Pathogenesis and management of fracture-related infection.

BACKGROUND: Both fracture-related infections (FRIs) and periprosthetic joint infections (PJIs) include orthopaedic implant-associated infections. However, key aspects of management differ due to the bone and soft tissue damage in FRIs and the option of removing the implant after fracture healing. In contrast to PJIs, research and guidelines for diagnosis and treatment in FRIs are scarce. OBJECTIVES: This narrative review aims to update clinical microbiologists, infectious disease specialists and surgeons on the management of FRIs. SOURCES: A computerized search of PubMed was performed to identify relevant studies. Search terms included 'Fracture' and 'Infection'. The reference lists of all retrieved articles were checked for additional relevant references. In addition, when scientific evidence was lacking, recommendations are based on expert opinion. CONTENT: Pathogenesis, prevention, diagnosis and treatment of FRIs are presented. Whenever available, specific data of patients with FRI are discussed. IMPLICATIONS: Management of patients with FRI should take into account FRI-specific features. Treatment pathways should implement a multidisciplinary approach to achieve a good outcome. Recently, international consensus guidelines were developed to improve the quality of care for patients suffering from this severe complication, which are highlighted in this review.

Debridement and implant retention in the management of hip periprosthetic joint infection: outcomes following guided and rapid treatment at a single centre.

AIMS: To analyse the effectiveness of debridement and implant retention (DAIR) in patients with hip periprosthetic joint infection (PJI) and the relationship to patient characteristics. The outcome was evaluated in hips with confirmed PJI and a follow-up of not less than two years. PATIENTS AND METHODS: Patients in whom DAIR was performed were identified from our hip arthroplasty register (between 2004 and 2013). Adherence to criteria for DAIR was assessed according to a previously published algorithm. RESULTS: DAIR was performed as part of a curative procedure in 46 hips in 42 patients. The mean age was 73.2 years (44.6 to 87.7), including 20 women and 22 men. In 34 hips in 32 patients (73.9%), PJI was confirmed. In 12 hips, the criteria for PJI were not fulfilled and antibiotics stopped. In 41 (89.1%) of all hips and in 32 (94.1%) of the confirmed PJIs, all criteria for DAIR were fulfilled. In patients with exogenous PJI, DAIR was performed not more than three days after referral. In haematogenous infections, the duration of symptoms did not exceed 21 days. In 28 hips, a single debridement and in six hips two surgical debridements were required. In 28 (87.5%) of 32 patients, the total treatment duration was three months. Failure was noted in three hips (9%). Long-term follow-up results (mean 4.0 years, 1.4 to 10) were available in 30 of 34 (88.2%) confirmed PJIs. The overall successful outcome rate was 91% in 34 hips, and 90% in 30 hips with long-term follow-up results. CONCLUSION: Prompt surgical treatment with DAIR, following strict diagnostic and therapeutic criteria, in patients with suspected periprosthetic joint infection, can lead to high rates of success in eradicating the infection. Cite this article: Bone Joint J 2017;99-B:330-6.

[Orthopaedic implant-associated infections: Update of antimicrobial therapy]. / Orthopädische implantatassozierte Infektionen : Update zur Antibiotikatherapie.

In infections related to prosthetic joints and internal fixation devices, microorganisms adhere as biofim on the surface of the implant. Biofilms are not only resistant to phagocytosis, but also to most antimicrobial agents. Therefore, spontaneous cure does never occur, and antibiotics have to be given for several months. According to traditional concepts, removal of all foreign material was considered as prerequisite for cure. Yet, during the last decades, it has been shown that staphylococcal biofilms can be eliminated by rifampin combination therapy, and Gram-negative biofilms by fluoroquinolones. However, reliable biofilm elimination is only possible, if the duration of infection does not exceed 3-4 weeks. Correct total duration of the antimicrobial therapy has never been tested in a controlled trial. Currently, treatment duration is 3 (hip prosthesis) and 6 (knee prosthesis) months in patients undergoing débridement with implant retention, one-stage exchange, and two-stage exchange with a short interval of 2-3 weeks. According to a recent observational trial, a treatment duration of 2 and 3 months, respectively, is equivalent to the longer duration in patients undergoing débridement and implant retention. The optimal surgical therapy should be chosen according to a rational algorithm. It is crucial choosing the optimal surgical intervention from the beginning, because the final functional success depends on the cure by the first attempt.

Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study.

OBJECTIVE: Prediction of long-term outcomes in patients with community-acquired pneumonia (CAP) is incompletely understood. We investigated the value of clinical risk scores [pneumonia severity index (PSI) and CURB-65] (Confusion, Urea, Respiratory rate, Blood Pressure, Age >65 years) and blood biomarkers of different physiopathological pathways in predicting long-term survival in a well-characterized cohort of patients with CAP enrolled in an antibiotic stewardship trial. DESIGN, SETTING AND SUBJECTS: Patients admitted with CAP to six medical centres in Switzerland were prospectively followed for 6 years. Cox regression models and area under the receiver operating characteristics curve (AUC) were used to investigate associations between initial risk assessment and all-cause mortality. MAIN OUTCOME MEASURE: All-cause mortality during a 6-year follow-up period. RESULTS: Six-year mortality in the present cohort (median age 73 years) was 45.1% [95% confidence interval (CI) 41.8-48.3%]. Initial PSI and CURB-65 scores both had excellent long-term prognostic accuracy, with a stepwise increase in mortality per risk class. The hazard ratios (95% CI) of the highest PSI and CURB-65 classes (reference: lowest class) were 38.0 (14.0-103.0) and 7.8 (2.2-14.5), respectively, after 6 years. The addition of inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers measured upon hospital admission further improved the prognostic capabilities of the PSI (AUC increase from 0.79 to 0.83; P < 0.0001) and the CURB-65 score (AUC increase from 0.73 to 0.80; P < 0.001). CONCLUSION: Risk assessment using clinical scores allowed accurate long-term prognostication, which was further improved by the addition of two inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers. These data provide a rationale for a more risk-adapted, 'personalized' strategy for long-term management of patients with CAP.

The treatment and outcome of peri-prosthetic infection of the ankle: a single cohort-centre experience of 34 cases.

The treatment of peri-prosthetic joint infection (PJI) of the ankle is not standardised. It is not clear whether an algorithm developed for hip and knee PJI can be used in the management of PJI of the ankle. We evaluated the outcome, at two or more years post-operatively, in 34 patients with PJI of the ankle, identified from a cohort of 511 patients who had undergone total ankle replacement. Their median age was 62.1 years (53.3 to 68.2), and 20 patients were women. Infection was exogenous in 28 (82.4%) and haematogenous in six (17.6%); 19 (55.9%) were acute infections and 15 (44.1%) chronic. Staphylococci were the cause of 24 infections (70.6%). Surgery with retention of one or both components was undertaken in 21 patients (61.8%), both components were replaced in ten (29.4%), and arthrodesis was undertaken in three (8.8%). An infection-free outcome with satisfactory function of the ankle was obtained in 23 patients (67.6%). The best rate of cure followed the exchange of both components (9/10, 90%). In the 21 patients in whom one or both components were retained, four had a relapse of the same infecting organism and three had an infection with another organism. Hence the rate of cure was 66.7% (14 of 21). In these 21 patients, we compared the treatment given to an algorithm developed for the treatment of PJI of the knee and hip. In 17 (80.9%) patients, treatment was not according to the algorithm. Most (11 of 17) had only one criterion against retention of one or both components. In all, ten of 11 patients with severe soft-tissue compromise as a single criterion had a relapse-free survival. We propose that the treatment concept for PJI of the ankle requires adaptation of the grading of quality of the soft tissues.

Clinical presentation and treatment of orthopaedic implant-associated infection.

Orthopaedic implants are highly susceptible to infection. The aims of treatment of infection associated with internal fixation devices are fracture consolidation and prevention of chronic osteomyelitis. Complete biofilm eradication is not the primary goal, as remaining adherent microorganisms can be removed with the device after fracture consolidation. By contrast, in periprosthetic joint infection (PJI), biofilm elimination is required. Surgical treatment of PJI includes debridement with retention, one- or two-stage exchange and removal without reimplantation. In addition, prolonged antibiotic treatment, preferably with an agent that is effective against biofilm bacteria, is required. Rifampicin is an example of an antibiotic with these properties against staphylococci. However, to avoid the emergence of resistance, rifampicin must always be combined with another antimicrobial agent. With this novel treatment approach, orthopaedic implant-associated infection is likely to be eradicated in up to 80-90% of patients. Because most antibiotics have a limited effect against biofilm infections, novel prophylactic and therapeutic options are needed. Surface coating with antimicrobial peptides that reduce bacterial attachment and biofilm formation can potentially prevent implant-associated infection. In addition, quorum-sensing inhibitors are a novel therapeutic option against biofilm infections.

Factors associated with rifampin resistance in staphylococcal periprosthetic joint infections (PJI): a matched case-control study.

PURPOSE: Rifampin combination therapy plays an important role in the management of staphylococcal periprosthetic joint infection (PJI). However, the emergence of rifampin resistance is a feared complication. We retrospectively analysed predetermined potential risk factors in patients with rifampin-resistant staphylococcal PJI in a multicentre case-control study. METHODS: Cases (n = 48) were defined as PJI caused by rifampin-resistant staphylococci. Rifampin-susceptible controls (n = 48) were matched for microorganism and type of prosthetic joint. Uni- and multivariable conditional logistic regression analyses were performed to estimate odds ratios (OR) with 95 % confidence intervals (95 % CI). RESULTS: Forty-eight cases (31 men; median age 67 years; age range 39-88 years) with hip- (n = 29), knee- (n = 13), elbow- (n = 4), shoulder- (n = 1) or ankle-PJI (n = 1) were enrolled in the study. Staphylococcus aureus and coagulase-negative staphylococci were isolated in ten and 38 episodes, respectively. Most of the cases (n = 44, 92 %) had a previous PJI, and 93 % (n = 41) of these had been treated with rifampin. There was an independent association of emergence of rifampin resistance with male sex (OR 3.6, 95 % CI 1.2-11), ≥ 3 previous surgical revisions (OR 4.7, 95 % CI 1.6-14.2), PJI treatment with high initial bacterial load (inadequate surgical debridement, <2 weeks of intravenous treatment of the combination medication; OR 4.9, 95 % CI 1.6-15) and inadequate rifampin therapy (OR 5.4, 95 % CI 1.2-25). CONCLUSIONS: Based on our results, extensive surgical debridement and adequate antibiotic therapy are needed to prevent the emergence of rifampin resistance.

Antimicrobial treatment concepts for orthopaedic device-related infection.

Successful management of orthopaedic device-related infections requires combined surgical and antimicrobial therapy. Because of the heterogeneity of clinical situations, controlled trials are lacking. Although rational concepts for surgical treatment have been published, many aspects of antimicrobial therapy are still not well documented. In this review, some of these knowledge gaps are discussed, and rational arguments for initial parenteral treatment are presented. In addition, the interpretation of data regarding bone penetration is discussed. Whereas rifampin is now a standard combination partner in the treatment of staphylococcal infections, its role against other microorganisms is still unclear. Finally, in view of the increasing prevalence of methicillin-resistant staphylococci and their decreasing susceptibility to vancomycin, data are provided on linezolid and daptomycin, which can potentially be used in bone and joint infections.

Group B streptococcus in prosthetic hip and knee joint-associated infections.

The incidence of invasive group B streptococcus (GBS) infections in non-pregnant adults is increasing. Little is known about GBS in periprosthetic joint infections (PJIs). We aimed to analyse the clinical presentation of GBS PJI and its treatment in association with the outcome. The characteristics of 36 GBS PJIs collected from 10 centres were investigated. In 34 episodes, follow-up examination of ≥ 2 years was available, allowing treatment and outcome analysis. Most infections (75%) occurred ≥ 3 months after implantation. Most patients (91%) had at least one comorbidity; 69% presented with acute symptoms and 83% with damaged periprosthetic soft tissue. In 20 of 34 episodes debridement and retention of implant was attempted, but in five of these the prosthesis was ultimately removed. Hence, in 19 (56%) episodes, the implant was removed, including 14 immediate removals. In four episodes the removal was permanent. Penicillin derivatives and clindamycin were the most common antimicrobials administered (68%). In 94% the infection was cured, and in 82% functional mobility preserved. Debridement with implant retention was successful if the duration of symptoms was short, the prosthesis stable, and the tissue damage minor (10/10 vs 3/10 episodes, P = 0.003). Surgery that complied with a published algorithm was associated with a favourable outcome (P = 0.049).

[Periprosthetic joint infections - a review for general practitioners]. / Protheseninfektionen - Eine Übersichtsarbeit für die Praxis.

The number of prosthetic joint implantation is continuously increasing. Periprosthetic joint infection is a rare but serious complication. The correct diagnosis is essential for successful treatment. It requires the close collaboration between general practitioners, orthopaedic surgeons and infectious disease specialists. A delayed diagnosis sets hurdles to the medical and surgical treatment. Also, antimicrobial treatment without proper microbiological sampling must be avoided. Swabs from wounds are not helpful, because the results represent the skin flora, but not the causative pathogen of infection. The general practitioner is the first physician that patients contact and has, therefore, a central role in diagnosing and managing periprosthetic joint infections. In this review, classification, diagnostic means and treatment concepts of periprosthetic joint infections are presented.

Clinical comparison between exogenous and haematogenous periprosthetic joint infections caused by Staphylococcus aureus.

Patient-related risk factors for invasive Staphylococcus aureus infection overlap with those for periprosthetic joint infections (PJIs). We compared these factors and clinical characteristics between 17 exogenous and 40 haematogenous PJIs caused by S. aureus. Exogenous cases presented significantly more often with damaged periprosthetic soft tissue, whereas haematogenous cases more often had systemic signs of infection, such as fever, chills, and sepsis syndrome. However, comorbid conditions associated with S. aureus infection and/or PJIs did not differ between the two groups. These findings imply that patient-related risk factors for S. aureus infection do not help to predict the mode of infection acquisition in prosthetic joints.

Antibiotic use in adult outpatients in Switzerland in relation to regions, seasonality and point of care tests.

The use of antibiotics is highest in primary care and directly associated with antibiotic resistance in the community. We assessed regional variations in antibiotic use in primary care in Switzerland and explored prescription patterns in relation to the use of point of care tests. Defined daily doses of antibiotics per 1000 inhabitants (DDD(1000pd) ) were calculated for the year 2007 from reimbursement data of the largest Swiss health insurer, based on the anatomic therapeutic chemical classification and the DDD methodology recommended by WHO. We present ecological associations by use of descriptive and regression analysis. We analysed data from 1 067 934 adults, representing 17.1% of the Swiss population. The rate of outpatient antibiotic prescriptions in the entire population was 8.5 DDD(1000pd) , and varied between 7.28 and 11.33 DDD(1000pd) for northwest Switzerland and the Lake Geneva region. DDD(1000pd) for the three most prescribed antibiotics were 2.90 for amoxicillin and amoxicillin-clavulanate, 1.77 for fluoroquinolones, and 1.34 for macrolides. Regions with higher DDD(1000pd) showed higher seasonal variability in antibiotic use and lower use of all point of care tests. In regression analysis for each class of antibiotics, the use of any point of care test was consistently associated with fewer antibiotic prescriptions. Prescription rates of primary care physicians showed variations between Swiss regions and were lower in northwest Switzerland and in physicians using point of care tests. Ecological studies are prone to bias and whether point of care tests reduce antibiotic use has to be investigated in pragmatic primary care trials.

Prognostic value of procalcitonin in community-acquired pneumonia.

The prognostic value of procalcitonin (PCT) levels to predict mortality and other adverse events in community-acquired pneumonia (CAP) remains undefined. We assessed the performance of PCT overall, stratified into four predefined procalcitonin tiers (< 0.1, 0.1-0.25, > 0.25-0.5, >0.5 µg·L⁻¹) and stratified by Pneumonia Severity Index (PSI) and CURB-65 (confusion, urea >7 mmol·L⁻¹, respiratory frequency ≥ 30 breaths·min⁻¹, systolic blood pressure < 90 mmHg or diastolic blood pressure ≤ 60 mmHg, and age ≥ 65 yrs) risk classes to predict all-cause mortality and adverse events within 30 days follow-up in 925 CAP patients. In receiver operating characteristic curves, initial PCT levels performed only moderately for mortality prediction (area under the curve (AUC) 0.60) and did not improve clinical risk scores. Follow-up measurements on days 3, 5 and 7 showed better prognostic performance (AUCs 0.61, 0.68 and 0.73). For prediction of adverse events, the AUC was 0.66 and PCT significantly improved the PSI (from 0.67 to 0.71) and the CURB-65 (from 0.64 to 0.70). In Kaplan-Meier curves, PCT tiers significantly separated patients within PSI and CURB-65 risk classes for adverse events prediction, but not for mortality. Reclassification analysis confirmed the added value of PCT for adverse event prediction, but not mortality. Initial PCT levels provide only moderate prognostic information concerning mortality risk and did not improve clinical risk scores. However, PCT was helpful during follow-up and for prediction of adverse events and, thereby, improved the PSI and CURB65 scores.

Inflammatory responses predict long-term mortality risk in community-acquired pneumonia.

Long-term outcomes in patients surviving community-acquired pneumonia (CAP) are still incompletely understood. This study investigates the association of clinical parameters and blood markers with long-term mortality. We prospectively followed 877 CAP patients from a previous multicentre trial for 18 months follow-up and investigated all-cause mortality following hospital discharge. Overall mortality was 17.3% (95% CI 14.8-19.8%) with a 12.8% (95% CI 10.9-15.0%) mortality incidence rate per year. Initial risk assignment using the Pneumonia Severity Index was accurate during the 18 month follow-up. Multivariable regression models (hazard ratio, 95% CI) designated the following as independent risk factors for long-term mortality: male sex (1.7, 1.2-2.5); chronic obstructive pulmonary disease (1.5, 1.1-2.1); neoplastic disease (2.5, 1.7-3.7); and highest quartile of peak pro-adrenomedullin level (3.3, 1.7-6.2). Initial presentation with temperature>38.7°C (0.4, 0.2-0.6), chills (0.6, 0.4-0.99) and highest quartile of the inflammatory marker C-reactive-protein (0.3, 0.2-0.5) were independent protective factors. A weighted risk score based on these variables showed good discrimination (area under receiver operating characteristic curve 0.78, 95% CI 0.74-0.82). Pronounced clinical and laboratory signs of systemic inflammatory host response upon initial hospital stay were associated with favourable long-term prognosis. Further studies should address whether closer monitoring of high-risk CAP patients after hospital discharge favourably impacts long-term mortality.

Cutaneous vasculitis associated with fluoroquinolones.

Cutaneous vasculitis is a clinical entity with a broad differential diagnosis, including an adverse drug reaction. It is defined as inflammation of skin blood vessel walls. During a 7-year-period, we observed three patients who developed isolated cutaneous vasculitis during antibiotic therapy of bacterial infection. All were treated with a fluoroquinolone (ciprofloxacin or levofloxacin) combined with rifampin (two cases) or flucloxacillin (three cases), respectively. In all three cases the lesions gradually resolved after treatment with the inciting fluoroquinolone had been stopped. In one patient, leukocytoclastic small-vessel vasculitis was histologically confirmed. Fluoroquinolone-associated cutaneous vasculitis consists of an isolated self-limiting disorder that is part of a systemic vasculitis, or even life-threatening disease. Clinicians should be aware of this serious adverse event because any continuation of treatment may be fatal.

The role of diabetes mellitus in patients with bloodstream infections.

BACKGROUND: Since diabetes mellitus predisposes to infection, we evaluated whether diabetes increases the risk of bloodstream infection and worsens its outcome. METHODS: During a 4-year period 71 diabetic and 252 non-diabetic patients with bloodstream infection were included. Risk factors for death were assessed by univariate and multivariate analysis. RESULTS: Bloodstream infection was more frequent in diabetics than in non-diabetics (25.8/1000 admissions vs. 5.8/1000 admissions, p <0.0001). Urinary tract infection was the predominant source, and Escherichia coli the most frequent microorganism in both groups. Klebsiella pneumoniae was more frequent in diabetics than in non-diabetics (18% vs 5%, p <0.001). Whereas sepsis of unknown origin was more common in diabetics (14% vs. 6%, p <0.05), catheter-related bloodstream infection predominated in non-diabetics (3% vs 10%, p <0.05). Secondary septic foci (p <0.05) and disseminated intravascular coagulation (p <0.05) were more frequent in diabetics. The in-hospital mortality rate was similar in the two groups (18% vs. 14%). Univariate analysis (RR [CI 95%]) in diabetics revealed glycaemia >20 mmol/L (3.9 [1.7-22]), ICU stay (7.1 [2-25]), mechanical ventilation (8.4 [1.2-57]) and chronic renal/hepatic failure (8.2 [1.6-43]) as significant risk factors. Hyperglycaemia (4.3 [3.4-5.2]) and ICU stay (3.3 [1.9-4.9]) remained significant in multivariate analysis. CONCLUSIONS: Diabetics had a 4.4-fold higher risk of bloodstream infection, were more prone to sepsis of unknown origin and had more septic complications than non-diabetics. The mortality rate was similar in the two groups.