Ertapenem for osteoarticular infections in obese patients: a pharmacokinetic study of plasma and bone concentrations.

PURPOSE: Ertapenem is used off-label to treat osteoarticular infections but there are few pharmacokinetic (PK) data to guide optimal dosing strategies in patients who may be obese with multiple co-morbidities including diabetes and peripheral vascular disease. METHODS: Participants undergoing lower limb amputation or elective joint arthroplasty received a dose of intravenous ertapenem prior to surgery. Eight plasma samples were collected over 24 h, together with at least one bone sample per patient. Ertapenem concentrations in plasma and bone were measured using liquid-chromatography/mass-spectroscopy and analysed using non-linear mixed effects PK modelling. RESULTS: Plasma and bone concentrations were obtained from 10 participants. The final population PK model showed that a fat free body mass was the most appropriate body size adjustment. Ertapenem diffused rapidly into bone but concentrations throughout the 24 h dosing period were on average 40-fold higher in plasma, corresponding to a bone to plasma ratio of 0.025, and highly variable between individuals. Simulations demonstrated a high probability of target attainment (PTA) for free plasma concentrations when the minimum inhibitory concentrations (MIC) were ≤ 0.25 mg/L. By contrast, at MICs of 0.5 mg/L and ≥ 1 mg/L, the fractions of patients attaining this target was ~ 80% and 40%, respectively. In bone, the PTA was ≤ 45% when the MIC was ≥ 0.25 mg/L. CONCLUSION: Local bone and free plasma concentrations appear adequate for osteoarticular infections where Enterobacteriaceae are the main causative pathogens, but for Staphylococcus aureus and other bacteria, conventional dosing may lead to inadequate PTA.

Treatment of infected non-unions of the femur and tibia in a French referral center for complex bone and joint infections: Outcomes of 55 patients after 2 to 11 years.

INTRODUCTION: An infected non-union is a major complication following bone fracture. While bone union can be obtained in 70% to 100% of cases, treatment of osteomyelitis is less predictable, with reported healing rates ranging from 40% to 100%. The primary aim of this study was to assess the success rate of treating infected non-unions of the tibia and femur by a team specializing in complex bone and joint infections. MATERIAL AND METHODS: This single-center retrospective study included all patients operated between 2002 and 2012 due to an infected non-union of the femur or tibia using standardized surgical methods. The procedure was typically done in two phases: excision of the infected site and stabilization, followed by bone reconstruction after a waiting period. Additional procedures (lavage and/or bone grafting) were performed in some cases. A minimum 6-week course of antibiotic therapy was given. The primary endpoint was successful medical and surgical treatment after a minimum 2 years' follow-up defined as healing of the infection (no local clinical signs of infection, ESR≤20mm and CRP≤10mg/L, no mortality attributed to the infection) and radiological and clinical bone union, with the lower limb spared. RESULTS: Fifty-five patients (39 men, 16 women) were included with an average age of 37±11 years. There were 40 tibial fractures and 15 femur fractures. A polymicrobial infection was present in 47% of cases. Repeat surgery was required in 56.4% of patients. At an average of 4±2 years from the first surgical procedure, the treatment was successful in 49 patients (89%): 36 tibia (90%) and 13 femur (87%). The mean time to union was 9±4 months. There were six failures: 3 amputations at 5, 6 and 16 months; 1 mechanical and infection-related failure; 2 failed union. CONCLUSION: This study found that 89% of patients with an infected tibial or femoral non-union treated by a team specialized in complex bone and joint infections using a standardized surgical protocol had bone union and healing of the infection in an average of 9 months. LEVEL OF EVIDENCE: IV, retrospective study.

Local transplantation of bone marrow concentrated granulocytes precursors can cure without antibiotics infected nonunion of polytraumatic patients in absence of bone defect.

PURPOSE: Infected, long bone non-unions present a significant clinical challenge. New and alternative therapies are needed to address this problem. The purposes of this study were to compare the number of circulating granulocyte-macrophage colony-forming units (CFU-GM) in the peripheral blood of polytraumatic patients with infected tibial non-unions and in the peripheral blood of control patients with the hypothesis that their number was decreased in polytraumatic patients; and to treat their infection without antibiotics and with local transplantation of bone marrow concentrated granulocytes precursors. METHODS: Thirty (18 atrophic and 12 hyperthrophic ) infected tibial non-unions (without bone defect) that occurred after open fractures in polytraumatic patients were treated without antibiotics and with percutaneous injection of autologous bone marrow concentrate (BMC) containing granulocytes precursors (CFU-GM). CFU-GM progenitors were assessed in the bone marrow aspirate, peripheral blood, and fracture site of these patients. The number of these progenitors was compared with the CFU-GM progenitors of control patient samples (healthy donors matched for age and gender). Outcome measures were: timing of union, callus formation (radiographs and CT scan), and recurrence of clinical infection. RESULTS: As compared to control patients, the number of CFU GM derived colonies was lower at peripheral blood in patients with infected nonunions. The bone marrow graft injected in nonunions contained after concentration 42 621 ± 20 350 CFU-GM-derived colonies/cc. Healing and cure of infection was observed at six months for 25 patients and at one year follow up for 30 patients. At the median ten year follow-up (range: 5 to 15), only one patient had clinical recurrent infection after healing (between 6 months and last follow-up). CONCLUSION: The peripheral blood of these polytraumatic patients with infected nonunions had a remarkable decrease in CFU-GM-derived colonies as compared with normal controls. Local transplantation of concentrated CFU-GM-derived colonies aspirated from bone marrow allowed cure of infection and healing without antibiotics.

Osteoarticular complications of brucellosis: The diagnostic value and importance of detection matrix metalloproteinases.

OBJECTIVES: Matrix metalloproteinases (MMPs) has been implicated in the pathogenesis of infective, cancer and autoimmune diseases. In this study, we investigated the serum level of MMPs and its clinical importance in human brucellosis. PATIENTS AND METHODS: This study included 60 brucellosis patients treated at the Clinic for Infectious Diseases, Clinical Centre, University of Sarajevo. Matrix metalloproteinases serum levels were quantified by ELISA. RESULTS: The investigation involved three groups: 30 patients with complications, 30 patients without complications of brucellosis and 30 healthy control examinees. The complications of human brucellosis varied but osteoarticular involvement dominated (n=21/30; 70%). Matrix metalloproteinases serum levels in the patients with complications were highest. The serum level of MMP-1 in patients with complications was the highest at 9.45; in patients without complications it was 3.78 and in the control examinees it was lowest at 3.62 (p=0.001). The serum level of MMP-9 in patients with complications was the highest at 105.66; in patients without complications 64.67, and in the control examinees it was lowest at 37.32 (p=0.001). The serum level of MMP-13 in patients with complications was highest at 138.86; in patients without complications at 64.85; and in the control examinees it was the lowest at 29.55 (p=0.001). Pearson's coefficient showed a statistically significant positive correlation between levels of tested matrix metalloproteinases and development complications in human brucellosis (p=0.001). CONCLUSION: This study showed the diagnostic value and importance of detection of matrix metalloproteinases in human brucellosis. MMPs are a useful serum biomarker for assessment of disease activity.

Discordance between labelled white blood cell scintigraphy and bone scan following suspicion of bone infection: what should be done about it?

BACKGROUND: Bone infection is a common issue in infectiology. The gold standard for evaluating bone infection is the white blood cell (WBC) scan. In our practice the WBC scan is coupled with a bone scan. Discordances in the results of these two examinations are a common occurrence in daily practice. We decided to investigate the meaning of these discordances. MATERIALS AND METHODS: Two hundred and ninety-six 99mTc-HMPA labelled white blood cells (WBC) and 99mTc-HMDP bone scanning (BS) examinations were performed in our department between 1997 and 2003 for evaluation of bone infection. Out of these 296 examinations, a first rating extracted 54 scans that were considered discordant. These 54 scans were reviewed by three observers. Clinical and paraclinical data were obtained for all the cases definitely considered as discordant by all three observers. RESULTS: The observers finally retained 18 cases as discordant from the initial 296 (6.1%). Thirteen patients were not infected,and five patients were considered infected based on clinical follow-up or bacteriological and histological data. For the 17 patients with WBC-, BS+, 4 (23.5%) were infected. CONCLUSION: Our study shows that in the vast majority(17 out of 18), discordances consist of a negative WBC scan with a positive bone scan. In these cases the accuracy of the WBC scan is diminished as 23.5% of the patients with a negative WBC and a positive bone scan are infected.

Interobserver reproducibility in the interpretation of 99mTc-labelled white blood cell scintigraphic images.

OBJECTIVE: This study was performed to investigate the interobserver reproducibility of the interpretation of Tc-labelled white blood cell scans combined or not with other nuclear medicine procedures. METHODS: Twenty nuclear medicine physicians working in Belgium received clinical data and scintigraphic images from 10 patients suspected of suffering from various infectious diseases. They had to choose, for each patient, one answer among 'high probability', 'intermediate probability' and 'low probability' of infection. In a first step the level of agreement, defined as the highest percentage obtained among the three proposed answers, was calculated for each case; complete agreement was arbitrarily defined when 80% or more of the observers gave the same answer. In a second step, a numerical score was given for each answer and for each observer. The scores were defined as 0 for the 'low probability' answer, 1 for the 'intermediate probability' and 2 for the 'high probability' answer. The scores of each observer were summed up allowing obtaining of a cumulated score for each observer; observers were thereafter classified as a function of their own cumulated score. RESULTS: An agreement of 80% or more was observed only in three patients. The cumulated scores of the observers were between 4 and 16, demonstrating that some observers were more sensitive than others. CONCLUSION: Interobserver reproducibility in the interpretation of the white blood cell scan was poor; several factors could explain these results, the most frequent being both the poor specificity of the labelled white blood cell scan and different concepts in interpreting combined nuclear medicine procedures in several situations. As observers received the anonymized overall results, this study may have a favourable impact on continuing education in medical imaging.

Effectivity of a T-cell-adapted induction therapy with anti-thymocyte globulin (Sangstat).

BACKGROUND: Cytolytic induction therapy with anti-thymocyte globulin (ATG) should induce effective immunosuppression, with a low rate of rejection in the initial phase after heart transplantation. Induction therapy with ATG allows post-operative renal recovery without the negative effects of highly nephrotoxic cyclosporine levels. An increased rate of infection is a common problem, however, and has been associated with "over-immunosuppression" early after transplantation. Therefore, we investigated whether reduced T-cell-adapted ATG induction therapy could be performed without increasing the risk of graft loss by rejection and whether reductions in infection rates and costs are possible. METHODS: Between March 1999 and December 2002, T-cell-adapted ATG induction therapy with ATG (Sangstat) (1.5 mg/kg) was given to 62 heart transplant recipients (study group) starting on post-operative Days 1 to 6. T-lymphocyte sub-populations were screened daily using flow cytometry. If total lymphocytes were <100/microl (reference 1,300 to 2,300/microl), T-helper lymphocytes (CD4+) <50/microl (reference >500/microl) and T-suppressor cells (CD8+) <50/microl (reference >300/microl), then no ATG was given. Further immunosuppression was continued with triple therapy consisting of methylprednisolone, azathioprine and cyclosporine. An historic group of heart transplant recipients given a full-dose ATG regimen for 8 days served as controls. These recipients were treated with ATG (Merieux 1.5 mg/kg) until reaching monoclonal cyclosporine levels of >300 mg/dl. Additional immunosuppressive treatment did not differ. Patients in both groups received systemic antibiotics (Imipenem) peri-operatively. Results of routine endomyocardial biopsies and rates of infections were examined. RESULTS: Study group patients were older (52 +/- 10 vs 49 +/- 14 years). In the study group, mean cumulative ATG dose was reduced significantly to 596 +/- 220 mg (p < 0.05) for 3.9 +/- 1.6 days compared with 1,159 +/- 376 mg for 6.9 +/- 1.1 days in the control group. The rate of cytomegalovirus (CMV) seroconversion was 23% in the study group compared with 13% in the control group. Rate of deep sternal infections was lower in the study group (1.6% vs 3.2%). The mean rejection rate in the first 3 months was 0.4 +/- 0.7 for the study patients (185 biopsies) vs 1.1 +/- 1.7 for controls (237 biopsies). All biopsies with ISHLT Grade >2 were treated successfully with 1,000 mg of methylprednisolone intravenously for 3 days. Both groups showed a similar 1-year survival rate (study 88%, control 89%). CONCLUSIONS: T-cell-adapted ATG induction therapy can be a helpful tool for individualized immunosuppression. It is not associated with an increased rate of rejection. Lower doses of immunosuppression help to minimize the rates of infection. In addition, cytolytic induction therapy combined with reduced ATG results in significant cost reduction.

Demineralization for inactivation of infectious retrovirus in systemically infected cortical bone: in vitro and in vivo experimental studies.

BACKGROUND: Clinical and experimental studies have demonstrated viral transmission through the transplantation of fresh-frozen infected bone. While sterilization methods sufficient to inactivate the human immunodeficiency virus (HIV) have been shown to markedly alter osteoconductive and osteoinductive properties of bone allografts, the ability of a process for creating demineralized bone matrix to abrogate transmission of a retrovirus has not been investigated, to our knowledge. We hypothesized that a clinically accepted demineralization procedure would alter the nucleic acids of the feline leukemia virus (FeLV, a retrovirus with a structure and replication cycle similar to those of HIV), inactivating the virus in infected bone and rendering it noninfectious. METHODS: Bone infected with FeLV was demineralized with a method employed for creating demineralized bone matrix powder. The effects of demineralization on cellular and (pro)viral nucleic acids were examined with use of gel electrophoresis and quantitative polymerase chain reaction, respectively. To compare the infectivity of the demineralized bone matrix with that of mineralized bone particles in cell cultures and in animals in which they had been implanted, we measured FeLV p27 antigen and (pro)viral nucleic acids as well as antiviral antibodies. RESULTS: Demineralization of FeLV-infected bone appeared to inactivate the virus by degradation and fragmentation of the DNA, rendering it noninfectious in both in vitro and in vivo test systems. In contrast, untreated mineralized FeLV-infected bone contained intact nucleic acids and readily transmitted the virus in both test systems. CONCLUSIONS: The demineralization process inactivated infectious retrovirus in infected cortical bone, thereby preventing disease transmission.

Mechanism of accumulation of 99mTc-sulesomab in inflammation.

UNLABELLED: 99mTc-Sulesomab, the Fab fragment of anti-NCA-90, is used as an in vivo granulocyte labeling agent for imaging inflammation. It is not clear to what extent it targets cells that have already migrated into the interstitial space of an inflammatory lesion as opposed to circulating cells. The contribution to signal of radioprotein diffusion in the setting of increased vascular permeability is also poorly documented. METHODS: We compared the local kinetics of (99m)Tc-sulesomab and (99m)Tc-labeled human serum albumin (HSA), which have similar molecular sizes, in 7 patients with orthopedic infection proven by clearly positive (111)In-leukocyte scintigraphy. (99m)Tc-Sulesomab and (99m)Tc-HSA were administered in sequence separated by an interval of 2-6 d. Images were obtained 1, 3, 4, and 6 h after injection, and multiple venous blood samples were obtained for blood clearance measurement. Patlak-Rutland (P-R) analysis was performed to measure lesion and control tissue protein clearance. Target-to-background tissue (T/Bkg) ratios were calculated for each radioprotein and compared with the T/Bkg ratio for (111)In-leukocytes. (99m)Tc-Sulesomab binding to granulocytes was measured in vitro and ex vivo and to primed and activated granulocytes in vitro. RESULTS: After intravenous injection, <5% of the circulating radioactivity was cell bound with both radioproteins so that the P-R curves could therefore be assumed to represent extravascular uptake of free protein. The blood clearance (mean +/- SD) of sulesomab was 23.4 +/- 11.7 mL/min, approximately 5 times greater than that of HSA, for which it was 4.8 +/- 3.1 mL/min. Likewise, clearance into the lesion of sulesomab was consistently higher than that of HSA, on average about 3 times as high. Nevertheless, the T/Bkg ratios for sulesomab and HSA were similar, except at 6 h when that of HSA (2.14 +/- 0.6) was higher than that of sulesomab (1.93 +/- 0.5; P approximately 0.01). Both values were considerably less than the T/Bkg ratio on the (111)In-leukocyte images, which, at 22 h, was 12.3 +/- 5.3. Moderate clearance of sulesomab, but not HSA, was seen in the control tissue. Granulocytes bound significantly more (99m)Tc-sulesomab in vitro when primed or activated. CONCLUSION: (a) Sulesomab does not localize in inflammation as a result of binding to circulating granulocytes; (b) sulesomab is cleared into inflammation nonspecifically via increased vascular permeability; nevertheless, it may be cleared after local binding to primed granulocytes or bind to activated, migrated extravascular granulocytes; and (c) HSA produces a similar or higher T/Bkg ratio than sulesomab because sulesomab is cleared into normal tissues and because image positivity in inflammation is significantly dependent on local blood-pool expansion.

New onset diabetes mellitus in patients presenting with extremity infections.

Although a relationship between diabetes and extremity infections has been established, the current literature notes little regarding the initial diagnosis of a patient's diabetic condition being made at the time of presentation with an extremity infection. The current study is an analysis of patients with extremity infections being diagnosed with diabetes for the first time. A chart review of 1166 patients who were admitted to the orthopaedic infection service revealed 385 patients with an admission glucose of 120 mg/dL or greater. One hundred seventy-four of these patients (45%) were diagnosed with diabetes. Thirty of these 174 patients (17.2%) previously had not been diagnosed with diabetes.