BACKGROUND:There is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children. OBJECTIVE:To assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA. DESIGN:(1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families' views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting. SETTING:Forty-four UK secondary and tertiary UK centres (service evaluation). PARTICIPANTS:Children with OM/SA. INTERVENTIONS:PCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study. RESULTS:Data were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcomes: rehospitalisation or recurrence of symptoms while on oral antibiotics, recurrence of infection, disability at follow-up, symptom free at 1 year, limb shortening or deformity, chronic OM or arthritis, amputation or fasciotomy, death, need for paediatric intensive care, and line infection. Oral switch criteria were identified, including resolution of fever for ≥ 48 hours, tolerating oral food and medicines, and pain improvement. LIMITATIONS:Data were collected in a 6-month period, which might not have been representative, and follow-up data for long-term complications are limited. CONCLUSIONS:A future RCT would need to recruit from all tertiary and most secondary UK hospitals. Clinicians have implemented early oral switch for selected patients with simple disease without formal clinical trial evidence of safety. However, the current criteria by which decisions to make the oral switch are made are not clearly established or evidence based. FUTURE WORK:A RCT in simple OM and SA comparing shorter- or longer-course i.v. therapy is feasible in children randomised after oral switch criteria are met after 7 days of i.v. therapy, excluding children meeting oral switch criteria in the first week of i.v. therapy. This study design meets clinician preferences and addresses parental concerns not to randomise prior to oral switch criteria being met. FUNDING:The National Institute for Health Research Health Technology Assessment programme.

Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa bioffim infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of bioffims have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases.

Background. Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point.Methods. Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data.Results. FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine-or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR.Conclusions. FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates.

Background. The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01(B)) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector.Method.aEuro integral Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01(B) (group 1; n = 20) or 3 doses of RTS,S/AS01(B) alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls.Results.aEuro integral No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected.Conclusions.aEuro integral The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.Clinical Trials Registration.aEuro integral NCT01883609.

Chapter 14 Osteomyelitis in Children Priya Sukhtankar, Priya SukhtankarSearch for more papers by this authorSaul N. Faust, Saul N. FaustSearch for more papers by this authorNicholas M.P. Clarke, Nicholas M.P. ClarkeSearch for more papers by this author Priya Sukhtankar, Priya SukhtankarSearch for more papers by this authorSaul N. Faust, Saul N. FaustSearch for more papers by this authorNicholas M.P. Clarke, Nicholas M.P. ClarkeSearch for more papers by this author Book Editor(s):Werner Zimmerli, Werner ZimmerliSearch for more papers by this author First published: 22 January 2015 https://doi.org/10.1002/9781118581742.ch14 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onFacebookTwitterLinked InRedditWechat Summary Osteomyelitis (OM) and septic arthritis are relatively uncommon infections in infants and children. This chapter discusses the pathophysiology of infection, pathogens implicated, diagnosis, and medical and surgical treatment options. Diagnosis and treatment depend on the age of the child, comorbidities, and causative organism. The infectious epidemiology of osteoarticular infection is changing in an era of resistant organisms, as well as congenital and acquired immunodeficiency. Improvements in microbiological diagnosis now mean that more organisms are identified. In all children with osteoarticular infection, the treatment is multidisciplinary and should include input from pediatric, orthopedic, radiology, and microbiology departments. Where the spine is involved or there is significant disability, orthotics and physiotherapy may also be required. Surgical management of OM is infrequently needed. If a collection in the periosteum, soft tissue, or a cyst is visible in an imaging procedure, surgery may be indicated for diagnostic (identification of a microorganism) and therapeutic purposes. Bone and Joint Infections: From Microbiology to Diagnostics and Treatment RelatedInformation

ABSTRACT Results from 3,263 QuantiFERON-TB Gold in-tube (QFT-GIT) assays were analyzed to determine the impact of age on test performance. The proportion of indeterminate results was significantly higher in pediatric and elderly (9.1% and 7.4%, respectively) than in adult (2.6%; chi-square test, P < 0.0001) patients. A detailed analysis of indeterminate QFT-GIT assay results is presented.

Bone and joint infections in children are uncommon, but they affect all ages and there is a wide range of disease. The mode of infection may be haematogenous or by direct inoculation from a wound. The child may present acutely unwell or with a chronic infection. Clinical features include fever, reluctance to move the affected limb, pain, and swelling. Laboratory tests and medical imaging are used to confirm diagnosis. Medical treatment is with initial intravenous antibiotic therapy, usually followed by oral treatment. Surgical treatment may be necessary if abscess or joint collection is present. In general prognosis is good with timely initiation of treatment, although complications such as pathological fracture are occasionally seen.

A 17-YEAR-OLD BOY PRESENTED TO OUR HOSpital with a 4-week history of pain and restriction of movement in his left shoulder. Two weeks prior to presentation, he had developed a skin lesion on the anterior aspect of the same shoulder. At that point, radiographs of the shoulder (Figure 1) and chest (Figure 2) were obtained. It was assumed that he had a superficial skin infection, which prompted treatment with amoxicillin–clavulanate potassium without improvement. The patient had been born in Nepal, where he had lived until 2 years prior when he had migrated to the United Kingdom with his family. He had persistent back pain for the last 3 years as well as intermittent pyrexia for the last 4 weeks. There was no history of recent travel or exposure to farm animals. On physical examination, a round ulcer (1.0 cm in diameter) with purulent discharge but without surrounding erythema was found on his left shoulder and he had marked kyphoscoliosis; no further abnormal findings were noted. However, magnetic resonance imaging of his spine revealed further significant pathology (Figure 3).

Dominant polycystic kidney disease is common and usually presents clinically in adulthood. Recessive polycystic kidney disease is much less common and frequently presents antenatally or in the neonatal period with severe renal involvement. These are usually thought of as clinically distinct entities but diagnostic confusion is not infrequent.