ESCMID elibrary. Symposium: Acinetobacter Infections from East to West. Molecular Epidemiology Worldwide

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1 Symposium: Acinetobacter Infections from East to West Molecular Epidemiology Worldwide Harald Seifert Institut für Medizinische Mikrobiologie, Immunologie und Hygiene der Universität zu Köln 26 th ECCMID, Amsterdam, 9-12 April 2016

2 Twenty-three soldiers wounded in Iraq and subsequently admitted to Brooke Army Medical Center, San Antonio, Texas from March 2003 to May 2004 had wound cultures positive for Acinetobacter baumannii. Eighteen had osteomyelitis, 2 burn infection, and 3 deep wound infection. All isolates were MDR, 4 were resistant to imipenem. Davis KA et al. Emerg Infect Dis. 2005; 11:

3 IRAQIBACTER Acinetobacter (pronounced a-sin-ee-toe-back-ter)

4 Microbiology/Taxonomy of Acinetobacter (Molecular) Epidemiology of A. baumannii

5 v v Genus Acinetobacter : Current Taxonomy ~57 named and 5 unnamed species Courtesy A. Nemec

6 Genus Acinetobacter : Current Taxonomy ~57 named and 5 unnamed species A. baumannii A. pittii (DNA group 3) A. calcoaceticus A. seifertii ( Close to DNA group 13TU ) A. haemolyticus A. bereziniae (DNA group 10) A. baumannii group* A. johnsonii A. guillouiae (DNA group 11) A. junii A. nosocomialis (DNA group 13TU) A. lwoffii DNA group 13 BJ/14 TU A. parvus A. courvalinii (DNA group 14 BJ) A. radioresistens A. variabilis (DNA group 15 TU) A. schindleri DNA group 16 A. ursingii A. dispersus (DNA group 17) *Peleg et al., CMR, 2008

7 Identification of Acinetobacter spp. in the routine diagnostic laboratory Scheme of ~28 physiological and biochemical tests Bouvet & Grimont (1986), Gerner-Smidt et al. (1990) Not suitable for routine microbiological diagnostics Manual commercial ID systems (Api 20NE etc..) Completely unreliable Automated commercial identification systems (VITEK ) Not very reliable, but improving Molecular reference methods (rpob, gyrb, Oxa-51) Not suitable for routine microbiological diagnostics MALDI-TOF Very promising, even within the A. baumannii group

8 Microbiology/Taxonomy of Acinetobacter (Molecular) Epidemiology of A. baumannii

9 Natural habitat of Acinetobacter A. nonbaumannii: Water, soil, plants, vegetables, human skin (Baumann et al., J Bact 1968; Seifert et al. JCM, 1997; Berlau et al. JHI, 1999; Berlau et al. EJCMID, 1999; Houang et al., JCM, 2001) A. baumannii is not an ubiquitous organism A hospital-adapted pathogen The colonized patient is the reservoir In the hospital: respiratory tubing, computer keyboards, cellphones (Cefai et al., JHI 1900; Neely et al., CID 1999; Borer et al., EID 2005) Natural habitat remains to be defined (although found in body lice, pets, domestic animals, meat, and birds droplings) (La Scola, EID 2004; Belmonte, Vet Microbiol 2014; Rafei, AEM 2015; Wilharm, unpublished)

10 Acinetobacter: Carbapenem-resistance in invasive infections 53.1% 65.4% 5.5% 89.9% 69.7% 78.8% 87.3% 81.3% 59.1% 93.2% EARS-Net annual report %

11 Susceptibility rates of A. baumannii group isolates to meropenem ( 2mg/L*) Region % (no.) of A. baumannii isolates susceptible, Asia 36.4 (165) 16.7 (66) (235) Europe 56.2 (1391) 49.7 (1076) 54.3 (832) 32.7 (883) 31.8 (711) 46.8 (4893) Latin America 30.9 (353) 18.2 (298) (61) 10.5 (105) 21.7 (828) North America 52.8 (409) 68.7 (367) 59.7 (467) 44.8 (290) 45.2 (177) 56.0 (1710) Middle East 34.4 (160) 21.9 (73) 10.9 (92) 6.2 (65) (390) * CLSI Breakpoint TEST Surveillance Data, IHMA, Schaumburg Illinois, USA; unpublished - courtesy Bob Badal

12 A. baumannii infection requires 1. a susceptible patient 2. presence of the organism (endemic or epidemic)

13 Chung DR et al. Am J Respir Crit Med 2011;184: Major organisms isolated from HAP and VAP in Asia

14 Transmission of A. baumannii Transmission from a common source Airborne transmission (Bernards et al., AJIC 1998) Patient-to-patient transmission Hands of hospital personnel Contamination of environmental surfaces Contamination of medical equipment Colonized patient is the primary reservoir

15 Outbreak of carbapenem-resistant A. baumannii carrying OXA-23 in a German university medical centre 61-year-old patient transferred from Thailand motor vehicle accident multiple During trauma the following 9 months 32 patients were found admission colonized/infected with soft-tissue with epidemic MDR A. baumannii infection and osteomyelitis to a surgical ward wound culture (02 06): Kohlenberg et al. J Med Microbiol. 2009; 58:

16 Epidemiology of A. baumannii Multiple hospital outbreak within a city New York (Landman et al., ArchIM 2002) London (Turton et al., JHI 2004) Johannesburg (Marais et al., AJIC 2004) Multiple city outbreaks within a country Czech Republic (Nemec et al., JMM 2004) Southeast England (Coelho et al., JCM 2004) France (Naas et al., EID 2006) Outbreaks from hospitals in several countries in Europe van Dessel et al., Res Microbiol 2004 Towner et al., CMI 2008 Higgins et al., JAC 2010

17 Molecular methods for typing Acinetobacter baumannii PFGE (Seifert et al., JCM 2005) MLST (Bartual et al., JCM 2005): pubmlst.org MLST (Diancourt et al., PLoS One 2010): pasteur.fr/mlst PCR/ESI-MS (Ecker et al., JCM 2006) Sequence-group typing (Turton et al., CMI 2007) RAPD, AFLP, rep-pcr, VNTR, Oxa51-like.. Next generation sequencing (NGS WGS)

18 Acinetobacter baumannii infections The European (EU) Clones There was published evidence that three pan-european A. baumannii clones (lineages) are spreading in Europe (Dijkshoorn et al., JCM 1996; Nemec et al., JMM 2004; Turton et al., CMI 2007)

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20 Acinetobacter baumannii infections The European (EU) Clones There is evidence that three pan-european A. baumannii clones (lineages) are spreading in Europe (Dijkshoorn et al., JCM 1996; Nemec et al., JMM 2004; Turton et al., CMI 2007) Unlike with MRSA, there was no estimate of the true contribution of the various EU clones to the global epidemiology of A. baumannii

21 Global Spread of Carbapenem-Resistant Acinetobacter baumannii (CRAb) Methods 492 carbapenem-non susceptible (MIC > 8 mg/l) A. baumannii isolates from a world-wide surveillance study (Tigecycline Evaluation and Surveillance Trial (T.E.S.T.), ) were typed by rep-pcr (DiversiLab) to assess clonal relatedness. Results The vast majority of isolates (91%) were grouped into 8 distinct clusters (WW1 WW8) including European clones EU I, II and III. Higgins P et al. JAC 2010; 65:

22 Acinetobacter baumannii clones Terminology issues European clones (EUI-III; Dijkshoorn et al., 1996) Worldwide clones (WW1-8; Higgins et al., 2010) Global clones (GC) International clones (IC)

23 IC3 IC2 IC4 IC5 IC7 IC6 IC8 IC1 IC 2 was the largest (241 isolates, 49%) and most widespread group, with isolates from USA, Honduras, Pan-Europe, Israel, India, Pakistan, China, Korea, Singapore, Taiwan, Australia and South Africa. Higgins P et al. JAC 2010; 65:

24 Higgins PG et al Global spread of carbapenem-resistant Acinetobacter baumannii. JAC 65:233-8 Proportion of carbapenem resistant A. baumannii clustering with the International clonal lineages (N = 492)

25 Higgins PG et al Global spread of carbapenem-resistant Acinetobacter baumannii. JAC 65:233-8 Austria Bulgaria France Germany Greece Hungary Ireland Italy Latvia Poland Portugal Spain Switzerland United Kingdom Europe (n = 116) IC3 1% others 24% IC2 57% IC1 18%

26 Higgins PG et al Global spread of carbapenem-resistant Acinetobacter baumannii. JAC 65:233-8 Asia (n= 45) others 13% IC2 60% IC1 27% China Korea India Pakistan Singapore Taiwan

27 Higgins PG et al Global spread of carbapenem-resistant Acinetobacter baumannii. JAC 65:233-8 USA, (n = 215) IC3 11% IC5 20% IC1 5% IC2 60%

28 Higgins PG et al Global spread of carbapenem-resistant Acinetobacter baumannii. JAC 65:233-8 Argentina Brazil Chile Colombia Honduras Mexico Puerto Rico Venezuela South and Central America, n = 93 others 43% IC1 2% IC4 18% IC5 37%

29 99% of isolates were IC2 (China) 91% of isolates were IC2 (Japan) 2013; 57: % of isolates were IC2 (USA) 71% of isolates were IC2 (Poland) 70% of isolates were IC2 (Brasil) 71% of isolates were IC2 (Australia)

30 Randomized, open label, multicenter, non-inferiority phase IV clinical trial to compare safety and efficacy of colistin vs. meropenem in ventilator-associated pneumonia (VAP). Patients were randomized to receive colistin 3 MU iv. / 8 h or meropenem 1 g iv / 8 h. Each group will receive levofloxacin 500 mg iv/12 h in addition to the treatment. At study close on October 13, 2015, 232 patients were enrolled in 35 centers in Greece, Italy and Spain (Principal Investigator: JM Cisneros, Sevilla, Spain).

31 Background: Whole genome sequencing (WGS) will revolutionise bacterial strain typing but data analysis is still a challenge. Methods: WGS was employed to define and evaluate a core genome multilocus sequence typing (cgmlst) scheme for A. baumannii using Ridom SeqSphere+ software. Using genomes from NCBI as well as representative isolates belonging to the 8 previously described A. baumannii ICs, a core genome of 2,390 alleles was defined. This was then employed against a total of 56 A. baumannii isolates, previously typed by PFGE and linked to hospital outbreaks. Results: Good correlation between PFGE and cgmlst clustering was found, with 0-8 allelic differences within a pulsotype, and 40-2,166 differences between pulsotypes. The highest number of allelic differences was between the isolates representing different ICs. Higgins PG, Prior K, Harmsen D, Seifert H. Defining and evaluating a core genome multilocus typing scheme for whole-genome sequence-based typing of Acinetobacter baumannii (submitted)

32 IC8 Minimum spanning tree based on cgmlst allelic profiles of all currently known A. baumannii ICs IC IC2 IC IC IC5 IC4 IC1 Higgins PG, et al., submitted

33 We are witnessing the continuing spread of carbapenem resistant A. baumannii This spread is caused by a few successful clonal lineages International clonal lineage 2 (IC2) is the most prevalent worldwide and obviously still increasing reppcr is a robust typing method that correlates well with MLST Conclusions cgmlst is a promising molecular typing method

34 11 th Acinetobacter 2017 September 20-22, 2017 Sevilla, Spain Alvaro Pascual and Jerónimo Pachón