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Coagulase-negative staphylococci in prosthetic hip infections
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

More than 11,000 primary total hip replacements were performed in Sweden in the year 2000, corresponding to 125 primary total hip replacements per 100,000 inhabitants, according to The Swedish Total Hip Replacement Register. In general, this procedure provides highly satisfactory results. The most common complications associated with prosthetic hip joints are aseptic biomechanical failures and infections. Delayed low-grade infections occur most often, and they are also the most difficult to distinguish from aseptic mechanical failures because of similar symptoms.

During the period 1994 to 2001, a prospective study was conducted to compare inflammatory markers in blood, synovial fluid, and histopathological specimens in patients diagnosed with aseptic or septic loosening of hip prostheses. Coagulase-negative staphylococci (CoNS) were found to be the most common pathogens in the patients with prosthetic hip joint infections.

Further characterisation of the CoNS revealed that patients were co-infected with the following: (i) CoNS and other bacterial species, (ii) various CoNS species, and (iii) different S. epidermidis clones. Expression of the icaADB gene complex, which is important for the biofilm mode-of-growth characteristic of S. epidermidis, was not necessary to allow S. epidermidis to infect orthopaedic prostheses. The majority of the S. epidermidis isolates, both from prostheses and normal bacteria flora, were able to bind to at least one of the extracellular matrix proteins we tested, this adhesion ability is a probable virulence factor. Histologically, the extent of cell infiltration differed between aseptic and septic loosening of prostheses, and neutrophils in tissue at a rate of ≥ 5 cells/high power field greatly favoured infection. Periprosthetic tissue contained the cells that are required not only for an innate, but also a specific, immune response, which supports the theory that the limited systemic inflammatory response in infections of hip prostheses is not due to failure of inflammatory cells to reach the infected area, but is more likely caused by an inadequate response to the infecting organisms.

Therefore, we studied the interactions between neutrophils and S. epidermidis (the most common CoNS species in hip prosthetic infections). Neutrophils phagocytosed both surfaceadherent and planktonic S. epidermidis, but they ingested adherent S. aureus isolates more readily than they consumed adherent S. epidermidis. The reduced phagocytosis of S. epidermidis by neutrophils is viewed as a virulence factor, together with the lack of an ability to prime or sufficiently activate the neutrophil oxidase, and thereby evade adequate killing by neutrophils. The weak oxidative activation agrees with the low inflammatory response seen in patients with S. epidermidis infections related to implanted devices. Furthermore, both planktonic and adherent S. epidermidis delayed neutrophil apoptosis, and we suggest that this leads to the accumulation of neutrophils at the site of inflammation. We propose that the complex interplay between the S. epidermidis-induced delay in apoptosis in neutrophils and the interaction of S. epidermidis-containing neutrophils with macrophages in periprosthetic tissue has negative impact on the outcome in patients with prosthetic hip joint infections, resulting in low grade inflammation, tissue damage, and finally loosening of the prosthesis.

Abstract [sv]

Fler än 11.000 primära totala höftutbytesoperationer utfördes i Sverige 2000, detta motsvarar 125 operationer per 100.000 innevånare enligt Svenska Nationella Höftplastikregistret. Höftprotesoperationer uppvisar vanligen mycket goda resultat, men komplikationer förekommer där de vanligaste är aseptisk lossning respektive infektioner i anslutning till proteserna. De sena, läggrarliga infektionerna är vanligast, och det är också dessa, som är svårast att skilja från mekaniska lossningar på grund av liknande symtom.

Under perioden 1994 till 2001 utfördes en prospektiv studie för att jämföra inflammatoriska markörer i blod, ledvätska och i vävnad hos patienter med diagnosen aseptisk respektive septisk (infektiös) lossning av höftproteser. Koagulas-negativa stafylokocker (KNS) var den vanligaste sjukdomsframkallande bakterien hos patienter med infekterade höftproteser. Vidare karakterisering av KNS visade att höftprotespatienterna var infekterade enligt följande: (i) KNS plus andra bakteriella arter, (ii) olika KNS arter, och (iii) olika kloner av S. epidermis. Uttryck av icaADB gen komplexet, som är viktigt för utvecklandet av biofilm vilket är ett sätt att växa som är karakteristiskt för S. epidermidis bakterier, visade sig inte vara nödvändigt för att utveckla protesinfektion med S. epidermidis. Majoriteten av S. epidermidis, både de som isolerades från höftproteser respektive från hudens normalflora, hade förmåga att binda in till åtminstone ett av de extracellular matrix proteiner som testades. Denna adhesionsförmåga är en trolig virulensfaktor. Histologiskt (i vävnaden) skiljde sig cellinfiltrationen mellan aseptiska och septiska lossningar, och neutrofiler i ett antal av ≥ 5 celler/högupplösningsfält talade starkt för infektion. Vävnaden kring protesen innehöll celler som behövs, inte bara för ett ospecifikt immunsvar utan också för ett specifikt immunsvar. Detta stödjer hypotesen att de begränsade systemiska inflammatoriska svaret vid höftprotesinfektioner inte beror på att immuncellerna inte förmår ta sig dit, utan troligare beror på att immuncellerna svarar inadekvat på de infekterande bakterierna.

Därför studerade vi vidare samspelet mellan neutrofiler och S. epidermidis (den vanligaste KNS-arten vid höftprotesinfektioner). Neutrofiler hade förmåga att fagocytera (äta upp) både ytbundna och i lösning förekommande S. epidermidis, men ytbundna S. aureus fagocyterades lättare än ytbundna S. epidermidis. Den sämre fagocytosen av S. epidermidis tolkas som en virulensfaktor hos S. epidermidis, tillsammans med frånvaro av förmåga att "prima" eller tillräckligt aktivera neutrofilemas oxidas och genom det undvika avdödning. Den svaga oxidativa aktiveringen stämmer med det låga inflammatoriska svar som ses hos patienter med S. epidermidis infektioner i anslutning till inopererade material. Vidare försenade både S. epidermidis i lösning och adhererade bakterier neutrofilemas apoptos (spontan celldöd), vilket föreslås leda till att neutrofilema samlas på stället för inflammation. Vi föreslår att det komplexa sambandet mellan S. epidermidis-inducerad försenad neutrofildöd och interaktionen mellan S. epidermidis-innehållande neutrofiler och makrofager i vävnaden kring proteser resulterar i en låggradig inflammation, vävnadsskada och slutligen lossning av protesen.

Place, publisher, year, edition, pages
Linköping: Linköping Universitet , 2005. , 103 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 902
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-30062Local ID: 15522ISBN: 91-85299-09-X (print)OAI: oai:DiVA.org:liu-30062DiVA: diva2:250883
Public defence
2005-06-03, Elsa Brändströmsalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2013-12-11Bibliographically approved
List of papers
1. Inflammatory response in 85 patients with loosened hip prostheses: A prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening
Open this publication in new window or tab >>Inflammatory response in 85 patients with loosened hip prostheses: A prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening
Show others...
2007 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 78, no 5, 629-639 p.Article in journal (Refereed) Published
Abstract [en]

Over the past decades, prosthetic hip joints have improved the quality oflife for many patients. The most common complications are aseptic biornechanical failures and prosthetic joint infections. For prosthetic hip joints, delayed low-grade infections are seen most often and they are also most difficult to distinguish from aseptic mechanical failures. A prospective study was conducted to campare inilammatory markers in patients diagnosed with aseptic or septic prosthetic loosenffig. The diagnostic criteria were based on the decisions of experienced orthoperlic surgeons and microbiological analys is of periprosthetic tissue samplestaken perioperatively. Coagulase-negative staphylococci were the most common pathogens in the infected patients. Pre- or perioperative results for C-reactive protein and erytlu-ocyte sedimentation rate were valuable tools for diagnosing most, hut not all, low virulence infections. White blood cell count in synavial fluid was an important marker of infection, which was not the case for lactate. Levels of the cytokines turnor necrosis factor-α, interleukin-1 ß. and interleukin-6 in synavial fluid were significantly higher in the infected group. Patterus of inilammatory cell infiltration in periprosthetic tissue differed significantly between the groups, and infiltration of polymorphonuclear cells proved to be the best marker of distinguish between septic and aseptic loosenffig. Treatment and outcome are described for the infected patients.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81959 (URN)10.1080/17453670710014329 (DOI)
Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2017-12-07Bibliographically approved
2. Interaction of staphylococcus epidermidis from infected hip prostheses with neutrophil granulocytes
Open this publication in new window or tab >>Interaction of staphylococcus epidermidis from infected hip prostheses with neutrophil granulocytes
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2001 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 33, no 6, 408-412 p.Article in journal (Refereed) Published
Abstract [en]

This study focuses on the interaction of Staphylococcus epidermis isolated from granulation tissue covering infected hip prostheses and neutrophil granulocytes. Bacterial strains isolated from normal flora were used as controls. The bacteria were well characterized with routine methods and further characterized with random amplified polymorphic DNA analyses and slime tests. Phagocytosis and chemiluminescence (CL) assays were used in the neutrophil interaction studies. The prostheses strains were ingested to a lesser extent than strains from normal flora (p ≤ 0.001). There was no significant difference between the prostheses strains and the normal flora strains in terms of total CL response. However, the extracellular CL response from the neutrophils was lower in comparison with the normal flora when interacting with the prostheses strains. The results of this study support the notion that S. epidermidis strains isolated from infected hip prostheses have an enhanced capacity to resist phagocytosis and that most of these strains elicit a reduced inflammatory response, measured as the production of extracellular oxidative metabolites from the neutrophils, compared to normal flora.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25771 (URN)10.1080/00365540152029855 (DOI)10205 (Local ID)10205 (Archive number)10205 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Staphylococcus aureus, but not Staphylococcus epidermidis, modulates the oxidative response and induces apoptosis in human neutrophils
Open this publication in new window or tab >>Staphylococcus aureus, but not Staphylococcus epidermidis, modulates the oxidative response and induces apoptosis in human neutrophils
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2004 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 112, no 2, 109-118 p.Article in journal (Refereed) Published
Abstract [en]

S. epidermidis is the most common isolate in foreign body infections. The aim of this study was to understand why S. epidermidis causes silent biomaterial infections. In view of the divergent inflammatory responses S. epidermidis and S. aureus cause in patients, we analyzed how they differ when interacting with human neutrophils. Neutrophils interacting with S. epidermidis strains isolated either from granulation tissue covering infected hip prostheses or from normal skin flora were tested by measuring the oxidative response as chemiluminescence and apoptosis as annexin V binding. Different S. aureus strains were tested in parallel. All S. epidermidis tested were unable to modulate the oxidative reaction in response to formyl-methionyl-leucyl-phenylalanine (fMLP) and did not provoke, but rather inhibited, apoptosis. In contrast, some S. aureus strains enhanced the oxidative reaction, and this priming capacity was linked to p38-mitogen-activated-protein-kinase (p38-MAPK) activation and induction of apoptosis. Our results may explain why S. epidermidis is a weak inducer of inflammation compared to S. aureus, and therefore responsible for the indolent and chronic course of S. epidermidis biomaterial infections.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-23732 (URN)10.1111/j.1600-0463.2004.apm1120205.x (DOI)3239 (Local ID)3239 (Archive number)3239 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
4. Adherence of Staphylococcus epidermidis to extracellular matrix proteins and effects of fibrinogen-bound bacteria on oxidase activity and apoptosis in neutrophils
Open this publication in new window or tab >>Adherence of Staphylococcus epidermidis to extracellular matrix proteins and effects of fibrinogen-bound bacteria on oxidase activity and apoptosis in neutrophils
Show others...
2005 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 113, no 5, 361-373 p.Article in journal (Refereed) Published
Abstract [en]

Staphylococcus epidermidis often causes foreign-body infections such as those associated with hip prostheses, but the underlying pathogenic mechanisms are not fully understood. We performed spectrophotometry to study the ability of S. epidermidis to bind to immobilised fibrinogen, fibronectin, vitronectin, and collagen. The strains were isolated from infected hip prostheses or from normal flora and the well-known protein-binding strain Staphylococcus aureus Cowan was used as positive control. We also analysed the interaction between neutrophils and a fibrinogen-bound prosthesis-derived strain of S. epidermidisby measuring chemiluminescence to determine the neutrophil oxidative response and binding of annexin V to indicate neutrophil apoptosis. We found that binding of S. epidermidis to extracellular matrix proteins varied under different growth conditions, and that prosthesis isolates adhered better to vitronectin than did strains from normal flora. The oxidative response caused by fibrinogen-bound S. epidermidis was not above the background level, which was in marked contrast to the distinct response induced by fibrinogen-associated S. aureus Cowan. Furthermore, fibrinogen-adhering S. epidermidis retarded neutrophil apoptosis. We conclude that surface-bound S. epidermidis induces only a weak inflammatory response, which in combination with the ability of the adherent bacteria to retard neutrophil apoptosis may contribute to low-grade inflammation and loosening of prostheses.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28719 (URN)10.1111/j.1600-0463.2005.apm_113508.x (DOI)13888 (Local ID)13888 (Archive number)13888 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
5. Characterization of coagulase-negative staphylococci isolated from patients with infected hip prostheses: use of phenotypic and genotypic analyses, including tests for the presence of the ica operon
Open this publication in new window or tab >>Characterization of coagulase-negative staphylococci isolated from patients with infected hip prostheses: use of phenotypic and genotypic analyses, including tests for the presence of the ica operon
2007 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 26, no 4, 255-265 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate phenotypic and/or genotypic heterogeneity in coagulase-negative staphylococci (CoNS) obtained from multiple tissue samples taken perioperatively during exchange surgery from each of 19 patients with clinically and/or microbiologically proven hip prosthesis infections. CoNS are important pathogens in prosthetic hip joint infections. Several virulence factors have been suggested for CoNS, such as phenotypic variation, yet the pathogenic processes that are involved remain unclear. The PhenePlate system (PhPlate AB, Stockholm Sweden) was used for phenotyping and pulsed-field gel electrophoresis for genotyping of polymorphisms in isolates of CoNS. Furthermore, polymerase chain reaction was used to determine the presence of the icaADB gene complex in the isolates. Some patients were infected with CoNS and other species, some were infected with multiple CoNS species, although infections with Staphylococcus epidermidis alone were most common, and some were infected with different S. epidermidis clones. Phenotypic variation was found among isolates both from the same tissue sample and from different samples from the same patient, and in some cases such variation represented the presence of different clones. One-third of the patients infected with S. epidermidis carried the icaADB genes. CoNS isolates showing phenotypic and/or genotypic heterogeneity were identified in tissue samples from half of the patients. The presence of the intercellular adhesion (ica) operon does not seem to be a prerequisite for establishing infection with CoNS.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81976 (URN)10.1007/s10096-007-0281-9 (DOI)
Note

On the day of the defence day the status of this article was

Manuscript

Available from: 2012-09-27 Created: 2012-09-27 Last updated: 2017-12-07Bibliographically approved

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