Publications by authors named "Kirsten Meyer"

27 Publications

  • Page 1 of 1

Biology and applications of co-produced, synergistic antimicrobials from environmental bacteria.

Nat Microbiol 2021 09 26;6(9):1118-1128. Epub 2021 Aug 26.

Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Environmental bacteria, such as Streptomyces spp., produce specialized metabolites that are potent antibiotics and therapeutics. Selected specialized antimicrobials are co-produced and function together synergistically. Co-produced antimicrobials comprise multiple chemical classes and are produced by a wide variety of bacteria in different environmental niches, suggesting that their combined functions are ecologically important. Here, we highlight the exquisite mechanisms that underlie the simultaneous production and functional synergy of 16 sets of co-produced antimicrobials. To date, antibiotic and antifungal discovery has focused mainly on single molecules, but we propose that methods to target co-produced antimicrobials could widen the scope and applications of discovery programs.
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http://dx.doi.org/10.1038/s41564-021-00952-6DOI Listing
September 2021

Cytosolic and Mitochondrial Hsp90 in Cytokinesis, Mitochondrial DNA Replication, and Drug Action in Trypanosoma brucei.

Antimicrob Agents Chemother 2021 10 23;65(11):e0063221. Epub 2021 Aug 23.

Division of Clinical Pharmacology, Departments of Medicine and of Pharmacology and Molecular Sciences, The Johns Hopkins Universitygrid.21107.35 School of Medicine, Baltimore, Maryland, USA.

Trypanosoma brucei subspecies cause African sleeping sickness in humans, an infection that is commonly fatal if not treated, and available therapies are limited. Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors have potent and vivid activity against bloodstream-form trypanosomes. Hsp90s are phylogenetically conserved and essential catalysts that function at the crux of cell biology, where they ensure the proper folding of proteins and their assembly into multicomponent complexes. To assess the specificity of Hsp90 inhibitors and further define the role of Hsp90s in African trypanosomes, we used RNA interference (RNAi) to knock down cytosolic and mitochondrial Hsp90s (HSP83 and HSP84, respectively). Loss of either protein led to cell death, but the phenotypes were distinctly different. Depletion of cytosolic HSP83 closely mimicked the consequences of chemically depleting Hsp90 activity with inhibitor 17-AAG. In these cells, cytokinesis was severely disrupted, and segregation of the kinetoplast (the massive mitochondrial DNA structure unique to this family of eukaryotic pathogens) was impaired, leading to cells with abnormal kinetoplast DNA (kDNA) structures. Quite differently, knockdown of mitochondrial HSP84 did not impair cytokinesis but halted the initiation of new kDNA synthesis, generating cells without kDNA. These findings highlight the central role of Hsp90s in chaperoning cell cycle regulators in trypanosomes, reveal their unique function in kinetoplast replication, and reinforce their specificity and value as drug targets.
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http://dx.doi.org/10.1128/AAC.00632-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522745PMC
October 2021

Predicting antimicrobial mechanism-of-action from transcriptomes: A generalizable explainable artificial intelligence approach.

PLoS Comput Biol 2021 03 29;17(3):e1008857. Epub 2021 Mar 29.

J. Craig Venter Institute, La Jolla, CA, United States of America.

To better combat the expansion of antibiotic resistance in pathogens, new compounds, particularly those with novel mechanisms-of-action [MOA], represent a major research priority in biomedical science. However, rediscovery of known antibiotics demonstrates a need for approaches that accurately identify potential novelty with higher throughput and reduced labor. Here we describe an explainable artificial intelligence classification methodology that emphasizes prediction performance and human interpretability by using a Hierarchical Ensemble of Classifiers model optimized with a novel feature selection algorithm called Clairvoyance; collectively referred to as a CoHEC model. We evaluated our methods using whole transcriptome responses from Escherichia coli challenged with 41 known antibiotics and 9 crude extracts while depositing 122 transcriptomes unique to this study. Our CoHEC model can properly predict the primary MOA of previously unobserved compounds in both purified forms and crude extracts at an accuracy above 99%, while also correctly identifying darobactin, a newly discovered antibiotic, as having a novel MOA. In addition, we deploy our methods on a recent E. coli transcriptomics dataset from a different strain and a Mycobacterium smegmatis metabolomics timeseries dataset showcasing exceptionally high performance; improving upon the performance metrics of the original publications. We not only provide insight into the biological interpretation of our model but also that the concept of MOA is a non-discrete heuristic with diverse effects for different compounds within the same MOA, suggesting substantial antibiotic diversity awaiting discovery within existing MOA.
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http://dx.doi.org/10.1371/journal.pcbi.1008857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031737PMC
March 2021

Pulse Dosing of Antibiotic Enhances Killing of a Biofilm.

Front Microbiol 2020 9;11:596227. Epub 2020 Nov 9.

Department of Biology, Antimicrobial Discovery Center, Northeastern University, Boston, MA, United States.

Biofilms are highly tolerant to antibiotics and underlie the recalcitrance of many chronic infections. We demonstrate that mature biofilms can be substantially sensitized to the treatment by pulse dosing of an antibiotic - in this case, oxacillin. Pulse (periodic) dosing was compared to continuous application of antibiotic and was studied in a novel flow system which allowed for robust biofilm growth and tractable pharmacokinetics of dosing regimens. Our results highlight that a subpopulation of the biofilm survives antibiotic without becoming resistant, a population we refer to as persister bacteria. When oxacillin was continuously present the persister level did not decline, but, importantly, providing correctly timed periodic breaks decreased the surviving population. We found that the length of the periodic break impacted efficacy, and there was an optimal length that sensitized the biofilm to repeat treatment without allowing resistance expansion. Periodic dosing provides a potential simple solution to a complicated problem.
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http://dx.doi.org/10.3389/fmicb.2020.596227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680849PMC
November 2020

Mechanism-of-Action Classification of Antibiotics by Global Transcriptome Profiling.

Antimicrob Agents Chemother 2020 02 21;64(3). Epub 2020 Feb 21.

Department of Human Biology, J. Craig Venter Institute, La Jolla, California, USA

Antimicrobial resistance (AMR) is an ever-growing public health problem worldwide. The low rate of antibiotic discovery coupled with the rapid spread of drug-resistant bacterial pathogens is causing a global health crisis. To facilitate the drug discovery processes, we present a large-scale study of reference antibiotic challenge bacterial transcriptome profiles, which included 37 antibiotics across 6 mechanisms of actions (MOAs) and provide an economical approach to aid in antimicrobial dereplication in the discovery process. We demonstrate that classical MOAs can be sorted based upon the magnitude of gene expression profiles despite some overlap in the secondary effects of antibiotic exposures across MOAs. Additionally, using gene subsets, we were able to subdivide broad MOA classes into subMOAs. Furthermore, we provide a biomarker gene set that can be used to classify most antimicrobial challenges according to their canonical MOA. We also demonstrate the ability of this rapid MOA diagnostic tool to predict and classify the expression profiles of pure compounds and crude extracts to their expression profile-associated MOA class.
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http://dx.doi.org/10.1128/AAC.01207-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038283PMC
February 2020

A new antibiotic selectively kills Gram-negative pathogens.

Nature 2019 12 20;576(7787):459-464. Epub 2019 Nov 20.

Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA.

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
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http://dx.doi.org/10.1038/s41586-019-1791-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188312PMC
December 2019

Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics.

Nat Commun 2019 07 22;10(1):3268. Epub 2019 Jul 22.

MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 100084, Beijing, China.

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block L-allo-Enduracidine in 30-gram scale in just one hour  and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin. In addition, they show high efficiency in Streptococcus pneumoniae septicemia mouse model and neutropenic mouse thigh infection model using methicillin-resistant Staphylococcus aureus. We also propose that the antiparallel β-sheet of teixobactin is important for its bioactivity and an antiparallel dimer of teixobactin is the minimal binding unit for lipid II via key amino acids variations and molecular docking.
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http://dx.doi.org/10.1038/s41467-019-11211-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646333PMC
July 2019

Optimal kinetic exposures for classic and candidate antitrypanosomals.

J Antimicrob Chemother 2019 08;74(8):2303-2310

Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: Efficacy is determined not only by size, but also by shape, of drug exposure. Here the critical importance of the temporal pattern of drug concentrations (pharmacokinetic profile) is examined for antitrypanosomals in vitro.

Methods: An in vitro hollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasite Trypanosoma brucei. Artificial kinetics were employed intentionally to favour either high peak concentration or sustained duration of drug.

Results: Changing the shape of drug exposure significantly impacted drug efficacy. Suramin, melarsoprol and pentamidine were concentration-driven and therefore more efficacious when applied as short-lived high peaks. In contrast, difluoromethylornithine (DFMO) was time-driven, and therefore maximally effective as a constant infusion. Kinetic preference was robust over a wide range of drug exposures. Promising clinical candidates SCYX-7158 (acoziborole) and fexinidazole (parent and sulfone) were concentration-driven, suggesting optimal clinical regimens would involve relatively high but intermittent dosing.

Conclusions: Antitrypanosomals have an intrinsic pharmacokinetic driver for optimal efficacy, with important implications for clinical management and future candidate development.
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http://dx.doi.org/10.1093/jac/dkz160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640303PMC
August 2019

Creative Arts Interventions to Address Depression in Older Adults: A Systematic Review of Outcomes, Processes, and Mechanisms.

Front Psychol 2018 8;9:2655. Epub 2019 Jan 8.

Music Therapy Lab, Faculty of Applied Social Sciences, University of Applied Sciences Würzburg-Schweinfurt, Würzburg, Germany.

Depression experienced by older adults is proving an increasing global health burden, with rates generally 7% and as high as 27% in the USA. This is likely to significantly increase in coming years as the number and proportion of older adults in the population rises all around the world. Therefore, it is imperative that the effectiveness of approaches to the prevention and treatment of depression are understood. Creative arts interventions, including art, dance movement, drama, and music modalities, are utilized internationally to target depression and depressive symptoms in older adults. This includes interventions led by trained arts therapists as well as other health and arts professionals. However, to date there has not been a systematic review that reports effects and examines the processes (why) and mechanisms (how) of creative arts interventions are used to address depression in this older age group. This systematic review of studies on creative arts interventions for older adults experiencing depression examined: outcomes of four creative arts modalities (art, dance movement, drama, and music); with particular attention paid to processes documented as contributing to change in each modality; and mechanisms considered to result from these processes. Our analysis of 75 articles (17 art, 13 dance, 4 drama, and 41 music) indicates mostly significant quantitative or positive qualitative findings, particularly for interventions led by creative arts therapists. Mechanisms of change gleaned from the studies that were common across modalities include physical (e.g., increased muscle strength; neurochemical effects, such as endorphin release), intra-personal (e.g., enhanced self-concept, strengthened agency and mastery; processing and communication of emotions), cultural (e.g., creative expression, aesthetic pleasure), cognitive (e.g., stimulation of memory), and social (e.g., increased social skills and connection), that were all considered to contribute to reduced depression and symptoms. Recommendations for future research includes stronger focus on testing of processes and mechanisms.
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http://dx.doi.org/10.3389/fpsyg.2018.02655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331422PMC
January 2019

Model System Identifies Kinetic Driver of Hsp90 Inhibitor Activity against African Trypanosomes and Plasmodium falciparum.

Antimicrob Agents Chemother 2018 08 27;62(8). Epub 2018 Jul 27.

Division of Clinical Pharmacology, Departments of Medicine and of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Hsp90 inhibitors, well studied in the laboratory and clinic for antitumor indications, have promising activity against protozoan pathogens, including which causes African sleeping sickness, and the malaria parasite, To progress these experimental drugs toward clinical use, we adapted an dynamic hollow-fiber system and deployed artificial pharmacokinetics to discover the driver of their activity: either concentration or time. The activities of compounds from three major classes of Hsp90 inhibitors in development were evaluated against trypanosomes. In all circumstances, the activities of the tested Hsp90 inhibitors were concentration driven. By optimally deploying the drug to match its kinetic driver, the efficacy of a given dose was improved up to 5-fold, and maximal efficacy was achieved with a significantly lower drug exposure. The superiority of concentration-driven regimens was evident over several logs of drug exposure and was predictive of efficacy in a mouse model of African trypanosomiasis. In studies with , antimalarial activity was similarly concentration driven. This experimental strategy offers an expedient and versatile translational tool to assess the impact of pharmacokinetics on antiprotozoal activity. Knowing kinetic governance early in drug development provides an additional metric for judging lead compounds and allows the incisive design of animal efficacy studies.
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http://dx.doi.org/10.1128/AAC.00056-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105818PMC
August 2018

Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin.

J Med Chem 2018 04 13;61(8):3409-3421. Epub 2018 Apr 13.

MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology , Tsinghua University , Beijing 100084 , P. R. China.

Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure-activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the l- allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the d-phenylalanine. On the basis of the antibacterial activities that resulted from corresponding modifications of the d-phenylalanine, we propose a hydrophobic interaction between lipid II and the N-terminal of teixobactin analogues, which we map out with our analogue 35. Finally, a representative analogue from our series showed high efficiency in a mouse model of Streptococcus pneumoniae septicemia.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01241DOI Listing
April 2018

Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo.

J Infect Dis 2013 Aug 22;208(3):489-99. Epub 2013 Apr 22.

Department of Pharmacology and Molecular Sciences, The Johns Hopkins UniversitySchool of Medicine, Baltimore, MD, USA.

African sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is universally fatal if untreated, and current drugs are limited by severe toxicities and difficult administration. New antitrypanosomals are greatly needed. Heat shock protein 90 (Hsp90) is a conserved and ubiquitously expressed molecular chaperone essential for stress responses and cellular signaling. We investigated Hsp90 inhibitors for their antitrypanosomal activity. Geldanamycin and radicicol had nanomolar potency in vitro against bloodstream-form T. brucei; novobiocin had micromolar activity. In structure-activity studies of geldanamycin analogs, 17-AAG and 17-DMAG were most selective against T. brucei as compared to mammalian cells. 17-AAG treatment sensitized trypanosomes to heat shock and caused severe morphological abnormalities and cell cycle disruption. Both oral and parenteral 17-DMAG cured mice of a normally lethal infection of T. brucei. These promising results support the use of inhibitors to study Hsp90 function in trypanosomes and to expand current clinical development of Hsp90 inhibitors to include T. brucei.
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http://dx.doi.org/10.1093/infdis/jit179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699005PMC
August 2013

Analogs of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases.

Bioorg Med Chem 2012 Jul 17;20(14):4507-13. Epub 2012 May 17.

Department of Pharmacology & Molecular Sciences, 725 North Wolfe Street, Baltimore, MD 21205, USA.

Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti-tuberculosis agents.
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http://dx.doi.org/10.1016/j.bmc.2012.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495175PMC
July 2012

Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.

Mar Drugs 2012 Apr 16;10(4):900-17. Epub 2012 Apr 16.

Centre for Biodiscovery and Schools of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.

Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC(50) 12.2-26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ(0) cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G(2)/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells.
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http://dx.doi.org/10.3390/md10040900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366682PMC
April 2012

Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.

Mar Drugs 2012 Apr 16;10(4):900-17. Epub 2012 Apr 16.

Centre for Biodiscovery and Schools of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.

Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC(50) 12.2-26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ(0) cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G(2)/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells.
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http://dx.doi.org/10.3390/md10040900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366682PMC
April 2012

The risk of emergency room treatment due to overdose in injection drug users.

J Addict Dis 2009 ;28(1):68-73

General Hospital Munich Schwabing, Munich, Germany.

This cohort study was conducted to identify risk factors for lifetime emergency room treatment due to overdose in injection drug users. Data of 1049 patients on admission for opioid detoxification were analyzed. More than every third injection drug user (34.7%) experienced emergency room treatment due to an overdose. Using multiple logistic regression not living with a significant other drug user (odds ratio [OR] = 1.78, P = .002), history of suicide attempt (OR = 3.0, P = .000), daily use of barbiturates (OR = 2.17, P = .006) and cannabis (OR = 1.89, P = .001) were independently associated with emergency room treatment, whereas shorter duration of opioid use (OR = 0.23, P = .001) was independently associated with lack of emergency room treatment. Suicidal thoughts and multiple use of central nervous system depressants should be considered in injection drug users entering the emergency room due to an overdose. Emergency rooms should be seen as important places for offering further assistance (e.g., counselling) or referral to an addiction unit to drug users.
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http://dx.doi.org/10.1080/10550880802545192DOI Listing
May 2009

Efficacy of a polyethylene glycol marker system in urine drug screening in an opiate substitution program.

Eur Addict Res 2008 27;14(4):186-9. Epub 2008 Jun 27.

Department of Addiction Medicine, Hospital München-Schwabing, Munich, Germany.

Aims: Screening for concomitant drug consumption is necessary in opiate substitution therapy of opiate-dependent patients. Adulteration of samples is a common problem in this setting. A recently developed polyethylene glycol marker system allows reliable identification of urine samples. In this study, we aimed to compare the rates of drug detection in conventional and marker urine samples.

Design: This cross-sectional evaluation was performed in an ambulatory opiate substitution program. We studied 55 opiate-dependent patients (32 men, 23 women). In all patients we compared the rates of drugs detected in the marker urine with the most recent conventional urine control. Additionally we assessed the rate of marker urine manipulation.

Findings: In the conventional urine controls, opiates and benzodiazepines were found in 3.6 and 27%, respectively, whereas in the marker urine controls, these rates were 33 and 40%, respectively. Signs of urine manipulation were present in 35%. The rates of concomitant consumption and urine manipulation were higher among the patients without than among those with take-home substitution.

Conclusions: With the marker urine, an unexpectedly high prevalence of concomitant consumption can be found. Marker urine testing has a significantly higher sensitivity for the detection of concomitant drug use.
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http://dx.doi.org/10.1159/000141642DOI Listing
May 2009

Factors associated with exposure to hepatitis B virus in injection drug users.

Drug Alcohol Depend 2006 Sep 14;84(2):154-9. Epub 2006 Feb 14.

Hospital Munich-Schwabing, Koelner Platz 1, D-80804 Munich, Germany.

This study was undertaken to describe factors associated with exposure to the hepatitis B virus (HBV) in treated injection drug users to better aim prevention and care in high risk subgroups. The naturalistic study was conducted in Munich, Germany, and 1,018 patients who ever shared needles admitted for opioid detoxification were included. Sociodemographic, drug and drug treatment related variables and the virological status (HCV, HIV) were included in the bivariate and multiple logistic regression analysis. Sera were tested positive for antibodies against HBc in 40.2%, against HCV in 60.9%, and against HIV in 4.7% of patients. Older age, living without partner, longer duration of IDU, positive drug treatment history, imprisonment, emergency treatment, daily alcohol consumption, type of opioid dependency, and being positive for anti-HCV or anti-HIV were significant individual factors associated with positive anti-HBc-serology. Using multiple logistic regression history of imprisonment and being positive for anti-HCV remained independently associated with positive anti-HBc-serology. HBV-infection in IDUs should alert for simultaneous HCV-infection. Contacts to the criminal justice system are to be used for HBV prevention programs, including vaccination when indicated. Prevention programs should be implemented early in or even before the begin of a drug career.
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http://dx.doi.org/10.1016/j.drugalcdep.2006.01.009DOI Listing
September 2006

Co-consumption of benzodiazepines in heroin users, methadone-substituted and codeine-substituted patients.

J Addict Dis 2005 ;24(4):17-29

Kolner Platz 1, München, 80804, Germany.

Concomitant consumption of benzodiazepines (BZDs) and opioids is a major problem in patients with opioid dependence. It may have substantial impact on morbidity, mortality and clinical course. The current retrospective study aims to determine whether there are differences in the additional use of BZDs among addicts regularly taking methadone or codeine medications in treatment and untreated addicts injecting heroin. The records of 1,685 patients admitted for detoxification were analyzed using bivariate analysis and multiple logistic regression analysis. Demographic and drug related variables were considered, both as possible confounders and predictors of concomitant BZD use. Daily intake of BZDs was reported in 44.4% of the patients. Patients treated with methadone or codeine medications report daily intake of BZDs significantly more often than the heroin-dependent patients (p < 0.01). Using multiple regression analyses, the results were confirmed as independent from the assessed possible confounders. Further we found that daily use of alcohol or barbiturates, early onset of opioid use (p < 0.01), unemployment, having a substance dependent family member with, and a history of imprisonment (for all p < 0.05) were associated with concomitant daily consumption of BZDs in opioid dependent subjects. These finding underline the need to further explore the causes, interactions and consequences of concomitant BZD and opiate use.
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http://dx.doi.org/10.1300/j069v24n04_02DOI Listing
June 2006

Risk Factors and predictors of human immunodeficiency virus infection among injection drug users.

Eur Addict Res 2005 ;11(3):138-44

Addiction Medicine, Clinic 3, General Hospital Munich Schwabing, Munich, Germany.

Background/aim: Injection drug users (IDUs) have a high risk of acquiring an infection with the human immunodeficiency virus (HIV). To improve counseling and prevention, a better understanding of risk factors and predictors for an infection must be gained. This retrospective study has the aim to determine the risk factors for acquisition of HIV infection other than sharing of needles/syringes.

Methods: The study population consisted of all patients admitted to the detoxification unit between 1991 and 1996 who met ICD-10 criteria for opioid dependency, who reported to share needles, and who agreed to have an antibody test. Possible risk factors were assessed by interview. Cross tables based on bivariate logistic regression were constructed to estimate the relative odds. Multiple logistic regression modeling procedures were used to adjust possible confounding factors.

Results: A total of 1,049 out of 1,656 patients admitted were included into the study. 4.8% of the patients were HIV-1 seropositive. The prevalence was higher among older patients and among patients living with a significant other substance drug user with substance dependency, after a longer duration of drug use, and after coinfection with hepatitis B virus and/or hepatitis C virus (HCV). Using multiple logistic regression analyses and including all individually significant risk factors, we found only coinfection with HCV to remain significant. 92% of the HIV-infected patients were also HCV infected. In the group younger than 23 years of age, a total of 53.5% of the IDUs were still seronegative for HIV, hepatitis A and B virus, and HCV.

Conclusions: Despite the high rate of HCV coinfection (92%) in HIV-infected patients, we found more than 50% of IDUs younger than 23 years to be neither infected with HCV nor with HIV. Early prevention strategies against infectious diseases should especially focus on young IDUs.
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http://dx.doi.org/10.1159/000085549DOI Listing
November 2005

Hepatitis C virus infection and injection drug users: prevention, risk factors, and treatment.

Clin Infect Dis 2005 Apr;40 Suppl 5:S330-5

Department of Addiction Medicine, General Hospital Munich-Schwabing, Munich, Germany.

Injection drug users (IDUs) are the largest group of persons infected with hepatitis C virus (HCV), with a prevalence of 50%-90%. The transmission of HCV is not the effect of the drug injected but of sharing contaminated equipment. For the sake of prevention, we have to know which factors are more likely to lead to HCV seroconversion and which particular situations and environments are risk factors for equipment sharing. As far as therapy is concerned, some studies have shown that treatment for HCV infection in IDUs during substitution treatment for drug dependency is as successful as is treatment of patients who are not IDUs. Screening and early treatment of IDUs could play an important role in controlling HCV infection. The rate of reinfection may not as high as supposed. All studies dealing with treatment for HCV infection in IDUs have stressed the necessity of collaboration among hepatologists and specialists in addiction medicine, social workers, and psychotherapists.
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http://dx.doi.org/10.1086/427475DOI Listing
April 2005

Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users.

Clin Infect Dis 2004 Nov 26;39(10):1540-3. Epub 2004 Oct 26.

Department of Addiction Medicine, General Hospital Munich-Schwabing, Munich, Germany.

We followed-up 18 injection drug users for a mean of 33.8 months (range, 4-55 months) after successful treatment for hepatitis C virus (HCV) infection. Fifteen (83%) of the patients remained HCV RNA-negative, 1 patient was not tested, and 2 patients had test results positive for HCV RNA. The estimated rate of reinfection as a result of injection drug use was 0-4.1 cases per 100 person-years (cumulative incidence, 0%-12.6% at 48 months after completion of treatment). Of 50 patients originally treated, 15 (30%) were HCV RNA-negative 3 years later.
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http://dx.doi.org/10.1086/425361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1510898PMC
November 2004

Comparative analysis of conventional training and a computer-based interactive training program for celiac disease patients.

Patient Educ Couns 2004 Sep;54(3):353-60

Department of Internal Medicine III, University of Leipzig, Philipp-Rosenthal Strasse 27, 04103 Leipzig, Germany.

Gluten-free diet (GFD) protects against the complications of celiac disease (CD). However, training in the dietetic field is rare in Germany. Thus, CD patients are likely to benefit from a computer-based interactive training program (CBITP) combined with interactive exercises. We compared a CBITP and a conventional training for CD patients regarding increased knowledge, transferability and sustainability. In that context we analyzed whether CD patients are more able to judge the risk of a food or a situation after practicing with the interactive training software. Sixty-four CD patients were included and randomized in two groups. While the first group used the CBITP, the control group received written instructions. Before and after taking part in the training program and 3 weeks later, the participants filled in a questionnaire for celiac knowledge. The results show that both intervention and control groups increased knowledge about CD. However, the intervention group showed significantly better outcome. A CBITP significantly increases knowledge and sustainability as compared to a conventional training for CD patients. CBITPs can enhance patients' training and treatment.
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http://dx.doi.org/10.1016/j.pec.2003.12.006DOI Listing
September 2004

Hepatitis C virus infection in injection drug users in Bavaria: risk factors for seropositivity.

Eur J Epidemiol 2003 ;18(6):563-8

Krankenhaus München Schwabing, Clinic 3, Addiction Medicine, Kölner Platz 1, München, Germany.

Background: Hepatitis C Virus (HCV) infection is the most common disease among intravenous drug users (IDUs).

Patients And Method: All patients admitted to the detoxification unit 1991-1997 and meeting ICD-10 diagnosis of opioid dependency were tested for anti-HCV serology.

Results: Thousand and forty nine patients were included in the study. About 61.3% of the IDUs were anti-HCV positive. Increasing age (PR: 1.46; 95% CI: 1.34-1.60), living with a significant other drug user (PR: 1.17; 95% CI: 1.05-1.31), history of therapy (PR: 1.62; 95% CI: 1.50-1.74), history of imprisonment (PR: 1.48; 95% CI: 1.36-1.61), history of emergency treatment (PR: 1.23; 95% CI: 1.12-1.35), additional daily consumption of benzodiazepines (PR: 1.10; 95% CI: 1.00-2.21) or alcohol (PR: 1.26; 95% CI: 1.14-1.38), frequency of injecting heroin (daily: PR: 0.86; 95% CI: 0.78-0.96; previously: PR: 1.14; 95% CI: 1.03-1.26) and type of opioid dependency (methadone: PR: 1.26; 95% CI: 1.13-1.41) were significant factors, considered as individual factors, for positive anti-HCV serology. Using multiple logistic regression we found that older age (OR: 3.54, 95% CI: 1.30-9.67), longer duration of opioid use (OR: 5.74; 95% CI: 1.82-18.13), living with a significant other drug user (OR: 1.47; 95% CI: 1.01-2.16), history of therapy (OR: 4.87; 95% CI: 1.67-14.20), history of imprisonment (OR: 1.92; 95% CI: 1.12-3.28), history of emergency treatment (OR: 1.45; 95% CI: 1.06-1.99) and additional daily consumption of alcohol (OR: 1.49; 95% CI: 1.04-2.13) remained independently associated with positive anti-HCV serology.

Conclusions: These data support the need for early prevention strategies, namely, education of teachers in schools and further training of counsellors informing IDUs of what they can do to minimise the risk of becoming infected or of transmitting infectious agents to others.
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http://dx.doi.org/10.1023/a:1024603517136DOI Listing
November 2003

Alcohol consumption in heroin users, methadone-substituted and codeine-substituted patients--frequency and correlates of use.

Eur Addict Res 2003 Jan;9(1):45-50

Addiction Medicine, General Hospital Munich-Schwabing, Germany.

This retrospective study aims to determine whether there is a difference in the additional consumption of alcohol between addicts treated with methadone or dihydrocodeine (DHC) and untreated addicts injecting heroin. 1685 patients admitted for opioid withdrawal between 1991 and 1997 were reviewed. Cross-reference tables and multiple logistic regression analyses were carried out. 28% of patients take more than 40 g of alcohol daily (on average 176 g). We found that patients who are treated with methadone or DHC drink alcohol significantly more often daily than the heroin-dependent patients (p < 0.01). Using multiple regression analyses, the results were confirmed. Additionally, we found that co-abuse of alcohol was predicted by male gender, longer duration of drug use, additional daily consumption of tetrahydrocannabinol and daily consumption of benzodiazepines. Alcohol consumption by opioid-addicted patients treated with methadone or DHC presents a serious medical problem. Co-abuse of alcohol will receive more attention.
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http://dx.doi.org/10.1159/000067733DOI Listing
January 2003
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