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  • 1. Di Paolo, Antonello
    et al.
    Tascini, Carlo
    Polillo, Marialuisa
    Gemignani, Giulia
    Nielsen, Elisabet I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bocci, Guido
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Menichetti, Francesco
    Danesi, Romano
    Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections2013In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 42, no 3, p. 250-255Article in journal (Refereed)
    Abstract [en]

    A population pharmacokinetic analysis of daptomycin was performed based on therapeutic drug monitoring (TDM) data from 58 patients receiving doses of 4–12 mg/kg for the treatment of severe Gram-positive infections. At a daily dose of 8 mg/kg, daptomycin plasma concentrations (mean ± S.D.) were 76.9 ± 9.8 mg/L at the end of infusion and 52.7 ± 15.4 mg/L and 11.4 ± 5.4 mg/L at 0.5 h and 23 h after drug administration, respectively. The final model was a one-compartmental model with first-order elimination, with estimated clearance (CL) of 0.80 ± 0.14 L/h and a volume of distribution (Vd) of 0.19 ± 0.05 L/kg. Creatinine clearance (CLCr) was identified as having a significant influence on daptomycin CL, and a decrease in CLCr of 30 mL/min from the median value (80 mL/min) was associated with a reduction of daptomycin CL from 0.80 L/h to 0.73 L/h. These results confirm that the presence of severe infection may be associated with an altered disposition of daptomycin, with an increased Vd. MICs were available in 41 patients and results showed that 38 and 31 subjects achieved AUC/MIC values associated with bacteriostatic (>400) and bactericidal effects (>800), respectively. Of note, 31 of these 41 subjects experienced a clinical improvement or were cured. Although daptomycin pharmacokinetics may be influenced by infections, effective AUC/MIC values were achieved in the majority of patients. The present model may be applied in clinical settings for a TDM routine on the basis of a sparse blood sampling protocol.

  • 2.
    Jönsson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Macrolide resistance can be transferred by conjugation from viridans streptococci to Streptococcus pyogenes2006In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 28, no 2, p. 101-103Article in journal (Refereed)
    Abstract [en]

    Efflux pumps encoded by mef genes are among the most common mechanisms of resistance to macrolides. These genes are often located on horizontally transferable elements such as transposons. We present data indicating conjugative transfer of the mef(E) gene from viridans streptococci to the pathogen Streptococcus pyogenes. The mef(E) gene is located on the previously described MEGA (macrolide efflux genetic assembly) element. Of 110 isolates tested, 85% of those that carried the mef(A/E) gene carried it on MEGA, and in all cases of conjugal transfer of the mef(E) gene it was carried on MEGA. It therefore appears reasonable to draw the conclusion that this element is important in the lateral transfer of macrolide resistance between streptococci.

  • 3.
    Karaiskos, Ilias
    et al.
    Hygeia Gen Hosp, Dept Internal Med 6, Athens, Greece.;Hygeia Gen Hosp, 4 Erythrou Stavrou Str & Kifisias, Athens 15123, Greece..
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Galani, Lambrini
    Hygeia Gen Hosp, Dept Internal Med 6, Athens, Greece..
    Ioannidis, Konstantinos
    Hygeia Gen Hosp, 4 Erythrou Stavrou Str & Kifisias, Athens 15123, Greece..
    Katsouda, Emmanouela
    Hygeia Gen Hosp, Intens Care Unit, Athens, Greece..
    Athanassa, Zoe
    Hygeia Gen Hosp, Intens Care Unit, Athens, Greece..
    Paskalis, Harris
    Hygeia Gen Hosp, Intens Care Unit, Athens, Greece..
    Giamarellou, Helen
    Hygeia Gen Hosp, Dept Internal Med 6, Athens, Greece..
    Challenge for higher colistin dosage in critically ill patients receiving continuous venovenous haemodiafiltration2016In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 48, no 3, p. 337-341Article in journal (Refereed)
    Abstract [en]

    Traditionally, reduced daily doses of colistin methanesulphonate (CMS) in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF) have resulted in suboptimal colistin concentrations. The necessity of a loading dose (LD) at treatment initiation has been proposed. A LD of 9 million IU (MU) [ca. 270 mg of colistin base activity (CBA)] was administrated with a maintenance dose of 4.5 MU (ca. 140 mg CBA) every 12 h (q12h) to eight critically ill patients receiving renal replacement therapy. Blood samples were collected immediately before and at different time intervals after the LD and the fourth dose, whilst pre-filter and post-filter blood samples were also collected. CMS and colistin concentrations were determined using an LC-MS/MS assay. Median maximum observed concentrations after the LD were 22.1 mg/L for CMS and 1.55 mg/L for colistin, whereas during maintenance dosing the corresponding values were 12.6 mg/L and 1.72 mg/L, respectively. CVVHDF clearance was determined as 2.98 L/h for colistin, equivalent to 62% of total apparent colistin clearance in CVVHDF patients. Both CMS and colistin were cleared by CVVHDF. Application of a LD of 9 MU CMS resulted in more rapid achievement of the target colistin concentration. Following implementation of a predicted pharmacokinetic model on plasma CMS/colistin concentrations, a LD of 12 MU CMS appears more appropriate, whilst a CMS maintenance dosage of at least 6.5-7.5 MU q12h is suggested in patients undergoing CVVHDF. However, further clinical studies are warranted to assess the safety of a LD of 12 MU CMS in patients receiving CVVHDF.

  • 4.
    Khan, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Malmberg, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Kristoffersson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gullberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cao, Sha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli2018In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 51, no 3, p. 399-406, article id S0924-8579(17)30392-8Article in journal (Refereed)
    Abstract [en]

    Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection.

  • 5. Kondori, N.
    et al.
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Dolphin, G. T.
    Mattsby-Baltzer, I.
    Fungicidal activity of human lactoferrin-derived peptides based on the antimicrobial alpha beta region2011In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 37, no 1, p. 51-57Article in journal (Refereed)
    Abstract [en]

    Owing to the increasing number of infections in hospitalised patients caused by resistant strains of fungi, there is a need to develop new therapeutic agents for these infections. Naturally occurring antimicrobial peptides may constitute models for developing such agents. A modified peptide sequence (CFQWKRAM-RKVR; HLopt2) based on amino acid residues 20-31 of the N-terminal end of human lactoferrin (hLF) as well as a double-sized human lactoferricin-like peptide (amino acid residues 16-40; HLBD1) were investigated for their antifungal activities in vitro and in vivo. By in vitro assay, HLopt2 was fungicidal at concentrations of 12.5-25 mu g/mL against Cryptococcus neoformans, Candida albicans, Candida krusei, Candida kefyr and Candida parapsilosis, but not against Candida glabrata. HLopt2 was demonstrated to have >= 16-fold greater killing activity than HLBD1. By inducing some helical formation caused by lactam bridges or by extending the assay time (from 2 h to 20 h), HLBD1 became almost comparable with HLopt2 in its fungicidal activity. Killing of C. albicans yeast cells by HLopt2 was rapid and was accompanied by cytoplasmic and mitochondrial membrane permeabilisation as well as formation of deep pits on the yeast cell surface. In a murine C. albicans skin infection model, atopic treatment with the peptides resulted in significantly reduced yields of Candida from the infected skin areas. The antifungal activities of HLopt2 in vitro and in vivo suggest possible potential as a therapeutic agent against most Candida spp. and C. neoformans. The greatly improved antifungal effect of the lactam-modified HLBD1 indicates the importance of amphipathic helix formation for lethal activity.

  • 6. Kostamo, Pirkko
    et al.
    Veijola, Lea
    Oksanen, Aino
    Sarna, Seppo
    Rautelin, Hilpi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Recent trends in primary antimicrobial resistance of Helicobacter pylori in Finland2011In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 37, no 1, p. 22-25Article in journal (Refereed)
    Abstract [en]

    The antimicrobial susceptibility of Helicobacter pylori is an important predictor of the success of eradication therapy. To evaluate recent changes in primary antimicrobial resistance of H. pylori isolated from Finnish patients, the clinical records of H. pylori-positive patients referred for endoscopy to Herttoniemi Hospital (Helsinki, Finland) during 2000-2008 were investigated retrospectively. Stored H. pylori strains from 505 patients without previous eradication therapy were tested for clarithromycin, metronidazole, levofloxacin, tetracycline and amoxicillin susceptibility by Etest. Data on local consumption of antimicrobials were collected and correlations between consumption and resistance were calculated. During the 9-year study period, metronidazole resistance was high (range 29-59%, overall 41%). After an initial increase in clarithromycin resistance (0% in 2000 to 16% in 2003), resistance to clarithromycin decreased to 4% in 2008. No significant correlation was detected between consumption of macrolides and resistance of clarithromycin. Resistance to levofloxacin varied between 0% and 12%. Primary metronidazole resistance in H. pylori is at a high level, however levofloxacin and clarithromycin resistances are still at a reasonable level. Thus, primary clarithromycin resistance in H. pylori in Finland has not become such a problem as in many other countries. Primary resistance to the antimicrobials studied varied considerably from year to year.

  • 7.
    Littmann, Jasper
    et al.
    Univ Kiel, Inst Expt Med, Div Biomed Eth, D-24105 Kiel, Germany..
    Buyx, Alena
    Univ Kiel, Inst Expt Med, Div Biomed Eth, D-24105 Kiel, Germany..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Antibiotic resistance: An ethical challenge2015In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 46, no 4, p. 359-361Article in journal (Refereed)
    Abstract [en]

    In this paper, we argue that antibiotic resistance (ABR) raises a number of ethical problems that have not yet been sufficiently addressed. We outline four areas in which ethical issues that arise in relation to ABR are particularly pressing. First, the emergence of multidrug-resistant and extensively drug-resistant infections exacerbates traditional ethical challenges of infectious disease control, such as the restriction of individual liberty for the protection of the public's health. Second, ABR raises issues of global distributive justice, both with regard to the overuse and lack of access to antibiotics. Third, the use of antibiotics in veterinary medicine raises serious concerns for animal welfare and sustainable farming practices. Finally, the diminishing effectiveness of antibiotics leads to questions about intergenerational justice and our responsibility for the wellbeing of future generations. We suggest that current policy discussions should take ethical conflicts into account and engage openly with the challenges that we outline in this paper.

  • 8.
    Marcusson, Linda L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindgren, Patricia Komp
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Olofsson, Sara K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Mutant prevention concentrations of pradofloxacin for susceptible and mutant strains of Escherichia coli with reduced fluoroquinolone susceptibility2014In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 44, no 4, p. 354-357Article in journal (Refereed)
    Abstract [en]

    Pharmacodynamic and mutant prevention properties of the fluoroquinolone pradofloxacin (PRA) were measured against a set of 17 Escherichia coli strains carrying no, one or two known mutations conferring reduced fluoroquinolone susceptibility. The strains included susceptible wild-types, isogenic constructed mutants, isogenic selected mutants and clinical isolates. The effectiveness of PRA was determined with regard to preventing the selection of resistant mutants, using static and changing concentrations of drug. Ciprofloxacin was used as a reference drug. Minimum inhibitory concentrations (MICs) and mutant prevention concentrations (MPCs) of PRA for the susceptible wild-type strains were in the range 0.012-0.016 mg/L and 0.2-0.3 mg/L, respectively, giving a mean +/- standard deviation mutant prevention index (MPI=MPC/MIC) of 17.7 +/- 1.1. The mean MPI PRA of the 14 mutant strains was 19.2 +/- 12, and the mean MPI across all 17 strains was 18.9 +/- 10.8. In an in vitro kinetic model in which PRA was diluted with a half-life of 7h to mimic in vivo conditions, an initial concentration of PRA of 1.6-2.4 mg/L (8-10x MPC), giving a PRA AUC/MPC ratio of 73-92, and a T->MPC of 21-23 h was sufficient to prevent the selection of resistant mutants from the three susceptible wild-type strains. Dosing to reduce selection for antibiotic resistance in veterinary therapy has a role in reducing the reservoir of resistant mutants. We conclude that a level of dosing that prevents the selection of resistant mutants during therapy should be achievable in vivo.

  • 9.
    Pulcini, Celine
    et al.
    Univ Lorraine, Ctr Hosp Reg Univ CHRU Nancy, Fac Med, Serv Malad Infect & Trop, Rue Morvan, F-54511 Nancy, France..
    Mohrs, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Beovic, Bojana
    Univ Med Ctr Ljubljana, Ljubljana, Slovenia..
    Gyssens, Inge
    Radboud Univ Nijmegen, Med Ctr, Dept Med, Nijmegen, Netherlands.;Canisius Wilhelmina Hosp, Dept Med Microbiol & Infect Dis, Nijmegen, Netherlands.;Hasselt Univ, Hasselt, Belgium..
    Theuretzbacher, Ursula
    Ctr Antiinfect Agents, Vienna, Austria..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Forgotten antibiotics: a follow-up inventory study in Europe, the USA, Canada and Australia2017In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 49, no 1, p. 98-101Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to update a 2011 survey, conducted on behalf of the ESCMID Study Group for Antibiotic Policies (ESGAP), studying the availability of old but clinically useful antibiotics in North America, Europe and Australia. This follow-up survey was performed in 2015 in 40 countries among specialists from the pharmaceutical, infectious diseases and microbiology sectors in North America, Europe and Australia in order to assess the availability through usual marketing processes of 36 systemic antibiotics (addition of 3 antibiotics compared with the 2011 survey) selected for their ability to treat infections caused by resistant bacteria and their unique value for specific criteria. The questionnaire was sent by e-mail to national contacts belonging to ESGAP and ReAct networks. In all, 39 of the 40 countries participated in this survey. The number of available antibiotics differed considerably from one drug to another as well as from one country to another (e.g. 7 antibiotics available in Estonia, 24 in France). Overall, 25/36 selected antibiotics were marketed in 20/39 countries or less. From 2011 to 2015 (data available for both periods in 37 countries for 33 antibiotics), the number of available selected antibiotics increased in 13 countries and decreased in 17. In conclusion, despite the ongoing bacterial resistance crisis, the situation regarding the availability of 'forgotten antibiotics' has worsened since 2011. Urgent measures are needed to ensure better availability of these antibiotics on a global scale as a conservation measure to ensure sustainable and responsible use of antibiotics. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

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