The Microbiological Etiology of Fracture-Related Infection.

Purpose: Fracture-related infection (FRI) is an important complication related to orthopaedic trauma. Although the scientific interest with respect to the diagnosis and treatment of FRI is increasing, data on the microbiological epidemiology remains limited. Therefore, the primary aim of this study was to evaluate the microbiological epidemiology related to FRI, including the association with clinical symptoms and antimicrobial susceptibility data. The secondary aim was to analyze whether there was a relationship between the time to onset of infection and the microbiological etiology of FRI. Methods: FRI patients treated at the University Hospitals of Leuven, Belgium, between January 1st 2015 and November 24th 2019 were evaluated retrospectively. The microbiological etiology and antimicrobial susceptibility data were analyzed. Patients were classified as having an early (<2 weeks after implantation), delayed (2-10 weeks) or late-onset (> 10 weeks) FRI. Results: One hundred ninety-one patients with 194 FRIs, most frequently involving the tibia (23.7%) and femur (18.6%), were included. Staphylococcus aureus was the most frequently isolated pathogen, regardless of time to onset (n=61; 31.4%), followed by S. epidermidis (n=50; 25.8%) and non-epidermidis coagulase-negative staphylococci (n=35; 18.0%). Polymicrobial infections (n=49; 25.3%), mainly involving Gram negative bacilli (GNB) (n=32; 65.3%), were less common than monomicrobial infections (n=138; 71.1%). Virulent pathogens in monomicrobial FRIs were more likely to cause pus or purulent discharge (n=45;54.9%; p=0.002) and fistulas (n=21;25.6%; p=0.030). Susceptibility to piperacillin/tazobactam for GNB was 75.9%. Vancomycin covered 100% of Gram positive cocci. Conclusion: This study revealed that in early FRIs, polymicrobial infections and infections including Enterobacterales and enterococcal species were more frequent. A time-based FRI classification is not meaningful to estimate the microbiological epidemiology and cannot be used to guide empiric antibiotic therapy. Large multicenter prospective studies are necessary to gain more insight into the added value of (broad) empirical antibiotic therapy.

Management of periprosthetic infection after reverse shoulder arthroplasty.

BACKGROUND: Periprosthetic shoulder infection (PSI) remains a devastating complication after reverse shoulder arthroplasty (RSA). Currently, scientific data related to the management of PSI are limited, and the optimal strategy and related clinical outcomes remain unclear. Guidelines from the Infectious Diseases Society of America for the management of periprosthetic joint infection are mainly based on data from patients after hip and knee arthroplasty. The aim of this study was to evaluate whether these guidelines are also valid for patients with PSI after RSA. In addition, the functional outcome according to the surgical intervention was assessed. METHODS: An RSA database was retrospectively reviewed to identify infections after primary and revision RSAs, diagnosed between 2004 and 2018. Data collected included age, sex, indication for RSA, causative pathogen, surgical and antimicrobial treatment, functional outcome, and recurrence. RESULTS: Thirty-six patients with a PSI were identified. Surgical treatment was subdivided into débridement and implant retention (DAIR) (n = 6, 17%); 1-stage revision (n = 1, 3%); 2-stage revision (n = 16, 44%); multiple-stage revision (>2 stages) (n = 7, 19%); definitive spacer implantation (n = 2, 6%); and resection arthroplasty (n = 4, 11%). The most common causative pathogens were Staphylococcus epidermidis (n = 11, 31%) and Cutibacterium acnes (n = 9, 25%). Recurrence was diagnosed in 4 patients (11%), all of whom were initially treated with a DAIR approach. The median follow-up period was 36 months (range, 24-132 months). CONCLUSION: PSI is typically caused by low-virulence pathogens, which often are diagnosed with a delay, resulting in chronic infection at the time of surgery. Our results indicate that treatment of patients with chronic PSI with DAIR has a high recurrence rate. In addition, implant exchange (ie, 1- and 2-stage exchange) does not compromise the functional result as compared with implant retention. Thus, patients with chronic PSI should be treated with implant exchange. Future research should further clarify which surgical strategy (ie, 1-stage vs. 2-stage exchange) has a better outcome overall.

The influence of duration of infection on outcome of debridement and implant retention in fracture-related infection.

AIMS: The principle strategies of fracture-related infection (FRI) treatment are debridement, antimicrobial therapy, and implant retention (DAIR) or debridement, antimicrobial therapy, and implant removal/exchange. Increasing the period between fracture fixation and FRI revision surgery is believed to be associated with higher failure rates after DAIR. However, a clear time-related cut-off has never been scientifically defined. This systematic review analyzed the influence of the interval between fracture fixation and FRI revision surgery on success rates after DAIR. METHODS: A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, in PubMed (including MEDLINE), Embase, and Web of Science Core Collection, investigating the outcome after DAIR procedures of long bone FRIs in clinical studies published until January 2020. RESULTS: Six studies, comprising 276 patients, met the inclusion criteria. Data from this review showed that with a short duration of infection (up to three weeks) and under strict preconditions, retention of the implant is associated with high success rates of 86% to 100%. In delayed infections with a fracture fixation-FRI revision surgery interval of three to ten weeks, absence of recurrent infection was reported in 82% to 89%. Data on late FRIs, with a fracture fixation-FRI revision surgery interval of more than ten weeks, are scarce and a success rate of 67% was reported. CONCLUSION: Acute/early FRI, with a short duration of infection, can successfully be treated with DAIR up to ten weeks after osteosynthesis. The limited available data suggest that chronic/late onset FRI treated with DAIR may be associated with a higher rate of recurrence. Successful outcome is dependent on managing all aspects of the infection. Thus, time from fracture fixation is not the only factor that should be considered in treatment planning of FRI. Due to the heterogeneity of the available data, these conclusions have to be interpreted with caution. Cite this article: Bone Joint J 2021;103-B(2):213-221.

Controversy about the Role of Rifampin in Biofilm Infections: Is It Justified?

Rifampin is a potent antibiotic against staphylococcal implant-associated infections. In the absence of implants, current data suggest against the use of rifampin combinations. In the past decades, abundant preclinical and clinical evidence has accumulated supporting its role in biofilm-related infections.In the present article, experimental data from animal models of foreign-body infections and clinical trials are reviewed. The risk for emergence of rifampin resistance and multiple drug interactions are emphasized. A recent randomized controlled trial (RCT) showing no beneficial effect of rifampin in patients with acute staphylococcal periprosthetic joint infection treated with prosthesis retention is critically reviewed and data interpreted. Given the existing strong evidence demonstrating the benefit of rifampin, the conduction of an adequately powered RCT with appropriate definitions and interventions would probably not comply with ethical standards.

Recommendations for Systemic Antimicrobial Therapy in Fracture-Related Infection: A Consensus From an International Expert Group.

Fracture-related infection (FRI) is a major complication in musculoskeletal trauma and one of the leading causes of morbidity. Standardization of general treatment strategies for FRI has been poor. One of the reasons is the heterogeneity in this patient population, including various anatomical locations, multiple fracture patterns, different degrees of soft-tissue injury, and different patient conditions. This variability makes treatment complex and hard to standardize. As these infections are biofilm-related, surgery remains the cornerstone of treatment, and this entails multiple key aspects (eg, fracture fixation, tissue sampling, debridement, and soft-tissue management). Another important aspect, which is sometimes less familiar to the orthopaedic trauma surgeon, is systemic antimicrobial therapy. The aim of this article is to summarize the available evidence and provide recommendations for systemic antimicrobial therapy with respect to FRI, based on the most recent literature combined with expert opinion. LEVEL OF EVIDENCE:: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.

A Trans-Atlantic Perspective on Stagnation in Clinical Translation of Antimicrobial Strategies for the Control of Biomaterial-Implant-Associated Infection.

Current regulatory requirements impede clinical translation and market introduction of many new antimicrobial combination implants and devices, causing unnecessary patient suffering, doctor frustration, and costs to healthcare payers. Regulatory requirements of antimicrobial combination implants and devices should be thoroughly revisited and their approval allowed based on enrichment of benefit demonstrations from high-risk patient groups and populations or device components to facilitate their clinical translation. Biomaterial implant and devices equipped with antimicrobial strategies and approved based on enrichment claims should be mandatorily enrolled in global registry studies supervised by regulatory agencies for a minimum five-year period or until statistically validated evidence for noninferiority or superiority of claims is demonstrated. With these recommendations, this trans-Atlantic consortium of academicians and clinicians takes its responsibility to actively seek to relieve the factors that stagnate downward clinical translation and availability of antimicrobial combination implants and devices. Improved dialogue between the various key players involved in the current translational blockade, which include patients, academicians and doctors, policymakers, regulatory agencies, manufacturers, and healthcare payers, is urgently needed.

Role of Rifampin against Staphylococcal Biofilm Infections In Vitro, in Animal Models, and in Orthopedic-Device-Related Infections.

Rifampin has been used as an agent in combination therapy in orthopedic device-related infections (ODRI) for almost three decades. The aim of this review is to provide data regarding the role of rifampin against biofilm infection in vitro, in animal models, and in clinical ODRI. Available data are gathered in order to present the rational use of rifampin combinations in patients with periprosthetic joint infection (PJI). The role of rifampin is well defined in patients with PJI and is indicated in those who fulfill the Infectious Diseases Society of America criteria for debridement and implant retention or one-stage exchange. It should be used with care because of the danger of rapid emergence of resistance. Potential drug interactions should be considered.

Dihydrotestosterone is a predictor for mortality in males with community-acquired pneumonia: results of a 6-year follow-up study.

BACKGROUND: Adrenal hormone metabolite levels are altered in acute illnesses such as community-acquired pneumonia (CAP). Our aim was to investigate associations of sex and mineralocorticoid hormone metabolites with short- and long-term mortality and severity of CAP in male and female patients. METHODS: We prospectively followed 285 patients (60.4% male, mean age 71 years) with CAP from a previous multicenter trial. At baseline, levels of different metabolites of sex hormones and mineralocorticoids were measured by liquid chromatography coupled to tandem mass spectrometry. We calculated Cox regression models adjusted for age and comorbidities. RESULTS: All-cause mortality was 5.3% after 30 days and increased to 47.4% after 6 years. In males, high levels of dihydrotestosterone were associated with higher 6-year mortality (adjusted HR 2.84, 95%CI 1.15-6.99, p = 0.023), whereas high levels of 17-OH-progesterone were associated with lower 6-year mortality (adjusted HR 0.72, 95%CI 0.54-0.97, p = 0.029). Testosterone levels in males correlated inversely with inflammatory markers (CRP rho = - 0.39, p < 0.001; PCT rho = - 0.34, p < 0.001) and disease severity as assessed by the Pneumonia severity index (PSI) (rho = - 0.23, p = 0.003). No similar association was found for female patients. CONCLUSION: Whereas in males with CAP, sex and mineralocorticoid hormone metabolite levels correlated with inflammation, disease severity and long-term survival, no similar association was found for females. Further study of sex and mineralocorticoid hormones in acute illness could generate predictive signatures with implementation in clinical practice.

Association of the Tyrosine/Nitrotyrosine pathway with death or ICU admission within 30 days for patients with community acquired pneumonia.

BACKGROUND: Oxidative stress is a modifiable risk-factor in infection causing damage to human cells. As an adaptive response, cells catabolize Tyrosine to 3-Nitrotyrosine (Tyr-NO2) by nitrosylation. We investigated whether a more efficient reduction in oxidative stress, mirrored by a lowering of Tyrosine, and an increase in Tyr-NO2 and the Tyrosine/Tyr-NO2 ratio was associated with better clinical outcomes in patients with community-acquired pneumonia (CAP). METHODS: We measured Tyrosine and Tyr-NO2 in CAP patients from a previous randomized Swiss multicenter trial. The primary endpoint was adverse outcome defined as death or ICU admission within 30-days; the secondary endpoint was 6-year mortality. RESULTS: Of 278 included CAP patients, 10.4% experienced an adverse outcome within 30 days and 45.0% died within 6 years. After adjusting for the pneumonia Severity Index [PSI], BMI and comorbidities, Tyrosine nitrosylation was associated with a lower risk for short-term adverse outcome and an adjusted OR of 0.44 (95% CI 0.20 to 0.96, p = 0.039) for Tyr-NO2 and 0.98 (95% CI 0.98 to 0.99, p = 0.043) for the Tyrosine/Tyr-NO2 ratio. There were no significant associations for long-term mortality over six-years for Tyr-NO2 levels (adjusted hazard ratio 0.81, 95% CI 0.60 to 1.11, p = 0.181) and Tyrosine/Tyr-NO2 ratio (adjusted hazard ratio 1.00, 95% CI 0.99 to 1.00, p = 0.216). CONCLUSIONS: Tyrosine nitrosylation in our cohort was associated with better clinical outcomes of CAP patients at short-term, but not at long term. Whether therapeutic modulation of the Tyrosine/Tyr-NO2 pathway has beneficial effects should be evaluated in future studies. TRIAL REGISTRATION: ISRCTN95122877. Registered 31 July 2006.

Are We Winning or Losing the Battle With Periprosthetic Joint Infection: Trends in Periprosthetic Joint Infection and Mortality Risk for the Medicare Population.

BACKGROUND: Periprosthetic joint infection (PJI) is a potentially deadly complication of total joint arthroplasty. This study was designed to address how the incidence of PJI and outcome of treatment, including mortality, are changing in the population over time. METHODS: Primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients with PJI from the 100% Medicare inpatient data set (2005-2015) were identified. Cox proportional hazards regression models for risk of PJI after THA/TKA (accounting for competing risks) or risk of all-cause mortality after PJI were adjusted for patient and clinical factors, with year included as a covariate to test for time trends. RESULTS: The unadjusted 1-year and 5-year risk of PJI was 0.69% and 1.09% for THA and 0.74% and 1.38% for TKA, respectively. After adjustment, PJI risk did not change significantly by year for THA (P = .63) or TKA (P = .96). The unadjusted 1-year and 5-year overall survival after PJI diagnosis was 88.7% and 67.2% for THA and 91.7% and 71.7% for TKA, respectively. After adjustment, the risk of mortality after PJI decreased significantly by year for THA (hazard ratio = 0.97; P < .001) and TKA (hazard ratio = 0.97; P < .001). CONCLUSION: Despite recent clinical focus on preventing PJI, we are unable to detect substantial decline in the risk of PJI over time, although mortality after PJI has declined. Because PJI risk appears not to be changing over time, the incidence of PJI is anticipated to scale up proportionately with the demand for THA and TKA, which is projected to increase substantially in the coming decade.

Gut, microbiota-dependent trimethylamine-N-oxide is associated with long-term all-cause mortality in patients with exacerbated chronic obstructive pulmonary disease.

OBJECTIVES: The gut, microflora-dependent metabolite trimethylamine-N-oxide (TMAO) has emerged as a dietary-associated risk factor for incident cardiovascular events. Chronic obstructive pulmonary disease (COPD) is a prevalent disease worldwide with a high associated risk for cardiovascular disease and death due to an infectious cause. AIMS: To study whether TMAO is predictive for adverse clinical outcomes in patients with exacerbated COPD. METHODS: A total of 189 patients with COPD exacerbation were prospectively followed for a median of 6.1 y. TMAO plasma levels at the time of emergency department admission were measured by liquid chromatography coupled with tandem mass spectrometry. Cox and linear regression models were used to investigate associations of TMAO with all-cause mortality and different comorbidities. RESULTS: All-cause mortality was 55.6% after 6 y. The deceased patients showed significantly higher median admission TMAO (µmol/L) levels compared with survivors (3.9 [interquartile range: 2.3-7.1] versus 2.9 [interquartile range: 1.8-4.7]; P = 0.01), which resulted in an unadjusted hazard ratio of 1.8 ([95% confidence interval: 1.2-3.0], P = 0.01). This association was no longer significant after multivariate adjustment. Median TMAO levels were similar in nonpneumonic and pneumonic COPD exacerbation. Higher age, higher body mass index, diabetes mellitus, and chronic kidney disease were predictors for increased plasma TMAO levels in linear regression analysis. CONCLUSIONS: Increased circulating TMAO levels per se were associated with long-term all-cause mortality in patients with COPD independent of type of exacerbation. However, this association was largely explained by comorbidities and age. Whether TMAO levels can additionally be influenced by nutritional interventions should be addressed in future studies.

Association of adrenal hormone metabolites and mortality over a 6-year follow-up in COPD patients with acute exacerbation.

BACKGROUND: The release of hormones from the adrenal gland is vital in acute and chronic illnesses such as chronic obstructive pulmonary disease (COPD) involving recurrent exacerbations. Using a metabolomic approach, we aim to investigate associations of different adrenal hormone metabolites with short- and long-term mortality in COPD patients. METHODS: We prospectively followed 172 COPD patients (median age 75 years, 62% male) from a previous Swiss multicenter trial. At baseline, we measured levels of a comprehensive spectrum of adrenal hormone metabolites, including glucocorticoid, mineralocorticoid and androgen hormones by liquid chromatography coupled with tandem mass spectrometry (MS). We calculated Cox regression models adjusted for gender, age, comorbidities and previous corticosteroid therapy. RESULTS: Mortality was 6.4% after 30 days and increased to 61.6% after 6 years. Higher initial androgen hormones predicted lower long-term mortality with significant results for dehydroepiandrosterone (DHEA) [adjusted hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.70-0.98; p=0.026] and dehydroepiandrosterone sulfate (DHEA-S) (adjusted HR, 0.68; 95% CI, 0.50-0.91; p=0.009). An activation of stress hormones (particularly cortisol and cortisone) showed a time-dependent effect with higher levels pointing towards higher mortality at short term, but lower mortality at long term. Activation of the mineralocorticoid axis tended to be associated with increased short-term mortality (adjusted HR of aldosterone, 2.76; 95% CI, 0.79-9.65; p=0.111). CONCLUSIONS: Independent of age, gender, corticosteroid exposure and exacerbation type, adrenal hormones are associated with mortality at short and long term in patients with COPD exacerbation with different time-dependent effects of glucocorticoids, androgens and mineralocorticoids. A better physiopathological understanding of the causality of these effects may have therapeutic implications.

Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

INTRODUCTION: In chronic obstructive pulmonary disease (COPD), there is an activation of the L-arginine nitric oxide pathway. Pulmonary obstruction causes to elevated nitric oxide (NO) levels, which lead to higher production of the NO-inhibiting metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). METHODS: We investigated the association of L-arginine, ADMA, and SDMA with clinical outcomes in a well-defined observational cohort of 150 patients with acute exacerbation of COPD. We measured L-arginine, ADMA, and SDMA by mass spectrometry in patients with pneumonic or non-pneumonic exacerbation of COPD included in a Swiss multicenter trial. We used Cox regression models to investigate the associations between blood marker levels and disease severity as well as all-cause mortality over a follow-up of 6.1 years. RESULTS: Six-year all-cause mortality was 54%. Admission levels of ADMA and SDMA (µmol L-1) were increased in 6-year non-survivors compared to survivors' median (0.60 vs. 0.46, p = 0.004; and 1.05 vs. 0.85, p = 0.012). In a multivariate Cox regression analysis, ADMA was associated with long-term mortality resulting in an age- and comorbidity-adjusted hazard ratio (HR) of 4.55 (95% confidence interval 1.02-20.43, p = 0.048). SDMA was only associated in univariate models and no association of L-arginine with outcome was found. CONCLUSION: ADMA was found to be an independent risk factor for long-term all-cause mortality in patients with acute exacerbation of COPD. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated in future interventional trials.

Activation of the Serotonin Pathway is Associated with Poor Outcome in COPD Exacerbation: Results of a Long-Term Cohort Study.

BACKGROUND/INTRODUCTION: Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine. An increase of its activity is associated with severity in patients with pneumonia. In chronic obstructive pulmonary disease (COPD) patients, an elevation of serotonin has been reported. Experimental models showed that cigarette smoke inhibits monoamine oxidase (MAO) leading to higher levels of serotonin. We investigated the prognostic ability of tryptophan, serotonin, kynurenine, IDO, and tryptophan hydroxylase (TPH) to predict short- and long-term outcomes in patients with a COPD exacerbation. METHODS: We measured tryptophan, serotonin, and kynurenine on admission plasma samples in patients with a COPD exacerbation from a previous trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). IDO and TPH were calculated as ratios of kynurenine over tryptophan, and serotonin over tryptophan, respectively. We studied their association with parameters measured in clinical routine at emergency department admission representing inflammation (C-reactive protein [CRP]), infection (procalcitonin [PCT]), oxygenation (SpO2), as well as patients' clinical outcome, confirmed by structured phone interviews. RESULTS: Mortality in the 149 included patients was 53.7% within six years of follow-up. While IDO activity showed strong positive correlations, tryptophan was negatively correlated with CRP and PCT. For 30-day adverse outcome defined as death and/or intensive care unit (ICU) admission, a multivariate regression analysis adjusted for age and comorbidities found strong associations for IDO activity (adjusted odds ratios of 31.4 (95%CI 1.1-857), p = 0.041) and TPH (adjusted odds ratios 27.0 (95%CI 2.2-327), p = 0.010). TPH also showed a significant association with mortality at 18 months, (hazard ratio 2.61 (95%CI 1.2-5.8), p = 0.020). CONCLUSION: In hospitalized patients with a COPD exacerbation, higher IDO and TPH activities independently predicted adverse short-term outcomes and TPH levels were also predictive of 18-month mortality. Whether therapeutic modulation of the serotonin pathway has positive effects on outcome needs further investigation.

Orthopaedic biofilm infections.

Many infections of the musculoskeletal system are biofilm infections that develop on non-living surfaces. Microorganisms adhere either on dead bone (sequesters) or implants. As a rule for a curative concept, chronic osteomyelitis or implant-associated bone infection must be treated with a combination of surgery and antimicrobial therapy. If an implant is kept in place, or a new device is implanted before complete healing of infection, a biofilm-active antibiotic should be used. Rifamycins are active against biofilms of staphylococci, and fluoroquinolones against those of Gram-negative bacilli. In this review, the management of chronic osteomyelitis, periprosthetic joint infection and implant-associated osteomyelitis of long bones is presented.

Time-dependent association of glucocorticoids with adverse outcome in community-acquired pneumonia: a 6-year prospective cohort study.

BACKGROUND: The hypothalamic-pituitary-adrenal stress axis plays a crucial role in community-acquired pneumonia (CAP), with high cortisol being associated with disease severity and corticosteroid treatment resulting in earlier time to recovery. Our aim in the present study was to compare different glucocorticoid hormones, including cortisol, 11-deoxycortisol, cortisone, and corticosterone, regarding their association with short- and long-term adverse outcomes in a well-defined CAP cohort. METHODS: We prospectively followed 285 patients with CAP from a previous Swiss multicenter trial for a median of 6.1 years and measured different admission glucocorticoid serum levels by liquid chromatography coupled with tandem mass spectrometry. We used adjusted Cox regression models to investigate associations between admission hormone levels and all-cause mortality at different time points. RESULTS: Mortality was 5.3% after 30 days and increased to 47.3% after 6 years. High admission cortisol was associated with adverse outcome after 30 days (adjusted OR 3.85, 95% CI 1.10-13.49, p = 0.035). In the long term (i.e.,), however, high admission cortisol was associated with better survival (adjusted HR after 3 years 0.53, 95% CI 0.32-0.89, p = 0.017; adjusted HR after 6 years 0.57, 95% CI 0.36-0.90, p = 0.015). Compared with 11-deoxycortisol, cortisone, and corticosterone, cortisol showed the highest association with mortality. CONCLUSIONS: Among different glucocorticoid hormones, cortisol showed the highest association with mortality in CAP. Whereas a more pronounced glucocorticoid stress response on hospital admission was associated with higher short-term adverse outcome, long-term outcome was favorable in these patients. These data should support the correct interpretation of glucocorticoid blood data.