Total flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with Staphylococcus aureus bacteraemia.

AIMS: Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (fu ) of around 0.04 in healthy individuals. The utility of measuring unbound flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare flucloxacillin fu in non-ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total flucloxacillin and plasma albumin concentrations. METHODS: Data from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma flucloxacillin concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Flucloxacillin fu for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland-Altman plots. RESULTS: The median (range) flucloxacillin fu for healthy (median albumin 45 g l-1 ) and hospitalized individuals (median albumin 30 g l-1 ) were 0.04 (0.02-0.07) and 0.10 (0.05-0.37), respectively (P < 0.0001). The prediction model underpredicted unbound flucloxacillin concentrations with a mean bias (95% limits of agreement) of -54% (-137%, +30%). CONCLUSIONS: The flucloxacillin fu values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients.

BACKGROUND: The proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations. PATIENTS AND METHODS: Unbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT≥1MIC, 50%fT≥2MIC). RESULTS: There were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT≥2MIC and 95 (95%) patients met the target of 50%fT≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0-8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8-28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations. CONCLUSIONS: Standard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.

Safety and clinical outcomes of outpatient parenteral antibiotic therapy for infective endocarditis in Christchurch, New Zealand: A retrospective cohort study.

OBJECTIVES: We examined the safety and clinical outcomes of outpatient parenteral antibiotic therapy (OPAT) for patients with infective endocarditis (IE) in Christchurch, New Zealand. METHODS: Demographic and clinical data were collected from all adult patients treated for IE over 5 years. Outcomes were stratified by receipt of at least partial OPAT vs entirely hospital-based parenteral therapy. RESULTS: There were 172 episodes of IE between 2014 and 2018. OPAT was administered in 115 cases (67%) for a median of 27 days after a median of 12 days of inpatient treatment. In the OPAT cohort, viridans group streptococci were the commonest causative pathogens (35%) followed by Staphylococcus aureus (25%) and Enterococcus faecalis (11%). There were six (5%) antibiotic-related adverse events and 26 (23%) readmissions in the OPAT treatment group. Mortality in OPAT patients was 6% (7/115) at 6 months and 10% (11/114) at 1 year and for patients receiving wholly inpatient parenteral therapy was 56% (31/56) and 58% (33/56), respectively. Three patients (3%) in the OPAT group had a relapse of IE during the 1-year follow-up period. CONCLUSION: OPAT can be used safely in patients with IE, even in selected cases with complicated or difficult-to-treat infections.

Clinical, Laboratory, and Molecular Epidemiology of an Outbreak of Aseptic Meningitis Due to a Triple-Recombinant Echovirus in Ashburton, New Zealand.

Here, we describe a small enterovirus outbreak including nine cases of aseptic meningitis in a New Zealand hospital in 2017. Most patients had a lymphocytic predominance in the CSF, their length of stay was short, and there were no paediatric cases or ICU admissions. VP1 genotyping revealed that the outbreak was caused by an echovirus E30 strain closely related to strains reported from the US, UK, Brazil, and Denmark. They all form a separate cluster within lineage "h", which leads to the proposal of establishing a new lineage tentatively named "j" for this group of echovirus E30 strains. However, whole genome sequencing and reference mapping to echovirus E30 sequences showed very poor mapping of reads to the 3' half of the genome. Further bioinformatic analysis indicated that the causative agent of this outbreak might be a mosaic triple-recombinant enterovirus composed of echovirus E6, echovirus E11, and echovirus E30 genome segments.

Elizabethkingia miricola bacteraemia in a haemodialysis patient.

We report a case of catheter-associated Elizabethkingia miricola bacteraemia in a haemodialysis patient. The patient was a 73-year-old home haemodialysis patient who presented with a history of recurrent falls and fevers. Blood cultures grew Gram-negative bacilli identified by MALDI-TOF MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry 6903 MSP Library) and 16S rRNA gene sequencing as E. miricola. E. miricola is an emerging human pathogen and is multidrug-resistant, making the choice of antimicrobial therapy challenging. There are only a small number of case reports of human infection worldwide and this is the second reported case of catheter-related bacteraemia. It has also been found in the hospital environment in South Korea and is pathogenic in black-spotted frogs.

Point prevalence surveys of antimicrobial use in adult inpatients at Canterbury District Health Board Hospitals.

AIMS: To determine the nature and appropriateness of antimicrobial prescribing in adult inpatients at Canterbury District Health Board (CDHB). METHODS: Multidisciplinary teams collected clinical details for all adult inpatients on antimicrobial therapy at three CDHB facilities (~1,100 beds) and made standardised assessments based on the Australian National Antimicrobial Prescribing Survey (http://naps.org.au) against local guidelines and national funding criteria. RESULTS: Antimicrobial therapy was prescribed to 42% of inpatients (322/760), usually to treat infections [377/480 prescriptions (79%)], with amoxicillin+clavulanic acid the agent most commonly prescribed [72/480 prescriptions (15%)]. Of assessable prescriptions, 74% (205/278) were guideline compliant, 98% (469/480) were funding criteria compliant, and 83% (375/451) were appropriate clinically. Prescriptions for the most common indications-surgical prophylaxis [66/480 (14%)] and community-acquired pneumonia [56/480 (12%)]-were often non-compliant with guidelines (32% and 41%, respectively) and inappropriate (18% and 21%, respectively). Overall, the indication was documented in 353/480 (74%) prescriptions, the review/stop date documented in 145/480 (30%) prescriptions, and surgical prophylaxis stopped within 24 hours in 53/66 (80%) prescriptions. CONCLUSIONS: Most antimicrobial prescriptions were appropriate and complied with guidelines. Compliance with key quality indicators (indication documented, review/stop date documented, and surgical prophylaxis ceased within 24 hours) were well below target (>95%) and needs improvement.

Determinants of vancomycin nephrotoxicity when administered to outpatients as a continuous 24-hour infusion.

Vancomycin continuous infusion (VCI) is used to treat serious Gram-positive infections in outpatients. This study was conducted to retrospectively investigate the rate of nephrotoxicity and associated risk factors in out-patients on VCI between May 2013 and November 2018. Vancomycin concentration was monitored twice-weekly to ensure adequate concentrations while avoiding high concentrations linked to nephrotoxicity (a rise in serum creatinine of ≥50% or 44 µmol/L from baseline). The likelihood of developing nephrotoxicity was evaluated using multivariable logistic regression. The 223 patients treated had a mean (standard deviation) age of 61 (16.7) years, baseline serum creatinine of 83.9 (21.2) µmol/L and estimated glomerular filtration rate (eGFR) of 80.6 (20.1) mL/min/1.73m2. Most patients (66%) were treated for bone and joint infections. Eight patients (3.6%) developed nephrotoxicity. In the most parsimonious model, nephrotoxicity was independently associated with an increased median (interquartile range) weighted-average serum vancomycin concentration (28.0 [24.3-32.6] vs. 22.4 [20.2-24.5] mg/L; odds ratio [OR] 1.25; 95% confidence interval [95% CI] 1.09-1.46; P<0.002) and Charlson co-morbidity index (OR 1.62; 95% CI 1.07-2.47; P=0.02). Post-hoc analysis identified 26 patients with a lower nephrotoxicity threshold (rise in serum creatinine of ≥30% or 27 µmol/L). Independent predictors of nephrotoxicity in this group were an increased weighted-average vancomycin concentration, diabetes, con-gestive heart failure and exposure to non-loop diuretics. The nephrotoxicity rate during VCI in this study was lower than previously reported (3.6% vs 15.0-17.0%).  Reducing the weighted-average serum vancomycin concentration may reduce nephrotoxicity while maintaining efficacy.

Outpatient parenteral antimicrobial therapy (OPAT) in Christchurch: 18 years on.

AIM: Outpatient parenteral antimicrobial therapy (OPAT) has become an established option for management infections requiring intravenous therapy. As the uptake of OPAT has increased, the clinical governance has changed and is now managed via virtual clinics and increased use of district nurses in addition to specialist outpatient review. The aim of this study was to report the characteristics, diagnoses, treatment and outcomes of patients managed by the service over 12 months in 2015/6 and compared these features with those of patients treated with OPAT in 1999. METHODS: Cases for 2015/6 were identified from the OPAT service database which records prospectively all information on diagnosis, antibiotic choice and duration of treatment, complications and requirement for review by the ID physicians and OPAT nurses prospectively. The outcomes, complications and readmissions were found by reviewing computerised records of Christchurch Hospital. All results were entered into a Microsoft® Excel database for analysis. Statistical analyses were performed using OpenEpi software. Data for 1999 was taken from an earlier publication. RESULTS: OPAT treatment in 12 months from 1 July 2015 was administered 407 times to 385 patients, which represented a 2.7 times increase in treatment courses than in 1999. The median age was 55 years in 1999 and 61 in 2015/6. There was a substantial increase in the proportion of bone and joint, abdominal and urinary tract infections but a fall in cellulitis and soft tissue infection. The number and proportion of patients treated with broad spectrum agents including piperacillin + tazobactam, ceftriaxone and carbapenems increased from 1% in 1999 to 20% in 2015/6. Unplanned readmission to hospital increased from 15 (10%) in 1999 to 62 patients (15%) in 2015/6. The most common reason for readmission in 2015/6 was for ongoing symptoms or progression of the infection requiring OPAT. Eight patients (2%) required readmission from adverse reactions to antimicrobial therapy. Two patients on palliative care died while on OPAT and 35 (9%) within 12 months of the index admission. CONCLUSION: OPAT use has increased and is used to treat patients with comorbidities, who are older, and with a different case-mix than 1999. Safety has not been compromised but the risk of treatment failure has increased. A better understanding of the reasons for treatment failure would improve patient selection and management with OPAT.

Diagnosis of abdominal tuberculosis in Christchurch New Zealand: a case series.

AIM: Abdominal tuberculosis presents with non-specific symptoms, including generalised abdominal pain. Prompt and accurate diagnosis is critical to improving outcomes and avoiding complications. We conducted a retrospective review of cases of abdominal tuberculosis presenting to Christchurch Hospital to explore the epidemiology, clinical features and diagnostic modalities used. METHOD: Cases were identified by searching for relevant ICD discharge codes from January 1996 to January 2016. Data on age, clinical presentation, investigations and microbiological results were obtained. RESULTS: There were 20 patients diagnosed with abdominal tuberculosis over the study period. The median age was 34. Thirteen patients were male (65%), seven female (35%). The majority (11) were from Asia (predominantly India), five were African, and three were New Zealand Europeans. Abdominal pain was the most common presenting symptom (70%) followed by fevers (50%) and night sweats (50%). The C-reactive protein was elevated in 15 patients (75%), anaemia was found in 11 (55%) and nine had abnormal liver function tests (45%). Abdominal ultrasound (US) and computed tomography (CT) showed generic inflammatory change in all patients in this series (100%). Laparoscopy was undertaken in 10 (50%) patients, all of which had positive laparoscopic biopsies. Ascitic fluid was obtained in nine, with stains for acid-fast bacilli uniformly negative, however three (33%) had mycobacterial growth from culture. Six colonoscopies were performed: in three (50%) culture and/or histology was positive. Three lymph node biopsies and two formal laparotomies were the remaining diagnostic techniques employed with two biopsies and one laparotomy yielding positive results. Overall, of the 20 cases, 15 (75%) were able to be definitively confirmed, with the remaining five treated presumptively for probable abdominal tuberculosis. CONCLUSION: Abdominal tuberculosis is an uncommon presentation at our institution, with an average of one case each year. The typical patient was a young immigrant from Asia or Africa. Diagnostic laparoscopy was the most common and uniformly reliable means of obtaining a definitive diagnosis.

Metronidazole stewardship initiative at Christchurch hospitals-achievable with immediate benefits.

AIMS: To evaluate an antimicrobial stewardship (AMS) initiative to change hospital prescribing practice for metronidazole. METHODS: In October 2015, the Canterbury District Health Board (CDHB) AMS committee changed advice for metronidazole to promote two times daily dosing for most indications, prioritisation of the oral route and avoidance of double anaerobic cover. Adoption of the initiative was facilitated via change in prescribing guidelines, education and ongoing pharmacy support. Usage and expenditure on metronidazole for adult inpatients were compared for the five years pre- and two years post-change. Other district health boards (DHBs) were surveyed to determine their dosing recommendation for metronidazole IV. RESULTS: Mean annual metronidazole IV use, as defined daily doses per 1,000 occupied bed days, decreased by 43% post-initiative. Use of non-IV (oral or rectal) formulations increased by 104%. Total savings associated with the initiative were approximately $33,400 in drug costs plus $78,200 per annum in IV giving sets and post-dose flushes. Twelve of 20 (60%) DHBs (including CDHB) endorse twice daily IV dosing. CONCLUSIONS: In addition to financial savings, reduction in IV doses has potential benefits, including avoidance of IV catheter-associated complications such as bloodstream infections. Approaches to metronidazole dosing vary across DHBs and could benefit from national coordination.

The current crisis in human resources for health in Africa: the time to adjust our focus is now.

The challenges as we strive towards universal health coverage are many, but the need for an improved health workforce is chief among them. Unfortunately the global deficit in skilled professionals continues to increase. Nevertheless, there are potential solutions, and success stories are well documented when the approach is on system building and sustainability. As we approach 2015 and the Millennium Development Goals, we must shift our focus to a more distant time point in order to achieve the dramatic gains in global health that are possible. However, we must understand that there can be no health without a workforce.