Susan Hopkins

Late Ebola virus relapse causing meningoencephalitis: a case report

Summary Background There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. Funding Royal Free London NHS Foundation Trust.

Drug-induced aseptic meningitis.

Drug-induced aseptic meningitis (DIAM) has been reported as an uncommon adverse reaction with numerous agents. It is a diagnosis of exclusion, and clinical signs and CSF findings vary greatly. The body of evidence regarding DIAM is largely in the form of anecdotal case reports and must be interpreted carefully bearing this in mind.The major categories of causative agents are nonsteroidal anti-inflammatory drugs, antimicrobials, intravenous immunoglobulin, intrathecal agents, vaccines and a number of other less frequently reported agents. There appears to be an association between DIAM and connective tissue disease, particularly systemic lupus erythematosus, and ibuprofen.There are 2 major proposed mechanisms for DIAM. The first involves direct irritation of the meninges by intrathecal administration of the drug, and the second involves immunological hypersensitivity to the drug, most likely type III and type IV hypersensitivity.Recognition and diagnosis of DIAM is important, as it is treatable by withdrawal of the drug and recurrence is prevented. The outcome of DIAM is generally good, usually without long term sequelae.This article describes the case reports of DIAM in the current literature and discusses the diagnosis and management of this rare complication.

Emergence of antiretroviral resistance in HIV-positive women receiving combination antiretroviral therapy in pregnancy.

Background:Antenatal antiretroviral therapy is integral to preventing vertical transmission of HIV-1. The impact of temporary triple antiretroviral therapy in pregnancy on the emergence of antiretroviral resistance has not been studied. Objective:To determine the impact of temporary triple antiretroviral therapy in pregnancy on emergence of antiretroviral resistance. Methods:Pregnant HIV-1 infected women with a pre-treatment CD4 cell count >300 × 106/l initiated triple antiretroviral therapy in the third trimester and discontinued postpartum. Genotypic resistance testing was performed after antiretroviral cessation and on pretreatment samples when postpartum samples showed primary mutations. Results:In a cohort of 50 women who initiated antiretroviral therapy in pregnancy, 39 (78%) had postpartum HIV-1 nucleotide sequences available for analysis: 35 of these (90%) were previously antiretroviral naive. Seven primary mutations, V106A (one), Y181C (two), G190A (one), K101E (one), M184V (one), T215S (one) were detected in five (13%) women. All five were on regimens that included nevirapine and all were antiretroviral therapy naive prior to the index pregnancy. Four had no mutations detected pretreatment (one did not have a pretreatment analysis available; viral load 83 copies/ml). The median duration of antiretroviral exposure was 70 days. Conclusion:Emergence of genotypic resistance is significant in this cohort of pregnant women. All mutations detected were in those that took nevirapine-containing regimens. The clinical implications of these mutations are unknown.

Effects of control interventions on Clostridium difficile infection in England: an observational study

Summary Background The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility. Methods Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses. Findings National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48–0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97–1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2). Interpretation Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes. Funding UK Clinical Research Collaboration (Medical Research Council, Wellcome Trust, National Institute for Health Research); NIHR Oxford Biomedical Research Centre; NIHR Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (Oxford University in partnership with Public Health England [PHE]), and on Modelling Methodology (Imperial College, London in partnership with PHE); and the Health Innovation Challenge Fund.

Maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy.

To describe the maternal tolerability of nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland and to determine risk factors for development of significant hepatotoxicity.

Resurgence in infectious syphilis in Ireland: an epidemiological study.

Introduction: In 2000, a syphilis outbreak was identified in Ireland. Materials and Methods: A prospective enhanced database was established in 2000. Crude incidence rates for the general population, men who have sex with men (MSM), and HIV-positive MSM were calculated. Results: Three hundred fifty-six cases of infectious syphilis were diagnosed at 1 center. Eighty-five percent of cases were identified as MSM. Crude incidence rates in MSM, ranging in age between 20 and 44 years, peaked in 2001 at 719 cases per 100,000 of the MSM population. A total of 17.4% of cases occurred in HIV-infected individuals. Crude incidence rates of syphilis in HIV-positive MSM in the center increased to 7280 per 100,000. Similar percentages of MSM with and without HIV infection had unprotected anal intercourse (37% and 41%, respectively). Conclusion: High-risk sexual behavior continues among HIV-infected and -noninfected MSM. Crude incidence rates among MSM in Ireland are alarming when compared with other outbreaks.

Healthcare-associated Staphylococcus aureus bacteremia and the risk for methicillin resistance: is the Centers for Disease Control and Prevention definition for community-acquired bacteremia still appropriate?

OBJECTIVE To evaluate a new classification for bloodstream infections that differentiates hospital acquired, healthcare associated, and community acquired in patients with blood cultures positive for Staphylococcus aureus. DESIGN Prospective, observational study. SETTING Three tertiary-care, university-affiliated hospitals in Dublin, Ireland, and Strasbourg, France. PATIENTS Two hundred thirty consecutive patients older than 18 years with blood cultures positive for S. aureus. METHODS S. aureus bacteremia (SAB) was defined as hospital acquired if the first positive blood culture was performed more than 48 hours after admission. Other SABs were classified as healthcare associated or community acquired according to the definition proposed by Friedman et al. When available, strains of methicillin-resistant Staphylococcus aureus (MRSA) were analyzed by pulsed-field gel electrophoresis (PFGE). RESULTS Eighty-two patients were considered as having community-acquired bacteremia according to the Centers for Disease Control and Prevention (CDC) classification. Of these 82 patients, 56% (46) had healthcare-associated SAB. MRSA prevalence was similar in patients with hospital-acquired and healthcare-associated SAB (41% vs 33%; P > .05), but significantly lower in the group with community-acquired SAB (11%; P < .03). PFGE of MRSA strains showed that most community-acquired and healthcare-associated MRSA strains were similar to hospital-acquired MRSA strains. On multivariate analysis, Friedmans classification was more effective than the CDC classification for predicting MRSA. CONCLUSION These results support the call for a new classification for community-acquired bacteremia that would account for healthcare received outside the hospital by patients with SAB.

Assessing limiting factors to the acceptance of antiretroviral therapy in a large cohort of injecting drug users.

A comprehensive questionnaire was designed to assess the knowledge and understanding of injecting drug users (IDUs) regarding their HIV disease, and to determine any factors that may increase the acceptance of antiretroviral therapy (ART) by this group.

Panton-Valentine leukocidin associated staphylococcal disease: a cross-sectional study at a London hospital, England.

Recently, there has been international concern at the rapid emergence of highly pathogenic strains of Staphylococcus aureus associated with a toxin called Panton-Valentine leukocidin (PVL). In the UK, these strains are considered to be rare and mainly severe. We estimate the proportion of staphylococcal infections that are caused by strains containing the PVL genes, and describe risk factors for these infections. Three hundred and ninety consecutive S. aureus clinical isolates, submitted for routine diagnostic purposes were screened for PVL genes. Risk factors for infection were identified from the patient medical record. 9.7% (95% CI 7.0-13.1%) of clinical isolates and 20.8% of skin and soft tissue specimens contained the genes for PVL. Methicillin-resistant S. aureus with PVL was rare (0.8% of all isolates) but PVL with methicillin-sensitive S. aureus was common (9.0% of all specimens). PVL infection was more frequent in males (OR 3.0, 95% CI 1.3-7.0), and in young adults aged 20-39 years (OR 3.7, 95% CI 1.3-10.4). Over half of PVL positive S. aureus infections originated in patients based in the community. Community-onset PVL-associated disease is common in the UK and mainly causes skin and soft tissue infections that do not require admission to hospital. Consideration should be given to current infection control strategy, which advocates household contact screening and decolonization on the assumption that PVL-associated disease is rare.

The antibiotic course has had its day

With little evidence that failing to complete a prescribed antibiotic course contributes to antibiotic resistance, it’s time for policy makers, educators, and doctors to drop this message, argue Martin Llewelyn and colleagues