Unexpected synergistic and antagonistic antibiotic activity against Staphylococcus biofilms.

Objectives: To evaluate putative anti-staphylococcal biofilm antibiotic combinations used in the management of periprosthetic joint infections (PJIs). Methods: Using the dissolvable bead biofilm assay, the minimum biofilm eradication concentration (MBEC) was determined for the most commonly used antimicrobial agents and combination regimens against staphylococcal PJIs. The established fractional inhibitory concentration (FIC) index was modified to create the fractional biofilm eradication concentration (FBEC) index to evaluate synergism or antagonism between antibiotics. Results: Only gentamicin (MBEC 64 mg/L) and daptomycin (MBEC 64 mg/L) were observed to be effective antistaphylococcal agents at clinically achievable concentrations. Supplementation of gentamicin with daptomycin, vancomycin or ciprofloxacin resulted in a similar or lower MBEC than gentamicin alone (FBEC index 0.25-2). Conversely, when rifampicin, clindamycin or linezolid was added to gentamicin, there was an increase in the MBEC of gentamicin relative to its use as a monotherapy (FBEC index 8-32). Conclusions: This study found that gentamicin and daptomycin were the only effective single-agent antibiotics against established Staphylococcus biofilms. Interestingly the addition of a bacteriostatic antibiotic was found to antagonize the ability of gentamicin to eradicate Staphylococcus biofilms.

Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

The dissolvable bead: A novel in vitro biofilm model for evaluating antimicrobial resistance.

In vitro biofilm assays are a vital first step in the assessment of therapeutic effectiveness. Current biofilm models have been found to be limited by throughput, reproducibility, and cost. We present a novel in vitro biofilm model, utilising a sodium alginate substratum for surface biofilm colony formation, which can be readily dissolved for accurate evaluation of viable organisms. The dissolving bead biofilm assay was evaluated using a range of clinically relevant strains. The reproducibility and responsiveness of the assay to an antimicrobial challenge was assessed using standardised methods. Cryo-scanning electron microscopy was used to image biofilm colonies. Biofilms were grown for 20h prior to testing. The model provides a reproducible and responsive assay to clinically-relevant antimicrobial challenges, as defined by established guidelines. Moreover cryo-scanning electron microscopy demonstrates that biofilm formation is localised exclusively to the alginate bead surface. Our results suggest that this simple model provides a robust and adaptable assay for the investigation of bacterial biofilms.

Metallic hemiarthroplasty for the treatment of end-stage hallux rigidus: mid-term implant survival, functional outcome and cost analysis.

AIMS: To examine the mid-term outcome and cost utility of the BioPro metallic hemiarthroplasty for the treatment of hallux rigidius. PATIENTS AND METHODS: We reviewed 97 consecutive BioPro metallic hemiarthroplasties performed in 80 patients for end-stage hallux rigidus, with a minimum follow-up of five years. There were 19 men and 61 women; their mean age was 55 years (22 to 74). No patient was lost to follow-up. RESULTS: A total of 12 patients (15 first metatarso-phalangeal joints (MTPJs)) required a revision; one for infection, two for osteolysis and 12 for pain. The all cause rate of survival at five years was 85.6% (95% confidence interval (CI) 83.5 to 87.9). Younger age was a significant predictor of revision (odds ratio 1.09, 95% CI 1.02 to 1.17, p = 0.014) on excluding infection and adjusting for confounding variables (Cox regression). Significant improvements were demonstrated at five years in the Manchester Oxford Foot Questionnaire (13.9, 95% CI 10.5 to 17.2) and in the physical component of the Short Form-12 score (6.5, 95% CI 4.1 to 8.9). The overall rate of satisfaction was 75%. The cost per quality adjusted life year at five years, accounting for a 14% rate of revision was between £4431 and £6361 depending on the complexity and morbidity of the patient. CONCLUSION: The BioPro hemiarthroplasty offers good short to mid-term functional outcome and is a cost effective intervention. The relatively high revision rate is associated with younger age and perhaps the use of this implant should be limited to older patients. Cite this article: Bone Joint J 2016;98-B:945-51.

Pharmacokinetically guided phase 1 trial of the IGF-1 receptor antagonist RG1507 in children with recurrent or refractory solid tumors.

PURPOSE: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses. EXPERIMENTAL DESIGN: Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred. RESULTS: Thirty-one evaluable patients aged 3-17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC(0-7d) (21,000 µg h/mL) exceeded the target (16,000 µg h/mL). At 16 mg/kg q3W, the mean AUC(021d) (70,000 µg h/mL) exceeded the target (59,400 µg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks. CONCLUSIONS: The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity.

The influence of pre-operative factors on the length of in-patient stay following primary total hip replacement for osteoarthritis: a multivariate analysis of 2302 patients.

We analysed which pre-operative factors could be used to predict the length of in-patient stay following unilateral primary total hip replacement undertaken for osteoarthritis. Data were collected prospectively from 2302 patients undergoing primary total hip replacement over a nine-year period. The relationships between the various pre-operative factors and length of stay were studied separately using either Student's t-test or Pearson's correlation, and then subjected to multiple linear regression analysis. The mean length of stay was 8.1 days (median 7; 3 to 58). After adjusting for the effects of other pre-operative factors, younger age, male gender, higher combined Harris hip function and activity score, higher general health perception dimension of the Short-Form 36 score, and non-steroidal anti-inflammatory drug use were all found to be significantly associated with a reduced length of stay.

Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours.

We studied 123 patients with malignant peripheral nerve sheath tumours (MPNSTs) between 1979 and 2002. However, 90 occurred sporadically whereas 33 were associated with neurofibromatosis type 1 (NF1). Survival was calculated using Kaplan-Meier survival curves and we used Cox's proportional hazards model to identify independent prognostic factors. A 5-year survival for 110 nonmetastatic patients was 54%; (33% NF1 and 63% sporadic P = .015). Tumour stage and site were significant prognostic indicators after univariate analysis. After multivariate analysis, however, only NF1 (P = .007) and tumour volume more than 200 m (P = .015) remained independent predictors of poor outcome. We recommend that NF1 be taken into account during MPNST staging. As the survival rate in the NF group was dependant on tumour volume, routine screening of these patients with FDG PET and/or MRI may be warranted, thereby staging and controlling them at the earliest possible opportunity.

Twentieth-century survival from osteosarcoma in childhood. Trends from 1933 to 2004.

We have reviewed the data from our regional Bone Tumour Registry on patients with osteosarcoma diagnosed between 1933 and 2004 in order to investigate the relationship between survival and changes in treatment. There were 184 patients with non-metastatic appendicular osteosarcoma diagnosed at the age of 18 or under. Survival was calculated using Kaplan-Meier curves, and multivariate analysis was performed using the Cox regression proportional hazards model. The five-year survival improved from 21% between 1933 and 1959, to 62% between 1990 and 1999. During this time, a multi-disciplinary organisation was gradually developed to manage treatment. The most significant variable affecting outcome was the date of diagnosis, with trends in improved survival mirroring the introduction of increasingly effective chemotherapy. Our experience suggests that the guidelines of the National Institute for Clinical Excellence on the minimum throughput of centres for treatment should be enforced flexibly in those that can demonstrate that their historical and contemporary results are comparable to those published nationally and internationally.

Severe sequelae after stonefish envenomation.

More tourists are visiting the idyllic waters of the South Pacific each year. They share the shallow waters with the native wildlife, including the venomous stonefish. Although the injection of its venom has been reported to have occasional fatal neuromuscular and cardiovascular sequelae, severe tissue necrosis at the injection site has not been described. We present a case of stonefish injury that describes serious localised sequelae of stonefish envenomation

[In vitro elution and mechanical properties of antibiotic-loaded SmartSet HV and Palacos R acrylic bone cements]. / In-vitro-Freisetzung von Antibiotika aus SmartSet HV- und Palacos R-Knochenzement und deren Einfluss auf die mechanischen Eigenschaften.

BACKGROUND: The continuing emergence of new bone cements with additional antibiotics makes it important to establish which one will provide the most favourable antibiotic elution. An in vitro antibiotic elution and mechanical study was therefore carried out to compare a newer bone cement, SmartSet, with the established Palacos R cement. METHODS: Samples were prepared with each cement adding 1 g gentamicin, 1 g of vancomycin, or 1 g of gentamicin and vancomycin. The samples were analysed using fluorescence polarisation immunoassay. Mechanical tests were performed to determine whether any significant degradation in the cement strength occurred following addition of the antibiotic. RESULTS: With regards to gentamicin release Palacos R eluted significantly more antibiotic over the study period than SmartSet (p<0.001). Both cements eluted significantly more gentamicin when two antibiotics were added. With respect to vancomycin release there was no significant difference. Palacos R was significantly stronger than SmartSet in the 4-point bending test when the gentamicin + vancomycin antibiotic groups were compared (p=0.01). Palacos R also demonstrated a higher elastic modulus than SmartSet when the gentamicin and gentamicin + vancomycin groups were compared (p=0.03, p=0.005). CONCLUSIONS: Gentamcin shows better release characteristics from Palacos R. Both cements exhibited synergistic release of combined antibiotics.

Core decompression for early atraumatic osteonecrosis of the femoral head.

We performed 41 core decompressions in 32 patients for stage I or stage II osteonecrosis of the femoral head. The intra-osseous pressure at the intertrochanteric level was raised in 28 (68%) and there was histological confirmation of necrosis in 36 hips (88%). After a follow-up of 10 to 84 months (mean 31) nine of the 12 stage I hips (75%) showed significant clinical or radiological deterioration; no evidence of necrosis had been found in the core specimens of the other three hips. Of the 29 hips in stage II, 25 (86%) showed significant radiological deterioration, and only five (17%) had improved clinically. We believe that once necrosis has occurred, core decompression will not significantly influence the subsequent course of the disease.

Long-term results of Charnley low-friction arthroplasty of the hip.

The long-term results of 73 Charnley low-friction arthroplasties with follow-up of 10-14 years are presented. Eight hips required revision for socket migration resulting from excessive medialisation of the cup (2, 2.7%); breakage of the femoral stem (5, 6.8%); and loosening (1). A further 5 hips had radiological changes suggesting that they would require revision in the foreseeable future. Sixty hips (82.2%) remained clinically excellent with minimal radiological changes.

Charnley low-friction arthroplasty of the hip. Long-term results in South Africa.

Long-term results of 98 Charnley low-friction arthroplasties were followed for a period of a mean of 12 years; 98 of 470 operations qualified for this strict long-term study, 78 (79.6%) with excellent results. If excessive medialization of the cup is avoided, socket complications appear to be minimal (4%). The majority of femoral component failures resulted from femoral stem breakage. Only four hips (4.08%) developed loosening of the femoral stem.

Dynamic assessment of the load distribution on the plantar surface of the foot using the University of Cape Town walkway and its clinical application.

The dynamic assessment of the plantar pressure profile is now possible, and an immediate visual display without the necessity for complicated computer-assisted analysis has been developed using a walkway designed at the University of Cape Town. Using the walkway, the author assessed the feet of 10 normal children and 10 normal adults. They showed consistently similar profiles with very minor variations. Using the walkway, the author also showed in four abnormal cases the effects of corrective surgical procedures and of an orthotic device.

Acute osteomyelitis and septic arthritis in children. A simple approach to treatment.

A 12-month prospective study of 45 patients with bacteriologically proven acute osteitis and septic arthritis is presented. Sodium fusidate and erythromycin at the recommended dosage of 30 mg/kg/d for 3 weeks was found to be an effective first-line antibiotic regimen. The hazards of Haemophilus infection are emphasized. Immediate Gram staining is therefore strongly recommended. It was found that adequate drainage of a subperiosteal abscess without drilling of the bone always resulted in complete cure, while cases of septic arthritis consequent upon decompression of a contiguous metaphysitis were adequately treated by arthrotomy and irrigation alone. The authors believe that early limited surgery with adequate administration of antibiotics aided by early circumspect mobilization will provide a good functional and cosmetically acceptable result in most cases.

Antibiotic therapy in acute infections of bone and joints in children.

Effective antibiotic therapy forms the mainstay of the treatment of acute bone and joint infections in children. The causal organisms and bacterial sensitivities encountered in a prospective study are presented. Initial antibiotic therapy is discussed, while the need for immediate Gram staining to identify resistant organisms is stressed.

The incidence of motorcycle accidents in South Africa--an alarming increase.

There has been a dramatic rise in the number of motorcycle accidents in South Africa. The need for prophylaxis is emphasized and the way in which the problem has been tackled in Japan (with striking results) is presented for serious consideration.