Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010-16.

Background: The need for antifungal stewardship is gaining recognition with increasing incidence of invasive fungal infection (IFI) and antifungal resistance alongside the high cost of antifungal drugs. Following an audit showing suboptimal practice we initiated an antifungal stewardship programme and prospectively evaluated its impact on clinical and financial outcomes. Patients and methods: From October 2010 to September 2016, adult inpatients receiving amphotericin B, echinocandins, intravenous fluconazole, flucytosine or voriconazole were reviewed weekly by an infectious diseases consultant and antimicrobial pharmacist. Demographics, diagnosis by European Organization for Research and Treatment of Cancer (EORTC) criteria, drug, indication, advice, acceptance and in-hospital mortality were recorded. Antifungal consumption and expenditure, and candidaemia species and susceptibility data were extracted from pharmacy and microbiology databases. Results: A total of 432 patients were reviewed, most commonly receiving AmBisome® (35%) or intravenous fluconazole (29%). Empirical treatment was often unnecessary, with 82% having no evidence of IFI. Advice was given in 64% of reviews (most commonly de-escalating or stopping treatment) and was followed in 84%. Annual antifungal expenditure initially reduced by 30% (£0.98 million to £0.73 million), then increased to 20% above baseline over a 5 year period; this was a significantly lower rise compared with national figures, which showed a doubling of expenditure over the same period. Inpatient mortality, Candida species distribution and rates of resistance were not adversely affected by the intervention. Conclusions: Provision of specialist input to optimize antifungal prescribing resulted in significant cost savings without compromising on microbiological or clinical outcomes. Our model is readily implementable by hospitals with high numbers of at-risk patients and antifungal expenditure.

The human transcriptome during nontyphoid Salmonella and HIV coinfection reveals attenuated NFkappaB-mediated inflammation and persistent cell cycle disruption.

BACKGROUND: Invasive nontyphoid Salmonella (iNTS) disease is common and severe in adults with human immunodeficiency virus (HIV) infection in Africa. We previously observed that ex vivo macrophages from HIV-infected subjects challenged with Salmonella Typhimurium exhibit dysregulated proinflammatory cytokine responses. METHODS: We studied the transcriptional response in whole blood from HIV-positive patients during acute and convalescent iNTS disease compared to other invasive bacterial diseases, and to HIV-positive and -negative controls. RESULTS: During iNTS disease, there was a remarkable lack of a coordinated inflammatory or innate immune signaling response. Few interferon γ (IFNγ)-induced genes or Toll-like receptor/transcription factor nuclear factor κB (TLR/NFκB) gene pathways were upregulated in expression. Ex vivo lipopolysacharide (LPS) or flagellin stimulation of whole blood, however, showed that convalescent iNTS subjects and controls were competent to mount prominent TLR/NFκB-associated patterns of mRNA expression. In contrast, HIV-positive patients with other invasive bacterial infections (Escherichia coli and Streptococcus pneumoniae) displayed a pronounced proinflammatory innate immune transcriptional response. There was also upregulated mRNA expression in cell cycle, DNA replication, translation and repair, and viral replication pathways during iNTS. These patterns persisted for up to 2 months into convalescence. CONCLUSIONS: Attenuation of NFκB-mediated inflammation and dysregulation of cell cycle and DNA-function gene pathway expression are key features of the interplay between iNTS and HIV.

Fever in the returning traveller.

Global travel is increasingly a fact of modern life, and the rapid spread of severe acute respiratory syndrome coronavirus 2 leading to lockdown across the world has demonstrated the interconnectedness of the world's population. Illness in the returning traveller can range from trivial to life-threatening, and the concept of imported infection can be an intimidating diagnostic and management challenge. An important caveat is that even if your patient has returned from cuddling multimammate rats in Guinea 1 week ago, they could be febrile from a distinctly non-tropical urinary tract infection. That said, antimicrobial resistance is an established concern among returned travellers, which has further infection control implications. Infection control issues regarding isolation, personal protective equipment and notification to public health should always be considered for returning travellers on presentation often before diagnostic confirmation has been made. Always consider the risk of high-consequence infectious diseases.

Spinal Syphilitic Gumma: A Rare Presentation of an Old Disease.

Syphilis is an ancient condition which still is of global concern today. Despite better awareness amongst clinicians and improving diagnostics, it remains likely underdiagnosed in part because of its namesake the 'great imitator.' While many patients suffer primary or secondary disease, tertiary syphilis characterised by gumma is rare, especially in the context of neurosyphilis. Here, we report a rare case of a well-controlled human immunodeficiency virus- (HIV-) positive gentleman with a history of previous syphilis and epilepsy who presented with progressive left leg weakness leading to immobility and altered bowels and, on neurological examination, Brown-Sequard syndrome. Magnetic resonance imaging (MRI) of the spine revealed two peripherally enhancing cavitating lesions at T4-T5 with associated meningeal thickening and cord oedema. Cerebrospinal fluid (CSF) analysis revealed high protein (3.07 g/dL) and white cell count (7 × 109/L) with negative cryptococcal antigen, tuberculosis molecular testing (GeneXpert), microscopy and culture, and viral polymerase chain reaction (PCR). CSF serology was positive for Treponema pallidum particle agglutination (TPPA) 10240 and RPR 1 in 2 suggesting active disease. While TB treatment had been started prior to these investigations on day 11, 14-day high-dose benzylpenicillin therapy commenced. Repeat MRI of the spine at days 12 and 22 showed incremental improvements in all parameters which correlated with improving functionality and neurology. According to our literature search, this represents the 13th case recorded for spinal syphilitic gumma and the only case recorded in a HIV-positive individual and adds to the evidence that, in the absence of rapidly changing neurology, medical management can lead to good clinical outcomes.

Presentations and outcomes of central nervous system TB in a UK cohort: The high burden of neurological morbidity.

OBJECTIVES: Most data for Central Nervous System Tuberculosis (CNS-TB) derive from high-incidence, resource-limited countries. We sought to determine the presentation, management and outcomes of CNS-TB in a low-incidence setting with accessible healthcare. METHODS: We undertook a retrospective, observational study of CNS-TB in adults at a single tertiary-referral London hospital (2001-2017). Cases were categorised as either TB meningitis (TBM) or TB mass lesions without meningitis (TBML), applying novel criteria for definite, probable, and possible TBML. RESULTS: We identified sixty-two cases of TBM (37% definite; 31% probable; 32% possible) alongside 14 TBML cases (36% definite; 29% probable; and 36% possible). Clinical presentation was highly variable. Among CSF parameters, hypoglycorrhachia proved most discriminatory for "definite" TBM. Neurosurgical intervention was required for mass-effect or hydrocephalus in 16%. Mortality was higher in TBM versus TBML (16% vs. 0%) but overall morbidity was significant; 33% of TBM and 29% of TBML survivors suffered persisting neurological disability at 12-months. In TBM, hydrocephalus, infarct, basal enhancement and low CSF white cell count were independently associated with worse neurological outcomes. CONCLUSION: Although mortality was lower than previously reported in other settings, morbidity was significant, highlighting the need for improved CNS-TB diagnostics, therapeutics and interventions to mitigate neurological sequelae.

XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing.

OBJECTIVES: We describe the first published cluster of extensively drug resistant Tuberculosis (XDR-TB) in the UK and show how early whole genome sequencing (WGS) of Mtb can assist in case management and contact investigations. METHODS: We describe the contact tracing investigation undertaken after the presentation of an adult with XDR-TB. Active cases were treated with an XDR-TB drug regimen and contacts underwent a programme of follow-up for 2 years. All isolates of Mycobacterium tuberculosis (Mtb) were assessed early using whole genome sequencing (WGS) as well as routine drug susceptibility testing (DST). RESULTS: Thirty-three contacts were screened. In the first year one confirmed and one probable case were identified through contact tracing. A further possible case was identified through epidemiological links. Two confirmed cases were identified through WGS 2 years later. Twenty-five (80%) contacts without evidence of tuberculosis were adherent to 1 year of follow-up and 14 (45%) were adherent to 2 years of follow-up. WGS of Mtb was used to guide drug choices, rapidly identify transmission events, and alter public health management. CONCLUSION: WGS of Mtb enabled rapid effective individualized treatment and facilitated public health interventions by early identification of transmission events.

Taurine transport into fetal cord blood cells: inhibition by cyclosporine A.

OBJECTIVES: Pregnant women undergoing long-term organ transplant treatment have an increased incidence of delivering infants with intrauterine growth restriction (IUGR). Cyclosporine A is used as an immunosuppressant in such women and indirect evidence suggests that IUGR might result from an effect of cyclosporine A on amino acid transport by the placenta. In this study we tested the hypothesis that the transport of an essential amino acid, taurine, by fetal tissue other than the placenta is modulated by cyclosporine A. METHODS: Cord blood cells (CBCs) were used to test this hypothesis as an easily obtainable fetal tissue. Transport of taurine into CBCs was measured using standard tracer flux assays. RESULTS: Uptake of [(3)H] taurine by CBCs was linear over 15 minutes (76.2 +/- 16.6 fmol/10(6) cells/min, mean +/- SEM, n = 6) and inhibitable by 10 mM beta-alanine, a substrate of the system-beta taurine transport protein (6.7 +/- 1.0 fmol/10(6) cells/min, n = 6, P <.05, paired Student t test). Pre-incubation with cyclosporine A (5 microM) inhibited [(3)H] taurine uptake by 29.3%-5.3% (n = 8, P <.05, paired Student t test). CONCLUSIONS: These data show that amino acid transport via system-beta can be measured in CBCs and may be a useful model for amino acid transport studies in fetal cells. We also show that system-beta was inhibited by the immunosuppressant, cyclosporine A. This suggests that the increased incidence of IUGR reported in mothers treated with cyclosporine A may be due partially to effects on taurine uptake into fetal cells outside the placenta.

A reduction in adult blood stream infection and case fatality at a large African hospital following antiretroviral therapy roll-out.

INTRODUCTION: Blood-stream infection (BSI) is one of the principle determinants of the morbidity and mortality associated with advanced HIV infection, especially in sub-Saharan Africa. Over the last 10 years, there has been rapid roll-out of anti-retroviral therapy (ART) and cotrimoxazole prophylactic therapy (CPT) in many high HIV prevalence African countries. METHODS: A prospective cohort of adults with suspected BSI presenting to Queen's Hospital, Malawi was recruited between 2009 and 2010 to describe causes of and outcomes from BSI. Comparison was made with a cohort pre-dating ART roll-out to investigate whether and how ART and CPT have affected BSI. Malawian census and Ministry of Health ART data were used to estimate minimum incidence of BSI in Blantyre district. RESULTS: 2,007 patients were recruited, 90% were HIV infected. Since 1997/8, culture-confirmed BSI has fallen from 16% of suspected cases to 10% (p<0.001) and case fatality rate from confirmed BSI has fallen from 40% to 14% (p<0.001). Minimum incidence of BSI was estimated at 0.03/1000 years in HIV uninfected vs. 2.16/1000 years in HIV infected adults. Compared to HIV seronegative patients, the estimated incidence rate-ratio for BSI was 80 (95% CI:46-139) in HIV-infected/untreated adults, 568 (95% CI:302-1069) during the first 3 months of ART and 30 (95% CI:16-59) after 3 months of ART. CONCLUSIONS: Following ART roll-out, the incidence of BSI has fallen and clinical outcomes have improved markedly. Nonetheless, BSI incidence remains high in the first 3 months of ART despite CPT. Further interventions to reduce BSI-associated mortality in the first 3 months of ART require urgent evaluation.

Reversible mental status change and renal dysfunction associated with the use of high-dose oral valaciclovir therapy for acute retinal necrosis.

PURPOSE: The purpose of this study was to report the case of a patient with acute retinal necrosis who developed neurotoxicity while being treated with oral valaciclovir antiviral therapy. METHODS: Testing used was clinical examination including fundus photographs, renal biochemistry, cerebrospinal fluid analysis, and renal ultrasound. RESULTS: A 63-year-old, healthy, white woman was being treated with oral valaciclovir for acute retinal necrosis. Several days later, she developed visual hallucinations and confusion. Renal biochemistry was abnormal, and renal ultrasound was normal. Cerebrospinal fluid cellularity was normal, but cerebrospinal fluid 9-carboxymethoxymethylguanine, an aciclovir metabolite, level was elevated. Treatment was changed to intravenous aciclovir titrated based on serum aciclovir levels with intravenous fluid supplementation to good effect. CONCLUSION: Regular monitoring of renal function and ample fluid intake are important when high doses of aciclovir/valaciclovir are used, even in patients with no previous history of renal failure. Monitoring of serum aciclovir level is useful in those with renal impairment to titrate doses, and high-dose oral valaciclovir should be used with caution.