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The chemokine polymorphisms CXCR6-3EK, In1.1TC, H7 haplotype, CX3CR1-V249I, and CX3CR1-T280M have been shown to affect the course of HIV infection. We studied their influence on immunologic and virologic response to HAART in a group of 143 HIV-1 patients. We performed Kaplan–Meier analysis using the following end-point criteria (1) time from HAART initiation to undetectable viral load (VL < 50 copiesml), (2) maximum duration of viral suppression, (3) time from HAART administration until CD4 elevation above 200 cellsμl for patients with baseline CD4 below 200 cellsμl and above 500 cellsμl for patients with baseline CD4 between 200 and 500 cellsμl, respectively, and (4) time from HAART initiation until CD4 reduction below baseline values. Our results revealed an improved immunologic response to HAART in patients with the CX3CR1-249I or CX3CR1-280M allele. On the contrary, patients with initial VL suppression due to HAART showed a faster virologic failure in the presence of the CXCR6-3K allele. The In1.1TC polymorphism and H7 haplotype did not reveal any specific effect on HAART response. [ABSTRACT FROM AUTHOR]

This phase 1, open-label, dose-escalation, multi-center study (NCT05477186) assessed the safety and immunogenicity of a booster dose of an mRNA COVID-19 vaccine (CV0501) encoding the SARS-CoV-2 Omicron BA.1 spike protein. Participants aged ≥ 18 years previously vaccinated with ≥ 2 doses of an mRNA COVID-19 vaccine received CV0501 doses ranging from 12 to 200 μg. After assessment of safety and immunogenicity of the 12 μg dose in 30 adults, 30 adults ≤ 64 years were randomized to receive either a 3 or 6 μg dose. Solicited adverse events (AEs) were collected for 7 days, unsolicited AEs for 28 days, and serious AEs (SAEs), medically attended AEs (MAAEs), and AEs of special interest (AESIs) until day (D) 181 post-vaccination. Serum neutralizing titers specific to SARS-CoV-2 BA.1, wild-type, Delta, and additional Omicron subvariants were assessed at D1, D15, D29, D91, and D181. Of 180 vaccinated participants (mean age: 49.3 years; 57.8% women), 70.6% had prior SARS-CoV-2 infection. Most solicited local (98.1%) and systemic (96.7%) AEs were of mild-to-moderate severity; the most common were injection site pain (57.5%; 33.3-73.3% across groups) and myalgia (36.9%; 13.3-56.7%). Unsolicited AEs were reported by 14.4% (6.7-26.7%) of participants (mild-to-moderate severity in 88.5% of the participants). Three participants (1.7%) reported SAEs, 16.7% (6.7-30.0%) reported MAAEs, and 8.3% (0.0-13.3%) reported AESIs (15 COVID-19 cases), none related to vaccination. Geometric means of serum neutralizing titers increased from baseline to D15 and D29 (dose-dependent), and then decreased over time. The safety and immunogenicity results supported advancement to a phase 2 trial.

Background: Bloodstream infections are associated with substantial morbidity and mortality. Early, appropriate antibiotic therapy is important, but the duration of treatment is uncertain., Methods: In a multicenter, noninferiority trial, we randomly assigned hospitalized patients (including patients in the intensive care unit [ICU]) who had bloodstream infection to receive antibiotic treatment for 7 days or 14 days. Antibiotic selection, dosing, and route were at the discretion of the treating team. We excluded patients with severe immunosuppression, foci requiring prolonged treatment, single cultures with possible contaminants, or cultures yielding Staphylococcus aureus . The primary outcome was death from any cause by 90 days after diagnosis of the bloodstream infection, with a noninferiority margin of 4 percentage points., Results: Across 74 hospitals in seven countries, 3608 patients underwent randomization and were included in the intention-to-treat analysis; 1814 patients were assigned to 7 days of antibiotic treatment, and 1794 to 14 days. At enrollment, 55.0% of patients were in the ICU and 45.0% were on hospital wards. Infections were acquired in the community (75.4%), hospital wards (13.4%) and ICUs (11.2%). Bacteremia most commonly originated from the urinary tract (42.2%), abdomen (18.8%), lung (13.0%), vascular catheters (6.3%), and skin or soft tissue (5.2%). By 90 days, 261 patients (14.5%) receiving antibiotics for 7 days had died and 286 patients (16.1%) receiving antibiotics for 14 days had died (difference, -1.6 percentage points [95.7% confidence interval {CI}, -4.0 to 0.8]), which showed the noninferiority of the shorter treatment duration. Patients were treated for longer than the assigned duration in 23.1% of the patients in the 7-day group and in 10.7% of the patients in the 14-day group. A per-protocol analysis also showed noninferiority (difference, -2.0 percentage points [95% CI, -4.5 to 0.6]). These findings were generally consistent across secondary clinical outcomes and across prespecified subgroups defined according to patient, pathogen, and syndrome characteristics., Conclusions: Among hospitalized patients with bloodstream infection, antibiotic treatment for 7 days was noninferior to treatment for 14 days. (Funded by the Canadian Institutes of Health Research and others; BALANCE ClinicalTrials.gov number, NCT03005145.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Urinary tract infections (UTIs) are common however the widespread use of antibiotics has led to a rise in antimicrobial resistance (AMR) amongst uropathogens, rendering a significant proportion of infections resistant to first line treatment. AMR in UTIs may differentially affect men and women, younger and older patients. The purpose of this study was to investigate MDR (multi-drug resistance) and AMR in males and females in an Australian health district., Methods: There were 85,844 E. coli urinary isolates (2007-2020) analysed from adult patients. An E. coli isolate with MDR was defined as resistant to at least 1 agent in ≥ 3 antimicrobial classes. Chi-square tests and relative risk were calculated by comparing resistance in males and females and by age for antibiotics commonly used to treat UTIs in hospital and community collected samples., Results: There was a higher proportion of MDR E. coli in males compared to females in both the community (6.4% vs. 5.2%, P < 0.001) and hospital datasets (16.5% vs. 12.8%, P < 0.001). The proportions of MDR for both males and females were significantly higher in the hospital setting. Resistance rates were higher in males compared to females for amoxicillin, amoxicillin/clavulanate, cephalexin and norfloxacin (p < 0.005), though not for trimethoprim. Antibiotic resistance was seen to increase over time., Conclusions: A higher proportion of MDR E. coli were noted in urine samples from males compared with females, possibly due to the increased likelihood of prior treatment for UTIs in men. Antimicrobial stewardship interventions could be targeted towards this cohort to address increasing rates of AMR., Competing Interests: Declarations Ethical approval Ethics approval was obtained through the ISLHD UOW Joint Human Research Ethics Committee (2019/ETH03729). As individual patients were not identified, the need for individual informed consent was waived by the same ethics committee. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Efforts to monitor and combat antimicrobial resistance (AMR) are typically focused on the hospital-based laboratory setting. The aim of this study was to longitudinally examine and compare trends in AMR among urine Escherichia coli isolates from a private community-based laboratory and a public hospital-based laboratory in an Australian local health district., Methods: A total of 108 262 urine E. coli isolates from a public hospital-based laboratory (N = 34 103) and a private community-based laboratory (N = 74 159) in a single health district between 2007-2019 were analysed. Linear regression was used to identify significance of change in AMR rates in both laboratories independently and detect any significant interaction of each setting in proportional change over the study period., Results: Similar AMR trends were detected among urinary E. coli isolates in private community-based laboratory and public hospital-based laboratory settings over 12 y. AMR rates were consistently higher in the public hospital-based setting. Ampicillin was the only antibiotic for which the E. coli resistance trend did not significantly change over the time period in either laboratory setting. All other antibiotics showed a significant increase in AMR rates over time in both settings., Conclusions: AMR rates in both the private community-based laboratory and public hospital-based laboratory settings increased over time and were consistently higher in the public hospital-based laboratory setting. Since private laboratories handle the vast majority of pathology volumes in community outpatient settings in Australia, interventions incorporating the community-based laboratory setting are critical to addressing AMR in the community., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Introduction: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial., Methods: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations., Results: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum β-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%)., Conclusions: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The Northern Sydney Local Health District was one of the first health regions to be affected by COVID-19 in Australia., Aims: To describe the clinical characteristics, risk factors and outcomes in our low-prevalence Australian population., Methods: This is a retrospective analysis of 517 laboratory-confirmed COVID-19 cases between January and June 2020. Patient information was collected as part of routine care within the COVID-19 Virtual Hospital system. Outcomes examined were death, recovery at 30 days and intensive care unit (ICU) admission., Results: The case fatality rate was 1.8%. Multivariate analysis showed factors independently associated with death, composite outcome of death/ICU admission or incomplete recovery at 30 days were age >80 years and presence of two or more comorbidities. Most cases acquired COVID-19 through international (50.9%) or cruise ship travel (9.1%). Healthcare workers comprised 12.8% of the cohort and represented a disproportionately high percentage of the 'unknown' source group (27.6%). The median incubation period was 5 days (interquartile range 3-8); one patient had an incubation period of 15 days. Hospitalisation was required in 11.8%, ICU admission in 2.1% and ventilation in 1.4%. A Radiographic Assessment of Lung Oedema score on chest X-ray of >10 was independently associated with death., Conclusions: In this low prevalence, well resourced Australian setting, we report an overall low mortality. Factors associated with adverse patient outcomes on multivariate analysis were age greater than 80 and the presence of two or more comorbidities. These data can assist in early risk stratification of COVID-19 patients, and in surge capacity planning for hospitals., (© 2021 Royal Australasian College of Physicians.)

Background: Carbapenemase-producing Enterobacterales (CPE) are increasingly seen in Australian hospitals. Antimicrobial stewardship (AMS) interventions have been shown to reduce rates of carbapenem-resistant organisms; data on their effect on CPE rates are limited., Objectives: To explore the effect of a multi-site computer-supported AMS programme on the rates of CPE in an Australian local health district., Methods: All laboratory CPE isolates between 2008 and 2018 were identified. Microbiological and demographic data, CPE risk factors and outcomes were collected. Monthly carbapenem use was expressed as DDD per 1000 occupied bed days (OBD). Hand hygiene compliance rates among healthcare workers were analysed. A computer-supported AMS programme was implemented district-wide in 2012. Bivariate relationships were examined using Pearson's r and predictors of CPE isolates using time series linear regression., Results: We identified 120 isolates from 110 patients. Numbers of CPE isolates and carbapenem use both showed a strong downward trend during the study period; the decreases were strongly correlated ( r =  0.80, P =  0.006). The positive relationship between carbapenem use and CPE isolation was maintained while adjusting for time ( b =  0.05, P <  0.001). Average yearly consumption of carbapenems fell by 20%, from 18.4 to 14.7 DDD/1000 OBD following implementation of the AMS programme. Hand hygiene compliance rates remained high throughout., Conclusions: We demonstrated a reduction of CPE isolates in conjunction with reduced carbapenem use, longitudinally consolidated by a formal AMS programme. Prospective studies are needed to validate the effect of AMS on carbapenem resistance, especially in high-prevalence settings., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: Sepsis following transrectal ultrasound (TRUS)-guided prostate biopsy is a major complication. With the emergence of multidrug-resistant organisms, empirical use of carbapenem antibiotics has been increasing. This study, conducted in the Illawarra Shoalhaven Local Health District (ISLHD), Australia, quantifies how much we can spare carbapenem use., Methods: A retrospective audit of patients who underwent TRUS prostate biopsy and were admitted post-operatively with proven bacteraemia between January 2007 and April 2016., Results: Of 2719 TRUS procedures, 50 (1.84%) cases had bacteraemia. The most common isolate was Escherichia coli in 44 of 50 (88%) of which six of 50 (12%) were extended-spectrum beta-lactamase (ESBL)-producing. Sixteen different empirical antimicrobial regimens were used, to which 42 of 50 (84%) of isolates were susceptible. Eight (16%) isolates were resistant to the chosen empiric combination, with five switched over to appropriate treatment once antimicrobial sensitivity results became available. Empirical carbapenem was utilized in 12 of 50 (24%) patients with only two of the ESBL isolates covered. A further 10 of 50 patients received carbapenems during their admission. Carbapenems could have been avoided in 18 of 22 (82%). A total of 86% of organisms (n = 43) were susceptible to the combination of amoxicillin-clavulanate and gentamicin., Conclusion: Although the rates of bacteraemia with ESBL-producing organisms post-TRUS biopsy are increasing, use of carbapenem-free combination antimicrobials as empirical therapy appears to be safe and effective in our setting. Clinicians can utilize local resistance patterns to inform targeted and appropriate therapy for septic patients., (© 2019 Royal Australasian College of Surgeons.)

Background: Q fever is an infection caused by Coxiella burnetii, a zoonotic disease acquired from both wild and domestic animals. Northern rural New South Wales (NSW) communities in Australia have an increased risk of exposure to this organism. Both the acute and chronic phases of the infection are associated with significant morbidity, which is often increased by delayed recognition and treatment. Recent termination of vaccination programs in Australia may increase the risk of infection in these populations., Materials and Methods: This cross-sectional study evaluated the current knowledge base and overall understanding of clinicians on the epidemiology, presentation, and diagnosis of Q fever in the Northern New South Wales Local Health District., Results: Forty-five participants responded to the survey. Among those, 35 participants (78%) were hospital based and 10 (22%) were from doctors working in the community. Thirty-one (72%) clinicians answered bacteria as the cause of Q fever, 34 (79.1%) participants selected animals as the reservoir of Q fever infection, and 22 (51%) identified inhalation as the form of transmission. The majority identified livestock rearing occupations (84%) as a high-risk group; however, only 65-70% identified stock yard and meat workers as groups also at risk. Furthermore, 23 (51%) of the participants considered those living in rural and remote communities as high risk., Conclusions: Our results identified gaps in knowledge of clinicians in the epidemiology and diagnosis of acute Q fever infection. With the termination of vaccination programs, this study highlights the need for education programs that can increase Q fever awareness toward prompt identification and treatment.

Importance: Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum β-lactamase producers., Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae., Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study., Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician., Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used., Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group., Conclusions and Relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting., Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Background: Diabetic foot infections (DFI) present a major morbidity, mortality and economic challenge for the tertiary health sector. However, lack of high quality evidence for specific treatment regimens for patients with DFIs may result in inconsistent management. This study aimed to identify DFI caseload proportion and patterns of clinical practice of Infectious Diseases (ID) Physicians and Trainees within Australia and New Zealand., Methods: A cross-sectional online survey of Australian and New Zealand ID Physicians and Trainees was undertaken, to estimate the overall ID caseload devoted to patients with DFIs and assess clinicians' management practices of patients with DFIs., Results: Approximately 28% (142/499) of ID Physicians and Trainees from Australia and New Zealand responded to the survey. DFI made up 19.2% of all ID consultations. Involvement in multidisciplinary teams (MDT) was common as 77.5% (93/120) of those responding indicated their patients had access to an inpatient or outpatient MDT. Significant heterogeneity of antimicrobial treatments was reported, with 82 unique treatment regimens used by 102 respondents in one scenario and 76 unique treatment regimens used by 101 respondents in the second scenario. The duration of therapy and the choice of antibiotics for microorganisms isolated from superficial swabs also varied widely., Conclusions: Patients with DFIs represent a significant proportion of an ID clinician's caseload. This should be reflected in the ID training program. Large heterogeneity in practice between clinicians reflects a lack of evidence from well-designed clinical trials for patients with DFI and highlights the need for management guidelines informed by future trials., Competing Interests: This project was conducted as a quality initiative benchmarking current practice against the national therapeutic guidelines. Participants were aware of the nature of the project. Case vignettes were written specifically for this project and contained no real patient information. Ethical approval was not required for this survey of health professionals as it was assessed to have no ethical risk.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Internet-based learning for health professional education is increasing. It offers advantages over traditional learning approaches, as it enables learning to be completed at a time convenient to the user and improves access where facilities are geographically disparate. We developed and implemented the Vancomycin Interactive (VI) e-learning tool to improve knowledge on the clinical use of the antibiotic vancomycin, which is commonly used for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA)., Objective: The aims of this study were to evaluate the effect of the VI e-learning tool on (1) survey knowledge scores and (2) clinical use of vancomycin among health professionals., Methods: We conducted a comparative pre-post intervention study across the 14 hospitals of two health districts in New South Wales, Australia. A knowledge survey was completed by nurses, doctors, and pharmacists before and after release of a Web-based e-learning tool. Survey scores were compared with those obtained following traditional education in the form of an email intervention. Survey questions related to dosing, administration, and monitoring of vancomycin. Outcome measures were survey knowledge scores among the three health professional groups, vancomycin plasma trough levels, and vancomycin approvals recorded on a computerized clinical decision support system., Results: Survey response rates were low at 26.87% (577/2147) preintervention and 8.24% (177/2147) postintervention. The VI was associated with an increase in knowledge scores (maximum score=5) among nurses (median 2, IQR 1-2 to median 2, IQR 1-3; P<.001), but not among other professional groups. The comparator email intervention was associated with an increase in knowledge scores among doctors (median 3, IQR 2-4 to median 4, IQR 2-4; P=.04). Participants who referred to Web-based resources while completing the e-learning tool achieved higher overall scores than those who did not (P<.001). The e-learning tool was not shown to be significantly more effective than the comparator email in the clinical use of vancomycin, as measured by plasma levels within the therapeutic range., Conclusions: The e-learning tool was associated with improved knowledge scores among nurses, whereas the comparator email was associated with improved scores among doctors. This implies that different strategies may be required for optimizing the effectiveness of education among different health professional groups. Low survey response rates limited conclusions regarding the tool's effectiveness. Improvements to design and evaluation methodology may increase the likelihood of a demonstrable effect from e-learning tools in the future., (©Stuart Evan Bond, Shelley P Crowther, Suman Adhikari, Adriana J Chubaty, Ping Yu, Jay P Borchard, Craig Steven Boutlis, Wilfred Winston Yeo, Spiros Miyakis. Originally published in JMIR Medical Education (http://mededu.jmir.org), 26.02.2018.)

Background: Gentamicin has historically been used prior to insertion and removal of indwelling urinary catheters (IDCs) around elective joint replacement surgery to prevent infection; however, this indication is not recognized in the Australian Therapeutic Guidelines: Antibiotic and the paradigm for safe use of gentamicin has shifted., Methods: The antimicrobial stewardship team of a 500 bed tertiary regional hospital performed a retrospective clinical study of gentamicin IDC prophylaxis around total hip and knee arthroplasties. Results were presented to the orthopaedic surgeons. A literature review identified no guidelines to support gentamicin prophylaxis and only a very low risk of bacteraemia associated with IDC insertion/removal in patients with established bacteriuria. Consensus was reached with the surgeons to discontinue this practice. Subsequent prospective data collection was commenced to determine effectiveness, with weekly feedback to the Department Head of Orthopaedics., Results: Data from 137 operations pre-intervention (6 months) were compared with 205 operations post-intervention (12 months). The median patient age was 72 years in both groups. Following the intervention, reductions in gentamicin use were demonstrated for IDC insertion (59/137 (42%) to 4/205 (2%), P < 0.01) and removal (39/137 (28%) to 6/205 (3%), P < 0.01). No gentamicin use was observed during the final 40 weeks of the post-intervention period. There were no significant differences between the groups for pre-operative bacteriuria, surgical site infections or acute kidney injury., Conclusion: A collaborative approach using quality improvement methodology can lead to an evidence-based reappraisal of established practice. Regular rolling audits and timely feedback were useful in sustaining change., (© 2016 Royal Australasian College of Surgeons.)

Background: Studies evaluating antimicrobial stewardship programmes (ASPs) supported by computerized clinical decision support systems (CDSSs) have predominantly been conducted in single site metropolitan hospitals., Objectives: To examine outcomes of multisite ASP implementation supported by a centrally deployed CDSS., Methods: An interrupted time series study was conducted across five hospitals in New South Wales, Australia, from 2010 to 2014. Outcomes analysed were: effect of the intervention on targeted antimicrobial use, antimicrobial costs and healthcare-associated Clostridium difficile infection (HCA-CDI) rates. Infection-related length of stay (LOS) and standardized mortality ratios (SMRs) were also assessed., Results: Post-intervention, antimicrobials targeted for increased use rose from 223 to 293 defined daily doses (DDDs)/1000 occupied bed days (OBDs)/month (+32%, P  <   0.01). Conversely, antimicrobials targeted for decreased use fell from 254 to 196 DDDs/1000 OBDs/month (-23%; P  <   0.01). These effects diminished over time. Antimicrobial costs decreased initially (-AUD$64551/month; P  <   0.01), then increased (+AUD$7273/month; P  <   0.01). HCA-CDI rates decreased post-intervention (-0.2 cases/10 000 OBDs/month; P  <   0.01). Proportional LOS reductions for key infections (respiratory from 4.8 to 4.3 days, P  <   0.01; septicaemia 6.8 to 6.1 days, P  <   0.01) were similar to background LOS reductions (2.1 to 1.9 days). Similarly, infection-related SMRs (observed/expected deaths) decreased (respiratory from 1.1 to 0.75; septicaemia 1.25 to 0.8; background rate 1.19 to 0.90., Conclusions: Implementation of a collaborative multisite ASP supported by a centrally deployed CDSS was associated with changes in targeted antimicrobial use, decreased antimicrobial costs, decreased HCA-CDI rates, and no observable increase in LOS or mortality. Ongoing targeted interventions are suggested to promote sustainability., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Community-acquired pneumonia (CAP) is the second commonest indication for antibiotic use in Australian hospitals and is therefore a frequent target for antimicrobial stewardship. A single-centre prospective study was conducted in a regional referral hospital comparing management of adult patients with CAP before and after an educational intervention. We demonstrated a reduction in duration of therapy and reduced inappropriate use of ceftriaxone-based regimens for non-severe CAP., (© 2017 Royal Australasian College of Physicians.)

Objective: Healthcare-associated Clostridium difficile infection (HCA-CDI) remains a major cause of morbidity and mortality in industrialized countries. However, few data exist on the burden of HCA-CDI in multi-site non-metropolitan settings. This study examined the introduction of an antimicrobial stewardship programme (ASP) in relation to HCA-CDI rates, and the effect of HCA-CDI on length of stay (LOS) and hospital costs., Methods: A comparative before-and-after intervention study of patients aged ≥16 years with HCA-CDI from December 2010 to April 2016 across the nine hospitals of a non-metropolitan health district in New South Wales, Australia was undertaken. The intervention comprised a multi-site ASP supported by a clinical decision support system, with subsequent introduction of email feedback of HCA-CDI cases to admitting medical officers., Main Outcome Measures: HCA-CDI rates, comparative LOS and hospital costs, prior use of antimicrobials and proton pump inhibitors, and appropriateness of CDI treatment., Results: HCA-CDI rates rose from 3.07 to 4.60 cases per 10,000 occupied bed-days pre-intervention, and remained stable at 4 cases per 10,000 occupied bed-days post-intervention (P=0.24). Median LOS (17 vs six days; P<0.01) and hospital costs (AU$19,222 vs $7861; P<0.01) were significantly greater for HCA-CDI cases (N=91) than for matched controls (N=172). Half of the patients with severe HCA-CDI (4/8) did not receive initial appropriate treatment (oral vancomycin)., Conclusions: HCA-CDI placed a significant burden on the regional and rural health service through increased LOS and hospital costs. Interventions targeting HCA-CDI could be employed to consolidate the effects of ASPs., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Background: Traditional approaches to health professional education are being challenged by increased clinical demands and decreased available time. Web-based e-learning tools offer a convenient and effective method of delivering education, particularly across multiple health care facilities. The effectiveness of this model for health professional education needs to be explored in context., Objectives: The study aimed to (1) determine health professionals' experience and knowledge of clinical use of vancomycin, an antibiotic used for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and (2) describe the design and implementation of a Web-based e-learning tool created to improve knowledge in this area., Methods: We conducted a study on the design and implementation of a video-enhanced, Web-based e-learning tool between April 2014 and January 2016. A Web-based survey was developed to determine prior experience and knowledge of vancomycin use among nurses, doctors, and pharmacists. The Vancomycin Interactive (VI) involved a series of video clips interspersed with question and answer scenarios, where a correct response allowed for progression. Dramatic tension and humor were used as tools to engage users. Health professionals' knowledge of clinical vancomycin use was obtained from website data; qualitative participant feedback was also collected., Results: From the 577 knowledge survey responses, pharmacists (n=70) answered the greatest number of questions correctly (median score 4/5), followed by doctors (n=271; 3/5) and nurses (n=236; 2/5; P<.001). Survey questions on target trough concentration (75.0%, 433/577) and rate of administration (64.9%, 375/577) were answered most correctly, followed by timing of first level (49%, 283/577), maintenance dose (41.9%, 242/577), and loading dose (38.0%, 219/577). Self-reported "very" and "reasonably" experienced health professionals were also more likely to achieve correct responses. The VI was completed by 163 participants during the study period. The rate of correctly answered VI questions on first attempt was 65% for nurses (n=63), 68% for doctors (n=86), and 82% for pharmacists (n=14; P<.001), reflecting a similar pattern to the knowledge survey. Knowledge gaps were identified for loading dose (39.2% correct on first attempt; 64/163), timing of first trough level (50.3%, 82/163), and subsequent trough levels (47.9%, 78/163). Of the 163 participants, we received qualitative user feedback from 51 participants following completion of the VI. Feedback was predominantly positive with themes of "entertaining," "engaging," and "fun" identified; however, there were some technical issues identified relating to accessibility from different operating systems and browsers., Conclusions: A novel Web-based e-learning tool was successfully developed combining game design principles and humor to improve user engagement. Knowledge gaps were identified that allowed for targeting of future education strategies. The VI provides an innovative model for delivering Web-based education to busy health professionals in different locations., (©Stuart Evan Bond, Shelley P Crowther, Suman Adhikari, Adriana J Chubaty, Ping Yu, Jay P Borchard, Craig Steven Boutlis, Wilfred Winston Yeo, Spiros Miyakis. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 30.03.2017.)

Background: Posaconazole therapeutic drug monitoring (TDM) is recommended to promote effective antifungal prophylaxis, but its utility has yet to be optimized. Breakthrough invasive fungal infections have been reported with serum concentrations <700 mcg/L, but there is little evidence to determine the optimal serum concentration for efficacy or concentrations associated with toxicity. Challenges for effective monitoring are greater in settings without posaconazole TDM facilities because of the long turnaround time before receipt of results., Methods: Thirty-eight TDM episodes were performed on 18 patients in a regional center in Australia during a 30-month period. Australian guidelines recommend a trough serum concentration of ≥700 mcg/L. The response to concentrations below the recommendation threshold (700 mcg/L), the final serum plasma concentration for each patient, and the appropriateness of TDM were evaluated., Results: A total of 19 (50%) concentrations were recorded to be < 700 mcg/L. Of these 19 concentrations, the drug dose was increased on only 4 occasions. Eleven of 18 patients (61%) had initial concentrations <700 mcg/L, with only 3 (27%) among those achieving final concentration ≥ 700 mcg/L; 5 patients with initial concentrations <700 mcg/L did not have any further TDM testing. Nine of the 18 (50%) patients had a final concentration <700 mcg/L. Five of 7 (71%) patients with initial concentrations ≥700 mcg/L had further TDM with no reasoning documented., Conclusions: The results demonstrate a lack of confidence and consistency in ordering, interpreting, and following up posaconazole concentrations. Therefore, the use of TDM should be carefully considered, especially in regional centers. Such settings should consider the practicalities of posaconazole TDM and try to improve the process to ensure consistency and optimization of patient care.

Infections represent a leading cause of mortality in patients with acute ischemic stroke, but it is unclear whether prophylactic antibiotic treatment improves the outcome. We aimed to evaluate the effects of this treatment on infection incidence and short-term mortality. This was a pragmatic, prospective multicenter real-world analysis of previously independent consecutive patients with acute ischemic stroke who were >18 years, and who had at admission National Institutes of Health Stroke Scale (NIHSS) >11. Patients with infection at admission or during the preceding month, with axillary temperature at admission >37 °C, with chronic inflammatory diseases or under treatment with corticosteroids were excluded from the study. Among 110 patients (44.5 % males, 80.2 ± 6.8 years), 31 (28.2 %) received prophylactic antibiotic treatment, mostly cefuroxime (n = 21). Prophylactic antibiotic treatment was administered to 51.4 % of patients who developed infection, and to 16.4 % of patients who did not (p < 0.001). Independent predictors of infection were NIHSS at admission [relative risk (RR) 1.16, 95 % confidence interval (CI) 1.08-1.26, p < 0.001] and prophylactic antibiotic treatment (RR 5.84, 95 % CI 2.03-16.79, p < 0.001). The proportion of patients who received prophylactic antibiotic treatment did not differ between patients who died during hospitalization and those discharged, or between patients who died during hospitalization or during follow-up and those who were alive 3 months after discharge. Prophylactic administration of antibiotics in patients with severe acute ischemic stroke is associated with an increased risk of infection during hospitalization, and does not affect short-term mortality risk.

Background: Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections., Methods/design: The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection., Trial Registration: The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014).

Limited therapeutic options exist for the treatment of vancomycin-resistant Enterococcus (VRE) bacteremia; the most commonly used are daptomycin and linezolid. We attempted a systematic review and meta-analysis of the comparative efficacy of those two agents. Studies comparing daptomycin to linezolid treatment for VRE bacteremia, published until August 2012, were identified from the MEDLINE, EMBASE, CENTRAL, ISI Web of Science, and SCOPUS databases. All comparative studies on patients older than 18 years of age that provided mortality data were considered eligible for this systematic review and meta-analysis. Τhe primary outcome of the meta-analysis was 30-day all-cause mortality. Ten retrospective studies including 967 patients were identified. Patients treated with daptomycin had significantly higher 30-day all-cause mortality (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.08 to 2.40) and infection-related mortality (OR, 3.61; 95% CI, 1.42 to 9.20) rates than patients treated with linezolid. When data from all 10 studies were combined, overall mortality was also significantly increased among patients treated with daptomycin (OR, 1.41; 95% CI, 1.06 to 1.89). These findings were confirmed when odds ratios adjusted for potential confounders were pooled. Relapse rates among patients treated with daptomycin were also higher (OR, 2.51; 95% CI, 0.94 to 6.72), although this difference did not reach statistical significance. Adverse event rates were not significantly different between the two groups. Notwithstanding the absence of randomized prospective data, available evidence suggests that mortality rates may be higher with daptomycin than with linezolid among patients treated for VRE bacteremia.

The killing activity of daptomycin against an isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) strains was enhanced by the addition of certain cell wall agents at 1× MIC. However, when high inocula of the DNS strain were used, no significant killing was observed in our experiments. Cytochrome c binding assays revealed d-cycloserine as the only agent associated with a reduction in the cell surface charge for both strains at the concentrations used., (Copyright © 2013, American Society for Microbiology. All Rights Reserved.)

Antimicrobial resistance threatens to compromise the treatment of bacterial infectious diseases. Strains resistant to most (if not all) antibiotics available have emerged. Gram-positive such representatives include strains of Methicillinresistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and highly-resistant to penicillin Streptococcus pneumoniae. Although the phenomenon of antimicrobial drug resistance is expanding, limited number of new antibiotics has been successfully developed in the last few decades. Several novel antimicrobial agents, however, are currently in diverse phases of development and undergoing clinical trials. This review will summarize the main candidates for novel antibacterial agents active against Gram-positive multi-resistant pathogens along with the discussion of some patents relevant to the topic.

No novel antimicrobial agents against multi-drug-resistant Gram-negative bacteria have been available to daily clinical practice during the last 5 years. On the other hand, resistance rates and mechanisms of those pathogens are increasing worldwide. Pan-resistant (against which none of the currently available antibiotics is effective) strains of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa have been described. Encouraging is the fact that several novel compounds (some of them with mechanisms of action different to those of the antibiotics commercially available) are through the development stages. We summarize the main such compounds that show potential for offering solution to the treatment of Gram-negative multi-resistant bacteria along with the discussion of some patents associated with the topic.

Introduction: We investigated the role of colonization pressure on multiresistant Acinetobacter baumannii acquisition and defined patient-related predictors for carriage at admission and acquisition during hospitalization in intensive care unit (ICU) patients., Methods: This was a 12-month, prospective, cohort study of all patients admitted to a single ICU of a tertiary hospital. Screening samples were collected at ICU admission to identify imported carriers, and weekly during hospitalization to identify acquisition. Colonization pressure (carriers' patient-days × 100/all patients' patient-days) and the absolute number of carriers were calculated weekly, and the statistical correlation between these parameters and acquisition was explored. Multivariable analysis was performed to identify predictors for A. baumannii carriage at admission and acquisition during hospitalization. A. baumannii isolates were genotyped by repetitive-extragenic-palindromic polymerase chain reaction (PCR; rep-PCR)., Results: At ICU admission, 284 patients were screened for carriage. A. baumannii was imported in 16 patients (5.6%), and acquisition occurred in 32 patients (15.7%). Acquisition was significantly correlated to weekly colonization pressure (correlation coefficient, 0.379; P = 0.004) and to the number of carriers per week (correlation coefficient, 0.499; P <0.001). More than one carrier per week significantly increased acquisition risk (two to three carriers, odds ratio (OR), 12.66; P = 0.028; more than four carriers, OR, 25.33; P = 0.004). Predictors of carriage at admission were infection at admission (OR, 11.03; confidence interval (CI), 3.56 to 34.18; P < 0.01) and hospitalization days before ICU (OR, 1.09; CI, 1.01 to 1.16; P = 0.02). Predictors of acquisition were a medical reason for ICU admission (OR, 5.11; CI, 1.31 to 19.93; P = 0.02), duration of antibiotic administration in the unit (OR, 1.24; CI, 1.12 to 1.38; P < 0.001), and duration of mechanical ventilation (OR, 1.08; CI, 1.04 to 1.13; P = 0.001). All strains were multiresistant. Rep-PCR analysis showed one dominant cluster., Conclusions: Acquisition of multiresistant A. baumannii in ICU patients is strongly correlated to colonization pressure. High levels of colonization pressure and more than two carriers per week independently increase acquisition risk. Patient-related factors, such as infection at admission and long hospitalization before the ICU, can identify imported A. baumannii carriers. Medical patients with extended administration of antibiotics and long duration of mechanical ventilation in the ICU were the most vulnerable to acquisition.

We report 570 carbapenemase-producing Klebsiella pneumoniae (CPKP) clinical isolates in a 1,040-bed Greek tertiary hospital during 2004 to 2010. The first CPKP (VIM-producing) was isolated in September 2004. Despite initial containment, VIM producers have become endemic since 2006. KPC-producing K. pneumoniae was first isolated in August 2007 from a patient who came from Israel, spread rapidly, and outcompeted VIM. Overall, 267 (47%) VIM-producing and 301 (53%) KPC-producing strains were isolated, including 141 (24.7%) from patients with bacteraemia. Two isolates carrying both VIM and KPC were isolated in two consecutive months in 2009, but not since. The prevalence of CPKP increased from 0% in 2003 to 38.3% in 2010 (p<0.0001). All genotyped KPC producers harboured blaKPC-2 and belonged to two clones, among which the hyperepidemic Greek clone, related to those from the United States and Israel, predominated. Most metallo-beta-lactamase (MBL) producers carried the blaVIM-1 gene and belonged to several clones, whereas all but one isolate with blaVIM-12 were clustered within a five-month period, arising from one clone. Resistance to non-beta-lactam antibiotics was also increased among CPKP. They were almost invariably resistant to ciprofloxacin and trimethoprim-sulfamethoxazole. Resistance to colistin increased from 3.5% (4/115) in 2008 to 20.8% (25/120) in 2010, and resistance to tigecycline also increased. Following reinforcement of infection control measures, prevalence of CPKP (mainly KPC) has been reduced since mid-2009 (from 46% in 2009 to 38.3% in 2010). In view of the exhaustion of available therapies, investment in infection control resources and optimal antibiotic use is urgently required.

We report a patient with the extremely rare familial multiple lipomatosis syndrome, who developed the uncommon autoimmune disease cytophagic histiocytic panniculitis, manifested as inflammation of preexisting lipomas. Despite his initial critical condition and unsuccessful treatment with steroids, he responded to cyclosporin and remains well 15 years after diagnosis. In contrast with most previous reports, our patient stays dependent on cyclosporin; repeated attempts of discontinuing or substituting treatment were quickly followed by relapse. Haemophagocytic panniculitis is considered as a T-cell disorder, but its exact pathophysiological mechanism has not been clarified. Differential diagnosis of cytophagic histiocytic panniculitis mainly includes malignant histiocytosis, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and lupus erythematosus panniculitis (lupus profundus). We discuss the main clinical features, diagnostic challenges and treatment issues of this usually benign, but at times life-threatening autoimmune condition.

We present a case of a patient treated with etanercept (TNF-a antagonist) for psoriatic arthritis, who then developed clinical symptoms of lepromatous leprosy. She presented with multiple erythematous plaques on trunk, face and extremities, saddle nose deformity, alopecia, articular deformities of the feet and peroneal neuropathy. The clinical suspicion of Hansen's Disase was confirmed by the biopsy findings (lepromatous leprosy). On further questioning, the patient stated that her father was diagnosed with leprosy 70 years ago and had spent some years in a leper colony in Spinalonga island in Southern Greece in the 1940s. This first report of Hansen's disease after administration of etanercept highlights the need of careful risk assessment of patients for whom antiTNF treatment is planned.

Background: Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus., Methods: Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed daptomycin-nonsusceptibility. Electron microscopy (EM) and lipid membrane studies were performed on selected isolates., Results: On average, six coding region mutations were observed across the genome in the clinical daptomycin exposed strains, whereas only two mutations on average were seen in the laboratory exposed pairs. All daptomycin-nonsusceptible strains had a mutation in a phospholipid biosynthesis gene. This included mutations in the previously described mprF gene, but also in other phospholipid biosynthesis genes, including cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA). EM and lipid membrane composition analyses on two clinical pairs showed that the daptomycin-nonsusceptible strains had a thicker cell wall and an increase in membrane lysyl-phosphatidylglycerol., Conclusion: Point mutations in genes coding for membrane phospholipids are associated with the development of reduced susceptibility to daptomycin in S. aureus. Mutations in cls2 and pgsA appear to be new genetic mechanisms affecting daptomycin susceptibility in S. aureus.

Differences in 24 h blood pressure (BP) monitoring parameters such as average 24 h BP, day to night BP ratio and BP variability could have an impact in arterial stiffness. The study hypothesis was that despite similar average BP values in ambulatory blood pressure monitoring subjects with increased 24 h BP variability may have increased arterial stiffness. The study population consisted of 115 consecutive young healthy volunteers. Carotid-femoral PWV was measured in all subjects. Clinic BP was measured and an appropriate cuff was fitted on the non-dominant arm of each subject for a 24 h ambulatory blood pressure monitoring session. Waist to hip ratio as well as BMI was measured. Family history and smoking habits were recorded. In univariate analysis, estimated carotid-femoral PWV showed a significant correlation with age, weight, waist circumference, height, clinic systolic and diastolic BP, 24-h systolic and diastolic BP, 24-h pulse pressure, 24-h systolic and diastolic BP variability, daytime systolic and diastolic BP, daytime pulse pressure, daytime systolic and diastolic BP variability, nighttime systolic BP, nighttime pulse pressure and nighttime systolic BP variability. In multivariate regression analysis, age (B=0.95, P<0.001) and 24 h systolic BP variability (B=0.28, P<0.001) were independent determinanats of arterial stiffness. In conclusions, increased 24 h systolic BP variability is associated with arterial stiffness in young healthy volunteers. Pulse wave velocity in a young healthy population is useful to identify determinants of premature arterial stiffness, thus further elucidating the aspects of early vascular ageing., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Mutations that change the same amino acid can result in different clinical phenotypes. Through in silico modeling and keratin filament assessment of genetically engineered HaCaT cells, Natsuga et al., as reported in this issue, have demonstrated how changes in charge and structure of a replacement amino acid in keratin 14 can cause disease (KRT14pA413P, EB simplex) or no clinical effect (KRT14pA413T, polymorphism).

Antimicrobial drug resistance rates in Greece are among the highest in Europe. The prevalence of carbapenem-resistant Gram-negative species has increased considerably, including endemic strains in intensive care units. Pandrug-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are sporadically reported. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus rates are also high in Greek hospitals. Multidrug resistance increases risk of mortality, hospitalization duration and costs, and undermines the medical system. Administrative responses initiated include action plans, monitoring systems, and guidelines. Common terminology among involved parties for defining and grading resistance is required. Multidrug-resistant microorganisms challenge clinical laboratories; uniform recommendations towards detection of resistance mechanisms need to be established. Prospective multicenter outcome studies comparing antibiotic regimens and containment methods are needed. Because new antimicrobials against Gram-negative pathogens are not foreseeable, judicious use of the existing and strict adherence to infection control best practice might restrain resistance spread. Awareness of resistance patterns and organisms prevailing locally by reporting laboratories and treating physicians is important.

Monitoring of serum voriconazole concentrations has been proposed to optimize therapeutic effect and minimize toxicity. However, little is known about the clinical use of voriconazole therapeutic drug monitoring (TDM) by treating physicians. Four hundred seventy-eight episodes corresponding with 161 adult patients (mean three TDM episodes per patient; range 1-31, at a mean interval 43.6 days [range 1-266] between repetitions) performed at a state reference laboratory in Australia during a 30-month period were reviewed. Information about voriconazole dose was provided on only nine (1.9%) request forms. Timing of voriconazole TDM in relation to the previous dose was stated in 189 (39%) episodes and corresponded with peak measurements in 16; interval measurements (taken on average 3.3 [range 3-10.5] hours from the preceding dose) in 15; and trough measurements in 158 episodes. Of the 158 trough concentration measurements, only 66 (42%) were between 1 and 5.5 mg/L, the suggested therapeutic range. Similarly, only 33% (98 of 298) of all the random TDM episodes achieved voriconazole concentrations greater than 2.05 mg/L, previously associated with favorable outcomes. Compared with trough TDM, random episodes were significantly more likely to result in undetectable (less than 0.1 mg/L) concentrations (45 of 298 [15.1%] versus 12 of 158 [7.6%]; P = 0.021, odds ratio 2.16, 95% confidence interval: 1.11-4.22). Among patients with multiple TDM episodes, there was no correlation between the initial and final trough or between the initial and final random concentrations. Only 44% (eight of 18) of patients with multiple trough TDM had final concentration within 1 to 5.5 mg/L; and only 26% (15 of 58) of patients with multiple random TDM had final concentration greater than 2.05 mg/L. Adoption of consistent and clear guidelines on voriconazole TDM use and education of physicians ordering the test is required because the majority of testing performed was inappropriate and prone to suboptimal interpretation.

We describe a 69-year-old male patient who was referred for the investigation of long-lasting fever, anemia and neutropenia. Hairy cell leukemia was diagnosed and treated successfully. However, fever persisted despite thorough investigation and use of broad-spectrum antibiotics. Four months after the initial diagnosis, the patient underwent explorative laparotomy and splenectomy. Spleen biopsy revealed multiple necrotizing mycobacterial granulomata while the patient's fever disappeared permanently. Isolated splenic mycobacterial disease is very rare. This case report emphasizes that investigation of chronic fever in hairy cell leukemia requires a high level of clinical suspicion. Early diagnostic procedures for evidence of atypical mycobacterial infection should be considered. When everything else fails, surgery can be helpful in selected cases.

Twenty-five patients with proven or probable invasive fungal infections (IFIs) who experienced two or more episodes of voriconazole therapeutic drug monitoring (TDM) at a tertiary referral hospital were reviewed to explore the association between serum trough concentrations and outcomes of IFI. Microbiological and/or clinical success, in addition to IFI-related mortality, was assessed. We performed two separate analyses, one based on the initial trough voriconazole concentration at steady state, and the other on the median trough voriconazole concentration (derived from repeated TDM episodes) for each patient. Large interpatient and intrapatient variability of trough plasma voriconazole concentrations was observed, with no correlation between dose and concentration (r = 0.065). Classification and regression tree analysis revealed an association between IFI-related mortality and initial trough voriconazole concentrations, with patients more likely to die when their initial steady-state concentration was ≤0.35 mg/L (p 0.004; OR 11, 95% CI 2.9-41.2). Successful outcomes were more likely among patients with a median trough voriconazole concentration >2.2 mg/L (p 0.003; OR 2.7, 95% CI 1.4-5). Nineteen adverse events, with four severe events, were documented in 14 patients. Patients with severe adverse events had higher median voriconazole concentrations than the remaining cohort (2.38 mg/L vs. 1.30 mg/L; p <0.04). All adverse events resolved after cessation of voriconazole treatment. Our data suggest that voriconazole TDM is appropriate for all patients as soon as steady state is achieved. For non-responding patients with low trough concentrations, the association with IFI-related mortality indicates the need for dose adjustments to achieve and sustain voriconazole concentrations.

Objectives: To identify risk factors associated with mortality and adverse outcome of community acquired cellulitis/erysipelas requiring hospital admission., Methods: A retrospective analysis of 395 episodes of cellulitis/erysipelas admitted to a tertiary referral hospital between January 1999 and December 2006., Results: Mortality was 2.5% (10/395). There were 112 complications (28.4%). Median hospitalisation was 5 days. Factors independently associated with mortality, adverse outcome and prolonged stay (>7 days) were bacteraemia and albumin <30 g/L. A risk stratification model was designed based on factors independently associated with adverse outcome: altered mental status, neutrophilia/paenia, discharge from the cellulitic area, hypoalbuminaemia and history of congestive cardiac failure. Adverse outcome risk among patients with scores <4, 6-9 and >9 was <20%, 55% and 100%, respectively. All patients who died had admission score >or=4. Factors independently associated with prolonged hospitalisation were: age >60, symptom duration >4 days, hypoalbuminaemia, bacteraemia, isolation of MRSA and time to effective antibiotics >8 h. MRSA was more frequent among patients admitted during 2003-2006 (OR 2.43, 95% CI: 1-12-5.27). Streptococci accounted for most bacteraemia (11/20). Infectious Disease physician input was independently associated with shorter hospitalisation., Conclusions: Cellulitis/erysipelas requiring hospitalisation confers considerable morbidity and mortality. Clinical markers present on admission can be used to stratify patient risk of mortality and adverse outcome., (Copyright (c) 2010 The British Infection Society. All rights reserved.)

Acalculous cholecystitis has been described in association with Q fever. We describe the first known case of Q fever cholecystitis diagnosed by polymerase chain reaction on gallbladder tissue. The presence of Coxiella burnetii genome in the diseased gallbladder tissue argues for direct involvement of the organism in the pathogenesis of Q fever cholecystitis.

Aim: The chemokine fractalikine is expressed in vascular endothelium, exerting a pro-atherogenic effect. Two single-nucleotide polymorphisms of the CX3CR1 gene (T280M and V249I) affect frac-talkine receptor expression and function. We aimed to assess the prevalence of CX3CR1 polymor-phisms and the association with ischemic cerebrovascular attacks in a cohort of carotid atheromatous disease patients and age-matched controls., Methods: Using PCR-RFLP, we analyzed allelotypes for T280M and V249I in 150 patients with and 151 controls without carotid atherosclerosis assessed using carotid duplex ultrasound; the subjects were patients admitted for any reason to a tertiary hospital. Genotype data were compared with modifiable risk factors for cerebrovascular disease and the reason for admission, using ischemic stroke as an endpoint. Stroke types associated with carotid atherosclerosis were analysed separately., Results: The M280 allelic frequency was lower among carotid atherosclerosis patients than controls (0.15 versus 0.23, adjusted OR 0.47, 95% CI 0.30-0.74). Absence of M280 allele was an indepen-dent factor associated with carotid atherosclerosis (OR 3.70, 95% CI 1.92-7.14), stronger than hypertension, dyslipidemia, diabetes and cigarette smoking. The I249 allele was also under-repre-sented in carotid atherosclerosis; this was not statistically significant. T280M and V249I genotypes were not associated with admission due to ischemic stroke of the large vessel subtype (TOAST classi-fication, 73 episodes), whereas carotid atherosclerosis, previous ischemic event, age, hypertension, diabetes, hyperlipidemia and cigarette smoking were all independently associated., Conclusions: The M280 fractalkine receptor gene allele is associated with a lower risk of carotid ath-eromatous disease, independent from the modifiable cerebrovascular risk factors.