Plasmid-mediated quinolone resistance in Salmonella enterica, United Kingdom.To the Editor: Fluoroquinolones are broad-spectrum antimicrobial antimicrobial /an·ti·mi·cro·bi·al/ (-mi-kro´be-al) 1. killing microorganisms or suppressing their multiplication or growth. 2. an agent with such effects. drugs used to treat many clinical infections. Salmonellosis salmonellosis (săl'mənĕlō`sĭs), any of a group of infectious diseases caused by intestinal bacteria of the genus Salmonella, is treated with fluoroquinolones only in elderly or immunocompromised immunocompromised /im·mu·no·com·pro·mised/ (-kom´pro-mizd) having the immune response attenuated by administration of immunosuppressive drugs, by irradiation, by malnutrition, or by certain disease processes (e.g., cancer). patients, but these drugs are also used for treating patients with enteric fever enteric fever n. 1. See typhoid fever. 2. See paratyphoid fever. Enteric fever A term that is sometimes used for either typhoid or paratyphoid fever. Mentioned in: Paratyphoid Fever , invasive disease, or long-term salmonellae carriage. High-level fluoroquinolone fluoroquinolone /flu·o·ro·quin·o·lone/ (-kwin´o-lon) any of a subgroup of fluorine-substituted quinolones, having a broader spectrum of activity than nalidixic acid. fluor·o·quin·o·lone n. resistance is uncommon, but reduced susceptibility is increasing. Since 1998, plasmid-mediated quinolone resistance encoded by qnr genes A, B, and S that confer low-level resistance to nalidixic acid nalidixic acid /nal·i·dix·ic ac·id/ (nal-i-dik´sik) a synthetic antibacterial agent used in the treatment of genitourinary infections caused by gram-negative organisms. na·li·dix·ic acid n. and reduced susceptibility to ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt. cip·ro·flox·a·cin n. has been identified in several enterobacterial species, including Salmonella. Their clinical importance is in facilitating resistance to potentially lethal levels of quinolone. Additionally, qnr genes are often associated with strains that produce extended-spectrum [beta]-lactamases. We recently reported identification of qnr genes in Salmonella in the United Kingdom (1). Most isolates were associated with the Far East. Two isolates of S. Virchow were part of an outbreak associated with imported cooked chicken from Thailand. During October 2006-April 2007, we monitored qnr genes in nontyphoidal salmonellae isolated in the United Kingdom that expressed reduced susceptibility to ciprofloxacin (MIC 0.125-1.0 [micro]g/mL) with concomitant susceptibility to nalidixic acid (MIC <16 [micro]g/mL). This resistance phenotype phenotype (fē`nətīp'): see genetics. phenotype All the observable characteristics of an organism, such as shape, size, colour, and behaviour, that result from the interaction of its genotype (total genetic makeup) with is a useful marker for the qnr gene as the sole quinolone resistance determinant (1). Recent studies showed that isolates of Salmonella spp. and Escherichia coli Escherichia coli (ĕsh'ərĭk`ēə kō`lī), common bacterium that normally inhabits the intestinal tracts of humans and animals, but can cause infection in other parts of the body, especially the urinary tract. with decreased susceptibility to ciprofloxacin (MICs >0.06 [micro]g/mL and 0.5 [micro]g/mL, respectively), but with susceptibility or intermediate resistance to nalidixic acid (MIC 8-16 [micro]g/mL and 4-8 [micro]g/mL, respectively), all had qnrA or qnrS genes but lacked mutations in the topoisomerase topoisomerase an enzyme involved in DNA replication that introduces a single-strand nick in the DNA enabling it to swivel and thereby relieve the accumulated winding strain generated during unwinding of the double helix. genes (2,3). Strains with ciprofloxacin MICs >1 [micro]g/mL were also included to monitor involvement of qnr genes in development of high-level ciprofloxacin resistance. Breakpoint The location in a program used to temporarily halt the program for testing and debugging. Lines of code in a source program are marked for breakpoints. When those instructions are about to be executed, the program stops, allowing the programmer to examine the status of the program concentrations used are based on long-term studies within the Health Protection Agency Laboratory of Enteric enteric /en·ter·ic/ (en-ter´ik) within or pertaining to the small intestine. en·ter·ic adj. 1. Of, relating to, or within the intestine. 2. Pathogens. Ciprofloxacin Etest (AB Biodisk, Solna, Sweden) results were interpreted according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. manufacturer's procedures. A total of 45 Salmonella spp. strains were tested. Screening for qnr genes by multiplex See multiplexing. PCR PCR polymerase chain reaction. PCR abbr. polymerase chain reaction Polymerase chain reaction (PCR) identified 37 isolates with qnrS and 2 carrying qnrB variants (Table) (4). However, the qnrB primer pair in this multiplex did not fully match all qnrB gene variants. PCR and sequencing using primers FQ1 and FQ2 (5) and qnrS-F and qnrS-R (1), were used to identify specific qnrB and qnrS gene variants. The qnrS1-positive salmonellae belong to serotypes Typhimurium (21 isolates), Virchow (10), and Corvallis (6). Most S. Typhimurium isolates were either definitive phage phage: see bacteriophage. phage - A program that modifies other programs or databases in unauthorised ways; especially one that propagates a virus or Trojan horse. See also worm, mockingbird. The analogy, of course, is with phage viruses in biology. type 120 or 193, and most S. Virchow isolates were phage type 43 (Table). Thirteen qnrS1-positive isolates were from patients who reported recent travel to Egypt, India, Malaysia, Morocco, Thailand, or an undisclosed destination. Twelve isolates from patients who had not traveled abroad were assumed to be from UK-acquired infections. S. Virchow isolates had been associated with cooked chicken from Thailand (1), and qnrS1 has recently been described in S. Corvallis strains from humans in Denmark or isolated in Thailand from humans, chicken, pork, and beef (3). Comparison of pulsed-field gel electrophoresis gel electrophoresis n. Electrophoresis performed in a gel composed of agarose, polyacrylamide, or starch. patterns and resistance phenotypes of qnrS1-positive S. Corvallis strains identified common types, suggesting that some UK patients may have acquired S. Corvallis from chicken from Thailand. Thirteen isolates showed resistance to ceftriaxone ceftriaxone /cef·tri·ax·one/ (cef?tri-ak´son) a semisynthetic, ß–resistant, third-generation cephalosporin effective against a wide range of gram-positive and gram-negative bacteria, used as the sodium salt. , cefotaxime, or ampicillin ampicillin (ăm'pĭsĭl`ĭn), a penicillin-type antibiotic that is effective against both gram-negative microorganisms and gram-positive microorganisms such as Escherichia coli. . Plasmids with qnr genes have been found to co-transfer TEM TEM 1. transmission electron microscope. 2. triethylenemelamine. 3. transmissible encephalopathy of mink. , SHV SHV Shareholder Value SHV Standard High Volume SHV Sheave SHV Steenkolen Handels Vereeniging SHV Shreveport, LA, USA - Regional Airport (Airport Code) SHV Sport Horse Versatility SHV Supersonic/Hypersonic Vehicle SHV Super Hybrid Vehicle , and CTX-M genes (1,5,6). Co-transmission of fluoroquinolone and [beta]-lactamase resistance is clinically important because co-selection of resistance by use of either drug may occur. Twenty-one qnrS1-positive S. Typhimurium were subtyped by variable number tandem repeat A variable number tandem repeats (VNTR) is a short nucleotide sequence ranging from 14 to 100 nucleotides long that is organized into clusters of tandem repeats, usually repeated in the range of between 4 and 40 times per occurrence. (VNTR VNTR Variable Number of Tandem Repeat(s) ) analysis to determine whether the increase was caused by spread of [greater than or equal to]1 distinct strains (7). Twenty isolates produced 1 of 3 related profiles (loci loci [L.] plural of locus. loci Plural of locus, see there of VNTR profiles are ordered STTR STTR Small Business Technology Transfer Program STTR Stator STTR Small Technology Transfer Innovation Research 9-STTR5STTR6-STTR10pl-STTR3): 1-4-0-03, 9 isolates; 1-5-0-0-3, 3 isolates; or 1-6-0-0-3, 8 isolates. Alleles 4 and 5, and 5 and 6 at locus STTR5 only differed by an extra 6-bp repeat, which suggests a clonal relationship between the qnrS1-positive S. Typhimurium in this study (Table) (8). S. Typhimurium isolates with the 1-6-0-0-3 profile have been isolated from tourists returning from Asia (7), which suggests that the UK qnrS1-positive S. Typhimurium isolates have originated in the Far East. These findings show increased occurrence of qnr genes, particularly qnrS1, in nontyphoidal salmonellae in the United Kingdom. These data are in contrast to those of recent studies in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. and France, which show low incidences of qnrS genes in larger strain collections (9,10). The qnr phenotype is in contrast to resistance mediated by mutations in the topoisomerase genes whereby 1 mutation confers low-level resistance to fluoroquinolones and full resistance to nalidixic acid. Our previous study demonstrated that qnrS1 was sufficient to cause decreased susceptibility to ciprofloxacin in the absence of mutations in gyrA (1). In this study, a qnr gene was sufficient to increase the ciprofloxacin MIC to 0.38-0.75 [micro]g/mL. In addition, a qnr gene contributed to high-level ciprofloxacin resistance in 10 isolates, thereby potentially jeopardizing first-line treatment A first-line treatment or first-line therapy is a medical therapy recommended for the initial treatment of a disease, sign or symptom, usually on the basis of empirical evidence for its efficacy. of vulnerable patient groups with ciprofloxacin. This study was supported by the Department of Environment, Food and Rural Affairs, United Kingdom, project VM02205. References (1.) Hopkins KL, Wootton L, Day M, Threlfall EJ. Plasmid-mediated quinolone resistance determinant qnrS1 found in Salmonella enterica Salmonella enterica is a rod shaped, flagellated, Gram-negative bacterium, and a member of the genus Salmonella.[1] Serovars S. enterica has an extraordinarily large number of serovars strains isolated in the UK. J Antimicrob Chemother. 2007;59:1071-5. (2.) Cavaco LM, Hansen DS, Friis-Moller A, Aarestrup FM, Hasman H, FrimodtMoller N. First detection of plasmid-mediated quinolone resistance (qnrA and qnrS) in Escherichia coli strains isolated from humans in Scandinavia. J Antimicrob Chemother. 2007;59:804-5. (3.) Cavaco LM, Hendriksen RS, Aarestrup FM. Plasmid-mediated quinolone resistance determinant qnrS1 detected in Salmonella enterica serovar Corvallis strains isolated in Denmark and Thailand. J Antimicrob Chemother. 2007;60:704-6. (4.) Robicsek A, Strahilevitz J, Sahm DF, Jacohy GA, Hooper DC. qnr prevalence in ceftazidime-resistant Enterobacteriaceae isolates from the United States. Antimicrob Agents Chemother. 2006;50:2872-4. (5.) Jacoby GA, Walsh KE, Mills DM, Walker VJ, Oh H, Robicsek A, et al. qnrB, another plasmid-mediated gene for quinolone resistance. Antimicrob Agents Chemother. 2006;50:1178-82. (6.) Jacoby GA, Chow N, Waites KB. Prevalence of plasmid-mediated quinolone resistance. Antimicrob Agents Chemother. 2003;47:559-62. (7.) Lindstedt BA, Torpdahl M, Nielsen EM, Vardund T, Aas L, Kapperud G. Harmonization har·mo·nize v. har·mo·nized, har·mo·niz·ing, har·mo·niz·es v.tr. 1. To bring or come into agreement or harmony. See Synonyms at agree. 2. Music To provide harmony for (a melody). of the multiple-locus variablenumber tandem repeat This is a term from genetics, which describes a pattern that helps determine an individual's inherited traits. Tandem repeats and variable number tandem repeats in DNA occur when a pattern of two or more nucleotides is repeated and the repetitions are directly adjacent to analysis method between Denmark and Norway for typing Salmonella Typhimurium Salmonella ty·phi·mu·ri·um n. A bacterium that causes food poisoning. isolates and closer examination of the VNTR loci. J Appl Microbiol. 2007;102:728-35. (8.) Hopkins KL, Maguire C, Best E, Liebana E, Threlfall EJ. Stability of multiple-locus variable-number tandem repeats in Salmonella enterica serovar Typhimurium. J Clin Microbiol. 2007;45:3058-61. (9.) Gay K, Robicsek A, Strahilevitz J, Park CH, Jacoby G, Barrett TJ, et al. Plasmid-mediated quinolone resistance in non-Typhi serotypes of Salmonella enterica. Clin Infect Dis. 2006;43:297-304. (10.) Cattoir V, Weill FX, Poirel L, Fabre L, Soussy C J, Nordmann R Prevalence of qnr genes in Salmonella in France. J Antimicrob Chemother. 2007;59:751-4. Address for correspondence: Katie L. Hopkins, Diagnostic and Specialist Identification Unit, Department of Gastrointestinal, Emerging and Zoonotic Zoonotic A disease which can be spread from animals to humans. Mentioned in: Zoonosis Infections, Laboratory of Enteric Pathogens, Health Protection Agency Centre for Infections, 61 Colindale Ave, London NW9 5EQ, United Kingdom; email: katie.hopkins@hpa.org.uk Katie L. Hopkins, * Martin Day, * and E. John Threlfall * * Health Protection Agency Centre for Infections, London, United Kingdom
Table. Isolates of Salmonella enterica with plasmid-mediated qnr genes,
United Kingdom, October 2006-April 2007
Salmonella VNTR
serotype Phage type * No. isolates profile ([dagger])
Corvallis -- 1 --
Corvallis -- 2 --
Corvallis -- 1 --
Corvallis -- 1 --
Corvallis -- 1 --
Schwarzengrund -- 1 --
Typhimurium DT120 4 1-6-0-0-3
Typhimurium DT120 3 1-6-0-0-3
Typhimurium DT120 3 1-4-0-0-3
Typhimurium DT120 1 1-4-0-0-3
Typhimurium DT120 1 1-4-0-0-3
Typhimurium DT120 1 1-5-0-0-3
Typhimurium DT193 1 1-6-0-0-3
Typhimurium DT193 1 1-4-0-0-3
Typhimurium DT193 1 1-4-0-0-3
Typhimurium DT193 2 1-5-0-0-3
Typhimurium DT193 1 1-4-0-0-3
Typhimurium 49b 1 1-4-19-1-3
Typhimurium NC 1 1-4-0-0-3
Typhimurium UT 1 3-8-19-1-2
Virchow 43 5 --
Virchow 43 2 --
Virchow 25a 1 --
Virchow 11 1 --
Virchow NC 1 --
Additional
resistance to
Salmonella Ciprofloxacin MIC ([micro]g antimicrobial
serotype /mL) ([double dagger]) drugs ([section])
Corvallis 0.25 S, Su, T
Corvallis 0.38 S, Su, T
Corvallis 1.00 S, Su, T, Cf
Corvallis 0.25 None
Corvallis 0.38 None
Schwarzengrund 0.25 T
Typhimurium 0.38 S, Su, T
Typhimurium 0.50 S, Su, T
Typhimurium 0.38 S, Su, T
Typhimurium 0.50 S, Su, T
Typhimurium 0.38 None
Typhimurium 0.38 S, Su, T
Typhimurium 0.50 S, Su, T
Typhimurium 0.38 C, S, Su, Sp, T, Tm
Typhimurium 0.38 S, Su, T
Typhimurium 0.38 S, Su, T
Typhimurium 0.50 A, Su
Typhimurium 0.25 A, G, Ne, K, S,
Su, Sp, T, Tm,
Ak, Cx, Cr,
Cf, Cn, Ct
Typhimurium 0.25 S, Su, T
Typhimurium >.32 A, C, G, S, Su,
Sp, T, Tm, Fu,
Nx
Virchow 1.00 A, Fu, Nx
Virchow 1.50 A, Fu, Nx
Virchow 0.75 Tm
Virchow 1.00 A, Fu, Nx
Virchow 1.50 A, C, G, Ne, K,
S, Su, Sp, T,
Tm, Fu, Nx, Cx,
Cr, Cf, Cn, Ct
Salmonella
serotype qnr identified
Corvallis qnrS1
Corvallis qnrS1
Corvallis qnrS1
Corvallis qnrS1
Corvallis qnrS1
Schwarzengrund qnrB5
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrS1
Typhimurium qnrB2
Typhimurium qnrS1
Typhimurium qnrS1
Virchow qnrS1
Virchow qnrS1
Virchow qnrS1
Virchow qnrS1
Virchow qnrS1
* DT, definitive type; NC, does not conform to a recognized
pattern; LIT, untypeable.
([dagger]) VNTR, variable number tandem repeat. Loci of the VNTR
profiles are presented in the following order: STTR9-STTR5-STTR6-
STTR10pl-STTR3. The number 0 in the VNTR profile represents cases
with no amplification of PCR product.
([double dagger]) Determined by Etest.
([section]) Antimicrobial drugs (breakpoint final concentrations):
S, streptomycin (16 mg/L); Su, sulfonamide (64 mg/L); T, tetracycline
(8 mg/L); Cf, cefuroxime (16 mg/L); C, chloramphenicol (8 mg/L);
Sp, spectinomycin (64 mg/L); Tm, trimethoprim (2 mg/L); A, ampicillin
(8 mg/L]; G, gentamicin (4 mg/L); Ne, neomycin (8 mg/L) K, kanamycin
(8 mg/L); Ak, amikacin (4 mg/L); Cx, cefalexin (16 mg/L); Cr, cefradine
(16 mg/L); Cn, ceftriaxone (1 mg/L); Ct, cefotaxime (I m,-/L); Fu,
furazolidone (8 mg/L); Nx, nalidixic acid (16 m,-/L).
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