Update of biomarkers to diagnose diabetic foot osteomyelitis: A meta-analysis and systematic review.

The aim of this study was to evaluate the diagnostic characteristics of biomarker for diabetic foot osteomyelitis (DFO). We searched PubMed, Scopus, Embase and Medline for studies who report serological markers and DFO before December 2022. Studies must include at least one of the following diagnostic parameters for biomarkers: area under the curve, sensitivities, specificities, positive predictive value, negative predictive value. Two authors evaluated quality using the Quality Assessment of Diagnostic Accuracy Studies tool. We included 19 papers. In this systematic review, there were 2854 subjects with 2134 (74.8%) of those patients being included in the meta-analysis. The most common biomarkers were erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and procalcitonin (PCT). A meta-analysis was then performed where data were evaluated with Forrest plots and receiver operating characteristic curves. The pooled sensitivity and specificity were 0.72 and 0.75 for PCT, 0.72 and 0.76 for CRP and 0.70 and 0.77 for ESR. Pooled area under the curves for ESR, CRP and PCT were 0.83, 0.77 and 0.71, respectfully. Average diagnostic odds ratios were 16.1 (range 3.6-55.4), 14.3 (range 2.7-48.7) and 6.7 (range 3.6-10.4) for ESR, CRP and PCT, respectfully. None of the biomarkers we evaluated could be rated as 'outstanding' to diagnose osteomyelitis. Based on the areas under the curve, ESR is an 'excellent' biomarker to detect osteomyelitis, and CRP and PCT are 'acceptable' biomarkers to diagnose osteomyelitis. Diagnostic odds ratios indicate that ESR, CRP and PCT are 'good' or 'very good' tools to identify osteomyelitis.

Meta-analysis of the accuracy of the serum procalcitonin diagnostic test for osteomyelitis in children.

OBJECTIVE: This study sought to assess the sensitivity, specificity, and predictive utility of serum procalcitonin (PCT) in the diagnosis of pediatric osteomyelitis. METHODS: A systematic computer-based search was conducted for eligible literature focusing on PCT for the diagnosis of osteomyelitis in children. Records were manually screened according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Statistical analysis was performed using Review Manager software 5.3, Meta-disc software1.4, STATA 12.0, and R 3.4 software. RESULT: A total of 5 investigations were included. Of these, 148 children with osteomyelitis were tested for bacterial cultures in PCT. For PCT in the diagnosis of pediatric osteomyelitis, diagnostic meta-analysis revealed a pooled sensitivity and specificity of 0.58 (95% confidence interval (CI): 0.49 to 0.68) and 0.92 (95% CI: 0.90 to 0.93) respectively. The PCT had the greatest area under the curve (AUC) at 0.80 for the diagnosis of osteomyelitis in children. The Deeks' regression test for asymmetry results indicated that there was no publication bias when evaluating publication bias (P = 0.90). CONCUSION: This study provided a comprehensive review of the literature on the use of PCT in pediatric osteomyelitis diagnosis. PCT may be used as a biomarker for osteomyelitis diagnosis; however, its sensitivity was low. It still needs to be validated by a large sample study.

Cytokine profile in patients with chronic non-bacterial osteomyelitis, juvenile idiopathic arthritis, and insulin-dependent diabetes mellitus.

OBJECTIVES: Our study aimed to evaluate the cytokine levels in pediatric chronic non-bacterial osteomyelitis (CNO) patients and compare these with other immune-mediated diseases and healthy controls. METHODS: In this prospective study, we included 42 children with CNO, 28 patients with non-systemic juvenile idiopathic arthritis (JIA), 17 children with insulin-dependent diabetes mellitus (IDDM), and 30 healthy age-matched controls. In each of the CNO patients and comparison groups, the levels of 14-3-3-η protein, S100A8/A9 protein, interleukin-4 (IL-4), interleukin-17 (IL-17), interleukin-18 (IL-18), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) were measured by ELISA assay. RESULTS: All studied cytokines in the CNO patients were significantly higher than controls, and IDDM, 14-3-3-η protein, IL-18, IL-4, IL-17, IL-1ß, and TNF-α were less than in JIA patients. In the discriminant analysis, ESR, 14-3-3 protein, S100A8/A9, IL-18, IL-4, and TNF-α can discriminate CNO from JIA, and 14-3-3 protein, S100A8/A9, IL-18, IL-17, IL-4, and TNF-α can distinguish CNO from other diseases and HC. CONCLUSION: The increased level of pro-inflammatory cytokines confirms the role of monocyte-driven inflammation in CNO patients. Cytokines may prove valuable as biomarkers and potential therapeutic targets for CNO.

Treatment of Chronic Hematogenous Osteomyelitis in Children With Antibiotic Impregnated Calcium Sulphate.

BACKGROUND: The purpose of this study was to evaluate the clinical and radiologic outcome of chronic hematogenous osteomyelitis (CHOM) in children, treated with single-stage debridement and dead space management using antibiotic impregnated calcium sulphate pellets. METHODS: The authors retrospectively evaluated a consecutive series of 34 patients who presented with CHOM from 2011 to 2017. In each case, CHOM was classified according to the Beit CURE classification. Following thorough surgical debridement, the resulting dead space in the bone was filled with the antibiotic impregnated beads before primary closure. RESULTS: Of the 31 patients available for follow up, effective regeneration of bone was confirmed in all cases, with radiographic bone healing typically observed at around 12 weeks. None of the children required reoperation for infection and none had recurrence of infection at the time of final review. The beads were completely absorbed within 3 months. No systemic adverse reactions to the local delivery of antibiotics were observed in this study. CONCLUSIONS: The authors found that single-stage debridement in conjunction with antibiotic impregnated calcium sulphate was an effective means of treating CHOM in children, with effective eradication of infection in every case. LEVEL OF EVIDENCE: Level IV-Retrospective case series. See instructions for authors for a complete description of levels of evidence.

Pamidronate in chronic non-bacterial osteomyelitis: a randomized, double-blinded, placebo-controlled pilot trial.

OBJECTIVE: This is the first randomized double-blinded, placebo-controlled pilot trial to investigate the efficacy of pamidronate in reducing radiological and clinical disease activity in chronic non-bacterial osteomyelitis (CNO). METHOD: Patients received pamidronate or placebo at baseline and weeks 12 and 24. Whole-body magnetic resonance imaging was performed at baseline and weeks 12 and 36, and computed tomography of the anterior chest wall (ACW) at baseline and week 36. Radiological disease activity was systematically scored in the ACW and spine. Patient-reported outcomes [visual analogue scale (VAS) pain, VAS global health, Health Assessment Questionnaire (HAQ), EuroQol-5 Dimensions (EQ-5D), and 36-item Short-Form Health Survey (SF-36)] and biomarkers of bone turnover and inflammation were assessed at baseline and weeks 1, 4, 12, 24, and 36. Data are expressed as median [interquartile range]. RESULTS: Fourteen patients were randomized and 12 were analysed. From baseline to week 36, the radiological disease activity score in the ACW decreased from 5 [4-7] to 2.5 [1-3] in the pamidronate group, but did not change in the placebo group (p = 0.04). From baseline to week 36, VAS pain and VAS global health tended to decrease more in the pamidronate than in the placebo group (p = 0.11, p = 0.08). Physical functioning (HAQ) and health-related quality of life (EQ-5D, SF-36) did not change. Biomarkers of bone turnover decreased only in the pamidronate group (p ≤ 0.02). CONCLUSION: Pamidronate may improve radiological and clinical disease activity in CNO. Methods to score radiological disease activity in adult CNO were suggested. Clinical Trials: NCT02594878.

External Validation of an Algorithm to Predict Adjacent Musculoskeletal Infection in Pediatric Patients With Septic Arthritis.

BACKGROUND: Septic arthritis (SA) remains a potentially morbid disease in the pediatric population. Magnetic resonance imaging (MRI) is the most sensitive tool for recognizing associated osteomyelitis and intramuscular abscess, but is a limited resource. The aim of this study is to externally validate a previously developed algorithm (Rosenfeld and colleagues) to predict adjacent infection in pediatric patients diagnosed with SA. METHODS: We identified 120 children under 16 with presumed SA presenting to a tertiary referral center between 2008 and 2018. Patients without confirmed SA, those with insufficient data, and patients who did not receive perioperative MRI were excluded, leaving 53 patients. The previous algorithm suggests that patient age (above 4 y), C-reactive protein (>8.9 mg/L), platelet count (<310×10cells/µL), duration of symptoms (>3 d), and absolute neutrophil count (>7.2×10cells/µL) are risk factors for adjacent infection, with 3 or more variables signifying a "positive" result. Comparing against the gold standard of MRI, the accuracy of the algorithm was validated in terms of sensitivity, specificity, likelihood ratio (LR), and positive and negative predictive value. Discrimination and calibration of this algorithm have been assessed using receiver operating curve analysis and calibration plots. RESULTS: The sensitivity and specificity of criteria from Rosenfeld algorithm were 73% and 44%, respectively. Receiver operating curve showed poor discrimination [area under the curve=0.54, confidence interval (CI): 0.26-0.83]. The positive predictive value was 55.9% and the negative predictive value was 63.1% with LR +1.23 (CI: 0.87-1.98) and LR -0.61 (CI 0.28-1.30). Only 53% of patients with 4 or more criteria had an adjacent infection on MRI. Examining our cohort, children with a positive MRI finding had higher mean C-reactive protein (77 vs. 122 mg/L, P=0.04) and were more likely to have waited >72 hours days between symptom onset and hospital presentation (P=0.03). CONCLUSION: Although treatment algorithms are an attractive tool to guide clinicians and resource allocation, they need to take into account the local population characteristics before routine implementation. LEVEL OF EVIDENCE: Level IV-retrospective cohort study.

Role of inflammatory markers in the healing time of diabetic foot osteomyelitis treated by surgery or antibiotics.

OBJECTIVE: To analyse the predictive role of inflammatory markers in the healing time of diabetic foot osteomyelitis treated by surgery or antibiotics. METHODS: An observational study of patients with diabetic foot ulcers (DFU) and clinically suspected osteomyelitis. The patients underwent surgical or antibiotic treatment for bone infection in a specialised diabetic foot unit. Blood samples were taken from each patient to analyse biomarkers. The main outcome was the number of weeks until healing occurred. RESULTS: A total of 116 patients took part in the study. The number of weeks until healing was similar for both groups (surgical n=96 and antiobiotic n=20, treatments). No association was observed among biomarkers as predictors of time-to-healing. CONCLUSION: There is not enough evidence to define the prognostic role of inflammatory markers in the healing time of DFUs complicated with diabetic foot osteomyelitis, regardless of the treatment administered.

Inflammatory markers limitations in the diagnosis of pediatric calcaneal osteomyelitis.

Calcaneal osteomyelitis is an uncommon, but clinically important emergent condition in the differential of the limping child. Early recognition is paramount to prevent complications from delayed diagnosis like formation of periosteal abscesses or growth plate injury. The diagnosis of pediatric osteoarticular infection relies on a combination of clinical exam, imaging and inflammatory markers. Erythrocyte sedation rate (ESR) and C-reactive protein (CRP) have reported sensitivities for osteomyelitis of 94% and 95%, respectively. However, clinicians should be aware that certain clinical factors can decrease the reliability of inflammatory markers in this pediatric condition. Location of infection in small bones like the calcaneus can lead to significantly lower sensitivities than in long bones. Pretreatment with antibiotics prior presentation can also decrease the reliability of ESR and CRP. In this case, we highlight two unique clinical factors that diminish the sensitivity of commonly used inflammatory markers in the diagnosis of pediatric osteomyelitis.

C-Reactive Protein Predicts Risk of Venous Thromboembolism in Pediatric Musculoskeletal Infection.

BACKGROUND: The rate of venous thromboembolism in children with musculoskeletal infections (MSKIs) is markedly elevated compared with hospitalized children in general. Predictive biomarkers to identify high-risk patients are needed to prevent the significant morbidity and rare mortality associated with thrombotic complications. We hypothesize that overactivation of the acute phase response is associated with the development of pathologic thrombi and we aim to determine whether elevations in C-reactive protein (CRP) are associated with increased rates of thrombosis in pediatric patients with MSKI. METHODS: A retrospective cohort study measuring CRP in pediatric MSKI patients with or without thrombotic complications. RESULTS: The magnitude and duration of elevation in CRP values correlated with the severity of infection and the development of pathologic thrombosis. In multivariable logistic regression, every 20 mg/L increase in peak CRP was associated with a 29% increased risk of thrombosis (P<0.001). Peak and total CRP were strong predictors of thrombosis with area under the receiver-operator curves of 0.90 and 0.92, respectively. CONCLUSIONS: Future prospective studies are warranted to further define the discriminatory power of CRP in predicting infection-provoked thrombosis. Pharmacologic prophylaxis and increased surveillance should be strongly considered in patients with MSKI, particularly those with disseminated disease and marked elevation of CRP. LEVEL OF EVIDENCE: Level III.

False-positive elevation of 1,3-beta-D-glucan caused by continuous administration of penicillin G.

The 1,3-beta-D-Glucan (BDG) assay is widely used for the diagnosis of fungal infections, especially in patients with hematologic malignancies. Some antimicrobials have been reported to cause false-positive results for BDG, but there has been no report on the effect of penicillin G (PCG) on BDG levels. We experienced a patient who developed false-positive BDG elevation during the administration of PCG for osteomyelitis due to Streptococcus pneumoniae infection. The serum BDG level increased up to 81.0 pg/ml during the continuous administration of PCG at 24 million units per day. However, chest and paranasal CT scan showed no evidence of fungal infection. The BDG level decreased to 38.0 pg/ml at 14 hours after the discontinuation of PCG. The amount of BDG in one vial of PCG inferred from these serum BDG levels is very similar to the actual BDG concentration in a vial of PCG. Therefore, during the administration of PCG, elevated BDG levels should be interpreted with caution, as they may be false-positive results.

Procalcitonin and Pancreatic Stone Protein Function as Biomarkers in Early Diagnosis of Pediatric Acute Osteomyelitis.

BACKGROUND High plasma levels of procalcitonin (PCT) are typically seen in children with severe bacterial infection, particularly in cases of septic shock or bacteremia. Similarly, pancreatic stone protein (PSP) is associated with inflammation, infection, and other disease-related stimuli. However, the prognostic value of PSP in critically ill pediatric patients is unknown. This study investigated the early diagnostic value of PCT and PSP in pediatric acute osteomyelitis. MATERIAL AND METHODS A total of 187 patients with suspected acute osteomyelitis and 80 healthy control children were enrolled. The serum expression of PTC and PSP was measured. Pearson correlation analysis was conducted to correlate PTC with PSP. ROC analysis was used to test the value of PTC and PSP in early diagnosis of pediatric acute osteomyelitis. RESULTS Acute osteomyelitis was diagnosed in 49.2% of the patients (n=92) based on the layered bone puncture. The serum levels of PTC and PSP in pediatric acute osteomyelitis were higher than in the non-acute osteomyelitis group (P<0.01). Serum PTC concentrations showed a significantly positive correlation with PSP levels (P<0.001). ROC analysis showed that the AUC values of PTC and PSP were 0.767 (95% CI, 0.700-0.826), and 0.796 (95% CI, 0.731-0.855), respectively. The AUC value of PTC & PSP was 0.903 (95% CI: 0.851-0.941), which was markedly increased compared with PTC or PSP (P<0.01). CONCLUSIONS Serum levels of PCT and PSP are promising biomarkers for early diagnosis of pediatric acute osteomyelitis.

Kocher Criteria Revisited in the Era of MRI: How Often Does the Kocher Criteria Identify Underlying Osteomyelitis?

BACKGROUND: The Kocher criteria are established clinical parameters that predict hip septic arthritis (SA) with a 93% or greater positive-predictive value when 3 or 4 variables are present. The incidence of osteomyelitis (OM) in these patients has not been reported. The purpose of this study is to evaluate the incidence of OM in patients who have 3 or 4 positive Kocher criteria. METHODS: A total of 71 consecutive patients (mean age, 4.7 y) treated between January 2007 and July 2013 for suspected hip SA who had 3 or 4 positive Kocher criteria were retrospectively reviewed. The Kocher criteria variables include: non-weight-bearing status, fever>38.5°C, white blood cell>12 K, and erythrocyte sedimentation rate>40 mm/h. All patients underwent ultrasound (US) and magnetic resonance imaging as part of their workup. RESULTS: There were a total of 71 patients with 3 or 4 positive Kocher criteria. Of these, 22.5% (n=16) had a diagnosis of SA and 47.9% (n=34) had a diagnosis of OM. Of the 71 patients, 52.1% (37/71) had a hip effusion on US. When an effusion was identified, 18.9% (7/37) had isolated SA, 18.9% (7/37) had isolated OM, and 24.3% (9/37) had combined SA and OM. When no effusion was identified, a total of 18/34 (52.9%) had underlying OM. CONCLUSIONS: Patients with 3 or 4 Kocher criteria have a high incidence (47.9%) of OM. Even in patients with a hip effusion on US, the incidence of OM was equal to that of SA. These results suggest that the combination of Kocher criteria and US alone is not sufficient to make a diagnosis in patients presenting with hip irritability and consideration should be given to adding magnetic resonance imaging to their workup. LEVEL OF EVIDENCE: Level III-retrospective chart review.

Lasiodiplodia species fungal osteomyelitis in a multiple myeloma patient.

Lasiodiplodia species are environmental fungi that have been reported as a cause of infection in both immunocompetent and immunocompromised patients. We present a case of fungal osteomyelitis caused by Lasiodiplodia species in a patient with multiple myeloma after autologous stem cell transplant. The patient was successfully treated with a combination of surgery and oral voriconzole. To the best of our knowledge, this is the first reported case of fungal osteomyelitis caused by Lasiodiplodia species.

Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO).

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn's disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn's disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn's disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn's disease patients with "bone pain" and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.

Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis.

BACKGROUND: Chronic post-traumatic and postoperative osteomyelitis is a refractory disease which results in significant morbidity and mortality. The effect of combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded polymethyl methacrylate (PMMA) was unknown. METHODS: Fifty-one patients suffering from chronic post-traumatic or postoperative osteomyelitis of the lower extremities were included in the retrospective investigation. The patients were assigned to the study group of the combination therapy with antibiotic-loaded calcium sulfate and antibiotic-loaded PMMA or the control group of the antibiotic-loaded PMMA. Hematological parameters, eradication of infection, rate of infection recurrence and reoperation rate were evaluated during the follow-up. RESULTS: The cases were followed up for an average of 24 months (range, 15-48 months) after the first-stage surgical operation. In the study group, all the patients revealed complete calcium sulfate resorption at an average of 6 weeks (range, 30-60 days). In the study group, infection was primarily eradicated in 92.31% (24 of 26) of patients and re-operation rate of 7.69% (2 of 26) after the first-stage surgery. Two patients underwent further surgical operation in the study group. One case achieved infection eradication in the recurrent two cases, with a secondary infection eradication rate of 96.15% (25 of 26). There was no persistent infection in the study group. In the control group, infection was eradicated in 64.00% (16 of 25) of patients and re-operation rate was 36.00% (9 of 25) after the first-stage surgery. Nine patients in the control group underwent further surgical operation. Two case achieved infection eradication in these cases who suffered from persistent or recurrent infection, with a secondary infection eradication rate of 72.00% (18 of 25). There was more re-operation rate in the control group (PMMA group, 9 vs combination therapy group, 2; P = 0.034). CONCLUSION: The combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA possibly achieved more effective control of infection in the treatment of osteomyelitis through synergistic effect. The immediate structural stabilization and higher concentration of antibiotic at the local site of infection may be achieved through the combination of biodegradable and non-biodegradable devices in the treatment of chronic post-traumatic and postoperative osteomyelitis. The study was retrospectively registered at 11/16/2016 (TRN: NCT02968693).

The Use of C-reactive Protein as a Guide for Transitioning to Oral Antibiotics in Pediatric Osteoarticular Infections.

BACKGROUND: In the treatment of pediatric osteoarticular infections, early transition to oral antibiotics is desirable to shorten hospital stays and complications of prolonged intravenous therapy. C-reactive protein (CRP) is an acute phase reactant with a short half-life and is utilized at our institution to monitor progress and determine the transition to oral antibiotics. We hypothesized that patients can be safely transitioned from parenteral antibiotics to oral antibiotics when patients improve clinically and CRP halves over a period of 4 days. MATERIALS AND METHODS: A retrospective review was conducted of all pediatric patients between the ages of 1 month and 18 years admitted and treated for acute bacterial osteomyelitis and/or septic arthritis at the authors' institution. We recorded all relevant data, inpatient progress, and outpatient follow-up. RESULTS: Thirty-seven patients fulfilled the selection criteria and were reviewed for this study. Patients were an average of 8.37±4.91 years old. Surgery was performed in 33 patients (89.2%). The average duration of intravenous antibiotics was 11.00±5.61 days and the average duration of oral antibiotics was 28.76±8.69 days, with an average total duration of antibiotics of 39.16±9.08 days. The average peak CRP was 156.91±97.81 mg/L and the average CRP at discharge was 24.94±22.36 mg/L. Thirty-four patients (91.89%) experienced a 50% decline in CRP over 4 days. Of these patients, only 1 (2.94%) went on develop complications in the follow-up period. The average hospitalization period was 11.50±6.55 days. The average duration of follow-up was 7.83±6.56 months. CONCLUSIONS: We found that the combination of clinical improvement and a specific reduction of 50% in CRP levels over 4 days, or 5 CRP half lives, could be used to determine when to transition children with osteoarticular infections from parenteral to oral therapy. Complicated outcomes were associated with negative cultures, longer hospitalizations, and persistently elevated CRP levels.

Challenges in diagnosing infection in the diabetic foot.

Diagnosing the presence of infection in the foot of a patient with diabetes can sometimes be a difficult task. Because open wounds are always colonized with microorganisms, most agree that infection should be diagnosed by the presence of systemic or local signs of inflammation. Determining whether or not infection is present in bone can be especially difficult. Diagnosis begins with a history and physical examination in which both classic and 'secondary' findings suggesting invasion of microorganisms or a host response are sought. Serological tests may be helpful, especially measurement of the erythrocyte sedimentation rate in osteomyelitis, but all (including bone biomarkers and procalcitonin) are relatively non-specific. Cultures of properly obtained soft tissue and bone specimens can diagnose and define the causative pathogens in diabetic foot infections. Newer molecular microbial techniques, which may not only identify more organisms but also virulence factors and antibiotic resistance, look very promising. Imaging tests generally begin with plain X-rays; when these are inconclusive or when more detail of bone or soft tissue abnormalities is required, more advanced studies are needed. Among these, magnetic resonance imaging is generally superior to standard radionuclide studies, but newer hybrid imaging techniques (single-photon emission computed tomography/computed tomography, positron emission tomography/computed tomography and positron emission tomography/magnetic resonance imaging) look to be useful techniques, and new radiopharmaceuticals are on the horizon. In some cases, ultrasonography, photographic and thermographic methods may also be diagnostically useful. Improved methods developed and tested over the past decade have clearly increased our accuracy in diagnosing diabetic foot infections.

Pharmacokinetic variability of clindamycin and influence of rifampicin on clindamycin concentration in patients with bone and joint infections.

PURPOSE: Clindamycin, a lincosamide antibiotic with a good penetration into bone, is widely used for treating bone and joint infections by Gram-positive pathogens. To be active against Staphylococcus spp, its concentration at the infection site, C, must be higher than 2× the minimal inhibitory concentration (MIC). The aims of the work were to study the determinants of plasma clindamycin trough concentration, C min, especially the effect of co-treatment with rifampicin, and the consequences on clinical outcome. METHODS: An observational study was performed, involving patients hospitalized for a bone and joint infection who received clindamycin as part of their antibiotic treatment. Target C min was 1.7 mg/L, to reach the desired bone concentration/MIC >2, assuming a 30% diffusion into bone and MIC = 2.5 mg/L. RESULTS: Sixty one patients (mean age: 56.8 years, 57.4% male) were included between 2007 and 2011. 72.1% underwent a surgery on a foreign material, and 91.1% were infected by at least a Gram-positive micro-organism. Median C min value was 1.39 mg/L, with 58% of the values below the threshold value of 1.7 mg/L. Median C min was significantly lower for patients taking rifampicin (0.46 vs 1.52 mg/L, p = 0.034). No patient with rifampicin co-administration reached the target concentration (maximal C min: 0.85 mg/L). After a median follow-up of 17 months (1.5-38 months), 4 patients relapsed, 2 died and 47 (88.7% of the patients with known outcome) were cured, independently of association with rifampicin. CONCLUSIONS: This study shows the high inter-variability of plasma clindamycin concentration and confirms that co-treatment with rifampicin significantly decreases clindamycin trough concentrations.

Th17 cytokine deficiency in patients with Aspergillus skull base osteomyelitis.

BACKGROUND: Fungal skull base osteomyelitis (SBO) is a severe complication of otitis externa or sinonasal infection, and is mainly caused by Aspergillus species. Here we investigate innate and adaptive immune responses in patients with Aspergillus SBO to identify defects in the immune response that could explain the susceptibility to this devastating disease. METHODS: Peripheral blood mononuclear cells isolated from six patients with Aspergillus SBO and healthy volunteers were stimulated with various microbial stimuli, among which also the fungal pathogens Candida albicans and Aspergillus fumigatus. The proinflammatory cytokines IL-6, TNFα and IL-1ß, and the T-helper cell-derived cytokines IFNγ, IL-17 and IL-22 were measured in cell culture supernatants by ELISA. RESULTS: Proinflammatory cytokine responses did not differ between SBO patients and healthy volunteers. The Candida- and Aspergillus-specific Th17 response (production of IL-17 and IL-22) was significantly decreased in the SBO patients compared to healthy individuals, while Th1 cytokine response (IFNγ production) did not differ between the two groups. CONCLUSIONS: We show that patients with Aspergillus skull base osteomyelitis infection have specific defects in Th17 responses. Since IL-17 and IL-22 are important for stimulating antifungal host defense, we hypothesize that strategies that have the ability to improve IL-17 and IL-22 production may be useful as adjuvant immunotherapy in patients with Aspergillus SBO.

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis.

BACKGROUND: Because immunity against Staphylococcus aureus has not been fully elucidated, there is no diagnostic test to gauge how robust a patient's host response is likely to be. Therefore, we aimed to develop a test for specific antibodies in serum with diagnostic and prognostic potential. QUESTIONS/PURPOSES: We describe the development and validation of a multiplex immunoassay for characterizing a patient's immune response against 14 known S aureus antigens, which we then used to answer four questions: (1) Do certain antigens predominate in the immune response against S aureus? (2) Is there a predominant pattern of antigens recognized by patients and mice with infections? (3) Is the immunoglobulin G (IgG) response to any single antigen a useful predictor of ongoing S aureus infection? (4) Does measurement of the combined response against all 14 antigens provide a better predictor of ongoing infection? METHODS: A case-control study was performed. Sera were collected from 35 consecutive patients with S aureus culture-confirmed (methicillin-sensitive S aureus or methicillin-resistant S aureus) musculoskeletal infections (deep implant-associated, osteomyelitis, and cases of established septic arthritis). Patients were excluded only if they did not give informed consent for participation. Twenty-four patients had implant infections after total joint replacements, five had fracture implant infections, four had native knee infections, and two had chronic osteomyelitis without an implant. Control patients were chosen from a group of healthy, medically optimized patients scheduled to undergo elective arthroplasty. Control patients were matched for age (± 3 years), BMI (± 3 kg/m(2)), and sex as closely as possible to patients with infections. Sera from patients with S aureus infections and murine S aureus tibial implant infections were used to evaluate a multiplex immunoassay for immunoglobulin titers against 14 recombinant S aureus antigens. All patients were treated with organism-targeted antibiotic therapy and appropriate, timely surgery. Treatment response was monitored with clinical examination, erythrocyte sedimentation rate, C-reactive protein, and resampling of the infection site for the pathogen as needed. Elevated inflammatory markers or persistent positive culture results were considered evidence of ongoing infection. Treatment provided was considered standard-of-care therapy in our medical center and all patients were treated jointly with a board-certified infectious disease specialist. RESULTS: Four antigens elicited more than 65% of the measurable IgG, the most dominant being against iron-regulated surface determinant protein B (IsdB). Patients with infections had different patterns of elevated IgG titers, so that no single titer was elevated in more than 50% of patients with infections (area under the curve [AUC] ≤ 0.80). Multivariate analysis of IgG titers yielded greater predictive power of S aureus infection (AUC = 0.896). Patients with infections who had high titers against IsdB (median of survivors, 7.28 [25%-75% range, 2.22-21.26] vs median of patients with infection-related death, 40.41 [25%-75% range, 23.57-51.37], difference of medians, 33.13; p = 0.043) and iron-regulated surface determinant protein A (IsdA) median of survivors, 2.21 [25%-75% range, 0.79-9.11] vs median of patients with infection-related death, 12.24 [25%-75% range, 8.85-15.95], difference of medians, 10.03; p = 0.043) were more likely to die from infections than those who did not have high titers of IsdB. CONCLUSIONS: Measurement of the host antibody response is a predictor of ongoing infection that may prove to have prognostic value. Future studies will seek to enlarge the patient population with infections to allow us to reduce the number of antigens required to achieve a stronger predictive power. CLINICAL RELEVANCE: Measurement of the immune response against S aureus with this diagnostic tool may help guide future studies on prophylaxis and therapy in an era of personalized medicine and pathogen-specific therapies.