Oral versus Intravenous Antibiotics for Bone and Joint Infection.

BACKGROUND: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).

Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomised controlled trial.

BACKGROUND: Bone and joint infection in adults arises most commonly as a complication of joint replacement surgery, fracture fixation and diabetic foot infection. The associated morbidity can be devastating to patients and costs the National Health Service an estimated £20,000 to £40,000 per patient. Current standard of care in most UK centres includes a prolonged course (4-6 weeks) of intravenous antibiotics supported, if available, by an outpatient parenteral antibiotic therapy service. Intravenous therapy carries with it substantial risks and inconvenience to patients, and the antibiotic-related costs are approximately ten times that of oral therapy. Despite this, there is no evidence to suggest that oral therapy results in inferior outcomes. We hypothesise that, by selecting oral agents with high bioavailability, good tissue penetration and activity against the known or likely pathogens, key outcomes in patients managed primarily with oral therapy are non-inferior to those in patients treated by intravenous therapy. METHODS: The OVIVA trial is a parallel group, randomised (1:1), un-blinded, non-inferiority trial conducted in thirty hospitals across the UK. Eligible participants are adults (>18 years) with a clinical syndrome consistent with a bone, joint or metalware-associated infection who have received ≤7 days of intravenous antibiotic therapy from the date of definitive surgery (or the start of planned curative therapy in patients treated without surgical intervention). Participants are randomised to receive either oral or intravenous antibiotics, selected by a specialist infection physician, for the first 6 weeks of therapy. The primary outcome measure is definite treatment failure within one year of randomisation, as assessed by a blinded endpoint committee, according to pre-defined microbiological, histological and clinical criteria. Enrolling 1,050 subjects will provide 90 % power to demonstrate non-inferiority, defined as less than 7.5 % absolute increase in treatment failure rate in patients randomised to oral therapy as compared to intravenous therapy (one-sided alpha of 0.05). DISCUSSION: If our results demonstrate non-inferiority of orally administered antibiotic therapy, this trial is likely to facilitate a dramatically improved patient experience and alleviate a substantial financial burden on healthcare services. TRIAL REGISTRATION: ISRCTN91566927 - 14/02/2013.

Radiological features do not predict failure of two-stage arthroplasty for prosthetic joint infection: a retrospective case-control study.

BACKGROUND: The management of prosthetic joint infection is complex and there is a lack of standardisation of approaches. We evaluated the role of plain film radiography in predicting prosthesis failure after the first stage of a two-stage revision procedure in a retrospective case-control study. METHODS: Plain films for 41 patients aged 46 to 87 years (mean 69) were assessed by two musculoskeletal specialist radiologists for seven features (retained or new metalwork, retained cement or restrictor, new fracture, local antimicrobial delivery system and drain) we hypothesised may predict for failure. Inter-observer agreement was assessed by Kappa score and logistic regression analysis was performed to evaluate the relationship of the seven radiological features adjusting for patient age, gender and number of previous revisions. RESULTS: There was substantial inter-observer agreement, with a Kappa score of 0.73 (95% CI 0.72-0.74) for all data points collected. Concordance was 100% for evaluating the presence or absence of an antimicrobial delivery system or drain, with lower consensus for evaluating cement (Kappa 0.60, 95% CI 0.35-0.84) and fractures (Kappa 0.59, 95% CI 0.31-0.87). None of the variables' conditions significantly predicted failure. CONCLUSIONS: Our findings support the opinion that surgical expertise which maximizes removal of foreign material is sufficient in conjunction with antibiotic therapy.

Electronic prescribing: Reducing delay to first dose of antibiotics for patients in intensive care.

Delays in antibiotic therapy in the context of severe sepsis are associated with increased mortality. One way to reduce such delays may be through modifications to electronic prescribing (EP) systems. The research team evaluated the role of one such EP system in reducing delays in antibiotic administration in an Intensive Care Unit (ICU). First, the delays in antibiotic administration in adult ICU patients was quantified. The EP system was then modified to remove deafult time settings for antibiotic doses, which ensured that all antibiotic doses were scheduled for administration within an hour of the prescription being generated. Enhanced training for clinicians and nurses was also implemented, focusing on the EP system and highlighting the importance of prompt antimicrobial prescribing and delivery to the patient. The antibiotic administration was re-audited, and a significant reduction in delays (p=0.002, Mann-Whitney U test) was found. This study demonstrates how prudent use of EP systems can help to reduce delays in antibiotic administration in an ICU setting, thus potentially contributing to reducing mortality in patients with sepsis.

Randomized controlled trial of the safety and efficacy of Daptomycin versus standard-of-care therapy for management of patients with osteomyelitis associated with prosthetic devices undergoing two-stage revision arthroplasty.

The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2- to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients.

Serial measurement of the C-reactive protein is a poor predictor of treatment outcome in prosthetic joint infection.

OBJECTIVES: Prosthetic joint infection is usually treated using surgery and antibiotics. The response to the treatment regimen is often evaluated using serial monitoring of plasma C-reactive protein (CRP) concentrations. In order to examine how useful this monitoring is, we calculated the sensitivity and specificity of CRP concentrations for predicting treatment failure. PATIENTS AND METHODS: We examined 3732 CRP measurements from 260 patients who were treated by either two-stage revision or debridement and retention. We tested the association between CRP concentration and outcome using logistic regression models, and assessed sensitivity and specificity by using receiver operator curves. RESULTS: The areas under receiver operator curves for CRP concentrations predicting outcome ranged from 0.55 to 0.65. CONCLUSIONS: CRP concentrations did not accurately predict treatment failure. Serial monitoring may not be of benefit.

Treatment of bacterial prostatitis.

Prostatitis is characterized by voiding symptoms and genitourinary pain and is sometimes associated with sexual dysfunction. Up to 25% of men receive a diagnosis of prostatitis in their lifetime, but <10% have a proven bacterial infection. The causes and treatment of nonbacterial prostatitis are largely unknown, but bacterial prostatitis is caused by infection with uropathogens, especially gram-negative bacilli, although infection is sometimes due to gram-positive and atypical microorganisms. Acute bacterial prostatitis is easily diagnosed (by abrupt urogential and often systemic symptoms, along with bacteriuria) and treated (by systemic antibiotic therapy). Chronic bacterial prostatitis is characterized by prolonged or recurrent symptoms and relapsing bacteriuria; diagnosis traditionally requires comparing urinary specimens obtained before with specimens obtained after prostatic massage. Treating chronic bacterial prostatitis requires prolonged therapy with an antibiotic that penetrates the prostate (ie, one with high lipid solubility, a low degree of ionization, high dissociation constant, low protein binding, and small molecular size). We review recent pharmacological and clinical data on treating bacterial prostatitis.

Central or atypical skull base osteomyelitis: diagnosis and treatment.

OBJECTIVE: We report cases of central or atypical skull base osteomyelitis and review issues related to the diagnosis and treatment. METHODS: The four cases presented, which were drawn from the Oxford, United Kingdom, skull base pathology database, had a diagnosis of central skull base osteomyelitis. RESULTS: Four cases are presented in which central skull base osteomyelitis was diagnosed. Contrary to malignant otitis externa, our cases were not preceded by immediate external infections and had normal external ear examinations. They presented with headache and a variety of cranial neuropathies. Imaging demonstrated bone destruction, and subsequent microbiological analysis diagnosed infection and prompted prolonged antibiotic treatment. CONCLUSION: We concluded that in the diabetic or immunocompromised patient, a scenario of headache, cranial neuropathy, and bony destruction on imaging should raise the possibility of skull base osteomyelitis, even in the absence of an obvious infective source. The primary goal should still be to exclude an underlying malignant cause.

Native hip joint septic arthritis in 20 adults: delayed presentation beyond three weeks predicts need for excision arthroplasty.

OBJECTIVES: Septic arthritis of native hip joints is an uncommon condition in adults in Western Europe, but continues to present a challenge to medical and surgical management. We set out to study the natural history and bacteriology of the disease in this group, with a particular focus on patients requiring excision arthroplasty (EA). METHODS: We retrospectively studied 26 secondary referral cases (20 adults) managed by a specialist bone infection unit over a 12 year period. RESULTS: Our patient cohort was diverse, affecting all age groups in the presence and absence of co-morbid conditions. The commonest pathogen was Staphylococcus aureus. Of 20 adults studied, five (25%) required EA. Symptom duration prior to presentation was a statistical predictor of the requirement for EA (p<0.003); in particular, symptom duration of over three weeks was strongly associated with requirement for this procedure (p<0.0003). CONCLUSIONS: In cases that present promptly, combined surgical drainage and intravenous antibiotics should be expected to eradicate infection and to salvage the femoral head. Cases presenting following a delay are more likely to require EA and subsequent hip reconstruction.

Teicoplanin levels in bone and joint infections: are standard doses subtherapeutic?

OBJECTIVES: Previously published data suggest that a trough serum teicoplanin level of > or = 20 mg/l is predictive of improved outcomes in serious staphylococcal infection. We investigated how dose regimen and patient characteristics impact on trough teicoplanin levels in patients with musculoskeletal infection, in order to help standardise teicoplanin use. METHODS: We prospectively collected data for 141 clinically stable adults with bone and joint infection treated as outpatients with teicoplanin. Patients with end stage renal failure were excluded. RESULTS: The most frequently used teicoplanin dose regimens were 400 mg or 600 mg i.v. once daily. Trough levels were available for 78% of episodes, of which 51% were > or = 20 mg/l. Unsurprisingly, a level of > or = 20 mg/l occurred more often with a dose of 600 mg than with lower doses (p=0.005). There was no significant relationship between teicoplanin level and age, body weight or creatinine clearance, but male gender was associated with lower trough levels than female gender (p=0.03). CONCLUSIONS: These data suggest that teicoplanin levels of > or = 20 mg/l for bone and joint infection in stable adult patients are best achieved with a daily dose of at least 600 mg.

Outpatient parenteral antimicrobial therapy (OPAT): is it safe for selected patients to self-administer at home? A retrospective analysis of a large cohort over 13 years.

OBJECTIVES: Provision of outpatient parenteral antimicrobial therapy (OPAT) is an evolving field, facilitating discharge from hospital for selected patients with serious infections. We report on a large OPAT cohort focusing on the practice of supervised parenteral antibiotic administration in the community by patients and relatives, which we collectively term 'self-administration'. To distinguish between healthcare professional OPAT and self-administered OPAT, we have coined the terms H-OPAT and S-OPAT, respectively. PATIENTS AND METHODS: We analysed data on 2059 OPAT episodes collected prospectively over a 13 year time period from 1993 to 2005. RESULTS: Clinical diagnosis, microbiology and antibiotics in this OPAT series are comparable to those previously reported. We identified no excess complications or hospital re-admissions in the S-OPAT group compared with the H-OPAT group. CONCLUSIONS: Self-administration of intravenous antimicrobial therapy, in selected patients under the supervision of a specialist team, is a safe and feasible strategy.

Tumid lupus erythematosus occurring following highly active antiretroviral therapy for HIV infection: a manifestation of immune restoration.

Tumid lupus erythematosus (LE) is a relatively rare and only recently recognized subset of chronic cutaneous lupus. We report a case occurring in a male with HIV infection whereby his rash was only unmasked by immune restoration following highly active antiretroviral therapy (HAART). The phenomenon of latent inflammatory or autoimmune disease appearing following HAART is now recognized as the "immune restoration syndrome" and tumid LE has not been reported in this setting previously. Fortunately this variant of lupus does not result in scarring and is responsive to anti-malarials, allowing continuation of HAART in this patient.