@article{MasotaOhlsenSchollmayeretal.2022,
  author    = {Masota, Nelson E. and Ohlsen, Knut and Schollmayer, Curd and Meinel, Lorenz and Holzgrabe, Ulrike},
  title     = {Isolation and characterization of galloylglucoses effective against multidrug-resistant strains of Escherichia coli and Klebsiella pneumoniae},
  series = {Molecules},
  volume    = {27},
  journal   = {Molecules},
  number    = {15},
  issn      = {1420-3049},
  doi       = {10.3390/molecules27155045},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286179},
  year      = {2022},
  abstract  = {The search for new antibiotics against multidrug-resistant (MDR), Gram-negative bacteria is crucial with respect to filling the antibiotics development pipeline, which is subject to a critical shortage of novel molecules. Screening of natural products is a promising approach for identifying antimicrobial compounds hosting a higher degree of novelty. Here, we report the isolation and characterization of four galloylglucoses active against different MDR strains of Escherichia coli and Klebsiella pneumoniae. A crude acetone extract was prepared from Paeonia officinalis Linnaeus leaves, and bioautography-guided isolation of active compounds from the extract was performed by liquid-liquid extraction, as well as open column, flash, and preparative chromatographic methods. Isolated active compounds were characterized and elucidated by a combination of spectroscopic and spectrometric techniques. In vitro antimicrobial susceptibility testing was carried out on E. coli and K. pneumoniae using 2 reference strains and 13 strains hosting a wide range of MDR phenotypes. Furthermore, in vivo antibacterial activities were assessed using Galleria mellonella larvae, and compounds 1,2,3,4,6-penta-O-galloyl-β-d-glucose, 3-O-digalloyl-1,2,4,6-tetra-O-galloyl-β-d-glucose, 6-O-digalloyl-1,2,3,4-tetra-O-galloyl-β-d-glucose, and 3,6-bis-O-digalloyl-1,2,4-tri-O-galloyl-β-d-glucose were isolated and characterized. They showed minimum inhibitory concentration (MIC) values in the range of 2-256 µg/mL across tested bacterial strains. These findings have added to the number of known galloylglucoses from P. officinalis and highlight their potential against MDR Gram-negative bacteria.},
  language  = {en}
}
@article{KurotschkaFulgenzioDaCasetal.2022,
  author    = {Kurotschka, Peter Konstantin and Fulgenzio, Chiara and Da Cas, Roberto and Traversa, Giuseppe and Ferrante, Gianluigi and Massidda, Orietta and G{\´a}gyor, Ildik{\´o} and Aschbacher, Richard and Moser, Verena and Pagani, Elisabetta and Spila Alegiani, Stefania and Massari, Marco},
  title     = {Effect of fluoroquinolone use in primary care on the development and gradual decay of Escherichia coli resistance to fluoroquinolones: a matched case-control study},
  series = {Antibiotics},
  volume    = {11},
  journal   = {Antibiotics},
  number    = {6},
  issn      = {2079-6382},
  doi       = {10.3390/antibiotics11060822},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278771},
  year      = {2022},
  abstract  = {The reversibility of bacterial resistance to antibiotics is poorly understood. Therefore, the aim of this study was to determine, over a period of five years, the effect of fluoroquinolone (FQ) use in primary care on the development and gradual decay of Escherichia coli resistance to FQ. In this matched case-control study, we linked three sources of secondary data of the Health Service of the Autonomous Province of Bolzano, Italy. Cases were all those with an FQ-resistant E. coli (QREC)-positive culture from any site during a 2016 hospital stay. Data were analyzed using conditional logistic regression. A total of 409 cases were matched to 993 controls (FQ-sensitive E. coli) by the date of the first isolate. Patients taking one or more courses of FQ were at higher risk of QREC colonization/infection. The risk was highest during the first year after FQ was taken (OR 2.67, 95\%CI 1.92-3.70, p < 0.0001), decreased during the second year (OR 1.54, 95\%CI 1.09-2.17, p = 0.015) and became undetectable afterwards (OR 1.09, 95\%CI 0.80-1.48, p = 0.997). In the first year, the risk of resistance was highest after greater cumulative exposure to FQs. Moreover, older age, male sex, longer hospital stays, chronic obstructive pulmonary disease (COPD) and diabetes mellitus were independent risk factors for QREC colonization/infection. A single FQ course significantly increases the risk of QREC colonization/infection for no less than two years. This risk is higher in cases of multiple courses, longer hospital stays, COPD and diabetes; in males; and in older patients. These findings may inform public campaigns and courses directed to prescribers to promote rational antibiotic use.},
  language  = {en}
}
@article{UmstaetterWernerZerlinetal.2022,
  author    = {Umst{\"a}tter, Florian and Werner, Julia and Zerlin, Leah and M{\"u}hlberg, Eric and Kleist, Christian and Klika, Karel D. and Hertlein, Tobias and Beijer, Barbro and Domhan, Cornelius and Zimmermann, Stefan and Ohlsen, Knut and Haberkorn, Uwe and Mier, Walter and Uhl, Philipp},
  title     = {Impact of linker modification and PEGylation of vancomycin conjugates on structure-activity relationships and pharmacokinetics},
  series = {Pharmaceuticals},
  volume    = {15},
  journal   = {Pharmaceuticals},
  number    = {2},
  issn      = {1424-8247},
  doi       = {10.3390/ph15020159},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255197},
  year      = {2022},
  abstract  = {As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity.},
  language  = {en}
}
@article{KurotschkaTiedemannWolfetal.2021,
  author    = {Kurotschka, Peter Konstantin and Tiedemann, Elena and Wolf, Dominik and Thier, Nicola and Forster, Johannes and Liese, Johannes G. and Gagyor, Ildiko},
  title     = {Management of common infections in German primary care: a cross-sectional survey of knowledge and confidence among General Practitioners and outpatient pediatricians},
  series = {Antibiotics},
  volume    = {10},
  journal   = {Antibiotics},
  number    = {9},
  issn      = {2079-6382},
  doi       = {10.3390/antibiotics10091131},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246272},
  year      = {2021},
  abstract  = {Outpatient antibiotic use is closely related to antimicrobial resistance and in Germany, almost 70\% of antibiotic prescriptions in human health are issued by primary care physicians (PCPs). The aim of this study was to explore PCPs, namely General Practitioners' (GPs) and outpatient pediatricians' (PDs) knowledge of guideline recommendations on rational antimicrobial treatment, the determinants of confidence in treatment decisions and the perceived need for training in this topic in a large sample of PCPs from southern Germany. Out of 3753 reachable PCPs, 1311 completed the survey (overall response rate = 34.9\%). Knowledge of guideline recommendations and perceived confidence in making treatment decisions were high in both GPs and PDs. The two highest rated influencing factors on prescribing decisions were reported to be guideline recommendations and own clinical experiences, hence patients' demands and expectations were judged as not influencing treatment decisions. The majority of physicians declared to have attended at least one specific training course on antibiotic use, yet almost all the participating PCPs declared to need more training on this topic. More studies are needed to explore how consultation-related and context-specific factors could influence antibiotic prescriptions in general and pediatric primary care in Germany beyond knowledge. Moreover, efforts should be undertaken to explore the training needs of PCPs in Germany, as this would serve the development of evidence-based educational interventions targeted to the improvement of antibiotic prescribing decisions rather than being focused solely on knowledge of guidelines.},
  language  = {en}
}
@article{SoundararajanMarincolaLiongetal.2023,
  author    = {Soundararajan, Manonmani and Marincola, Gabriella and Liong, Olivia and Marciniak, Tessa and Wencker, Freya D. R. and Hofmann, Franka and Schollenbruch, Hannah and Kobusch, Iris and Linnemann, Sabrina and Wolf, Silver A. and Helal, Mustafa and Semmler, Torsten and Walther, Birgit and Schoen, Christoph and Nyasinga, Justin and Revathi, Gunturu and Boelhauve, Marc and Ziebuhr, Wilma},
  title     = {Farming practice influences antimicrobial resistance burden of non-aureus staphylococci in pig husbandries},
  series = {Microorganisms},
  volume    = {11},
  journal   = {Microorganisms},
  number    = {1},
  issn      = {2076-2607},
  doi       = {10.3390/microorganisms11010031},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312750},
  year      = {2023},
  abstract  = {Non-aureus staphylococci (NAS) are ubiquitous bacteria in livestock-associated environments where they may act as reservoirs of antimicrobial resistance (AMR) genes for pathogens such as Staphylococcus aureus. Here, we tested whether housing conditions in pig farms could influence the overall AMR-NAS burden. Two hundred and forty porcine commensal and environmental NAS isolates from three different farm types (conventional, alternative, and organic) were tested for phenotypic antimicrobial susceptibility and subjected to whole genome sequencing. Genomic data were analysed regarding species identity and AMR gene carriage. Seventeen different NAS species were identified across all farm types. In contrast to conventional farms, no AMR genes were detectable towards methicillin, aminoglycosides, and phenicols in organic farms. Additionally, AMR genes to macrolides and tetracycline were rare among NAS in organic farms, while such genes were common in conventional husbandries. No differences in AMR detection existed between farm types regarding fosfomycin, lincosamides, fusidic acid, and heavy metal resistance gene presence. The combined data show that husbandry conditions influence the occurrence of resistant and multidrug-resistant bacteria in livestock, suggesting that changing husbandry practices may be an appropriate means of limiting the spread of AMR bacteria on farms.},
  language  = {en}
}
@article{MarincolaLiongSchoenetal.2021,
  author    = {Marincola, Gabriella and Liong, Olivia and Schoen, Christoph and Abouelfetouh, Alaa and Hamdy, Aisha and Wencker, Freya D. R. and Marciniak, Tessa and Becker, Karsten and K{\"o}ck, Robin and Ziebuhr, Wilma},
  title     = {Antimicrobial Resistance Profiles of Coagulase-Negative Staphylococci in Community-Based Healthy Individuals in Germany},
  series = {Frontiers in Public Health},
  volume    = {9},
  journal   = {Frontiers in Public Health},
  issn      = {2296-2565},
  doi       = {10.3389/fpubh.2021.684456},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240881},
  year      = {2021},
  abstract  = {Coagulase-negative staphylococci (CoNS) are common opportunistic pathogens, but also ubiquitous human and animal commensals. Infection-associated CoNS from healthcare environments are typically characterized by pronounced antimicrobial resistance (AMR) including both methicillin- and multidrug-resistant isolates. Less is known about AMR patterns of CoNS colonizing the general population. Here we report on AMR in commensal CoNS recovered from 117 non-hospitalized volunteers in a region of Germany with a high livestock density. Among the 69 individuals colonized with CoNS, 29 had reported contacts to either companion or farm animals. CoNS were selectively cultivated from nasal swabs, followed by species definition by 16S rDNA sequencing and routine antibiotic susceptibility testing. Isolates displaying phenotypic AMR were further tested by PCR for presence of selected AMR genes. A total of 127 CoNS were isolated and Staphylococcus epidermidis (75\%) was the most common CoNS species identified. Nine isolates (7\%) were methicillin-resistant (MR) and carried the mecA gene, with seven individuals (10\%) being colonized with at least one MR-CoNS isolate. While resistance against gentamicin, phenicols and spectinomycin was rare, high resistance rates were found against tetracycline (39\%), erythromycin (33\%) and fusidic acid (24\%). In the majority of isolates, phenotypic resistance could be associated with corresponding AMR gene detection. Multidrug-resistance (MDR) was observed in 23\% (29/127) of the isolates, with 33\% (23/69) of the individuals being colonized with MDR-CoNS. The combined data suggest that MR- and MDR-CoNS are present in the community, with previous animal contact not significantly influencing the risk of becoming colonized with such isolates.},
  language  = {en}
}
@article{KleinertHillermannJablonkaetal.2021,
  author    = {Kleinert, Evelyn and Hillermann, Nele and Jablonka, Alexandra and Happle, Christine and M{\"u}ller, Frank and Simmenroth, Anne},
  title     = {Prescription of antibiotics in the medical care of newly arrived refugees and migrants},
  series = {Pharmacoepidemiology and Drug Safety},
  volume    = {30},
  journal   = {Pharmacoepidemiology and Drug Safety},
  number    = {8},
  doi       = {10.1002/pds.5254},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244771},
  pages     = {1074 -- 1083},
  year      = {2021},
  abstract  = {Purpose Unnecessary and inappropriate use of antibiotics is a widespread problem in primary care. However, current data on the care of refugees and migrants in initial reception centers is pending. This article provides data on prescription frequencies of various antibiotics and associated diagnoses. Methods In this retrospective observational study, patient data of 3255 patients with 6376 medical contacts in two initial reception centers in Germany were analyzed. Patient data, collected by chart review, included sociodemographic characteristics, diagnoses, and prescriptions. Antibiotic prescription behavior and corresponding physician-coded diagnoses were analyzed. Results Nineteen percent of all patients in our study received systemic antibiotics during the observation period, with children below the age of 10 years receiving antibiotics most frequently (24\%). The most commonly prescribed antibiotics were penicillins (65\%), macrolides (12\%), and cephalosporins (7\%). The most frequent diagnoses associated with antibiotic prescription were acute tonsillitis (26\%), bronchitis (21\%), infections of the upper respiratory tract (14\%), and urinary tract infections (10\%). In case of acute bronchitis 74\% of the antibiotic prescriptions were probably not indicated. In addition, we found a significant number of inappropriate prescriptions such as amoxicillin for tonsillitis (67\%), and ciprofloxacin and cotrimoxazol for urinary tract infections (49\%). Conclusion Regarding inappropriate prescription of antibiotics in refugee healthcare, this study shows a rate ranging from 8\% for upper respiratory tract infections to 75\% for acute bronchitis. Unnecessary use of antibiotics is a global problem contributing to gratuitous costs, side effects, and antimicrobial resistance. This research contributes to the development of stringent antibiotic stewardship regiments in the particularly vulnerable population of migrants and refugees.},
  language  = {en}
}
@article{MoremiClausMshana2016,
  author    = {Moremi, Nyambura and Claus, Heike and Mshana, Stephen E.},
  title     = {Antimicrobial resistance pattern: a report of microbiological cultures at a tertiary hospital in Tanzania},
  series = {BMC Infectious Diseases},
  volume    = {16},
  journal   = {BMC Infectious Diseases},
  number    = {756},
  doi       = {10.1186/s12879-016-2082-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161185},
  year      = {2016},
  abstract  = {Background Antimicrobial resistance has been declared by the World Health Organization as a threat to the public health. The aim of this study was to analyze antimicrobial resistance patterns of the common pathogens occurring at the Bugando Medical Centre (BMC), Mwanza, Tanzania to provide data for antimicrobial stewardship programmes. Methods A total of 3330 microbiological culture results scripts representing non-repetitive specimens reported between June 2013 and May 2015 were retrieved and analyzed for pathogens and their susceptibility patterns using STATA-11 software. Results Out of 3330 specimens, 439 (13.2\%) had positive culture. Staphylococcus aureus (n = 100; 22.8\%), Klebsiella pneumoniae (n = 65; 14.8\%) and Escherichia coli (n = 41; 9.3\%) were the most frequently isolated bacteria. Of 78 Staphylococcus aureus tested, 27 (34.6\%) were found to be methicillin resistant Staphylococcus aureus (MRSA). Rates of resistance of Klebsiella pneumoniae and Escherichia coli isolates to third generation cephalosporins were 38.5\% (25/65) and 29.3\% (12/41) respectively. Staphylococcus aureus and Klesbiella pneumoniae were commonly isolated from bloodstream infections while Escherichia coli and Pseudomonas aeruginosa were the predominant isolates from urinary tract and wounds infections respectively. Of 23 Salmonella species isolated, 22 (95\%) were recovered from the blood. Nine of the 23 Salmonella species isolates (39\%) were found to be resistant to third generation cephalosporins. The resistance rate of gram-negative bacteria to third generation cephalosporins increased from 26.5\% in 2014 to 57.9\% in 2015 (p = 0.004) while the rate of MRSA decreased from 41.2\% in 2013 to 9.5\% in 2015 (p = 0.016). Multidrug-resistant gram-negative isolates were commonly isolated from Intensive Care Units and it was noted that, the majority of invasive infections were due to gram-negative bacteria. Conclusion There is an increase in proportion of gram-negative isolates resistant to third generation cephalosporins. The diversity of potential pathogens resistant to commonly prescribed antibiotics underscores the importance of sustained and standardized antimicrobial resistance surveillance and antibiotic stewardship programmes in developing countries.},
  language  = {en}
}
@article{HampeFriedmanEdgertonetal.2017,
  author    = {Hampe, Irene A. I. and Friedman, Justin and Edgerton, Mira and Morschh{\"a}user, Joachim},
  title     = {An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses},
  series = {PLoS Pathogens},
  volume    = {13},
  journal   = {PLoS Pathogens},
  number    = {9},
  doi       = {10.1371/journal.ppat.1006655},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158883},
  pages     = {e1006655},
  year      = {2017},
  abstract  = {The opportunistic fungal pathogen Candida albicans frequently produces genetically altered variants to adapt to environmental changes and new host niches in the course of its life-long association with the human host. Gain-of-function mutations in zinc cluster transcription factors, which result in the constitutive upregulation of their target genes, are a common cause of acquired resistance to the widely used antifungal drug fluconazole, especially during long-term therapy of oropharyngeal candidiasis. In this study, we investigated if C. albicans also can develop resistance to the antimicrobial peptide histatin 5, which is secreted in the saliva of humans to protect the oral mucosa from pathogenic microbes. As histatin 5 has been shown to be transported out of C. albicans cells by the Flu1 efflux pump, we screened a library of C. albicans strains that contain artificially activated forms of all zinc cluster transcription factors of this fungus for increased FLU1 expression. We found that a hyperactive Mrr1, which confers fluconazole resistance by upregulating the multidrug efflux pump MDR1 and other genes, also causes FLU1 overexpression. Similarly to the artificially activated Mrr1, naturally occurring gain-of-function mutations in this transcription factor also caused FLU1 upregulation and increased histatin 5 resistance. Surprisingly, however, Mrr1-mediated histatin 5 resistance was mainly caused by the upregulation of MDR1 instead of FLU1, revealing a previously unrecognized function of the Mdr1 efflux pump. Fluconazole-resistant clinical C. albicans isolates with different Mrr1 gain-of-function mutations were less efficiently killed by histatin 5, and this phenotype was reverted when MRR1 was deleted. Therefore, antimycotic therapy can promote the evolution of strains that, as a consequence of drug resistance mutations, simultaneously have acquired increased resistance against an innate host defense mechanism and are thereby better adapted to certain host niches.},
  language  = {en}
}
@article{KasangKalluvyaMajingeetal.2011,
  author    = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Stich, August and Bodem, Jochen and Kongola, Gilbert and Jacobs, Graeme B. and Mlewa, Mathias and Mildner, Miriam and Hensel, Irina and Horn, Anne and Preiser, Wolfgang and van Zyl, Gert and Klinker, Hartwig and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten and Weissbrich, Benedikt},
  title     = {HIV Drug Resistance (HIVDR) in Antiretroviral Therapy-Na{\"i}ve Patients in Tanzania Not Eligible for WHO Threshold HIVDR Survey Is Dramatically High},
  series = {PLoS One},
  volume    = {6},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0023091},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137988},
  pages     = {e23091},
  year      = {2011},
  abstract  = {Background The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5\%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-na{\"i}ve population. Methods and Findings HIVDR was determined in 88 sequentially enrolled ART-na{\"i}ve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8\% (95\%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1\%; 95\% CI 0.095-0.28) versus 0\%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. Conclusions ART-na{\"i}ve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-na{\"i}ve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-na{\"i}ve HIV-infected population.},
  language  = {en}
}