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  • 1. Akkoyunlu, Mustafa
    et al.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Capiau, Carine
    van Opstal, Omer
    Forsgren, Arne
    The acylated form of protein D of Haemophilus influenzae is more immunogenic than the nonacylated form and elicits an adjuvant effect when it is used as a carrier conjugated to polyribosyl ribitol phosphate1997In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 65, no 12, p. 5010-5016Article in journal (Refereed)
    Abstract [en]

    The nonacylated form of protein D (PDm) of Haemophilus influenzae has been shown to induce the production of antibodies that are bactericidal to homologous and heterologous nontypeable H. influenzae (NTHi) strains. In this study, immunization of rats with lipoprotein D (LPD) induced higher levels of anti-protein D immunoglobulin G and A serum antibodies than immunization with PDm, and the bactericidal activities of sera from LPD-immunized rats were greater than those of sera from PDm-immunized rats. Immunization with LPD or PDm did not prevent the development of acute otitis media (AOM) when rats were challenged with 10(4) CFU of an NTHi strain. However, on the eighth day of bacterial challenge, 50% (5 of 10) of LPD-immunized rats had recovered from otitis media and 30% (3 of 10) had negative middle ear cultures, whereas only 30% (3 of 10) of PDm-immunized rats had recovered, though none was culture positive. Immunization with an inactivated homologous bacterial strain elicited 70% protection (i.e., 7 of 10 rats) in the rat otitis media model. LPD and PDm were also conjugated to the H. influenzae type b (Hib) capsular polysaccharide, polyribosyl ribitol phosphate (PRP), to test protein D-conjugated PRP vaccine's potential for protection against Hib infection. When two LPD-conjugated and two PDm-conjugated PRP vaccines, each containing a different protein concentration, and a tetanus toxoid-conjugated vaccine (ACT-HIB) were tested in the experimental model of rat otitis induced with a Hib strain (Minn A), both of the LPD-conjugated and one of the PDm-conjugated vaccines induced significant protection from AOM, the level of protection being highest in animals given the vaccine with the highest LPD content. Sera from these rats also manifested the highest anti-PRP and anti-LPD antibody levels and the highest bactericidal activities against a Hib strain and an NTHi strain.

  • 2.
    Bergman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Lignell, Anders
    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.
    The first documented case of Aspergillus cardiac surgical site infection in Sweden: an epidemiology study using arbitrarily primed PCR2009In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 8, p. 568-74Article in journal (Refereed)
    Abstract [en]

    Here we report two rare cases of severe thoracic Aspergillus fumigatus infections after lung and heart surgery at the same thoracic intensive care unit at the same time. The main objective was to identify a possible source of transmission. With arbitrarily primed polymerase chain reaction a patient-to-patient transmission could rapidly be ruled out as the cause of the first documented case of aspergillosis after open-heart surgery in Sweden. Although no definitive source was identified, a genetically similar strain was found in a contaminated supply room.

  • 3.
    Bonnedahl, Jonas
    et al.
    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.
    Gauthier-Clerc, Michel
    Hernandez, Jorge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Granholm, Susanne
    Kayser, Yves
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Kahlmeter, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Waldenström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Johansson, Anders
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Dissemination of Escherichia coli with CTX-M type ESBL between humans and yellow-legged gulls in the south of France2009In: PloS one, ISSN 1932-6203, Vol. 4, no 6, p. e5958-Article in journal (Refereed)
    Abstract [en]

    Extended Spectrum beta-Lactamase (ESBL) producing Enterobacteriaceae started to appear in the 1980s, and have since emerged as some of the most significant hospital-acquired infections with Escherichia coli and Klebsiella being main players. More than 100 different ESBL types have been described, the most widespread being the CTX-M beta-lactamase enzymes (bla(CTX-M) genes). This study focuses on the zoonotic dissemination of ESBL bacteria, mainly CTX-M type, in the southern coastal region of France. We found that the level of general antibiotic resistance in single randomly selected E. coli isolates from wild Yellow-legged Gulls in France was high. Nearly half the isolates (47.1%) carried resistance to one or more antibiotics (in a panel of six antibiotics), and resistance to tetracycline, ampicillin and streptomycin was most widespread. In an ESBL selective screen, 9.4% of the gulls carried ESBL producing bacteria and notably, 6% of the gulls carried bacteria harboring CTX-M-1 group of ESBL enzymes, a recently introduced and yet the most common clinical CTX-M group in France. Multi locus sequence type and phylogenetic group designations were established for the ESBL isolates, revealing that birds and humans share E. coli populations. Several ESBL producing E. coli isolated from birds were identical to or clustered with isolates with human origin. Hence, wild birds pick up E. coli of human origin, and with human resistance traits, and may accordingly also act as an environmental reservoir and melting pot of bacterial resistance with a potential to re-infect human populations.

  • 4.
    Cai, Yanling
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Welch, Ken
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Photocatalytic inactivation of biofilms on bioactive dental adhesives2014In: Journal of Biomedical Materials Research. Part B - Applied biomaterials, ISSN 1552-4973, E-ISSN 1552-4981, Vol. 102, no 1, p. 62-67Article in journal (Refereed)
    Abstract [en]

    Biofilms are the most prevalent mode of microbial life in nature and are 10-1000 times more resistant to antibiotics than planktonic bacteria. Persistent biofilm growth associated at the margin of a dental restoration often leads to secondary caries, which remains a challenge in restorative dentistry. In this work, we present the first in vitro evaluation of on-demand photocatalytic inactivation of biofilm on a novel dental adhesive containing TiO2 nanoparticles. Streptococcus mutans biofilm was cultured on this photocatalytic surface for 16 h before photocatalytic treatment with ultraviolet-A (UV-A) light. UV-A doses ranging from 3 to 43 J/cm(2) were applied to the surface and the resulting viability of biofilms was evaluated with a metabolic activity assay incorporating phenol red that provided a quantitative measure of the reduction in viability due to the photocatalytic treatments. We show that an UV-A irradiation dose of 8.4 J/cm(2) leads to one order of magnitude reduction in the number of biofilm bacteria on the surface of the dental adhesives while as much as 5-6 orders of magnitude reduction in the corresponding number can be achieved with a dose of 43 J/cm(2). This material maintains its functional properties as an adhesive in restorative dentistry while offering the possibility of a novel dental procedure in the treatment or prevention of bacterial infections via on-demand UV-A irradiation. Similar materials could be developed for the treatment of additional indications such as peri-implantits.

  • 5. Darkahi, Bahman
    et al.
    Sandblom, Gabriel
    Liljeholm, Hakan
    Videhult, Per
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Rasmussen, Ib Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Biliary Microflora in Patients Undergoing Cholecystectomy2014In: Surgical Infections, ISSN 1096-2964, E-ISSN 1557-8674, Vol. 15, no 3, p. 262-265Article in journal (Refereed)
    Abstract [en]

    Background: The management of acute cholecystitis requires a sound knowledge of the biliary microflora. Methods: Bile samples were taken for culture according to a standard routine during all cholecystectomies performed from April 2007 to February 2009 in the Department of Surgery at Enkoping Hospital. The use of antibiotics within the 3-mo period before surgery, indication for surgery, prophylactic antibiotics, and post-operative complications were recorded prospectively. Results: Altogether, 246 procedures were performed during the study period, of which 149 (62%) were done on women. The mean (SD) age of the study subjects was 49 +/- 16y. Bacterial growth was seen in cultures from 34 (14%) of the subjects. The mean age of subjects with positive cultures was 64y and that of subjects with negative cultures was 47y (p<0.001). Positive culture was seen in 16 (31%) of the 51 patients who underwent operations for acute cholecystitis, whereas positive cultures were obtained in 18 of 195 patients without acute cholecystitis (9%) (p<0.001). Resistance to ampicillin was recorded in three of 34 (9%) of the cultures with bacterial growth, to co-trimoxazole in one of the 34 (3%) cultures, to fluoroquinolones in one of the 34 (3%) cultures, and to cephalosporins in one of the 34 (3%) cultures. Resistance to piperacillin-tazobactam was not observed in any of the cultures. In multivariable logistic regression analysis, a positive culture was the only factor significantly associated with risk for post-operative infectious complications (p<0.05). Discussion: Bacterial growth in the bile is observed more often in patients undergoing surgery for acute cholecystitis. The microflora of the bile is probably important for the outcome of surgery, but further studies are required for assessing the effectiveness of measures for preventing infectious post-operative complications.

  • 6.
    Eriksson, Britt-Marie
    et al.
    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 Microbiology and Infectious Medicine.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nya rekommendationer för akut faryngotonsillit kan leda felRisk att patienter inte får nödvändig antibiotikabehandling: [New recommendations for acute pharyngotonsillitis can cause errors. There is a risk that patients will not receive proper antibiotic treatment].2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 3-4, p. 86-88Article in journal (Refereed)
    Abstract [sv]

    Akut faryngotonsillit är en av de vanligaste anledningarna till besök i öppen vård. 

    Cirka en tredjedel av fallen orsakas av bakterier, vanligen betahemolytiska streptokocker grupp A, men även grupp C och G förekommer. På senare år har Fusobacterium necrophorum uppmärksammats som en vanlig orsak, framför allt i åldersgruppen 16–30 år. 

    Akut faryngotonsillit kan ibland leda till allvarliga lokala eller generella komplikationer.

    Nuvarande svenska rekommendationer riskerar medföra att vissa patienter inte får erforderlig antibiotikabehandling.

  • 7. Foglé-Ansson, Margaretha
    et al.
    White, Peter
    Hermansson, Ann
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Otomicroscopic findings and systemic interleukin-6 levels in relation to etiologic agent during experimental acute otitis media2006In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 114, no 4, p. 285-291Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to explore whether it was possible to differentiate the clinical course and the otomicroscopic appearance of acute otitis media (AOM) caused by common otitis pathogens in an animal model. Systemic interleukin (IL)-6 levels as early markers for bacterial AOM were also studied. Four groups of rats were inoculated with either Streptococcus pneumoniae, Streptococcus pyogenes, non-typeable Haemophilus influenzae or Moraxella catarrhalis. The animals were monitored by otomicroscopy, photos of the tympanic membrane, cultures and IL-6 detection in serum the following 4 days. The gram-positive S. pneumoniae and S. pyogenes induced severe AOM with opaque effusion behind the tympanic membrane, pronounced dilation of the vessels and spontaneous perforations. The gram-negative H. influenzae and M. catarrhalis induced a less severe infection with cloudy, sometimes foamy effusion, and no spontaneous perforations. With the otomicroscopic findings it was possible to distinguish between infections induced by gram-positive bacteria and gram-negative bacteria. Detection of interleukin-6 in serum appeared to be of limited use for all infections except the pneumococcal AOM, but this needs to be further investigated.

  • 8. Forséni, M.
    et al.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ryan, A. F.
    Bagger-Sjöbäck, D.
    Hultcrantz, M.
    Detection and localization of interleukin-6 in the rat middle ear during experimental acute otitis media, using mRNA in situ hybridization and immunohistochemistry2001In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 57, no 2, p. 115-121Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Otitis media is one of the most common diseases among children. A well-known sequela of acute, chronic, and secretory otitis media is tympanosclerosis. With the exception of surgery, there is no causal treatment available for this condition, which may cause hearing disabilities. This study aimed to describe the localization of interleukin (IL)-6 mRNA and its gene product in the rat middle ear during pneumococcal otitis media. IL-6 is known to be involved in inflammatory and bone remodeling processes. METHODS: Using an experimental model of pneumococcal acute otitis media, the expression of interleukin IL-6, was analyzed. Sprague-Dawley rats were sacrificed at different time points varying from 1 h to 6 days intervals after inoculation. The middle ears were analyzed by messenger RNA in situ hybridization, and by immunohistochemistry with cell-type specific antibodies directed against IL-6. RESULTS: Transcripts of IL-6 were observed only on day 1 post-inoculation, whereas the final gene product was observed at all intervals after inoculation. IL-6 was localized in the bony part of the bulla nearest to the mucosa, around mucosal vessels, and in the ciliae of the mucosal epithelium. The results demonstrated that IL-6 was synthesized locally as early as 1 h after bacterial middle ear challenge, and that although transcription could not be detected after 24 h, the cytokine product persisted for at least 5 days after the infection was introduced. CONCLUSIONS: IL-6 was shown to be produced early in the inflammatory process during induced pneumococcal otitis media in the rat. No production was seen after 24 h although the protein remained in the tissue for at least 5 days. IL-6 could initiate a differentiation of macrophages to osteoclasts and thereby participate in a bone remodeling process leading to tympanosclerosis development.

  • 9. Fraenkel, Carl-Johan
    et al.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Enterococcus faecium coisolated with Lactobacillus species can mimic vancomycin-resistant enterococci2011In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 1, p. 7335-Article in journal (Refereed)
  • 10. Fraenkel, Carl-Johan
    et al.
    Ullberg, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Bernander, Sverker
    Ericson, Evalena
    Larsson, Peter
    Rydberg, Johan
    Törnqvist, Eva
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    In vitro activities of three carbapenems against recent bacterial isolates from severely ill patients at Swedish hospitals2006In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 38, no 10, p. 853-859Article in journal (Refereed)
    Abstract [en]

    To study the in vitro activity of imipenem, meropenem and ertapenem against common pathogens isolated from patients in intensive care, haematology and dialysis/nephrology units at 7 Swedish university hospitals, a total of 788 isolates were collected during 2002-2003. The distribution of the isolates was as follows: Escherichia coli (n = 140), Klebsiella spp. (n = 132), Proteus spp. (n = 97), Enterobacter spp. (n = 113), Pseudomonas aeruginosa (n = 126), Acinetobacter spp. (n = 53) and Enterococcus faecalis (n = 127). The susceptibility to the 3 carbapenems was determined by E-test, and the MICs were interpreted according to SRGA criteria. All 3 carbapenems were highly active against Enterobacteriaceae. The overall susceptibility to imipenem, meropenem and ertapenem was 90%, 98% and 93%, respectively. Against Enterobacteriaceae, Enterobacter spp. excluded, ertapenem had an equal or lower MIC(90) than meropenem. Apart from being the most active carbapenem against Enterobacteriaceae, meropenem was also the most active carbapenem against P. aeruginosa, whereas imipenem was the most active drug against Acinetobacter spp. The carbapenems are still potent antibiotics. With the introduction of ertapenem, and an expected increase in the carbapenem consumption due to an increased prevalence of strains with extended-spectrum beta-lactamases, continuous surveillance of carbapenem resistance appears to be warranted, with special attention to P. aeruginosa, Enterobacter and Proteus spp.

  • 11.
    Furukawa, Masayuki
    et al.
    Department of Surgery/Otolaryngology, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California.
    Ebmayer, Jörg
    Department of Surgery/Otolaryngology, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California.
    Pak , Kwang
    Department of Surgery/Otolaryngology, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California.
    Austin, Darrell A.
    Department of Medicine, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California.
    Melhus , Åsa
    Department of Microbiology, University of Lund, Lund, Sweden.
    Webster, Nicholas J. G.
    Department of Medicine, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California.
    Ryan, Allen F.
    Department of Surgery/Otolaryngology, UCSD School of Medicine, and Veterans Affairs Medical Center, La Jolla, California.
    Jun N-terminal protein kinase enhance middle ear mucosal proliferation during bacterial otitis media2007In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 75, no 5, p. 2562-2571Article in journal (Refereed)
  • 12. Gisselsson-Solen, Marie
    et al.
    Henriksson, Gunnel
    Hermansson, Ann
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Effect of pneumococcal conjugate vaccination on nasopharyngeal carriage in children with early onset of acute otitis media - a randomized controlled trial2015In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 135, no 1, p. 7-13Article in journal (Refereed)
    Abstract [en]

    Conclusion: Although children vaccinated with heptavalent pneumococcal conjugate vaccine (PCV) had fewer episodes of acute otitis media (AOM), this trial was unable to prove a simultaneous decrease in nasopharyngeal carriage. Objective: Carriage rates of AOM pathogens in the nasopharynx are high among children, and colonization is the first step towards infection. The possible impact of PCV on carriage is therefore of interest, particularly in children with recurrent AOM. The aims of this study were to examine the effect of heptavalent PCV on carriage of AOM pathogens in children at high risk of developing recurrent disease, and to monitor carriage of resistant pathogens in vaccinated and unvaccinated children. Methods: A total of 109 children with an onset of AOM before 6 months of age, 89 of whom developed recurrent disease, were enrolled in a trial. Fifty-two children were vaccinated and all were closely monitored for 3 years. Results: There was no difference statistically between vaccinated children and controls concerning the carriage of any of the major AOM pathogens. There was evidence of within-child clustering for S. pneumoniae (p = 0.002) and H. influenzae (p < 0.001), indicating that children continued to carry either species over time. Resistance rates were generally low and comparable with national levels.

  • 13. Gisselsson-Solen, Marie
    et al.
    Henriksson, Gunnel
    Hermansson, Ann
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Risk factors for carriage of AOM pathogens during the first 3 years of life in children with early onset of acute otitis media2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 7, p. 684-690Article in journal (Refereed)
    Abstract [en]

    Conclusion: Risk factors associated with increased carriage rates are the same in children with recurrent acute otitis media (rAOM) as in healthy children. These are also known to be risk factors for the development of AOM itself. Objectives: The aim of this study was to describe risk factors for nasopharyngeal carriage in a cohort of young children at high risk of developing rAOM. Methods: Children with an onset of AOM before 6 months of age, indicating an 80% risk of developing rAOM, were enrolled in a vaccination trial on heptavalent PCV. These children were monitored for 3 years during healthy and AOM periods with nasopharyngeal cultures, physical examinations, and questionnaires. Results: A total of 109 children were included at a mean age of 5 months; 105 were followed for 3 years, 89 (82%) of whom developed rAOM. Risk factors associated with increased carriage of all major AOM pathogens were age < 2 years, concurrent AOM, and fulfilment of rAOM criteria. Having siblings in day care was associated with increased carriage of Streptococcus pneumoniae and Haemophilus influenzae, recent antibiotic treatment was associated with H. influenzae and Moraxella catarrhalis carriage, and winter season was associated with M. catarrhalis carriage alone.

  • 14. Gisselsson-Solen, Marie
    et al.
    Hermansson, Ann
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Brodszki, Nicholas
    Immunologic findings in young children with early onset of acute otitis media2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 10, p. 1022-1028Article in journal (Refereed)
    Abstract [en]

    Conclusion: No significant differences in the number of immune aberrations were seen between children with or without severe recurrent acute otitis media (rAOM); however, subnormal values of immunological markers were found more often than expected, and 4 of the 60 children had treatment-requiring immune deficiencies. Objective: Minor immunologic aberrations have been reported to be more frequent in children with rAOM. Immune investigation is recommended in children with severe rAOM, defined as six or more AOM episodes per year. The purpose of this study was to describe immunological findings in young children at high risk of developing rAOM, and to relate these to the number of expected aberrations and to the presence of severe rAOM. Methods: A total of 109 children at risk of developing rAOM were offered immune investigation including complement function, immunoglobulins with subclasses and cellular immunity. Results: Sixty patients were tested, 31 of whom had severe rAOM and 12 of whom did not develop rAOM. Low levels of IgG2 (27%), C1q (31%) and mannan-binding lectin (21%) were found up to eight times as often as expected. Although subnormal values were more frequent among children with severe rAOM, the study was too small to provide reliable evidence of any difference. Four children were diagnosed with immune deficiencies that required treatment.

  • 15. Gisselsson-Solén, Marie
    et al.
    Bylander, Anita
    Wilhelmsson, Christina
    Hermansson, Ann
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The Binax NOW test as a tool for diagnosis of severe acute otitis media and associated complications2007In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 45, no 9, p. 3003-3007Article in journal (Refereed)
    Abstract [en]

    The diagnosis of acute otitis media (AOM) is often difficult, depending heavily on the experience and skills of the examiner. However, it is important to identify episodes of AOM that involve the risk of complications and to treat these episodes appropriately. The present study was performed in order to evaluate the use of a rapid antigen assay for Streptococcus pneumoniae, the Binax NOW test, as a diagnostic tool in patients with severe AOM and associated complications. The study included 70 patients with 74 episodes of AOM, 18 of them with complications. Cultures, Binax NOW tests, and a PCR assay were performed on nasopharyngeal secretions, middle ear fluid, and in some cases mastoid bone, cerebrospinal fluid, and urine. According to culture and PCR of the middle ear fluid, 30 (41%) of the episodes were caused by S. pneumoniae. The Binax NOW test was positive in 24 of these episodes (80%). It identified pneumococcal AOM independent of antibiotic treatment, and it was easily adapted to bone tissue. The test yielded sensitivity, specificity, and positive and negative predictive values for middle ear specimens of 85%, 100%, 100%, and 89%, respectively. The corresponding positive and negative values for predicting the bacterial etiology with nasopharyngeal secretions were 51% and 75%. This study showed that the Binax NOW test is a useful diagnostic tool for patients with severe AOM with or without complications.

  • 16. Hanberger, Håkan
    et al.
    Edlund, Charlotta
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    G Giske, Christian
    Melhus, Asa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Nilsson, Lennart E
    Petersson, Johan
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ternhag, Anders
    Werner, Maria
    Eliasson, Erik
    Rational use of aminoglycosides-Review and recommendations by the Swedish Reference Group for Antibiotics (SRGA)2013In: Scandinavian journal of infectious diseases, ISSN 1651-1980, Vol. 45, no 3, p. 161-175Article, review/survey (Refereed)
    Abstract [en]

    The Swedish Reference Group for Antibiotics (SRGA) has carried out a risk-benefit analysis of aminoglycoside treatment based on clinical efficacy, antibacterial spectrum, and synergistic effect with beta-lactam antibiotics, endotoxin release, toxicity, and side effects. In addition, SRGA has considered optimal dosage schedules and advice on serum concentration monitoring, with respect to variability in volume of drug distribution and renal clearance. SRGA recommends that aminoglycoside therapy should be considered in the following situations: (1) progressive severe sepsis and septic shock, in combination with broad-spectrum beta-lactam antibiotics, (2) sepsis without shock, in combination with broad-spectrum beta-lactam antibiotics if the infection is suspected to be caused by multi-resistant Gram-negative pathogens, (3) pyelonephritis, in combination with a beta-lactam or quinolone until culture and susceptibility results are obtained, or as monotherapy if a serious allergy to beta-lactam or quinolone antibiotics exists, (4) serious infections caused by multi-resistant Gram-negative bacteria when other alternatives are lacking, and (5) endocarditis caused by difficult-to-treat pathogens when monotherapy with beta-lactam antibiotics is not sufficient. Amikacin is generally more active against extended-spectrum beta-lactamase (ESBL)-producing and quinolone-resistant Escherichia coli than other aminoglycosides, making it a better option in cases of suspected infection caused by multidrug-resistant Enterobacteriaceae. Based on their resistance data, local drug committees should decide on the choice of first-line aminoglycoside. Unfortunately, aminoglycoside use is rarely followed up with audiometry, and in Sweden we currently have no systematic surveillance of adverse events after aminoglycoside treatment. We recommend routine assessment of adverse effects, including hearing loss and impairment of renal function, if possible at the start and after treatment with aminoglycosides, and that these data should be included in hospital patient safety surveillance and national quality registries.

  • 17.
    Hasan, Badrul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alam, Munirul
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    The Gull (Chroicocephalus brunnicephalus) as an Environmental Bioindicator and Reservoir for Antibiotic Resistance on the Coastlines of the Bay of Bengal2014In: Microbial Drug Resistance, ISSN 1076-6294, E-ISSN 1931-8448, Vol. 20, no 5, p. 466-471Article in journal (Refereed)
    Abstract [en]

    The presence and frequency of multiresistant bacteria in wild birds act as indicators of the environmental contamination of antibiotic resistance. To explore the rate of contamination mediated by Escherichia coli, 150 fecal samples from the brown-headed gull (Chroicocephalus brunnicephalus) and 8 water samples from the Bay of Bengal area were collected, cultured, and tested for antibiotic susceptibility. Special attention was paid to extended-spectrum beta-lactamase (ESBL)-producing isolates, which were further characterized genetically. Antibiotic resistance was found in 42.3% (36/85) of the E. coli isolates and multidrug resistance in 11.8%. Isolates from the area with a higher human activity were more resistant than those from an area with a lower level of activity. Most frequent was resistance to ampicillin (29.4%), followed by trimethoprim-sulfamethoxazole (24.7%) and quinolones (22.4%). Carriage of ESBL-producing E. coli was relatively high (17.3%) in the gulls, whereas no ESBL producers were found in the water. All ESBL-producing E. coli isolates, but one, carried blaCTX-M-15 or blaCTX-M-15-like genes. A blaCTX-M-14-like enzyme was found as an exception. Gulls from two different colonies shared E. coli clones and harbored the clinically relevant sequence types ST10, ST48, and ST131. The high frequency of antibiotic resistance and ESBL production among E. coli isolates from gulls indicates that the environmental contamination of antibiotic resistance has already gone far on the coastlines of the Bay of Bengal. Considering the limited control over the antibiotic consumption and waste from human activities in Bangladesh, there is no easy solution in sight.

  • 18.
    Hasan, Badrul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Alam, A
    Akter, L
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dissemination of the multidrug-resistant extended-spectrum β-lactamase-producing Escherichia coli O25b-ST131 clone and the role of house crow (Corvus splendens) foraging on hospital waste in Bangladesh.2015In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 21, no 11, article id UNSP 1000.e1Article in journal (Refereed)
    Abstract [en]

    Two hundred and thirty-eight faecal samples from crows foraging on hospital wastes were analysed for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. ESBL-producing crow isolates were characterized and compared with 31 patient isolates. Among the crows, 59% carried ESBL producers. These included Escherichia coli, Klebsiella pneumoniae, Raoultella terrigena and Enterobacter cloacae harbouring the genes for CTX-M-1, CTX-M-15, CTX-M-55, CTX-M-79, and CTX-M-14. Human isolates carried only the CTX-M-15 gene. Two-thirds of crow E. coli isolates and all human E. coli isolates were multidrug resistant. Crows and patients shared E. coli sequence types, including the epidemic E. coli O25b-ST131 clone. The scavenging behaviour of crows at poorly managed hospital waste dumps made them potential reservoirs of antibiotic resistance, including ESBLs.

  • 19.
    Hasan, Badrul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Drobni, Mirva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Hernandez, Jorge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Waldenström, Jonas
    Alam, Munirul
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Antimicrobial Drug-Resistant Escherichia coli in Wild Birds and Free-range Poultry, Bangladesh2012In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 18, no 12, p. 2055-2058Article in journal (Refereed)
    Abstract [en]

    Multidrug resistance was found in 22.7% of Escherichia coli isolates from bird samples in Bangladesh; 30% produced extended-spectrum β-lactamases, including clones of CTX-M genes among wild and domestic birds. Unrestricted use of antimicrobial drugs in feed for domestic birds and the spread of resistance genes to the large bird reservoir in Bangladesh are growing problems.

  • 20. Janson, Håkan
    et al.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Forsgren, Arne
    Protein D, the glycerophosphodiester phosphodiesterase from Haemophilus influenzae with affinity for human immunoglobulin D, influences virulence in a rat otitis model1994In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 62, no 11, p. 4848-4854Article in journal (Refereed)
    Abstract [en]

    A mutant lacking the ability to express the surface-exposed lipoprotein protein D was constructed by linker insertion and deletion mutagenesis of a cloned DNA insert containing the protein D structural gene from a nontypeable Haemophilus influenzae strain (NTHi). An isogenic NTHi mutant was isolated after transformation of genetically competent bacteria. The transformant was unreactive to a protein D-specific monoclonal antibody in a colony immunoassay. In addition, the mutant lacked the ability to synthesize detectable levels of protein D by protein staining, immunoblot methods, glycerophosphodiester phosphodiesterase activity, and binding studies of radiolabelled immunoglobulin D. The isogenic protein D-deficient mutant was compared with its parental strain for its ability to induce experimental otitis media in rats challenged with bacteria. An approximately 100-times-higher concentration of the mutant compared with that of the wild-type strain was required in order to cause otitis among all rats challenged with that given dose. The protein D mutant exhibited a generation time that was equal to that of the wild-type strain in complex broth medium. No difference in lipopolysaccharide expression was found between the mutant and the parental strain. These results suggest that protein D may influence the pathogenesis of NTHi in the upper respiratory tract.

  • 21.
    Jonsson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Tängdén, Thomas
    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 Biochemistry and Microbiology.
    Lannergård, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A trial with IgY chicken antibodies to eradicate faecal carriage of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamases2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 28224Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is an emerging therapeutic challenge, especially in the treatment of urinary tract infections. Following an outbreak of CTX-M-15 Klebsiella pneumoniae in Uppsala, Sweden, an orphan drug trial on IgY chicken antibodies was undertaken in an attempt to eradicate faecal carriage of ESBL-producing K. pneumoniae and Escherichia coli.

    METHODS: Hens were immunised with epitopes from freeze-dried, whole-cell bacteria (ESBL-producing K. pneumoniae and E. coli) and recombinant proteins of two K. pneumoniae fimbriae subunits (fimH and mrkD). The egg yolks were processed according to good manufacturing practice and the product was stored at-20°C until used. Using an internal database from the outbreak and the regular laboratory database, faecal carriers were identified and recruited from May 2005 to December 2013. The participants were randomised in a placebo-controlled 1:1 manner.

    RESULTS: From 749 eligible patients, 327 (44%) had deceased, and only 91 (12%) were recruited and signed the informed consent. In the initial screening performed using the polymerase chain reaction, 24 participants were ESBL positive and subsequently randomised and treated with either the study drug or a placebo. The study was powered for 124 participants. Because of a very high dropout rate, the study was prematurely terminated. From the outbreak cohort (n=247), only eight patients were screened, and only one was positive with the outbreak strain in faeces.

    CONCLUSIONS: The present study design, using IgY chicken antibodies for the eradication of ESBL-producing K. pneumonia and E. coli, was ineffective in reaching its goal due to high mortality and other factors resulting in a low inclusion rate. Spontaneous eradication of ESBL-producing bacteria was frequently observed in recruited participants, which is consistent with previous reports.

  • 22.
    Kaarme, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Molin, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Olsen, Björn
    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 Microbiology and Infectious Medicine, Clinical Bacteriology.
    Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae in healthy Swedish preschool children2013In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 012, no 6, p. 655-660Article in journal (Refereed)
    Abstract [en]

    AIM:

    The objective was to determine the prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in faeces from healthy Swedish preschool children and to establish whether transmission took place between children in preschools.

    METHODS:

    Diapers from children attending preschools in Uppsala city were collected during September to October 2010, and the faeces was cultured. Antibiotic profiles and carriage of CTX-M, TEM, SHV and AmpC type enzymes were determined. PCR-positive isolates were further characterized by sequencing and epidemiological typing. Statistics on antibiotic use and ESBL producers in paediatric patients at Uppsala University Hospital were extracted for comparison.

    RESULTS:

    A total of 313 stool specimens were obtained, representing 24.5% of all preschool children in Uppsala city. The carriage rate of ESBL-producing Enterobacteriaceae was 2.9% among these healthy children. The corresponding figure for patients in the same age group was 8.4%. Escherichia coli with CTX-M type enzymes predominated, and only one E. coli isolate carried genes-encoding CMY. CTX-M-producing E. coli isolates with identical genotypes were found in children with no familial relation at two different preschools.

    CONCLUSIONS:

    Using diapers, the prevalence of ESBL-producing Enterobacteriaceae in children was quickly established, and, most likely, a transmission of ESBL-producing E. coli was for the first time documented between children at the same preschool.

  • 23. Karlsson, Eva
    et al.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nontypeable Haemophilus influenzae strains with the capsule-associated insertion element IS1016 may mimic encapsulated strains2006In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 114, no 9, p. 633-640Article in journal (Refereed)
    Abstract [en]

    With the elimination of Haemophilus influenzae type b through vaccination, it has been suggested that other types of H. influenzae strains might acquire virulence traits and emerge as important pathogens. The gene sequence IS1016 has been associated with an increased capacity to cause severe infections. It is usually present in encapsulated strains but is sometimes harbored by nontypeable H. influenzae strains. To explore this further, 118 H. influenzae isolates, collected from both patients and healthy carriers, were investigated with PCR with reference to this gene sequence. Isolates positive for the insertion element were bio- and serotyped. The presence of hmw genes for adherence, the genetic profile, and the ability to form biofilm in vitro were investigated. A total of 15 isolates were IS1016-positive, whereof 12 were nontypeable. All 12 nontypeable isolates were obtained from healthy carriers, and 92% of the isolates were biotype I. They cross-reacted to some extent with type-specific antisera or exhibited a restricted genetic diversity like encapsulated strains. Furthermore, they lacked hmw-genes, and their ability to form biofilms was comparable with a capsule-deficient type b strain. Although this subset of strains mimicked traits usually exhibited by encapsulated strains, the isolation frequency did not seem to have been affected by vaccination.

  • 24.
    Korsgren, Stella
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Molin, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salmela, K.
    Lundgren, T.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    On the etiology of type 1 diabetes: A new animal model signifying a decisive role for bacteria eliciting an adverse innate immunity response2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 181, no 5, p. 1735-1748Article in journal (Refereed)
    Abstract [en]

    The cause of type 1 diabetes (T1D) remains unknown; however, a decisive role for environmental factors is recognized. The increased incidence of T1D during the last decades, as well as regional differences, is paralleled by differences in the intestinal bacterial flora. A new animal model was established to test the hypothesis that bacteria entering the pancreatic ductal system could trigger β-cell destruction and to provide new insights to the immunopathology of the disease. Obtained findings were compared with those present in two patients dying at onset of T1D. Different bacterial species, present in the human duodenum, instilled into the ductal system of the pancreas in healthy rats rapidly induced cellular infiltration, consisting of mainly neutrophil polymorphonuclear cells and monocytes/macrophages, centered around the pancreatic ducts. Also, the islets of Langerhans attracted polymorphonuclear cells, possibly via release of IL-6, IL-8, and monocyte chemotactic protein 1. Small bleedings or large dilatations of the capillaries were frequently found within the islets, and several β-cells had severe hydropic degeneration (ie, swollen cytoplasm) but with preserved nuclei. A novel rat model for the initial events in T1D is presented, revealing marked similarities with the morphologic findings obtained in patients dying at onset of T1D and signifying a decisive role for bacteria in eliciting an adverse innate immunity response. The present findings support the hypothesis that T1D is an organ-specific inflammatory disease.

  • 25.
    Lindbäck, Heidi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Inadequate adherence to Swedish guidelines for uncomplicated lower urinary tract infections among adults in general practice2017In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 125, no 9, p. 816-821Article in journal (Refereed)
    Abstract [en]

    In a primary care study of urinary tract infections (UTIs) performed 2008 in Uppsala County, Sweden, 43% of the patients were culture negative. In order to investigate the background to the observed overdiagnosis of UTI, study invitations were sent to the previously included patients. A total of 256 patients (88% women) approved to participate. Patient charts and recorded laboratory data were reviewed. Two or more of the cardinal symptoms were reported in 53% of the women and in 19% of the men. A dipstick test was performed in 93% of the consultations. The highest positive predicted values in women had a positive nitrite test (95%, 95% CI 87; 99) and dysuria in combination with urgency (81%, 95% CI 72; 88). Seventy-one percent of the women who fulfilled the symptom criteria received an antibiotic prescription directly, 87% of these had a positive culture. The drug of choice was pivmecillinam for women (51%) and quinolones (50%) for men. The treatment duration was too long for the women; 68% were treated for 7 days. In conclusion, the adherence to national guidelines/recommendations was inadequate. To reduce the selection of multiresistant bacteria, an improvement of the use of diagnostic criteria/tools and antibiotic drugs in primary care is necessary.

  • 26.
    Lytsy, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Torell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The first major extended-spectrum beta-lactamase outbreak in Scandinavia was caused by clonal spread of a multiresistant Klebsiella pneumoniae producing CTX-M-152008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 4, p. 302-8Article in journal (Refereed)
    Abstract [en]

    Between May and December 2005, 64 multidrug-resistant isolates of Klebsiella pneumoniae were detected from patients admitted to Uppsala University Hospital. This represented a dramatic increase in ESBL-producing K. pneumoniae compared to previous years. To investigate the epidemiology and to characterize the resistance mechanisms of the isolates, a study was initiated. Antibiotic susceptibility was determined by means of the Etest and the disc diffusion method. Extended-spectrum beta-lactamase (ESBL) production was identified by clavulanic acid synergy test and confirmed with PCR amplification followed by DNA sequencing. DNA profiles of the isolates were examined with pulsed-field gel electrophoresis (PFGE). All isolates were resistant or exhibited reduced susceptibility to cefadroxil, cefuroxime, cefotaxime, ceftazidime, aztreonam, piperacillin/tazobactam, ciprofloxacin, tobramycin, and trimethoprim-sulfamethoxazole. They produced ESBL of the CTX-M-15 type, and the involvement of a single K. pneumoniae clone was shown. This is the first major clonal outbreak of multiresistant ESBL-producing K. pneumoniae in Scandinavia. The outbreak demonstrates the epidemic potential of enterobacteria containing ESBLs of the CTX-M type, even in a country with a relatively low selective pressure and a low prevalence of multiresistant bacteria.

  • 27. Magnuson, K.
    et al.
    Hermansson, A.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellström, S.
    The tympanic membrane and middle ear mucosa during non-typeable Haemophilus influenzae and Haemophilus influenzae type b acute otitis media: a study in the rat1997In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 117, no 3, p. 396-405Article in journal (Refereed)
    Abstract [en]

    Non-typeable Haemophilus influenzae (NTHi) and encapsulated Haemophilus influenzae type b (Hib) were inoculated into the middle ears of Sprague-Dawley rats. Tympanic membrane (TM) status was assessed otomicroscopically and specimens from various middle ear areas were prepared for light microscopy at various times during the acute phase and up to 6 months after inoculation. Irrespective of bacteria strain, acute otitis media (AOM) was present in all ears 4 days after inoculation. The Hib-infected ears showed initially a severe course of AOM, but all were otomicroscopically resolved by day 12, at which time a few NTHi-inoculated ears still exhibited middle ear effusion. The TMs infected with Hib had normalized without scar formation, whereas NTHi induced a persistent thickening of the TMs in half of all cases. The middle ear mucosa of NTHi-infected ears initially showed vigorous activity among the goblet cells, but the mucosa normalized after the acute phase. Hib, by contrast, induced prominent changes in the middle ear mucosa. Initially, no goblet cell granules or ciliated cells could be observed in the mucosa. Later on, the epithelium contained large, active goblet cells. Glands appeared beneath the mucosa which persisted as streaks of epithelial cells throughout the study period. The findings show that NTHi and Hib both induce AOM but with differing clinical courses, and affect different targets in the middle ear.

  • 28. Magnúsdóttir, Anna Björk
    et al.
    Hermansson, Ann
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Experimental study of the virulence of Streptococcus pneumoniae with reduced susceptibility to penicillin2000In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 55, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Streptococcus pneumoniae is a major cause of morbidity and mortality in all age groups. In a few years, penicillin non-susceptible pneumococci (PNSP) have emerged worldwide as a new threat. In order to better understand the mechanisms behind the rapid expansion of these strains, the virulence of 10 clinical and two transformed PNSP strains were compared with the virulence of three fully susceptible strains in a mouse model of bacteremia and a rat model of acute otitis media. Serotype, antibiotic susceptibility, and to some extent also genetic profile and growth rate of the strains were investigated before inoculation. The animals were monitored for up to 7 days after challenge by clinical examinations/otomicroscopy and cultures from middle ears and blood. The results of the study demonstrated that the PNSP strains had a significantly reduced ability to persist at the infectious site, and to some extent also to induce infections, compared with fully susceptible strains. The reduction was most evident for strains isolated from sources other than blood. It is therefore possible that other factors than virulence factors are of importance for the ability of PNSP strains to expand.

  • 29.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Effects of amoxicillin on the expression of cytokines during experimental acute otitis media caused by non-typeable Haemophilus influenzae2001In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 48, no 3, p. 397-402Article in journal (Refereed)
    Abstract [en]

    Antibiotics are frequently prescribed when a diagnosis of acute otitis media (AOM) is made in childhood, but the effects of antibiotics on host-parasite interactions in the middle ear are not well defined. A rat model and PCR techniques were used to explore host responses during amoxicillin treatment of AOM caused by non-typeable Haemophilus influenzae (NTHi). The 5 day course of amoxicillin initiated at the otomicroscopic peak of the infection eradicated the bacteria and induced significant changes in the expression of cytokines. Interleukin (IL)-6, tumour necrosis factor-alpha and IL-10 were upregulated by the treatment, and the downregulation was slower than during the natural course. Amoxicillin inhibited the upregulation of transforming growth factor-beta, whereas IL-1alpha expression remained unaffected by the treatment. By comparing inflammatory host responses during treated and untreated NTHi AOM, new targets for modification of the course, or more specified and individualized treatments, may evolve.

  • 30.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    First documented case of Aeromonas veronii biovar sobria infection in northern Europe2002In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 34, no 3, p. 218-219Article in journal (Refereed)
    Abstract [en]

    The first Scandinavian case of Aeromonas veronii biovar sobria infection, an episode of peritonitis in a patient suffering from a cirrhotic liver and an earlier unrecognized appendiceal cancer, is described.

  • 31.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fluoroquinolones and tendon disorders2005In: Expert Opinion on Drug Safety, ISSN 1474-0338, E-ISSN 1744-764X, Vol. 4, no 2, p. 299-309Article in journal (Refereed)
    Abstract [en]

    Fluoroquinolones are the most potent oral antibiotics in clinical use today. Increasingly, these drugs are being prescribed for relatively benign infections and for new categories of patients, including paediatric patients. As their use becomes more frequent, so will the adverse events. This review focuses on a rare but debilitating adverse reaction, the fluoroquinolone-associated tendinopathy. Despite many published case reports and approximately 3500 cases reported to the World Health Organization Collaborating Centre for Drug Monitoring, little is known about the mechanisms behind this fluoroquinolone-specific toxicity. Data on chemical properties, mode of action, pharmacokinetic features, clinical presentation and risk factors in relation to tendon toxicity are discussed and the literature reviewed. As long as the musculoskeletal toxicity cannot be predicted by in vitro or in vivo models and this class of antibiotics is one of the most commonly linked to selection of resistant bacteria, a more prudent use of fluoroquinolones is warranted.

  • 32.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isolation of dysgonic fermenter 3, a rare isolate associated with diarrhoea in immunocompromised patients1997In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 29, no 2, p. 195-6Article in journal (Refereed)
    Abstract [en]

    CDC group DF-3 is a rare isolate from blood, stools and wounds. During the last few years attention to this bacterium has increased due to its association with diarrhoea and bacteremia in immunocompromised patients. This report presents an isolation of this bacterium from a decubitus ulcer of a subfebrile patient with diarrhoea.

  • 33.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Opastöriserad dryck inte alltid så nyttig som utlovas2003In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 100, no 19, p. 1738-Article in journal (Refereed)
  • 34.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Apelqvist, Jan
    Larsson, Jan
    Eneroth, Magnus
    Levofloxacin-associated Achilles tendon rupture and tendinopathy2003In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 35, no 10, p. 768-770Article in journal (Refereed)
    Abstract [en]

    Fluoroquinolones have a documented ability to induce Achilles tendinopathy. Hitherto, few published reports have implicated levofloxacin. This article reports 5 cases of Achilles tendon disorders, including 3 complicated by rupture of the tendon, during levofloxacin treatment of patients with chronic obstructive pulmonary disease.

  • 35.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hemansson, Ann
    Haemophilus influenzae type b vaccination1997In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 350, no 9072, p. 222-Article in journal (Refereed)
  • 36.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Controversies: treatment of acute otitis media1998In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 279, no 22, p. 1783-4; author reply 1785Article in journal (Refereed)
  • 37.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Akkoyunlu, Mustafa
    Forsgren, Arne
    Prellner, Karin
    Experimental recurrent otitis media induced by Haemophilus influenzae: protection and serum antibodies1995In: American Journal of Otolaryngology, ISSN 0196-0709, E-ISSN 1532-818X, Vol. 16, no 6, p. 383-390Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study whether acute otitis media caused by encapsulated or nontypeable Haemophilus influenzae confers cross-reactive protective immunity in an animal model system and to explore the possible involvement of various humoral specific antibodies in protection. MATERIALS AND METHODS: Rats were intrabullarly challenged with H influenzae type b and two different nontypeable H influenzae strains. One month after the initial infection, the animals were rechallenged ipsilaterally or contralaterally with either a homologous or heterologous strain, and the susceptibility to reinfection was investigated by otomicroscopy. RESULTS: The animals challenged and rechallenged with the type b strain were well-protected ipsilaterally and contralaterally, while the protection after homologous rechallenge with a nontypeable strain was partial in the ipsilateral ear and very poor in the contralateral ear. Middle ears previously infected with a nontypeable strain remained fully susceptible to infections with heterologous strains, but there was an indication of cross-protection in the animal groups where the first episode of acute otitis media was caused by type b and the second by a nontypeable strain. Using the Western blot technique and an enzyme linked immunosorbant assay, the serological response to different outer membrane proteins, especially protein D, of H influenzae during and after middle ear infection were investigated. The serological response from the type b infected animals were generally more distinct, while the antibody levels against protein D were lower in these groups compared with the groups infected with nontypeable strains. CONCLUSIONS: These data indicate that H influenzae type-b-induced experimental otitis media results in a better protection than a nontypeable-induced, and H influenzae b confers a cross protection.

  • 38.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Forsgren, A.
    Prellner, Karin
    Intra- and interstrain differences of virulence among nontypeable Haemophilus influenzae strains1998In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 106, no 9, p. 858-868Article in journal (Refereed)
    Abstract [en]

    Nontypeable Haemophilus influenzae (NTHi) is sometimes the causative agent of invasive diseases, and it has been suggested that there may be differences in virulence among NTHi strains. Whilst studying clinical isolates of NTHi in a rat model of acute otitis media, intra- and interstrain differences in virulence were observed. Two strains with suddenly reduced capacity to cause middle ear infections and one highly virulent strain with dose requirements comparable only to encapsulated H. influenzae strains were further investigated, together with 15 other H. influenzae strains. The strains were characterized by analyzing the lipopolysaccharide, the outer membrane proteins, the hemagglutinating ability, and the polymerase chain reaction products after amplification of a gene sequence associated with encapsulation. The pathogenic capacity was assessed in two different in vivo models. It was found that the two strains with reduced pathogenic capacity could regain their virulence after animal passage. The LPS analysis and the results from the chicken embryo model suggested that the observed change in virulence might be associated with the lipopolysaccharide. For the non-animal-passaged strain 3655 there were indications that an undefined factor(s) contributed to its relatively potent virulence. As all three strains lacked genes necessary for encapsulation, in no case could any part of the increased virulence be attributed to the expression of small amounts of capsule.

  • 39.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Forsgren, Arne
    Prellner, Karin
    A resolved pneumococcal infection protects against nontypeable Haemophilus influenzae: an evaluation of different routes of whole cell immunization in protection against experimental acute otitis media1997In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 39, no 2, p. 119-131Article in journal (Refereed)
    Abstract [en]

    A conferred cross-protection between Haemophilus influenzae type b (Hib) and nontypeable H. influenzae (NTHi) was demonstrated in a previous study of experimental recurrent otitis media. To explore cross-protection further, and to compare oral administration of whole cells with two more conventional routes for vaccination against acute otitis media (AOM), a total number of 79 rats were immunized perorally, subcutaneously and intrabullarly with H. influenzae or pneumococci and thereafter challenged in the middle ear with NTHi or Hib 4 or 9 weeks later. Otomicroscopic changes, bacterial cultures, and serum IgG antibody levels were monitored. The study demonstrated that while peroral administration did not elicit any protection, a resolved pneumococcal AOM could reduce the susceptibility to reinfection with NTHi. In the latter case no cross-reacting antibodies were detected, but the protective rate was 50% or more, and it was comparable with that found after subcutaneous or intrabullar immunization with homologous NTHi or Hib strains. The results suggest that the protection of the rat middle ear mucosa may involve unspecific responses.

  • 40.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Forsgren, Arne
    Prellner, Karin
    Effect of Haemophilus influenzae type b conjugate vaccine in combination with peroral immunization with Escherichia coli on experimental otitis media1996In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 36, no 1, p. 1-12Article in journal (Refereed)
    Abstract [en]

    The protective ability of a conjugated Haemophilus influenzae type b vaccine, ACT-HIB, used singly or in combination with orally administered Escherichia coli, was investigated in a rat model for acute otitis media. The humoral response to ACT-HIB was also analyzed. The study demonstrated that ACT-HIB vaccination resulted in a prompt antibody response, and that ACT-HIB was efficient in preventing middle ear infections caused by Haemophilus influenzae type b. The efficiency increased if the vaccine was combined with Escherichia coli. The results suggest that Escherichia coli could possibly be useful in the future as a vaccine vehicle, and since Haemophilus influenzae acute mastoiditis seems to be almost exclusively due to serotype b, the incidence of this infection may be reduced with the conjugated Haemophilus influenzae type b vaccines.

  • 41.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Ann
    Prellner, Karin
    Nontypeable and encapsulated Haemophilus influenzae yield different clinical courses of experimental otitis media1994In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 114, no 3, p. 289-294Article in journal (Refereed)
    Abstract [en]

    Middle ears of male Sprague-Dawley rats were injected with suspensions of thirteen Haemophilus influenzae strains of different sero- and biotypes and at various concentrations. Systemic and local changes were monitored by clinical observations, otomicroscopy, and analysis of bacterial samples from blood and middle ears. Two patterns of response were recognized, a nontypeable and an encapsulated pattern. The nontypeable H. influenzae middle ear infection required a high bacterial dose and was well past its peak 8 days after challenge, when the encapsulated H. influenzae otitis media was still purulent. The most severe infections were caused by H. influenzae type b strains. The overall mortality rate was zero and the animals recovered without permanent deterioration or otomicroscopically discernable changes. The results of this study show the rat to be a suitable animal model for the study of H. influenzae otitis media.

  • 42.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holmdahl, T.
    Tjernberg, I.
    First documented case of bacteremia with Vibrio vulnificus in Sweden1995In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 27, no 1, p. 81-82Article in journal (Other academic)
    Abstract [en]

    A few days after a mild trauma to a toe, a 90-year-old woman presented with fever, malaise and cellulitis. On suspicion of erysipelas the patient was initially treated with benzylpenicillin and cefuroxime. Her general condition improved rapidly, but there was local progression with numerous necrotic areas with surrounding bullae. Vibrio vulnificus was isolated from the blood. After susceptibility testing, the patient was finally treated with ciprofloxacin and pivampicillin, and recovered slowly. To our knowledge, this is the first reported case of bacteremia with V. vulnificus in Sweden.

  • 43.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Håkan
    Westman, Eva
    Hermansson, Ann
    Forsgren, Arne
    Prellner, Karin
    Amoxicillin treatment of experimental acute otitis media caused by Haemophilus influenzae with non-beta-lactamase-mediated resistance to beta-lactams: aspects of virulence and treatment1997In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 41, no 9, p. 1979-1984Article in journal (Refereed)
    Abstract [en]

    Through alterations primarily in the penicillin-binding proteins, a non-beta-lactamase-mediated resistance to beta-lactams has evolved in Haemophilus influenzae. The virulence of these chromosomally changed strains has been questioned. To ascertain whether these alterations involve a reduction in virulence of H. influenzae and whether they could be advantageous for the bacterium during amoxicillin treatment of acute otitis media, a total of 70 Sprague-Dawley rats were challenged with a susceptible recipient strain or a genetically similar resistant transformant strain. Antibiotic therapy was started on day 3 after inoculation, and the animals were monitored by daily otomicroscopy and analysis of bacterial samples from middle ear effusions obtained on day 8, the last day of observation. The animals were also sacrificed on days 4 and 8 and after 2 months for morphological examination. Compared with the susceptible recipient strain, recovery from infections caused by the resistant transformant strain was delayed, and the late structural changes were more severe in the animals challenged with the latter strain. The results of the study indicate that chromosomal alterations mediating a relatively low level of resistance to beta-lactams may be advantageous for H. influenzae during antibiotic treatment of a local infection in the rat, and the alterations may occur without any significant loss of virulence.

  • 44.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Charlotte
    Schliamser, Silvia
    Vibrio vulnificus: Havsbakterie med dödlig potential2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, no 32-33, p. 3400-3402Article in journal (Refereed)
    Abstract [en]

    Vibrio vulnificus is a halophilic gram-negative rod widespread in the aquatic environment and associated with primary septicemia and severe wound infections. The first Swedish case was reported in 1994. Ever since, sporadic cases have occurred in the south of Sweden whenever the coastal water temperature has exceeded 20 degrees C. Critical for a successful outcome in these infections has been early diagnosis with appropriate antibiotic and surgical treatment. A review of this subject was prompted by two cases of fulminant septicemia, which both presented themselves as atypical erysipelas.

  • 45.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ryan, Allen F.
    A mouse model for acute otitis media2003In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 111, no 10, p. 989-994Article in journal (Refereed)
    Abstract [en]

    To induce acute otitis media in the mouse and to describe the clinical and bacteriological course of the infection, middle ears of BALB/c, Swiss-Webster and C57BL/6 mice were inoculated with Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Systemic and local changes were monitored by clinical observations, otomicroscopy, and analysis of bacterial samples from blood and middle ears. Agglutination of mouse erythrocytes by M. catarrhalis was also tested. Depending on bacterial strain, bacterial dose, and mouse strain three responses were identified: acute otitis media, otitis media with serous effusion, or no reaction. BALB/c mice were the most susceptible animals. On day 3, 76% of the BALB/c mice had developed middle ear infection, 50% had a positive middle ear culture, 56% were bacteremic, and 10% had succumbed to a disseminated infection. The local infections lasted approximately a week. Animals which survived recovered without permanent deterioration or otomicroscopically discernible changes. In no case did M. catarrhalis induce a culture-positive middle ear infection, possibly due to an inability to agglutinate the mouse erythrocytes. The mouse model can become a useful tool in studies of pneumococcal and H. influenzae-induced otitis media, but the bacterial dose has to be carefully titrated and adjusted to the chosen mouse strain.

  • 46.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ryan, Allen F.
    Effects of amoxicillin on cytokine and osteocalcin expression in bone tissue during experimental acute otitis media2004In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 25, no 6, p. 254-259Article in journal (Refereed)
    Abstract [en]

    There are indications that bone regulatory and immune systems are closely related. Of special interest in this context is the acute otitis media (AOM), which mainly affects immunologically immature patients and, when complicated, involves bone tissue. To explore host responses in bone tissue during Haemophilus influenzae-induced AOM modified by amoxicillin, a rat model and PCR techniques were used. The treatment eradicated the bacteria and induced changes in the expression profile of osteocalcin, a bone formation marker. The maximum levels of osteocalcin transcripts in the treatment group were delayed by about a week. The mRNA levels never reached the same high levels as in the untreated animal group, but the downregulation was slow and entailed higher osteocalcin mRNA levels for a longer time period in the treated animals. The expression of IL-6 and TNF-alpha, two cytokines associated with bone resorption, remained unaffected by the amoxicillin treatment, whereas the downregulation of IL-10, with suppressive effects on bone resorption, was slower than that during the natural course. By comparing the host responses on the molecular level in different tissues during treated and untreated AOM, new approaches to how to minimize the risks of severe AOM complications may evolve.

  • 47.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ryan, Allen F.
    Expression of cytokine genes during pneumococcal and nontypeable Haemophilus influenzae acute otitis media in the rat2000In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 68, no 7, p. 4024-4031Article in journal (Refereed)
    Abstract [en]

    Acute otitis media (AOM) elicits potent inflammatory responses from the cells of the middle ear mucosa as well as from infiltrating leukocytes. To explore host responses during experimental AOM induced by Streptococcus pneumoniae type 3 and nontypeable Haemophilus influenzae (NTHi), otomicroscopy findings and expression of cytokine genes in the middle ear were monitored up to 1 month postinoculation. The mucosa and infiltrating cells responded rapidly to the bacterial challenge. Otomicroscopically, AOM appeared 1 day after NTHi inoculation and 3 days after pneumococcus inoculation. Pneumococcal AOM was more severe than NTHi otitis, but in general, lower transcript levels were detected in pneumococcus-infected than in NTHi-infected animals. Interleukin-6 (IL-6) mRNA levels peaked at 3 to 6 h for both pneumococcus-infected and NTHi-infected animals. IL-1alpha, tumor necrosis factor alpha, and IL-10 mRNA levels peaked at 6 h for NTHi otitis and 1 to 3 days for pneumococcal otitis. Comparing otomicroscopy with expression profiles, it would appear that the majority of cytokine mRNAs had passed their peak before the AOM diagnosis could be made clinically. Only transforming growth factor beta mRNA followed a slower time course, peaking very late and continuing expression even after the AOM was otomicroscopically resolved. IL-2 and IL-4 mRNAs were not detected in any animal at any time. Most of the investigated cytokines are very early markers for AOM and may be involved in initiation of inflammation, but they would be poor targets for pharmacological manipulation since their levels decline before clinical signs appear.

  • 48.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ryan, Allen F.
    Expression of molecular markers for bone formation increases during experimental acute otitis media2001In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 30, no 3, p. 111-120Article in journal (Refereed)
    Abstract [en]

    Bony tissues are integral parts of the function of the middle ear and the protection of adjacent vital structures. To explore the reaction of middle ear bone to acute otitis media, rats were challenged with Streptococcus pneumoniae and Haemophilus influenzae. Local changes were monitored for up to 1 month. After reverse transcription, competitive polymerase chain reaction was used to determine the expression levels of two molecular markers of bone formation, osteocalcin and procollagen I, and the two cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, in the bone. Middle ear bone responded rapidly to bacterial challenge, and the reaction depended upon the causative agent. On day 1, IL-6 and TNF-alpha transcripts were detected in the bone from all middle ears. After a short period of decreased expression of osteocalcin, during which the otitis diagnosis could not be made clinically, the levels of bone formation markers increased dramatically. The maximum levels of these markers were reached on days 6 and 14 for animals challenged with H. influenzae and pneumococci, respectively. Infections induced by pneumococci had a longer duration, and after the initial phase the production of osteocalcin and procollagen transcript were significantly higher in the pneumococcus-infected animals. The results indicate that even in an uncomplicated infection, the bone of the bulla reacts to an acute otitis media with a short period of inhibited osteoblast activity followed by a longer period of new bone formation.

  • 49.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Svernell, O.
    Polyarticular septic arthritis caused by non-encapsulated haemophilus influenzae biotype I in a rheumatic adult1998In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 30, no 6, p. 630-631Article in journal (Refereed)
    Abstract [en]

    Haemophilus influenzae causes less than 1% of all septic arthritis cases in adults. Most often serotype b is responsible. Here we describe a rare case of non-encapsulated H. influenzae-induced polyarticular septic arthritis in a rheumatic patient with no other infectious focus.

  • 50.
    Melhus, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tjernberg, Ingela
    Blood culture bottles for transportation and recovery of anaerobic bacteria from non-blood samples2000In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 108, no 6, p. 453-458Article in journal (Refereed)
    Abstract [en]

    Using bacterial suspensions as simulated non-blood specimens, the capacity of three different BacT/ Alert blood culture bottles for the transportation and recovery of anaerobic bacteria with different sensitivity to air was evaluated. To better assess the performance of the BacT/Alert bottles, three other liquid media specially designed for anaerobes were included in the study. Attention was paid to recovery rates in relation to species, initial bacterial concentration, and time needed for detection. Of the BacT/Alert blood culture bottles, the anaerobic FAN bottle yielded the highest recovery rates, but its performance was limited compared with chopped meat broth in tubes. This broth allowed detection of all the tested species within 48 h. Since collection and transportation of anaerobic bacteria are of major importance for a reliable culture result, improvements are necessary.

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