Publications by authors named "Harald Seifert"

185 Publications

Impact of immunosuppressive agents on clinical manifestations and outcome of Staphylococcus aureus bloodstream infection - A propensity score matched analysis in two large, prospectively evaluated cohorts.

Clin Infect Dis 2021 Apr 29. Epub 2021 Apr 29.

Division of Infectious Diseases, Department of Medicine II, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Staphylococcus aureus bloodstream infection (SAB) is a common, life-threatening infection. The impact of immunosuppressive agents on the outcome of patients with SAB is incompletely understood.

Methods: Data from two large prospective, international, multicenter cohort studies (INSTINCT and ISAC) between 2006 and 2015 were analyzed. Patients receiving immunosuppressive agents were identified and a 1:1 propensity score (PS) matched analysis was performed to adjust for baseline characteristics of patients. Overall survival and time to SAB-related late complications (SAB relapse, infective endocarditis, osteomyelitis, or other deep-seated manifestations) were analyzed by Cox regression and competing risk analyses, respectively. This approach was then repeated for specific immunosuppressive agents (corticosteroids [CSMT] and immunosuppressive agents other than steroids [IMOTS]).

Results: Of 3,188 analyzed patients, 309 were receiving immunosuppressive treatment according to our definitions and were matched to 309 non-immunosuppressed patients. After PS matching, baseline characteristics were well balanced. In the Cox regression analysis, we observed no significant difference in survival between the two groups (death during follow-up: 105/309 (33.9 %) immunosuppressed patients vs. 94/309 (30.4 %) non-immunosuppressed, hazard ratio 1.20 (95% CI 0.84-1.71). Competing risk analysis showed a cause-specific hazard ratio (CSHR) of 1.81 (95% CI 0.85-3.87) for SAB-related late-complications in patients receiving immunosuppressive agents. CSHR was higher in patients taking IMOTS (3.69; 95% CI 1.41-9.68).

Conclusions: Immunosuppressive agents were not associated with an overall higher mortality. The risk for SAB-related late complications in patients receiving specific immunosuppressive agents such as IMOTs warrants further investigations.
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http://dx.doi.org/10.1093/cid/ciab385DOI Listing
April 2021

Prevalence of RND efflux pump regulator variants associated with tigecycline resistance in carbapenem-resistant Acinetobacter baumannii from a worldwide survey.

J Antimicrob Chemother 2021 Jun;76(7):1724-1730

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany.

Objectives: To determine the most common tigecycline resistance mechanisms in carbapenem-resistant Acinetobacter baumannii isolates obtained during the global Tigecycline Evaluation Surveillance Trial (TEST).

Methods: Tigecycline MICs were determined by broth microdilution. WGS was used to screen for the previously identified tigecycline resistance mechanisms, as well as mutations in resistance-nodulation-cell division (RND)-type efflux pump regulators.

Results: From a total 313 isolates, 113 genetically unique tigecycline-resistant isolates were analysed. The most frequent and worldwide distributed mechanism associated with tigecycline resistance was disruption of adeN, which encodes the repressor of the RND efflux pump AdeIJK, either by IS elements or nucleotide deletions causing premature stop codons. However, mutations leading to amino acid substitutions and disruption by IS elements within the two-component regulatory system adeRS, which regulates expression of the AdeABC efflux pump, correlate with higher tigecycline MICs, but these were found less frequently and were mainly restricted to Southern European countries. Furthermore, an altered version of tviB was identified in several tigecycline-resistant isolates that did not have putative resistance mutations within RND-type regulators. The resistance determinants tet(A) and tet(X), as well as resistance mutations in putative resistance determinants trm, plsC, rrf, msbA and genes encoding 30S ribosomal proteins, were not identified in any isolate.

Conclusions: The most prevalent tigecycline resistance mechanisms were caused by alterations in the regulators of RND-type efflux pumps. These data provide the basis for further characterization of regulator alterations and their contribution to increased efflux and tigecycline resistance, and also should be taken into account in drug discovery programmes to overcome the contribution of efflux pumps.
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http://dx.doi.org/10.1093/jac/dkab079DOI Listing
June 2021

Molecular Epidemiology of Carbapenem-Resistant From Khartoum State, Sudan.

Front Microbiol 2021 26;12:628736. Epub 2021 Feb 26.

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.

Carbapenem resistant (CRAb) is an important global pathogen contributing to increased morbidity and mortality in hospitalized patients, due to limited alternative treatment options. Nine international clonal (IC) lineages have been identified in many countries worldwide, however, data still lacks from some parts of the world, particularly in Africa. We hereby present the molecular epidemiology of MDR from four hospitals in Khartoum, Sudan, collected from 2017 to 2018. Forty-two isolates were whole-genome sequenced, and subsequent molecular epidemiology was determined by core genome MLST (cgMLST), and their resistomes identified. All isolates had an array of diverse antibiotic resistance mechanisms conferring resistance to multiple classes of antibiotics. We found a predominance (88%) of IC2 (with the intrinsic OXA-66 and acquired OXA-23), and some with NDM-1. IC2 isolates were sub-divided into 4 STs separated by 5 to 431 allelic differences, and with evidence of seven transmission clusters. Isolates belonging to IC1, IC5, and IC9 were also identified. These data illustrate that MDR IC2 are widely distributed in Khartoum hospitals and are in possession of multiple antibiotic resistance determinants.
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http://dx.doi.org/10.3389/fmicb.2021.628736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952628PMC
February 2021

Novel multiplex PCRs for detection of the most prevalent carbapenemase genes in Gram-negative bacteria within Germany.

J Med Microbiol 2021 Mar 15;70(3). Epub 2021 Jan 15.

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50923 Köln, Germany.

Gram-negative bacteria are a common source of infection both in hospitals and in the community, and antimicrobial resistance is frequent among them, making antibiotic therapy difficult, especially when these isolates carry carbapenem resistance determinants.. A simple method to detect all the commonly found carbapenemases in Germany was not available. The aim of this study was to develop a multiplex PCR for the rapid and reliable identification of the most prevalent carbapenemase-encoding genes in Gram-negative bacteria in Germany. Data from the German Gram-negative reference laboratory revealed the most prevalent carbapenemase groups in Germany were (in order of prevalence): , , , , , , , , , , IS, , and . We developed and tested two multiplex PCRs against 83 carbapenem-resistant Gram-negative clinical isolates. Primers were designed for each carbapenemase group within conserved regions of the encoding genes obtained from publicly available databases. Multiplex-1 included the carbapenemase groups , , , , and , while multiplex-2 included , , , , IS and . In the initial evaluation, all but one of the carbapenemases encoded by 75 carbapenemase-positive isolates were detected using the two multiplex PCRs, while no false-positive results were obtained from the remaining eight isolates. After evaluation, we tested 546 carbapenem-resistant isolates using the multiplex PCRs, and all carbapenemases were detected. A rapid and reliable method was developed for detection and differentiation of 12 of the most prevalent carbapenemase groups found in Germany. This method allows for the rapid testing of clinical isolates prior to species identification and does not require prior phenotypical characterization, constituting a rapid and valuable tool in the management of infections in hospitals.
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http://dx.doi.org/10.1099/jmm.0.001310DOI Listing
March 2021

Evaluation of a Phenotypic Algorithm to Direct Carbapenemase Testing in : Validation in a Multicenter German Cohort.

Microb Drug Resist 2021 Jan 8. Epub 2021 Jan 8.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.

remains a prominent nosocomial pathogen. Detection of carbapenemase-producing is vital to dictate antimicrobial therapy and infection control measures. A pragmatic, minimum inhibitory concentration-based algorithm using imipenem AND meropenem-resistant plus ceftazidime-, cefepime-, and piperacillin/tazobactam-nonsusceptible criterion was derived to guide carbapenemase testing in . This study was an assessment of the algorithm's test performance in a cohort of 985 nonduplicate isolates collected from 20 German medical laboratories. Susceptibility data were assessed in the algorithm using both Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretations. Sensitivity and specificity were calculated to evaluate algorithm test performance. The original algorithm criteria resulted in high specificity (95-97%) using both CLSI and EUCAST criteria; however, it failed to capture five carbapenemase-harboring isolates testing piperacillin/tazobactam susceptibility (CLSI/EUCAST). Two carbapenemase-producing isolates were also meropenem susceptible per EUCAST. A modified algorithm utilizing imipenem OR meropenem-resistant plus ceftazidime and cefepime nonsusceptible, improved the sensitivity of the criteria without significantly compromising specificity (CLSI sensitivity/specificity: 96%/94% and EUCAST sensitivity/specificity: 96%/95%). Application of the modified algorithm criteria resulted in high sensitivity and specificity using both CLSI and EUCAST interpretations in a large cohort of clinical . Utilization of this algorithm can improve the efficiency of carbapenemase testing in the clinical laboratory.
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http://dx.doi.org/10.1089/mdr.2020.0476DOI Listing
January 2021

Characterization of a vancomycin-resistant Enterococcus faecium isolate and a vancomycin-susceptible E. faecium isolate from the same blood culture.

J Antimicrob Chemother 2021 Mar;76(4):883-886

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.

Objectives: To characterize two Enterococcus faecium isolates with different resistance phenotypes obtained from the same blood culture.

Methods: The isolates were identified by MALDI-TOF MS and antimicrobial susceptibility testing (AST) was performed using a VITEK® 2 AST P592 card and Etest. WGS was performed on the MiSeq and MinION sequencer platforms. Core-genome MLST (cgMLST) and seven-loci MLST were performed. Plasmid analysis was performed using S1-PFGE followed by Southern-blot hybridization.

Results: Both E. faecium isolates were ST203. AST revealed that one was a vancomycin-resistant E. faecium (VREfm) isolate and the other was a vancomycin-susceptible E. faecium (VSEfm) isolate. The VREfm isolate harboured the vanA gene cluster as part of a Tn1546-type transposon encoded on a 49 kb multireplicon (rep1, rep2 and rep7a) plasmid (pAML0157.1). On the same plasmid, ant(6)-Ia, cat-like and erm(B) were encoded. The VSEfm isolate harboured a rep2 plasmid (pAML0158.1), 12 kb in size, which was present in full length as part of pAML0157.1 from the VREfm isolate. The vanA-encoding pAML0157.1 was a chimera of the rep2 pAML0158.1 and a second DNA segment harbouring vanA, ant(6)-Ia, erm(B) and cat-like, as well as the replicons rep1 and rep7a. By cgMLST analysis, the VREfm and VSEfm isolates were identical.

Conclusions: Our results demonstrate that the VREfm and VSEfm blood culture isolates represented ST203 and were identical. The investigated heterogeneous resistance phenotypes resulted from the acquisition or loss of plasmid segments in the enterococcal isolates. These data illustrate that mobile genetic elements may contribute to the spread of vancomycin resistance among enterococci and to the genotypic and phenotypic variation within clonal isolates.
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http://dx.doi.org/10.1093/jac/dkaa532DOI Listing
March 2021

Genomic Analysis of Carbapenem-Resistant Isolates Belonging to Major Endemic Clones in South America.

Front Microbiol 2020 30;11:584603. Epub 2020 Nov 30.

Universidade Federal de São Paulo (UNIFESP), Laboratório Alerta, Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina (EPM), São Paulo, Brazil.

Carbapenem-resistant (CRAB) are emerging worldwide. In South America, clinical isolates presenting such a phenotype usually do not belong to the globally distributed international clone 2 (IC2). The majority of these isolates are also resistant to multiple other antimicrobials and are often designated extremely drug-resistant (XDR). The aim of this study was to characterize the resistance mechanisms presented by 18 carbapenem-resistant isolates from five different Brazilian hospitals. Species identification was determined by sequencing, and antimicrobial susceptibility was determined by broth microdilution. Isolates were submitted to whole genome sequencing using Illumina platform and genetic similarity was determined by PFGE, MLST, and cgMLST. Genome analysis was used to identify intrinsic and acquired resistance determinants, including mutations in the AdeRSABC efflux system and in outer membrane proteins (OMPs). All isolates were identified as and grouped into 4 pulsotypes by PFGE, which belonged to clonal complexes (CC) 15 /103 ( = 4) and 79 /113 ( = 14), corresponding to IC4 and IC5, respectively. High MIC values to carbapenems, broad-spectrum cephalosporins, amikacin, and ciprofloxacin were observed in all isolates, while MICs of ampicillin/sulbactam, gentamicin, and tigecycline varied among the isolates. Minocycline was the most active antimicrobial agent tested. Moreover, 12 isolates (66.7%) were considered resistant to polymyxins. Besides intrinsic OXA-51 and ADC variants, all isolates harbored an acquired carbapenem-hydrolyzing class D β-lactamase (CHDL) encoding gene, either or . A diversity of aminoglycoside modifying enzymes and resistance determinants to other antimicrobial classes were found, as well as mutations in and . Non-synonymous mutations have also been identified in the AdeRSABC efflux system and in most OMPs, but they were considered natural polymorphisms. Moreover, resistance to polymyxins among isolates belonging to IC5 were associated to non-synonymous mutations in , but no known polymyxin resistance mechanism was identified in isolates belonging to IC4. In conclusion, clinical isolates belonging to South America's major clones present a myriad of antimicrobial resistance determinants. Special attention should be paid to natural polymorphisms observed in each clonal lineage, especially regarding non-synonymous mutations in constitutive genes associated with distinct resistance phenotypes.
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http://dx.doi.org/10.3389/fmicb.2020.584603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734285PMC
November 2020

First Report of New Delhi Metallo--Lactamase-6 (NDM-6) in a Clinical Isolate From Northern Spain.

Front Microbiol 2020 10;11:589253. Epub 2020 Nov 10.

Department of Immunology, Microbiology, and Parasitology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Bilbao, Spain.

The objective of this study was the phenotypic and genotypic characterization of a carbapenem resistant (CRAB) isolate. The isolate, recovered in Northern Spain in 2019, was identified by MALDI-TOF to the species level. Antimicrobial susceptibility testing was performed using the Phoenix BD NMIC-502 Panel, E-test, and broth microdilution methods. The presence of a metallo--lactamase (MBL) was verified by PCR and immunochromatographic assays. The genetic location of the MBL was confirmed using S1-pulsed-field gel electrophoresis (S1-PFGE) followed by Southern blot hybridization. Whole genome sequencing (WGS) was completed using the Miseq and MinION platforms, followed by core-genome MLST (cgMLST) and seven-locus MLST analysis. The CRAB was assigned ST85 (Pasteur scheme) and ST957 (Oxford scheme) representing international clone (IC) 9 and harbored the intrinsic -lactamase OXA-94 with IS upstream of it, and the MBL . Hybridization experiments revealed that the was encoded on the chromosome. Using WGS the environment could be identified arranged in the following order: IS, , IS, , , , , , and IS. Downstream, a 10,462 bp duplication was identified, including a second copy of in the following genetic composition: IS, , , , , , and IS. To our knowledge, this is the first description of in . The MBL was present in two copies in the chromosome in a new genetic environment associated with IS elements highlighting the contribution of mobile genetic elements in the dissemination of this gene.
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http://dx.doi.org/10.3389/fmicb.2020.589253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683408PMC
November 2020

Epidemiological situation, laboratory capacity and preparedness for carbapenem-resistant in Europe, 2019.

Euro Surveill 2020 11;25(45)

The EURGen-Net carbapenem-resistant Acinetobacter baumannii capacity survey group members are listed below.

To update information on the epidemiological situation and national capacity for detection, surveillance and containment of carbapenem-resistant (CRAb) in Europe, we performed a survey in 37 countries. Nine countries reported regional or inter-regional spread and seven an endemic situation. Laboratories with a reference function, surveillance systems, and a national containment plan for CRAb existed in 30, 23 and eight countries, respectively. A pan-European molecular survey would provide in-depth understanding of the CRAb epidemiology.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.45.2001735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667627PMC
November 2020

Antibiotic Resistance and Mobile Genetic Elements in Extensively Drug-Resistant Sequence Type 147 Recovered from Germany.

Antibiotics (Basel) 2020 Oct 5;9(10). Epub 2020 Oct 5.

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50935 Cologne, Germany.

Mobile genetic elements (MGEs), especially multidrug-resistance plasmids, are major vehicles for the dissemination of antimicrobial resistance determinants. Herein, we analyse the MGEs in three extensively drug-resistant (XDR) isolates from Germany. Whole genome sequencing (WGS) is performed using Illumina and MinION platforms followed by core-genome multi-locus sequence typing (MLST). The plasmid content is analysed by conjugation, S1-pulsed-field gel electrophoresis (S1-PFGE) and Southern blot experiments. The isolates belong to the international high-risk clone ST147 and form a cluster of closely related isolates. They harbour the carbapenemase on a ColKP3 plasmid, and 12 antibiotic resistance determinants on an multidrug-resistant (MDR) IncR plasmid with a recombinogenic nature and encoding a large number of insertion elements. The IncR plasmids within the three isolates share a high degree of homology, but present also genetic variations, such as inversion or deletion of genetic regions in close proximity to MGEs. In addition, six plasmids not harbouring any antibiotic resistance determinants are present in each isolate. Our study indicates that genetic variations can be observed within a cluster of closely related isolates, due to the dynamic nature of MGEs. The mobilome of the isolates combined with the emergence of the XDR ST147 high-risk clone have the potential to become a major challenge for global healthcare.
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http://dx.doi.org/10.3390/antibiotics9100675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600919PMC
October 2020

A quality improvement study on the reduction of central venous catheter-associated bloodstream infections by use of self-disinfecting venous access caps (STERILE).

Am J Infect Control 2021 05 21;49(5):586-592. Epub 2020 Sep 21.

University of Cologne, Department I of Internal Medicine, Center for Integrated Oncology, Aachen, Bonn, Cologne, Düsseldorf, Germany; Department of Internal Medicine II, Infectious Diseases, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany; German Centre for Infection Research (DZIF), Bonn, Cologne, Germany.

Background: Contamination of the catheter hub is an important source of central line-associated bloodstream infections (CLABSI); catheter hub caps incorporating a 70% isopropyl alcohol aim are designed to reduce contamination and hence CLABSI rates. Supporting data in high-risk hematological and oncological patients on the clinical effectiveness of this approach are sparse.

Methods: We conducted a before-after single center study accompanying the introduction of such caps at our department. Retrospective data from the year prior to the introduction were compared to 1 year of prospective data.

Results: The control and antiseptic barrier cap (ABC) groups consisted of 309 and 289 patients presenting a CLABSI rate of 15.28 and 10.38 per 1,000 catheter days (P= .042), respectively. However, after multivariate analysis, ABCs were not identified as a statistically significant independent protective factor for the occurrence of CLABSI (hazard ratio 0.69, P= .120). There was no significant difference between the groups with respect to time to CLABSI (P= .681), nor the proportion of catheters removed due to suspicion of infection (P= .076).

Conclusions: The introduction of ABCs in this high-risk population did not significantly alter CLABSI rates.
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http://dx.doi.org/10.1016/j.ajic.2020.09.002DOI Listing
May 2021

Attributable mortality of candidemia after introduction of echinocandins.

Mycoses 2020 Dec 27;63(12):1373-1381. Epub 2020 Sep 27.

Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Excellence Center for Medical Mycology (ECMM), University of Cologne, Cologne, Germany.

Objectives: Candidemia is among the most frequent nosocomial bloodstream infections. Landmark case-control studies on amphotericin B and fluconazole estimated attributable mortality rates of 38% and 49%, respectively. After introduction of echinocandins, these may have decreased.

Methods: In a case-control design, 100 consecutive, hospitalised patients with candidemia were enrolled at the University Hospital of Cologne, Germany between 2014 and 2017. Controls were patients without candidemia matched for age, sex, year and duration of hospitalisation, main admission diagnosis and Patient Clinical Complexity Level (PCCL). Main data captured were risk factors for candidemia, attributable mortality rates and diagnostic and therapeutic adherence according to the EQUAL Candida score.

Results: Overall mortality rates for cases and controls were 43% and 17% (P < .001), respectively; day 30 mortality rates were 38% and 11% (P = .03), accounting for an attributable mortality of 26% and 27%. Guideline adherence was higher in surviving vs non-surviving patients: while survivors reached a median of 17 (IQR: 16-19) points, non-surviving cases reached a median 16 (IQR: 14-18) points out of 22 maximum achievable points (P = .028). Risk factors for candidemia were more frequent in cases compared to control patients, especially chronic pulmonary disease (25% vs 16%; P = n.s.), chronic liver disease (21% vs 6%; P = .002), stay on intensive care unit (70% vs 64%; P = n.s.), respiratory failure (56% vs 50%; P = n.s.) and central venous catheter (97% vs 35%; P < .001).

Conclusions: Attributable mortality of nosocomial candidemia is still substantial but has decreased compared to previous studies with similar design.
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http://dx.doi.org/10.1111/myc.13177DOI Listing
December 2020

Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study.

Lancet Infect Dis 2020 12 4;20(12):1409-1417. Epub 2020 Aug 4.

Service of Infectious Diseases, Hospital Clínic of Barcelona, Barcelona, Spain. Electronic address:

Background: Staphylococcus aureus persistent bacteraemia is only vaguely defined and the effect of different durations of bacteraemia on mortality is not well established. Our primary aim was to analyse mortality according to duration of bacteraemia and to derive a clinically relevant definition for persistent bacteraemia.

Methods: We did a secondary analysis of a prospective observational cohort study at 17 European centres (nine in the UK, six in Spain, and two in Germany), with recruitment between Jan 1, 2013, and April 30, 2015. Adult patients who were consecutively hospitalised with monomicrobial S aureus bacteraemia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood-culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture. The primary outcome was 90-day mortality. Univariable and time-dependent multivariable Cox regression analysis were used to assess predictors of mortality. Duration of bacteraemia was defined as bacteraemic days under active antibiotic therapy counting the first day as day 1.

Findings: Of 1588 individuals assessed for eligibility, 987 were included (median age 65 years [IQR 51-75]; 625 [63%] male). Death within 90 days occurred in 273 (28%) patients. Patients with more than 1 day of bacteraemia (315 [32%]) had higher Charlson comorbidity index and sequential organ failure assessment scores and a longer interval from first symptom to first blood culture. Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteraemia, to 39% (85 of 218) with 2-4 days, 43% (30 of 69) with 5-7 days, and 36% (10 of 28) with more than 7 days of bacteraemia. Metastatic infections developed in 39 (6%) of 672 patients with 1 day of bacteraemia versus 40 (13%) of 315 patients if bacteraemia lasted for at least 2 days. The second day of bacteraemia had the highest HR and earliest cutoff significantly associated with mortality (adjusted hazard ratio 1·93, 95% CI 1·51-2·46; p<0·0001).

Interpretation: We suggest redefining the cutoff duration for persistent bacteraemia as 2 days or more despite active antibiotic therapy. Our results favour follow-up blood cultures after 24 h for early identification of all patients with increased risk of death and metastatic infection.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(20)30447-3DOI Listing
December 2020

In vitro activity of cefiderocol against aerobic Gram-negative bacterial pathogens from Germany.

Int J Antimicrob Agents 2020 Oct 3;56(4):106128. Epub 2020 Aug 3.

Robert Koch Institute, Department of Infectious Diseases, FG13 Nosocomial Pathogens and Antibiotic Resistances, Wernigerode, Germany.

Objectives: Cefiderocol (CID), also known as S-649266, a novel siderophore cephalosporin, possesses potent activity against multidrug-resistant aerobic Gram-negative bacteria (GNB). This study aimed to determine the in vitro activity of CID against two different sets of GNB: i) a random sample of 213 clinical isolates, including 17 extended-spectrum beta-lactamase (ESBL) producers, obtained from intensive care unit patients with nosocomial infections collected during a multicentre surveillance study (set I); and ii) a group of 59 challenge GNB producing various types of carbapenemases (CP; set II).

Methods: Minimum inhibitory concentrations (MICs) were determined using the microdilution method according to the standard ISO 20776-1. Iron-depleted medium was used for testing CID.

Results: CID inhibited 97.2% of set I isolates at the EUCAST susceptibility breakpoint of ≤ 2 mg/L. The concentrations of CID inhibiting 50% and 90% (MIC) of the Enterobacterales isolates (n = 146) were 0.12/1.0 mg/L, with ESBL-positive isolates tending to exhibit higher MICs than ESBL-negative isolates to CID. MIC values of CID for isolates of the Acinetobacter baumannii group (n = 13) and Pseudomonas aeruginosa (n = 54) were 0.06/0.12 mg/L and 0.12/0.5 mg/L, respectively. Further, CID inhibited 88.1% of set II CP-producing isolates at ≤ 2 mg/L. All seven class D CP-producing Acinetobacter baumannii were inhibited at ≤ 0.25 mg/L. MIC values for CP-producing Enterobacterales (n = 30) and Pseudomonas aeruginosa (n = 22) were 1/4 mg/L and 0.5/2 mg/L, respectively.

Conclusion: CID showed potent activity against Acinetobacter baumannii, Enterobacterales and Pseudomonas aeruginosa, including CP-producing isolates. Overall, CID inhibited 259 of 272 (95.2%) GNB at ≤ 2 mg/L.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106128DOI Listing
October 2020

Vancomycin-resistant Enterococcus faecium colonizing patients on hospital admission in Germany: prevalence and molecular epidemiology.

J Antimicrob Chemother 2020 10;75(10):2743-2751

German Centre for Infection Research (DZIF), Braunschweig, Germany.

Objectives: To analyse the rectal carriage rate and the molecular epidemiology of vancomycin-resistant Enterococcus faecium (VREfm) recovered from patients upon hospital admission.

Methods: Adult patients were screened at six German university hospitals from five different federal states upon hospital admission for rectal colonization with VREfm between 2014 and 2018. Molecular characterization of VREfm was performed by WGS followed by MLST and core-genome MLST analysis.

Results: Of 16350 patients recruited, 263 were colonized with VREfm, with increasing prevalence rates during the 5 year study period (from 0.8% to 2.6%). In total, 78.5% of the VREfm were vanB positive and 20.2% vanA positive, while 1.2% harboured both vanA and vanB. The predominant ST was ST117 (56.7%) followed by ST80 (15%), ST203 (10.9%), ST78 (5.7%) and ST17 (3.2%). ST117/vanB VREfm isolates formed a large cluster of 96 closely related isolates extending across all six study centres and four smaller clusters comprising 13, 5, 4 and 3 isolates each. In contrast, among the other STs inter-regional clonal relatedness was rarely observed.

Conclusions: To our knowledge, this is the largest admission prevalence and molecular epidemiology study of VREfm. These data provide insight into the epidemiology of VREfm at six German university hospitals and demonstrate the remarkable inter-regional clonal expansion of the ST117/vanB VREfm clone.
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http://dx.doi.org/10.1093/jac/dkaa271DOI Listing
October 2020

In vitro activity of ceftazidime-avibactam against Gram-negative isolates collected in 18 European countries, 2015-2017.

Int J Antimicrob Agents 2020 Sep 6;56(3):106045. Epub 2020 Jun 6.

Division of Clinical Microbiology, Department of Laboratory Medicine Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Background: Between 2015-2017, 21 850 Enterobacterales isolates and 6156 Pseudomonas aeruginosa (P. aeruginosa) isolates were collected by 77 centers in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) study (which was included into the Antimicrobial Testing Leadership and Surveillance [ATLAS] study in 2018).

Methods: A central reference laboratory performed antimicrobial susceptibility testing using broth microdilution panels according to Clinical and Laboratory Standards Institute guidelines. The presence of β-lactamases was confirmed using multiplex PCR assays.

Results: Among Enterobacterales isolates, the highest rates of susceptibility were to ceftazidime-avibactam (99.0%; MIC 0.5 mg/L), meropenem (96.3%), amikacin (95.2%), and imipenem (92.8%). All Enterobacterales organisms were highly susceptible to colistin (≥ 94.6%), apart from Proteus mirabilis, which is intrinsically resistant to colistin. Susceptibility rates among ceftazidime-resistant isolates were 95.7% for ceftazidime-avibactam and 87.9% for colistin, and 78.5% and 71.1%, respectively, among carbapenemase-positive isolates. Colistin was the only agent with activity against metallo-β-lactamases (100% susceptibility) among Enterobacterales and P. aeruginosa isolates. Overall susceptibility rates among P. aeruginosa were highest to colistin (99.5%) and ceftazidime-avibactam (92.3%), and were similar to ceftazidime-resistant isolates for colistin (98.9%) and reduced to 66.2% for ceftazidime-avibactam. Susceptibility rates among multidrug-resistant P. aeruginosa isolates were 98.9% to colistin and 71.7% to ceftazidime-avibactam.

Conclusions: Clinical isolates of Enterobacterales and P. aeruginosa collected from Europe, between 2015-2017, were highly susceptible to ceftazidime-avibactam, suggesting it is a useful alternative agent for patients whose treatment options may be limited. Persistent antimicrobial resistance requires continued surveillance and monitoring.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106045DOI Listing
September 2020

In vitro activity of sulbactam/durlobactam against global isolates of carbapenem-resistant Acinetobacter baumannii.

J Antimicrob Chemother 2020 09;75(9):2616-2621

Antiinfectives Intelligence GmbH, Rheinbach, Germany.

Objectives: To evaluate the activity of the novel broad-spectrum serine β-lactamase inhibitor durlobactam (ETX2514) combined with sulbactam against global isolates of carbapenem-resistant Acinetobacter baumannii with defined carbapenem resistance mechanisms compared with reference antimicrobials with known activity against Acinetobacter spp.

Methods: The susceptibility of 246 carbapenem-resistant non-duplicate A. baumannii isolates to sulbactam/durlobactam, amikacin, colistin, imipenem/sulbactam/durlobactam, imipenem, meropenem, minocycline and sulbactam was tested using broth microdilution. Isolates were obtained from various body sites from patients in 37 countries and from six world regions between 2012 and 2016. Identification of carbapenem resistance mechanisms and assignment to A. baumannii clonal lineages was based on WGS.

Results: Sulbactam/durlobactam showed excellent activity comparable to colistin but superior to amikacin, minocycline and sulbactam. The sulbactam/durlobactam MIC50/90 values were 1/4 and 2/4 mg/L and the colistin MIC50/90 values were 0.5 and 1 mg/L, respectively. Comparatively, amikacin, minocycline and sulbactam MIC50/90 values were 256/≥512, 2/16 and 16/64 mg/L, respectively.

Conclusions: Sulbactam/durlobactam had excellent in vitro potency against A. baumannii isolates, including those that were resistant to imipenem/meropenem, amikacin, minocycline and colistin, compared with other compounds. Sulbactam/durlobactam has the potential to become a useful addition to the limited armamentarium of drugs that can be used to treat this problem pathogen.
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http://dx.doi.org/10.1093/jac/dkaa208DOI Listing
September 2020

Mobile Genetic Elements Harboring Antibiotic Resistance Determinants in Isolates From Bolivia.

Front Microbiol 2020 13;11:919. Epub 2020 May 13.

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.

Using a combination of short- and long-read DNA sequencing, we have investigated the location of antibiotic resistance genes and characterized mobile genetic elements (MGEs) in three clinical multi-drug resistant . The isolates, collected in Bolivia, clustered separately with three different international clonal lineages. We found a diverse array of transposons, plasmids and resistance islands related to different insertion sequence (IS) elements, which were located in both the chromosome and in plasmids, which conferred resistance to multiple antimicrobials, including carbapenems. Carbapenem resistance might be caused by a carrying the gene. Some plasmids were shared between the isolates. Larger plasmids were less conserved than smaller ones and they shared some homologous regions, while others were more diverse, suggesting that these big plasmids are more plastic than the smaller ones. The genetic basis of antimicrobial resistance in Bolivia has not been deeply studied until now, and the mobilome of these isolates, combined with their multi-drug resistant phenotype, mirror the transfer and prevalence of MGEs contributing to the spread of antibiotic resistance worldwide and require special attention. These findings could be useful to understand the antimicrobial resistance genetics of in Bolivia and the difficulty in tackling these infections.
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http://dx.doi.org/10.3389/fmicb.2020.00919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237729PMC
May 2020

Vertebral Osteomyelitis After Spine Surgery: A Disease With Distinct Characteristics.

Spine (Phila Pa 1976) 2020 Oct;45(20):1426-1434

Department 1 for Internal Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.

Study Design: Prospective cohort study.

Objective: We aimed to determine the 2-year survival and to identify clinical and microbiological characteristics of patients with native vertebral osteomyelitis (VO) as compared to postoperative VO to find further strategies for improvement of the management of VO.

Summary Of Background Data: A relevant subgroup (20%-30%) of patients with VO has a history of spine surgery. Infection in these patients might be clinically different from native VO. However, clinical, microbiological, and outcome characteristics of this disease entity have not been well studied as most trials either excluded these patients or are limited by a small cohort and short observation period.

Methods: Between 2008 and 2013, patients who presented at a tertiary care center with symptoms and imaging findings suggestive of VO were reviewed by specialists in infectious diseases, clinical microbiology, and orthopedics to confirm the diagnosis and followed prospectively for a period of 2 years. Statistical analysis for group comparisons, survival analysis, and uni- and multivariable Cox regression models were performed.

Results: Thirty percent of the patients with VO (56/189) reported a history of spine surgery in the same segment. Patients with postoperative infection had a lower ASA score (American Society of Anesthesiologists) (P = 0.01) and were less likely to suffer from comorbidities compared to native cases (P = 0.003). Infections caused by coagulase-negative staphylococci (33.3 vs. 6.5%, P < 0.001) and other bacteria of the skin flora (15.2 vs. 0%, P = 0.002) were more prevalent in postoperative patients. Suffering from native VO increased the 2-year mortality risk 3-fold, also when adjusted for the remaining risk factors ASA score and number of comorbidities (hazard ratio 2.916 [95% confidence interval 1.215 -6.999], P = 0.017).

Conclusion: Beside clear microbiological differences, the significant better 2-year survival supports the concept of postoperative VO presenting a distinct disease entity. The subtle disease presentation of patients with postoperative VO should not attenuate clinical suspicion of physicians.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000003542DOI Listing
October 2020

Combination therapy with rifampicin or fosfomycin in patients with Staphylococcus aureus bloodstream infection at high risk for complications or relapse: results of a large prospective observational cohort.

J Antimicrob Chemother 2020 08;75(8):2282-2290

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50937 Cologne, Germany.

Objectives: To investigate whether Staphylococcus aureus bloodstream infection (SAB) patients at high risk for complications or relapse benefit from combination therapy with adjunctive rifampicin or fosfomycin.

Methods: In this post hoc analysis, SAB patients with native valve infective endocarditis, osteoarticular infections or implanted foreign devices were included. The co-primary endpoints were all-cause 90 day mortality and death or SAB-related late complications within 180 days. To overcome treatment selection bias and account for its time dependence, inverse probability of treatment weights were calculated and included in marginal structural Cox proportional hazard models (MSCMs).

Results: A total of 578 patients were included in the analysis, of which 313 (54%) received combination therapy with either rifampicin (n = 242) or fosfomycin (n = 58). In the multivariable MSCM, combination therapy was associated with a better outcome, that is, a lower rate of death or SAB-related late complications within 180 days (HR 0.65, 95% CI 0.46-0.92). This beneficial effect was primarily seen in patients with implanted foreign devices, in which combination therapy was associated with a lower rate of death or SAB-related late complications within 180 days (HR 0.53, 95% CI 0.35-0.79) and a lower 90 day mortality (HR 0.57, 95% CI 0.36-0.91). Upon agent-specific stratification, we found no significant differences in outcomes between combination therapy containing rifampicin and fosfomycin; however, the number of patients in most subgroups was not large enough to draw firm conclusions.

Conclusions: In patients with implanted foreign devices, combination therapy was associated with a better long-term outcome. Larger prospective studies are needed to validate these findings.
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http://dx.doi.org/10.1093/jac/dkaa144DOI Listing
August 2020

Dissemination of carbapenem-resistant Pseudomonas aeruginosa isolates and their susceptibilities to ceftolozane-tazobactam in Germany.

Int J Antimicrob Agents 2020 Jun 20;55(6):105959. Epub 2020 Apr 20.

Institute for Medical Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany; German Centre for Infection Research, Cologne, Germany.

Pseudomonas aeruginosa (PA) is a major cause of healthcare-associated infections. Antipseudomonal carbapenems are among the antimicrobial agents used to treat PA infections, but several mechanisms of resistance, including the production of a carbapenemase (CP), may compromise their clinical efficacy. The objectives of this study were to determine: (i) the dissemination of carbapenem-resistant CP-negative and CP-positive PA isolates; and (ii) the in-vitro activity of ceftolozane-tazobactam (CTT) against carbapenem-susceptible and carbapenem-resistant isolates. Isolates were collected prospectively from January 2016 to April 2017 at 20 German medical laboratories. Each centre was asked to provide 50 consecutive isolates from hospitalized patients. Overall, 985 isolates were collected, of which 34% were obtained from intensive care patients. Seven hundred and thirty-eight (74.9%) isolates were susceptible to both imipenem and meropenem (Subgroup I), and 247 (25.1%) isolates were resistant to carbapenems (Subgroup II): 125 (12.7%) were imipenem-resistant but meropenem-susceptible, 12 (1.2%) were meropenem-resistant but imipenem-susceptible, and 110 (11.2%) were resistant to both carbapenems (Subgroup III). A CP was detected in 28 (2.8%) isolates (predominantly VIM-2). Nine hundred and fifty (96.4%) isolates were CTT-susceptible. Susceptibility to CTT was seen in 99.6% of Subgroup I isolates, 87% of Subgroup II isolates and 74.5% of Subgroup III isolates. Overall, 2.8% of PA produced a CP, while 22.2% were carbapenem-resistant, CP-non-producing isolates. Based on these findings, CTT may be considered for treatment of PA infections, particularly those caused by multi-drug-resistant CP-non-producing isolates.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.105959DOI Listing
June 2020

Prevalence of third-generation cephalosporin-resistant Enterobacterales colonization on hospital admission and ESBL genotype-specific risk factors: a cross-sectional study in six German university hospitals.

J Antimicrob Chemother 2020 06;75(6):1631-1638

German Centre for Infection Research Association (DZIF), Braunschweig Germany.

Objectives: To assess the admission prevalence of third-generation cephalosporin-resistant Enterobacterales (3GCREB) and to assess whether risk factors vary by β-lactamase genotype.

Methods: Adult patients were recruited within 72 h of admission to general wards of six university hospitals in 2014 and 2015. Rectal swabs were screened for 3GCREB and isolates were analysed phenotypically and genotypically. Patients were questioned on potential risk factors. Multivariable analyses were performed to identify risk factors for 3GCREB colonization and for specific β-lactamases.

Results: Of 8753 patients screened, 828 were 3GCREB positive (9.5%). Eight hundred and thirteen isolates were available for genotyping. CTX-M-15 was the most common ESBL (38.0%), followed by CTX-M-1 (22.5%), CTX-M-14 (8.7%), CTX-M-27 (7.5%) and SHV-ESBL (4.4%). AmpC was found in 11.9%. Interestingly, 18 Escherichia coli isolates were AmpC positive, 12 of which (67%) contained AmpC on a gene of plasmid origin [CMY (n = 10), DHA (n = 2)]. Risk factors for 3GCREB colonization varied by genotype. Recent antibiotic exposure and prior colonization by antibiotic-resistant bacteria were risk factors for all β-lactamases except CTX-M-14 and CTX-M-27. Travel outside Europe was a risk factor for CTX-M-15 and CTX-M-27 [adjusted OR (aOR) 3.49, 95% CI 2.88-4.24 and aOR 2.73, 95% CI 1.68-4.43]. A previous stay in a long-term care facility was associated with CTX-M-14 (aOR 3.01, 95% CI 1.98-4.59). A preceding hospital stay in Germany increased the risk of CTX-M-15 (aOR 1.27, 95% CI 1.14-1.41), while a prior hospital stay in other European countries increased the risk of SHV-ESBL colonization (aOR 3.85, 95% CI 1.67-8.92).

Conclusions: The detection of different ESBL types is associated with specific risk factor sets that might represent distinct sources of colonization and ESBL-specific dissemination routes.
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http://dx.doi.org/10.1093/jac/dkaa052DOI Listing
June 2020

causing nosocomial transmission among neonates - an emerging pathogen?

J Med Microbiol 2020 Mar;69(3):396-401

German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Germany.

Transmission of Enterobacterales in neonatal intensive care units (NICU) can cause outbreaks of colonization and invasive infections among neonates. Two clusters of nosocomial transmission of identified by MALDI-ToF mass-spectrometry were suspected at two NICUs in July and August 2016. To assess the potential transmission of among neonates. Whole-genome sequencing (WGS) was performed of isolates obtained through targeted surveillance of patients and environmental sampling. WGS data revealed that patient and environmental isolates represented two species, and . Core-genome multi-locus sequence typing (cgMLST) of the isolates identified three separate transmission clusters, in Hospital A a cluster of isolates in 12 children and two environmental samples and a second cluster of isolates in five children. In Hospital B a cluster of isolates from three children and five unrelated isolates of and two unrelated isolates of were found. can cause hospital outbreaks of colonization and infection similar to other spp.Preliminary results from this study were presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases, April 22-25, 2018, Vienna, Austria.
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http://dx.doi.org/10.1099/jmm.0.001143DOI Listing
March 2020

Protocol update for the SABATO trial: a randomized controlled trial to assess early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection.

Trials 2020 Feb 12;21(1):175. Epub 2020 Feb 12.

German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany.

Background: SABATO (Staphylococcus aureus bacteremia antibiotic treatment options) is a randomized, parallel-group, clinical non-inferiority trial designed to examine the efficacy and safety of early oral switch therapy in low-risk Staphylococcus aureus infection. The original trial protocol was published in Trials (accessible at https://doi.org/10.1186/s13063-015-0973-x ). Here we describe final amendments to the study protocol and discuss the underlying rationale.

Methods/design: Three major changes were introduced into the study protocol: (1) the inclusion and exclusion criteria were refined so that patients with certain comorbidities (end-stage renal disease, severe liver disease) and uninfected foreign bodies (orthopedic prosthesis, pacemaker, implanted cardiac cardioverter-defibrillator) became eligible for enrollment under certain conditions; (2) the target sample size was decreased by choosing a conventional non-inferiority margin of 10% and converting the interim analysis (215 patients) into the final analysis; and (3) an additional follow-up visit after 30 days was introduced to allow for a closer follow-up of patients.

Conclusion: Changes to the study protocol were introduced to improve the enrollment and follow-up of patients. Furthermore, the decrease of the sample size will facilitate completion of the trial.

Trial Registration: ClinicalTrials.gov, NCT01792804. Registered on 13 February 2013. German Clinical trials register, DRKS00004741. Registered on 4 October 2013, EudraCT 2013-000577-77.
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http://dx.doi.org/10.1186/s13063-020-4102-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017556PMC
February 2020

Ceftobiprole versus daptomycin in bacteremia: a novel protocol for a double-blind, Phase III trial.

Future Microbiol 2020 01 10;15:35-48. Epub 2020 Jan 10.

Department of Medicine, Duke University Medical Center & Duke Clinical Research Institute, Durham, NC, USA.

Although is a common cause of bacteremia, treatment options are limited. The need for new therapies is particularly urgent for methicillin-resistant bacteremia (SAB). Ceftobiprole is an advanced-generation, broad-spectrum cephalosporin with activity against both methicillin-susceptible and -resistant . This is a Phase III, randomized, double-blind, active-controlled, parallel-group, multicenter, two-part study to establish the efficacy and safety of ceftobiprole compared with daptomycin in the treatment of SAB, including infective endocarditis. Anticipated enrollment is 390 hospitalized adult patients, aged ≥18 years, with confirmed or suspected complicated SAB. The primary end point is overall success rate. Target completion of the study is in the second half of 2021. Clinicaltrials.gov identifier: NCT03138733.
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http://dx.doi.org/10.2217/fmb-2019-0332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046132PMC
January 2020

Diversity of amino acid substitutions in PmrCAB associated with colistin resistance in clinical isolates of Acinetobacter baumannii.

Int J Antimicrob Agents 2020 Mar 16;55(3):105862. Epub 2019 Dec 16.

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstraße 19-21, 50935 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Germany. Electronic address:

This study aimed to investigate the mechanisms of colistin resistance in 64 Acinetobacter baumannii isolates obtained from patients with ventilator-associated pneumonia hospitalised in Greece, Italy and Spain. In total, 31 A. baumannii isolates were colistin-resistant. Several novel amino acid substitutions in PmrCAB were found in 27 colistin-resistant A. baumannii. Most substitutions were detected in PmrB, indicating the importance of the histidine kinase for colistin resistance. In two colistin-resistant isolates, 93 amino acid changes were observed in PmrCAB compared with A. baumannii ACICU, and homologous recombination across different clonal lineages was suggested. Analysis of gene expression revealed increased pmrC expression in isolates harbouring pmrCAB mutations. Complementation of A. baumannii ATCC 19606 and ATCC 17978 with a pmrAB variant revealed increased pmrC expression but unchanged colistin MICs, indicating additional unknown factors associated with colistin resistance. Moreover, a combination of PmrB and PmrC alterations was associated with very high colistin MICs, suggesting accumulation of mutations as the mechanism for high-level resistance. The pmrC homologue eptA was detected in 29 colistin-susceptible and 26 colistin-resistant isolates. ISAba1 was found upstream of eptA in eight colistin-susceptible and one colistin-resistant isolate and eptA was disrupted by ISAba125 in two colistin-resistant isolates. Whilst in most isolates an association of eptA with colistin resistance was excluded, in one isolate an amino acid substitution in EptA (R127L) combined with a point mutation in ISAba1 upstream of eptA contributed to elevated colistin MICs. This study helps to gain an insight into the diversity and complexity of colistin resistance in A. baumannii.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.105862DOI Listing
March 2020

and Virulence Potential of the Emergent Species of the (Ab) Group.

Front Microbiol 2019 24;10:2429. Epub 2019 Oct 24.

ISGlobal, Hospital Clínic - University of Barcelona, Barcelona, Spain.

The increased use of molecular identification methods and mass spectrometry has revealed that spp. of the (Ab) group other than are increasingly being recovered from human samples and may pose a health challenge if neglected. In this study 76 isolates of 5 species within the Ab group ( = 16, = 12, = 16, = 20, and = 12), were compared in terms of antimicrobial susceptibility, carriage of intrinsic resistance genes, biofilm formation, and the ability to kill in an infection assay. In agreement with previous studies, antimicrobial resistance was common among while all other species were generally more susceptible. Carriage of genes encoding different efflux pumps was frequent in all species and the presence of intrinsic class D β-lactamases was reported in , (heterotypic synonym of ) and but not in and . and presented weaker pathogenicity in our and models than , and, especially, . Isolates from the former species showed decreased biofilm formation and required a longer time to kill nematodes. These results suggest relevant differences in terms of antibiotic susceptibility patterns among the members of the Ab group as well as highlight a higher pathogenicity potential for the emerging species of the group in this particular model. Nevertheless, the impact of such potential in the human host still remains to be determined.
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http://dx.doi.org/10.3389/fmicb.2019.02429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821683PMC
October 2019

In vitro activity of the novel fluorocycline TP-6076 against carbapenem-resistant Acinetobacter baumannii.

Int J Antimicrob Agents 2020 Jan 16;55(1):105829. Epub 2019 Dec 16.

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Germany.

The activity of the novel, fully synthetic fluorocycline antibiotic TP-6076 against carbapenem-resistant Acinetobacter baumannii (CRAB) isolates with defined carbapenem resistance mechanisms was compared against reference antimicrobials with known activity against Acinetobacter spp. The susceptibility of 323 non-duplicate CRAB isolates to TP-6076, amikacin, ampicillin/sulbactam (SAM), cefepime, colistin, doxycycline, eravacycline, imipenem, levofloxacin, meropenem, minocycline, rifampicin, sulbactam, tigecycline, tobramycin and trimethoprim/sulfamethoxazole (SXT) was determined by the broth microdilution method. TP-6076 showed greater activity than comparator antimicrobials of the tetracycline class, SAM, levofloxacin, amikacin, tobramycin, SXT and colistin. MIC and MIC values for TP-6076 were 0.06 mg/L and 0.25 mg/L, respectively. In comparison, doxycycline, eravacycline, minocycline and tigecycline MIC values were 32/≥64, 0.5/1, 4/8 and 1/2 mg/L, respectively. Compared with other compounds, TP-6076 was the most active antimicrobial against CRAB, including isolates that were resistant to other anti-Acinetobacter reference drugs including SAM, colistin, the aminoglycosides amikacin and tobramycin, and levofloxacin. TP-6076 is a promising new agent that may be a useful addition to the limited armamentarium of drugs targeting this problematic pathogen.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.10.010DOI Listing
January 2020

Genetic Features of Antarctic Strain A154 Harboring Multiple Antibiotic-Resistance Genes.

Front Cell Infect Microbiol 2019 13;9:328. Epub 2019 Sep 13.

Laboratorio de Investigación en Agentes Antibacterianos (LIAA), Departamento de Microbiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.

While antibiotic-resistant bacteria have been detected in extreme environments, including Antarctica, to date there are no reports of species isolated from this region. Here, we characterized by whole-genome sequencing (WGS) the genetic content of a single antibiotic-resistant spp. isolate (A154) collected in Antarctica. The isolate was recovered in 2013 from soil samples at Fildes Peninsula, Antarctica, and was identified by detection of the intrinsic OXA-23 gene, and confirmed by Tetra Correlation Search (TCS) and WGS. The antibiotic susceptibility profile was determined by disc diffusion, E-test, and broth microdilution methods. From WGS data, the acquired resistome and insertion sequence (IS) content were identified by analyses. Plasmids were studied by the alkaline lysis method followed by pulsed-field gel electrophoresis and conventional PCR. The A154 isolate was identified as by WGS analysis and displayed >99.9 of similarity by TCS in relation with the databases. Moreover, it was resistant to ampicillin, ceftriaxone, ceftazidime, cefepime, cefotaxime, streptomycin, and kanamycin. Likewise, in addition to the intrinsic gene, A154 harbored the plasmid-encoded antibiotic-resistance genes , ', and , as well as a large diversity of ISs. This is the first report of antibiotic-resistant in Antarctica. Our findings show the presence of several resistance genes which could be either intrinsic or acquired in the region.
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http://dx.doi.org/10.3389/fcimb.2019.00328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755334PMC
June 2020

Distinct impact of antibiotics on the gut microbiome and resistome: a longitudinal multicenter cohort study.

BMC Biol 2019 09 18;17(1):76. Epub 2019 Sep 18.

Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.

Background: The selection pressure exercised by antibiotic drugs is an important consideration for the wise stewardship of antimicrobial treatment programs. Treatment decisions are currently based on crude assumptions, and there is an urgent need to develop a more quantitative knowledge base that can enable predictions of the impact of individual antibiotics on the human gut microbiome and resistome.

Results: Using shotgun metagenomics, we quantified changes in the gut microbiome in two cohorts of hematological patients receiving prophylactic antibiotics; one cohort was treated with ciprofloxacin in a hospital in Tübingen and the other with cotrimoxazole in a hospital in Cologne. Analyzing this rich longitudinal dataset, we found that gut microbiome diversity was reduced in both treatment cohorts to a similar extent, while effects on the gut resistome differed. We observed a sharp increase in the relative abundance of sulfonamide antibiotic resistance genes (ARGs) by 148.1% per cumulative defined daily dose of cotrimoxazole in the Cologne cohort, but not in the Tübingen cohort treated with ciprofloxacin. Through multivariate modeling, we found that factors such as individual baseline microbiome, resistome, and plasmid diversity; liver/kidney function; and concurrent medication, especially virostatic agents, influence resistome alterations. Strikingly, we observed different effects on the plasmidome in the two treatment groups. There was a substantial increase in the abundance of ARG-carrying plasmids in the cohort treated with cotrimoxazole, but not in the cohort treated with ciprofloxacin, indicating that cotrimoxazole might contribute more efficiently to the spread of resistance.

Conclusions: Our study represents a step forward in developing the capability to predict the effect of individual antimicrobials on the human microbiome and resistome. Our results indicate that to achieve this, integration of the individual baseline microbiome, resistome, and mobilome status as well as additional individual patient factors will be required. Such personalized predictions may in the future increase patient safety and reduce the spread of resistance.

Trial Registration: ClinicalTrials.gov, NCT02058888 . Registered February 10 2014.
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http://dx.doi.org/10.1186/s12915-019-0692-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749691PMC
September 2019