Emerging Infectious Diseases Volume 17 Issue 10

2011·6.6 MB·English

by  CDC

Peer-Reviewed Journal Tracking and Analyzing Disease Trends pages 1791–1992
EDITOR-IN-CHIEF
D. Peter Drotman
Managing Senior Editor EDITORIAL BOARD
Polyxeni Potter, Atlanta, Georgia, USA
Dennis Alexander, Addlestone Surrey, United Kingdom
Senior Associate Editor Timothy Barrett, Atlanta, GA, USA
Brian W.J. Mahy, Bury St. Edmunds, Suffolk, UK Barry J. Beaty, Ft. Collins, Colorado, USA
Martin J. Blaser, New York, New York, USA
Associate Editors
Sharon Bloom, Atlanta, GA, USA
Paul Arguin, Atlanta, Georgia, USA
Christopher Braden, Atlanta, GA, USA
Charles Ben Beard, Ft. Collins, Colorado, USA
Mary Brandt, Atlanta, Georgia, USA
Ermias Belay, Atlanta, GA, USA
Arturo Casadevall, New York, New York, USA
David Bell, Atlanta, Georgia, USA Kenneth C. Castro, Atlanta, Georgia, USA
Corrie Brown, Athens, Georgia, USA Louisa Chapman, Atlanta, GA, USA
Charles H. Calisher, Ft. Collins, Colorado, USA Thomas Cleary, Houston, Texas, USA
Michel Drancourt, Marseille, France Vincent Deubel, Shanghai, China
Paul V. Effl er, Perth, Australia Ed Eitzen, Washington, DC, USA
David Freedman, Birmingham, AL, USA Daniel Feikin, Baltimore, MD, USA
Peter Gerner-Smidt, Atlanta, GA, USA Anthony Fiore, Atlanta, Georgia, USA
Stephen Hadler, Atlanta, GA, USA Kathleen Gensheimer, Cambridge, MA, USA
Nina Marano, Atlanta, Georgia, USA Duane J. Gubler, Singapore
Martin I. Meltzer, Atlanta, Georgia, USA Richard L. Guerrant, Charlottesville, Virginia, USA
David Morens, Bethesda, Maryland, USA Scott Halstead, Arlington, Virginia, USA
J. Glenn Morris, Gainesville, Florida, USA David L. Heymann, London, UK
Patrice Nordmann, Paris, France Charles King, Cleveland, Ohio, USA
Tanja Popovic, Atlanta, Georgia, USA Keith Klugman, Atlanta, Georgia, USA
Didier Raoult, Marseille, France Takeshi Kurata, Tokyo, Japan
Pierre Rollin, Atlanta, Georgia, USA S.K. Lam, Kuala Lumpur, Malaysia
Ronald M. Rosenberg, Fort Collins, Colorado, USA Stuart Levy, Boston, Massachusetts, USA
Dixie E. Snider, Atlanta, Georgia, USA John S. MacKenzie, Perth, Australia
Frank Sorvillo, Los Angeles, California, USA Marian McDonald, Atlanta, Georgia, USA
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J. Todd Weber, Atlanta, Georgia, USA
Philip P. Mortimer, London, United Kingdom
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Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011
October 2011
On the Cover Multidrug-Resistant Tuberculosis,
People’s Republic of China,
Rembrandt van Rijn (1606–1669)
Aristotle with a Bust of Homer 2007–2009..................................................1831
(1653) Oil on canvas G.X. He et al.
(143.5 cm × 136.5 cm). Early detection, effective treatment, and infection
The Metropolitan Museum of Art,
control measures are needed to reduce transmission.
New York, NY
Bacterial Causes of Empyema in
About the Cover p. 1985
Children, Australia, 2007–2009 ................1839
R.E. Strachan et al.
Most cases were caused by non–7-valent
pneumococcal conjugate vaccine serotypes.
Perspective
Global Spread of Carbapenemase-
Azole Resistance in Aspergillus
producing Enterobacteriaceae ................1791
P. Nordmann et al. fumigatus, the Netherlands,
2007–2009..................................................1846
These resistance traits have been identifi ed among
J.W.M. van der Linden et al.
nosocomial and community-acquired infections.
Antifungal drug resistance is associated with
Research high death rates among patients with invasive
aspergillosis.
Plasmodium knowlesi Malaria
in Humans and Macaques, Thailand.......1799
S. Jongwutiwes et al. Invasive Mold Infections in
This parasite may be transmitted from macaques to p. 1866 Transplant Recipients, United States,
humans. 2001–2006..................................................1855
B.J. Park et al.
Oseltamivir-Resistant Pandemic Non–Aspergillus mold infections increased
(H1N1) 2009 Virus Infection in England substantially during the surveillance period.
and Scotland, 2009–2010 .........................1807
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Humans Infected with
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The attack rate was low; major risk factors were Equine Encephalosis Virus in Israel
having contact with an ill household member and K. Aharonson-Raz et al.
younger age.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011
1887 Prevalence and Molecular Characterization
of Cyclospora cayetanensis, Henan, China
Y. Zhou et al. October 2011
1891 Yellow Fever Virus Vaccine–associated
1954 Placental Transmission of Human
Deaths in Young Women
Parvovirus 4 in Newborns with Hydrops,
S.J. Seligman
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1894 Unexpected Rift Valley Fever Outbreak, M.-Y. Chen et al.
Northern Mauritania

A.B.O. El Mamy et al.
Letters
1897 Seroconversion to Pandemic (H1N1) 2009
Virus and Cross-Reactive Immunity to
1957 Shiga Toxin–producing Escherichia coli
Other Swine Infl uenza Viruses
O104:H4 Strains from Italy and Germany
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1958 Complicated Pandemic (H1N1) 2009 during
1900 Plasmodium knowlesi Infection in Humans,
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Infl uenza A (H3N2) in Children’s Hospital,
1903 Equine Piroplasmosis Associated with
Australia
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G.A. Scoles et al. 1962 Global Health Security in an Era of Global
Health Threats
1906 Timeliness of Surveillance during Outbreak p. 1888
of Shiga Toxin–producing Escherichia coli 1963 Use of Workplace Absenteeism
Infection, Germany, 2011 Surveillance Data for Outbreak Detection
M. Altmann et al. 1964 Zoonotic Ascariasis, United Kingdom
1910 Global Distribution of Shigella sonnei 1966 Early Failure of Antiretroviral Therapy in
Clones HIV-1–infected Eritrean Immigrant
I. Filliol-Toutain et al.
1968 Diagnosis of Rickettsioses from Eschar
1913 Drug-Resistant Tuberculosis, KwaZulu- Swab Samples, Algeria
Natal, South Africa, 2001–2007
1970 Livestock-associated MRSA ST398
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Infection in Woman, Colombia
1917 Antimicrobial Ointments and Methicillin-
1971 Granulicatella adiacens and Early Onset
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1925 Pandemic (H1N1) 2009 Encephalitis in
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1979 Dengue Virus Serotype 4, Roraima State,
1932 Group B Streptococcus and HIV Infection Brazil (response)
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1981 Novel Hepatitis E Virus Genotype in
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1936 Hantavirus Infections without Pulmonary
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1940 Crimean-Congo Hemorrhagic Fever, 1984 Antibiotic Resistance: Understanding and
Afghanistan, 2009 Responding to an Emerging Crisis
L. Mustafa et al.
1942 Extensively Drug-Resistant Tuberculosis in About the Cover
Women, KwaZulu-Natal, South Africa
M.R. O’Donnell et al. 1985 Much have I travel’d in the realms of gold
1946 Clostridium diffi cile Infection in Etymologia
Outpatients, Maryland and Connecticut 1815 Plasmodium knowlesi
J.M. Hirshon et al.

1950 CTX-M-15–producing Enteroaggregative

Escherichia coli as Cause of Travelers’
Diarrhea
E. Guiral et al.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011
Global Spread of Carbapenemase-
producing Enterobacteriaceae
Patrice Nordmann, Thierry Naas, and Laurent Poirel
Carbapenemases increasingly have been reported has been reported worldwide (1). It is therefore mandatory
in Enterobacteriaceae in the past 10 years. Klebsiella to maintain the clinical effi cacy of carbapenems (imipenem,
pneumoniae carbapenemases have been reported in ertapenem, meropenem, doripenem), which have
the United States and then worldwide, with a marked become antimicrobial drugs of last resort. These agents
endemicity at least in the United States and Greece. Metallo-
are crucial for preventing and treating life-threatening
enzymes (Verona integron–encoded metallo-β-lactamase,
nosocomial infections, which are often associated with
IMP) also have been reported worldwide, with a higher
techniques developed in modern medicine (transplantation,
prevalence in southern Europe and Asia. Carbapenemases
hospitalization in an intensive care unit, highly technical
of the oxacillinase-48 type have been identifi ed mostly
surgery).
in Mediterranean and European countries and in India.
Recent identifi cation of New Delhi metallo-β-lactamase-1 Carbapenem-resistant Enterobacteriaceae have been
producers, originally in the United Kingdom, India, and reported worldwide as a consequence largely of acquisition
Pakistan and now worldwide, is worrisome. Detection of carbapenemase genes (2). The fi rst carbapenemase
of infected patients and carriers with carbapenemase producer in Enterobacteriaceae (NmcA) was identifi ed
producers is necessary for prevention of their spread. in 1993 (3). Since then, a large variety of carbapenemases
Identifi cation of the carbapenemase genes relies mostly has been identifi ed in Enterobacteriaceae belonging
on molecular techniques, whereas detection of carriers is
to 3 classes of β-lactamases: the Ambler class A, B,
possible by using screening culture media. This strategy
and D β-lactamases (2). In addition, rare chromosome-
may help prevent development of nosocomial outbreaks
encoded cephalosporinases (Ambler class C) produced by
caused by carbapenemase producers, particularly K.
Enterobacteriaceae may possess slight extended activity
pneumoniae.
toward carbapenems, but their clinical role remains
unknown (2,4).
Enterobacteriaceae are inhabitants of the intestinal fl ora
and are among the most common human pathogens, Class A Carbapenemases
causing infections such as cystitis and pyelonephritis with A variety of class A carbapenemases have been
fever, septicemia, pneumonia, peritonitis, meningitis, and described; some are chromosome encoded (NmcA, Sme,
device-associated infections. Enterobacteriaceae are the IMI-1, SFC-1), and others are plasmid encoded (Klebsiella
source of community- and hospital-acquired infections. pneumoniae carbapenemases [KPC], IMI-2, GES,
They have the propensity to spread easily between humans derivatives), but all effectively hydrolyze carbapenems
(hand carriage, contaminated food and water) and to and are partially inhibited by clavulanic acid (2). KPCs
acquire genetic material through horizontal gene transfer, are the most clinically common enzymes in this group.
mediated mostly by plasmids and transposons. The fi rst KPC producer (KPC-2 in K. pneumoniae) was
Since 2000, spread of community-acquired identifi ed in 1996 in the eastern United States (5).Within
enterobacterial isolates (Escherichia coli) that produce a few years, KPC producers had spread globally and have
extended-spectrum β-lactamases (ESBLs) capable of been described across the contiguous United States (still
hydrolyzing almost all cephalosporins except carbapenems mostly in eastern coast states) and, in particular, in Puerto
Rico, Colombia, Greece, Israel, and the People’s Republic
of China (6,7) (Figure 1). Outbreaks of KPC producers
Author affi liation: Bicêtre Hospital, Le Kremlin-Bicêtre, France
also have been reported in many European countries and in
DOI: http://dx.doi.org/10.3201/eid1710.110655 South America (6,7) (Figure 1).
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011 1791
PERSPECTIVE
Figure 1. A) Worldwide geographic distribution of Klebsiella pneumoniae carbapenemase (KPC) producers. Gray shading indicates
regions shown separately: B) distribution in the United States; C) distribution in Europe; D) distribution in China.
KPC producers have been reported, mostly from IMP types and, more recently, of the New Delhi metallo-
nosocomial K. pneumoniae isolates and to a much lesser β-lactamase-1 (NDM-1) type (2,12).The fi rst acquired
extent from E. coli (especially in Israel) and from other MBL, IMP-1, was reported in Serratia marcescens in
enterobacterial species (6). A single K. pneumoniae clone Japan in 1991 (13). Since then, MBLs have been described
(sequence type [ST]-258) was identifi ed extensively worldwide (2,12) (Figure 3). Endemicity of VIM- and
worldwide, indicating that it may have contributed to the IMP-type enzymes has been reported in Greece, Taiwan,
spread of the bla genes (8).Within a given geographic and Japan (2,12), although outbreaks and single reports
KPC
location, several KPC clones are disseminating that differ of VIM and IMP producers have been reported in many
by multilocus sequence type; additional β-lactamase other countries (Figure 3). These enzymes hydrolyze all
content; and by size, number, and structure of plasmids, β-lactams except aztreonam (12).Their activity is inhibited
but the bla genes are associated with a single genetic by EDTA but not by clavulanic acid (12). Most MBL
KPC
element (transposon Tn4401) (8). Although community- producers are hospital acquired and multidrug-resistant K.
acquired KPC producers have been reported, they are pneumoniae (2,12). Resistance levels to carbapenems of
rare, with the exception of isolates from Israel a few MBL producers may vary (Table 1). Death rates associated
years ago (6).The level of resistance to carbapenems with MBL producers range from 18% to 67% (14).
of KPC producers may vary markedly; ertapenem is the Discovered in 2008 in Sweden from an Indian
carbapenem that has the lowest activity (5–7), (Table 1). patient hospitalized previously in New Delhi (15), NDM-
KPC producers are usually multidrug resistant (especially
to all β-lactams), and therapeutic options for treating KPC- Table 1. MIC range of carbapenems for Enterobacteriaceae that
related infections remain limited (6) (Figure 2, panel A). produce several types of carbapenemases*
Death rates attributed to infections with KPC producers are MIC, mg/L
high (>50%) (9–11). Carbapenemase Imipenem Meropenem Ertapenem
KPC 0.5–>64 1–>64 0.5–>64
Metallo (cid:533)-lactamases† 0.5–>64 0.25–>64 0.5–>64
Class B Metallo-β-Lactamases
OXA-48 type 1–>64 0.5–>64 0.25–>64
Class B metallo-β-lactamases (MBLs) are mostly of the
*KPC, Klebsiella pneumoniae carbapenemase; OXA-48, oxacillinase-48.
Verona integron–encoded metallo-β-lactamase (VIM) and †Including New Delhi metallo-(cid:533)-lactamase-1.
1792 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011
Carbapenemase-producing Enterobacteriaceae
1–positive Enterobacteriaceae are now the focus of In contrast to several other carbapenemase genes,
worldwide attention (15–17). Since mid-August 2010, the bla gene is not associated with a single clone
NDM-1
NDM-1 producers have been identifi ed on all continents but rather with nonclonally related isolates and species
except in Central and South America with, in most of (16,17). It has been identifi ed mostly in E. coli and K.
the cases, a direct link with the Indian subcontinent (17) pneumoniae and to a lesser extent in other enterobacterial
(Figure 4). Few cases have been reported from the United species (16,17). The level of resistance to carbapenems of
States and Canada (17). Recent fi ndings suggest that the NDM-1 producers may vary (Table 1). Plasmids carrying
Balkan states and the Middle East may act as secondary the bla gene are diverse and can harbor a high number
NDM-1
reservoirs of NDM-1 producers (17) (Figure 4). of resistance genes associated with other carbapenemase
genes (oxacillinase-48 [OXA-48] types, VIM types),
plasmid-mediated cephalosporinase genes, ESBL genes,
aminoglycoside resistance genes (16S RNA methylases),
macrolide resistance genes (esterase), rifampin (rifampin-
modifying enzymes) and sulfamethoxazole resistance
genes as a source of multidrug resistance and pandrug
resistance (16,17) (Figure 2, panel B). The association of
such a high number of resistance genes in single isolates has
been rarely observed, even among the other carbapenemase
producers. Many NDM-1 producers remain susceptible
only to tigecycline, colistin (Figure 2, panel B), and to a
lesser extent fosfomycin (16,17).
Compared with other carbapenemases, NDM-1 has
several characteristics that are deeply disconcerting for
public health worldwide. These characteristics are 1)
occurrence of the bla gene not in a single species but in
NDM-1
many unrelated species and its spread in the environment, at
least in the Indian subcontinent (18); 2) frequent acquisition
by K. pneumoniae, a typical nosocomial pathogen, but also
by E. coli that is by far the main (community-acquired)
human pathogen; and 3) size of the reservoir—the Indian
subcontinent has >1.4 billion persons. In certain areas
in Pakistan, <20% of the population may carry NDM-1
producers (P. Nordmann, unpub. data).
Of particular concern, NDM-1 has been identifi ed in
E. coli ST-type 131 as a source of community-acquired
infection (19), an ST type that is known to mobilize
effi ciently the ESBL CTX-M-15 worldwide (20). E.
coli is the most common cause of diarrhea in children in
Figure 2. Disk diffusion antibacterial drug susceptibility testing of A)
Klebsiella pneumoniae carbapenemase-2 (KPC-2)–, B) New Delhi India. Therefore, this organism may increase the risk of
metallo-β-lactamase-1 (NDM-1)–, and C) oxacillinase-48 (OXA-48)– drug-resistant strains being released into the environment
producing K. pneumoniae clinical isolates. Clinical isolates producing and further spread among humans. Accordingly, NDM-1
KPC-2 and OXA-48 do not co-produce other extended-spectrum
producers have been recently identifi ed in tap and
β-lactamase, but the isolate producing NDM-1 co-produces the
environmental water in New Delhi, among many unrelated
extended-spectrum β-lactamase CTX-M-15. Wild-type susceptibility
to β-lactams of K. pneumoniae includes resistance to amoxicillin, gram-negative species (18).
ticarcillin, and reduced susceptibility to piperacillin and cefalotin
(data not shown).TZP, piperacillin/tazobactam; PIP, piperacillin; Class D Enzymes of the OXA-48 Type
TIC, ticarcillin; AMX, amoxicillin; ETP, ertapenem; TCC, ticarcillin/
The fi rst identifi ed OXA-48 producer was from a
clavulanic acid; CAZ, ceftazidime; CF, cefalotin; FOX, cefoxitin; IMP,
K. pneumoniae strain isolated in Turkey in 2003 (21).
imipenem; AMC, amoxicillin/clavulanic acid; CTX, cefotaxime; CXM,
cefuroxime; MEM, meropenem; ATM, aztreonam; FEP, cefepime; Since then, OXA-48 producers have been extensively
CIP, ciprofl oxacin; CS, colistin; NET, netilmicin; RA, rifampin; OFX, reported from Turkey as a source of nosocomial outbreaks
ofl oxacin; TE, tetracycline; C, chloramphenicol; TM, tobramycin; (22–26). Their worldwide distribution now includes
NOR, norfl oxacin; TGC, tigecycline; SXT, sulfamethoxazole/
countries in Europe, in the southern and eastern part of the
trimethoprim; AN, amikacin; FT, nitrofurantoin; FOS, fosfomycin;
Mediterranean Sea, and Africa (21–26) (Figure 5). OXA-48
SSS, sulfamethoxazole; GM gentamicin.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011 1793
PERSPECTIVE
Figure 3. Worldwide (A) and European (B)
geographic distribution of Verona integron–
encoded metallo-β-lactamase (VIM) and
IMP enterobacterial producers.
producers have not been reported from the United States Thus, their true prevalence could be underestimated. The
and Canada. A point mutant analog of OXA-48, OXA-181, attributed mortality rate from infections with OXA-48
with similar carbapenemase activity, has been identifi ed in producers is unknown.
strains from India or of Indian origin (27,28). There is an
increasing trend of identifi cation of OXA-48 producers in Identifi cation of Carbapenemase Producers
countries such as France, Germany, Spain, the Netherlands, The detection of carbapenemase producers in clinical
and the United Kingdom through transfer of hospitalized infections is based fi rst on susceptibility testing results
patients from disease-endemic areas that are the source of obtained by disk diffusion or by automated systems (29). The
hospital outbreaks (Figure 5). Clinical and Laboratory Standards Institute (CLSI; Wayne,
Several OXA-48–producing clones have been PA, USA) breakpoints of carbapenems have been lowered
identifi ed, and dissemination of this resistance trait is substantially in 2010 for a better detection of carbapenem-
associated with a 62.5-kb plasmid (previously identifi ed resistant isolates and carbapenemase producers (Table 2).
as a plasmid of ≈70 kb) (22). OXA-48/OXA-181 are The CLSI breakpoints of carbapenems are now lower than
peculiar because they weakly hydrolyze carbapenems and those of the European guidelines (Table 2). Applying the
broad-spectrum cephalosporins, such as ceftazidime, and CLSI breakpoints is all that is needed for making treatment
aztreonam (21,27), (Figure 2, panel C). Their activity is decisions according to CLSI recommendations. Special
not inhibited by EDTA or clavulanic acid (resistance to tests for carbapenemase detection are recommended for
amoxicillin/clavulanic acid; Figure 2, panel C). Although epidemiology and infection issues.
reported in various enterobacterial species, OXA-48 However, low-level resistance and even susceptibility
producers are mostly identifi ed in K. pneumoniae and E. to carbapenems have been observed for producers of any
coli, and the level of resistance to carbapenems is usually type of carbapenemases (Table 1). We believe, as do others
higher when ESBL and permeability defects are associated (30), that the search for carbapenemase producers should
(22–28), (Table 1). The OXA-48–type producers are likely be made for any enterobacterial isolates with decreased
the most diffi cult carbapenemase producers to be identifi ed. susceptibility to carbapenems. Our opinion is based on
1794 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011
Carbapenemase-producing Enterobacteriaceae
Figure 4. Geographic distribution of New
Delhi metallo-β-lactamase-1 producers,
July 15, 2011. Star size indicates
number of cases reported. Red stars
indicate infections traced back to India,
Pakistan, or Bangladesh; green stars
indicate infections traced back to the
Balkan states or the Middle East; and
black stars indicate contaminations of
unknown origin. (Most of the information
corresponds to published data; other
data are from P. Nordmann.)
the paucity of clinical experience for treating infections The standard for identifi cation of carbapenemases
caused by carbapenemase producers, on the unknown level is based on use of molecular techniques, mostly
of carbapenemase production in the site of the infection PCR (29,33). A list of primers of the most prevalent
in vivo, and on the possibility of selecting in vivo for carbapenemase genes identifi ed in Enterobacteriaceae
strains with increased levels of resistance to carbapenems is shown in Table 3 (34). Standard conditions may be
and additional mechanisms of carbapenem resistance used for PCR-based detection (34). PCR performed on
(carbapenemase, outer-membrane permeability defects). colonies may give results within 4–6 hours with excellent
Specifi c tests may help identify phenotypically a sensibility and specifi city. Similarly, other molecular
carbapenemase activity. The modifi ed Hodge test based on techniques, such as the Check-Points DNA technology,
in vivo production of carbapenemase has been suggested for are useful for this purpose (35). Sequencing of PCR
detecting carbapenemase producers (29,31,32). However, products may be of interest mostly for epidemiologic
this test is time consuming and may lack specifi city (high- purposes. The main disadvantages of molecular-based
level AmpC producers) and sensitivity (weak detection technologies for detection of carbapenemases are their
of NDM producers) (27,29). This test may be useful for cost, the requirement of trained personal, and the absence
detecting KPC and OXA-48 producers (P. Nordmann, of detection of any novel carbapenemase gene. Thus, there
unpub. data). Boronic acid–based inhibition testing is is an urgent need for an inexpensive, rapid, sensitive, and
reported to be specifi c for KPC detection in K. pneumoniae specifi c test for detection of carbapenemase activity.
when performed with imipenem or meropenem but not with The prevention of spread of carbapenemase producers
ertapenem if corresponding isolates co-produce a plasmid- relies on early detection of carriers (29,33). Patients who
mediated AmpC β-lactamase (29,30). The Etest MBL undergo screening should include patients who were
strip (bioMérieux, Solna, Sweden) is one of the methods hospitalized while abroad and then transferred to another
advocated for detecting MBL producers on the basis of country, and patients at risk (e.g., patients in intensive care
inhibition of MBL activity by EDTA (12). The Etest MBL, units, transplant patients, immunocompromised patients).
using imipenem and imipenem/EDTA, is effi cient for Screened patients should be kept in strict isolation before
detection of MBL producers with high resistance (12), but obtaining results of the screening (at least 24–48 hours).
may be defi cient for detecting MBL producers with low Because the reservoir of carbapenemase producers remains
resistance to imipenem. No inhibition test is available for the intestinal fl ora, fecal and rectal swab specimens are
detection of OXA-48/OXA-181 producers. adequate for performing this screening. Those specimens
Spectrophotometric assay is needed for detecting may be plated directly on screening media.
carbapenemase activity. However, this assay is time There is no universal screening medium able to detect
consuming, requires specifi c training, and does not easily all types of carbapenemase producers with high sensitivity
discriminate between different types of carbapenemases. and high specifi city, however. Agar plates containing
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011 1795
PERSPECTIVE
Conclusions
Carbapenemase producers in Enterobacteriaceae are
not the source of specifi c types of clinical infections. The role
of these bacteria is related to the diffi cult-to-treat infections
rather than to expression of specifi c virulence traits.
We believe we are now at the edge of 2 concomitant
epidemics of carbapenemase producers worldwide. The
fi rst epidemic will be caused mainly by carbapenemase
producers in E. coli as a source of community-acquired
infections. These carbapenemases are thus far primarily
of the NDM and of the OXA-48 types. A few published
reports of community-acquired infections caused by
carbapenemase producers are available, but it is more
likely that the numbers of cases in disease-endemic areas
are already high. The example of the spread of ESBL
producers in the community within the past 10 years shows
us that a high rate of carbapenemase producers in E. coli
Figure 5. Geographic distribution of oxacillinase-48 (OXA-48) type may be reached rapidly worldwide. As opposed to a viral
producers. epidemic, such as pandemic (H1N1) 2009, the epidemic
of carbapenemase producers cannot stop spontaneously.
Such community-based outbreaks will be diffi cult to
imipenem at a concentration of 1 mg/L have been control. Modulation of the factors that enhance spread of
proposed for screening only KPC producers (36). We have carbapenemase producers in the community is diffi cult
demonstrated that a culture medium designed to screen because these factors are multiple and are associated
for ESBL producers (ChromID ESBL; bioMérieux, La- with lack of hygiene, overuse and over-the-counter use
Balme-Les-Grotte, France) may be used also for screening of antibacterial drugs, and increased worldwide travel. In
carbapenemase producers. Although this medium may addition, many carbapenemase producers carry unrelated
lack specifi city (co-detection of ESBL producers), its drug-resistance determinants. Therefore, selection pressure
sensitivity is higher than a culture medium designed with structurally unrelated antibacterial drugs (not only
to screen for carbapenemase producers (CHROMagar β-lactams) may contribute to their spread.
KPC; CHROMagar, Paris, France) (33,37). The main We cannot predict either the speed of diffusion of
problem remains detection of OXA-48 producers that are those carbapenemase producers in the community or
susceptible to cephalosporins and have low-level resistance their prevalence at a steady state (5%–50%?). The actual
to carbapenems when not co-producing an ESBL (Figure prevalence of carbapenemase producers is still unknown
2, panel C) (37). None of these culture media detect those because many countries that are likely to be their main
OXA-48 producers (37). reservoirs have not established any search protocol for
After this screening procedure, carbapenemase their detection. The prevalence may substantially differ,
producers may be identifi ed according to the techniques depending on the country, as known with the current
described above (antibacterial drug susceptibility testing, prevalence rate of ESBL producers in E. coli. The
molecular techniques). Recently, PCR-based techniques prevalence is estimated to be 3%–5% in France and >80%
performed directly on fecal specimens have been proposed in India (38).
for detection of KPC and NDM-1 producers. The second epidemic will likely be caused mainly by
nosocomial carbapenemase producers in K. pneumoniae of
all types (KPC, IMP, VIM, NDM, and OXA-48). It is likely
Table 2. Breakpoint values (MIC, mg/L) for carbapenems that in certain countries high rates of different types of
according to guidelines in Europe (EUCAST) and the United
carbapenemase producers may already exist, for example,
States (CLSI), September 2010*
in Greece (VIM and KPC) and in the Indian subcontinent
EUCAST CLSI
(NDM, KPC, OXA-181). K. pneumoniae will play a major
Carbapenem S R S R
role because it has been repeatedly identifi ed to be the most
Ertapenem <0.5 >1 <0.25 >1
Imipenem <2 >8 <1 >4 common enterobacterial species for spreading ESBL genes
Meropenem <2 >8 <1 >4 in health care facilities during the past 30 years. It may
*EUCAST, European Committee on Antimicrobial Susceptibility Testing play the same role for spreading carbapenemase producers
(www.eucast.org/clinical_breakpoints); CLSI, Clinical and Laboratory
Standards Institute; S, sensitive; R, resistant. in patients with identical risk factors (patients receiving
1796 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 10, October 2011