Unlocking the DOOR-how to design, apply, analyse, and interpret desirability of outcome ranking endpoints in infectious diseases clinical trials.

BACKGROUND: Desirability of outcome ranking (DOOR) outcomes, with or without response adjusted for antibiotic risk (RADAR), are increasingly used in infectious diseases randomized clinical trials (RCTs), with the advantage of being able to combine multiple clinical outcomes and antibiotic duration in a single metric. However, it remains poorly understood, and there is considerable heterogeneity in its use. OBJECTIVES: In this scoping review, we explain how to design, use and analyse a DOOR endpoint, and highlight several pitfalls and potential improvements that can be made to DOOR/RADAR. SOURCES: The Ovid MEDLINE database was searched for terms related to DOOR in English-language articles published up to 31 December 2022. Articles discussing DOOR methodology and/or reporting clinical trial analyses (as either primary, secondary, or post-hoc analysis) using a DOOR outcome were included. CONTENT: Seventeen articles were included in the final review, of which nine reported DOOR analyses of 12 RCTs. Eight articles discussed DOOR methodology. We synthesised information from these articles and discuss (a) how to develop a DOOR scale, (b) how to conduct a DOOR/RADAR analysis, (c) use in clinical trials, (d) use of alternative tiebreakers apart from RADAR, (e) partial credit analyses, and (f) criticisms and pitfalls of DOOR/RADAR. IMPLICATIONS: DOOR is an important innovation for RCTs in infectious diseases. We highlight potential areas of methodological improvement for future research. There remains considerable heterogeneity in its implementation, and further collaborative efforts, with a more diverse range of perspectives, should be made to develop consensus scales for use in prospective studies.

COVID-19 and sotrovimab: The Moree experience.

The pathways developed in Moree, NSW, illustrate the importance and impact of community ownership and leadership for effective delivery of a public health intervention.

A desirability of outcome ranking (DOOR) for periprosthetic joint infection - a Delphi analysis.

Background: Treatment outcomes in studies on prosthetic joint infection are generally assessed using a dichotomous outcome relating to treatment success or failure. These outcome measures neither include patient-centred outcome measures including joint function and quality of life, nor do they account for adverse effects of treatment. A desirability of outcome ranking (DOOR) measure can include these factors and has previously been proposed and validated for other serious infections. We aimed to develop a novel DOOR for prosthetic joint infections (PJIs). Methods: The Delphi method was used to develop a DOOR for PJI research. An international working group of 18 clinicians (orthopaedic surgeons and infectious disease specialists) completed the Delphi process. The final DOOR comprised the dimensions established to be most important by consensus with > 75  % of participant agreement. Results: The consensus DOOR comprised four main dimensions. The primary dimension was patient-reported joint function. The secondary dimensions were infection cure and mortality. The final dimension of quality of life was selected as a tie-breaker. Discussion: A desirability of outcome ranking for periprosthetic joint infection has been proposed. It focuses on patient-centric outcome measures of joint function, cure and quality of life. This DOOR provides a multidimensional assessment to comprehensively rank outcomes when comparing treatments for prosthetic joint infection.

Short- versus standard-course intravenous antibiotics for peri-prosthetic joint infections managed with debridement and implant retention: a randomised pilot trial using a desirability of outcome ranking (DOOR) endpoint.

BACKGROUND: Peri-prosthetic joint infection (PJI) is a devastating complication of joint replacement surgery. Determining the optimal duration of intravenous (IV) antibiotics for PJI managed with debridement and implant retention (DAIR) is a research priority. METHODS: Patients undergoing DAIR for early and late-acute PJI of the hip or knee were randomised to receive 2 (short-course) or 6 (standard-course) weeks of IV antibiotics, with both groups completing 12 weeks of antibiotics in total. The primary endpoint of this pilot, open-label, randomised trial was a 7-point ordinal desirability of outcome ranking (DOOR) score, which accounted for mortality, clinical cure and treatment adverse events at 12 months. Duration of IV treatment was used as a tiebreaker, with shorter courses ranked higher. Outcome adjudication was performed by expert clinicians blinded to the allocated intervention (Australia and New Zealand Clinical Trials Registry ACTRN12617000127303). RESULTS: 60 patients were recruited; 31 and 29 were allocated to short- and standard-course treatment, respectively. All had an evaluable outcome at 12 months and were analysed by intention-to-treat. Clinical cure was demonstrated in 44 (73%) overall; 22 (71%) in the short-course group and 22 (76%) in the standard-care group (P=0.77). Using the DOOR approach, the probability that short- was better than standard-course treatment was 59.7% (95% confidence interval 45.1-74.3). CONCLUSIONS: In selected patients with early and late-acute PJI managed with DAIR, shorter courses of IV antibiotics may be appropriate. Due to small sample size, these data accord with, but do not confirm, results from other international trials of early transition to oral antibiotics.

Predictors of Treatment Success After Periprosthetic Joint Infection: 24-Month Follow up From a Multicenter Prospective Observational Cohort Study of 653 Patients.

BACKGROUND: Periprosthetic joint infection (PJI) is a devastating condition and there is a lack of evidence to guide its management. We hypothesized that treatment success is independently associated with modifiable variables in surgical and antibiotic management. METHODS: The is a prospective, observational study at 27 hospitals across Australia and New Zealand. Newly diagnosed large joint PJIs were eligible. Data were collected at baseline and at 3, 12, and 24 months. The main outcome measures at 24 months were clinical cure (defined as all of the following: alive, absence of clinical or microbiological evidence of infection, and not requiring ongoing antibiotic therapy) and treatment success (clinical cure plus index prosthesis still in place). RESULTS: Twenty-four-month outcome data were available for 653 patients. Overall, 449 patients (69%) experienced clinical cure and 350 (54%) had treatment success. The most common treatment strategy was debridement and implant retention (DAIR), with success rates highest in early postimplant infections (119 of 160, 74%) and lower in late acute (132 of 267, 49%) and chronic (63 of 142, 44%) infections. Selected comorbidities, knee joint, and Staphylococcus aureus infections were independently associated with treatment failure, but antibiotic choice and duration (including rifampicin use) and extent of debridement were not. CONCLUSIONS: Treatment success in PJI is associated with (1) selecting the appropriate treatment strategy and (2) nonmodifiable patient and infection factors. Interdisciplinary decision making that matches an individual patient to an appropriate management strategy is a critical step for PJI management. Randomized controlled trials are needed to determine the role of rifampicin in patients managed with DAIR and the optimal surgical strategy for late-acute PJI.

Safety of prolonged outpatient courses of intravenous antibiotics: a prospective cohort study.

OBJECTIVES: The perceived need for prolonged intravenous antibiotic courses has become a major driver behind the growth of outpatient parenteral antimicrobial therapy (OPAT) services. Several recent randomized controlled trials demonstrate noninferiority of an early switch to oral therapy and highlight the need to accurately quantify harms associated with OPAT. METHODS: We conducted a 10-year prospective cohort study in a tertiary hospital OPAT service. Adults admitted to the service between 1 June 2009 and 30 June 2019 who received an intravenous antimicrobial agent were included. Adverse events (AEs) attributable to intravenous antibiotics or intravenous access were recorded in a prospectively maintained database and analyzed. RESULTS: There were 4160 admissions (median length of stay: 20 days) and a total of 88 432 patient-days of observation; 135 patients (3.3% of admissions) experienced at least one major AE (1.54 per 1000 patient-days; 95% CI, 1.29-1.82). The risk of a major AE peaked in the second week of OPAT admission, with acute kidney injury (43 of 136; 32%) and severe cytopenia (42 of 136; 31%) being the most common. At least one minor AE occurred in 38.3% of admissions (1592 of 4160; 26.4 per 1000 patient-days; 95% CI, 25.4-27.5), with central venous catheter-related complications accounting for 71% of AEs (1658 of 2338). DISCUSSION: The incidence of major AEs during long courses of intravenous antibiotics is low, peaking in week 2 and tailing off thereafter. These results should inform decisions concerning the choice of intravenous versus oral antimicrobials.

Concerns and psychological well-being of healthcare workers during the COVID-19 pandemic in a tertiary care hospital in New South Wales.

BACKGROUND: In early 2020, the impending COVID-19 pandemic placed a once-in-a-generation professional and personal challenge on healthcare workers. Publications on direct physical disease abound. The authors wanted to focus on doctors' psychological well-being. AIMS: To assess the impact of the COVID-19 pandemic on doctors' well-being and evaluate their concerns as the pandemic progressed. METHODS: A mixed-methods, hospital-based survey was sent to doctors at the 650-bed tertiary referral hospital in NSW at two different periods (late-March and early May 2020). A validated mental well-being tool (Short Warwick Edinburgh Mental Well-being Scale (SWEMWBS)) was combined with COVID-19-specific questions. RESULTS: Two hundred and thirty-five responses were obtained from 450 doctors, with a response rate of 32% in the first survey and 20% in the second. The majority (35%) of respondents were doctors-in-training, followed by staff-specialists (23%). The highest response was from frontline workers in both surveys, including the intensive care unit (27%), anaesthesia (21%) and emergency department (13%). 'Extreme concern' regarding personal protective equipment (PPE) shortage dropped from 22.6% to 2.2% and 'extreme concern' of contracting COVID-19 fell from 22.6% to 3.4% in the second survey. The proportion of respondents with a 'low' psychological well-being score improved from 38% to 27% between the two surveys. The resulting mean improvement in the SWEMWBS was 3.49 (95% confidence interval = 3.06-3.91, P < 0.001). CONCLUSION: Both COVID-19 specific concerns and psychological well-being improved greatly in the second survey. Possible explanations are the fall in COVID-19 cases in the district, improvements in PPE supply and supportive measures communicated to doctors during this period.

Open Debridement is Superior to Arthroscopic Debridement for the Infected Total Knee Arthroplasty.

BACKGROUND: Acutely infected total knee arthroplasty (TKA) is commonly treated with debridement, antibiotics, and implant retention (DAIR). There are no direct comparative studies to determine whether debridement should be performed open or arthroscopically for infected TKA. The aim of this study is to compare the outcomes of open vs arthroscopic debridement of infected TKAs. METHODS: All patients at a university teaching hospital with an infected TKA treated with DAIR between 2002 and 2017 were analyzed. The primary outcome was successful treatment defined using international consensus criteria. Secondary outcomes included antibiotic suppression, prosthesis retention, mortality, postoperative range of motion, and length of stay. Clinical, laboratory, surgical, and antibiotic treatment data were collected. Propensity score matching was performed to control for selection bias. RESULTS: DAIR was used in 141 patients. The initial DAIR procedure was open for 96 patients and arthroscopic for 45 patients. The success rate was 29% greater for open DAIR (45% open vs 16% arthroscopic; P < .001). After propensity score matching, this benefit was estimated to be 36% (95% confidence interval, 22%-50%; P < .0001). When those on antibiotic suppression were also considered successfully treated, open DAIR was still superior by 34% (95% confidence interval, 18%-51%; P < .0001). CONCLUSION: For infected TKA, open DAIR is a more successful index procedure compared with arthroscopic DAIR. Open DAIR remained more successful even when antibiotic suppression is considered successful treatment.

Clinical Characteristics, Etiology, and Initial Management Strategy of Newly Diagnosed Periprosthetic Joint Infection: A Multicenter, Prospective Observational Cohort Study of 783 Patients.

BACKGROUND: Periprosthetic joint infection (PJI) is a devastating complication of joint replacement surgery. Most observational studies of PJI are retrospective or single-center, and reported management approaches and outcomes vary widely. We hypothesized that there would be substantial heterogeneity in PJI management and that most PJIs would present as late acute infections occurring as a consequence of bloodstream infections. METHODS: The Prosthetic joint Infection in Australia and New Zealand, Observational (PIANO) study is a prospective study at 27 hospitals. From July 2014 through December 2017, we enrolled all adults with a newly diagnosed PJI of a large joint. We collected data on demographics, microbiology, and surgical and antibiotic management over the first 3 months postpresentation. RESULTS: We enrolled 783 patients (427 knee, 323 hip, 25 shoulder, 6 elbow, and 2 ankle). The mode of presentation was late acute (>30 days postimplantation and <7 days of symptoms; 351, 45%), followed by early (≤30 days postimplantation; 196, 25%) and chronic (>30 days postimplantation with ≥30 days of symptoms; 148, 19%). Debridement, antibiotics, irrigation, and implant retention constituted the commonest initial management approach (565, 72%), but debridement was moderate or less in 142 (25%) and the polyethylene liner was not exchanged in 104 (23%). CONCLUSIONS: In contrast to most studies, late acute infection was the most common mode of presentation, likely reflecting hematogenous seeding. Management was heterogeneous, reflecting the poor evidence base and the need for randomized controlled trials.

Vancomycin: Audit of American guideline-based intermittent dose administration with focus on overweight patients.

AIMS: Vancomycin dosing and monitoring recommendations are poorly adhered to in many institutions internationally, with concerns of treatment failure and propelling antibiotic resistance. The primary aim of this study was to audit the rate of adherence to American guidelines, with particular interest in loading dose administration. The secondary aims were (i) to determine whether or not guideline adherence results in therapeutic concentrations across body mass index (BMI) groups and (ii) to determine whether or not this was in turn associated with morbidity and hospital mortality. METHOD: Data were collected in a single tertiary hospital on all patients who had two or more serum vancomycin concentrations measured. RESULT: In total, 107 patients met the inclusion criteria. Overall, 38.3% of patients were commenced on guideline adherent vancomycin doses, and 28.3% of overweight patients received an adherent first dose compared to 51.1% of non-overweight people (difference 23%, 95% CI 4% to 41%, P = 0.024). Overweight patients were more frequently underdosed compared to non-overweight patients (P = 0.039). The frequency and proportion of underdosing increased with BMI. Overweight patients spent a smaller fraction of their course within the therapeutic range, although the difference was not statistically significant (difference 7.7%; 95% CI 4% to 19.4%; P = 0.195). The overweight group had longer hospital length of stay (LOS), higher mortality and more treatment failures. CONCLUSION: Adherence to guideline-based prescription is poor, particularly in overweight patients. Patients who are initially underdosed have fewer therapeutic vancomycin days, regardless of BMI. Overweight patients have increased hospital LOS, hospital mortality and treatment failure.

Outcomes of paediatric septic arthritis of the hip and knee at 1-20 years in an Australian urban centre.

BACKGROUND: Septic arthritis in children is a joint threatening condition with potentially severe consequences; however, long-term outcome data is lacking. This study aims to determine 1-20-year outcomes following septic arthritis of hip and knee joints in children in an Australian population. METHODS: All paediatric patients with septic arthritis of the hip or knee from 1995 to 2015 treated at our Australian institution were retrospectively assessed. Clinical features, treatment and investigation results were recorded. Long-term functional and radiological outcomes, infection recurrence and reoperation rate at final follow-up (mean 8.5 years, range 1.0-20.3; hip versus mean 7.7 years, range 1.1-20.3; knee) were recorded. RESULTS: Sixty-four patients (37 hip, 27 knee) met inclusion criteria. Fifty-two patients (81.3%) attended follow-up. No mortalities or late infection recurrence occurred. Three patients (1; hip versus 2; knee) had a later operation. Median Oxford scores were excellent (48; hip versus 48; knee); however, a significant proportion had a degree of impaired function (31.3%; hip versus 42.1%; knee). Radiological outcomes were excellent in knees more commonly than hips (81.3%; hip versus 100%; knee). CONCLUSIONS: Outcomes at 1-20 years for the majority of patients following septic arthritis of the hip and knee are excellent with early joint irrigation and intravenous antibiotics. Our results demonstrate a significant proportion of patients following septic hip arthritis have mild to moderately poor functional and radiological outcomes. Those with septic knee arthritis demonstrated universally excellent radiological outcomes and mild functional impairment in approximately one-third of cases.

Infective endocarditis: a Hunter New England perspective.

BACKGROUND: Infective endocarditis (IE) is a severe infection conferring significant morbidity and mortality. It is associated with geographical variation, complicating diagnosis and treatment of patients in a standardised manner. AIM: To evaluate the presentation, treatment and outcomes of patients with IE in the Hunter New England Local Health District (HNELHD). METHODS: A total of 112 patients with definite IE admitted to hospitals within the HNELHD between 2011 and 2015 was retrospectively analysed. RESULTS: The mean age of patients was 56.8 (standard deviation 20.3) and 62.5% were male. The most common valve affected was the mitral valve, in 41% of patients, and the most common organism was Staphylococcus aureus, in 47.7% of patients. A history of IE was present in 10% of patients and 19.6% presented with prosthetic valve IE. Survival among patients treated surgically was 100% at 30 days, 92% at 1 year and 83% at 3 years, versus 82% at 30 days, 65% at 1 year and 51% at 3 years for those not operated (P = 0.004). Valve type, organism and Australian Standard Geographical Classification remoteness area did not have a statistically significant effect on mortality (P-value 0.095, 0.456 and 0.186, respectively). Factors associated with improved survival by univariate analysis included surgery and multidisciplinary team review. CONCLUSION: IE in the HNELHD affects a relatively young cohort of patients and is associated with a high mortality. Outcomes could be improved by implementation of a multidisciplinary team approach and inpatient cardiac surgery.

Arthroscopic Versus Open Treatment for Acute Septic Arthritis of the Knee in Children.

BACKGROUND: Acute septic arthritis of the knee in children may be treated by arthroscopic or open methods; however, pediatric data comparing these methods is limited regarding both short- and long-term outcomes. This study aimed to compare outcomes after arthroscopic versus open surgery for acute pediatric septic knee arthritis. METHODS: Pediatric patients with acute knee septic arthritis treated at our institution from 1996 to 2016 were retrospectively assessed. The clinical presentations, operations, microorganisms, laboratory results, knee radiologic findings and antibiotics administered were compared. Patients' long-term outcomes were assessed at mean 6.9 (range 1.1-20.3) years. RESULTS: Twenty-four patients met the inclusion criteria. Eleven patients received arthroscopic irrigation and 13 had open irrigation. Five patients in the open group (38.5%) required a second irrigation compared with none in the arthroscopic group [95% confidence interval (CI): 12%-65%; P = 0.041]. Time to range the knee occurred earlier in the arthroscopic group (5.0 days; arthroscopic vs. 10.6 days; open, difference 5.6 days: 95% CI: 0.84-10.3, P = 0.023), as well as weight-bearing (2.7 days; arthroscopic vs. 10.3 days; open, difference 7.6 days: 95% CI: 2.3-12.9, P = 0.008). Eighty-three percent of patients attended follow-up. No infections recurred. No significant differences were found in Knee injury and Osteoarthritis Outcome Scores for children, Lysholm scores, range-of-motion, leg length, gait and radiologic findings. CONCLUSIONS: For acute pediatric septic knee arthritis, arthroscopic irrigation is associated with less repeat surgical irrigations and allows earlier knee ranging and weight-bearing compared with open irrigation. At long-term follow-up, no significant difference was found between groups.

Determining the Risk of Sepsis Using Nurse-Compounded Elastomeric Pumps for Continuous Infusion in Outpatient Parenteral Antibiotic Therapy.

Limited availability of compounded antibiotics used for continuous infusion outpatient parenteral antibiotic therapy (OPAT) can delay or interrupt an OPAT course. To solve this problem, OPAT nurses at a hospital in Australia have been compounding elastomeric pumps for immediate use. The incidence of sepsis in 5014 patients before and after the introduction of nurse compounding was compared. There were no cases of laboratory-confirmed bloodstream infection among the nurse-compounded group compared with 2 cases (0.045/1000 catheter days) among the control group without nurse compounding (P = .16). No compounding medication errors occurred in more than 180 patient years of follow-up among the nurse compounding group. Nurse compounding can be a safe and convenient alternative when immediate access to preloaded elastomeric pumps is required.

Open Compared with Arthroscopic Treatment of Acute Septic Arthritis of the Native Knee.

BACKGROUND: Acute native knee septic arthritis is a joint-threatening emergency. Operative treatments by open or arthroscopic methods are available to surgeons. To our knowledge, the literature to date has primarily consisted of case series and no large study has yet compared these methods. The aim of this study was to compare open and arthroscopic treatment for acute native knee septic arthritis. METHODS: All adult patients with acute native knee septic arthritis treated at our institution with either open or arthroscopic irrigation from 2000 to 2015 were retrospectively evaluated. The clinical findings, laboratory evidence, arthrocentesis and microbiology results, knee radiographs, and outcomes were compared. RESULTS: There were 161 patients (166 knees) with acute native knee septic arthritis treated between 2000 and 2015. Initially, 123 knees were treated by arthroscopic irrigation and 43 knees were treated by open irrigation; however, 71% in the open treatment group required repeat irrigation compared with 50% in the arthroscopic treatment group. The superiority of an arthroscopic procedure persisted after adjustment for potential confounders by multivariable analysis, with an odds ratio of 2.56 (95% confidence interval, 1.1 to 5.9; p = 0.027). After 3 irrigation procedures, the cumulative success rate was 97% in the arthroscopic treatment group and 83% in the open treatment group (p = 0.011). The total number of irrigation procedures required was fewer in the arthroscopic treatment group (p = 0.010). In the arthroscopic treatment group, the mean postoperative range of motion was greater (p = 0.016) and there was a trend toward a shorter median length of stay (p = 0.088). CONCLUSIONS: Arthroscopic treatment for acute native knee septic arthritis was a more successful index procedure and required fewer total irrigation procedures compared with open treatment. Long-term postoperative range of motion was significantly greater following arthroscopic treatment. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Chlorhexidine 2% and choice of transparent dressing increase skin reactions at central venous catheter insertion sites.

Infection at central venous catheter (CVC) sites remains a common problem, particularly with long-term use. This report discusses the influence of choice of transparent dressing type and chlorhexidine concentration on skin reactions at CVC insertion sites. A concentration of 2% chlorhexidine is associated with a higher rate of skin reactions than either 0.5% or 1% chlorhexidine. Higher chlorhexidine concentrations may not decrease the number of central line-associated bloodstream infections.

An outbreak of scrub typhus in military personnel despite protocols for antibiotic prophylaxis: doxycycline resistance excluded by a quantitative PCR-based susceptibility assay.

Scrub typhus is caused by the obligate intracellular bacterium Orientia tsutsugamushi and is endemic to many countries in the Asia-Pacific region, including tropical Australia. We describe a recent large outbreak amongst military personnel in north Queensland. A total of 45 clinical cases were identified (36% of all potentially exposed individuals). This occurred despite existing military protocols stipulating the provision of doxycycline prophylaxis. Doxycycline resistance in O. tsutsugamushi has been described in South-East Asia, but not Australia. In one case, O. tsutsugamushi was cultured from eschar tissue and blood. Using quantitative real-time PCR to determine susceptibility to doxycycline for the outbreak strain, a minimum inhibitory concentration (MIC) of ≤0.04 µg/mL was found, indicating susceptibility to this agent. It seems most probable that failure to adhere to adequate prophylaxis over the duration of the military exercise accounted for the large number of cases encountered rather than doxycycline resistance.

Serum sickness-like reaction after influenza vaccination.

Serum sickness (SS) and SS-like reaction (SSLR) are rare immune complex-mediated hypersensitivity illnesses characterised by key features of fever, rash, polyarthralgia or polyarthritis. They are self-limiting with an excellent prognosis, settling as the antigen is cleared. We describe a 30-year-old man who presented with fever, rash, polyarthralgia and subcutaneous soft tissue swelling in his hands and feet at day 5 after influenza vaccination. A thorough investigation for infective and autoimmune causes for the presenting symptoms was negative. Given the temporal relationship between the symptoms and influenza vaccination, clinical evidence and biological plausibility of influenza vaccination causing SSLR, a clinical diagnosis of SSLR was made. The patient was treated with anti-histamines, non-steroidal anti-inflammatories and glucocorticoids with gradual resolution of symptoms over 5 weeks.