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Highly drug-resistant salmonella enterica serotype kentucky st198-x1: a microbiological study

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Highly drug-resistant Salmonella enterica serotype Kentucky
ST198-X1: a microbiological study
Simon Le Hello, Dorothée Harrois, Brahim Bouchrif, Lucile Sontag, Dalèle Elhani, Véronique Guibert, Khalid Zerouali, François-Xavier Weill
Background Salmonella enterica is a major global food-borne pathogen, causing life-threatening infections. Published Online
Ciprofl oxacin and extended-spectrum cephalosporins (ESCs) are the drugs of choice for severe infections. We
May 28, 2013
previously reported a ciprofl oxacin-resistant S enterica serotype Kentucky (S Kentucky) ST198-X1 strain that emerged http://dx.doi.org/10.1016/
in Egypt and spread throughout Africa and the Middle East from 2002 to 2008. We aimed to monitor recent trends in See Online/Comment
the location of transmission and antimicrobial resistance of this strain.
http://dx.doi.org/10.1016/S1473-3099(13)70141-5 Methods We analysed isolates of S Kentucky collected by the French national surveillance system for salmonellosis in Institut P asteur, Unité des
France from Jan 1, 2000, to Dec 31, 2011, and at two sites in Casablanca, Morocco, between Jan 1, 2003, and Dec 31, 2011. Bactéries Pathogènes
We analysed patterns of travel of patients infected with a ciprofl oxacin-resistant strain of S
Kentucky. We identifi ed isolates Entériques, Centre National de
showing resistance to ESCs or decreased susceptibility to carbapenems, characterised isolates by Xba
I-pulsed fi eld gel Référence des Escherichia coli,
Shigella et Salmonella, WHO
electrophoresis and multilocus sequence typing, and assessed mechanisms of bacterial resistance to antimicrobial drugs. Collaborating Centre for
Reference and Research on
Findings 954 (1%) of 128 836 serotyped Salmonella spp isolates in France were identifi ed as S Kentucky, as were 30 (13%) Salmonella, Paris, France
of 226 Salmonella
spp isolates from Morocco. During 2000–08, 200 (40%) of 497 subculturable isolates of S Kentucky (S Le Hello PharmD,
obtained in France were resistant to ciprofl oxacin, compared with 376 (83%) of 455 isolates in 2009–11, suggesting a D Elhani PhD, V Guibert,
recent increase in ciprofl oxacin resistance in France. Travel histories suggested S Kentucky infections originated F-X Weill MD); Institut Pasteur
predominantly in east Africa, north Africa, west Africa, and the Middle East, but also arose in India. We report several du Maroc, Sécurité Alimentaire

et Environnement, Casablanca,
occurrences of acquisition of extended-spectrum β-lactamase (CTX-M-1, CTX-M-15), plasmid-encoded Morocco (B Bouchrif PhD); and
cephalosporinase (CMY-2), or carbapenemase (OXA-48, VIM-2) genes by ciprofl oxacin-resistant isolates of S Kentucky Laboratoire de Microbiologie,
ST198-X1
from the Mediterranean area since 2009. Many of these highly drug-resistant isolates were also resistant to CHU Ibn Rochd, Casablanca,
most aminoglycosides, to co-trimoxazole (trimethoprim-sulfamethoxazole), and to azithromycin.

Morocco (K Zerouali MD)
Correspondence to:
Interpretation The potential risk to public health posed by ciprofl oxacin-resistant S Kentucky ST198-X1 warrants its Dr François-Xavier Weil , Centre
inclusion in national programmes for the control of S enterica in food-producing animals, in particular in poultry.
Escherichia coli, Shigella et Salmonella, Unité des Bactéries Funding Institut Pasteur, Institut de Veille Sanitaire, Fondation pour la Recherche Médicale, French Government Pathogènes Entériques, Institut
Investissement d’Avenir programme.
75724 Paris Cedex 15, France
francois-xavier.weill@pasteur.fr
Introduction
non-typhoidal strain of Salmonella spp, which was resistant, Antimicrobial drug-resistant bacteria present a serious in particular, to ESCs and fl uoroquinolones. This choice challenge for the clinical care of patients and for public was based on the following observations: fi rst, Salmonel a health in the 21st century.1 Gram-negative superbugs, enterica is a prevalent zoonotic agent causing an estimated such as those resistant to extended-spectrum cephalo- 1·7 million infections per year and resulted in 2800 deaths sporins (ESCs) because of their ability to produce either in high-income regions of North America in 2006;4 second, extended-spectrum β-lactamases or cephamycinases S enterica can cause major food-borne outbreaks, such as (AmpC), seem to have now eclipsed Gram-positive one in the USA in 1994 associated with manufactured ice superbugs (ie, meticillin-resistant Staphylococcus aureus cream con taminated with S enterica serotype Enteritidis, and vancomycin-resistant Enterococcus spp). Further- which caused sickness in an estimated 224 000 people;5 more, the recent emergence of Enterobacteriaceae third, fl uoroquinolones, including ciprofl oxacin, and ESCs resistant to all β-lactam antibiotics, including ESCs and are the drugs of choice for treatment of severe S enterica carbapenems, is of particular concern because infections and for people at risk of such infections (infants, carbapenems are in many cases the last option available the elderly, and immunocompromised patients); and for treatment of serious infection with ESC-resistant fourth, infections with drug-resistant Salmonella spp are Gram-negative bacteria. Indeed, the development associated with increased morbidity and mortality.6pipeline for new antimicrobial drugs with bactericidal We previously reported the international emergence of a activity against Gram-negative bacteria has now run dry.2,3 multidrug-resistant S enterica serotype Kentucky In a 2004 report entitled Bad Bugs, No Drugs, the (S Kentucky) strain, identifi ed as being multilocus sequence Infectious Diseases Society of America imagined a type (MLST) ST198 and as belonging to XbaI-pulsed fi eld catastrophic scenario with an explosive epidemic of 220 000 gel electrophoresis (PFGE) cluster X1.7 S Kentucky cases and 1730 deaths caused by a multidrug-resistant ST198-X1 isolates are resistant to several antimicrobial www.thelancet.com/infection Published online May 28, 2013 http://dx.doi.org/10.1016/S1473-3099(13)70141-5
Articles
drugs, including ciprofl oxacin (mini mum inhibitory ceftazidime, imipenem, ertapenem, meropenem, concentration ≥4 mg/L), which is an unusual resistance ciprofl oxacin, azithromycin, colistin, and tigecycline by trait in S enterica.8,9 The fi rst ciprofl oxacin-resistant use of Etests (AB Biodisk, Solna, Sweden). We For the Antibiogram Committee S Kentucky to be identifi ed was isolated from a French
interpreted results with the Antibiogram Co of the French Society for tourist who visited Egypt in 2002. From then until 2008, the
Microbiology see http://www.
laboratory surveillance systems for salmonellosis in France, breakpoints. In particular, we defi ned susceptible England, and Denmark detected 489 cases of infection with isolates as having a minimum inhibitory concentration this strain in people who had travelled to or stayed in Africa of 0·5 mg/L or less for ciprofl oxacin, and resistant or the Middle East.7 Admission to hospital was more isolates were defi ned as having a minimum inhibitory frequent in patients infected with ciprofl oxacin-resistant concentration of more than 1 mg/L for ciprofl oxacin, S Kentucky than it was among those infected with Kentucky irrespective of isolate source (ie, intestinal or strains that were susceptible to ciprofl oxacin.7 extraintestinal). We defi ned isolates as highly drug- All S Kentucky isolates that were resistant to cipro- resistant if they were resistant to at least four antibiotic fl oxacin in our previous survey7 were susceptible to classes, including fl uoro quinolones (ie, ciprofl oxacin) ESCs. However, one case report described a Belgian and ESCs (ie, ceftriaxone or ceftazidime).
traveller who was infected with ciprofl oxacin-resistant For molecular typing, we used PulseNet standard S Kentucky during a trip to Libya in 2005, who required pulsed-fi eld gel electrophoresis of XbaI-digested treatment with meropenem due to ESC resistance chromosomal DNA and multilocus sequence typing as (CTX-M-1 extended-spectrum β-lactamase production) previously described.7 after multiple treatment failures for a severe infection.10 To determine resistance mechanisms, we assessed The aim of our present study was to monitor recent presence of β-lactam resistance genes (bla , bla , trends in the global epidemiology and antimicrobial bla resistance of the ciprofl oxacin-resistant S Kentucky bla ), plasmid-mediated quinolone resistance genes (qnrA, qnrB, qnrS, qnrD, aacA4-cr [also known as aac(6´)-Ib-cr], and qepA), macrolide resistance genes (ermA, ermB, ermC, mph[A], ereA, ereB, mrsA, mrsB, Data collection
mefA, and mefE), aminoglycoside resistance genes We did our study in parallel in France, where S Kentucky (armA, rmtA, rmtB, rmtC, rmtD, and npmA), class 1 infection occurs mostly in travellers or migrants, and in integron gene cassettes, and Salmonella genomic Morocco, where most French travellers or migrants island 1 (SGI1) by PCR as previously described.7,11–14acquire the infection. We assessed data from the French We sequenced the quinolone resistance-determining National Reference Centre for Salmonella (FNRC-Salm), region (QRDR) of gyrA, gyrB, parC, and parE (encoding which was established in 1947. In 2000–11, the FNRC- subunits of the DNA gyrase and the topoisomerase IV) Salm network included a stable number of about 1400 as previously described.7 We analysed nucleotide and hospital and private clinical laboratories. In 2008, an deduced aminoacid sequences and compared them unpublished survey of all 3375 French clinical laboratories with sequences available from the National Center for For the National Center for (response rate 95%) estimated that about 65% of all
Biotechnology Information human isolates of Salmonella spp in France were reported
We assessed resistance transfer by mating, sequences see http://www.ncbi.
to the FNRC-Salm (S Le Hello and F-X Weill, extended-spectrum β-lactamase, cephamycinase, and unpublished). Basic epidemiological data (date and site carbapenemase producers, using liquid and solid media, of isolation, sex and age of the patient, and international with Escherichia coli K-12 BM14 resistant to sodium azide travel) were recorded for each isolate. as the recipient strain. Transconjugants were selected on For Morocco, we used data obtained from two sites in Drigalski agar (Bio-Rad) supplemented with ceftriaxone Casablanca, the largest city in the country. The fi rst site (4 mg/L), ceftazidime (16 mg/L), or imipenem (3 mg/L) was the microbiology laboratory at the University plus sodium azide (500 mg/L). Three E coli trans-Hospital Centre Ibn Rochd (UHCIR), which is a 1700-bed conjugants were arbitrarily selected in each experiment. teaching hospital. The second site was the Pasteur We used S1 nuclease treatment and pulsed-fi eld gel Institute of Morocco (PIM), which receive clinical strains electrophoresis to determine the sizes of bacterial of Salmonella spp for serotyping from private plasmids accurately, and PCR-based replicon typing laboratories. analysis was done as previously described.15 Microbiological investigations
Role of the funding source
We did antimicrobial susceptibility testing on all The sponsor had no role in study design, data collection, S Kentucky isolates with the disk diff usion method, data analysis, data interpretation, or writing of the report. with a panel of 32 antimicrobial drugs (Bio-Rad, SLH and F-XW had full access to all the data in the study Marnes-La-Coquette, France).7 We determined the and had fi nal responsibility for the decision to submit for minimum in hibitory concentration of ceftriaxone, publication.
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From Jan 1, 2000, to D ec 31, 2011, 128 836 serotyped 371 patients had travelled internationally in the 15 days Salmonella spp isolates were registered at the FNRC- before the onset of illness. Most patients who provided Salm, including 954 non-repeated S Kentucky isolates isolates between 2002 and 2005 had travelled to (1% of all Salmonella spp isolates). All but two (which northeast or east Africa. Since 2006, patients could not be subcultured) of the 954 S Kentucky isolates predominantly reported travel to northeast and east obtained were included in this study.
Africa, north Africa, west Africa, and the Middle East. Between Jan 1, 2003, and Dec 31, 2011, 226 Salmonella Since 2009, the area of infection has extended to include spp isolates were obtained in Morocco and serotyped, India.
including 30 non-repeated S Kentucky isolates (13% of 19 (63%) of 30 clinical isolates of S Kentucky obtained all Salmonella spp isolates). We included all 30 isolates in Casablanca between Jan 1, 2003, and Dec 31, 2011 (26 from UHCIR and four from PIM) in this study. One were resistant to ciprofl oxacin. The fi rst S Kentucky additional isolate from the FNRC-Salm was studied, isolate resistant to ciprofl oxacin was obtained in 2006 which was a serotype Saintpaul isolated from a patient and the annual number of isolates obtained has since co-infected with S Kentucky in 2009.
fl uctuated between one and eight (one in 2007, fi ve in As reported elsewhere,7 200 (40%) of 497 isolates of 2008, two in 2009, eight in 2010, and two in 2011).
S Kentucky obtained in France between Jan 1, 2000, and Three key fi ndings in the antimicrobial resistance of Dec 31, 2008, were resistant to ciprofl oxacin. From Jan 1, S Kentucky should be noted. First, we found that 2009, to Dec 31, 2011, 376 (83%) of 455 isolates of S Kentucky that is resistant to ciprofl oxacin and ESCs has S Kentucky tested were resistant to ciprofl oxacin (fi gure fi gure). emerged in the Mediterranean region since 2009. Based The near doubling of the number of S Kentucky isolates on the FNRC-Salm 2000–11 data, the fi rst S Kentucky resistant to ciprofl oxacin that we noted, in a third of the isolate resistant to ESCs was isolated in 2009 (fi gure). time, with a stable network of laboratories, against a From Jan 1, 2009, to Dec 31, 2011, we identifi ed ten backdrop of a general decrease in the number of isolates of S Kentucky resistant to ESCs (2% of all isolations of Salmonella spp (~11 000 clinical isolates 455 S Kentucky isolates identifi ed during this period): six received per year during 2000–08 vs ~10 000 during of these isolates were susceptible to ciprofl oxacin and 2009–11), suggests that this ciprofl oxacin-resistant had a cephamycinase-like profi le and four were resistant S Kentucky strain continued to circulate and spread.
to ciprofl oxacin and ESCs. These four isolates were Travel information was available for 371 (64%) of acquired in Algeria, Morocco, Egypt, and Turkey 576 patients infected with ciprofl oxacin-resistant (tables 2 and 33), and produced the cephamycinase CMY-2 Isolates resistant to extended-spectrum cephalosporins Figure: Human Salmonella enterica serotype Kentucky isolates identifi ed at the French National Reference Centre for Salmonella in 2000–11
Overal yearly number of Salmonella enterica serotype Kentucky isolates is shown with blue triangles. During this period, 128 836 isolates of Salmonella spp were
registered at the French National Reference Centre (12 883 in 2000, 12 601 in 2001, 11 775 in 2002, 10 472 in 2003, 10 589 in 2004, 11 439 in 2005, 10 154 in 2006,
8124 in 2007, 10 378 in 2008, 9947 in 2009, 9405 in 2010, and 11 069 in 2011).
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2002–05 2006–08 2009–11 Overall
determined that the serotype Saintpaul isolate IncL/M plasmid of about 70 kb. The three sequential S Kentucky isolates that were resistant to ciprofl oxacin belonged to the ST198-X1 strain, and carried the gyrA and parC mutations previously encountered in Kentucky isolates from Egypt and west Africa.7 The three isolates also contained the phospho transferase mph(A) gene, conferring high-level resistance to azithromycin. The three isolates presented diff erent resistance profi les, due to the acquisition or loss of various R plasmids and also, probably, due to IS26 rearrangements of the SGI1.7 The fi rst isolate was resistant to ESCs due to the presence of the bla gene, whereas the most recent isolate, collected 1 year four isolates were susceptible to colistin and tigecycline.
Third, highly drug-resistant S Kentucky isolates producing VIM-2 were identifi ed in Morocco in 2010. Five (17%) of 30 S Kentucky isolates obtained in Casablanca, Morocco, between Jan 1, 2003, and Dec 31, 2011, were resistant to ESCs. These fi ve doubly resistant (to ciprofl oxacin and ESCs) S Kentucky ST198-X1 isolates had decreased susceptibility to imipenem (minimum inhibitory con centration 1–3 mg/L). They all gene within In58,16 itself carried on a 30 kb plasmid. Three isolates originated from patients admitted to hospital in three diff erent intensive-care units (one blood culture, two urine cultures) of the UHCIR during January, 2010, and the other two isolates were obtained from stool cultures done at the PIM in Discussion
We characterised several highly drug-resistant isolates of the emerging S Kentucky ST198-X1 strain, since 2009. Data from the French National Reference Centre for Salmonella. *France is These ciprofl oxacin-resistant isolates acquired in the indicated as the country of infection when patients reported no international Mediterranean area produce various carbapenemases, travel for at least 2 months before the onset of symptoms.
cephamycinase, or extended-spectrum β-lactamases. Our Table 1: Countries visited by patients infected with ciprofl oxacin-
fi ndings that S enterica has taken a major step towards resistant Salmonella enterica serotype Kentucky in the 15 days before
resistance to all antibiotics (panresistance) and suggests onset of illness
that the catastrophic scenario imagined by the Infectious Diseases Society of America might become all too real in (two isolates) or the extended-spectrum β-lactamases the near future.
CTX-M-1 (one isolate) or CTX-M-15 (one isolate), encoded The S Kentucky ST198-X1 isolates we report were by 90–200 kb plasmids from the IncI1, IncL/M, or resistant to both fl uoroquinolones and ESCs (apart from IncA/C incompatibility groups. for the OXA-48-producing strain), and some also displayed The second notable fi nding was the detection of two full or intermediate resistance to carbapenems. Many S enterica strains producing carbapenemase OXA-48 in were also resistant to most aminoglycosides (various a traveller returning from Egypt in 2009. One of the genes, including armA), to co-trimoxazole (trimethoprim-four isolates of S Kentucky resistant to ciprofl oxacin sulfamethoxazole; class 1 integron-borne dfrA12 gene), and ESCs (isolate 09-9322), was isolated from a patient and to azithromycin (mph(A) gene). S Kentucky ST198-X1 co-infected with another serotype of S enterica, is a particularly successful strain that has accumulated Saintpaul, which produced a carbapenamase not various chromosomal resistance deter minants since the present in isolate 09-9322, but was subsequently mid-1990s, with the integration of SGI1 (encoding identifi ed in one of the three sequential S Kentucky resistance to multiple antimicrobial drugs, including www.thelancet.com/infection Published online May 28, 2013 http://dx.doi.org/10.1016/S1473-3099(13)70141-5
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Serotype Date of
Antimicrobial
MLST/ PFGE SGI1 Minimum inhibitory concentration (mg/L)*
isolation
resistance profi les
infection
Isolates recovered through the French National Reference Centre for Salmonella
09-8391 Kentucky Nov 2,
Isolates recovered through the survey in Casablanca, Morocco
10-1923 Kentucky Jan 4,
Isolates recovered from one patient‡
09-7981 Saintpaul Oct 16,
A=amoxicillin. AK=amikacin. AZI=azithromycin. CA-SFM=Antibiogram Committee of the French Society for Microbiology. CAZ=ceftazidime. CHL=chloramphenicol. CLSI=Clinical and Laboratory Standards Institute.
CIP=ciprofl oxacin. CRO=ceftriaxone. CST=colistin. ETP=ertapenem. FOX=cefoxitin. G=gentamicin. IMP=imipenem. IS=isepamicin. K=kanamycin. MEM=meropenem. MLST=multilocus sequence type. N=netilmicin.
NAL=nalidixic acid. PFGE=pulsed-fi eld gel electrophoresis. S=streptomycin. SGI1=Salmonella genomic island 1. SP=spectinomycin. SUL=sulfamethoxazole. T=tobramycin. TE= tetracycline. TGC=tigecycline.
TMP=trimethoprim. *CA-SFM and CLSI (M100 S22) breakpoints for carbapenems: IMP and MEM (CA-SFM, S ≤2 mg/L, R >8 mg/L; CLSI, S ≤1 mg/L, and R ≥4 mg/L); ETP (CA-SFM, S ≤0·5 mg/L, R >1 mg/L; CLSI,
S ≤0·5 mg/L, and R ≥2 mg/L). For categorisation, Etest minimum inhibitory concentration between standard dilutions were rounded up to the next twofold dilution. Intermediate resistance according to CA-SFM,
resistance according to CLSI. ‡Isolate 09-9322 recovered by the French national surveillance system was also isolated from this patient, who had travelled to Egypt.
Table 2: Antimicrobial drug-resistant Salmonella enterica isolates included in this study
amoxicillin, gentamicin, and sulfona mides), followed by 2012 (data not shown), a number akin to that obtained in cumulative mutations in the gyrA and parC genes, leading 2010 (155 isolates). The cipro fl oxacin-resistant S Kentucky to resistance to nalidixic acid, and then to ciprofl oxacin, in ST198-X1 strain was fi rst identifi ed in the Indian 2002. This strain was mostly identifi ed in Egypt before subcontinent in 2009, and a pattern of spread across Asia 2005,7 but has since spread rapidly throughout Africa and is also suggested by the isolation of two ciprofl oxacin-the Middle East. The slight decrease in isolation rates for resistant S Kentucky isolates from French patients this strain in 2011 probably resulted from the Arab Spring, reporting travel to Vietnam and Indonesia in 2012 (data which might have discouraged travel to the area in which not shown). The geographical spread of this strain shown this strain is endemic. Thus, 150 isolates of ciprofl oxacin- by the French surveillance system might be biased by the resistant S Kentucky were obtained at the FNRC-Salm in preferred destinations of French travellers and particular www.thelancet.com/infection Published online May 28, 2013 http://dx.doi.org/10.1016/S1473-3099(13)70141-5
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Serotype Main determinants of resistance (incompatibility group, plasmid size) to:
Class 1 integrons
Carbapenems
Ciprofl oxacin*
Aminoglycosides†
Isolates recovered through the French National Reference Centre for Salmonella
09-8391 Kentucky bla
mph(A) (NT) armA (IncL/M, 90 kb) 1·8 kb (dfrA12, aadA2) Isolates recovered through the survey in Casablanca, Morocco
10-1923
1·5 kb (aacA5, aadA7), 3 kb (aacA7, bla , aacC1, aacA4) 1·5 kb (aacA5, aadA7), 3 kb (aacA7, bla , aacC1, aacA4) 1·5 kb (aacA5, aadA7), 3 kb (aacA7, bla , aacC1, aacA4) 1·5 kb (aacA5, aadA7), 3 kb (aacA7, bla , aacC1, aacA4) 1·5 kb (aacA5, aadA7), 3 kb (aacA7, bla , aacC1, aacA4) Isolates recovered from one patient‡
09-7981 Saintpaul ··
AZI=azithromycin. ESC=extended-spectrum cephalosporin. Inc=incompatibility group. NT=not transferable. UT=untypeable. ··=absence of the tested genes.*No plasmid-mediated quinolone resistance genes were identifi ed. †Class 1 integron-borne genes were excluded. ‡Isolate 09-9322 recovered by the French national surveillance system was also isolated from this patient, who had travelled to Egypt.
Table 3: Mechanisms of resistance to antimicrobial drugs in the antimicrobial drug-resistant Salmonella enterica isolates included in this study
migrant populations with historical links to France. Where The diversity of recently acquired β-lactamases (CTX-M possible, these data need to be confi rmed by local studies.
extended-spectrum β-lactamases, CMY-2 AmpC, and This epidemic was previously associated with a native VIM-2 and OXA-48 carbapenemases) suggests that the livestock (poultry) reservoir of this ciprofl oxacin- increasingly common ciprofl oxacin-resistant S Kentucky resistant S Kentucky strain in Africa. Common use of ST198-X1 strain has been obtaining genes for resistance fl uoroquinolones in poultry and the dearth of laboratory- to ESCs and carbapenems. Resistance to carbapenems based surveillance of infections and control measures is otherwise extremely rare in Salmonella spp (panel 2). in the countries in which this strain circulates might The simultaneous presence of ESCs and carbapenem have had a role in the rapid spread of this strain after determinants (CMY-2 and OXA-48) was documented in 2002.7 A survey of 92 poultry farms in Sudan, in 2008, this study in ciprofl oxacin-resistant S Kentucky ST198-X1 showed that enrofl oxacin, a fl uoroquinolone, was isolated from one patient.
commonly added to the drinking water in 14% of the A similar scenario, but without the acquisition of farms surveyed.17 In this and our previous study,7 about carbapenemase, occurred in Taiwan for S enterica 11% of patients reported no history of travel outside serotype Choleraesuis (S Choleraesuis), a serotype Europe, suggesting that these infections might have acquired from pigs and associated with extraintestinal resulted from the consumption of contaminated foods infection in man.8 The fi rst ciprofl oxacin-resistant or secondary contamination in Europe. Indeed, isolates appeared in 2000 and, in the third quarter of contaminated spices from north Africa have previously 2001, 60% of the S Choleraesuis isolates from human been identifi ed in France and the USA.7 This strain also beings were resistant to ciprofl oxacin.8 This trait was seems to have become established in some European attributed to the use of enrofl oxacin in pigs. Additional domestic poultry fl ocks, another key source of concern. resistance to ESCs mediated by the cephamycinase In 2010, ciprofl oxacin-resistant S Kentucky isolates were CMY-2 has appeared since 2002.26 This enzyme is reported in turkey meat products in Germany and in frequent in many S enterica serotypes, including Newport turkey meat or fl ocks in Poland.18,19 One of the in the USA, where its emergence has been associated ciprofl oxacin-resistant S Kentucky isolates recovered with the use of ceftiofur, an ESC licensed for use in cattle, from a fl ock in Poland in 2010 was also resistant to pigs, and other food animals.27 Unlike ciprofl oxacin-ESCs, due to the production of a CTX-M extended- resistant S Choleraesuis and ESC-resistant S Newport, ciprofl oxacin-resistant S Kentucky ST198-X1 is not www.thelancet.com/infection Published online May 28, 2013 http://dx.doi.org/10.1016/S1473-3099(13)70141-5
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Panel 1: Case study
Panel 2: Research in context
On Oct 14, 2009, a 69-year-old woman living in western Systematic review
France was admitted to hospital with an upper respiratory tract We searched PubMed without language restrictions for infection, fever, and diarrhoea. The symptoms began during a articles published before Jan 30, 2013, with the search terms holiday in Egypt (Sept 19–Oct 2, 2009). The patient’s clinical “Salmonella” and “carbapenemases” or “carbapenems” or history included a high-grade fol icular lymphoma in 2003, “NDM-1”. We identifi ed only six studies20–25 describing various treated with chemotherapy and al ogeneic transplantation, sporadic Salmonella enterica isolates resistant to carbapenems. that had been in remission since 2005. The patient had had None of these isolates was also resistant to fl uoroquinolones. repetitive respiratory infections owing to sequel ar Two of these studies assessed isolates resistant to hypogammaglobulinaemia. Her last hospital admission was carbapenems owing to mechanisms other than for right hemicolectomy surgery in 2007. 1 day after carbapenemase production: two clinical isolates of serotype admission, a Salmonella enterica serotype Saintpaul isolate that Wien, which had lost a porin and produced cephamycinase was resistant to ampicil in, susceptible to extended-spectrum CMY-4, in Tunisia in 2001, and one clinical isolate of serotype cephalosporins, and had intermediate resistance to imipemem Typhimurium, which had lost two porins and produced (minimum inhibitory concentration 3 mg/L) was obtained cephamycinase CMY-2, in Taiwan in 2010.20,21 The fi rst from blood and stool cultures (tables 2, 3). Treatment with 1 g carbapenemase producer was a clinical isolate of serotype per day of ciprofl oxacin was provided for 10 days. The patient Cubana, which produced carbapenemase KPC-2 and was was given a blood transfusion (two units) and an intravenous obtained in the USA in 1998.22 In 2011 and 2012, the fi rst two polyclonal immunoglobulin perfusion and rapidly recovered. clinical isolates of NDM-1-producing S enterica of serotypes 1 month later, the patient presented with a new episode of Senftenberg and Westhampton were reported, isolated from febrile bronchial and diarrhoeal infection, which was treated patients returning from India.23,24 In 2012, the fi rst with 1 g per day ceftriaxone for 5 days. No bacteriological carbapenemase (VIM-1)-producing S enterica isolates were testing was done and the patient recovered slowly, with isolated from food animals in Europe.25 persistent digestive disorders. A new stool culture was done Interpretation
on Dec 16, 2009, and was positive for ciprofl oxacin-resistant Our study confi rms the emergence of highly drug-resistant S Kentucky, resistant to extended-spectrum cephalosporins, S enterica serotype Kentucky (S Kentucky), constituting a co-trimoxazole, and azithromycin, but susceptible to potential risk to public health, in the Mediterranean basin. imipenem (tables 2, 3). No antimicrobial drugs were given, This ciprofl oxacin-resistant S Kentucky ST198-X1 strain, but a series of stool samples was collected over time and which is increasingly frequently isolated, has recently cultured, to follow the elimination of the Salmonella spp acquired β-lactamases (CTX-M extended-spectrum strains. Ciprofl oxacin-resistant S Kentucky was isolated in β-lactamases, CMY-2 cephamycinase, and VIM-2 and OXA- January, 2010, and January, 2011, (tables 2, 3); additional stool 48 carbapenemases) encoding resistance to extended- cultures for Salmonella spp in March, 2011, and April, 2011, spectrum cephalosporins and carbapenems. Further eff orts were also positive (isolates not sent to the French National are required from national and international health, food, Reference Centre for Salmonella), despite the patient being and agricultural authorities to control the spread of this highly drug-resistant strain in humans and food animals. We propose the inclusion of ciprofl oxacin-resistant S Kentucky restricted to one country or region, rendering control as a new target strain, in national programmes for the control of Salmonella spp in poultry.
We noted that S Kentucky ST198-X1 had a broad geo- graphical distribution, overlapping with that of certain extended-spectrum β-lactamases or cephamycinase and plasmid-borne carbapenemases, such as OXA-48 and permeability defects. Indeed, carbapenem minimum VIM.12,16 Thus, carbapenemase-producing S enterica will inhibitory concentrations were reported to be low for the probably become more frequent in the Mediterranean carbapenemase area in the near future, especially if such carbapenemase OXA-48-positive and one VIM-2-positive Kentucky producers become established in livestock, as previously isolate, were classifi ed as susceptible to the three noted for S enterica strains that produce extended- carbapenems tested, on the basis of the CLSI or CA-SFM spectrum β-lactamases and cephamycinase in industrial- breakpoints. The use of rapid diagnostic tests, such as ised countries.27–29 Isolation of the VIM-1-producing the recently developed Carba NP test, would facilitate the S enterica serotype Infantis from two pig farms and one early detection of carbapenemase producers.30 poultry farm in Germany was reported in 2012.25 The recent emergence of highly drug-resistant Another issue is the diffi culty of phenotypic detection S enterica emphasises the need to screen S enterica for several carbapenemase producers.12 This problem is isolated from people or food-producing animals for particularly acute for OXA-48, which weakly hydrolyses carbapenemase producers. The main types of carbapenems but not ESCs in the absence of additional carbapenemase (KPC, OXA-48, NDM, VIM) have now www.thelancet.com/infection Published online May 28, 2013 http://dx.doi.org/10.1016/S1473-3099(13)70141-5
Articles
been identifi ed in S enterica, and half of these enzymes 12 Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-have been reported in the S Kentucky ST198-X1 strain. producing Enterobacteriaceae. Emerg Infect Dis 2011; 17: 1791–98.
National and international health, food, and agricultural 13 Accou-Demartin M, Gaborieau V, Song Y, et al. Salmonella enterica serotype Typhi with nonclassical quinolone resistance phenotype. authorities need to recognise rapidly the potential risk to Emerg Infect Dis 2011; 17: 1091–94.
public health posed by ciprofl oxacin-resistant S Kentucky 14 Fritsche TR, Castanheira M, Miller GH, et al. Detection of ST198-X1, so that it can be included as a new targeted methyltransferases conferring high-level resistance to aminoglycosides in Enterobacteriaceae from Europe, North America, strain in national programmes for the control of and Latin America. Antimicrob Agents Chemother 2008; 52: 1843–45.
15 Fabre L, Delauné A, Espié E, et al. Chromosomal integration of the extended-spectrum beta-lactamase gene bla Contributors
enterica serotype Concord isolates from internationally adopted SLH and F-XW conceived and designed the experiments, analysed the children. Antimicrob Agents Chemother 2009; 53: 1808–16.
data, and wrote the report. DH, LS, DE, and VG did the experiments. 16 Poirel L, Potron A, Nordmann P. OXA-48-like carbapenemases: the BB and KZ contributed reagents, materials, or analysis tools. DH, BB, phantom menace. J Antimicrob Chemother 2012; 67: 1597–606.
17 Sirdar MM, Picard J, Bisschop S, Gummow B. A questionnaire Confl icts of interest
survey of poultry layer farmers in Khartoum State, Sudan, to study We declare that we have no confl icts of interest. their antimicrobial awareness and usage patterns. Onderstepoort J Vet Res 2012; 79: E1–8.
Acknowledgments
18 Beutlich J, Guerra B, Schroeter A, Arvand M, Szabo I, Helmuth R. We thank Isabelle Loirat (Nantes, France) for providing clinical Highly ciprofl oxacin resistant Salmonella enterica serovar Kentucky information, Erwan Trochu (Paris, France) for expert technical assistance isolates in turkey meat and a human patient (in German). and all corresponding laboratories of the French National Reference Centre Berl Munch Tierarztl Wochenschr 2012; 125: 89–95.
for Escherichia coli, Shigella, and Salmonella. The French National Reference 19 Wasyl D, Hoszowski A. First isolation of ESBL-producing Centre for Escherichia coli, Shigella, and Salmonella is funded by the Institut Salmonella and emergence of multiresistant Salmonella Kentucky in Pasteur and the Institut de Veille Sanitaire. DH was supported by a grant turkey in Poland. Food Research International 2012; 45: 958–61.
from “La Fondation pour la Recherche Médicale”. The Unité des Bactéries 20 Armand-Lefèvre L, Lefl on-Guibout V, Bredin J, et al. Imipenem Pathogènes Entériques belongs to the Integrative Biology of Emerging resistance in Salmonella enterica serovar Wien related to porin loss Infectious Diseases Laboratory of Excellence funded by the French and CMY-4 β-lactamase production. Antimicrob Agents Chemother Government “Investissement d’Avenir” programme (grant number 2003; 47: 1165–68.
21 Su LH, Wu TL, Chiu CH. Development of carbapenem resistance during therapy for non-typhoid Salmonella infection. References
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Arias CA, Murray BE. Antibiotic-resistant bugs in the 21st 22 Miriagou V, Tzouvelekis LS, Rossiter S, Tzelepi E, Angulo FJ, century—a clinical super-challenge. N Engl J Med 2009; 360: 439–43.
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Nordmann P, Poirel L, Walsh TR, Livermore DM. The emerging 23 Savard P, Gopinath R, Zhu W, et al. First NDM-positive Salmonella carbapenemases. Trends Microbiol 2011; 18: 588–95.
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