Sophia Archuleta

Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 years Phase II randomized controlled trial in Singapore

This was a multicenter, blinded, Phase II study (NCT00880893) conducted in Singapore. The primary objectives were to evaluate the safety of a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated viruses (CYD-TDV) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination. Participants were randomized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0, 6 and 12 mo. Control vaccine was placebo for the first dose (all ages) and for subsequent doses, licensed hepatitis-A for children (aged 2–11 years) or influenza vaccine for adolescents (12–17 years) and adults (18–45 years). Between April and October 2009, 317 children, 187 adolescents and 696 adults were enrolled. In all age groups, reactogenicity was higher after the first injection of CYD-TDV than after placebo control. Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose, and tended to be lower or similar to that seen after active control vaccination. Seropositivity rates and geometric mean neutralizing antibody titers (GMTs; 1/dil) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses. Post-dose 3, 66.5% of all participants were seropositive to all four serotypes, and 87.2% were seropositive to ≥ 3 serotypes; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4. GMTs were higher in children than in adolescents. These results support the continued development of CYD-TDV for the prevention of dengue disease.This was a multicenter, blinded, Phase II study (NCT00880893) conducted in Singapore. The primary objectives were to evaluate the safety of a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated viruses (CYD-TDV) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination. Participants were randomized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0, 6 and 12 mo. Control vaccine was placebo for the first dose (all ages) and for subsequent doses, licensed hepatitis-A for children (aged 2-11 y) or influenza vaccine for adolescents (12-17 y) and adults (18-45 y). Between April and October 2009, 317 children, 187 adolescents and 696 adults were enrolled. In all age groups, reactogenicity was higher after the first injection of CYD-TDV than after placebo control. Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose, and tended to be lower or similar to that seen after active control vaccination. Seropositivity rates and geometric mean neutralizing antibody titers (GMTs; 1/dil) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses. Post-dose 3, 66.5% of all participants were seropositive to all four serotypes, and 87.2% were seropositive to ≥ 3 serotypes; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4. GMTs were higher in children than in adolescents. These results support the continued development of CYD-TDV for the prevention of dengue disease.

CT Appearance of Pyogenic Liver Abscesses Caused by Klebsiella pneumoniae

PURPOSE To retrospectively compare the computed tomographic (CT) features of liver abscesses caused by Klebsiella pneumoniae with those caused by other bacterial pathogens. MATERIALS AND METHODS This retrospective study was approved by the institutional review board, with waiver of informed consent. Hospital records of all patients with a diagnosis of liver abscess between July 2003 and July 2010 were retrieved from an electronic hospital database. One hundred and thirty-one consecutive patients with confirmed pyogenic liver abscesses were studied. Data on clinical presentation, comorbid conditions, septic hematogenous complications, hospitalization duration, and abscess-related mortality were obtained. CT characteristics of abscesses including number, distribution, unilocular or multilocular appearance, cystic or solid appearance, gas in cavity, pylephlebitis, thrombophlebitis, and pneumobilia were reviewed. Etiology was established by pus and/or blood culture. Patients were placed into a monomicrobial K pneumoniae liver abscess group and a comparison group. A comparison of the CT features and clinical findings between the two groups was performed. The χ(2) analysis or Fisher exact test was used for categorical variables, and Student t and log-rank tests were used for continuous variables. A P value of less than .05 was considered to indicate a significant difference. RESULTS Monomicrobial K pneumoniae liver abscesses were present in 92 cases (70.2%). On CT images, characteristics more likely to be associated with monomicrobial K pneumoniae liver abscesses than other pyogenic liver abscesses were a single abscess (79.3% vs 56.4%, P = .01), unilobar involvement (82.6% vs 61.5%, P = .01), solid appearance (57.6% vs 35.9%, P = .03), multilocular (94.6% vs 71.8%, P = .01), association with thrombophlebitis (30.4% vs 5.1%, P < .01), and hematogenous complications (28.3% vs 7.7%, P < .01). Thrombophlebitis was associated with higher incidence of hematogenous septic complications (50.0% vs 13.9%, P < .001). Monomicrobial K pneumoniae liver abscesses were associated with significantly shorter duration of antibiotic treatment (P = .018) and hospital stay (P = .005), but there was no significant difference in incidence of septic shock and abscess-related mortality as compared with other pyogenic liver abscesses. CONCLUSION Monomicrobial K pneumoniae liver abscesses appear as single, solid, or multiloculated liver abscesses and are associated with thrombophlebitis and septic hematogenous complications.

Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial

BACKGROUND Chloroquine has in-vitro activity against influenza and could be an ideal candidate for worldwide prevention of influenza in the period between onset of a pandemic with a virulent influenza strain and the development and widespread dissemination of an effective vaccine. We aimed to assess the efficacy of such an intervention. METHODS In this randomised, double-blind, placebo-controlled trial done at a single centre in Singapore, we randomly assigned (1:1) healthy adults to receive chloroquine phosphate (500 mg/day for 1 week, then once a week to complete 12 weeks) or matching placebo by use of a computer-generated randomisation list. Participants filled an online symptom diary every week, supplemented by daily diaries and self-administered nasal swabs when unwell. Haemagglutination-inhibition assays for influenza A (H1N1, H3N2) and B were done on blood samples taken at baseline and after 12 weeks. The primary outcome was laboratory-confirmed clinical influenza defined by specific symptoms accompanied by influenza RNA on nasal swabs or a four-fold increase in haemagglutination-inhibition titres over the 12-week study period. Analysis was by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01078779. FINDINGS From November, 2009, to February, 2010, we recruited 1516 eligible participants. 1496 (96%) returned at week 12 and were included in the efficacy analysis. Adherence to study intervention was 97%, and 94% of the scheduled weekly diaries were completed. Eight (1%) of 738 participants had laboratory-confirmed clinical influenza in the placebo group and 12 (2%) of 724 in the chloroquine group (relative risk 1·53, 95% CI 0·63-3·72; p=0·376). 29 (4%) of 738 had laboratory-confirmed influenza infection (symptomatic or asymptomatic) in the placebo group and 38 (5%) of 724 in the chloroquine group (1·34, 0·83-2·14; p=0·261). 249 (33%) of 759 participants reported adverse events (mostly mild) in the placebo group and 341 (45%) of 757 in chloroquine group (p<0·0001). Headache, dizziness, nausea, diarrhoea, and blurred vision were more common in the chloroquine group, but rarely resulted in treatment discontinuation. One serious adverse event (hepatitis) was possibly related to chloroquine. INTERPRETATION Although generally well tolerated by a healthy community population, chloroquine does not prevent infection with influenza. Alternative drugs are needed for large-scale prevention of influenza. FUNDING National Medical Research Council, Singapore.

Safe and successful treatment of intravenous drug users with a peripherally inserted central catheter in an outpatient parenteral antibiotic treatment service

BACKGROUND The enrollment of intravenous drug users (IVDUs) into an outpatient parenteral antibiotic treatment (OPAT) service using a peripherally inserted central catheter (PICC) is controversial and often avoided. The National University Hospital in Singapore has a policy of permitting OPAT-based treatment of IVDU patients with appropriate medical indications. We report on our experiences. METHODS A prospective observational study was conducted on IVDU patients requiring parenteral antibiotics via an OPAT service from January 2005 to December 2009. Clinically appropriate patients were screened using pre-defined criteria and enrolled into our service, where standardized measures were enforced to prevent and detect PICC abuse and optimize treatment. Outcomes measured included mortality, completion of therapy, PICC abuse, and readmission for infective or treatment-related complications during OPAT and a 30 day follow-up period. RESULTS Twenty-nine IVDU patients received treatment in our OPAT service (total 675 patient-days). The median duration of therapy was 18 days (range 1-85). Infective endocarditis was the primary diagnosis in 42% of cases. Two patients (7%) had recrudescent infection after absconding during their inpatient stay. These two patients subsequently completed treatment in OPAT. There were no deaths or cases of PICC abuse. Five patients (17%) during OPAT and one patient (3%) during the 30-day follow-up period required readmission for infective or treatment-related complications. CONCLUSIONS Appropriately selected, counselled and monitored patients with a history of being an IVDU can be treated safely and successfully via OPAT centres. It is likely that some will respond better to treatment in an outpatient setting.

Persistence of Th1/Tc1 responses one year after tetravalent dengue vaccination in adults and adolescents in Singapore

To characterize the cell mediated immunity (CMI) induced by the investigational CYD tetravalent dengue vaccine (TDV), we developed a whole-blood, intracellular cytokine staining (ICS) assay and a multiplex assay, each requiring 3 mL of blood. We assessed CMI before and 28 d after a first and third injection of CYD-TDV and one year after the third injection in a subset of 80 adolescents and adults enrolled in a phase II trial in Singapore (ClinicalTrial.gov NCT NCT00880893). CD4/IFNγ/TNFα responses specific to dengue NS3 were detected before vaccination. Vaccination induced YF-17D-NS3-specific CD8/IFNγ responses, without significant TNFα, and a CYD-specific Th1/Tc1 cellular response in all participants, which was characterized by predominant IFNγ secretion compared with TNFα, associated with low level IL-13 secretion in multiplex analysis of peripheral blood mononuclear cells (PBMC) supernatants after restimulation with each the CYD vaccine viruses. Responses were directed mainly against CYD-4 after the first vaccination, and were more balanced against all four serotypes after the third vaccination. The same qualitative profile was observed one year after the third vaccination, with approximately 2-fold lower NS3-specific responses, and 3-fold lower serotype-specific cellular responses. These findings confirm previous observations regarding both the nature and specificity of cellular responses induced by CYD-TDV, and for the first time demonstrate the persistence of cellular responses after one year. We also established the feasibility of analyzing CMI with small blood samples, allowing such analysis to be considered for pediatric trials.

Standardized outpatient management of Klebsiella pneumoniae liver abscesses

OBJECTIVES Community-acquired Klebsiella pneumoniae has emerged as a major cause of liver abscess in Asia. Using a standardized protocol, we conducted a prospective cohort study of all cases of K. pneumoniae liver abscess treated from 2005 to 2011 at two outpatient parenteral antimicrobial therapy (OPAT) centers in Singapore, to assess the safety and efficacy of treatment. METHODS We included all OPAT eligible patients with radiologically confirmed (computed tomography or ultrasound) liver abscesses and K. pneumoniae-positive microbiological cultures obtained from abscess fluid and/or blood at two university teaching hospitals. The endpoints investigated were cure, clinical response, readmission, and mortality. RESULTS All 109 patients enrolled in the study successfully completed treatment in OPAT. Nine patients required a short-term readmission due to clinical deterioration. There were no deaths or relapses at 30 days post cessation of antibiotics. Abscess size greater than 5 cm was associated with a delayed clinical response (odds ratio 5.34, 95% confidence interval 1.25-22.91, p = 0.02). CONCLUSION The management of K. pneumoniae liver abscesses via OPAT using a standardized protocol is a safe and effective alternative to inpatient intravenous antibiotics.

Differential host susceptibility and bacterial virulence factors driving Klebsiella liver abscess in an ethnically diverse population

Hypervirulent Klebsiella pneumoniae is an emerging cause of community-acquired pyogenic liver abscess. First described in Asia, it is now increasingly recognized in Western countries, commonly afflicting those with Asian descent. This raises the question of genetic predisposition versus geospecific strain acquisition. We leveraged on the Antibiotics for Klebsiella Liver Abscess Syndrome Study (A-KLASS) clinical trial ongoing in ethnically diverse Singapore, to prospectively examine the profiles of 70 patients together with their isolates’ genotypic and phenotypic characteristics. The majority of isolates belonged to capsule type K1, a genetically homogenous group corresponding to sequence-type 23. The remaining K2, K5, K16, K28, K57 and K63 isolates as well as two novel cps isolates were genetically heterogeneous. K1 isolates carried higher frequencies of virulence-associated genes including rmpA (regulator of mucoid phenotype A), kfu (Klebsiella ferric uptake transporter), iuc (aerobactin), iro (salmochelin) and irp (yersiniabactin) than non-K1 isolates. The Chinese in our patient cohort, mostly non-diabetic, had higher prevalence of K1 infection than the predominantly diabetic non-Chinese (Malays, Indian and Caucasian). This differential susceptibility to different capsule types among the various ethnic groups suggests patterns of transmission (e.g. environmental source, familial transmission) and/or genetic predisposition unique to each race despite being in the same geographical location.

Atypical hand, foot, and mouth disease: eczema coxsackium can also occur in adults

We read with interest the case report by Henry Feder and colleagues describing an atypical vesiculobullous eruption in an infant with Coxsackievirus A6 and hand, foot, and mouth disease. Here, we report a case of an adult patient with preexisting eczema who presented with hand, foot, and mouth disease and atypical lesions distributed in areas of eczematous skin. A 25-year-old Malaysian woman with a history of mild asthma and eczema affecting her groin, lower abdomen, buttocks, and thighs presented with fever, sore throat, and rhinorrhoea for 1 day. She developed painful, non-pruritic vesicular lesions on her palms, and blisters and vesicles on the eczematous areas on her lower abdomen, groins, thighs, and buttocks. Subsequently, the soles of her feet and face were also involved (fi gure). She reported close contact with a niece and a nephew 1 week before the onset of her symptoms, both of whom were diagnosed with hand, foot, and mouth disease. Enterovirus was identified with RT-PCR from swabs of her throat, from faeces, and from the lesions on the right thigh. Limited sequencing of the VP1 coding region confi rmed the virus as Coxsackievirus A6. All samples were negative for varicella zoster virus and herpes simplex virus 1 and 2 by PCR. Her symptoms improved and she was discharged from hospital by the third day of admission without complications. Herpes simplex virus is known to cause superinfection of pre-existing skin disease — termed ec zema herpeticum. This phenomenon has been occasionally described in association with Coxsackievirus in children and has been labelled eczema coxsackium. Other atypical dermatological manifestations of Coxsackievirus A6 have been described, including a 2-yearold child with lesions mimicking disseminated herpes zoster. Hand, foot, and mouth disease is common in children and has resulted in large outbreaks in several parts of the world. The disease can also occur in adults, but to our knowledge only one previous report exists of eczema coxsackium, in an adult with HIV infection. With the emergence of the previously obscure Coxsackievirus A6 as a notable cause of hand, foot, and mouth disease, this virus should be considered in patients with atypical cutaneous lesions in addition to typical symptoms of hand, foot, and mouth disease — especially those with a background presence of eczema. As shown by Feder and colleagues, Coxsackievirus A6 seems to be associated with atypical skin presentations and a benign outcome. Our case also shows that this phenomenon is not limited to infants or young children.

Low antibody titers 5 years after vaccination with the CYD-TDV dengue vaccine in both pre-immune and naïve vaccinees

ABSTRACT Globally, dengue virus (DENV) is one of the most widespread vector-borne viruses. Dengue disease affects populations in endemic areas and, increasingly, tourists who travel to these countries, but there is currently no approved vaccine for dengue. A phase 3 efficacy trial with Sanofi-Pasteurs recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) conducted in South East Asia showed an overall efficacy of 56% against virologically confirmed dengue infections of any severity and any of the 4 serotypes, but the long-term protection of the vaccine has yet to be demonstrated. To address longevity of antibody titers and B cell memory, we recalled study participants from an earlier CYD immunogenicity study (Phase 2) conducted in Singapore that enrolled healthy volunteers in the year 2009. Depending on the age group, 57–84% of the participants initially generated a neutralizing antibody titer ≥ 10 to all 4 DENV serotypes 28 d after the third and final dose. We observed very low antibody titers in blood samples collected from 23 vaccinees 5 y after the first dose, particularly titers of antibodies binding to virus particles compared with those binding to recombinant E protein. The in vivo efficacy of plasma antibodies against DENV-2 challenge was also tested in a mouse model, which found that only 2 out of 23 samples were able to reduce viremia. Although the sample size is too small for general conclusions, dengue immune memory after vaccination with CYD-TDV appears relatively low.

Efficacy of continuous infusion of vancomycin for the outpatient treatment of methicillin-resistant Staphylococcus aureus infections

OBJECTIVES Recently published guidelines on the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend against administering vancomycin by continuous infusion on the basis of insufficient studies comparing this with intermittent infusion. We compared outcomes of patients treated with continuous infusion and intermittent infusion of vancomycin. PATIENTS AND METHODS Data for outpatients treated with continuous infusion and intermittent infusion of vancomycin were compared utilizing rates of clinical failure defined as the need for unplanned re-admission, change of antibiotics or extension of therapy. RESULTS A total of 244 patients met the inclusion criteria, with 188 receiving continuous infusion and 56 intermittent infusion of vancomycin. The endpoint occurred in 21.3% and 30.4% of those receiving continuous infusion and intermittent infusion, respectively (relative risk 0.701, 95% CI 0.432-1.136, P = 0.159). Patient characteristics differed slightly between the two groups; however, logistic regression to adjust for differences in age, co-morbidity, subtherapeutic levels and prosthetic devices did not substantially alter this result. CONCLUSIONS No difference in rates of clinical failure of continuous infusion and intermittent infusion of vancomycin was observed in this outpatient cohort.