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AG Higgins
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AG Higgins

Of porins, pumps and carbapenemases; multi-drug resistance mechanisms of Gram negative bacteria, and Molecular epidemiology of ESKAPE organisms and Neisseria gonorrhoeae

Phone: +49 221 478-32011

E-mail: [Email protection active, please enable JavaScript.]

(ORCID 0000-0001-8677-9454)



Prof. Dr. Harald Seifert [Email protection active, please enable JavaScript.]

Julia Wille [Email protection active, please enable JavaScript.]

Kai Lucaßen [Email protection active, please enable JavaScript.]

Kyriaki Xanthopoulou [Email protection active, please enable JavaScript.]

Lea Biniossek

Stefanie Gerson

Alexander Wunderlich


Research Topics

We are interested in the antimicrobial resistance mechanisms and molecular epidemiology of what are termed ESKAPE pathogens; Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). These organisms are the leading cause of nosocomial infections throughout the world and are particularly problematic because of their ability to escape the action of antibiotics. Furthermore, we are also interested in Neisseria gonorrhoeae because of the rise of multi-drug resistant strains.

Bacteria can become resistant to antimicrobials through a variety of mechanisms; resistance gene acquisition (e.g. beta-lactamases), mutations in drug targets leading to lower affinity to antibiotics (e.g. GyrA and fluoroquinolones), reduced permeability through loss or downregulation of porins (e.g. carbapenem-resistance), or through upregulation of broad substrate efflux pumps (a single RND pump can efflux multiple antimicrobial drug classes such as tetracyclines, aminoglycosides, fluoroquinolones, trimethoprim, beta-lactams, macrolides, tigecycline, and chloramphenicol, as well as antiseptics). We are particularly interested in the role of RND efflux pumps in multi-drug resistant A. baumannii (their regulation and characterising new pumps), colistin resistance in A. baumannii, and non-carbapenemase mechanisms of carbapenem-resistance in K. pneumoniae (porin loss combined with ESBLs), and the class D beta-lactamases (oxacillinases, or OXA).

We use a variety of methodologies to investigate and characterise antimicrobial resistance, both phenotypically and genotypically, but more recently have utilised the power of whole genome sequencing to reveal their mechanisms. For this, we use the MiSeq for short reads combined with MinION for long reads. This approach allows for a high-resolution molecular epidemiology, plasmid characterisation, and to chart and identify high-risk clones.


Recent publications 2013-date

Seifert H, Stefanik D, Olesky M, Higgins PG. In-vitro activity of the novel fluorocycline TP-6076 against carbapenem-resistant Acinetobacter baumannii. International Journal of Antimicrobial Agents. 2019. Accepted, in print.

Günther SD, Fritsch M, Schiffmann LM, Seeger JM, Snipas SJ, Coutelle M, Kufer TA, Higgins PG, Hornung V, Bernardini ML, Höning S, Krönke M, Salvesen GS, Kashkar H. Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through LPS. Nature Microbiology. 2019. Accepted, in print.

Cosgaya C, Ratia C, Marí-Almirall M, Rubio L, Higgins PG, Seifert H, Roca I, Vila J. In vitro and in vivo virulence potential of the emergent species of the Acinetobacter baumannii (Ab) group. Frontiers in Microbiology. 2019. 10: 2429.

Betts JW, Hornsey M, Higgins PG, Lucassen K, Wille J, Salguero FJ, Seifert H, La Ragione RM. Restoring the activity of the antibiotic aztreonam using the polyphenol epigallocatechin gallate (EGCG) against multidrug-resistant clinical isolates of Pseudomonas aeruginosa. J Med Microbiol. 2019. 68: 1552-1559.

Opazo-Capurro AF, Higgins PG, Wille J, Seifert H, Cigarroa C, Gonzalez-Muñoz P, Quezada-Aguiluz MA, Dominguez M, Bello HM, Vergara L, González-Rocha GE. Genetic features of Antarctic Acinetobacter radioresistens strain A154 harboring multiple antibiotic-resistance genes. Frontiers in Cellular and Infection Microbiology. 2019. 9: article 328

Biehl L, Higgins PG*, Wille T, Peter K, Hamprecht A, Peter S, Dörfel D, Vogel W, Haefner H, Lemmen S, Panse J, Rohde H, Klupp E,Schafhausen P, Imirzalioglu C, Falgenhauer  L, Salmanton Garcia J, Stecher M, Vehreschild JJ, Seifert H, Vehreschild M. Impact of single room contact precautions on hospital-acquisition and transmission of multidrug-resistant Escherichia coli: a prospective multicentre cohort-study in haematological and oncological wards. Clin Microbiol Infect. 2019. 25: 1013-1020.

Dimitriou V, Biehl L, Hamprecht A, Vogel W, Dörfel D, Peter S, Schafhausen P, Rohde H, von Lilienfeld-Toal M, Klassert TE, Slickers P, Ehricht R, Slevogt H, Christ H, Hellmich M, Farowski F, Tsakmaklis A, Higgins PG, Seifert H, Vehreschild MJGT. Controlling intestinal colonisation of high-risk hematology patients with extended- spectrum beta-lactamase producing Enterobacteriaceae – a randomized controlled trial (CLEAR). 2019. J Antimicrob Chemo. 74: 2065-2074.

Fuchs F, Wille J, Hamprecht A, Parcina M, Lehmann C, Schwarze-Zander C, Seifert H, Higgins PG. In vitro activity of mecillinam and nitroxoline against Neisseria gonorrhoeae – re-purposing old antibiotics in the multi-drug resistance era. J Med Microbiol. 2019.  68: 991-995.

Mertins S, Higgins PG, González Rodríguez M, Borlon C, Gilleman Q, Mertens P, Seifert H, Krönke M, Klimka M. Generation and selection of antibodies for a novel immunochromatographic lateral flow test to rapidly identify OXA-23-like mediated carbapenem-resistance in Acinetobacter baumannii. J Med Microbiol. 2019. 68: 1021-1032.

Farowski F, Solbach P, Tsakmaklis A, Brodesser S, Cruz AMR, Cornely OA, Dettmer K, Higgins PG, Suerbaum S, Jazmati N, Oefner PJ, Vehreschild MJGT, for the German Clinical Microbiome Study Group (GCMSG). Potential biomarkers to predict outcome of faecal microbiota transfer for recurrent Clostridioides difficile infection. Digestive and Liver Disease. 2019. DOI:  51: 944-951.

Tietgen M, Kramer J, Brunst S, Djahanschiri B, Wohra S, Higgins PG, Weidensdorfer M, Christ S, Pos KM, Gonzaga A, Steglich M, Nübel U, Ebersberger I, Proschak E, Göttig S. Identification of the novel class D β-lactamase OXA-679 involved in carbapenem resistance in Acinetobacter calcoaceticus. 2019. J Antimicrob Chemo. 74: 1494-1502.

Cerezales M, Xanthopoulou K, Ertel J, Bustamante Z, Seifert H, Gallego L, Higgins PG. Acinetobacter baumannii analysis by core genome MLST in two hospitals in Bolivia: endemicity of international clone 7 isolates (CC25). Int J Antimicrob Agents. 2019. 53: 844-849.

W.A. Rossen JWA, Dombrecht J, Vanfleteren D, De Bruyne K, van Belkum A, Rosema S, Lokate M, Bathoorn E, Reuter S, Grundmann H, Ertel J, Higgins PG, Seifert H Epidemiological typing of Serratia marcescens by whole genome multi-locus sequence typing. J Clin Microbiol. 2019. 57: UNSP e01652-18

D’Souza R, Pinto NA, Nguyen LP, Higgins PG, Vu NT, Byun JH, Cho YL, Choi JR, Yong D. Phenotypic and genotypic characterization of Acinetobacter spp. panel strains: a cornerstone to facilitate antimicrobial development. Front Microbiol. 2019.  10:559. doi: 10.3389/fmicb.2019.00559

Gerson S, Betts JW, Lucaßen K, Nodari CS, Wille J, Josten M, Göttig S, Nowak J, Stefanik D, Roca I, Vila J, Cisneros JM, La Ragione RM, Seifert H, Higgins PG. Investigation of novel pmrB and eptA mutations in isogenic Acinetobacter baumannii isolates associated with colistin resistance and increased virulence in vivo.  Antimicrob Agents Chemother. 2019. 3: e01586-18.

Klotz P, Higgins PG, AR , Failing K, Leidner U, Seifert H, Scheufen S, Semmler T, Ewers C. Seasonal occurrence and carbapenem susceptibility of bovine Acinetobacter baumannii in Germany. Frontiers in Microbiology. 2019. 10: 272. doi: 10.3389/fmicb.2019.00272

Farowski F, Els G, Tsakmaklis A, Higgins PG, Kahlert CR, Stein-Thoeringer CK, Bobardt JS, Dettmer-Wilde K, Oefner PJ, Vehreschild JJ, Vehreschild MJGT. Assessment of urinary 3-indoxyl sulfate as a marker for gut microbiota diversity and abundance of Clostridiales. Gut Microbes. 2019. 10: 133-141.

Cerezales M, Ocampo-Sosa AA, Alvarez L, Diaz C, Bustamente Z, Santos J, Martinez-Martinez L, Higgins PG, Gallego L. High prevalence of extensively drug-resistant Acinetobacter baumannii at a Children Hospital in Bolivia. Pediatr Infect Dis J. 2018. 11:1118-1123.

Higgins PG, Hrenovic J, Seifert H, Dekic S. Characterization of Acinetobacter baumannii from water and sludge line of secondary wastewater treatment plant. Water Research. 2018. 140:261-267.

Gerson S, Nowak J, Zander E, Ertel J, Wen Y, Krut O, Seifert H, Higgins PG. Diversity of mutations in regulatory genes of resistance-nodulation-cell division efflux pumps in association with tigecycline resistance in Acinetobacter baumannii. J Antimicrob Chemother. 2018. 73:1501-1508.

Cerezales M, Xanthopoulou K, Ertel J, Nemec A, Bustamante Z, Seifert H, Gallego L, Higgins PG. Identification of Acinetobacter seifertii isolated from Bolivian hospitals. J Med Microbiol. 2018. 67:834-837.

Blaschke U, Skiebe E, Kaatz M, Higgins PG, Pfeifer Y, Wilharm G. Complete genome sequencing of Acinetobacter sp. strain LoGeW2-3, isolated from the pellet of a white stork, reveals a novel class D beta-lactamase gene. Microbiol Resour Announc. 2018. e01405-17.  

Seifert H, Stefanik D, Sutcliffe JA, Higgins PG. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int. J. Antimicrob. Agents. 2018. 51: 62-64.

Nowak J, Zander E, Stefanik D, Higgins PG, Roca I, Vila J, McConnel MJ, Cisneros JM, Seifert H. High incidence of pandrug-resistant Acinetobacter baumannii isolates collected from Greece, Italy and Spain as part of the MagicBullet clinical trial. J Antimicrob Chemother. 2017. 72: 3277-3282.

Buser GL, Cassidy PM, Cunningham MC, Rudin S, Hujer AM, Vega R, Furuno JP, Marshall SH, Higgins PG, Jacobs MR, Wright MS, Adams MD, Bonomo RA, Pfeiffer CD, Beldavs ZG. Failure to communicate: transmission of extensively drug-resistant blaOXA-237-containing Acinetobacter baumannii-multiple facilities in Oregon, 2012-2014. Infect Control Hosp Epidemiol. 2017. 38: 1135-1341.

Hujer A, Higgins PG, Rudin S, Buser G, Marshall S, Xanthopoulou K, Seifert H, Rojas L, Domitrovic T, Cassidy PM, Cunningham M, Vega R, Furuno J, Pfeiffer C, Beldavs Z, Wright M, Jacobs M, Adams M, Bonomo R. Nosocomial outbreak of extensively drug resistant (XDR) Acinetobacter baumannii isolates containing blaOXA-237 encoded on a plasmid. Antimicrob Agents Chemother. 2017. 61: pii: e00797-17.

Wilharm G, Skiebe E, Higgins PG, Poppel MT, Blaschke U, Leser S, Heider C, Heindorf M, Brauner P, Jäckel U, Böhland K, Cuny C, Łopińska A, Kaminski P, Kasprzak M, Bochenski M, Ciebiera O, Tobółka M, Żołnierowicz KM, Siekiera J, Seifert H, Gagné S, Salcedo SP, Kaatz M, Layer F, Bender JK, Fuchs S, Semmler T, Pfeifer Y, Jerzak L. Relatedness of wildlife and livestock avian isolates of the nosocomial pathogen Acinetobacter baumannii to lineages spread in hospitals worldwide. Environ Microbiol. 2017. 19:4349-4364.

Wen Y, Ouyang Z, Yu Y, Zhou X, Pei Y, Devreese B, Higgins PG, Zheng F. Mechanistic insight of multidrug resistant Acinetobacter baumannii response regulator AdeR recognize an intercistronic region. Nucleic Acids Res. 2017. 45: 9773-9787.

Ladavac R , Bedenić B ,  Vranić-Ladavac M, Barišić N, Karčić N , Pompe K, Ferenčić A, Stojanović A, Seifert H, Katić S, Higgins PG. Emergence of different Acinetobacter baumannii clones in a Croatian hospital and correlation with antibiotic susceptibility. J Global Antimicrob Resist. 2017. 10: 213-218.

Higgins PG, Prior P, Harmsen D, Seifert H. Development and evaluation of a core genome multilocus typing scheme for whole-genome sequence-based typing of Acinetobacter baumannii. PLoS One. 2017. 12:e0179228

D’Souza R, Pinto N, Higgins PG, Hwang I, Yong D, Choi J, Lee K, Chong Y. First report of blaOXA-499 as a carbapenemase gene from Acinetobacter pittii. Antimicrob Agents Chemother. 2017. 61: e0276-16.

Marí-Almirall M, Cosgaya C, Higgins PG, Van Assche A, Telli M, Huys G, Lievens B, Seifert H, Dijkshoorn L, Roca I, Vila J. MALDI-TOF/MS identification of species from the Acinetobacter baumannii (Ab) group revisited: inclusion of the novel A. seifertii and A. dijkshoorniae species. Clin Microbiol Infect. 2017. 23: 210.e1-210.e9.

Evans SR, Hujer AM, Jiang H, Hill CB, Hujer KM, Mediavilla JR, Manca C, Tran TT, Domitrovic TN, Higgins PG, Seifert H, Kreiswirth BN, Patel R, Jacobs MR, Chen L, Sampath R, Hall T, Marzan C, Fowler VG Jr, Chambers HF, Bonomo RA; Antibacterial Resistance Leadership Group (ARLG). Informing antibiotic treatment decisions: evaluating rapid molecular diagnostics (RMDs) to identify susceptibility and resistance to carbapenems against Acinetobacter spp. PRIMERS III.  J Clin Microbiol. 2017. 55: 134-144.

Cosgaya C, Marí-Almirall M, Van Assche A, Fernández-Orth D, Mosqueda N, Telli M, Huys G, Higgins PG, Seifert H, Lievens B, Vila J, Roca A. Acinetobacter dijkshoorniae sp. nov., a new member of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex recovered from clinical samples in different countries. Int J Syst Evol Microbiol. 2016. 66:4105-4111.

Zander E, Seifert H, Higgins PG. The effect of NaCl, pH 5.8 and sodium-salicylate on OXA-mediated carbapenem resistance in Acinetobacter baumannii. Antimicrob Agents Chemother. 2016. 60: 3415-3418.

Pfeifer Y, Hunfeld KP, Borgmann S, Maneg D, Blobner W, Werner G, Higgins PG. Carbapenem-resistant Acinetobacter baumannii ST78 with OXA-72 carbapenemase and ESBL gene blaCTX-M-2-like (blaCTX-M-115). J Antimicrob Chemother. 2016. 71: 1426-1428.

Higgins PG, Koehler D, Chan JZM, Cornely OA, Fätkenheuer G, Gillis M, Pallen MJ, Tien J, Seifert H, Vehreschild MJGT, Millard AD. Draft genome sequence of nine clinical isolates of vancomycin resistant Enterococci. Microbiol Resour Announc. 2016. July/August 2016 4:e00803-16

Tomaschek F, Higgins PG, Stefanik D, Wisplinghoff H, Seifert H. Head-to-head comparison of two multi-locus sequence typing (MLST) schemes for characterization of Acinetobacter baumannii outbreak and sporadic isolates. PLoS One. 2016. 11: e0153014.

Komp Lindgren P, Higgins PG, Seifert H, Cars O. Prevalence of hypermutators among clinical Acinetobacter baumannii isolates. J Antimicrob Chemother. 2016. 71: 661-665.

Molte, G, Seifert H, Mandraka F, Kasperm G, Weidmann B, Hornei B, Öhler M, Schwimmbeck P, Kröschel P, Higgins PG, Reuter S. Outbreak of carbapenem-resistant Acinetobacter baumannii in the intensive care unit: a multi-level strategic management approach. J Hospital Infect. 2016. 92:194-198.

Nowak J, Schneiders T, Seifert H, Higgins PG. The Asp20→Asn substitution in the response regulator AdeR leads to enhanced efflux activity of AdeB in Acinetobacter baumannii. Antimicrob Agents Chemother. 2016. 60:1085-1090.

Higgins PG, Chan J Z-M, Pallen MJ, Seifert H, Millard AD. Draft genome sequence of 11 clinical isolates of Acinetobacter baumannii. Microbiol Resour Announc. 2016. 4: e00269-16.

Nowak J, Seifert H, Higgins PG. Prevalence of eight RND-efflux pump genes in epidemiologically characterised Acinetobacter baumannii of worldwide origin. J Med Microbiol. 2015. 64: 630-635.

Nemec A, Krizova L, Maixnerova M, Sedo O, Brisse S, Higgins PG. Acinetobacter seifertii sp. nov., a member of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex isolated from human clinical specimens. Int J Syst Evol Microbiol. 2015. 65: 934-942.

Hos NJ, Rieg S, Kern WV, Jonas D, Fowler VG, Higgins PG, Seifert H, Kaasch AJ. Amino acid alterations in fibronectin binding protein A (FnBPA) and bacterial genotype are associated with cardiac-device related infection in Staphylococcus aureus bacteremia. J Infect. 2015. 70: 153-159.

Stoeva T, Higgins PG, Bojkova K, Seifert H. Molecular epidemiology of multidrug resistant Acinetobacter baumannii clinical isolates from two Bulgarian hospitals. Scripta Scientifica Medica. 2014: 3; 47-50.

Göttig S, Gruber T, Higgins PG, Wachsmuth M, Seifert H, Kempf V. Detection of pan drug-resistant Acinetobacter baumannii in Germany. J Antimicrob Chemother. 2014. 69: 2578-2579.

Zander E, Bonnin RA, Seifert H, Higgins PG. Characterization of blaOXA-143 variants in Acinetobacter baumannii and Acinetobacter pittii. Antimicrob Agents Chemother. 2014; 58: 2704-2708.

Zander E, Fernández-González A, Schleicher X, Dammhayn C, Kamolvit W, Seifert H, Higgins PG. Worldwide dissemination of acquired carbapenem-hydrolysing class D beta-lactamases in Acinetobacter spp. other than A. baumannii. Int J Antimicrob Agents. 2014; 43: 375-377.

Kamolvit W, Higgins PG, Paterson D, Seifert H. Multiplex PCR to detect the genes encoding naturally occurring oxacillinases in Acinetobacter spp. J Antimicrob Chemother. 2014; 69: 959-963.

Zander E, Seifert H, Higgins PG. Insertion sequence IS18 mediates overexpression of blaOXA-257 in a carbapenem resistant Acinetobacter bereziniae isolate. J Antimicrob Chemother. 2014; 69: 270-271.