Clinical Implementation of Routine Whole-genome Sequencing for Hospital Infection Control of Multi-drug Resistant Pathogens.

BACKGROUND: Prospective whole-genome sequencing (WGS)-based surveillance may be the optimal approach to rapidly identify transmission of multi-drug resistant (MDR) bacteria in the healthcare setting. METHODS: We prospectively collected methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Acinetobacter baumannii (CRAB), extended-spectrum beta-lactamase (ESBL-E), and carbapenemase-producing Enterobacterales (CPE) isolated from blood cultures, sterile sites, or screening specimens across three large tertiary referral hospitals (2 adult, 1 paediatric) in Brisbane, Australia. WGS was used to determine in silico multi-locus sequence typing (MLST) and resistance gene profiling via a bespoke genomic analysis pipeline. Putative transmission events were identified by comparison of core genome single nucleotide polymorphisms (SNPs). Relevant clinical meta-data were combined with genomic analyses via customised automation, collated into hospital-specific reports regularly distributed to infection control teams. RESULTS: Over 4 years (April 2017 to July 2021) 2660 isolates were sequenced. This included MDR gram-negative bacilli (n = 293 CPE, n = 1309 ESBL), MRSA (n = 620), and VRE (n = 433). A total of 379 clinical reports were issued. Core genome SNP data identified that 33% of isolates formed 76 distinct clusters. Of the 76 clusters, 43 were contained to the 3 target hospitals, suggesting ongoing transmission within the clinical environment. The remaining 33 clusters represented possible inter-hospital transmission events or strains circulating in the community. In 1 hospital, proven negligible transmission of non-multi-resistant MRSA enabled changes to infection control policy. CONCLUSIONS: Implementation of routine WGS for MDR pathogens in clinical laboratories is feasible and can enable targeted infection prevention and control interventions.

Effect of infusion set replacement intervals on catheter-related bloodstream infections (RSVP): a randomised, controlled, equivalence (central venous access device)-non-inferiority (peripheral arterial catheter) trial.

BACKGROUND: The optimal duration of infusion set use to prevent life-threatening catheter-related bloodstream infection (CRBSI) is unclear. We aimed to compare the effectiveness and costs of 7-day (intervention) versus 4-day (control) infusion set replacement to prevent CRBSI in patients with central venous access devices (tunnelled cuffed, non-tunnelled, peripherally inserted, and totally implanted) and peripheral arterial catheters. METHODS: We did a randomised, controlled, assessor-masked trial at ten Australian hospitals. Our hypothesis was CRBSI equivalence for central venous access devices and non-inferiority for peripheral arterial catheters (both 2% margin). Adults and children with expected greater than 24 h central venous access device-peripheral arterial catheter use were randomly assigned (1:1; stratified by hospital, catheter type, and intensive care unit or ward) by a centralised, web-based service (concealed before allocation) to infusion set replacement every 7 days, or 4 days. This included crystalloids, non-lipid parenteral nutrition, and medication infusions. Patients and clinicians were not masked, but the primary outcome (CRBSI) was adjudicated by masked infectious diseases physicians. The analysis was modified intention to treat (mITT). This study is registered with the Australian New Zealand Clinical Trials Registry ACTRN12610000505000 and is complete. FINDINGS: Between May 30, 2011, and Dec, 9, 2016, from 6007 patients assessed, we assigned 2944 patients to 7-day (n=1463) or 4-day (n=1481) infusion set replacement, with 2941 in the mITT analysis. For central venous access devices, 20 (1·78%) of 1124 patients (7-day group) and 16 (1·46%) of 1097 patients (4-day group) had CRBSI (absolute risk difference [ARD] 0·32%, 95% CI -0·73 to 1·37). For peripheral arterial catheters, one (0·28%) of 357 patients in the 7-day group and none of 363 patients in the 4-day group had CRBSI (ARD 0·28%, -0·27% to 0·83%). There were no treatment-related adverse events. INTERPRETATION: Infusion set use can be safely extended to 7 days with resultant cost and workload reductions. FUNDING: Australian National Health and Medical Research Council.

Dressings and securements for the prevention of peripheral intravenous catheter failure in adults (SAVE): a pragmatic, randomised controlled, superiority trial.

BACKGROUND: Two billion peripheral intravenous catheters (PIVCs) are used globally each year, but optimal dressing and securement methods are not well established. We aimed to compare the efficacy and costs of three alternative approaches to standard non-bordered polyurethane dressings. METHODS: We did a pragmatic, randomised controlled, parallel-group superiority trial at two hospitals in Queensland, Australia. Eligible patients were aged 18 years or older and required PIVC insertion for clinical treatment, which was expected to be required for longer than 24 h. Patients were randomly assigned (1:1:1:1) via a centralised web-based randomisation service using random block sizes, stratified by hospital, to receive tissue adhesive with polyurethane dressing, bordered polyurethane dressing, a securement device with polyurethane dressing, or polyurethane dressing (control). Randomisation was concealed before allocation. Patients, clinicians, and research staff were not masked because of the nature of the intervention, but infections were adjudicated by a physician who was masked to treatment allocation. The primary outcome was all-cause PIVC failure (as a composite of complete dislodgement, occlusion, phlebitis, and infection [primary bloodstream infection or local infection]). Analysis was by modified intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000769987. FINDINGS: Between March 18, 2013, and Sept 9, 2014, we randomly assigned 1807 patients to receive tissue adhesive with polyurethane (n=446), bordered polyurethane (n=454), securement device with polyurethane (n=453), or polyurethane (n=454); 1697 patients comprised the modified intention-to-treat population. 163 (38%) of 427 patients in the tissue adhesive with polyurethane group (absolute risk difference -4·5% [95% CI -11·1 to 2·1%], p=0·19), 169 (40%) of 423 of patients in the bordered polyurethane group (-2·7% [-9·3 to 3·9%] p=0·44), 176 (41%) of 425 patients in the securement device with poplyurethane group (-1·2% [-7·9% to 5·4%], p=0·73), and 180 (43%) of 422 patients in the polyurethane group had PIVC failure. 17 patients in the tissue adhesive with polyurethane group, two patients in the bordered polyurethane group, eight patients in the securement device with polyurethane group, and seven patients in the polyurethane group had skin adverse events. Total costs of the trial interventions did not differ significantly between groups. INTERPRETATION: Current dressing and securement methods are commonly associated with PIVC failure and poor durability, with simultaneous use of multiple products commonly required. Cost is currently the main factor that determines product choice. Innovations to achieve effective, durable dressings and securements, and randomised controlled trials assessing their effectiveness are urgently needed. FUNDING: Australian National Health and Medical Research Council.

Infectious Complications Following Kidney Transplantation-A Focus on Hepatitis C Infection, Cytomegalovirus Infection and Novel Developments in the Gut Microbiota.

The incidence of infectious complications, compared with the general population and the pre-transplant status of the recipient, increases substantially following kidney transplantation, causing significant morbidity and mortality. The potent immunosuppressive therapy given to prevent graft rejection in kidney transplant recipients results in an increased susceptibility to a wide range of opportunistic infections including bacterial, viral and fungal infections. Over the last five years, several advances have occurred that may have changed the burden of infectious complications in kidney transplant recipients. Due to the availability of direct-acting antivirals to manage donor-derived hepatitis C infection, this has opened the way for donors with hepatitis C infection to be considered in the donation process. In addition, there have been the development of medications targeting the growing burden of resistant cytomegalovirus, as well as the discovery of the potentially important role of the gastrointestinal microbiota in the pathogenesis of post-transplant infection. In this narrative review, we will discuss these three advances and their potential implications for clinical practice.

Ureaplasma urealyticum necrotizing soft tissue infection.

Ureaplasma urealyticum is a urogenital commensal and often associated with localised infection. With the advent of monoclonal immunosuppressive therapy and improved diagnostic methods, reports of non-urogenital infections are accumulating. We report a rare case of U. urealyticum necrotizing soft tissue infection and left hip septic arthritis in a hypogammaglobulinaemic patient. Consideration of this organism as an etiological agent, and potential early use of nucleic-acid diagnostic investigation with empiric therapy including activity against Ureaplasma in this patient population may be warranted.

Problematic Dichotomization of Risk for Intensive Care Unit (ICU)-Acquired Invasive Candidiasis: Results Using a Risk-Predictive Model to Categorize 3 Levels of Risk From a Multicenter Prospective Cohort of Australian ICU Patients.

BACKGROUND: Delayed antifungal therapy for invasive candidiasis (IC) contributes to poor outcomes. Predictive risk models may allow targeted antifungal prophylaxis to those at greatest risk. METHODS: A prospective cohort study of 6685 consecutive nonneutropenic patients admitted to 7 Australian intensive care units (ICUs) for ≥72 hours was performed. Clinical risk factors for IC occurring prior to and following ICU admission, colonization with Candida species on surveillance cultures from 3 sites assessed twice weekly, and the occurrence of IC ≥72 hours following ICU admission or ≤72 hours following ICU discharge were measured. From these parameters, a risk-predictive model for the development of ICU-acquired IC was then derived. RESULTS: Ninety-six patients (1.43%) developed ICU-acquired IC. A simple summation risk-predictive model using the 10 independently significant variables associated with IC demonstrated overall moderate accuracy (area under the receiver operating characteristic curve = 0.82). No single threshold score could categorize patients into clinically useful high- and low-risk groups. However, using 2 threshold scores, 3 patient cohorts could be identified: those at high risk (score ≥6, 4.8% of total cohort, positive predictive value [PPV] 11.7%), those at low risk (score ≤2, 43.1% of total cohort, PPV 0.24%), and those at intermediate risk (score 3-5, 52.1% of total cohort, PPV 1.46%). CONCLUSIONS: Dichotomization of ICU patients into high- and low-risk groups for IC risk is problematic. Categorizing patients into high-, intermediate-, and low-risk groups may more efficiently target early antifungal strategies and utilization of newer diagnostic tests.

Determination of a suitable voriconazole pharmacokinetic model for personalised dosing.

Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a 'hybrid' model for voriconazole that incorporated information from prior models in a biologically plausible manner. Voriconazole is a triazole antifungal with difficult to predict PK, although it does have a defined exposure-response relationship. Nine population PK models of voriconazole were identified from the literature. The models differed significantly in structural components. The hybrid model contained a two-compartment disposition model with mixed linear and nonlinear time-dependent clearance. The parameters for the hybrid model were determined using simulation techniques. Validation of the hybrid model was assessed via visual predictive checks, which indicated the majority of the variability in the literature models was captured by the hybrid model. The predictive performance was assessed using four different sampling strategies of limited concentrations from ten richly PK sampled subjects to predict future concentrations. Overall, the hybrid model predicted future concentrations with good precision. Further prospective and retrospective validation of the hybrid model is required before it could be used in clinical practice.

Candida colonization as a risk marker for invasive candidiasis in mixed medical-surgical intensive care units: development and evaluation of a simple, standard protocol.

Colonization with Candida species is an independent risk factor for invasive candidiasis (IC), but the minimum and most practicable parameters for prediction of IC have not been optimized. We evaluated Candida colonization in a prospective cohort of 6,015 nonneutropenic, critically ill patients. Throat, perineum, and urine were sampled 72 h post-intensive care unit (ICU) admission and twice weekly until discharge or death. Specimens were cultured onto chromogenic agar, and a subset underwent molecular characterization. Sixty-three (86%) patients who developed IC were colonized prior to infection; 61 (97%) tested positive within the first two time points. The median time from colonization to IC was 7 days (range, 0 to 35). Colonization at any site was predictive of IC, with the risk of infection highest for urine colonization (relative risk [RR]=2.25) but with the sensitivity highest (98%) for throat and/or perineum colonization. Colonization of ≥2 sites and heavy colonization of ≥1 site were significant independent risk factors for IC (RR=2.25 and RR=3.7, respectively), increasing specificity to 71% to 74% but decreasing sensitivity to 48% to 58%. Molecular testing would have prompted a resistance-driven decision to switch from fluconazole treatment in only 11% of patients infected with C. glabrata, based upon species-level identification alone. Positive predictive values (PPVs) were low (2% to 4%) and negative predictive values (NPVs) high (99% to 100%) regardless of which parameters were applied. In the Australian ICU setting, culture of throat and perineum within the first two time points after ICU admission captures 84% (61/73 patients) of subsequent IC cases. These optimized parameters, in combination with clinical risk factors, should strengthen development of a setting-specific risk-predictive model for IC.

Cost-effectiveness analysis of anidulafungin for the treatment of candidaemia and other forms of invasive candidiasis.

BACKGROUND: Candidaemia and other forms of invasive candidiasis (C/IC) in the intensive care unit are challenging conditions that are associated with high rates of mortality. New guidelines from the European Society for Clinical Microbiology and Infectious Diseases strongly recommend echinocandins for the first-line treatment of C/IC. Here, a cost-effectiveness model was developed from the United Kingdom perspective to examine the costs and outcomes of antifungal treatment for C/IC based on the European Society for Clinical Microbiology and Infectious Diseases guidelines. METHODS: Costs and treatment outcomes with the echinocandin anidulafungin were compared with those for caspofungin, micafungin and fluconazole. The model included non-neutropenic patients aged ≥16 years with confirmed C/IC who were receiving intravenous first-line treatment. Patients were categorised as either a clinical success or failure (patients with persistent/breakthrough infection); successfully treated patients switched to oral therapy, while patients categorised as clinical failures switched to a different antifungal class. Other inputs were all-cause mortality at 6 weeks, costs of treatment-related adverse events and other medical resource utilisation costs. Resource use was derived from the published literature and from discussion with clinical experts. Drug-acquisition/administration costs were taken from standard United Kingdom costing sources. RESULTS: The model indicated that first-line anidulafungin could be considered cost-effective versus fluconazole (incremental cost-effectiveness ratio £813 per life-year gained) for the treatment of C/IC. Anidulafungin was cost-saving versus caspofungin and micafungin due to lower total costs and a higher rate of survival combined with a higher probability of clinical success. DISCUSSION: European Society for Clinical Microbiology and Infectious Diseases guidelines recommend echinocandins for the first-line treatment of C/IC; our model indicated that anidulafungin marries clinical effectiveness and cost-effectiveness. CONCLUSIONS: From the United Kingdom perspective, anidulafungin was cost-effective compared with fluconazole for the treatment of C/IC and was cost-saving versus the other echinocandins.

Parenteral nutrition-associated bloodstream infection in an Australian teaching hospital--an 8-year retrospective study of over 11,000 PN-days.

BACKGROUND: Bloodstream infections (BSIs) are a well-recognized complication of parenteral nutrition (PN). However, their epidemiology and clinical consequences are incompletely described. METHODS: A retrospective cohort study was performed, from 2002 to 2009, of all hospital inpatients who were administered PN, outside the intensive care setting, at a major tertiary hospital in Queensland, Australia. RESULTS: In 780 episodes of PN administration, 120 BSIs occurred, giving an incidence of 10.0/1000 PN-days. The majority of PN-associated BSIs were classified as central line-associated (n = 98, 81.7%). Candida spp. were the most frequent pathogens. Observed BSI management revealed that over 8% of intravascular devices were inappropriately retained, over 30% of empirical antibiotic therapy was inappropriate, and 62% of antifungal therapy was delayed ≥ 48 h. All-cause hospital mortality was over 2-fold greater in patients with a PN-associated BSI compared to those without (17.9% vs 8.3%, crude odds ratio (OR) 2.4, 95% confidence interval (CI) 1.29-4.35, p = 0.002). BSI was identified as an independent risk factor for mortality (adjusted OR 3.54, 95% CI 1.76-7.12, p < 0.001). Low baseline albumin levels and a requirement for intravenous insulin infusion (a marker of sustained hyperglycaemia) were independent risk factors for the development of PN-associated BSIs. CONCLUSIONS: PN-associated BSI in hospital inpatients is common and is associated with mortality. The implementation of standardized evidence-based infection prevention strategies, particularly targeting IVD maintenance, is a priority. PN-associated BSI management pathways require optimization, with timely IVD removal and appropriate antimicrobial therapy. Depending on local epidemiology patterns, empirical antifungal therapy should be considered.

Incidence and risk factors for central venous access device failure in hospitalized adults: A multivariable analysis of 1892 catheters.

BACKGROUND: Central venous access devices (CVADs) allow intravenous therapy, haemodynamic monitoring and blood sampling but many fail before therapy completion. OBJECTIVE: To quantify CVAD failure and complications; and identify risk factors. DESIGNS, SETTINGS AND PARTICIPANTS: Secondary analysis of multicentre randomised controlled trial including patients aged ≥16 years with a non-tunnelled CVAD (NTCVAD), peripherally-inserted central catheter (PICC) or tunnelled CVAD (TCVAD). Primary outcome was incidence of all-cause CVAD failure (central line-associated bloodstream infection [CLABSI], occlusion, accidental dislodgement, catheter fracture, thrombosis, pain). Secondary outcomes were CLABSI, occlusion and dislodgement. Cox regression was used to report time-to-event associations. RESULTS: In 1892 CVADs, all-cause failure occurred in 10.2% of devices: 49 NTCVADs (6.1%); 100 PICCs (13.2%); 44 TCVADs (13.4%). Failure rates for CLABSI, occlusion and dislodgement were 5.3%, 1.8%, and 1.7%, respectively. Independent CLABSI predictors were blood product administration through PICCs (hazard ratio (HR) 2.62, 95% confidence interval (CI) 1.24-5.55); and in TCVADs, one or two lumens, compared with three to four (HR 3.36, 95%CI 1.68-6.71), intravenous chemotherapy (HR 2.96, 95%CI 1.31-6.68), and diabetes (HR 3.25, 95%CI 1.40-7.57). Independent factors protective for CLABSI include antimicrobial NTCVADs (HR 0.23, 95%CI 0.08-0.63) and lipids in TCVADs (HR 0.32, 95%CI 0.14-0.72). NTCVADs inserted at another hospital (HR 7.06, 95%CI 1.48-33.7) and baseline infection in patients with PICCs (HR 2.72, 95%CI 1.08-6.83) were predictors for dislodgement. No independent occlusion predictors were found. Modifiable risk factors were identified for CVAD failure, which occurred for 1-in-10 catheters. Strict infection prevention measures and improved CVAD securement could reduce CLABSI and dislodgement risk.

Antifungal therapy and management of complications of cryptococcosis due to Cryptococcus gattii.

BACKGROUND: We describe antifungal therapy and management of complications due to Cryptococcus gattii infection in 86 Australian patients followed for at least 12 months. METHODS: Patient data from culture-confirmed cases (2000-2007) were recorded at diagnosis, 6 weeks, 6 months, and 12 months. Clinical, laboratory, and treatment variables associated with raised intracranial pressure (ICP) and immune reconstitution inflammatory syndrome (IRIS) were determined. RESULTS: Seven of 10 patients with lung infection received amphotericin B (AMB) induction therapy (6 with 5-flucytosine [5-FC] for a median of 2 weeks); median duration of therapy including azole eradication therapy was 41 weeks, with a complete/partial clinical response in 78%. For neurologic disease, 88% of patients received AMB, 78% with 5-FC, for a median of 6 weeks. The median total course was 18 months. Nine patients receiving fluconazole induction therapy were reinduced with AMB plus 5-FC for clinical failure. Raised ICP (31 patients) was associated with initial abnormal neurology, and neurologic sequelae and/or death at 12 months (both P = .02); cerebrospinal fluid drains/shunts were placed in 58% of patients and in 64% of 22 patients with hydrocephalus. IRIS developed 2-12 months after starting antifungals in 8 patients, who presented with new/enlarging brain lesions. Risk factors included female sex, brain involvement at presentation, and higher median CD4 counts (all P < .05); corticosteroids reduced cryptococcoma-associated edema. CONCLUSIONS: Induction AMB plus 5-FC is indicated for C. gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks). Shunting was often required to control raised ICP. IRIS presents with cerebral manifestations.

Association of ertapenem and antipseudomonal carbapenem usage and carbapenem resistance in Pseudomonas aeruginosa among 12 hospitals in Queensland, Australia.

OBJECTIVES: The objective of this study was to determine the association between ertapenem and antipseudomonal carbapenem use and carbapenem resistance in Pseudomonas aeruginosa in 12 hospitals in Queensland, Australia. METHODS: Data on usage of ertapenem and other antipseudomonal carbapenems, measured in defined daily doses per 1000 occupied bed-days, were collated using statewide pharmacy dispensing and distribution software from January 2007 until June 2011. The prevalence of unique carbapenem-resistant P. aeruginosa isolates derived from statewide laboratory information systems was collected for the same time period. Mixed-effects models were used to determine any relationship between ertapenem and antipseudomonal carbapenem usage and carbapenem resistance among P. aeruginosa isolates in the 12 hospitals analysed. RESULTS: No relationship between ertapenem usage and P. aeruginosa carbapenem resistance was observed. The introduction of ertapenem did not replace antipseudomonal carbapenem prescribing to any significant extent. However, an association between greater usage of antipseudomonal carbapenems and greater P. aeruginosa carbapenem resistance was demonstrated. CONCLUSIONS: It is likely that the only mechanism by which ertapenem can improve P. aeruginosa resistance patterns is by being used as a substitute for, rather than in addition to, antipseudomonal carbapenems.

Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death.

BACKGROUND: Longer-term morbidity and outcomes of Cryptococcus gattii infection are not described. We analyzed clinical, microbiological, and outcome data in Australian patients followed for 12 months, to identify prognostic determinants. METHODS: Culture-confirmed C. gattii cases from 2000 to 2007 were retrospectively evaluated. Clinical, microbiological, radiological, and outcome data were recorded at diagnosis and at 6 weeks, 6 months, and 12 months. Clinical and laboratory variables associated with mortality and with death and/or neurological sequelae were determined. RESULTS: Annual C. gattii infection incidence was 0.61 per 10(6) population. Sixty-two of 86 (72%) patients had no immunocompromise; 6 of 24 immunocompromised hosts had idiopathic CD4 lymphopenia, and 1 had human immunodeficiency virus/AIDS. Clinical and microbiological characteristics of infection were similar in immunocompromised and healthy hosts. Isolated lung, combined lung and central nervous system (CNS), and CNS only disease was reported in 12%, 51% and 34% of the cases, respectively. Complications in CNS disease included raised intracranial pressure (42%), hydrocephalus (30%), neurological deficits (27%; 6% developed during therapy) and immune reconstitutionlike syndrome (11%). Geometric mean serum cryptococcal antigen (CRAG) titers in CNS disease were 563.9 (vs 149.3 in isolated lung infection). Patient immunocompromise was associated with increased mortality risk. An initial cerebrospinal fluid CRAG titer of ≥256 predicted death and/or neurological sequelae (P = .05). CONCLUSIONS: Neurological C. gattii disease predominates in the Australian endemic setting. Lumbar puncture and cerebral imaging, especially if serum CRAG titers are ≥512, are essential. Long-term follow up is required to detect late neurological complications. Immune system evaluation is important because host immunocompromise is associated with reduced survival.

A randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemodialysis patients--the HEALTHY-CATH trial.

BACKGROUND: Tunnelled central venous dialysis catheter use is significantly limited by the occurrence of catheter-related infections. This randomised controlled trial assessed the efficacy of a 48 hour 70% ethanol lock vs heparin locks in prolonging the time to the first episode of catheter related blood stream infection (CRBSI). METHODS: Patients undergoing haemodialysis (HD) via a tunnelled catheter were randomised 1:1 to once per week ethanol locks (with two heparin locks between other dialysis sessions) vs thrice per week heparin locks. RESULTS: Observed catheter days in the heparin (n=24) and ethanol (n=25) groups were 1814 and 3614 respectively. CRBSI occurred at a rate of 0.85 vs. 0.28 per 1000 catheter days in the heparin vs ethanol group by intention to treat analysis (incident rate ratio (IRR) for ethanol vs. heparin 0.17; 95%CI 0.02-1.63; p=0.12). Flow issues requiring catheter removal occurred at a rate of 1.6 vs 1.4 per 1000 catheter days in the heparin and ethanol groups respectively (IRR 0.85; 95% CI 0.20-3.5 p =0.82 (for ethanol vs heparin). CONCLUSIONS: Catheter survival and catheter-related blood stream infection were not significantly different but there was a trend towards a reduced rate of infection in the ethanol group. This study establishes proof of concept and will inform an adequately powered multicentre trial to definitively examine the efficacy and safety of ethanol locks as an alternative to current therapies used in the prevention of catheter-associated blood stream infections in patients dialysing with tunnelled catheters. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000493246.

Needleless connector decontamination for prevention of central venous access device infection: A pilot randomized controlled trial.

Pilot randomized controlled trial (180 patients) of needleless connector decontamination. Central line-associated bloodstream infection occurred in 2% (1/61) of 70% isopropyl alcohol (IPA) wipe, 2% (1/59) of 70% IPA cap, and zero (0/58) infections in 2% chlorhexidine gluconate in 70% IPA wipe patients. Larger definitive trials are feasible and needed.

Hepatitis B virus infection in hemodialysis populations: progress toward prevention.

Hemodialysis patients are at increased risk of acquiring hepatitis B virus (HBV) infection. Administration of the standard HBV vaccine is suboptimal as a means of prevention because of an impaired seroconversion response in individuals with chronic kidney disease. Surquin and colleagues describe a novel vaccine adjuvant system that increases speed of seroconversion and duration of seroprotection compared with older vaccine formulations. However, its ability to improve overall seroconversion response remains unproven.

Comparison of whole blood, serum, and plasma for early detection of candidemia by multiplex-tandem PCR.

We applied multiplex-tandem PCR (MT-PCR) to 255 EDTA whole-blood specimens, 29 serum specimens, and 24 plasma specimens from 109 patients with Candida bloodstream infection (candidemia) to determine whether a diagnosis could be expedited in comparison with the time to diagnosis by the use of standard blood culture. Overall, the MT-PCR performed better than blood culture with DNA extracted from whole blood from 52/74 (70%) patients, accelerating the time to detection (blood culture flagging) and determination of the pathogenic species (by use of the API 32C system [bioMérieux, Marcy l'Etoile, France]) by up to 4 days (mean, 2.2 days; range, 0.5 to 8 days). Candida DNA was detected more often in serum (71%) and plasma (75%) than in whole blood (54%), although relatively small numbers of serum and plasma specimens were tested. The sensitivity, specificity, positive predictive value, and negative predictive value of the assay with whole blood were 75%, 97%, 95%, and 85%, respectively. Fungal DNA was not detected by MT-PCR in 6/24 (25%) whole-blood samples drawn simultaneously with the positive blood culture sample. MT-PCR performed better with whole-blood specimens stored at -20 degrees C (75%) and when DNA was extracted within 1 week of sampling (66%). The molecular and culture identification results correlated for 61 of 66 patients (92%); one discrepant result was due to misidentification by culture. All but one sample from 53 patients who were at high risk of candidemia but did not have proven disease were negative by MT-PCR. The results demonstrate the good potential of MT-PCR to detect candidemia, to provide Candida species identification prior to blood culture positivity, and to provide improved sensitivity when applied to with serum and plasma specimens.

Intradermal versus intramuscular hepatitis B vaccination in hemodialysis patients: a prospective open-label randomized controlled trial in nonresponders to primary vaccination.

BACKGROUND: Primary hepatitis B virus (HBV) vaccination through the intramuscular (IM) route is less efficacious in dialysis patients than in the general population. Previous studies suggest improved seroconversion with intradermal (ID) vaccination. STUDY DESIGN: Prospective open-label randomized controlled trial. SETTING & PARTICIPANTS: Hemodialysis patients nonresponsive to primary HBV vaccination. INTERVENTION: Revaccination with either ID (10 microg of vaccine every week for 8 weeks) [DOSAGE ERROR CORRECTED] or IM (40 microg of vaccine at weeks 1 and 8) HBV vaccine . PRIMARY OUTCOME: proportion of patients achieving HBV surface antibody (anti-HBs) titer of 10 IU/L or greater within 2 months of vaccination course. SECONDARY OUTCOMES: time to seroconversion, predictors of seroconversion, peak antibody titer, duration of seroprotection, and safety and tolerability of vaccine. MEASUREMENTS: Anti-HBs titer to 24 months. RESULTS: 59 patients were analyzed. Seroconversion rates were 79% ID versus 40% IM (P = 0.002). The unadjusted odds ratio for seroconversion for ID versus IM was 5.5 (95% confidence interval [CI], 1.6 to 18.4) and increased with adjustment for baseline differences. The only factor predictive of seroconversion was the ID vaccination route. The geometric mean peak antibody titer was significantly greater in the ID versus IM group: 239 IU/L (95% CI, 131 to 434) versus 78 IU/L (95% CI, 36 to 168; P < 0.001). There was a trend toward longer duration of seroprotection with ID vaccination. ID vaccine was safe and well tolerated. LIMITATIONS: Inability to distinguish whether the mechanism of the greater efficacy of ID vaccination was the cumulative effect of multiple injections or route of administration; use of anti-HBs as a surrogate marker of protection; lack of evidence of long-term protection. CONCLUSIONS: Significantly greater seroconversion rates and peak antibody titers can be achieved with ID compared with IM vaccination in hemodialysis patients nonresponsive to primary vaccination. ID vaccination should become the standard of care in this setting.

Determinants of mortality in non-neutropenic ICU patients with candidaemia.

INTRODUCTION: Candidaemia in critically-ill intensive care unit (ICU) patients is associated with high crude mortality. Determinants of mortality--particularly those amenable to potential modification--are incompletely defined. METHODS: A nationwide prospective clinical and microbiological cohort study of all episodes of ICU-acquired candidaemia occurring in non-neutropenic adults was undertaken in Australian ICUs between 2001 and 2004. Multivariate Cox regression analyses were performed to determine independently significant variables associated with mortality. RESULTS: 183 episodes of ICU-acquired candidaemia occurred in 183 patients during the study period. Of the 179 with microbiological data, Candida albicans accounted for 111 (62%) episodes and Candida glabrata, 32 (18%). Outcome data were available for 173: crude hospital mortality at 30 days was 56%. Host factors (older age, ICU admission diagnosis, mechanical ventilation and ICU admission diagnosis) and failure to receive systemic antifungal therapy were significantly associated with mortality on multivariate analysis. Among the subset who received initial fluconazole therapy (n = 93), the crude mortality was 52%. Host factors (increasing age and haemodialysis receipt), but not organism- (Candida species, fluconazole MIC), pharmacokinetic- (fluconazole dose, time to initiation), or pharmacodynamic-related parameters (fluconazole dose:MIC ratio) were associated with mortality. Process of care measures advocated in recent guidelines were implemented inconsistently: follow-up blood cultures were obtained in 68% of patients, central venous catheters removed within five days in 80% and ophthalmological examination performed in 36%. CONCLUSIONS: Crude mortality remains high in Australian ICU patients with candidaemia and is overwhelmingly related to host factors but not treatment variables (the time to initiation of antifungals or fluconazole pharmacokinetic and pharmacodynamic factors). The role and timing of early antifungal intervention in critically-ill ICU patients requires further investigation.