Clindamycin- Resistant Clone of Clostridium difficile PCR Ribotype by jlhd32


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Mayboun Heuangvongsy, Chanpheng                     4.   Jiang J, Chan TC, Temenak JJ, Dasch GA,
                                                         Ching WM, Richards AL. Development
Thammavong, Bouachanh Rasachack,
Bounkong Syhavong, Nicholas J. White,
                                                         of a quantitative real-time polymerase           Resistant Clone of
                                                                                                          Clostridium difficile
                                                         chain reaction assay specific for Orien-
Suriyasack     Thongpaseuth,   Anisone                   tia tsutsugamushi. Am J Trop Med Hyg.
Changthongthip, Viengmone Davong,
                                                         Fournier PE, Siritantikorn S, Rolain
                                                                                                             PCR Ribotype
Olay Lattana, Manivanh Vongsouvath,
Kai-amporn Keopaseuth, Sengmani
                                                         JM, Suputtamongkol Y, Hoontrakul S,                  027, Europe
                                                         Charoenwat S, et al. Detection of new
Symanivong, Viengmala Sihalath, and                      genotypes of Orientia tsutsugamushi in-               To the Editor: Since 2003, out-
Alatsany Chandara for participating in                   fecting humans in Thailand. Clin Micro-
                                                         biol Infect. 2008;14:168–73.
                                                                                                          breaks of Clostridium difficile–as-
the study; and Ponmek Dalaloy and Som-
                                                    6.   Blacksell SD, Luksameetanasan R, Ka-             sociated disease (CDAD) associated
mone Phounsavath for support.                            lambaheti T, Aukkanit N, Paris DH,               with the emergence of a hypervirulent
                                                         McGready R, et al. Genetic typing of             strain have been reported worldwide
     This study was supported by the
                                                         the 56-kDa type-specific antigen gene of
Wellcome Trust–Mahosot Hospital–Ox-                      contemporary Orientia tsutsugamushi iso-
ford Tropical Medicine Research Collabo-                 lates causing human scrub typhus at two          v12n06/1206-221.asp). This strain has
ration, which was supported by the Well-                 sites in north-eastern and western Thai-         been associated with increased dis-
                                                         land. FEMS Immunol Med Microbiol.                ease severity and attributable mortal-
come Trust of Great Britain.
                                                    7.   Qiang Y, Tamura A, Urakami H, Makisaka
                                                                                                          ity. Patients infected with C. difficile
                                                         Y, Koyama S, Fukuhara M, et al. Phylo-           027 fail to respond to metronidazole
        Philippe Parola,
                                                         genetic characterization of Orientia tsut-       therapy (1). Several typing methods
      Stuart D. Blacksell,                               sugamushi isolated in Taiwan according to        have been applied to further charac-
  Rattanaphone Phetsouvanh,                              the sequence homologies of 56-kDa type-
                                                         specific antigen genes. Microbiol Immu-
                                                                                                          terize C. difficile PCR ribotype-027,
      Simaly Phongmany,
                                                         nol. 2003;47:577–83.                             including pulsed-field gel electropho-
       Jean-Marc Rolain,
                                                    8.   Kawamura A, Tanaka H. Tsutsugamushi              resis (PFGE) (North American pulsed
       Nicholas P.J. Day,                                disease: an overview. Tokyo: University          field type 1) and restriction enzyme
        Paul N. Newton,                                  of Tokyo Press; 1995.
                                                    9.   Seong SY, Kim MK, Lee SM, Odgerel Z,
                                                                                                          analysis (REA) (BI). PFGE and REA
       and Didier Raoult
                                                         Choi MS, Kim IS, et al. Neutralization           are widely used in the United States;
Author affiliations: World Health Organiza-
                                                         epitopes on the antigenic domain II of the       PCR ribotyping is more commonly
tion Collaborative Center for Rickettsial Dis-           Orientia tsutsugamushi 56-kDa protein            used throughout Europe. More re-
eases and Other Arthropod Borne Bacte-                   revealed by monoclonal antibodies. Vac-
                                                         cine. 2000;19:2–9. DOI: 10.1016/S0264-
                                                                                                          cently, 2 multiple-locus variable-num-
rial Diseases, Marseille, France (P. Parola,
                                                         410X(00)00167-5                                  ber tandem-repeat analysis (MLVA)
J.-M. Rolain, D. Raoult); Mahosot Hospital,
                                                   10.   Suttinont C, Losuwanaluk K, Niwatayakul          protocols have been applied to type
Vientiane, Laos (S.D. Blacksell, R. Phetsou-             K, Hoontrakul S, Intaranongpai W, Silpa-         C. difficile, and these proved more
vanh, S. Phongmany, N.P.J. Day, P.N. New-                sakorn S, et al. Causes of acute, undifferen-
                                                         tiated, febrile illness in rural Thailand: re-
                                                                                                          discriminatory compared to other
ton); University of Oxford, Oxford, United
                                                         sults of a prospective observational study.      methods (3,4). Furthermore, MLVA
Kingdom (S.D. Blacksell, N.P.J. Day, P.N.
                                                         Ann Trop Med Parasitol. 2006;100:363–            can subgroup geographically diverse
Newton); and Mahidol University, Bangkok,                70. DOI: 10.1179/136485906X112158                027 isolates (G. Killgore et al., unpub
Thailand (S.D. Blacksell, N.P.J. Day)
                                                                                                          data) as well as 027 isolates that are
                                                   Address for correspondence: Didier Raoult,
DOI: 10.3201/eid1409.071259                                                                               common to 1 institution (5).
                                                   Unité des Rickettsies, Centre National de la
References                                                                                                     We reported a case of C. difficile
                                                   Recherche Scientifique–Institut de Recherche
                                                                                                          PCR 027 in Ireland, where the isolate
                                                   pour le Développement, Unité Mixte de
 1.   Phongmany S, Rolain JM, Phetsouvanh                                                                 had an identical antibiogram profile
      R, Blacksell SD, Soukkhaseum V, Rasa-        Recherche 6236, World Health Organization
                                                                                                          compared with those strains reported
      chack B, et al. Rickettsial infections and   Collaborative Center for Rickettsioses and Other
      fever, Vientiane, Laos. Emerg Infect Dis.                                                           across Europe (6,7) (i.e., resistant to
                                                   Arthropod Borne Bacterial Diseases, Faculté de
      2006;12:256–62.                                                                                     fluoroquinolones and erythromycin,
                                                   Médecine, 27 Bd Jean Moulin, 13005 Marseille,
 2.   Tamura A, Yamamoto N, Koyama S,                                                                     susceptible to clindamycin). We have
      Makisaka Y, Takahashi M, Urabe K, et         France; email:
                                                                                                          subsequently identified C. difficile
      al. Epidemiological survey of Orientia
      tsutsugamushi distribution in field rodents                                                          027 in 6 more healthcare settings. To
      in Saitama Prefecture, Japan, and discov-       The opinions expressed by authors con-              date >100 Irish C. difficile 027 isolates
                                                      tributing to this journal do not necessar-
      ery of a new type. Microbiol Immunol.                                                               have been characterized by analysis of
      2001;45:439–46.                                 ily reflect the opinions of the Centers for
                                                      Disease Control and Prevention or the               their antibiogram profiles, toxinotyp-
 3.   Mahajan SK, Rolain JM, Kashyap R, Bak-
      shi D, Sharma V, Prasher BS, et al. Scrub       institutions with which the authors are af-         ing, and 16S–23S rDNA PCR ribotyp-
      typhus in Himalayas. Emerg Infect Dis.          filiated.                                            ing. All C. difficile 027 isolates were
      2006;12:1590–2.                                                                                     resistant to moxifloxaxin, gatifloxacin,

                              Emerging Infectious Diseases • • Vol. 14, No. 9, September 2008                               1485

ciprofloxacin (MIC >32 mg/L), and            The nonrelated reference strain of the         classified as less susceptible (MIC 4
erythromycin (MIC >256 mg/L) but            Stoke-Mandeville outbreak (R20291)             mg/L) or resistant (MIC 8 mg/L) to clin-
susceptible to metronidazole (MIC           differed considerably from all Irish           damycin when Clinical and Laboratory
0.25 mg/L) and vancomycin (MIC              isolates but was more related to the           Standards Institute criteria were used
>0.5 mg/L). Clindamycin suscepti-           clindamycin-sensitive cluster than to          (2). Unfortunately, MIC values were
bility varied between isolates from         the clindamycin-resistant cluster (Fig-        not reported, and the corresponding re-
unrelated institutions. Isolates from 2     ure). We thus linked a defined genetic          sistance genes were not investigated. In
healthcare settings were susceptible to     marker with the clindamycin-resistant          contrast, Canadian studies to date have
clindamycin (n = 11: MIC90 4 mg/L).         phenotype in C. difficile PCR-027.              not reported clindamycin resistance in
However, clindamycin-resistant PCR          MLVA could clearly differentiate               this strain type. The MIC90 of Canadian
027 isolates (n = 96: MIC90 >256            clindamycin-resistant and -susceptible         NAP 1 isolates for clindamycin was 4
mg/L) were identified in the other 5         isolates from the same geographic re-          mg/L (9,10). Although outbreaks and
healthcare institutions. All clindamy-      gion and subgrouped them into 2 dis-           sporadic cases of PCR 027 have been
cin-resistant PCR 027 isolates were         tinct clusters (Figure).                       identified in several European coun-
positive for the ermB gene, encoding             Although high-level resistance to         tries, to date no clindamycin-resistant
the    macrolide-lincosamide-strepto-       fluoroquinolone antimicrobial agents            clone has been reported.
gramin-B genotype.                          has been well documented in PCR 027                  Detection of clindamcyin-resistant
     A subset of clindamycin-sensitive      (1,6), resistance to clindamycin is rare.      C. difficile PCR 027 strains is an im-
and -resistant Irish 027 strains isolated   Subsequently, clindamycin has been             portant and worrying development. Re-
throughout 2006 (n = 22) were fur-          considered as a “protective” antimi-           sistance to this antimicrobal agent in-
ther characterized by using a recently      crobial agent for the development of           creases the risk for CDAD in patients,
described MLVA protocol (3). Six            CDAD in an epidemiologic survey in             and its use may be an important fac-
clindamycin-susceptible isolates were       the Netherlands (8). Currently, resis-         tor contributing to the persistence and
selected from 2 healthcare settings.        tance to this agent in NAP 1/PCR 027           spread of PCR 027. A similar feature
One hospital conducted active routine       has been restricted to the United States.      has already been observed when fluo-
laboratory surveillance and molecular       McDonald and colleagues reported that          roquinolones and cephalosporins are
genotyping (n = 3). The second hos-         19 (79%) of 24 NAP 1 isolates were             prescribed. Clindamcyin-resistant PCR
pital submitted only random isolates
(n = 3) for typing during a C. dif-
ficile outbreak. Sixteen clindamycin-
resistant PCR 027 isolates were also
included in the MLVA. Resistant iso-
lates were selected from 5 healthcare
settings. These included isolates from
2 C. difficile outbreaks with ongoing
laboratory surveillance (n = 5, n = 6,
respectively); a third hospital with on-
going laboratory surveillance (n = 3)
and 2 hospitals that each submitted fe-
cal samples from patients with severe
cases of C. difficile disease (n = 1).
The Stoke-Mandeville control strain
R20291 was included for comparison.
     MLVA determined that all strains       Figure. Minimal spanning tree of 23 Clostridium difficile isolates. In the circles, the
within the clindamycin-resistant clus-      individual isolates are mentioned. The numbers between the circles represent the summed
                                            tandem repeat differences (STRDs) between multiple-locus variable-number tandem-
ter were closely related and were
                                            repeat analysis types. Straight lines represent single-locus variants, dashed lines double-
single- or double-locus variants with       locus variants. Curved lines represent triple-locus variants. Two related clusters can be
a maximum 5 summed tandem-re-               discriminated: the light gray cluster (isolates B1, B4, M246, B6, and M216) and the cluster
peat difference (STRD). In contrast,        within dotted lines (isolates V6–44, V6–142, V6–81, 1ML, C1, 4108, V6–35, V6–80, L1,
the closest relationship between the        2191cc, C4, C8, 3ML, C44, C37, and 13ML) The isolates in the light gray cluster are
                                            sensitive to clindamycin; isolates in the cluster surrounded by dotted lines are resistant.
clindamycin-resistant and the clin-
                                            Two isolates (M278 and R20291) did not belong to a cluster but were more related to the
damycin-sensitive clusters was a tri-       sensitive cluster than to the resistant cluster. Genetically related clusters were defined by
ple-locus variant with an STRD of 17.       an STRD <10.

1486                     Emerging Infectious Diseases • • Vol. 14, No. 9, September 2008

027 probably reflects the emergence                  6.   Long S, Fenelon L, Fitzgerald S, Nolan N,
                                                         Burns K, Hannan M, et al. First isolation
of a new clone because MLVA clearly
differentiates between clindamycin-
                                                         and report of clusters of Clostridium dif-         Incidence of
susceptible and -resistant isolates.
                                                         ficile PCR 027 cases in Ireland. Eurosur-
                                                         veillance 2007;12:E070426.3.                        Clostridium
 Denise Drudy, Bram Goorhuis,
                                                    7.   Drudy D, Kyne L, O’Mahony R, Fanning
                                                         S. GyrA mutations in fluoroquinolone-
 Dennis Bakker, Lorraine Kyne,                           resistant Clostridium difficile PCR-027.        Disease, Singapore
                                                         Emerg Infect Dis. 2007;13:504–5.
     Renate van den Berg,                           8.   Goorhuis A, Van der Kooi T, Vaessen                 To the Editor: Clostridium dif-
        Lynda Fenelon,                                   N, Dekker FW, Van den Berg R, Har-
                                                                                                        ficile–associated disease (CDAD) has
       Seamus Fanning,                                   manus C, et al. Spread and epidemiol-
                                                         ogy of Clostridium difficile polymerase         increased in incidence across North
    and Edward J. Kuijper
                                                         chain reaction ribotype 027/toxinotype         America and Europe (1). Recent re-
Author affiliations: University College Dub-              III in The Netherlands. Clin Infect Dis.       ports document the emergence of an
lin, Dublin, Ireland (D. Drudy, L. Kyne, L.              2007;45:695–703. DOI: 10.1086/520984
                                                                                                        epidemic strain of C. difficile, NAP1/
Fenelon, S. Fanning); Leiden University             9.   Bourgault AM, Lamothe F, Loo VG, Poiri-
                                                         er L; CDAD-CSI Study Group. In vitro sus-      BI/027, associated with increased vir-
Medical Center, Leiden, the Netherlands
                                                         ceptibility of Clostridium difficile clinical   ulence (2,3). However, less informa-
(B. Goorhuis, D. Bakker, R. van den Berg,                isolates from a multi-institutional outbreak   tion is available regarding CDAD epi-
E.J. Kuijper); and European Centre for Dis-              in Southern Québec, Canada. Antimicrob
                                                                                                        demiology in Asia. We examined the
ease Prevention and Control, Stockholm,                  Agents Chemother. 2006;50:3473–5.
                                                         DOI: 10.1128/AAC.00479-06                      incidence of C. difficile among hos-
Sweden (E.J. Kuijper)
                                                   10.   MacCannell DR, Louie TJ, Gregson DB,           pitalized patients in Singapore from
DOI: 10.3201/eid1409.071346                              Laverdiere M, Labbe AC, Laing F, et al.        2001 through 2006 and conducted a
                                                         Molecular analysis of Clostridium dif-
                                                         ficile PCR ribotype 027 isolates from
                                                                                                        case–control study to evaluate risk
References                                               Eastern and Western Canada. J Clin Mi-         factors for testing positive for C. dif-
                                                         crobiol. 2006;44:2147–52. DOI: 10.1128/        ficile toxin (CDT) in our population.
 1. Kuijper EJ, Coignard B, Tull P. the ES-
    CMID Study Group for Clostridium dif-
                                                         JCM.02563-05                                        Tan Tock Seng Hospital (TTSH)
    ficile (ESGCD)*; EU Member States and                                                                is a 1,200-bed, acute-care general hos-
                                                   Address for correspondence: Denise Drudy,
    the European Centre for Disease Preven-                                                             pital in Singapore that serves an urban
                                                   Centre for Food Safety, Veterinary Sciences
    tion and Control (ECDC). Emergence of                                                               population of 4 million. We calculated
    Clostridium difficile-associated disease in     Centre, University College Dublin, Belfield,
    North America and Europe. Clin Micro-
                                                                                                        CDAD incidence using the number of
                                                   Dublin 4, Ireland; email:
    biol Infect. 2006;12:2–18. DOI: 10.1111/                                                            patients testing positive for CDT per
    j.1469-0691.2006.01580.x                                                                            10,000 patient days from 2001 through
 2. McDonald LC, Killgore GE, Thompson                                                                  2006. We used this calculation because
    A, Owens RC Jr, Kazakova SV, Sambol
    SP, et al. An epidemic, toxin gene-variant
                                                                                                        CDT testing would have been ordered
    strain of Clostridium difficile. N Engl J         Letters                                            for clinical indications. CDT testing
    Med. 2005;353:2433–41. DOI: 10.1056/
                                                     Letters commenting on recent articles
                                                                                                        was performed by using the same
    NEJMoa051590                                                                                        ELISA (Premier Toxins A&B; Merid-
 3. van den Berg RJ, Schaap I, Templeton             as well as letters reporting cases, out-
                                                                                                        ian Bioscience, Inc., Cincinnati, OH,
    KE, Klaassen CH, Kuijper EJ. Typing and          breaks, or original research are wel-
    subtyping of Clostridium difficile isolates                                                          USA) throughout the entire period of
    by using multiple-locus variable-number
                                                     come. Letters commenting on articles               investigation.
    tandem-repeat analysis. J Clin Micro-            should contain no more than 300                         Case-patients and controls were
    biol. 2007;45:1024–8. DOI: 10.1128/              words and 5 references; they are more
                                                                                                        selected from patients hospitalized at
 4. Marsh JW, O’Leary MM, Shutt KA, Pas-             likely to be published if submitted                TTSH from January 1 through Decem-
    culle AW, Johnson S, Gerding DN, et al.          within 4 weeks of the original article’s           ber 31, 2004. Microbiology laboratory
    Multilocus variable-number tandem-re-            publication. Letters reporting cases,              records were used to define 3 groups.
    peat analysis for investigation of Clostrid-
    ium difficile transmission in hospitals. J        outbreaks, or original research should             Case-patients were defined as CDT-
    Clin Microbiol. 2006;44:2558–66. DOI:            contain no more than 800 words and                 positive inpatients (group 1). Two sets
    10.1128/JCM.02364-05                             10 references. They may have one                   of negative controls were defined: the
 5. Fawley WN, Freeman J, Smith C, Har-
                                                     Figure or Table and should not be di-
                                                                                                        first (group 2) consisted of patients
    manus C, van den Berg RJ, Kuijper EJ,
                                                                                                        who tested negative for CDT. How-
    et al. Use of highly discriminatory finger-       vided into sections. All letters should
    printing to analyze clusters of Clostridium                                                         ever, because false-negatives could
                                                     contain material not previously pub-
    difficile infection cases due to epidemic                                                            nullify differences between groups 1
    ribotype 027 strains. J Clin Micro-              lished and include a word count.                   and 2, we defined a second set of neg-
    biol. 2008;46:954–60. DOI: 10.1128/
                                                                                                        ative controls (group 3) from among
                                                                                                        18,000 inpatients not tested for CDT.

                             Emerging Infectious Diseases • • Vol. 14, No. 9, September 2008                              1487

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