| 1. |
- Frimodt-Møller, Niels, et al.
(författare)
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Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models
- 2024
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 64:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed.MethodsThe resistance gene annotations of 40 888 blood-culture isolates were analysed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for a total of nine Escherichia coli and Klebsiella pneumoniae isolates.ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10-9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia.ConclusionEncouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI.
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| 2. |
- Sou, Tomás, et al.
(författare)
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Model-Informed Drug Development for Antimicrobials : Translational PK and PK/PD Modeling to Predict an Efficacious Human Dose for Apramycin
- 2021
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 109:4, s. 1063-1073
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Tidskriftsartikel (refereegranskat)abstract
- Apramycin represents a subclass of aminoglycoside antibiotics that has been shown to evade almost all mechanisms of clinically relevant aminoglycoside resistance. Model-informed drug development may facilitate its transition from preclinical to clinical phase. This study explored the potential of pharmacokinetic/pharmacodynamic (PK/PD) modeling to maximize the use of in vitro time-kill and in vivo preclinical data for prediction of a human efficacious dose (HED) for apramycin. PK model parameters of apramycin from four different species (mouse, rat, guinea pig, and dog) were allometrically scaled to humans. A semimechanistic PK/PD model was developed from the rich in vitro data on four Escherichia coli strains and subsequently the sparse in vivo efficacy data on the same strains were integrated. An efficacious human dose was predicted from the PK/PD model and compared with the classical PK/PD index methodology and the aminoglycoside dose similarity. One-compartment models described the PK data and human values for clearance and volume of distribution were predicted to 7.07 L/hour and 26.8 L, respectively. The required fAUC/MIC (area under the unbound drug concentration-time curve over MIC ratio) targets for stasis and 1-log kill in the thigh model were 34.5 and 76.2, respectively. The developed PK/PD model predicted the efficacy data well with strain-specific differences in susceptibility, maximum bacterial load, and resistance development. All three dose prediction approaches supported an apramycin daily dose of 30 mg/kg for a typical adult patient. The results indicate that the mechanistic PK/PD modeling approach can be suitable for HED prediction and serves to efficiently integrate all available efficacy data with potential to improve predictive capacity.
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| 3. |
- Juhas, Mario, et al.
(författare)
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In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 944-952
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Widespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.Methods: A thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.Results: MIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.Conclusions: Its superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.
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| 4. |
- Björnsson Hallgren, Hanna C, et al.
(författare)
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Specific exercises for subacromial pain : Good results maintained for 5 years
- 2017
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Ingår i: Acta Orthopaedica. - : Taylor & Francis. - 1745-3674 .- 1745-3682. ; 88:6, s. 600-605
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose — We have previously shown that specific exercises reduced the need for surgery in subacromial painpatients at 1-year follow-up. We have now investigated whetherthis result was maintained after 5 years and compared the outcomesof surgery and non-surgical treatment.Patients and methods — 97 patients were included in the previouslyreported randomized study of patients on a waiting list forsurgery. These patients were randomized to specifi c or unspecifi cexercises. After 3 months of exercises the patients were asked ifthey still wanted surgery and this was also assessed at the present5-year follow-up. The 1-year assessment included Constant–Murley score, DASH, VAS at night, rest and activity, EQ-5D, andEQ-VAS. All these outcome assessments were repeated after 5years in 91 of the patients.Results — At the 5-year follow-up more patients in the specifi cexercise group had declined surgery, 33 of 47 as compared with16 of 44 (p = 0.001) in the unspecifi c exercise group. The meanConstant–Murley score continued to improve between the 1- and5-year follow-ups in both surgically and non-surgically treatedgroups. On a group level there was no clinically relevant changebetween 1 and 5 years in any of the other outcome measuresregardless of treatment.Interpretation — This 5-year follow-up of a previously publishedrandomized controlled trial found that specifi c exercisesreduced the need for surgery in patients with subacromial pain.Patients not responding to specifi c exercises may achieve similargood results with surgery. These fi ndings emphasize that a specifi cexercise program may serve as a selection tool for surgery.
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| 5. |
- Petersson, Anna, 1973-
(författare)
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Characteristics and Consequences of Use of Anabolic Androgenic Steroids in Poly Substance Abuse
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The use of anabolic androgenic steroids (AAS) has been associated with use of illegal or unprescribed prescription drugs, as well as different adverse psychiatric effects, such as ma-nia, psychosis and hostility. Further, there is an association between use of AAS and other different risk behaviours, including carrying guns and reckless driving. Taken together, these data suggest that there is a group of AAS users that are not elite athletes, but rather young men at risk for psychiatric illness and criminality, and who use AAS primarily for their aes-thetic effects and possibly for their psychoactive effects. The aim of this thesis is to investi-gate further the connection between use of AAS and use of other drugs, and to investigate whether the proposed side effects of AAS cause an increase in morbidity and mortality. The first study (Paper I) investigates morbidity and mortality in persons testing positive for AAS compared to persons testing negative for AAS at a doping laboratory. Paper II of this thesis studies the presence of psychoactive drugs in diseased men who tested positive for AAS upon autopsy and whether there is any difference between deceased users of AAS and deceased users of heroin or amphetamine (control group). The third article (Paper III) dis-cusses a surprising finding in paper I of increased seizures NOS in users of AAS. Paper IV and V are interview studies from an out-patient substance abuse clinic. The main findings in Paper I was that the majority of deceased users of AAS were also positive for other drugs and/or alcohol on autopsy, and that users of AAS more often than the control group had died from intentional death (suicide or homicide). The main finding of Paper II was that users of AAS were severely at risk for premature death compared to both the control group and the general population. Paper III concluded that the high prevalence of Convulsion NOS in users of AAS most likely was the result of concomitant substance abuse and withdrawal from such use. Paper IV concluded that twelve percent of the patients at the substance abuse clinic had used AAS for at least one cycle. Users of AAS had a higher risk of having been convicted of a violent offence, and users of AAS more often reported having been physically abused. In Paper V, long-terme users of AAS were found to have an increased risk for developing depression in connection with cessation of AAS use. AAS was also re-ported to be used in preparation for crime. In summary, this thesis concludes that there is a solid association between use of AAS and use of other psychotropic drugs in certain subpopulations, and that users of AAS are at risk for premature death due to unnatural causes that may be secondary to use of AAS.
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