-1 and MIR-1 to enzymes of enter-
obacter species; some CMY enzymes as well as
genetics of b -lactamases LAT-1 and LAT-3 to enzymes of citrobacter species;
other CMY enzymes and the FOX and MOX families
Plasmids are responsible for the spread of most of to enzymes of aeromonas species; and DHA-1 to the
the new b-lactamases, but the genes encoding these enzyme of Morganella morganii.7 Carbapenemases
enzymes may also be located on the bacterial chro- of the IMP and VIM families are also found within
mosome. The genes encoding some b-lactamases integrons (Fig. 2), but the origin of their genes is
are carried by transposons.39 Genes for many of the not yet known.
new b-lactamases are found in integrons, which of-
ten include genes conferring resistance to other an- prevalence
tibiotics. For this reason, the new b-lactamases are
usually produced by organisms that are resistant to Despite worldwide use of b-lactam antibiotics, the
multiple antimicrobial agents. distribution of the enzymes responsible for resis-
Occasionally, the ESBL phenotype emerges in an tance to oxyimino-cephalosporins and carbapen-
organism isolated from a patient treated for multi- ems is far from uniform. Some hospitals in the Unit-
ple episodes of bacteremia,40 but much more often ed States seem to have no ESBLs, whereas in other
an ESBL-producing plasmid or strain disseminates hospitals as many as 40 percent of K. pneumoniae
fections. In Greece and Italy, outbreaks due to car- and AmpC-producing K. pneumoniae and E. coli were
bapenem-resistant P. aeruginosa producing VIM-1 sent as unknown specimens to 38 hospital-affil-
carbapenemase were identified in separate hospi- iated and commercial clinical laboratories in Con-
tals and associated with a high mortality rate.69,70 necticut. Six laboratories failed to test for resistance
In Brazil, a strain of A. baumannii resistant to imi- to any oxyimino-b-lactam, and only nine included
penem and meropenem due to an OXA-type carba- both ceftazidime and cefotaxime in their evaluation.
penemase infected eight patients in two hospitals; Depending on the strain tested, between 24 and 32
five of the patients died, despite therapy with mul- percent of laboratories incorrectly reported it as sus-
tiple antibiotics, including polymyxin B.71 K. pneu- ceptible.74 In a recent evaluation of the ability of
moniae strains with reduced susceptibility to carba- rural laboratories in the United States to identify
penems due to KPC-2 or KPC-3 has been found specific resistance mechanisms, only 5 of 60 lab-
recently in several hospitals in New York City.72 oratories screened K. pneumoniae isolates for ESBL
production.75 In a proficiency test of 129 laborato-
detection ries outside the United States, 7 misreported a high-
ly resistant ESBL-producing K. pneumoniae strain as
Detection of the new b-lactamases is less straight- susceptible to all cephalosporins, and only 2 specif-
forward than implied by the properties listed in Ta- ically reported the strain as an ESBL producer.76
ble 1 because of the heterogeneity of the enzymes,
their variable activity against potential substrates, risk factors for infection
their coexistence with other b-lactamases, and the
confounding factors that modify their expression. Risk factors for colonization or infection by ESBL-
The procedure currently recommended by the Clin- producing organisms are little different from the
ical and Laboratory Standards Institute (CLSI) to de- risk factors for other nosocomial infections.77
tect ESBL-producing K. pneumoniae, K. oxytoca, and Reported risks, many of which are linked, include
E. coli involves an initial disk-diffusion or broth- an increased length of stay in the hospital,78,79 an
dilution screening test with one or more oxyimino- increased length of stay in the intensive care
b-lactams, followed by a confirmatory test to mea- unit,80,81 increased severity of illness,82-84 the use
sure susceptibility to ceftazidime and to cefotaxime of a central venous or arterial catheter,80-82,84,85
alone and in combination with clavulanic acid. Au- the use of a urinary catheter,78,80-84 ventilatory as-
tomated procedures have also been developed. sistance,81,82,86 hemodialysis,87 emergency ab-
Currently there are no CLSI-recommended tests dominal surgery,81 the use of a gastrostomy or je-
for detecting AmpC b-lactamases or carbapenemas- junostomy tube,84 gut colonization,80,88 prior
es, nor are there recommended tests for detecting administration of an oxyimino-b-lactam antibiot-
ESBLs in P. aeruginosa or in enteric bacteria other ic,84,88-92 and prior administration of any antibi-
than E. coli and klebsiella species. Cefoxitin or ce- otic.84,85,93 Similar risk factors are emerging for
fotetan resistance along with oxyimino-b-lactam infection with P. aeruginosa producing IMP-type
resistance raises the suspicion of an AmpC-type en- carbapenemases.94
zyme, although there are other possibilities.7 Car-
bapenem resistance in an enteric gram-negative or- treatment
ganism is currently rare enough to ensure that such
an isolate would receive special attention. Unfortu- in vitro data
nately, with so many different ESBLs and other new ESBL-producing organisms vary in their suscepti-
b-lactamases, no test is completely reliable73; bet- bility to different oxyimino-b-lactams, and despite
ter tests continue to be proposed, and recommen- resistance to some they may appear sensitive to
dations continue to evolve. others. For organisms producing TEM and SHV-
Success in identifying these mechanisms of re- type ESBLs, apparent in vitro sensitivity to cefepime
sistance in clinical laboratories is rather poor, sug- and to piperacillintazobactam is common, but
gesting that patients are at risk for receiving inap- both drugs show an inoculum effect, with dimin-
propriate treatment and that the prevalence of ished susceptibility as the size of the inoculum is
ESBLs and AmpC b-lactamases is underreported. increased from 105 to 107 organisms.95-97
In a study published in 1999, before the current Strains with some CTX-Mtype and OXA-type
CLSI detection criteria were widely known, ESBL- ESBLs are resistant to cefepime on testing, despite
in clinical laboratories is imperfect. Carbapenems tamases. Available agents need to be used judicious-
are the surest agents for therapy, but the variety of ly and infection-control measures implemented in
b-lactamases that confer resistance to carbapenems outbreak situations to prevent the further spread of
is increasing, and overuse of any single class of an- pathogens with these all-too-successful mecha-
tibiotic is likely to be followed by the selection of nisms of resistance.
pathogens resistant to that agent. There are no Dr. Jacoby reports having received consultation or lecture fees
from Bayer and Ortho-McNeil and grant support from Merck. Dr.
b-lactams in development that can treat infections Munoz-Price reports having received grant support from Merck.
with organisms producing some of the new b-lac-
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