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  • 1. Ahlqvist Rastad, Jane
    et al.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Norman, Christer
    Lågdos-DT bättre än vanlig röntgen vid diagnostik av rinosinuit - en kommentar från Läkemedelsverket och Strama2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 46, p. 3478-Article in journal (Other academic)
    Abstract [en]

    [Low dosage CT better than conventional radiography in the diagnosis of rhinosinusitis--a comment from the Medical Products Agency and Strama]

  • 2.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Securing access to effective antibiotics for current and future generations. Whose responsibility?2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 209-214Article in journal (Other academic)
  • 3.
    Cars, Otto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Mölstad, Sigvard
    Norman, Christer
    Ternhag, Anders
    André, Malin
    Erntell, Mats
    Replik från Smittskyddsinstitutet och Strama-rådet: Nationella rekommendationer för behandling av faryngotonsillit gäller2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 3, p. 108-109Article in journal (Refereed)
  • 4. Daulaire, Nils
    et al.
    Bang, Abhay
    Tomson, Goran
    Kalyango, Joan N.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Universal Access to Effective Antibiotics is Essential for Tackling Antibiotic Resistance2015In: Journal of Law, Medicine & Ethics, ISSN 1073-1105, E-ISSN 1748-720X, Vol. 43, no S3, p. 17-21Article in journal (Refereed)
    Abstract [en]

    Universal access to effective antimicrobials is essential to the realization of the right to health. At present, 5.7 million people die from treatable infections each year because they lack this access. Yet, community-based diagnosis and appropriate treatment for many of the leading causes of avoidable infectious deaths has been shown to be feasible and effective, demonstrating that strategies to reach the under-served need to receive high priority. This is a necessary part of a broad strategy to assure the long-term benefits of antimicrobials and to combat antimicrobial resistance, both because the lack of systematic and rigorous efforts to assure effective coverage increases the likelihood of antimicrobial resistance, and because global efforts aimed at antimicrobial stewardship and innovation cannot succeed without explicitly addressing the needs of the under-served. Elements of this strategy will include clear evidence-based treatment protocols, a robust international framework and locally tailored regulations, active engagement with communities and local health providers, strong attention to program management and cost considerations, a focus on the end user, and robust surveillance and response to emerging resistance patterns. Only by balancing the needs of universal access with stewardship and innovation, and assuring that they are mutually reinforcing can a global strategy hope to effectively address antimicrobial resistance.

  • 5. Goossens, Herman
    et al.
    Guillemot, Didier
    Ferech, Matus
    Schlemmer, Benoit
    Costers, Michiel
    van Breda, Marije
    Baker, Lee J
    Cars, Otto
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Davey, Peter G
    National campaigns to improve antibiotic use.2006In: Eur J Clin Pharmacol, ISSN 0031-6970, Vol. 62, no 5, p. 373-9Article in journal (Refereed)
  • 6.
    Gustafsson, Ingegerd
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Sjölund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Torell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Johannesson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Andersson, Dan I.
    Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage2003In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 52, no 4, p. 645-650Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We examined how prolonged antibiotic treatment affected the resistance and mutation frequency of human microflora isolated from intestine (Escherichia coli, enterococci spp.), pharynx (alpha-streptococci) and nostril (coagulase-negative staphylococci, CoNS).

    METHODS: Samples were collected from patients at the Center of Cystic Fibrosis (n=18) and the haematology ward (n=18) of the University Hospital, Uppsala, Sweden. The individually used amount of antibiotics for 1 year was recorded as the defined daily dose (DDD). Primary health care patients (n=30), with no antibiotic treatment for 1 year before sampling, were used as controls. Three isolates of each bacterium from each patient were examined. Antibiotic susceptibilities were determined by disc diffusion. Mutation frequencies to rifampicin resistance were measured on 30 independent cultures of each bacterial species from each individual by plating on rifampicin agar plates. For alpha-streptococci the mutation frequency to streptomycin resistance was also determined.

    RESULTS: Isolates from patients with high antibiotic use showed a pronounced shift towards increased resistance and a small but significant increase in the mutation frequency compared with isolates from the controls. For E. coli, enterococci and CoNS the increase in geometric mean mutation frequency in the patient group was 3-, 1.8- and 1.5-fold, respectively (P values 0.0001, 0.016 and 0.012). For alpha-streptococci there was a significant difference in geometric mean mutation frequency between patient and control groups for streptomycin resistance (P=0.024) but not for rifampicin resistance (P=0.74).

    CONCLUSIONS: High antibiotic use selected for commensals with highly increased resistance and a slight increase in mutation frequency.

  • 7.
    Heyman, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bejarano, Maria-Teresa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Access, excess, and ethics—towards a sustainable distribution model for antibiotics2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 134-141Article, review/survey (Refereed)
    Abstract [en]

    The increasing antibiotic resistance is a global threat to health care as we know it. Yet there is no model of distribution ready for a new antibiotic that balances access against excessive or inappropriate use in rural settings in low-and middle-income countries (LMICs) where the burden of communicable diseases is high and access to quality health care is low. Departing from a hypothetical scenario of rising antibiotic resistance among pneumococci, 11 stakeholders in the health systems of various LMICs were interviewed one-on-one to give their view on how a new effective antibiotic should be distributed to balance access against the risk of inappropriate use. Transcripts were subjected to qualitative 'framework' analysis. The analysis resulted in four main themes: Barriers to rational access to antibiotics; balancing access and excess; learning from other communicable diseases; and a system-wide intervention. The tension between access to antibiotics and rational use stems from shortcomings found in the health systems of LMICs. Constructing a sustainable yet accessible model of antibiotic distribution for LMICs is a task of health system-wide proportions, which is why we strongly suggest using systems thinking in future research on this issue.

  • 8.
    Hickman, Rachel A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Cars, Thomas
    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.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cell-wall-inhibiting antibiotic combinations with activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli2014In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 4, p. O267-O273Article in journal (Refereed)
    Abstract [en]

    The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is rapidly limiting the options for effective antibiotic therapy. Systematic studies on combinations of already available antibiotics that could provide an effective treatment against MDR bacteria are needed. We tested combinations of antibiotics that target one important physiological function (peptidoglycan synthesis) at several steps, and studied Enterobacteriaceae (Klebsiella pneumoniae and Escherichia coli) for which multidrug resistance associated with ESBL-producing plasmids has become a major problem. To measure the effectiveness of antibiotics alone and in combination, we used checkerboard assays, static antibiotic concentration time-kill assays, and an improved in-vitro kinetic model that simulates human pharmacokinetics of multiple simultaneously administered antibiotics. The target strains included an MDR K. pneumoniae isolate responsible for a recent major hospital outbreak. A double combination (fosfomycin and aztreonam) and a triple combination (fosfomycin, aztreonam and mecillinam) were both highly effective in reducing bacterial populations in all assays, including the in vitro kinetic model. These combinations were effective even though each of the MDR strains was resistant to aztreonam alone. Our results provide an initial validation of the potential usefulness of a combination of antibiotics targeting peptidoglycan synthesis in the treatment of MDR Gram-negative bacteria. We suggest that a combination of fosfomycin with aztreonam could become a useful treatment option for such infections and should be further studied.

  • 9. Hoffman, Steven J.
    et al.
    Outterson, Kevin
    Rottingen, John-Arne
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Clift, Charles
    Rizvi, Zain
    Rotberg, Fiona
    Tomson, Goran
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    An international legal framework to address antimicrobial resistance2015In: Bulletin of the World Health Organization, ISSN 0042-9686, E-ISSN 1564-0604, Vol. 93, no 2, p. 66-66Article in journal (Other academic)
  • 10. Hogberg, Liselotte
    et al.
    Oke, Thimothy
    Geli, Patricia
    Lundborg, Cecilia
    Cars, Otto
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Ekdahl, Karl
    Reduction in outpatient antibiotic sales for pre-school children: interrupted time series analysis of weekly antibiotic sales data in Sweden 1992-2002.2005In: J Antimicrob Chemother, ISSN 0305-7453, Vol. 56, no 1, p. 208-15Article in journal (Other scientific)
  • 11.
    Högberg, Liselotte Diaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Heddini, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The global need for effective antibiotics: challenges and recent advances2010In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 31, no 11, p. 509-515Article, review/survey (Refereed)
    Abstract [en]

    The emerging problem of antibiotic resistance is a serious threat to global public health. The situation is aggravated by a substantial decline in the research and development of antibacterial agents. Hence, very few new antibacterial classes are brought to market when older classes lose their efficacy. There has been renewed and growing attention within policy groups to: (i) address the problem; (ii) discuss incentives for the development of urgently needed new treatments; (iii) preserve the efficacy of existing therapeutic options. We briefly review the basic principles of antibiotic resistance, and contrast the increasing resistance to the dwindling antibacterial 'pipeline'. We also highlight some recent policy initiatives aiming to secure the future need of effective antibiotics.

  • 12.
    Högberg, Liselotte Diaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Muller, Arno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Monnet, Dominique L.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Antibiotic use worldwide2014In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 14, no 12, p. 1179-1180Article in journal (Refereed)
  • 13.
    Karvanen, Matti
    et al.
    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.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Colistin is Extensively Lost during Standard in Vitro Experimental Conditions2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 11, article id e00857-17Article in journal (Refereed)
    Abstract [en]

    Colistin adheres to a range of materials, including plastics in labware. The loss caused by adhesion influences an array of methods detrimentally, including MIC assays and in vitro time-kill experiments. The aim of this study was to characterize the extent and time course of colistin loss in different types of laboratory materials during a simulated time-kill experiment without bacteria or plasma proteins present. Three types of commonly used large test tubes, i.e., soda-lime glass, polypropylene, and polystyrene, were studied, as well as two different polystyrene microplates and low-protein-binding microtubes. The tested concentration range was 0.125 to 8 mg/liter colistin base. Exponential one-phase and two-phase functions were fitted to the data, and the adsorption of colistin to the materials was modeled with the Langmuir adsorption model. In the large test tubes, the measured start concentrations ranged between 44 and 102% of the expected values, and after 24 h, the concentrations ranged between 8 and 90%. The half-lives of colistin loss were 0.9 to 12 h. The maximum binding capacities of the three materials ranged between 0.4 and 1.1 μg/cm2, and the equilibrium constants ranged between 0.10 and 0.54 ml/μg. The low-protein-binding microtubes showed start concentrations between 63 and 99% and concentrations at 24 h of between 59 and 90%. In one of the microplates, the start concentrations were below the lower limit of quantification at worst. In conclusion, to minimize the effect of colistin loss due to adsorption, our study indicates that low-protein-binding polypropylene should be used when possible for measuring colistin concentrations in experimental settings, and the results discourage the use of polystyrene. Furthermore, when diluting colistin in protein-free media, the number of dilution steps should be minimized.

  • 14.
    Karvanen, Matti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Malmberg, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Reply to Prim et al., "Is Colistin Susceptibility Testing Finally on the Right Track?"2018In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 4, article id e02507-17Article in journal (Other academic)
  • 15.
    Karvanen, Matti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Plachouras, Diamantis
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Paramythiotou, Elisabeth
    Papadomichelakis, Evangelos
    Karaiskos, Ilias
    Tsangaris, Iraklis
    Armaganidis, Apostolos
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Giamarellou, Helen
    Colistin methanesulfonate and colistin pharmacokinetics in critically ill patients receiving continuous venovenous hemodiafiltration2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 1, p. 668-671Article in journal (Refereed)
    Abstract [en]

    This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (C(max)) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (f(m)) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.

  • 16.
    Khan, David D.
    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.
    Cao, Sha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lustig, Ulrika
    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.
    Cars, Otto
    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.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A mechanism-based pharmacokinetic/pharmacodynamic model allows prediction of antibiotic killing from MIC values for WT and mutants2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 11, p. 3051-3060Article in journal (Refereed)
    Abstract [en]

    Objectives: In silico pharmacokinetic/pharmacodynamic (PK/PD) models can be developed based on data from in vitro time-kill experiments and can provide valuable information to guide dosing of antibiotics. The aim was to develop a mechanism-based in silico model that can describe in vitro time-kill experiments of Escherichia coli MG1655 WT and six isogenic mutants exposed to ciprofloxacin and to identify relationships that may be used to simplify future characterizations in a similar setting. Methods: In this study, we developed a mechanism-based PK/PD model describing killing kinetics for E. coli following exposure to ciprofloxacin. WT and six well-characterized mutants, with one to four clinically relevant resistance mutations each, were exposed to a wide range of static ciprofloxacin concentrations. Results: The developed model includes susceptible growing bacteria, less susceptible (pre-existing resistant) growing bacteria, non-susceptible non-growing bacteria and non-colony-forming non-growing bacteria. The non-colony-forming state was likely due to formation of filaments and was needed to describe data close to the MIC. A common model structure with different potency for bacterial killing (EC50) for each strain successfully characterized the time-kill curves for both WT and the six E. coli mutants. Conclusions: The model-derived mutant-specific EC50 estimates were highly correlated (r(2) = 0.99) with the experimentally determined MICs, implying that the in vitro time-kill profile of a mutant strain is reasonably well predictable by the MIC alone based on the model.

  • 17.
    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.

  • 18.
    Komp Lindgren, Patricia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Higgins, Paul G
    Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50935 Cologne, Germany .
    Seifert, Harald
    Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50935 Cologne, Germany .
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Prevalence of hypermutators among clinical Acinetobacter baumannii isolates2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 3, p. 661-665Article in journal (Refereed)
    Abstract [en]

    Objectives: The objectives of this study were to study the presence of mutators in a set of Acinetobacter baumannii isolates and to explore whether there is a correlation between mutation rates and antibiotic resistance.

    Methods: The variation in mutation rate was evaluated for 237 clinical A. baumannii isolates by determining the frequency of their mutation to rifampicin resistance. For each isolate, the antibiotic resistance profile was determined by disc diffusion and/or Etest. Isolates were divided into susceptible, resistant and MDR groups according to their resistance to five groups of different antibiotics. A comparison between differences in mutation frequency (f) and strain-specific factors was performed.

    Results: Of the 237 isolates 32%, 18% and 50% were classified as susceptible, resistant and MDR, respectively. The f of rifampicin resistance varied between 2.2×10210 and 1.2×1026 . Of the strains under investigation, 16% had an ≥2.5- to 166-fold higher f. The presence of mutators (definition ≥2.5-fold increase in f compared with ATCC 19606) in the MDR group (22%) was significantly higher (P,0.05) than that in the susceptible and resistant groups (11% and 7%, respectively). Furthermore, f was significantly higher in the MDR group compared with that in the susceptible and resistant groups.

    Conclusions: The facts that 26 of 37 mutator isolates (70%) in the population were MDR and that there was a significantly higher general f in isolates exhibiting an MDR profile suggest that hypermutability can be of advantage for the organism in a selective environment with extensive exposure to antimicrobials.

  • 19.
    Komp Lindgren, Patricia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Klockars, Oscar
    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.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Pharmacodynamic studies of nitrofurantoin against common uropathogens2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 4, p. 1076-1082Article in journal (Refereed)
    Abstract [en]

    Objectives

     To determine the pharmacokinetic/pharmacodynamic index that best correlates to nitrofurantoin's antibacterial effect, we studied nitrofurantoin activity against common causative pathogens in uncomplicated urinary tract infection (UTI).

    Methods 

    Five isolates [two Escherichia coli (one isolate producing the ESBL CTX-M-15), two Enterococcus faecium (including one that was vancomycin resistant) and one Staphylococcus saprophyticus] were used. The MICs of nitrofurantoin were determined by Etest. Time–kill curves with different concentrations of nitrofurantoin (based on multiples of isolate-specific MICs) were followed over 24 h. An in vitro kinetic model was used to simulate different time–concentration profiles, exposing E. coli to nitrofurantoin for varying proportions of the dosing interval. The outcome parameters reduction in cfu 0–24 h (Δcfu0–24) and the area under the bactericidal curve (AUBC), were correlated with time over MIC (T>MIC) and area under the antibiotic concentration curve divided by the MIC (AUC/MIC).

    Results 

    A bactericidal effect at varying static drug concentrations was achieved for all isolates. All isolates showed similar kill curve profiles. In the kinetic model, the effect of nitrofurantoin on E. coli displayed a 4 log reduction in cfu/mL within 6 h at 8 × MIC. The outcome parameters Δcfu0–24 and AUBC had a good correlation with T>MIC (R ≈ 0.83 and R ≈ 0.67, respectively), whereas log(AUC/MIC) was significantly poorer (R ≈ 0.39 andR ≈ 0.53, respectively).

    Conclusions 

    Nitrofurantoin was highly effective against E. coli and S. saprophyticus isolates; the killing effect against E. faecium was not as rapid, but still significant. Against E. coli, nitrofurantoin was mainly associated with a concentration-dependent action; this was confirmed in the kinetic model, in which T>MIC displayed the best correlation.

  • 20.
    Laxminarayan, Ramanan
    et al.
    Ctr Dis Dynam Econ & Policy, Washington, DC 20005 USA.;Princeton Univ, Princeton Environm Inst, Princeton, NJ 08544 USA.;Publ Hlth Fdn India, New Delhi, India..
    Amabile-Cuevas, Carlos F.
    Fdn Lusara Invest Cient, Mexico City, DF, Mexico..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Evans, Timothy
    World Bank, 1818 H St NW, Washington, DC 20433 USA..
    Heymann, David L.
    Ctr Global Hlth Secur, Chatham House, London, England..
    Hoffman, Steven
    Univ Ottawa, Ottawa, ON, Canada..
    Holmes, Alison
    Imperial Coll, London, England..
    Mendelson, Marc
    Univ Cape Town, Cape Town, South Africa..
    Sridhar, Devi
    Univ Edinburgh, Edinburgh, Midlothian, Scotland..
    Woolhouse, Mark
    Univ Edinburgh, Edinburgh, Midlothian, Scotland..
    Rottingen, John-Arne
    Norwegian Inst Publ Hlth, Oslo, Norway.;Univ Oslo, Inst Hlth & Soc, Oslo, Norway.;Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
    UN High-Level Meeting on antimicrobials-what do we need?2016In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, no 10041, p. 218-220Article in journal (Other academic)
  • 21. Laxminarayan, Ramanan
    et al.
    Duse, Adriano
    Wattal, Chand
    Zaidi, Anita K. M.
    Wertheim, Heiman F. L.
    Sumpradit, Nithima
    Vlieghe, Erika
    Levy Hara, Gabriel
    Gould, Ian M.
    Goossens, Herman
    Greko, Christina
    So, Anthony D.
    Bigdeli, Maryam
    Tomson, Goeran
    Woodhouse, Will
    Ombaka, Eva
    Peralta, Arturo Quizhpe
    Qamar, Farah Naz
    Mir, Fatima
    Kariuki, Sam
    Bhutta, Zulfigar A.
    Coates, Anthony
    Bergstrom, Richard
    Wright, Gerard D.
    Brown, Eric D.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Antibiotic resistance-the need for global solutions2013In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 13, no 12, p. 1057-1098Article in journal (Refereed)
    Abstract [en]

    The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

  • 22.
    Lignell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Johansson, A.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A new in-vitro kinetic model to study the pharmacodynamics of antifungal agents: inhibition of the fungicidal activity of amphotericin B against Candida albicans by voriconazole2007In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 13, no 6, p. 613-619Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop and validate a new in-vitro kinetic model for the combination of two drugs with different half-lives, and to use this model for the study of the pharmacodynamic effects of amphotericin B and voriconazole, alone or in combination, against a strain of Candida albicans. Bolus doses of voriconazole and amphotericin B were administered to a starting inoculum of C. albicans. Antifungal-containing medium was eliminated and replaced by fresh medium using a peristaltic pump, with the flow-rate adjusted to obtain the desired half-life of the drug with the shorter half-life. A computer-controlled dosing pump compensated for the agent with the longer half-life. Voriconazole and amphotericin B half-lives were set to 6 and 24 h, respectively. Pharmacokinetic parameters were close to target values when both single doses and sequential doses were simulated. Voriconazole and amphotericin B administered alone demonstrated fungistatic and fungicidal activity, respectively. Simultaneous administration resulted in fungicidal activity, whereas pre-exposure of C. albicans to voriconazole, followed by amphotericin at 8 and 32 h, resulted in fungistatic activity similar to that observed with voriconazole alone. Using this model, which allowed a combination of antifungal agents with different half-lives, it was possible to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of amphotericin B. The characteristics and clinical relevance of this interaction require further investigation.

  • 23.
    Lignell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Chryssanthou, Erja
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Posaconazole in human serum: A greater pharmacodynamic effect than predicted by the non-protein-bound serum concentration2011In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 55, no 7, p. 3099-3104Article in journal (Refereed)
    Abstract [en]

    It is generally accepted that only the unbound fraction of a drug is pharmacologically active. Posaconazole is an antifungal agent with a protein binding of 98 to 99%. Taking into account the degree of protein binding, plasma levels in patients, and MIC levels of susceptible strains, it can be assumed that the free concentration of posaconazole sometimes will be too low to exert the expected antifungal effect. The aim was therefore to test the activity of posaconazole in serum in comparison with that of the calculated unbound concentrations in protein-free media. Significant differences (P < 0.05) from the serum control were found at serum concentrations of posaconazole of 1.0 and 0.10 mg/liter, with calculated free concentrations corresponding to 1× MIC and 0.1× MIC, respectively, against one Candida lusitaniae strain selected for proof of principle. In RPMI 1640, the corresponding calculated unbound concentration of 0.015 mg/liter resulted in a significant effect, whereas that of 0.0015 mg/liter did not. Also, against seven additional Candida strains tested, there was an effect of the low posaconazole concentration in serum, in contrast to the results in RPMI 1640. Fluconazole, a low-grade-protein-bound antifungal, was used for comparison at corresponding concentrations in serum and RPMI 1640. No effect was observed at the serum concentration, resulting in a calculated unbound concentration of 0.1× MIC. In summary, there was a substantially greater pharmacodynamic effect of posaconazole in human serum than could be predicted by the non-protein-bound serum concentration. A flux from serum protein-bound to fungal lanosterol 14α-demethylase-bound posaconazole is suggested.

  • 24.
    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.

  • 25. Lytsy, Birgitta
    et al.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Torell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kinoloner - bot som blivit hot: Accelererande resistensutveckling kräver skärpta indikationer2005In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 102, no 48, p. 3651-3659Article in journal (Refereed)
    Abstract [en]

    Fluoroquinolones are important antibiotics for treatment of serious infections. Increased usage has, in many countries, resulted in rapid development of resistance towards this class of antibiotics. Moreover, it has been shown that use of fluoroquinolones is associated with selection of multi-resistant bacteria, such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. The risks related to overuse of fluoroquinolones among both humans and animals are reviewed and strict indications for use are suggested.

  • 26.
    Malmberg, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Gradientech AB, Uppsala, Sweden..
    Yuen, Pikkei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Spaak, Johanna
    Gradientech AB, Uppsala, Sweden..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A Novel Microfluidic Assay for Rapid Phenotypic Antibiotic Susceptibility Testing of Bacteria Detected in Clinical Blood Cultures2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0167356Article in journal (Refereed)
    Abstract [en]

    Background Appropriate antibiotic therapy is critical in the management of severe sepsis and septic shock to reduce mortality, morbidity and health costs. New methods for rapid antibiotic susceptibility testing are needed because of increasing resistance rates to standard treatment. Aims The purpose of this study was to evaluate the performance of a novel microfluidic method and the potential to directly apply this method on positive blood cultures. Methods Minimum inhibitory concentrations (MICs) of ciprofloxacin, ceftazidime, tigecycline and/or vancomycin for Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus were determined using a linear antibiotic concentration gradient in a microfluidic assay. Bacterial growth along the antibiotic gradient was monitored using automated time-lapse photomicrography and growth inhibition was quantified by measuring greyscale intensity changes in the images. In addition to pure culture MICs, vancomycin MICs were determined for S. aureus from spiked and clinical blood cultures following a short centrifugation step. The MICs were compared with those obtained with the Etest and for S. aureus and vancomycin also with macrodilution. Results The MICs obtained with the microfluidic assay showed good agreement internally as well as with the Etest and macrodilution assays, although some minor differences were noted between the methods. The time to possible readout was within the range of 2 to 5 h. Conclusions The examined microfluidic assay has the potential to provide rapid and accurate MICs using samples from positive clinical blood cultures and will now be tested using other bacterial species and antibiotics.

  • 27.
    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.

  • 28. Melander, Eva
    et al.
    Burman, Lars G
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Antibiotikaresistenta S aureus ger ökad dödlighet och dyrare sjukvård2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 42, p. 3052-3056Article in journal (Other academic)
    Abstract [sv]

    En litteraturgenomgång kring konsekvenserna av meticillinresistens vid S aureus-bakteriemi visar att MRSA-bakteriemi är förenad med en signifikant ökad risk för dödlig utgång jämfört med MSSA-bakteriemi samt att behandling av MRSA-bakteriemi är 1,5–3 gånger dyrare än behandling av MSSA-bakteriemi.

    Under 1990-talet fördubblades antalet S aureus-bakteriemier i Storbritannien, huvudsakligen på grund av spridning av två epidemiska MRSA-stammar på brittiska sjukhus. En utveckling i Sverige till en situation liknande den i Storbritannien skulle grovt räknat innebära ett tillskott av 637 dödsfall årligen och kraftigt ökade kostnader.

    Eftersom utvecklingen av antibiotika med nya verkningsmekanismer står stilla är det högaktuellt att vi vidtar åtgärder mot fortsatt spridning av antibiotikaresistens i Sverige.

  • 29.
    Mohamed, Ami F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A pharmacokinetic/pharmacodynamic model developed for the effect of colistin on Pseudomonas aeruginosa in vitro with evaluation of population pharmacokinetic variability on simulated bacterial killing2014In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 5, p. 1350-1361Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: An optimized dosing regimen of the prodrug of colistin, colistin methanesulphonate (CMS), against resistant Pseudomonas aeruginosa is needed to ensure effective bacterial killing. The objectives of this study were to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model that characterizes the time course of the antibacterial activity of colistin against P. aeruginosa in a static in vitro system and to perform simulations of different dosing regimens and dosing algorithms to evaluate the effect of interindividual variability and interoccasion variability in PK on bacterial killing.

    METHODS: Static in vitro time-kill curve experiments were conducted on two different strains of P. aeruginosa (MIC 1 and 1.5 mg/L). Mechanism-based PK/PD models were fitted in NONMEM7 and the final model was combined with a previously developed population PK model of CMS and colistin to perform simulations of variability based on different dosing algorithms.

    RESULTS: A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of colistin to reduce upon increasing colistin exposure, characterized both the fast bactericidal effect and the adaptive resistance. The variability in PK was shown to translate into pronounced interoccasion variability in bacterial killing. A flat fixed loading dose was demonstrated to result in less variability than an algorithm based on weight.

    CONCLUSIONS: The developed PK/PD model described the growth, death and resistance development of P. aeruginosa in response to colistin for two different strains. Based on simulations, a flat fixed loading dose followed by an 8 or 12 hourly maintenance dose with an infusion duration of up to 2 h appeared adequate.

  • 30.
    Mohamed, Ami F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kristoffersson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karvanen, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nielsen, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1279-1290Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa.

    METHODS: In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem.

    RESULTS: A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h.

    CONCLUSIONS: The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance.

  • 31.
    Mohamed, Ami F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetic-pharmacodynamic model for gentamicin and its adaptive resistance with predictions of dosing schedules in newborn infants2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 1, p. 179-188Article in journal (Refereed)
    Abstract [en]

    Gentamicin is commonly used in the management of neonatal infections. Development of adaptive resistance is typical for aminoglycosides and reduces the antibacterial effect. There is, however, a lack of understanding of how this phenomenon influences the effect of different dosing schedules. The aim was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that describes the time course of the bactericidal activity of gentamicin and its adaptive resistance and to investigate different dosing schedules in preterm and term newborn infants based on the developed model. In vitro time-kill curve experiments were conducted on a strain of Escherichia coli (MIC of 2 mg/liter). The gentamicin exposure was either constant (0.125 to 16 mg/liter) or dynamic (simulated concentration-time profiles in a kinetic system with peak concentrations of 2.0, 3.9, 7.8, and 16 mg/liter given as single doses or as repeated doses every 6, 12, or 24 h). Semimechanistic PKPD models were fitted to the bacterial counts in the NONMEM (nonlinear mixed effects modeling) program. A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of gentamicin to reduce with exposure, characterized both the fast bactericidal effect and the adaptive resistance. Despite a lower peak concentration, preterm neonates were predicted to have a higher bacterial killing effect than term neonates for the same per-kg dose because of gentamicin's longer half-life. The model supported an extended dosing interval of gentamicin in preterm neonates, and for all neonates, dosing intervals of 36 to 48 h were as effective as a 24-h dosing interval for the same total dose.

  • 32.
    Mohamed, Ami Fazlin Syed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karaiskos, Ilias
    Plachouras, Diamantis
    Karvanen, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Pontikis, Konstantinos
    Jansson, Britt
    Papadomichelakis, Evangelos
    Antoniadou, Anastasia
    Giamarellou, Helen
    Armaganidis, Apostolos
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 8, p. 4241-4249Article in journal (Refereed)
    Abstract [en]

    A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

  • 33. Mouton, Johan W
    et al.
    Dudley, Michael N
    Cars, Otto
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Derendorf, Hartmut
    Drusano, George L
    Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update.2005In: J Antimicrob Chemother, ISSN 0305-7453, Vol. 55, no 5, p. 601-7Article in journal (Other scientific)
  • 34. Mölstad, S.
    et al.
    Erntell, M.
    Hanberger, H.
    Melander, E.
    Norman, C.
    Skoog, G.
    Lundborg, C. Stålsby
    Söderström, A.
    Torell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme2008In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 8, no 2, p. 125-132Article, review/survey (Refereed)
    Abstract [en]

    Increasing use of antibiotics and the spread of resistant pneumococcal clones in the early 1990s alarmed the medical profession and medical authorities in Sweden. Strama (Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance) was therefore started in 1994 to provide surveillance of antibiotic use and resistance, and to implement the rational use of antibiotics and development of new knowledge. Between 1995 and 2004, antibiotic use for outpatients decreased from 15.7 to 12.6 defined daily doses per 1000 inhabitants per day and from 536 to 410 prescriptions per 1000 inhabitants per year. The reduction was most prominent in children aged 5-14 years (52%) and for macrolides (65%). During this period, the number of hospital admissions for acute mastoiditis, rhinosinusitis, and quinsy (peritonsillar abscess) was stable or declining. Although the epidemic spread in southern Sweden of penicillin-resistant Streptococcus pneumoniae was curbed, the national frequency increased from 4% to 6%. Resistance remained low in most other bacterial species during this period. This multidisciplinary, coordinated programme has contributed to the reduction of antibiotic use without measurable negative consequences. However, antibiotic resistance in several bacterial species is slowly increasing, which has led to calls for continued sustained efforts to preserve the effectiveness of available antibiotics.

  • 35. Nathan, Carl
    et al.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Antibiotic resistance: problems, progress, and prospects2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 19, p. 1761-1763Article in journal (Other academic)
  • 36. Nation, Roger L.
    et al.
    Li, Jian
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Couet, William
    Dudley, Michael N.
    Kaye, Keith S.
    Mouton, Johan W.
    Paterson, David L.
    Tam, Vincent H.
    Theuretzbacher, Ursula
    Tsuji, Brian T.
    Turnidge, John D.
    Consistent Global Approach on Reporting of Colistin Doses to Promote Safe and Effective Use2014In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 58, no 1, p. 139-+Article in journal (Refereed)
  • 37. Nation, Roger L
    et al.
    Li, Jian
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Couet, William
    Dudley, Michael N
    Kaye, Keith S
    Mouton, Johan W
    Paterson, David L
    Tam, Vincent H
    Theuretzbacher, Ursula
    Tsuji, Brian T
    Turnidge, John D
    Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus2015In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 15, no 2, p. 225-234Article, review/survey (Refereed)
    Abstract [en]

    In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

  • 38.
    Nielsen, Elisabet I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Predicting in vitro antibacterial efficacy across experimental designs with a semimechanistic pharmacokinetic-pharmacodynamic model2011In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 55, no 4, p. 1571-1579Article in journal (Refereed)
    Abstract [en]

    We have previously described a general semimechanistic pharmacokinetic-pharmacodynamic (PKPD) model that successfully characterized the time course of antibacterial effects seen in bacterial cultures when exposed to static concentrations of five antibacterial agents of different classes. In this PKPD model, the total bacterial population was divided into two subpopulations, one growing drug-susceptible population and one resting drug-insensitive population. The drug effect was included as an increase in the killing rate of the drug-susceptible bacteria with a maximum-effect (Emax) model. The aim of the present study was to evaluate the ability of this PKPD model to describe and predict data from in vitro experiments with dynamic concentration-time profiles. Dynamic time-kill curve experiments were performed by using an in vitro kinetic system, where cultures of Streptococcus pyogenes were exposed to benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, or vancomycin using different starting concentrations (2 and 16 times the MIC) and elimination conditions (human half-life, reduced half-life, and constant concentrations). The PKPD model was applied, and the observations for the static as well as dynamic experiments were compared to model predictions based on parameter estimation using (i) static data, (ii) dynamic data, and (iii) combined static and dynamic data. Differences in experimental settings between static and dynamic experiments did not affect the growth kinetics of the bacteria significantly. With parameter reestimation, the structure of our previously proposed PKPD model could well characterize the bacterial growth and killing kinetics when exposed to dynamic concentrations with different elimination rates of all five investigated antibiotics. Furthermore, the model with parameter estimates based on data from only the static time-kill curve experiments could predict the majority of the time-kill curves from the dynamic experiments reasonably well. Adding data from dynamic experiments in the estimation improved the model fit for cefuroxime and vancomycin, indicating some differences in sensitivity to experimental conditions among the antibiotics studied.

  • 39.
    Nielsen, Elisabet I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Viberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sandström, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments2007In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 51, no 1, p. 128-136Article in journal (Refereed)
    Abstract [en]

    Dosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of Streptococcus pyogenes exposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (Emax) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.

  • 40. Norman, Christer
    et al.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Söderström, Ann
    Groth, Anita Bylander
    Hermansson, Ann
    STRAMA håller fast vid Otitkonsensus2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 26-27, p. 1996-1997Article in journal (Other academic)
    Abstract [en]

    [STRAMA sticks to the otitis consensus]

     

  • 41.
    Odenholt, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pharmacodynamics of moxifloxacin and levofloxacin against Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli: simulation of human plasma concentrations after intravenous dosage in an in vitro kinetic model2006In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 58, no 5, p. 960-965Article in journal (Refereed)
    Abstract [en]

    Objectives: To compare in an in vitro kinetic model the pharmacodynamics of moxifloxacin and levofloxacin with a concentration-time profile simulating the human free non-protein bound concentrations of 400 mg moxifloxacin intravenous (iv) once daily, 500 mg levofloxacin iv once daily and 750 mg levofloxacin iv once daily against strains of Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli with variable susceptibility to fluoroquinolones.

    Methods: The strains used in the study included S. pneumoniae ATCC 6306 (native strain), S. pneumoniae 19397 (double mutation; gyrA and parC), S. pneumoniae 4241 (single mutation; parC), S. aureus ATCC 13709 (native strain), S. aureus MB5 (single mutation; gyrA), E. coli M12 (single mutation; gyrA), E. coli ATCC 25922 (native strain) and K. pneumoniae ATCC 29655 (native strain). The strains were exposed to moxifloxacin and levofloxacin in an in vitro kinetic model simulating the free human serum concentration-time profile of moxifloxacin 400 mg once daily, levofloxacin 500 mg once daily and 750 mg once daily. Repeated samples were taken regularly during 24 h and viable counts were carried out.

    Results and conclusions: A correlation was seen between both the area under the serum concentration curve and MIC (AUC/MIC) and the peak concentration/MIC (C-max/MIC) versus area under the bactericidal killing curve (AUBKC) or Delta log(0-24) cfu/mL. Compiling all data, an AUC/MIC of similar to 100 and a Cmax/MIC of 10 gave a maximal bactericidal effect for both levofloxacin and moxifloxacin. In accordance with the results from others, our study indicated that a lower AUC/MIC was needed for S. pneumoniae in comparison with the Gram-negative bacteria studied. Moxifloxacin yielded higher AUC/MIC and Cmax/MIC against the investigated Gram-positive bacteria in comparison with levofloxacin 500 mg once daily and 750 mg once daily.

  • 42.
    Odenholt, Inga
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Cars, Otto
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Löwdin, Elisabeth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Pharmacodynamic studies of amoxicillin against Streptococcus pneumoniae: comparison of a new pharmacokinetically enhanced formulation (2000 mg twice daily) with standard dosage regimens.2004In: J Antimicrob Chemother, ISSN 0305-7453, Vol. 54, no 6, p. 1062-6Article in journal (Other scientific)
  • 43.
    Odenholt, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Pharmacodynamic effects of telavancin against methicillin-resistant and methicillin-susceptible Staphylococcus aureus strains in the presence of human albumin or serum and in an in vitro kinetic model2007In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 51, no 9, p. 3311-3316Article in journal (Refereed)
    Abstract [en]

    Telavancin is a novel bactericidal lipoglycopeptide with multiple mechanisms of action against gram-positive pathogens. The aim of this study was to describe the dynamics of the antimicrobial effect of telavancin against two strains of Staphylococcus aureus (methicillin susceptible and methicillin resistant) in an in vitro kinetic model with simulated human pharmacokinetics. Also, static experiments were performed to determine the rate and extent of killing by telavancin in the presence and absence of human albumin and human serum. Experiments in broth and in nutrient-depleted medium were performed to study the rate and extent of killing by telavancin of bacteria in different growth phases. In the in vitro kinetic model regrowth was noted at 24 h for both strains when exposed to initial concentrations below 5 mg/liter. There was a >3-log10 killing at all concentrations from 0.5 x MIC and above at 24 h both in broth and in the presence of 40-g/liter human albumin. In contrast to the methicillin-susceptible strain, the methicillin-resistant strain in 40-g/liter human albumin showed a regrowth at concentrations of 0.5 x MIC and 1x MIC at 24 h. At all the other concentrations >3-log10 killing was seen at 24 h. Concordant results were seen in 50% human serum. At a target area under the curve/MIC ratio of 50 (corresponding to the human dose of 10 mg/kg of body weight, administered intravenously), >3-log10 killing was observed at 6 to 8 h. Unlike most antibiotics, telavancin was able to kill both strains in a nongrowing phase.

  • 44.
    Olofsson, Sara K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Optimizing drug exposure to minimize selection of antibiotic resistance2007In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 45, no SUPPL.2, p. S129-S136Article in journal (Refereed)
    Abstract [en]

    The worldwide increase in antibiotic resistance is a concern for public health. The fact that the choice of dose and treatment duration can affect the selection of antibiotic-resistant mutants is becoming more evident, and an increased number of studies have used pharmacodynamic models to describe the drug exposure and pharmacodynamic breakpoints needed to minimize and predict the development of resistance. However, there remains a lack of sufficient data, and future work is needed to fully characterize these target drug concentrations. More knowledge is also needed of drug pharmacodynamics versus bacteria with different resistance mutations and susceptibility levels. The dosing regimens should exhibit high efficacy not only against susceptible wild-type bacteria but, preferably, also against mutated bacteria that may exist in low numbers in "susceptible" populations. Thus, to prolong the life span of existing and new antibiotics, it is important that dosing regimens be carefully selected on the basis of pharmacokinetic and pharmacodynamic properties that prevent emergence of preexisting and newly formed mutants.

  • 45.
    Olofsson, Sara K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Klinisk bakt.
    Geli, Patricia
    Andersson, Dan I
    Department of Medical Biochemistry and Microbiology.
    Cars, Otto
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Pharmacodynamic model to describe the concentration-dependent selection of cefotaxime-resistant Escherichia coli.2005In: Antimicrob Agents Chemother, ISSN 0066-4804, Vol. 49, no 12, p. 5081-91Article in journal (Refereed)
  • 46.
    Pulcini, C.
    et al.
    Lorraine Univ, EA APEMAC 4360, Nancy, France.;Nancy Univ Hosp, Infect Dis Dept, Nancy, France.;ESCMID Study Grp Antimicrobial Stewardship ESGA, Basel, Switzerland..
    Beovic, B.
    ESCMID Study Grp Antimicrobial Stewardship ESGA, Basel, Switzerland.;Univ Ljubljana, Univ Med Ctr Ljubljana, Ljubljana, Slovenia.;Univ Ljubljana, Fac Med, Ljubljana, Slovenia..
    Beraud, G.
    ESCMID Study Grp Antimicrobial Stewardship ESGA, Basel, Switzerland.;Univ Poitiers, Ctr Hosp Univ Poitiers, Dept Infect Dis, Poitiers, France.;Univ Droit & Sante Lille 2, EA2694, Lille, France.;Hasselt Univ, Interuniv Inst Biostat & Stat Bioinformat, Hasselt, Belgium.;WAAAR, Paris, France..
    Carlet, J.
    WAAAR, Paris, France..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Howard, P.
    ESCMID Study Grp Antimicrobial Stewardship ESGA, Basel, Switzerland.;Leeds Teaching Hosp NHS Trust, Leeds, W Yorkshire, England..
    Levy-Hara, G.
    ISC, Antimicrobial Stewardship Working Grp, Birmingham, W Midlands, England.;Hosp Carlos G Durand, Buenos Aires, DF, Argentina..
    Li, G.
    St Georges Univ London, Paediat Infect Dis Res Grp, London, England..
    Nathwani, D.
    BSAC, Birmingham, W Midlands, England..
    Roblot, F.
    Univ Poitiers, Ctr Hosp Univ Poitiers, Dept Infect Dis, Poitiers, France.;French Infect Dis Soc, Soc & Pathol Infect Langue Francaise, SPILF, Paris, France..
    Sharland, M.
    Ensuring universal access to old antibiotics: a critical but neglected priority2017In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 23, no 9, p. 590-592Article in journal (Other academic)
  • 47.
    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.

  • 48.
    Rochford, Connor
    et al.
    Univ Oxford, Blavatnik Sch Govt, Oxford, England..
    Sridhar, Devi
    Univ Edinburgh, Global Hlth Governance Programme, Edinburgh, Midlothian, Scotland..
    Woods, Ngaire
    Univ Oxford, Blavatnik Sch Govt, Oxford, England..
    Saleh, Zia
    Univ Oxford, Blavatnik Sch Govt, Oxford, England..
    Hartenstein, Lars
    McKinsey & Co Inc, Social Sect Hub, Geneva, Switzerland..
    Ahlawat, Hemant
    McKinsey & Co Inc, Social Sect Hub, Geneva, Switzerland..
    Whiting, Ed
    Wellcome Trust Res Labs, London, England..
    Dybul, Mark
    Georgetown Univ, Ctr Global Hlth & Qual, Washington, DC USA..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Goosby, Eric
    Univ Calif San Francisco, Inst Global Hlth Sci, San Francisco, CA 94143 USA..
    Cassels, Andrew
    Grad Inst, Global Hlth Ctr, Geneva, Switzerland..
    Velasquez, German
    South Ctr, Special Adviser Hlth & Dev, Geneva, Switzerland..
    Hoffman, Steven
    York Univ, Global Strategy Lab, York, N Yorkshire, England..
    Baris, Enis
    World Bank Grp, Washington, DC USA..
    Wadsworth, Jonathan
    World Bank Grp, Washington, DC USA..
    Gyansa-Lutterodt, Martha
    Minist Hlth, Accra, Ghana..
    Davies, Sally
    Dept Hlth & Social Care, London SW1H 0EU, England..
    Global governance of antimicrobial resistance2018In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 391, no 10134, p. 1976-1978Article in journal (Other academic)
  • 49. So, Anthony D
    et al.
    Gupta, Neha
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tackling antibiotic resistance2010In: BMJ. British Medical Journal (International Ed.), ISSN 0959-8146, E-ISSN 0959-535X, Vol. 340, p. c2071-Article in journal (Other academic)
  • 50. So, Anthony D.
    et al.
    Ruiz-Esparza, Quentin
    Gupta, Neha
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    3Rs for innovating novel antibiotics: sharing resources, risks, and rewards2012In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 344, p. e1782-Article in journal (Refereed)
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