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  • 1.
    Abdelwahab, Mahmoud Tareq
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Wasserman, Sean
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Brust, James C. M.
    Albert Einstein Coll Med, Div Gen Internal Med, New York, NY USA.;Albert Einstein Coll Med, Div Infect Dis, New York, NY USA..
    Gandhi, Neel R.
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA.;Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA.;Emory Univ, Emory Sch Med, Dept Med Infect Dis, Atlanta, GA USA..
    Meintjes, Graeme
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Everitt, Daniel
    Global Alliance TB Drug Dev, New York, NY USA..
    Diacon, Andreas
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Dept Med, Cape Town, South Africa..
    Dawson, Rodney
    Univ Cape Town, Lung Inst, Cape Town, South Africa.;Univ Cape Town, Div Pulmonol, Dept Med, Cape Town, South Africa..
    Wiesner, Lubbe
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Clofazimine pharmacokinetics in patients with TB: dosing implications2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 11, p. 3269-3277Article in journal (Refereed)
    Abstract [en]

    Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-Linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a Loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a Long elimination half-Life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

  • 2.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    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.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1188-1198Article in journal (Refereed)
    Abstract [en]

    The worldwide spread of ESBL-producing Enterobacteriaceae has led to an increased use of carbapenems, the group of beta-lactams with the broadest spectrum of activity. Bacterial resistance to carbapenems is mainly due to acquired carbapenemases or a combination of ESBL production and reduced drug influx via loss of outer-membrane porins. Here, we have studied the development of carbapenem resistance in Escherichia coli in the absence of beta-lactamases. We selected mutants with high-level carbapenem resistance through repeated serial passage in the presence of increasing concentrations of meropenem or ertapenem for similar to 60 generations. Isolated clones were whole-genome sequenced, and the order in which the identified mutations arose was determined in the passaged populations. Key mutations were reconstructed, and bacterial growth rates of populations and isolated clones and resistance levels to 23 antibiotics were measured. High-level resistance to carbapenems resulted from a combination of downstream effects of envZ mutation and target mutations in AcrAB-TolC-mediated drug export, together with PBP genes [mrdA (PBP2) after meropenem exposure or ftsI (PBP3) after ertapenem exposure]. Our results show that antibiotic resistance evolution can occur via several parallel pathways and that new mechanisms may appear after the most common pathways (i.e. beta-lactamases and loss of porins) have been eliminated. These findings suggest that strategies to target the most commonly observed resistance mechanisms might be hampered by the appearance of previously unknown parallel pathways to resistance.

  • 3.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    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.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 1, p. 51-59Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the influence of plasmid-borne β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli and the fitness costs associated with resistance. Methods: Stepwise selection of carbapenem-resistant mutants with or without the extended-spectrum β-lactamase (ESBL)-encoding plasmid pUUH239.2 was performed. Mutation rates and mutational pathways to resistance were determined. In vitro-selected and constructed mutants were characterized regarding the MICs of the carbapenems, porin expression profiles, growth rates and the presence of mutations in the porins ompC/ompF and their regulatory genes. The influence of the plasmid-encoded β-lactamases TEM-1, OXA-1 and CTX-M-15 on resistance development was determined. Results: Results show that E. coli readily developed reduced carbapenem susceptibility and clinical resistance levels by a combination of porin loss and increased β-lactamase expression, especially towards ertapenem. All tested β-lactamases (CTX-M-15, TEM-1 and OXA-1) contributed to reduced carbapenem susceptibility in the absence of porin expression. However, complete loss of porin expression conferred a 20% fitness cost on the bacterial growth rate. Increased β-lactamase expression through spontaneous gene amplification on the plasmid was a major resistance factor. Conclusions: Plasmid-encoded β-lactamases, including non-ESBL enzymes, have a strong influence on the frequency and resistance level of spontaneous carbapenem-resistant mutants. The fitness cost associated with the loss of OmpC/OmpF in E. coli most likely reduces the survivability of porin mutants and could explain why they have not emerged as a clinical problem in this species.

  • 4.
    André, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Center for Clinical Research Dalarna.
    Vernby, Åsa
    Berg, Johanna
    Lundborg, Cecilia Stalsby
    A survey of public knowledge and awareness related to antibiotic use and resistance in Sweden2010In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 65, no 6, p. 1292-1296Article in journal (Refereed)
    Abstract [en]

    To examine the level of knowledge about antibiotic treatment and awareness of antibiotic resistance among the general public in Sweden. A quantitative, cross-sectional interview study based on a structured questionnaire used during telephone interviews. The sample comprised 1000 randomly selected individuals aged 21-80 years throughout Sweden. Demographic data as well as level of agreement with various statements concerning antibiotics and antibiotic use were provided by the respondents. The response rate was 74.7%. Of the respondents, 19.1% agreed that antibiotics cure common colds more quickly; this belief was higher in those who had not previously received antibiotics. A high proportion, 80.7%, agreed that bacteria could become resistant to antibiotics. Trust in doctors was high, and significantly more respondents reported trusting the doctor not prescribing an antibiotic, 87.0%, than the doctor prescribing an antibiotic, 81.0%. The respondents showed some confusion surrounding the terms 'bacteria' and 'viruses', and the meaning of these in relation to the prescribing decision. The high level of trust in restrictive prescribing as well as the awareness of antibiotic resistance expressed by the Swedish public should be recognized by health professionals and utilized in future campaigns.

  • 5. Bengtsson, Stina
    et al.
    Naseer, Umaer
    Sundsfjord, Arnfinn
    Kahlmeter, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Sundqvist, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sequence types and plasmid carriage of uropathogenic Escherichia coli devoid of phenotypically detectable resistance2012In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 67, no 1, p. 69-73Article in journal (Refereed)
    Abstract [en]

    Objectives

    Plasmids play a major role in the dissemination of antibiotic resistance, and several studies have shown the association between specific resistance mechanisms and certain plasmid types and/or Escherichia coli lineages. This study describes the distribution of plasmids, replicon types, sequence types (STs) and ST complexes (STCs) of E. coli devoid of phenotypic resistance to 24 antibiotics.

    Methods

    Eighty E. coli isolates from urinary tract infections from four European countries were selected because of their lack of phenotypically detectable antibiotic resistance. The isolates were characterized to the phylogenetic group level using PCR and to ST by multilocus sequence typing. Plasmid carriage was assessed using S1 nuclease PFGE profiling and PCR-based replicon typing.

    Results

    Plasmids were detected in only 38/80 (47%) of the isolates; one (n = 18), two (n = 14), three (n = 5) and four (n = 1) plasmids. Six different replicon types were identified, the most common being a combination of IncFII and IncFIB. Most isolates belonged to phylogenetic group B2 and STC73 (n = 20), STC95 (n = 7) and ST420 (n = 6). A high proportion of STC73 isolates (75%) was devoid of plasmids. No association could be found between specific STs and replicon type.

    Conclusions

    A large proportion of E. coli strains phenotypically devoid of antibiotic resistance were plasmid naive. Those isolates that harboured plasmids displayed replicon types similar to those of resistant isolates, but the distributions of STs and STCs were different. This may indicate chromosomally encoded mechanisms important for the stabilization of plasmids harbouring antibiotic resistance.

  • 6.
    Bonnedahl, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Drobni, P.
    Johansson, A.
    Hernandez, Jorge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Stedt, J.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Drobni, Mirva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Characterization, and comparison, of human clinical and black-headed gull (Larus ridibundus) extended-spectrum β-lactamase-producing bacterial isolates from Kalmar, on the southeast coast of Sweden2010In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 65, no 9, p. 1939-1944Article in journal (Refereed)
    Abstract [en]

    Antibiotic resistance is one of the great challenges for modern healthcare. In Gram-negative bacteria, CTX-M-type extended-spectrum beta-lactamases (ESBLs) have been rapidly spreading through Europe since the early 2000s. In Sweden, ESBL-producing Escherichia coli are still rare, but a 3-fold increase has been seen from 2004 to 2007. Enterobacteria and normal flora of wild animals, with or without antibiotic resistance traits, constitute a potential source of human infection and colonization. We studied wild birds with the aim to understand the environmental dissemination of antibiotic resistance and, focusing on clinically relevant resistance types, we made comparisons with human clinical samples. In this study, ESBL-producing human clinical isolates and isolates from juvenile black-headed gulls from Kalmar County hospital and the city of Kalmar, respectively, on the southeast coast of Sweden, were characterized and compared. Despite a low frequency of antibiotic resistance among the isolates from gulls, ESBL-producing E. coli isolates were found, two with bla(CTX-M-14) and one with bla(CTX-M-15). The same CTX-M types were dominant among human ESBL isolates. In addition, gull isolates were dispersed among the human samples in the PhenePlate (TM) clustering system, indicating that they neither differ from the human isolates nor form any separate clonal clustering. The finding of CTX-M-type ESBLs in E. coli isolated from black-headed gulls in Sweden, where 'background resistance' is low, is consistent with an ongoing environmental spread of these plasmid-borne resistance genes. The results indicate that a potential for transfer between the human population and environment exists even in countries with a low level of antibiotic resistance.

  • 7.
    Brandis, Gerrit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gockel, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Garoff, Linnéa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Guy, Lionel
    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.
    Expression of the qepA1 gene is induced under antibiotic exposure2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 6, p. 1433-1440Article in journal (Refereed)
    Abstract [en]

    Background

    The qepA1 gene encodes an efflux pump that reduces susceptibility to ciprofloxacin. Little is known about the regulation of qepA1 expression.

    Objectives

    To assess the potential role of ciprofloxacin and other antibiotics in the regulation of qepA1 gene expression. To identify the promoter that drives qepA1 expression and other factors involved in expression regulation. To assess whether the identified features are universal among qepA alleles.

    Methods

    A translational qepA1-yfp fusion under the control of the qepA1 upstream region was cloned into the Escherichia coli chromosome. Expression of the fusion protein was measured in the presence of various antibiotics. Deletions within the upstream region were introduced to identify regions involved in gene expression and regulation. The qepA1 coding sequence and upstream region were compared with all available qepA sequences.

    Results

    Cellular stress caused by the presence of various antibiotics can induce qepA1 expression. The qepA1 gene is fused to a class I integron and gene expression is driven by the Pc promoter within the integrase gene. A segment within the integron belonging to a truncated dfrB4 gene is essential for the regulation of qepA1 expression. This genetic context is universal among all sequenced qepA alleles.

    Conclusions

    The fusion of the qepA1 gene to a class I integron has created a novel regulatory unit that enables qepA1 expression to be under the control of antibiotic exposure. This setup mitigates potential negative effects of QepA1 production on bacterial fitness by restricting high-level expression to environmental conditions in which QepA1 is beneficial.

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  • 8.
    Brandis, Gerrit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Granström, Susanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leber, Anna T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bartke, Katrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Garoff, Linnéa
    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.
    Huseby, Douglas L.
    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.
    Mutant RNA polymerase can reduce susceptibility to antibiotics via ppGpp-independent induction of a stringent-like response2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 3, p. 606-615Article in journal (Refereed)
    Abstract [en]

    Background

    Mutations in RNA polymerase (RNAP) can reduce susceptibility to ciprofloxacin in Escherichia coli, but the mechanism of transcriptional reprogramming responsible is unknown. Strains carrying ciprofloxacin-resistant (CipR) rpoB mutations have reduced growth fitness and their impact on clinical resistance development is unclear.

    Objectives

    To assess the potential for CipRrpoB mutations to contribute to resistance development by estimating the number of distinct alleles. To identify fitness-compensatory mutations that ameliorate the fitness costs of CipRrpoB mutations. To understand how CipRrpoB mutations reprogramme RNAP.

    Methods

    E. coli strains carrying five different CipRrpoB alleles were evolved with selection for improved fitness and characterized for acquired mutations, relative fitness and MICCip. The effects of dksA mutations and a ppGpp0 background on growth and susceptibility phenotypes associated with CipRrpoB alleles were determined.

    Results

    The number of distinct CipRrpoB mutations was estimated to be >100. Mutations in RNAP genes and in dksA can compensate for the fitness cost of CipRrpoB mutations. Deletion of dksA reduced the MICCip for strains carrying CipRrpoB alleles. A ppGpp0 phenotype had no effect on drug susceptibility.

    Conclusions

    CipRrpoB mutations induce an ppGpp-independent stringent-like response. Approximately half of the reduction in ciprofloxacin susceptibility is caused by an increased affinity of RNAP to DksA while the other half is independent of DksA. Stringent-like response activating mutations might be the most diverse class of mutations reducing susceptibility to antibiotics.

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  • 9.
    Brandis, Gerrit
    et al.
    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.
    Genetic characterization of compensatory evolution in strains carrying rpoB Ser531Leu, the rifampicin resistance mutation most frequently found in clinical isolates2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 11, p. 2493-2497Article in journal (Refereed)
    Abstract [en]

    Objectives

    The evolution of rifampicin resistance in Mycobacterium tuberculosis is a major threat to effective tuberculosis therapy. Much is known about the initial emergence of rifampicin resistance, but the further evolution of these resistant strains has only lately been subject to investigation. Although resistance can be caused by many different mutations in rpoB, among clinical M. tuberculosis isolates the mutation rpoB S531L is overwhelmingly the most frequently found. Clinical isolates with rpoB S531L frequently carry additional mutations in genes for RNA polymerase subunits, and it has been speculated that these are fitness-compensatory mutations, ameliorating the fitness cost of the primary resistance mutation. We tested this hypothesis using Salmonella as a model organism.

    Methods

    We created the rpoB S531L mutation in Salmonella and then evolved independent lineages with selection for mutants with increased relative fitness. Relative fitness associated with putative compensatory mutations was measured after genetic reconstruction in isogenic strains.

    Results

    Compensatory mutations were identified in genes coding for different subunits of RNA polymerase: rpoA, rpoB and rpoC. Genetic reconstructions demonstrated that each of these secondary mutations reduced the fitness cost of the rpoB S531L resistance mutation.

    Conclusions

    The compensatory mutations identified in Salmonella cluster in similar locations to the additional mutations found in M. tuberculosis isolates. These new data strongly support the idea that many of the previously identified rpoA, rpoB and rpoC mutations in rifampicin-resistant M. tuberculosis (rpoB S531L) are indeed fitness-compensatory mutations.

  • 10.
    Brandis, Gerrit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pietsch, Franziska
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alemayehu, Rahel
    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.
    Comprehensive phenotypic characterization of rifampicin resistance mutations in Salmonella provides insight into the evolution of resistance in Mycobacterium tuberculosis2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 3, p. 680-685Article in journal (Refereed)
    Abstract [en]

    Objectives

    Mutations in the β-subunit of RNA polymerase (RNAP), encoded by rpoB, are responsible for rifampicin resistance (RifR). Although many mutations in rpoB can reduce susceptibility, only a few are frequent amongst RifR clinical Mycobacterium tuberculosis (MTB) isolates. It has been suggested that there is a negative correlation between the fitness costs of RifR mutations and their respective clinical frequency, but so far comparable fitness cost measurements have only been conducted for a very limited number of RifR mutations. We tested this hypothesis using Salmonella and Mycobacterium smegmatis as model organisms.

    Methods

    We constructed 122 different RifR mutations in Salmonella. MICs and relative fitness costs in the presence and absence of rifampicin were determined for each mutant, including for a smaller number of RifRM. smegmatis strains. Results were compared with available mutation frequency data from clinical MTB isolates.

    Results

    (i) RifR mutations frequently found in MTB isolates have a fitness cost in Salmonella Typhimurium and M. smegmatis. (ii) Clinically frequent RifR mutations have a high rifampicin MIC. (iii) There is a strong correlation between the magnitude of the fitness cost of a RifR mutation in Salmonella Typhimurium or M. smegmatis and the frequency with which that mutation is associated with secondary (putative compensatory) mutations in RNAP of clinical MTB isolates.

    Conclusions

    This suggests that the success of RifR mutations in clinical MTB isolates may be dependent not only on a low initial fitness cost, but rather the results of three factors: (i) a high rifampicin MIC; (ii) a relatively low initial fitness cost; and (iii) the ability to additionally acquire compensatory mutations selected to further reduce fitness cost.

  • 11. Byakika-Kibwika, Pauline
    et al.
    Lamorde, Mohammed
    Okaba-Kayom, Violet
    Mayanja-Kizza, Harriet
    Katabira, Elly
    Hanpithakpong, Warunee
    Pakker, Nadine
    Dorlo, Thomas P C
    Tarning, Joel
    Lindegardh, Niklas
    de Vries, Peter J
    Back, David
    Khoo, Saye
    Merry, Concepta
    Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults.2012In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 67, no 5, p. 1217-23Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir.

    METHODS: A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured.

    RESULTS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (C(max)) and area under the concentration-time curve (AUC) [median (range): 112 (20-362) versus 56 (17-236) ng/mL, P = 0.03; and 264 (92-1129) versus 151 (38-606) ng · h/mL, P < 0.01]. Dihydroartemisinin C(max) and AUC were not affected [66 (10-111) versus 73 (31-224) ng/mL, P = 0.55; and 213 (68-343) versus 175 (118-262) ng · h/mL P = 0.27]. Lumefantrine C(max) and AUC increased during co-administration [2532 (1071-5957) versus 7097 (2396-9462) ng/mL, P < 0.01; and 41,119 (12,850-125,200) versus 199,678 (71,205-251,015) ng · h/mL, P < 0.01].

    CONCLUSIONS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.

  • 12. Chryssanthou, Erja
    et al.
    Loebig, Alissha
    Sjölin, Jan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Post-antifungal effect of amphotericin B and voriconazole against germinated Aspergillus fumigatus conidia2008In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 61, no 6, p. 1309-11Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The post-antifungal effect (PAFE) of amphotericin B and voriconazole on germinated Aspergillus fumigatus conidia was studied using the BacT/Alert detection system based on fungal CO(2) production. METHODS: Germinated conidia of A. fumigatus were exposed to 1-10x MIC of amphotericin B for 1 and 4 h and to 2.5-40x MIC of voriconazole for 4 and 24 h. After removal of the drug by washing, similar numbers of exposed and control germlings were inoculated into Pedi-BacT culture bottles. CO(2) production was automatically monitored until the bottles signalled positive. The difference in time for positive signals in drug-exposed and control bottles was used to calculate the PAFE. RESULTS: The killing rate of amphotericin B against germlings was both concentration- and time-dependent, as has been previously found for actively growing hyphae. Similarly, voriconazole showed fungicidal effect after 24 h of exposure, but not after 4 h. Amphotericin B induced a long concentration- and time-dependent PAFE, whereas voriconazole resulted in a short and dose-independent PAFE that was significantly longer after 24 h than after 4 h of exposure. CONCLUSIONS: An automated method is presented for the determination of PAFE on filamentous fungi using quantifiable numbers of germinated conidia. In contrast to previous results obtained from conidia, this method could demonstrate a PAFE of amphotericin B on Aspergillus that shared characteristics similar to that on Candida spp.

  • 13.
    Chu, Wan-Yu
    et al.
    Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands..
    Dorlo, Thomas P. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.
    Pyronaridine: a review of its clinical pharmacology in the treatment of malaria2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, article id dkad260Article, review/survey (Refereed)
    Abstract [en]

    Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based combination therapy (ACT) for both uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Pyronaridine-artesunate, available as a tablet and paediatric granule formulations, is being adopted in regions where malaria treatment outcome is challenged by increasing chloroquine resistance. Pyronaridine is an old antimalarial agent that has been used for more than 50 years as a blood schizonticide, which exerts its antimalarial activity by interfering with the synthesis of the haemozoin pigment within the Plasmodium digestive vacuole. Pyronaridine exhibits a high blood-to-plasma distribution ratio due to its tendency to accumulate in blood cells. This feature is believed to play a crucial role in its pharmacokinetic (PK) properties and pharmacological activity. The PK characteristics of pyronaridine include rapid oral absorption, large volumes of distribution and low total body clearance, resulting in a long terminal apparent half-life. Moreover, differences in PK profiles have been observed between healthy volunteers and malaria-infected patients, indicating a potential disease-related impact on PK properties. Despite a long history, there is only limited knowledge of the clinical PK and pharmacodynamics of pyronaridine, particularly in special populations such as children and pregnant women. We here provide a comprehensive overview of the clinical pharmacology of pyronaridine in the treatment of malaria.

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  • 14.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aulin, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hu, Yanmin
    Coates, Anthony R. M.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 4, p. 964-974Article in journal (Refereed)
    Abstract [en]

    Objectives

    Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states.

    Methods

    The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time–kill curves from log-phase (0.25–16 mg/L) and stationary-phase (0.5–64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure–response relationships.

    Results

    The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R2 = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively.

    Conclusions

    The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.

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  • 15.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wicha, Sebastian G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Vogel, Corne P.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.
    de Steenwinkel, Jurriaan E. M.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 2, p. 437-447Article in journal (Refereed)
    Abstract [en]

    Background: Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development.

    Methods: In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The multistate TB pharmacometric (MTP) model was used to characterize the natural growth and exposure-response relationships of each drug after mono exposure. Pharmacodynamic interactions during combination exposure were characterized by linking the MTP model to the general pharmacodynamic interaction (GPDI) model with successful separation of the potential effect on each drug's potency (EC50) by the combining drug(s).

    Results: All combinations showed pharmacodynamic interactions at cfu level, where all combinations, except isoniazid plus ethambutol, showed more effect (synergy) than any of the drugs alone. Using preclinical information, the MTP-GPDI modelling approach was shown to correctly predict clinically observed pharmacodynamic interactions, as deviations from expected additivity.

    Conclusions: With the ability to predict clinical pharmacodynamic interactions, using preclinical information, the MTP-GPDI model approach outlined in this study constitutes groundwork for model-informed input to the development of new and enhancement of existing anti-TB combination regimens.

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  • 16. Contejean, Adrien
    et al.
    Ayral, Xavier
    Dorlo, Thomas P. C.
    Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute , Amsterdam, The Netherlands.
    Roseboom, Ignace C
    Yera, Hélène
    Gana, Inès
    Chouchana, Laurent
    Canouï, Etienne
    Buffet, Pierre
    Charlier, Caroline
    Relapsing leishmanial arthritis: report of a tricky localization and evidence of miltefosine diffusion in synovial fluid.2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 10, p. 2740-2741Article in journal (Refereed)
  • 17. Dorlo, Thomas P C
    et al.
    Balasegaram, Manica
    Beijnen, Jos H
    de Vries, Peter J
    Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis.2012In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 67, no 11, p. 2576-97Article in journal (Refereed)
    Abstract [en]

    Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of miltefosine, either alone or in combination, in the treatment of VL and CL.

  • 18. Dorlo, Thomas P C
    et al.
    Balasegaram, Manica
    Lima, María Angeles
    de Vries, Peter J
    Beijnen, Jos H
    Huitema, Alwin D R
    Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine.2012In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 67, no 8, p. 1996-2004Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Use of miltefosine in the treatment of visceral leishmaniasis (VL) is hampered by its potential teratogenicity. The duration of adequate contraceptive cover in females of child-bearing potential after cessation of a potentially teratogenic drug therapy remains debated. The objective of this study was to provide a rational approach to suggest durations of contraceptive cover for various miltefosine regimens.

    METHODS: A human reproductive safety threshold exposure limit was derived using animal-to-human dose conversion. Pharmacokinetic (PK) data for miltefosine in females are lacking; a previously developed population PK model and a comprehensive anthropometric dataset were used to simulate PK data for Indian female VL patients receiving miltefosine for 5, 7, 10 or 28 days. Probability of supra-threshold miltefosine exposure was used to evaluate adequate durations of post-treatment contraceptive cover for the various regimens.

    RESULTS: PK data were simulated for 465 treated Indian female VL patients of child-bearing potential with a median age of 25 years (IQR 16-31 years) and median weight of 38 kg (IQR 34-42 kg). From animal reproductive toxicity studies, a human reproductive safety threshold exposure limit was derived of 24.5 μg · day/mL. Probability of 'unprotected' supra-threshold miltefosine exposure was very low (<0.2%) for a post-treatment contraceptive cover period of 4 months for the standard 28 day regimen, and of 2 months for the shorter regimens.

    CONCLUSIONS: To our knowledge, this is the first study providing rational suggestions for contraceptive cover for a teratogenic drug based on animal-to-human dose conversion. For the 28 day miltefosine regimen, post-treatment contraceptive cover may be extended to 4 months, whereas for all shorter regimens 2 months may be adequate.

  • 19.
    Dorlo, Thomas P. C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Netherlands Canc Inst, Antoni Van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands..
    Kip, Anke E.
    Netherlands Canc Inst, Antoni Van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands..
    Younis, Brima M.
    Univ Khartoum, Inst Endem Dis, Khartoum, Sudan..
    Ellis, Sally J.
    Drugs Neglected Dis initiat, Geneva, Switzerland..
    Alves, Fabiana
    Drugs Neglected Dis initiat, Geneva, Switzerland..
    Beijnen, Jos. H.
    Netherlands Canc Inst, Antoni Van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands..
    Njenga, Simon
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Kirigi, George
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Hailu, Asrat
    Addis Ababa Univ, Addis Ababa, Ethiopia..
    Olobo, Joseph
    Makerere Univ, Kampala, Uganda..
    Musa, Ahmed M.
    Univ Khartoum, Inst Endem Dis, Khartoum, Sudan..
    Balasegaram, Manica
    Drugs Neglected Dis initiat, Geneva, Switzerland..
    Wasunna, Monique
    Drugs Neglected Dis initiat, Nairobi, Kenya..
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Khalil, Eltahir A. G.
    Univ Khartoum, Inst Endem Dis, Khartoum, Sudan..
    Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study2017In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 11, p. 3131-3140Article in journal (Refereed)
    Abstract [en]

    Background: Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. Objectives: To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. Methods: Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. Results: A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (- 74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time. > EC90 6.97 days for monotherapy). Conclusions: Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children.

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  • 20.
    Dreesen, Erwin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Clin Pharmacol & Pharmacotherapy Unit, Leuven, Belgium.
    Gijsen, Matthias
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Clin Pharmacol & Pharmacotherapy Unit, Leuven, Belgium.;Univ Hosp Leuven, Dept Pharm, Leuven, Belgium..
    Elkayal, Omar
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Clin Pharmacol & Pharmacotherapy Unit, Leuven, Belgium..
    Annaert, Pieter
    Katholieke Univ Leuven, Drug Delivery & Disposit, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium.;BioNotus, Niel, Belgium..
    Debaveye, Yves
    Univ Hosp Leuven, Intens Care Unit, Leuven, Belgium.;Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Intens Care Med, Leuven, Belgium..
    Wauters, Joost
    Univ Hosp Leuven, Med Intens Care Unit, Leuven, Belgium.;Katholieke Univ Leuven, Lab Clin Infect & Inflammatory Disorders, Dept Microbiol Immunol & Transplantat, Leuven, Belgium..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Spriet, Isabel
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Clin Pharmacol & Pharmacotherapy Unit, Leuven, Belgium.;Univ Hosp Leuven, Dept Pharm, Leuven, Belgium..
    Ceftriaxone dosing based on the predicted probability of augmented renal clearance in critically ill patients with pneumonia2022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 9, p. 2479-2488, article id dkac209Article in journal (Refereed)
    Abstract [en]

    Objectives: PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (P-ARC,P-d+1; www.arcpredictor.com). Patients and methods: Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (+/- 7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n= 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval. Results: A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and P-ARC,P-d+1 determined on the previous day. A high P-ARC,P-d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal P-ARC,P-d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% P-ARC,P-d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing. Conclusions: Critically ill patients with CAP with a high P-ARC,P-d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.

  • 21.
    Duthaler, Urs
    et al.
    Univ & Univ Hosp Basel, Dept Biomed, Div Clin Pharmacol & Toxicol, Basel, Switzerland.
    Leisegang, Rory
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Krähenbühl, Stephan
    Univ & Univ Hosp Basel, Dept Biomed, Div Clin Pharmacol & Toxicol, Basel, Switzerland.
    Hammann, Felix
    Univ & Univ Hosp Basel, Dept Biomed, Div Clin Pharmacol & Toxicol, Basel, Switzerland;Univ Bern, Bern Univ Hosp, Dept Gen Internal Med, Inselspital,Clin Pharmacol & Toxicol, Bern, Switzerland;Univ Bern, Inst Pharmacol, Bern, Switzerland.
    The effect of food on the pharmacokinetics of oral ivermectin2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 2, p. 438-440Article in journal (Refereed)
    Abstract [en]

    Background: Ivermectin is an older anthelminthic agent that is being studied more intensely given its potential for mass drug administration against scabies, malaria and other neglected tropical diseases. Its pharmacokinetics (PK) remain poorly characterized. Furthermore, the majority of PK trials are performed under fasted-state dosing conditions, and the effect of food is therefore not well known. To better plan and design field trials with ivermectin, a model that can account for both conditions would be valuable.

    Objectives: To develop a PK model and characterize the food effect with single oral doses of ivermectin.

    Patients and methods: We performed a population-based PK analysis of data pooled from two previous trials of a single dose of 12mg ivermectin, one with dosing after a high-fat breakfast (n=12) and one with fasted-state dosing (n=3).

    Results: The final model described concentration-time profiles after fed and fasted dosing accurately, and estimated the food effect associated with relative bioavailability to 1.18 (95% CI 1.10-1.67).

    Conclusions: In this analysis, the effect of a high-fat breakfast compared with a fasted-state administration of a single oral dose of 12mg ivermectin was minimal.

  • 22.
    Elkayal, Omar
    et al.
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium..
    Allegaert, Karel
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium.;Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium.;Erasmus MC, Dept Clin Pharm, Rotterdam, Netherlands..
    Spriet, Isabel
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium.;Univ Hosp Leuven, Pharm Dept, Leuven, Belgium..
    Smits, Anne
    Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium.;Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium..
    Seghaye, Marie-Christine
    Ctr Hosp Univ Liege, Dept Paediat, Liege, Belgium..
    Charlier, Corinne
    Ctr Hosp Univ Liege, Dept Toxicol, Liege, Belgium..
    Dreesen, Erwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium.
    Population pharmacokinetics of cefazolin in maternal and umbilical cord plasma, and simulated exposure in term neonates2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 12, p. 3229-3236Article in journal (Refereed)
    Abstract [en]

    Background

    Intra-partum cefazolin is used to prevent group B Streptococcus (GBS) vertical transmission in mothers allergic to penicillin without a history of anaphylaxis.

    Objectives

    To investigate the maternal cefazolin dose–exposure relationship and subsequent maternal and neonatal target attainment at delivery.

    Methods

    Data were obtained from 24 healthy, GBS-colonized pregnant women (20–41 years), undergoing vaginal delivery (gestational age ≥37 weeks). During labour, all women received a 2 g cefazolin IV infusion. Eight hours later, eight women received another 1 g in the event of delayed (>8 h) delivery. Next to maternal plasma concentrations (up to 10 per dosing interval, until delivery), venous and arterial umbilical cord concentrations were determined at delivery. Target attainment in maternal/neonatal plasma was set at 1 mg/L for 60% of the dosing interval (unbound cefazolin, worst-case clinical breakpoint). A population pharmacokinetic (popPK) model was built (NONMEM 7.4). ClinicalTrials.gov Identifier: NCT01295606.

    Results

    At delivery, maternal blood and arterial umbilical cord unbound cefazolin concentrations were >1 mg/L in 23/24 (95.8%) and 11/12 (91.7%), respectively. The popPK of cefazolin in pregnant women was described by a two-compartment model with first-order elimination. Two additional compartments described the venous and arterial umbilical cord concentration data. Cefazolin target attainment was adequate in the studied cohort, where delivery occurred no later than 6.5 h after either the first or the second dose. PopPK simulations showed adequate maternal and umbilical cord exposure for 12 h following the first dose.

    Conclusions

    PopPK simulations showed that standard pre-delivery maternal cefazolin dosing provided adequate target attainment up to the time of delivery.

  • 23.
    Fortin, Anny
    et al.
    Dafra Pharma Res & Dev, Slachthuisstr 30-7, Turnhout, Belgium.;McGill Univ, Dept Biochem, 1650 Cedar Ave, Montreal, PQ, Canada..
    Dorlo, Thomas P. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..
    Hendrickx, Sarah
    Univ Antwerp, Lab Microbiol Parasitol & Hyg LMPH, Univ Pl 1, Antwerp, Belgium..
    Maes, Louis
    Univ Antwerp, Lab Microbiol Parasitol & Hyg LMPH, Univ Pl 1, Antwerp, Belgium..
    Pharmacokinetics and pharmacodynamics of oleylphosphocholine in a hamster model of visceral leishmaniasis2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 7, p. 1892-1898Article in journal (Refereed)
    Abstract [en]

    Objectives: This study evaluated the pharmacokinetic properties of oleylphosphocholine (OlPC) in hamsters following a single oral dose. Its prophylactic activity was tested to establish exposure-activity relationships, while a 5+5 day oral regimen at 20 mg/kg with long post-treatment follow-up was performed to assess its curative potential. Methods: Single oral doses of 20, 50 and 100 mg/kg were administered for pharmacokinetic analysis while a 100 mg/kg single oral dose was given on day 7, 4 or 1, or 4 h prior to infection in the prophylactic efficacy study. The animals were infected on day 0 with Leishmania infantum and the resulting parasite burdens were measured in target organs on day 21. In the curative model, treatment started on day 21 post-infection at 20 mg/kg for 5+5 days and amastigote burdens were determined in target organs either on day 42 [10 days after the end of treatment (dpt)] or day 72 (40 dpt). Results: OlPC showed elimination t(1/2) of similar to 50 h and dose-proportional exposure. The prophylactic action of OlPC was in agreement with model-simulated drug exposures, showing dose-dependent residual activity. Interestingly, the 100 mg/kg single dose administered 4 days before infection (day -4) still reduced the overall parasite burden by similar to 50%. In the curative model, >99% clearance of infection was observed at 10 dpt in all OlPC-treated animals and remained so at 40 dpt. Conclusions: This study reveals that total plasma exposure (AUC(t-infinity)) correlates well with the prophylactic and curative efficacy of OlPC in the L. infantum hamster model.

  • 24.
    Frenk, Sammy
    et al.
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel..
    Temkin, Elizabeth
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel..
    Lurie-Weinberger, Mor N.
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel..
    Keren-Paz, Alona
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel..
    Rov, Reut
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel..
    Rakovitsky, Nadya
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel..
    Wullfhart, Liat
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel..
    Nutman, Amir
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel.;Tel Aviv Sourasky Med Ctr, Div Epidemiol & Prevent Med, Tel Aviv, Israel.;Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel..
    Daikos, George L.
    Laikon Gen Hosp, Dept Med 1, Athens, Greece.;Natl & Kapodistrian Univ Athens, Athens, Greece..
    Skiada, Anna
    Laikon Gen Hosp, Dept Med 1, Athens, Greece.;Natl & Kapodistrian Univ Athens, Athens, Greece..
    Durante-Mangoni, Emanuele
    Univ Campania Luigi Vanvitelli, Dept Precis Med, Naples, Italy.;AORN dei Colli Monaldi Hosp, Naples, Italy..
    Benattar, Yael Dishon
    Rambam Hlth Care Campus, Inst Infect Dis, Haifa, Israel.;Univ Haifa, Cheryl Spencer Inst Nursing Res, Haifa, Israel..
    Bitterman, Roni
    Rambam Hlth Care Campus, Inst Infect Dis, Haifa, Israel..
    Yahav, Dafna
    Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel.;Beilinson Med Ctr, Rabin Med Ctr, Infect Dis Unit, Petah Tiqwa, Israel..
    Daitch, Vered
    Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel.;Beilinson Med Ctr, Rabin Med Ctr, Dept Med E, Petah Tiqwa, Israel..
    Bernardo, Mariano
    Univ Campania Luigi Vanvitelli, Dept Precis Med, Naples, Italy.;AORN dei Colli Monaldi Hosp, Naples, Italy..
    Iossa, Domenico
    Univ Campania Luigi Vanvitelli, Dept Precis Med, Naples, Italy.;AORN dei Colli Monaldi Hosp, Naples, Italy..
    Zusman, Oren
    Beilinson Med Ctr, Rabin Med Ctr, Dept Med E, Petah Tiqwa, Israel..
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharm, Uppsala, Sweden..
    Mouton, Johan W.
    Theuretzbacher, Ursula
    Ctr Antiinfect Agents, Vienna, Austria..
    Leibovici, Leonard
    Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel.;Beilinson Med Ctr, Rabin Med Ctr, Dept Med E, Petah Tiqwa, Israel..
    Geffen, Yuval
    Rambam Hlth Care Campus, Microbiol Lab, Haifa, Israel..
    Gershon, Rina
    Rambam Hlth Care Campus, Microbiol Lab, Haifa, Israel..
    Paul, Mical
    Rambam Hlth Care Campus, Inst Infect Dis, Haifa, Israel.;Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Haifa, Israel..
    Carmeli, Yehuda
    Israel Minist Hlth, Natl Inst Antibiot Resistance & Infect Control, Tel Aviv, Israel.;Tel Aviv Sourasky Med Ctr, Div Epidemiol & Prevent Med, Tel Aviv, Israel.;Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel..
    Large-scale WGS of carbapenem-resistant Acinetobacter baumannii isolates reveals patterns of dissemination of ST clades associated with antibiotic resistance2022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 4, p. 934-943Article in journal (Refereed)
    Abstract [en]

    Objectives: To describe the population genetics and antibiotic resistance gene distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates causing infections in three Mediterranean countries.

    Methods: Isolates were collected during the 2013-17 AIDA clinical trial in six hospitals in Israel, Greece and Italy. WGS, bioinformatic characterization and antibiotic resistance profiling were performed.

    Results In the 247 CRAB isolates characterized in this study, ST distribution varied by country: 29/31 (93.5%) Greek isolates, 34/41 (82.9%) Italian isolates and 70/175 (40.0%) Israeli isolates belonged to ST2. The identified ST2 isolates included eight distinct clades: 2C, 2D and 2H were significantly more common in Italy, while 2F was unique to Greece. The uncommon ST3 was not present among Greek isolates and constituted only 5/41 (12%) Italian isolates. On the other hand, it was much more common among Israeli isolates: 78/175 (44.6%) belonged to ST3. The vast majority of isolates, 240/247 (97.2%), were found to harbour acquired carbapenemases, primarily bla(OXA-23.) The chromosomal oxaAb (bla(OXA-51-like)) and ampC genes characteristic of this organism were also ubiquitous. Most (96.4%) ST3 isolates carried a broad-host-range plasmid IncP1 alpha.

    Conclusions The geographical differences in CRAB populations support the theory that clonal spread of CRAB leads to endemicity in hospitals and regions. The close association between antibiotic resistance genes and clades, and between plasmids and STs, suggest that de novo creation of MDR A. baumannii is rare. The clustering of antibiotic resistance genes and plasmids that is unique to each clade/ST, and nearly uniform within clades/STs, suggests that horizontal transmission is rare but crucial to the clade's/ST's success.

  • 25.
    Garcia-Prats, Anthony J.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa.;Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, 2870 Univ Ave,Suite 200, Madison, WI 53705 USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Winckler, Jana
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Draper, Heather R.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Fairlie, Lee
    Univ Witwatersrand, Fac Hlth Sci, Wits Reprod Hlth & HIV Inst Shandukani CRS, 22 Esselen St, ZA-2001 Hilbrow, South Africa..
    van der Laan, Louvina E.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Masenya, Masebole
    Univ Witwatersrand, Fac Hlth Sci, Wits Reprod Hlth & HIV Inst Shandukani CRS, 22 Esselen St, ZA-2001 Hilbrow, South Africa..
    Schaaf, H. Simon
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Wiesner, Lubbe
    Univ Cape Town, Groote Schuur Hosp, Dept Med, Div Clin Pharmacol, K45 Old Main Bldg, ZA-7925 Cape Town, South Africa..
    Norman, Jennifer
    Univ Cape Town, Groote Schuur Hosp, Dept Med, Div Clin Pharmacol, K45 Old Main Bldg, ZA-7925 Cape Town, South Africa..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Denti, Paolo
    Univ Cape Town, Groote Schuur Hosp, Dept Med, Div Clin Pharmacol, K45 Old Main Bldg, ZA-7925 Cape Town, South Africa..
    Hesseling, Anneke C.
    Stellenbosch Univ, Fac Med & Hlth Sci, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, POB 241, ZA-8000 Cape Town, South Africa..
    Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 12, p. 3237-3246Article in journal (Refereed)
    Abstract [en]

    Background: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. Objectives: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. Patients and methods: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L.h, the geometric mean area under the concentration-time curve from 0 to 24h (AUC(0-24)) among adults receiving a 35mg/kg dose]. Results: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range=0.4-11.7). Evaluated doses were similar to 35 mg/kg (days 1-14) and similar to 50 mg/kg (day 15) for cohort 2 and similar to 60 mg/kg (days 1-14) and similar to 75mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. Conclusions: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.

  • 26.
    Garoff, Linnéa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huseby, Douglas L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Praski Alzrigat, Lisa
    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.
    Effect of aminoacyl-tRNA synthetase mutations on susceptibility to ciprofloxacin in Escherichia coli2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 12, p. 3285-3292Article in journal (Refereed)
    Abstract [en]

    Background: Chromosomal mutations that reduce ciprofloxacin susceptibility in Escherichia coli characteristically map to drug target genes (gyrAB and parCE), and genes encoding regulators of the AcrAB-TolC efflux pump. Mutations in RNA polymerase can also reduce susceptibility, by up-regulating the MdtK efflux pump.

    Objectives: We asked whether mutations in additional chromosomal gene classes could reduce susceptibility to ciprofloxacin.

    Methods: Experimental evolution, complemented by WGS analysis, was used to select and identify mutations that reduce susceptibility to ciprofloxacin. Transcriptome analysis, genetic reconstructions, susceptibility measurements and competition assays were used to identify significant genes and explore the mechanism of resistance.

    Results: Mutations in three different aminoacyl-tRNA synthetase genes (leuS, aspS and thrS) were shown to re- duce susceptibility to ciprofloxacin. For two of the genes (leuS and aspS) the mechanism was partially dependent on RelA activity. Two independently selected mutations in leuS (Asp162Asn and Ser496Pro) were studied in most detail, revealing that they induce transcriptome changes similar to a stringent response, including up-regulation of three efflux-associated loci (mdtK, acrZ and ydhJK). Genetic analysis showed that reduced susceptibility depended on the activity of these loci. Broader antimicrobial susceptibility testing showed that the leuS mutations also reduce susceptibility to additional classes of antibiotics chloramphenicol, rifampicin, mecillinam, ampicillin and trimethoprim).

    Conclusions: The identification of mutations in multiple tRNA synthetase genes that reduce susceptibility to ciprofloxacin and other antibiotics reveals the existence of a large mutational target that could contribute to re- sistance development by up-regulation of an array of efflux pumps.

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  • 27.
    Garoff, Linnéa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yadav, Kavita
    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.
    Increased expression of Qnr is sufficient to confer clinical resistance to ciprofloxacin in Escherichia coli2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 2, p. 348-352Article in journal (Refereed)
    Abstract [en]

    Background: Ciprofloxacin, a fluoroquinolone, targets two essential bacterial enzymes, DNA gyrase and topoisomerase IV. Plasmid-borne qnr genes, encoding proteins that protect DNA gyrase and topoisomerase IV from inhibition by fluoroquinolones, contribute to resistance development. However, the presence of a plasmid-borne qnr gene alone is insufficient to confer clinical resistance. Objectives: We asked whether the level of expression of qnr was a limiting factor in its ability to confer clinical resistance and whether expression could be increased without reducing fitness or viability. Methods: qnrB and qnrS were recombineered onto the chromosome of Escherichia coli under the control of constitutive promoters of various strengths. Expression was measured by qPCR, MIC and relative fitness as a function of expression level were determined. Results: For both qnr genes there was a positive relationship between the level of qnr mRNA and the MIC of ciprofloxacin. The highest MICs achieved with qnrB or qnrS as the sole resistance determinant were 0.375 and 1 mg/L, respectively, and were reached at expression levels that did not affect growth rate or viability. The qnrS-mediated MIC is above the EUCAST clinical breakpoint for resistance to ciprofloxacin. In the absence of Lon protease activity, overexpression of qnr genes was associated with high fitness cost, possibly explaining observations of toxicity in other genetic backgrounds. Conclusions: The ability to generate a high MIC without incurring a fitness cost shows that, in an appropriate genetic context, qnrS has the potential to generate clinical resistance to ciprofloxacin in one step.

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  • 28.
    Germovsek, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. UCL, Great Ormond St Inst Child Hlth, Dept Infect Inflammat & Rheumatol, London, England.
    Lutsar, Irja
    Univ Tartu, Dept Microbiol, Tartu, Estonia.
    Kipper, Karin
    Univ Tartu, Dept Microbiol, Tartu, Estonia; St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London, England.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Planche, Tim
    St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London, England.
    Chazallon, Corine
    INSERM SC10 US019, Villejuif, France.
    Meyer, Laurence
    INSERM SC10 US019, Villejuif, France.
    Trafojer, Ursula M. T.
    Univ Padua, Dept Women & Child Hlth, Neonatal Intens Care Unit, Padua, Italy.
    Metsvaht, Tuuli
    Tartu Univ Hosp, Tartu, Estonia.
    Fournier, Isabelle
    INSERM SC10 US019, Villejuif, France.
    Sharland, Mike
    St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London, England.
    Heath, Paul
    St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London, England.
    Standing, Joseph F.
    St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London, England; UCL, Great Ormond St Inst Child Hlth, Dept Infect Inflammat & Rheumatol, London, England.
    Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 7, p. 1908-1916Article in journal (Refereed)
    Abstract [en]

    Background: Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.

    Objectives: To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).

    Methods: Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.

    Results: A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.

    Conclusions: Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.

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  • 29.
    Germovsek, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. UCL, UCL Great Ormond St Inst Child Hlth, Inflammat Infect & Rheumatol Sect, 30 Guilford St, London WC1N 1EH, England.
    Osborne, Leanne
    Barts Hlth NHS Trust, Royal London Hosp, Neonatal Unit, Whitechapel Rd, London E1 1BB, England.
    Gunaratnam, Flora
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Genom & Child Hlth, 4 Newark St, London E1 2AT, England.
    Lounis, Shehrazed A.
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Genom & Child Hlth, 4 Newark St, London E1 2AT, England.
    Bossacoma Busquets, Ferran
    UCL, UCL Great Ormond St Inst Child Hlth, Inflammat Infect & Rheumatol Sect, 30 Guilford St, London WC1N 1EH, England;Hosp St Joan de Deu, Passeig Hosp St Joan de Deu 2, Barcelona 08950, Spain.
    Standing, Joseph F.
    UCL, UCL Great Ormond St Inst Child Hlth, Inflammat Infect & Rheumatol Sect, 30 Guilford St, London WC1N 1EH, England.
    Sinha, Ajay K.
    Barts Hlth NHS Trust, Royal London Hosp, Neonatal Unit, Whitechapel Rd, London E1 1BB, England;Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Genom & Child Hlth, 4 Newark St, London E1 2AT, England.
    Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 4, p. 1003-1011Article in journal (Refereed)
    Abstract [en]

    Background: Vancomycin is commonly used for nosocomial bacterial pathogens causing late-onset septicaemia in preterm infants. We prospectively collected pharmacokinetic data aiming to describe pharmacokinetics and determine covariates contributing to the variability in neonatal vancomycin pharmacokinetics. Further, we aimed to use the model to compare the ratio of AUC(24) at steady-state to the MIC (AUC(24,ss)/MIC) of several intermittent and continuous dosing regimens.

    Methods: Newborns receiving vancomycin for suspected or confirmed late-onset sepsis were included. Peak and trough concentrations for intermittent vancomycin dosing and steady-state concentrations for continuous vancomycin dosing were measured. NONMEM 7.3 was used for population pharmacokinetic analysis. Monte Carlo simulations were performed to compare dosing schemes.

    Results: Data from 54 infants were used for model development and from 34 infants for the model evaluation {corrected gestational age [median (range)]=29 (23.7-41.9) weeks and 28 (23.4-41.7) weeks, respectively}. The final model was a one-compartment model. Weight and postmenstrual age were included a priori, and then no additional covariate significantly improved the model fit. Final model parameter estimates [mean (SEM)]: CL=5.7 (0.3) L/h/70kg and V=39.3 (3.7) L/70kg. Visual predictive check of the evaluation dataset confirmed the model can predict external data. Simulations using MIC of 1mg/L showed that for neonates with gestational age 25weeks and postnatal age 2weeks AUC(24,ss)/MIC was lower with the intermittent regimen (median 482 versus 663).

    Conclusions: A population pharmacokinetic model for continuous and intermittent vancomycin administration in infants was developed. Continuous administration might be favourable for treating infections caused by resistant microorganisms in very young and immature infants.

  • 30.
    Goscinski, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tano, Eva
    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.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: Higher release after the second dose2007In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 60, no 2, p. 328-333Article in journal (Refereed)
    Abstract [en]

    Objectives: To study endotoxin release from two strains of Escherichia coli after exposure to two repeated doses of cefuroxime in an in vitro kinetic model.

    Methods: Cefuroxime in concentrations simulating human pharmacokinetics was added to the bacterial solution with a repeated dose after 12 h. In another experiment, tobramycin was given concomitantly with the second dose of cefuroxime. Samples for viable counts and endotoxin analyses were drawn before the addition of antibiotics and at 2 and 4 h after each dose.

    Results: The propensity to release endotoxin, expressed as log10 endotoxin release (EU)/log10 killed bacteria, was higher after the second than after the first dose, 0.80 ± 0.04 and 0.65 ± 0.01, respectively, in the ATCC strain and 0.80 ± 0.04 and 0.65 ± 0.02, respectively, in the clinical strain (P < 0.001). Endotoxin was released earlier after the second dose (P < 0.001). Addition of tobramycin at the second dose reduced the endotoxin release in comparison with that of cefuroxime alone (P < 0.001).

    Conclusions: The propensity to liberate endotoxin is higher after the second dose of cefuroxime than after the first, resulting in a higher release of endotoxin than expected from bacterial count. The release after the second dose can be reduced by the addition of tobramycin.

  • 31.
    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.

  • 32. Harbarth, S
    et al.
    Theuretzbacher, U
    Hackett, J
    Antibiotic research and development: business as usual?2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 6, p. 1604-7Article in journal (Refereed)
    Abstract [en]

    The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a €9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents.

  • 33.
    Hedenmalm, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Spigset, Olav
    Peripheral sensory disturbances related to treatment with fluoroquinolones1996In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 37, no 4, p. 831-837Article in journal (Refereed)
    Abstract [en]

    The symptoms and possible risk factors of peripheral sensory disturbances related to fluoroquinolones are reviewed on the basis of 37 reports submitted to the Swedish Adverse Drug Reactions Advisory Committee. In 25 patients (68%), symptoms occurred within 1 week after start of treatment. Paraesthesia was the most common complaint and occurred in 81% of the cases. Fifty-one per cent of the reports concerned numbness/hypoaesthesia, 27% pain/hyperaesthesia and 11% muscle weakness. Seventy-one per cent of the patients recovered within 2 weeks after drug discontinuation. Possible predisposing factors were impaired renal function, diabetes, lymphatic malignancy and treatment with another drug known to cause neuropathy.

  • 34.
    Hennig, Stefanie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Elin M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Niebecker, Ronald
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fourie, P Bernard
    Weiner, Marc H
    Bonora, Stefano
    Peloquin, Charles A
    Gallicano, Keith
    Flexner, Charles
    Pym, Alex
    Vis, Peter
    Olliaro, Piero L
    McIlleron, Helen
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1330-1340Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs.

    METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV).

    RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs.

    CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.

  • 35.
    Howard-Anderson, Jessica
    et al.
    Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA.;Georgia Emerging Infect Program, Decatur, GA 30033 USA.;Emory Antibiot Resistance Ctr, Atlanta, GA 30329 USA..
    Davis, Michelle
    Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA.;Georgia Emerging Infect Program, Decatur, GA 30033 USA..
    Page, Alexander M.
    Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA.;Georgia Emerging Infect Program, Decatur, GA 30033 USA..
    Bower, Chris W.
    Georgia Emerging Infect Program, Decatur, GA 30033 USA.;Atlanta VA Med Ctr, Decatur, GA USA.;Fdn Atlanta Vet Educ & Res, Decatur, GA USA..
    Smith, Gillian
    Georgia Emerging Infect Program, Decatur, GA 30033 USA.;Atlanta VA Med Ctr, Decatur, GA USA.;Fdn Atlanta Vet Educ & Res, Decatur, GA USA..
    Jacob, Jesse T.
    Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA.;Georgia Emerging Infect Program, Decatur, GA 30033 USA.;Emory Antibiot Resistance Ctr, Atlanta, GA 30329 USA..
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Weiss, David S.
    Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA.;Emory Antibiot Resistance Ctr, Atlanta, GA 30329 USA.;Atlanta VA Med Ctr, Decatur, GA USA..
    Satola, Sarah W.
    Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA.;Georgia Emerging Infect Program, Decatur, GA 30033 USA.;Emory Antibiot Resistance Ctr, Atlanta, GA 30329 USA.;Atlanta VA Med Ctr, Decatur, GA USA..
    Prevalence of colistin heteroresistance in carbapenem-resistant Pseudomonas aeruginosa and association with clinical outcomes in patients: an observational study2022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 3, p. 793-798Article in journal (Refereed)
    Abstract [en]

    Objectives: To describe the prevalence of colistin heteroresistance in carbapenem-resistant Pseudomonas aeruginosa (CRPA) and evaluate the association with clinical outcomes.

    Methods: Colistin heteroresistance was evaluated in CRPA isolates collected from patients without cystic fibrosis in Atlanta, Georgia, USA using two definitions: HR1, growth at 4 and 8 mg/L of colistin at a frequency >= 1 x 10(-6) the main population; and HR2, growth at a colistin concentration >= 8x the MIC of the main population at a frequency >= 1 x 10(-7). A modified population analysis profile (mPAP) technique was compared with reference PAP for detecting heteroresistance. For adults hospitalized at the time of or within 1 week of CRPA culture, multivariable logistic regression estimated the association between heteroresistance and 90 day mortality.

    Results: Of 143 colistin-susceptible CRPA isolates, 8 (6%) met the HR1 definition and 37 (26%) met the HR2 definition. Compared with the reference PAP, mPAP had a sensitivity and specificity of 50% and 100% for HR1 and 32% and 99% for HR2. Of 82 hospitalized patients, 45 (56%) were male and the median age was 63 years (IQR 49-73). Heteroresistance was not associated with 90 day mortality using HR1 (0% in heteroresistant versus 22% in non-heteroresistant group; P = 0.6) or HR2 (12% in heteroresistant versus 24% in non-heteroresistant group; P = 0.4; adjusted OR 0.8; 95% CI 0.2-3.4).

    Conclusions: Colistin heteroresistance was identified in up to 26% of patients with CRPA in our sample, although the prevalence varied depending on the definition. We did not observe an apparent association between colistin heteroresistance and 90 day mortality.

  • 36.
    Jacobs, Tom G.
    et al.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands.
    Musiime, Victor
    Joint Clin Res Ctr, Res Dept, Kampala, Uganda.;Makerere Univ, Coll Hlth Sci, Sch Med, Dept Paediat & Child Hlth, Kampala, Uganda..
    Rojo, Pablo
    Univ Complutense, Hosp 12 Octubre, Fac Med, Pediat Infect Dis Unit, Madrid, Spain..
    Dooley, Kelly E.
    Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Pharmacol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA..
    McIlleron, Helen
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Aarnoutse, Rob E.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Burger, David M.
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Turkova, Anna
    UCL, Inst Clin Trials & Methodol, MRC Clin Trials Unit UCL, London, England..
    Colbers, Angela
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Dept Pharm, Nijmegen, Netherlands..
    Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 12, p. 3433-3457Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Management of concomitant use of ART and TB drugs is difficult because of the many drug-drug interactions (DDIs) between the medications. This systematic review provides an overview of the current state of knowledge about the pharmacokinetics (PK) of ART and TB treatment in children with HIV/TB co-infection, and identifies knowledge gaps. Methods: We searched Embase and PubMed, and systematically searched abstract books of relevant conferences, following PRISMA guidelines. Studies not reporting PK parameters, investigating medicines that are not available any Longer or not including children with HIV/TB co-infection were excluded. ALL studies were assessed for quality. Results: In total, 47 studies met the inclusion criteria. No dose adjustments are necessary for efavirenz during concomitant first-Line TB treatment use, but intersubject PK variability was high, especially in children <3 years of age. Super-boosted Lopinavir/ritonavir (ratio 1:1) resulted in adequate Lopinavir trough concentrations during rifampicin co-administration. Double-dosed raltegravir can be given with rifampicin in children >4 weeks old as well as twice-daily dolutegravir (instead of once daily) in children older than 6 years. Exposure to some TB drugs (ethambutol and rifampicin) was reduced in the setting of HIV infection, regardless of ART use. Only Limited PK data of second-Line TB drugs with ART in children who are HIV infected have been published. Conclusions: Whereas integrase inhibitors seem favourable in older children, there are Limited options for ART in young children (<3 years) receiving rifampicin-based TB therapy. The PK of TB drugs in HIV-infected children warrants further research.

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  • 37.
    Juhas, Mario
    et al.
    Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland.
    Widlake, Emma
    Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales.
    Teo, Jeanette
    Natl Univ Singapore Hosp, Dept Lab Med, 5 Lower Kent Ridge Rd, Singapore 119074, Singapore.
    Huseby, Douglas L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tyrrell, Jonathan M.
    Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales.
    Polikanov, Yury S.
    Univ Illinois, Coll Liberal Arts & Sci, Dept Biol Sci, 900 South Ashland Ave,MBRB 4170, Chicago, IL 60607 USA.
    Ercan, Onur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Petersson, Anna
    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.
    Aboklaish, Ali F.
    Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales.
    Rominski, Anna
    Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland.
    Crich, David
    Wayne State Univ, Dept Chem, 5101 Cass Ave, Detroit, MI 48202 USA.
    Bottger, Erik C.
    Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland.
    Walsh, Timothy R.
    Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hobbie, Sven N.
    Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland.
    In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 4, p. 944-952Article in journal (Refereed)
    Abstract [en]

    Objectives: Widespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.

    Methods: A thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.

    Results: MIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.

    Conclusions: Its superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.

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  • 38.
    Khan, David D.
    et al.
    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.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A pharmacokinetic-pharmacodynamic (PKPD) model based on in vitro time-kill data predicts the in vivo PK/PD index of colistin2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 7, p. 1881-1884Article in journal (Refereed)
    Abstract [en]

    Objectives: For antibiotics, extensive animal PKPD studies are often performed to evaluate the PK/PD driver for subsequent use when recommending dosing regimens. The aim of this work was to evaluate a PKPD model, developed based on in vitro time-kill data for colistin, in predicting the relationships between PK/PD indices and the bacterial killing previously observed in mice. Methods: An in silico PKPD model for Pseudomonas aeruginosa exposed to colistin was previously developed based on static in vitro time-kill data. The model was here applied to perform an in silico replication of an in vivo study where the effect of colistin on P. aeruginosa was studied in the thigh infection model. Concentration-time profiles of unbound colistin were predicted and used as input to drive the bacterial killing in the PKPD model. The predicted bacterial count at 24 h was related to each of the PK/PD indices and the results were compared with reported observations in vivo. Results: The model was found to adequately predict in vivo results from mice; both in terms of which PK/PD index best correlates to effect (fAUC/MIC) as well as the magnitude needed for a 2 log kill. The fAUC/MIC needed to achieve a 2 log reduction in bacterial counts after 24 h was here predicted to be 9 compared with 31 previously reported in vivo. Conclusions: This study provides further support that PKPD models based on longitudinal data can be a useful tool to make drug development more efficient within the infectious diseases area.

  • 39.
    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.

  • 40. Kip, Anke E
    et al.
    Blesson, Séverine
    Alves, Fabiana
    Wasunna, Monique
    Kimutai, Robert
    Menza, Peninah
    Mengesha, Bewketu
    Beijnen, Jos H
    Hailu, Asrat
    Diro, Ermias
    Dorlo, Thomas P C
    Netherlands Cancer Institute.
    Low antileishmanial drug exposure in HIV-positive visceral leishmaniasis patients on antiretrovirals: an Ethiopian cohort study.2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 5, p. 1258-1268Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown.

    METHODS: HIV-VL co-infected patients received the recommended liposomal amphotericin B (LAmB) monotherapy (total dose 40 mg/kg over 24 days) or combination therapy of LAmB (total dose 30 mg/kg over 11 days) plus 28 days 100 mg/day miltefosine, with possibility to extend treatment for another cycle. Miltefosine, total amphotericin B and ARV concentrations were determined in dried blood spots or plasma using LC-MS/MS.

    RESULTS: Median (IQR) amphotericin B Cmax on Day 1 was 24.6 μg/mL (17.0-34.9 μg/mL), which increased to 40.9 (25.4-53.1) and 33.2 (29.0-46.6) μg/mL on the last day of combination and monotherapy, respectively. Day 28 miltefosine concentration was 18.7 (15.4-22.5) μg/mL. Miltefosine exposure correlated with amphotericin B accumulation. ARV concentrations were generally stable during antileishmanial treatment, although efavirenz Cmin was below the 1 μg/mL therapeutic target for many patients.

    CONCLUSIONS: This study demonstrates that antileishmanial drug exposure was low in this cohort of HIV co-infected VL patients. Amphotericin B Cmax was 2-fold lower than previously observed in non-VL patients. Miltefosine exposure in HIV-VL co-infected patients was 35% lower compared with adult VL patients in Eastern Africa, only partially explained by a 19% lower dose, possibly warranting a dose adjustment. Adequate drug exposure in these HIV-VL co-infected patients is especially important given the high proportion of relapses.

  • 41. Kip, Anke E
    et al.
    Castro, María Del Mar
    Gomez, Maria Adelaida
    Cossio, Alexandra
    Schellens, Jan H M
    Beijnen, Jos H
    Saravia, Nancy Gore
    Dorlo, Thomas P C
    Netherlands Cancer Institute.
    Simultaneous population pharmacokinetic modelling of plasma and intracellular PBMC miltefosine concentrations in New World cutaneous leishmaniasis and exploration of exposure-response relationships.2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 8, p. 2104-2111Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens.

    PATIENTS AND METHODS: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day miltefosine for 28 days.

    RESULTS: A three-compartment model with miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation.

    CONCLUSIONS: The developed population PK model described the rate and extent of miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study.

  • 42.
    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.

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  • 43.
    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.

  • 44.
    Kostyanev, T.
    et al.
    Univ Antwerp, Dept Med Microbiol, Vaccine & Infect Dis Inst, B-2020 Antwerp, Belgium..
    Bonten, M. J. M.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    O'Brien, S.
    AstraZeneca, Infect Global Med Dev, Macclesfield, Cheshire, England..
    Steel, H.
    GlaxoSmithKline, Infect Dis Therapy Area Unit, London, England..
    Ross, S.
    GlaxoSmithKline, Infect Dis Therapy Area Unit, London, England..
    Francois, B.
    Ctr Hosp Univ Dupuytren, Limoges, France..
    Tacconelli, E.
    Univ Tubingen Hosp, DZIF TTU HAARBI, Infect Dis, Internal Med 1, Tubingen, Germany..
    Winterhalter, M.
    Jacobs Univ Bremen, Sch Sci & Engn, D-28759 Bremen, Germany..
    Stavenger, R. A.
    GlaxoSmithKline, Antibacterial Discovery Performance Unit, Collegeville, PA USA..
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Harbarth, S.
    Univ Geneva, Geneva, Switzerland.;Fac Med, Geneva, Switzerland..
    Hackett, J.
    AstraZeneca, Infect Global Med Dev, Gaithersburg, MD USA..
    Jafri, H. S.
    MedImmune, Gaithersburg, MD USA..
    Vuong, C.
    AiCuris GmbH & Co KG, Wuppertal, Germany..
    MacGowan, A.
    North Bristol NHS Trust & Publ Hlth England, Dept Infect Sci, Bristol Ctr Antimicrobial Res & Evaluat, Bristol, Avon, England..
    Witschi, A.
    Basilea Pharmaceut Int Ltd, Basel, Switzerland..
    Angyalosi, G.
    Novartis Pharma AG, Basel, Switzerland..
    Elborn, J. S.
    Queens Univ Belfast, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland..
    dewinter, R.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Goossens, H.
    Univ Antwerp, Dept Med Microbiol, Vaccine & Infect Dis Inst, B-2020 Antwerp, Belgium.;Univ Antwerp Hosp, Lab Med Microbiol, Antwerp, Belgium..
    The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 2, p. 290-295Article, review/survey (Refereed)
    Abstract [en]

    Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than a,not sign660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

  • 45.
    Kristoffersson, Anders N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bissantz, Caterina
    Okujava, Rusudan
    Haldimann, Andreas
    Walter, Isabelle
    Shi, Tianlai
    Zampaloni, Claudia
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 2, p. 400-408Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Diazabicyclooctanes (DBOs) are an increasingly important group of non β-lactam β-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the β-lactamase inhibitor has an antibiotic effect of its own.

    OBJECTIVES: To develop a novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation.

    METHODS: Four β-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time-kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations.

    RESULTS: The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an 'enhancer' effect of avibactam on ceftazidime in addition to the β-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam.

    CONCLUSIONS: A novel mechanism-based PKPD model for the DBO/β-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/β-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.

  • 46.
    Kubicek-Sutherland, Jessica Z.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lofton, Hava
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vestergaard, Martin
    Univ Copenhagen, Dept Vet Dis Biol, Stigbojlen 4, DK-1870 Copenhagen C, Denmark..
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ingmer, Hanne
    Univ Copenhagen, Dept Vet Dis Biol, Stigbojlen 4, DK-1870 Copenhagen C, Denmark..
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides2017In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 1, p. 115-127Article in journal (Refereed)
    Abstract [en]

    Background: The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in MDR bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system and the ramifications of prolonged bacterial exposure to AMPs are not fully understood. Objectives: We show that in vitro serial passage of a clinical USA300 MRSA strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP resistance. Methods: Serial passage experimentswere conducted using steadily increasing concentrations of LL-37, PR-39 or wheat germ histones. WGS and proteomic analysis by MS were used to identify the molecular mechanism associated with increased tolerance of AMPs. AMP-resistant mutants were characterized by measuring in vitro fitness, AMP and antibiotic susceptibility, and virulence in a mouse model of sepsis. Results: AMP-resistant Staphylococcus aureus mutants often displayed little to no fitness cost and caused invasive disease in mice. Further, this phenotype coincided with diminished susceptibility to both clinically prescribed antibiotics and human defence peptides. Conclusions: These findings suggest that therapeutic use of AMPs could select for virulent mutants with crossresistance to human innate immunity as well as antibiotic therapy. Thus, therapeutic use of AMPs and the implications of cross-resistance need to be carefully monitored and evaluated.

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  • 47. Kugelberg, Elisabeth
    et al.
    Löfmark, Sonja
    Wretlind, Bengt
    Andersson, Dan I
    Swedish Institute for Infectious Disease Control, Department of Bacteriology & Karolinska Institute, Stockholm .
    Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa2005In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 55, no 1, p. 22-30Article in journal (Refereed)
    Abstract [en]

    Objectives: Quinolone resistance in the opportunistic pathogen Pseudomonas aeruginosa is commonly caused by mutations that alter the target molecules DNAgyrase/topoisomerase IV, or cause activation of various efflux systems.We have analysed the effect of quinolone resistance caused by DNA gyrase/topoisomerase IV mutations on bacterial fitness.

    Methods: Norfloxacin-resistant mutants were isolated and by DNA sequencing the mutations conferring resistance were identified. Mutant fitnesswas determined by measuring growth rates in vitro. Mutants with reducedgrowth rates were serially passaged to obtain growth-compensatedmutants. The level of DNA supercoiling was determined by isolatingplasmid DNA from the susceptible, resistant and compensated mutants andcomparing the topoisomer distribution patterns by gel electrophoresis inthe presence of chloroquine.

    Results: Low-level resistance (4-48 mg/L) was caused by single mutations in gyrA or gyrB. Among these strains, three out of eight mutants showed lower fitness,whereas high-level resistant (>256 mg/L) mutants with doublemutations in gyrA and parC, parE, nfxB or unknown genes all showed areduced fitness. Slow-growing resistantmutants with a gyrA mutation had decreased DNA supercoiling. Afterserial passage in laboratory medium, mutant fitnesswas increased by compensatory mutation(s) that restored supercoiling tonormal levels. The compensatory mutation(s) was not located in any ofthe genes (gyrAB, topA, parCE, hupB, fis, hupN, himAD or PA5348) thatwere expected to affect supercoiling.

    Conclusions: Our results show that 'no cost' and compensatory mutations are common in quinolone-resistant P. aeruginosa.

  • 48.
    Lagerbäck, Pernilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Khine, Wei W. T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Giske, C. G.
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Evaluation of antibacterial activities of colistin, rifampicin and meropenem combinations against NDM-1-producing Klebsiella pneumoniae in 24 h in vitro time-kill experiments2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 8, p. 2321-2325Article in journal (Refereed)
    Abstract [en]

    To investigate the activity of colistin alone or in double and triple combination with rifampicin and meropenem against NDM-1-producing Klebsiella pneumoniae. Eight isolates of NDM-1-producing K. pneumoniae were exposed to clinically relevant antibiotic concentrations in 24 h time-kill experiments. Three colistin concentrations were used for two of the strains. Resistance development was assessed with population analysis and sequencing of the mgrB and pmrB genes. Initial killing was achieved with colistin alone, but with considerable regrowth at 24 h. Combinations including colistin and rifampicin were bacteriostatic or bactericidal against all strains. Colistin plus meropenem was bactericidal against one strain, but, overall, meropenem showed little additive effects. Higher concentrations of colistin did not enhance antibacterial activity. Resistant populations and deletion or mutations in the mgrB and pmrB genes were frequently detected in endpoint samples after exposure to colistin alone. Based on the results of this and previous studies, the combination of colistin and rifampicin seems promising and should be further explored in vivo and considered for clinical evaluation. Meropenem seems less useful in the treatment of infections caused by high-level carbapenem-resistant NDM-1-producing K. pneumoniae. Higher colistin concentrations did not result in significantly better activity, suggesting that combination therapy might be superior to monotherapy also when colistin is prescribed using high-dose regimens in accordance with current recommendations.

  • 49.
    Leangapichart, Thongpan
    et al.
    Norwegian Vet Inst, Sect Food Safety & Anim Hlth Res, Dept Anim Hlth Welf & Food Safety, Oslo, Norway..
    Lunha, Kamonwan
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Jiwakanon, Jatesada
    Khon Kaen Univ, Res Grp Anim Hlth Technol, Khon Kaen, Thailand..
    Angkititrakul, Sunpetch
    Khon Kaen Univ, Res Grp Anim Hlth Technol, Khon Kaen, Thailand..
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Magnusson, Ulf
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Sunde, Marianne
    Norwegian Vet Inst, Sect Food Safety & Anim Hlth Res, Dept Anim Hlth Welf & Food Safety, Oslo, Norway..
    Characterization of Klebsiella pneumoniae complex isolates from pigs and humans in farms in Thailand: population genomic structure, antibiotic resistance and virulence genes2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 8, p. 2012-2016Article in journal (Refereed)
    Abstract [en]

    Objectives: To define characteristics of Klebsiella pneumoniae complex (hereafter KP) isolates from healthy pigs, farm workers and their householdmembers in Thailand. Methods: A total of 839 individual rectal swabs from pigs on 164 farms and 271 faecal samples of humans working on pig farms and persons living in the same household in Khon Kaen, Thailand were screened for gut colonization by KP. Genomic sequenceswere investigated for antibiotic resistance and virulence genes. Phylogenetic analyseswere performed in addition to comparison with isolates from previous studies from Thailand. Results: KP was detected in approximately 50% of pig and human samples. In total, 253 KP isolates were obtained: 39% from pigs, 34% from farmers and 26% from individuals living on the same farm but without animal contact. MLST revealed high genetic diversity with 196 different STs distributed over four phylogroups (Kp1 to Kp4). Low prevalence of ESBL-KP (7.5%) and colistin-resistant KP (3.2%) was observed among pigs and humans. Remarkably, four convergent MDR and hypervirulent strains were observed: one from pigs (ST290) and three from humans [ST35, ST3415 (strain 90CP1), ST17 (strain 90CM2)]. Sharing of KP clones among pigs and humans was identified for some STs including ST4788, ST661, ST3541 and ST29. Conclusions: The study indicated a low prevalence of ESBL and mcr genes among KP isolated from pigs and healthy humans in Thailand and suggested the possibility of zoonotic transmission for a subset of circulating KP clones.

  • 50.
    Leangapichart, Thongpan
    et al.
    Section for Food Safety and Animal Health Research, Norwegian Veterinary Institute , Ås , Norway.
    Stosic, Milan S
    Section for Food Safety and Animal Health Research, Norwegian Veterinary Institute , Ås , Norway.
    Hickman, Rachel A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lunha, Kamonwan
    Department of Clinical Sciences, Swedish University of Agricultural Sciences , Uppsala , Sweden.
    Jiwakanon, Jatesada
    Research Group for Animal Health Technology, Faculty of Veterinary Medicine, Khon Kaen University , Khon Kaen , Thailand.
    Angkititrakul, Sunpetch
    Research Group for Animal Health Technology, Faculty of Veterinary Medicine, Khon Kaen University , Khon Kaen , Thailand.
    Magnusson, Ulf
    Department of Clinical Sciences, Swedish University of Agricultural Sciences , Uppsala , Sweden.
    Van Boeckel, Thomas P
    Health Geography and Policy Group, ETH Zurich , Zurich , Switzerland;Center for Diseases Dynamics Economics & Policy , Washington, DC , USA.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sunde, Marianne
    Section for Food Safety and Animal Health Research, Norwegian Veterinary Institute , Ås , Norway.
    Exploring the epidemiology of mcr genes, genetic context and plasmids in Enterobacteriaceae originating from pigs and humans on farms in Thailand2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 6, p. 1395-1405Article in journal (Refereed)
    Abstract [en]

    Objectives In veterinary medicine, colistin has been widely used as therapeutic and prophylactic agent, and for growth promotion. However, colistin has been re-introduced into treatment of human MDR bacterial infections. We assessed the characteristics and spread of plasmid-borne colistin resistance among healthy pigs, workers with animal-contact and their household members in Thailand.

    Methods WGS and MIC data of 146 mcr-positive isolates from a cross-sectional One Health study were analysed. Long-read sequencing and conjugation were performed for selected isolates.

    Results mcr-carrying isolates were detected in 38% of pooled-pig samples and 16% of human faecal samples. Of 143 Escherichia coli and three Escherichia fergusonii, mcr-1, mcr-3, and mcr-9 variants were identified in 96 (65.8%), 61 (41.8%) and one (0.7%) isolate, respectively. Twelve E. coli co-harboured two mcr variants (mcr-1 and mcr-3). Clonal transmission was detected in five out of 164 farms. mcr-1 was mostly harboured by epidemic IncX4 and IncHI1 plasmids (89.9%). Conversely, mcr-3 was harboured by a range of different plasmids. Comparative plasmid studies suggested IncP and IncFII plasmids as possible endemic mcr-3 plasmids in Asian countries. Moreover, mcr-3 was associated with different mobile genetic elements including TnAs2, ISKpn40 and IS26/15DI. Detected genetic signatures (DRs) indicated recent mcr-3 transpositions, underlining the mobilizable nature of the mcr-3 cassette.

    Conclusions The epidemiology of mcr and the possible evolution of successful plasmids and transposition modules should be carefully monitored. Of special concern is the growing number of different horizontal gene transferring pathways encompassing various transposable modules the mcr genes can be shared between bacteria.

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