A switch to a raltegravir containing regimen does not lower platelet reactivity in HIV-infected individuals.

OBJECTIVE: Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are associated with increased cardiovascular risk and inflammation. In a previous cross-sectional study, individuals using a raltegravir (RAL)-based regimen were found to have reduced platelet reactivity and PMA compared with other antiretroviral regimens. Our aim was to investigate whether switching from a nonintegrase inhibitor regimen to a RAL-based regimen reduces platelet reactivity or PMA. DESIGN: An investigator initiated, single-centre, prospective randomized, open-label, blinded endpoint trial. METHODS: Forty HIV-infected adults using a nonintegrase inhibitor containing regimen with undetectable viral load were randomized to either continue their regimen or switch to a RAL-based regimen for 10 weeks, continuing the same backbone. The primary outcome was the change in platelet reactivity at week 10, which was determined as the expression of the platelet activation marker P-selectin and binding of fibrinogen before and after ex-vivo stimulation with different platelet agonists. Secondary outcomes included PMA, plasma markers of platelet activation and markers of inflammation and immune cell activation. RESULTS: Twenty-one participants were enrolled in the continuation group and 19 in the RAL group. Baseline characteristics were comparable between groups. There were no differences in the change in platelet reactivity to either platelet agonist at week 10, nor in plasma markers of platelet activation. PMA, C-reactive protein, T-cell activation (CD38HLA-DR) and monocyte (CD14CD16) subsets. CONCLUSION: Switching a nonintegrase inhibitor containing regimen to a RAL-based regimen does not reduce platelet reactivity, platelet-leukocyte aggregation, inflammation and immune activation in virologically suppressed HIV-infected individuals. CLINICAL TRIAL NUMBER: NCT02383355.

Increase in imported malaria in the Netherlands in asylum seekers and VFR travellers.

BACKGROUND: Malaria is a notifiable disease in the Netherlands, a non-endemic country. Imported malaria infections occur regularly among travellers, migrants and visitors. Surveillance data were analysed from 2008 to 2015. Trends in amounts of notifications among risk groups were analysed using Poisson regression. For asylum seekers, yearly incidence was calculated per region of origin, using national asylum request statistics as denominator data. For tourists, denominator data were used from travel statistics to estimate incidence per travel region up to 2012. RESULTS: A modest increase in overall imported malaria notifications occurred in 2008-2015 (from 222 in 2008 to 344 in 2015). Notably, in 2014 and 2015 sharp increases were seen in malaria among travellers visiting friends and relatives (VFR), and in asylum seekers. Of all Plasmodium falciparum infections, most (1254/1337; 93.8%) were imported from Africa; 1037/1337 (77.6%) were imported from Central and West Africa. Malaria in VFR was mostly caused by P. falciparum infection after visiting Ghana (22%) or Nigeria (19%). Malaria in asylum seekers was mostly caused by Plasmodium vivax infection from the Horn of Africa. The large number of notifications in asylum seekers resulted from both an increase in number of asylum seekers and a striking increase of malaria incidence in this group. Incidence of malaria in asylum seekers from the Horn of Africa ranged between 0.02 and 0.3% in 2008-2013, but rose to 1.6% in 2014 and 1.3% in 2015. In 2008-2012, incidence in tourists visiting Central and West Africa dropped markedly. CONCLUSIONS: Imported malaria is on the rise again in the Netherlands, most notably since 2013. This is mostly due to immigration of asylum seekers from the Horn of Africa. The predominance of P. vivax infection among asylum seekers warrants vigilance in health workers when a migrant presents with fever, as relapses of this type of malaria can occur long after arrival in the Netherlands.

Viruses and Gram-negative bacilli dominate the etiology of community-acquired pneumonia in Indonesia, a cohort study.

OBJECTIVE: Knowledge about the etiology of community-acquired pneumonia (CAP) is essential for adequate management. Presently, few studies about CAP are available from Southeast Asia. This study aimed to investigate the etiology, severity, and outcome of CAP in the most populous Southeast Asia country, Indonesia. METHODS: From October 2007 to April 2009, adult patients admitted with CAP to two hospitals in Semarang, Indonesia, were included to detect the etiology of CAP using a full range of diagnostic methods. The severity of disease was classified according to the Pneumonia Severity Index (PSI). The outcome was assessed as 30-day mortality. RESULTS: In total, 148 consecutive patients with CAP were included. Influenza virus (18%), Klebsiella pneumoniae (14%), and Streptococcus pneumoniae (13%) were the most common agents identified. Other Gram-negative bacilli, Mycobacterium tuberculosis, Chlamydia pneumoniae each accounted for 5%. The bacteria presented wild type antibiotic susceptibility profiles. Forty-four percent of subjects were high-risk patients (PSI class IV-V). The mortality rate (30%) was significantly associated with disease severity score (P<0.001), and with failure to establish an etiological diagnosis (P=0.027). No associations were found between etiology and underlying diseases, PSI class, nor mortality. CONCLUSIONS: Viruses and Gram-negative bacilli are dominant causes of CAP in this region, more so than S. pneumoniae. Most of the bacteria have wild type susceptibility to antimicrobial agents. Patients with severe disease and those with unknown etiology have a higher mortality risk.

Improvement of Depression and Anxiety After Discontinuation of Long- Term Efavirenz Treatment.

Neuropsychiatric symptoms in human immunodeficiency virus (HIV)-infected patients may be a late complication of efavirenz treatment. This study: 1) assessed the level of neuropsychiatric symptoms in HIV-infected patients on long-term efavirenz therapy; 2) explored the effect of a switch to non-efavirenz containing anti-retroviral treatment on neuropsychiatric symptoms. A consecutive series of 47 HIV-infected participants on long-term efavirenz treatment were included in an observational clinical trial. Participants completed three self-report questionnaires on neuropsychiatric symptoms. Patients switching to a non-efavirenz regimen were retested 2 weeks and 3 months after switching. Data were analyzed using repeated measures ANOVA to assess the effect of switching over time. A change in the percentage of patients scoring above norm scores after switching was analyzed using Chi square. Neuropsychiatric symptoms were common among HIV-infected patients on long-term efavirenz therapy, mainly depression, anxiety, stress, insufficiency in thinking and paranoia. After switching, these symptoms improved significantly to (near) normal levels. Our results show that neuropsychiatric symptoms are common among HIV-infected subjects and may be caused by long-term efavirenz use. Neuropsychiatric assessment, such as the Depression, Anxiety and Stress scale and Symptom Checklist 90, can identify those that may benefit from the discontinuation of efavirenz.

Development of quality indicators to evaluate antibiotic treatment of patients with community-acquired pneumonia in Indonesia.

OBJECTIVE: To develop an instrument for evaluating the quality of antibiotic management of patients with community-acquired pneumonia (CAP) applicable in a middle-income developing country. METHOD: A previous study and Indonesian guidelines were reviewed to derive potential quality of care indicators (QIs). An expert panel performed a two-round Delphi consensus procedure on the QI's relevance to patient recovery, reduction of antimicrobial resistance and cost containment. Applicability in practice, including reliability, feasibility and opportunity for improvement, was determined in a data set of 128 patients hospitalised with CAP in Semarang, Indonesia. RESULTS: Fifteen QIs were selected by the consensus procedure. Five QIs did not pass feasibility criteria, because of inappropriate documentation, inefficient laboratory services or patient factors. Three QIs provided minor opportunity for improvement. Two QIs contradicted each other; one of these was considered not valid and excluded. A final set of six QIs was defined for use in the Indonesian setting. CONCLUSION: Using the Delphi method, we defined a list of QIs for assessing the quality of care, in particular antibiotic treatment, for CAP in Indonesia. For further improvement, a modified Delphi method that includes discussion, a sound medical documentation system, improvement of microbiology laboratory services, and multi-center applicability tests are needed to develop a valid and applicable QI list for the Indonesian setting.

[Travel advice and vaccinations in patients with chronic inflammatory diseases: the earlier, the better]. / Reisadvies en vaccinaties bij chronische ontstekingsziekten: hoe eerder, hoe beter.

The number of patients with chronic inflammatory diseases who have been travelling to the tropics or subtropics has been rising. Use of immunomodulating drugs increases the risk for infectious diseases and may reduce seroprotection rates following vaccination. In addition, live vaccines, such as the yellow fever vaccine, are contra-indicated. Patients and their physicians are not always aware of the consequences of the use of immunomodulating drugs for travel and this may lead to undesirable situations, including last-minute cancellation of the trip. Informing and vaccinating patients early after the diagnosis of the inflammatory disease may prevent these undesirable situations.

Nasopharyngeal carriage of Streptococcus pneumonia in pneumonia-prone age groups in Semarang, Java Island, Indonesia.

INTRODUCTION: Streptococcus pneumoniae is a worldwide occurring pathogen Nasopharyngeal carriage of Streptococcus pneumoniae precedes pneumonia and other pneumococcal diseases in the community. Little is known about S. pneumoniae carriage in Indonesia, complicating strategies to control pneumococcal diseases. We investigated nasopharyngeal carriage of S. pneumoniae in Semarang, Indonesia. METHODS: A population-based survey was performed in Semarang, Indonesia. Nasopharyngeal swabs and questionnaires were taken from 496 healthy young (6-60 month-old) children and 45-70 year-old adults. RESULTS: Forty-three percent of children aged 6-60 months and 11% of adults aged 45-75 years carried S. pneumoniae. Determinants of carriage were being a child (OR 7.7; 95% CI = 4.5-13.0), passive smoking (OR 2.1; 95% CI = 1.3-3.4), and contact with toddler(s) at home (OR 3.0; 95% CI = 1.9-4.7). The most frequent serotypes found were 6A/B and 15B/C. The current commercially available vaccines cover <50% serotypes found in children. Twenty-four percent of S. pneumoniae strains were penicillin non-susceptible, and 45% were resistant to cotrimoxazol. CONCLUSIONS: The limited coverage of commercially available vaccines against the serotypes found in this population, and the high proportion of non-susceptibility to penicillin and cotrimoxazol suggest the need for region-specific information and strategies to control S. pneumoniae.

Nasopharyngeal carriage of Klebsiella pneumoniae and other Gram-negative bacilli in pneumonia-prone age groups in Semarang, Indonesia.

Gram-negative bacilli (GNB) cause many cases of pneumonia in Indonesia. We investigated nasopharyngeal carriage of GNB in Semarang, Indonesia. Klebsiella pneumoniae carriage in adults (15%) was higher than in children (7%) (P = 0.004), while that of other GNB was comparable. Poor food and water hygiene are determinants of carriage of these bacteria.

Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitantly treated with rosuvastatin and lopinavir/ritonavir.

The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care.

Malaria diagnostic testing and treatment practices in three different Plasmodium falciparum transmission settings in Tanzania: before and after a government policy change.

BACKGROUND: Patterns of decreasing malaria transmission intensity make presumptive treatment of malaria an unjustifiable approach in many African settings. The controlled use of anti-malarials after laboratory confirmed diagnosis is preferable in low endemic areas. Diagnosis may be facilitated by malaria rapid diagnostic tests (RDTs). In this study, the impact of a government policy change, comprising the provision of RDTs and advice to restrict anti-malarial treatment to RDT-positive individuals, was assessed by describing diagnostic behaviour and treatment decision-making in febrile outpatients <10 years of age in three hospitals in the Kagera and Mwanza Region in northern Tanzania. METHODS: Prospective data from Biharamulo and Rubya Designated District Hospital (DDH) were collected before and after policy change, in Sumve DDH no new policy was implemented. Diagnosis of malaria was confirmed by RDT; transmission intensity was evaluated by a serological marker of malaria exposure in hospital attendees. RESULTS: Prior to policy change, there was no evident association between the actual level of transmission intensity and drug-prescribing behaviour. After policy change, there was a substantial decrease in anti-malarial prescription and an increase in prescription of antibiotics. The proportion of parasite-negative individuals who received anti-malarials decreased from 89.1% (244/274) to 38.7% (46/119) in Biharamulo and from 76.9% (190/247) to 10.0% (48/479) in Rubya after policy change. CONCLUSION: This study shows that an official policy change, where RDTs were provided and healthcare providers were advised to adhere to RDT results in prescribing drugs can be followed by more rational drug-prescribing behaviour. The current findings are promising for improving treatment policy in Tanzanian hospitals.

Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1α, IL-1ß or IL-1 receptor type I.

The role of intereukin-1 (IL-1) in mortality caused by endotoxaemia remains controversial. While IL-1 receptor antagonist (IL-1Ra) protects mice from lethal endotoxaemia, mice deficient in IL-1ß (IL-1ß⁻( /)⁻) display normal susceptibility to lipopolysaccharide (LPS). The aim of this study was to identify the source of these discrepancies. Mice deficient in IL-1α, IL-1ß or IL-1R type I were injected intraperitoneally with Escherichia coli or Salmonella typhimurium LPS. Survival of the mice was examined and compared with C57/Bl6 wild-type mice. In addition, serum cytokine concentrations were determined after LPS challenge and in vitro cytokine production by peritoneal macrophages was analysed. Clearance of radioactive IL-1α was examined in IL-1α⁻(/)⁻ and wild-type mice. IL-1ß⁻(/)⁻ mice were normally susceptible to endotoxaemia and cytokine production did not differ from that in control mice. Surprisingly, LPS mortality in IL-1α⁻(/)⁻ mice was significantly greater than that in control mice, accompanied by higher interferon-γ release. These effects were mediated by a distorted homeostasis of IL-1RI receptors, as shown by a strongly delayed clearance of IL-1α. In contrast to the IL-1α⁻(/)⁻ and IL-1ß⁻(/)⁻ mice, IL-1RI⁻(/)⁻ mice were completely resistant to high doses of LPS. In conclusion, IL-1RI-mediated signals are crucial in mediating mortality occurring as a result of lethal endotoxaemia. Investigation of IL-1-mediated pathways in IL-1 knock-out mice is complicated by a distorted homeostasis of IL-1Rs.

Declining incidence of imported malaria in the Netherlands, 2000-2007.

BACKGROUND: To describe the epidemiology and trends of imported malaria in the Netherlands from 2000 through 2007. METHODS: Based on national surveillance data regarding all reported infections of imported malaria, diagnosed 2000 through 2007, incidence and trends of imported malaria in the Netherlands were estimated. Travellers statistics were used to estimate incidence, and data on malaria chemoprophylaxis prescriptions were used to estimate the number of unprotected travellers. RESULTS: Importation of malaria to the Netherlands is declining even as more travellers visit malaria-endemic countries. On average, 82% were acquired in sub-Saharan Africa, and 75% were caused by Plasmodium falciparum. The overall incidence in imported falciparum malaria fell from 21.5 to 6.6/10,000 of unprotected travellers. The percentage of unprotected travellers rose from 47% to 52% of all travellers. The incidence of imported falciparum infections is greatest from Middle and West Africa, and decreased from 121.3 to 36.5/10,000 travellers. The import of malaria from this region by immigrants visiting friends and relatives (VFR) decreased from 138 infections in 2000, to 69 infections in 2007. CONCLUSION: The annual number of imported malaria shows a continuing declining trend, even with an increasing number of travellers visiting malaria endemic countries. VFR import less malaria than previously, and contribute largely to the declining incidence seen. The decline is not readily explained by increased use of chemoprophylaxis and may reflect a reduced risk of infection due to decreasing local malaria transmission as observed in some malaria endemic areas. Nevertheless, the increasing number of unprotected travellers remains worrisome.

Determinants of carriage of resistant Staphylococcus aureus among S. aureus carriers in the Indonesian population inside and outside hospitals.

SUMMARY OBJECTIVES: To identify determinants of carriage of resistant Staphylococcus aureus in both hospitalized patients and individuals from the community in two urban centres in Indonesia. METHODS: Staphylococcus aureus cultures and data on recent antibiotic use, demographic, socioeconomic, disease-related and healthcare-related variables were collected from 3995 community dwellers and hospitalized persons. Nasal S. aureus carriage was found in 362 persons (9.1%). Logistic regression analysis was performed to identify which variables were independently associated with carriage of resistant S. aureus. RESULTS: The penicillins were the most frequently used antibiotics both in the community and in hospitalized patients. In the community, admission to a hospital was associated with carriage of S. aureus resistant to any of the tested antibiotics [odds ratio (OR) 2.5, 95% confidence interval (95% CI) 1.3-4.9] and any tetracycline resistance (OR 2.4, 95% CI 1.1-5.1). Having no symptoms was associated with less carriage of S. aureus with resistance to any of the tested antibiotics (OR 0.5, 95% CI 0.3-0.9) and any tetracycline resistance (OR 0.5, 95% CI 0.3-0.9). Crowding (OR 4.5, 95% CI 1.2-4.9) and low income (OR 8.9, 95% CI 1.8-43.9) were associated with multidrug resistance. In hospitalized patients, the use of penicillins was associated with resistance to any of the tested antibiotics (OR 3.9, 95% CI 1.4-11.6) and any tetracycline resistance (OR 3.7, 95% CI 1.1-12.0). CONCLUSIONS: Antibiotic policies including proper diagnosis, treatment and drug delivery process should be made by healthcare providers in Indonesia to help limit the emergence of antibiotic resistance.

Circulating lipoproteins are a crucial component of host defense against invasive Salmonella typhimurium infection.

BACKGROUND: Circulating lipoproteins improve the outcome of severe Gram-negative infections through neutralizing lipopolysaccharides (LPS), thus inhibiting the release of proinflammatory cytokines. METHODS/PRINCIPAL FINDINGS: Low density lipoprotein receptor deficient (LDLR-/-) mice, with a 7-fold increase in LDL, are resistant against infection with Salmonella typhimurium (survival 100% vs 5%, p<0.001), and 100 to 1000-fold lower bacterial burden in the organs, compared with LDLR+/+ mice. Protection was not due to differences in cytokine production, phagocytosis, and killing of Salmonella organisms. The differences were caused by the excess of lipoproteins, as hyperlipoproteinemic ApoE-/- mice were also highly resistant to Salmonella infection. Lipoproteins protect against infection by interfering with the binding of Salmonella to host cells, and preventing organ invasion. This leads to an altered biodistribution of the microorganisms during the first hours of infection: after intravenous injection of Salmonella into LDLR+/+ mice, the bacteria invaded the liver and spleen within 30 minutes of infection. In contrast, in LDLR-/- mice, Salmonella remained constrained to the circulation from where they were efficiently cleared, with decreased organ invasion. CONCLUSIONS: plasma lipoproteins are a potent host defense mechanism against invasive Salmonella infection, by blocking adhesion of Salmonella to the host cells and subsequent tissue invasion.

Survey of antibiotic use of individuals visiting public healthcare facilities in Indonesia.

OBJECTIVES: To estimate the antibiotic use of individuals visiting public healthcare facilities in Indonesia and to identify determinants of use against a background of high resistance rates. METHODS: Patients on admission to hospital (group A), visiting a primary health center (group B), and healthy relatives (group C) were included in the study. A questionnaire on demographic, socioeconomic, and healthcare-related items including health complaints and consumption of antibiotics was used. Logistic regression was performed to determine the co-variables of antibiotic use. RESULTS: Of 2996 individuals interviewed, 486 (16%) had taken an antibiotic. Compared to group C (7% consumption), groups B and A exhibited a three-fold and four-fold higher use of antibiotics, respectively. Respiratory (80%) and gastrointestinal (13%) symptoms were most frequent. Aminopenicillins and tetracyclines accounted for 80% of the prescribed antibiotics. Similar antibiotics were self-medicated (17% of users). Age less than 18 years and health insurance were independent determinants of antibiotic use. Urban provenance, being adult, male, and having no health insurance were independent determinants of self-medication. CONCLUSIONS: In addition to health complaints, other factors determined antibiotic consumption. In view of the likely viral origin of respiratory complaints and the resistance of intestinal pathogens, most antibiotic use was probably unnecessary or ineffective. Future interventions should be directed towards healthcare providers.

Optimizing antibiotic usage in adults admitted with fever by a multifaceted intervention in an Indonesian governmental hospital.

OBJECTIVE: To optimize antimicrobial treatment of patients with fever upon admission to the department of internal medicine of Dr Soetomo Hospital in Surabaya, Indonesia. METHOD: Prospective intervention study. The intervention comprised development of a consensus guideline, an official declaration of the guideline by the head of department, distributing a guideline pocketbook, carrying out blood cultures free of charge, teaching sessions and refresher courses. The outcome was measured with reference to (i) percentage of patients with fever started on antibiotic therapy, (ii) amount of antibiotics used expressed as defined daily doses (DDD)/100 patient-days, (iii) percentage of appropriate prescriptions and of prescriptions without indication as assessed by independent reviewers, (iv) percentage of treatments in accordance with guidelines, (v) percentage of patients in whom blood cultures were taken before starting antimicrobial therapy, (vi) percentage of treatments appropriately stopped on re-evaluation of the patients at 72 h and (vii) mortality. RESULTS: The study involved 501 patients, 95 residents and 60 specialists. After the intervention 17% patients less were treated with antibiotics upon admission and antibiotic use fell from 99.8 to 73 DDD/100 patient-days. The percentage of patients with sepsis and dengue treated in accordance with the guideline increased by 23% and 30%. The percentage of appropriate therapies, therapies without indication and mortality did not change significantly. The percentage of patients for whom a blood culture was taken upon admission increased from 3% to 81%; however, almost all were taken after they commenced antibiotic therapy. Therapy was not adjusted after 72 h in any case. Interrupted time series analysis showed that the start of development of the guideline and the declaration of the guideline were the interventions with the greatest impact. CONCLUSION: The multifaceted intervention had limited success. A very important drawback to the prudent use of antibiotics was the absence of adequate microbiological diagnostics.

Determinants of carriage of resistant Escherichia coli in the Indonesian population inside and outside hospitals.

OBJECTIVES: Antibiotic resistance is a worldwide healthcare problem exacerbated by antibiotic use and transmission of resistant bacteria. Not much is known about resistance in commensal flora and about determinants for resistance in Indonesia. This study analysed recent antibiotic use as well as demographic, socioeconomic, disease-related and healthcare-related determinants of rectal carriage of resistant Escherichia coli in the community and in hospitals in Indonesia. METHODS: Carriers of susceptible E. coli were compared with carriers of E. coli with resistance to any of the tested antibiotics. Logistic regression analysis was performed to determine which variables were associated with carriage of resistant E. coli. Individuals in the community with varying levels of contact with healthcare institutions and hospitalized patients were analysed as separate populations. RESULTS AND CONCLUSIONS: Of 3275 individuals (community 2494, hospital 781), 54% carried resistant E. coli. Recent antibiotic use was the most important determinant of resistance in both populations [community: odds ratio (OR) 1.8, 95% confidence interval (95% CI) 1.5-2.3; hospital: OR 2.5, 95% CI 1.6-3.9]. In the community, hospitalization (OR 2.4, 95% CI 2.0-3.0), diarrhoeal symptoms (OR 1.9, 95% CI 1.3-2.7) and age under 16 years (adults: OR 0.4, 95% CI 0.3-0.5) were associated with carriage of resistant E. coli. For hospitalized patients, having no health insurance was associated with less resistance (OR 0.6, 95% CI 0.4-0.9) and differences were observed between hospitals (Semarang: OR 2.2, 95% CI 1.5-3.3) and departments (Paediatrics: OR 4.3, 95% CI 1.7-10.7). Further research is needed to investigate whether transmission is responsible for these differences.