Neurotuberculosis with paradoxical reaction treated with infliximab: case report and literature review.

Paradoxical reactions are immune-mediated disease exacerbations that can occur in Mycobacterium tuberculosis (TB) following initiation of treatment. They are rare, challenging to manage and often fatal. We present a case of neurotuberculosis in a young woman, complicated by a paradoxical reaction in which infliximab was trialled without success. This case demonstrates the severity of presentation that can occur in neurotuberculosis, and the complications that paradoxical reactions can present. It also highlights the difficulty of delivering palliative care within the context of communicable disease with challenges posed by both TB and the COVID-19 pandemic.

Ethnic differences in those presenting for outpatient management of venous leg ulcers.

AIM: To describe the demographics of those presenting to Capital & Coast DHB District Nursing Service with venous leg ulcers (VLU). METHODS: Electronic records were searched between January 2015 and December 2020 for those presenting with VLU and matched to the national minimum dataset to obtain ethnicity, age at presentation and gender. Numbers were standardised against the census data for the DHB population, to allow comparison of ethnic differences. Analysis was by prioritised ethnicity: comparing Pasifika, Maori and Other. RESULTS: Of 999 patients with VLU treated by the DN service, there were 91 Maori, 114 Pasifika, and 794 other ethnicities. Five hundred and fifty-nine were female and 440 were male. Pasifika men and women were greatly over-represented with relative risks of 20 and 19, respectively. Maori men and women had lower relative risk of 6.6 and 5.0, respectively. In addition, Maori and Pasifika presented earlier, with standardised rates greater than other ethnicities in all age groups up to the age of 70. Average age at presentation for Maori was 14-16, and Pasifika 17-18 years, younger than Other. CONCLUSION: This analysis shows for the first time that Maori and Pasifika have higher rates and present earlier than those of other ethnicities. Further investigation is required to understand the causes of earlier presentation and thereby prevent VLU.

Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors.

The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, 5c and 3k, originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as in vitro absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor 3k guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an in vitro SARS-CoV-2 infection model, justifying further optimization.

COVID-19 serology: use and interpretation in New Zealand.

Serology is now a well-established diagnostic tool for the diagnosis of COVID-19 infections in New Zealand. Using local and international experience, we provide an overview of serological response to infection and vaccination as well as the use and interpretation of antibody tests in our setting. We also discuss the potential future role of post-vaccination serology testing as a correlate of immunity. We conclude that, given the pitfalls of testing, clinical microbiologist advice is necessary for interpretation of high-consequence cases.

COVID-19 serology: use and interpretation in New Zealand.

Serology is now a well-established diagnostic tool for the diagnosis of COVID-19 infections in New Zealand. Using local and international experience, we provide an overview of serological response to infection and vaccination as well as the use and interpretation of antibody tests in our setting. We also discuss the potential future role of post-vaccination serology testing as a correlate of immunity. We conclude that, given the pitfalls of testing, clinical microbiologist advice is necessary for interpretation of high-consequence cases.

Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2.

The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin-binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self-processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.

Towards elimination of tuberculosis in New Zealand.

New Zealand could be the first country in the world to eliminate tuberculosis (TB). We propose a TB elimination strategy based on the eight-point World Health Organization (WHO) action framework for low incidence countries. Priority actions recommended by the WHO include 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) identify active TB and undertake screening for latent tuberculosis infection (LTBI) in recent TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. In New Zealand, central government needs to take greater responsibility for TB policy and programme governance. Urgent action is required to prevent TB in higher risk groups including Maori communities, and to enable immigration screening to detect and treat LTBI. Clinical services need to be supported to implement new guidelines for LTBI that enable better targeting of screening and shorter, safer treatment regimens. Access to WHO recommended treatment regimens needs to be guaranteed for drug-resistant TB. Better use of existing data could better define priority areas for action and assist in the evaluation of current control activities. Access to GeneXpert® MTB-RIF near the point of care and whole genome sequencing nationally would greatly improve clinical and public health management through early identification of drug resistance and outbreaks. New Zealand already has a world-class TB research community that could be better deployed to assist high-incidence countries through research and training.

Optimization of 5-substituted thiazolyl ureas and 6-substituted imidazopyridines as potential HIV-1 latency reversing agents.

A persistent latent reservoir of virus in CD4+ T cells is a major barrier to cure HIV. Activating viral transcription in latently infected cells using small molecules is one strategy being explored to eliminate latency. We previously described the use of a FlpIn.FM HEK293 cellular assay to identify and then optimize the 2-acylaminothiazole class to exhibit modest activation of HIV gene expression. Here, we implement two strategies to further improve the activation of viral gene expression and physicochemical properties of this class. Firstly, we explored rigidification of the central oxy-carbon linker with a variety of saturated heterocycles, and secondly, investigated bioisosteric replacement of the 2-acylaminothiazole moiety. The optimization process afforded lead compounds (74 and 91) from the 2-piperazinyl thiazolyl urea and the imidazopyridine class. The lead compounds from each class demonstrate potent activation of HIV gene expression in the FlpIn.FM HEK293 cellular assay (both with LTR EC50s of 80 nM) and in the Jurkat Latency 10.6 cell model (LTR EC50 220 and 320 nM respectively), but consequently activate gene expression non-specifically in the FlpIn.FM HEK293 cellular assay (CMV EC50 70 and 270 nM respectively) manifesting in cellular cytotoxicity. The lead compounds have potential for further development as novel latency reversing agents.

The burden of Legionnaires' disease in New Zealand (LegiNZ): a national surveillance study.

BACKGROUND: Legionnaires' disease is under-diagnosed because of inconsistent use of diagnostic tests and uncertainty about whom to test. We assessed the increase in case detection following large-scale introduction of routine PCR testing of respiratory specimens in New Zealand. METHODS: LegiNZ was a national surveillance study done over 1-year in which active case-finding was used to maximise the identification of cases of Legionnaires' disease in hospitals. Respiratory specimens from patients of any age with pneumonia, who could provide an eligible lower respiratory specimen, admitted to one of 20 participating hospitals, covering a catchment area of 96% of New Zealand's population, were routinely tested for legionella by PCR. Additional cases of Legionnaires' disease in hospital were identified through mandatory notification. FINDINGS: Between May 21, 2015, and May 20, 2016, 5622 eligible specimens from 4862 patients were tested by PCR. From these, 197 cases of Legionnaires' disease were detected. An additional 41 cases were identified from notification data, giving 238 cases requiring hospitalisation. The overall incidence of Legionnaires' disease cases in hospital in the study area was 5·4 per 100 000 people per year, and Legionella longbeachae was the predominant cause, found in 150 (63%) of 238 cases. INTERPRETATION: The rate of notified disease during the study period was three-times the average over the preceding 3 years. Active case-finding through systematic PCR testing better clarified the regional epidemiology of Legionnaires' disease and uncovered an otherwise hidden burden of disease. These data inform local Legionnaires' disease testing strategies, allow targeted antibiotic therapy, and help identify outbreaks and effective prevention strategies. The same approach might have similar benefits if applied elsewhere in the world. FUNDING: Health Research Council of New Zealand.

Genomic correlates of extraintestinal infection are linked with changes in cell morphology in Campylobacter jejuni.

Campylobacter jejuni is the most common cause of bacterial diarrheal disease in the world. Clinical outcomes of infection can range from asymptomatic infection to life-threatening extraintestinal infections. This variability in outcomes for infected patients has raised questions as to whether genetic differences between C. jejuni isolates contribute to their likelihood of causing severe disease. In this study, we compare the genomes of ten C. jejuni isolates that were implicated in extraintestinal infections with reference gastrointestinal isolates, in order to identify unusual patterns of sequence variation associated with infection outcome. We identified a collection of genes that display a higher burden of uncommon mutations in invasive isolates compared with gastrointestinal close relatives, including some that have been previously linked to virulence and invasiveness in C. jejuni. Among the top genes identified were mreB and pgp1, which are both involved in determining cell shape. Electron microscopy confirmed morphological differences in isolates carrying unusual sequence variants of these genes, indicating a possible relationship between extraintestinal infection and changes in cell morphology.

Choosing wisely in infectious serology: the merits of triaging send-away tests.

Over-utilisation of pathology requests can incur unnecessary costs and be detrimental to patient care. The choosing wisely campaign has helped to reduce the use of tests with limited or no value. This report describes the estimated benefits and costs of implementing a triage process of infectious serology requests in a single mixed hospital and community laboratory. Data analysis of triaging of send away infectious serology was conducted from 1 November 2016 to 31 October 2017. A total of 618 tests were triaged over a 1-year period. Of these 379 (61.3%) were declined. The total gross savings was $45,066. The total cost for implementing this change was estimated to be $4220 per year. The total saving was $40,846.37. There was significant cost saving secondary to this intervention, with other more difficult to measure tangible benefits including fostering communication between laboratory staff and clinicians.

Caesarean section wound infection surveillance: Information for action.

Surgical site infection (SSI) following caesarean section is common, resulting in significant morbidity. Several factors are known to contribute to wound infection, including maternal, procedural and antibiotic factors. We sought to clarify these issues and sought opportunities to make improvements. A retrospective cohort study was performed assessing all women who underwent caesarean section in 2014 and 2015 at Wellington Hospital. Any women with culture-positive wound samples within 30 days of surgery were identified, and clinical notes reviewed. Odds ratios (OR) were calculated for available maternal, procedural and antibiotic risk factors. Two simplified surveillance techniques were also tested for their abilities to identify significant trends. The study included 2231 women, of whom 116 (5.2%) were identified as having SSI. Maternal obesity (body mass index (BMI) ≥ 30) was associated with significant SSI risk (OR 4.1, P < 0.001). The pathogen distribution was significantly different between women with BMI < 30 and BMI ≥ 30 (P < 0.001). Increased cefazolin dose based on BMI (3 g dose for BMI ≥ 30) was associated with a significant reduction in SSI (OR 0.309, P < 0.001) and was administered in 74.1% of obese women receiving cefazolin. Maori women had an increased SSI risk (OR 2.1, P = 0.019), as did Samoan women (OR 3.0, P = 0.002). The study reinforces other studies showing that raised BMI is the single biggest risk factor for surgical site infection post-caesarean section. Surveillance using simplified techniques appears to be adequate to identify trends. We believe that concentrating on appropriate antibiotic dosing and targeting special wound care measures will be pivotal interventions in improving outcomes in high-risk groups.

Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination.

AIM: To assess the impact of the introduction of rotavirus vaccination in New Zealand at a regional and national level, underlining the utility of a passively collected laboratory dataset. METHOD: Retrospective laboratory data for rotavirus testing from Wellington and Hutt Hospitals from 1 January 2010 to 31 December 2016, matched with hospital admissions data of children under 5years of age with gastroenteritis primary and secondary coded admissions. The second part of the study examined the national dataset of primary coded hospital gastroenteritis admissions from the same period. RESULTS: Rotavirus testing was performed in 1054 (64.1%) of the 1645 gastroenteritis admissions to Wellington and Hutt Hospitals. Four hundred and nine of these tests (38.8%) were positive. Children who were not given a primary code of gastroenteritis accounted for 5.7% of rotavirus admissions. The estimated annual rotavirus hospitalisation rate in the Hutt and Wellington regions for children under 5years during the pre-vaccination period was 427.1 per 100,000. In the post-vaccination period (2015-2016), there was a 94.6% reduction in confirmed rotavirus gastroenteritis hospitalisations with only 8 confirmed cases. The total number of gastroenteritis admissions declined by 51.4%. On a national scale, there was a decline of 34.4% in the average annual number of gastroenteritis admissions and the number of coded rotavirus admissions was 87.1% lower than the pre-vaccination average. CONCLUSION: The non-restrictive continuous approach to rotavirus testing has provided a detailed description of the epidemiology of rotavirus gastroenteritis hospitalisations in the Wellington and Hutt regions. Rotavirus vaccination introduced on the crest of a peak in rotavirus cases has lead to a marked reduction in the number of admissions with gastroenteritis in New Zealand in the two years following vaccine introduction. The national figures likely underestimate the impact of the vaccine.

Routine Ertapenem Prophylaxis for Transrectal Ultrasound Guided Prostate Biopsy does Not Select for Carbapenem Resistant Organisms: A Prospective Cohort Study.

PURPOSE: Sepsis after transrectal ultrasound guided prostate biopsy is an increasing problem in this era of rising antibiotic resistance. Although ertapenem prophylaxis has proved effective at our institution to reduce this, it has raised local and regional antimicrobial stewardship concerns. We investigated the possible selective effect of single dose ertapenem prophylaxis on fecal colonization with carbapenem resistant Enterobacteriaceae. MATERIALS AND METHODS: Patients underwent a rectal swab prior to receiving prebiopsy ertapenem prophylaxis. A second swab was obtained at followup 4 to 6 weeks later. Swabs were screened for carbapenem resistant Enterobacteriaceae using an enhanced CDC (Centers for Disease Control) method. Prebiopsy swabs were also screened for extended spectrum ß-lactamase producing and ciprofloxacin resistant Enterobacteriaceae. Patients were monitored for post-biopsy sepsis. RESULTS: A total of 326 patients were enrolled in the study. At baseline 6.4% and 9.0% of patients had colonization with extended spectrum ß-lactamase producing and ciprofloxacin resistant Enterobacteriaceae, respectively. Carbapenem resistant Enterobacteriaceae were not detected at baseline or followup in any patients. Colonization with nonfermentative organisms with intrinsic ertapenem resistance was detected in 29.4% of patients at baseline and followup (p = 1.0). Three cases (0.9%, 95% CI 0.2-2.8) of probable post-biopsy sepsis were identified during the study period. None was bacteremic or required intensive care unit admission. CONCLUSIONS: Single dose ertapenem prophylaxis did not appear to have a significant selective effect on fecal colonization with carbapenem resistant Enterobacteriaceae or other ertapenem resistant gram-negative organisms in this outpatient group. It is highly effective prophylaxis for transrectal ultrasound guided prostate biopsy. In the right setting ertapenem may represent a useful prophylactic option to prevent post-transrectal ultrasound guided prostate biopsy sepsis.

Randomized controlled trial of the effect of regular paracetamol on influenza infection.

BACKGROUND AND OBJECTIVE: Anti-pyretic treatment is recommended in the management of influenza infection. In animal models anti-pyretic treatment increases mortality from influenza. We investigated the effects of paracetamol on viral and clinical outcomes in adults with influenza infection. METHODS: This is a randomized, double-blind, placebo-controlled trial of adults aged 18-65 years with influenza-like illness and positive influenza rapid antigen test. Treatments were 1 g paracetamol four times a day, or matching placebo, for 5 days. Pernasal swabs were taken for influenza quantitative RT-PCR at Baseline and Days 1, 2 and 5. Temperature and symptom scores were recorded for 5-14 days or time of resolution respectively. The primary outcome variable was area under the curve (AUC) for quantitative PCR log10 viral load from Baseline to Day 5. RESULTS: A total of 80 participants were randomized: no one was lost to follow up, and one withdrew after 4 days. There were 22 and 24 participants who were influenza PCR-positive in placebo and in paracetamol groups respectively. Mean (SD) AUC PCR log10 viral load was 4.40 (0.91) in placebo and 4.64 (0.88) in paracetamol; difference was -0.24, 95% CI: -0.78 to 0.29, P = 0.36. In all participants there were no differences in symptom scores, temperature, time to resolution of illness and health status, with no interaction between randomized treatment and whether influenza was detected by PCR. CONCLUSION: Regular paracetamol had no effect on viral shedding, temperature or clinical symptoms in patients with PCR-confirmed influenza. There remains an insufficient evidence base for paracetamol use in influenza infection. CLINICAL TRIAL REGISTRATION: ACTRN12611000497909 at the Australian New Zealand Clinical Trials Registry.