- Carbapenemase producing Enterobacteriaceae (CPE), including Klebsiella pneumoniae and Escherichia coli, are only sporadically seen in the Netherlands and then mainly in patients who have been transferred from foreign hospitals.- CPE are resistant to virtually all beta-lactam antibiotics, including carbapenems, e.g., meropenem and imipenem. Several genes, e.g., OXA-48, KPC and NDM-1, code for carbapenemase enzymes that deactivate carbapenems.- Control of CPE focuses on timely identification of patients who are infected or are carriers and the application of preventive measures to prevent spread.- Genotypic analysis of CPE isolates submitted to the national CPE surveillance revealed close relationships between 8 NDM-1 positive K. pneumoniae isolates of patients from different parts of the Netherlands and isolates obtained through contact tracing during a known hospital outbreak.- Based on retrospective epidemiological investigation, no shared exposure could be found.- These findings indicate unnoticed spread of CPE in the Netherlands.

Objectives To elucidate new risk factors for MRSA carriers without known risk factors (MRSA of unknown origin; MUO). These MUO carriers are neither pre-emptively screened nor isolated as normally dictated by the Dutch Search & Destroy policy, thus resulting in policy failure. Methods We performed a prospective case control study to determine risk factors for MUO acquisition/carriage (Dutch Trial Register: NTR2041). Cases were MUO carriers reported by participating medical microbiological laboratories to the RIVM from September 1st 2011 until September 1st 2013. Controls were randomly selected from the community during this period. Results Significant risk factors for MUO in logistic multivariate analysis were antibiotic use in the last twelve months, aOR 8.1 (5.6–11.7), screened as contact in a contact tracing but not detected as a MRSA carrier at that time, aOR 4.3 (2.1–8.8), having at least one foreign parent, aOR 2.4 (1.4–3.9) and receiving ambulatory care, aOR 2.3 (1.4–3.7). Our found risk factors explained 83% of the MUO carriage. Conclusions Identifying new risk factors for MRSA carriers remains crucial for countries that apply a targeted screening approach as a Search and Destroy policy or as vertical infection prevention measure.

Laboratory detection of carbapenemase-producing Enterobacteriaceae (CPE) is complicated. Screening with MIC values below clinical breakpoints followed by genotypic confirmation is recommended. We evaluated the application of recommended CPE screening and confirmation methods and provide an overview of CPE epidemiology in E. coli and K. pneumoniae in the Netherlands. Data on E. coli and K. pneumoniae isolates with elevated meropenem (>0.25 mg/L) and/or imipenem (>1 mg/L) MIC values in 2013–2014 were selected from the Infectious Disease Surveillance Information System for Antibiotic Resistance. Laboratories were requested to provide additional results of any confirmatory testing performed. Confirmation of elevated carbapenem MIC values using gradient testing was performed in 59.8 % of eligible isolates. Confirmatory testing showed elevated MIC values in 8 % of E. coli and 32 % of K. pneumoniae isolates. The overall proportion of confirmed non-susceptible E. coli and K. pneumoniae was 0.01 % and 0.16 %, respectively. Genotypic confirmation was performed in 61.0 % of isolates with confirmed elevated carbapenem MIC values. A carbapenemase gene was identified in 47 % of E. coli and 65 % of K. pneumoniae isolates. OXA-48, NDM and KPC were the most frequently found carbapenemase genes. The majority (62 %) of CPE isolates was detected through targeted screening. CPE are a rare finding in the Netherlands. Adherence to the national guideline is suboptimal and differs between laboratories, implying a risk of inadequate CPE detection. Since accurate identification of CPE is the first step in prevention of CPE spread, successful implementation of guidelines for testing and reporting of CPE is essential.

Rabies is a deadly disease, and current preexposure vaccination schedules are lengthy and expensive. We identified nine studies investigating abbreviated schedules. Although initial responses were lower, accelerated adequate immune responses were elicited after booster vaccinations. Lower-dose (and therefore cheaper) vaccination schedules may constitute a valid alternative to current vaccination schedules.

In a retrospective, observational study involving 34 patients with Leishmania major infection, 31 of whom had experienced unsuccessful treatment with intralesional antimony (ilSb(v)), miltefosine proved effective. Thirty patients experienced cure after receipt of miltefosine, 3 after receipt of additional ilSb(v), and 1 after 28 daily intravenous injections of antimony. Temporary diminution of ejaculate volume was reported by 21 patients.

BACKGROUND/OBJECTIVES:Iron deficiency anemia is a major public health problem in developing countries and may affect school performance and physical work capacity in nonpregnant adolescents, and may increase the risk of anemia during subsequent teenage pregnancies. We assessed the effect of weekly iron (120 mg elemental iron) and vitamin A (25 000 IU) supplementation on hemoglobin, iron status and malaria and nonmalaria morbidity in adolescent schoolgirls.SUBJECTS/METHODS:A total of 279 schoolgirls aged 12-18 years from public primary schools in Kisumu, western Kenya. Double-blind randomized placebo-controlled trial using a factorial design.RESULTS:Five months of iron supplementation was associated with a 0.52 g dl(-1) (0.21, 0.82) greater increase in hemoglobin relative to iron placebo. The effect was only observed in girls with iron deficiency on enrollment (1.34 g dl(-1) (0.79, 1.88)), but not in iron-replete girls (-0.20 g dl(-1) (-0.59, 0.18)). Similar differences in treatment effect were seen between menstruating and nonmenstruating girls. The effect of iron was independent of vitamin A. The baseline prevalence of vitamin A deficiency was low (6.7%) and no sustained increase in hemoglobin was seen with weekly vitamin A (-0.07 g dl(-1) (-0.38, 0.25)). Incidence of malaria parasitemia was higher in the iron than iron-placebo groups (Rate ratio 1.33 (0.94, 1.88)).CONCLUSIONS:Weekly iron supplementation results in substantial increases in hemoglobin concentration in adolescent schoolgirls in western Kenya, which may outweigh possible risks caused by malaria, but only in iron-deficient or menstruating girls and not in iron-replete and nonmenstruating girls.

BACKGROUND:In communities where Schistosoma species are endemic, the prevalence and intensity of schistosomiasis is disproportionately high among children, compared with adults. This epidemiologic pattern is consistent with either the slow development of resistance or the requirement of host developmental changes for the expression of resistance.METHODS:We enrolled 87 individuals aged 7-18 years who did not have Schistosoma japonicum infection and 641 individuals aged 7-30 years with S. japonicum infection, all of whom reside in 3 villages in Leyte, Philippines. At baseline, S. japonicum infection was assessed by Kato-Katz thick-smear stool examination, and the levels of the pubertal hormone dehydroepiandrosterone sulfate (DHEA-S) in serum were determined. Individuals with S. japonicum infection were treated with praziquantel, after which stool examination and DHEA-S level measurement were performed every 3 months for 18 months.RESULTS:In cross-sectional analyses, the intensity of infection among individuals with high DHEA-S levels was 43% lower (28 eggs per g, n = 243), compared with individuals with low DHEA-S levels (50 eggs per g, n = 242), even after adjusting for age, sex, and village (P = .01). Following praziquantel treatment, increased DHEA-S levels were associated with resistance to reinfection (P = .006). The intensity of reinfection among individuals with high DHEA-S levels was 42% lower, compared with individuals with low DHEA-S levels, even after adjusting for age, baseline intensity of S. japonicum infection, village, sex and water contact (P < .001).CONCLUSIONS:Increased DHEA-S levels in serum, a marker for adrenal development, is associated with reduced S. japonicum infection and reinfection, even after adjusting for age and, by proxy, cumulative exposure. These data suggest that an intrinsic property of host pubertal development mediates, in part, the resistance to infection observed in older individuals.

BACKGROUND Observational and interventional evidence supports a relation between human schistosomiasis and anemia; however, the exact causal mechanisms remain unclear. Eggs translocating across the intestinal or bladder wall may result in extracorporeal blood loss with subsequent iron deficiency. Alternatively, anemia may result from cytokine-mediated dyserythropoiesis, as seen in anemia of inflammation. OBJECTIVES By evaluating the cross-sectional relation between the intensity of Schistosoma japonicum infection, hemoglobin concentration, and iron status in 7-30-y-old persons from S. japonicum-endemic rice-farming villages in the province of Leyte, Philippines, we assessed the relative contribution of iron deficiency and anemia of inflammation to schistosomiasis-associated anemia. DESIGN We enrolled 627 S. japonicum-infected and 111 S. japonicum-uninfected persons. We obtained stool samples to quantify S. japonicum infection and venous blood samples for hemograms and measures of iron status and inflammation. RESULTS Intensity of S. japonicum infection was independently associated with hemoglobin (beta = -0.24; 95% CI: -0.31, -0.17). Persons with high-intensity infection had a greater risk of iron deficiency anemia (adjusted prevalence odds ratio: 6.6; 95% CI: 2.9, 14.7), but there was no evidence of this relation in low-intensity infections. In contrast, anemia without iron deficiency was prevalent across all intensities (adjusted prevalence odds ratio: 3.8; 95% CI: 1.5, 9.5). CONCLUSIONS Storage iron deficiency is a major contributor to anemia in high-intensity S. japonicum infection. A high prevalence of anemia without iron deficiency, exclusion of other mechanisms of anemia, and the evidence of low bioavailable iron suggest that anemia of inflammation contributes to S. japonicum-associated anemia at all infection intensities.

1 Center for International Health Research (CIHR), Rhode Island Hospital, Brown University School of Medicine, Providence, RI, United States 2 Department of Pediatrics, Rhode Island Hospital, Brown University School of Medicine, Providence, RI, United States 3 Research Institute of Tropical Medicine, Manila, the Philippines 4 Center for Statistical Sciences, Brown University, Providence, RI, United States 5 Epidemiology Section, Department of Community Health and International Health Institute, Brown University, Providence, RI, United States 6 Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI, United States

Although schistosomiasis is effectively treated with Praziquantel, rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. Using a longitudinal treatment-reinfection study design with 616 participants 7 to 30 years of age, we evaluated the relationship between cytokine responses to Schistosoma japonicum soluble adult worm extract (SWAP), Sj97, Sj22.6, and Sj67, measured 4 weeks after treatment with Praziquantel, and resistance to reinfection in a population from Leyte, The Philippines, where S. japonicum is endemic. S. japonicum transmission was high: 54.8% and 91.1% were reinfected within 6 and 18 months, respectively. A Th2 bias in the following cytokine ratios, interleukin-4 (IL-4)/IL-12, IL-5/IL-12, IL-13/IL-12, IL-4/gamma-IFN (IFN-gamma), IL-5/ IFN-gamma, and IL-13/IFN-gamma, in response to SWAP predicted a 1.4- to 2.9-month longer time to reinfection (P < 0.05) and a 27 to 55% lower intensity of reinfection (P < 0.05). Similarly, a Th2 bias in response to Sj97 predicted a 1.6- to 2.2-month longer time to reinfection (P < 0.05) and a 30 to 41% lower intensity of reinfection (P < 0.05). Only a high IL-5/IL-10 ratio in response to Sj22.6 predicted a 3.0-month-longer time to reinfection (P = 0.03). Cytokine responses to Sj67 were not associated with protection. In a large population-based treatment-reinfection study we found that Th2 responses to SWAP and Sj97 consistently predicted resistance to reinfection. These findings underscore Th2-type immune responses as central in human resistance to S. japonicum and support Sj97 as a leading vaccine candidate for this parasite.

In a cross-sectional study of 641 Schistosoma japonicum-infected individuals in Leyte, Philippines, who were 7-30 years old, we determined the grade of hepatic fibrosis (HF) by ultrasound and used anthropometric measurements and hemoglobin levels to assess nutritional status. Serum levels of interleukin (IL)-1, IL- 6, and IL10; tumor-necrosis factor (TNF)-alpha; soluble TNF-alpha receptor I; and C-reactive protein (CRP) were measured to examine the association between these markers of inflammation and HF grade. HF was present in 8.9% of the cohort; the majority of cases were mild ( grade I), and severe (grade II or grade III) cases occurred only in male individuals. Compared with individuals without HF, those with severe HF - and, to a lesser degree, those with mild HF - had a significantly lower body-mass index (BMI) and BMI z-score, a higher prevalence of anemia, and a higher level of CRP and were more likely to produce IL- 6; furthermore, those with severe HF had a significantly higher level of IL- 1, compared with those either without HF or with mild HF. These findings suggest that even mild HF is associated with nutritional morbidity and underscore the importance of early recognition and treatment. In addition, our data are consistent with the hypothesis that, by systemically increasing the levels of the proinflammatory cytokines IL- 1 and IL- 6, HF causes undernutrition and anemia.

Objective: Nutritional status is an important marker of overall health and linear growth retardation has serious long-term physiological and economic consequences. Approximately 35 and 29% of preschool children in sub-Saharan Africa are stunted and underweight, respectively. There is relatively little information available about the nutritional status in adolescents, the age group with the highest growth velocity after infancy. We conducted a series of cross-sectional surveys to determine the prevalence and main risk groups for malnutrition and to describe the associations between age, sexual maturation and nutritional status in adolescent schoolgirls in western Kenya. Design: Three cross-sectional surveys; one in Mumias, using random sampling in all schools, and two surveys in Asembo, using a multi-stage random sample design. Setting: Public primary schools in two different rural malaria endemic areas in western Kenya with high levels of malnutrition in preschool children. Subjects: In all, 928 randomly selected adolescent schoolgirls aged 12–18 y. Results: Overall prevalence of stunting and thinness was 12.1 and 15.6%, respectively. Of the total, 2% were severely stunted. Menarche and start of puberty were delayed by approximately 1.5–2 y compared to a US reference population. The prevalence of stunting and thinness decreased with age and mean height for age z-scores converged towards the median of the US reference curve. Girls who had not yet started menstruating were more likely to be stunted than the girls of the same age who were post-menarche. Conclusions: Stunting and thinness are common in young adolescent schoolgirls in these poor rural settings in western Kenya, but the prevalence decreases with age, providing observational support that children catch up on incomplete growth attained earlier in life due to a maturational delay of 1.5–2 y allowing prolonged growth. Sponsorship: This study was supported by a grant from The Netherlands Foundation for the Advancement of Tropical Research (WOTRO), the Netherlands.

Objective: Anemia is a major public health concern in preschool children and pregnant women in the developing world. While many studies have examined these two at-risk groups, there is a paucity of data on anemia in adolescents living in developing countries in the complex ecologic context of poverty, parasitism, and malnutrition. We evaluated the prevalence, severity, and risk factors of anemia in adolescent schoolgirls in an area with intense malaria transmission in western Kenya. Design: Two cross-sectional surveys were conducted, using a multistage random sample design. Setting: Public primary schools in an area with intense malaria transmission in western Kenya. Subjects: A total of 648 randomly selected adolescent schoolgirls aged 12–18 y. Results: The prevalence of anemia (Hb <120 g/l) was 21.1%; only one girl had an Hb less than 70 g/l. Ferritin levels were available from a subsample of 206 girls. The prevalence of iron deficiency (ferritin <12 μg/l) was 19.8, and 30.4% of anemic girls were iron deficient. Malaria and schistosomiasis were the main risk factors for anemia in younger girls (12–13 y), while menstruation was the principal risk factor in older girls (14–18 y). Conclusions: Iron deficiency and anemia in school-attending girls in western Kenya were more prevalent than in developed countries, but considerably less prevalent than in preschool children and pregnant women from the same study area. Our findings are consistent with other recent school-based surveys from western Kenya, but not with recent community- and school-based cross-sectional surveys from other parts of sub-Saharan Africa. It deserves further study to determine if adolescent girls not attending school are at higher risk of anemia. Sponsorship: This study was supported by a grant from The Netherlands Foundation for the Advancement of Tropical Research (WOTRO), the Netherlands.

In areas where Plasmodium falciparum malaria is endemic, parasite density, morbidity, and mortality decrease with increasing age, which supports the view that years of cumulative exposure are necessary for the expression of maximal protective immunity. Developmental changes in the host also have been implicated in the expression of maximal resistance. To further evaluate the contribution of host developmental factors in malaria resistance, we examined the relationship between P. falciparum parasitemia and pubertal development in a cross-sectional sample of 12-18-year-old schoolgirls from an area of intense transmission in western Kenya. Among pubertal girls, dehydroepiandrosterone sulfate (DHEAS) levels were significantly associated with decreased parasite density, even after adjustment for age. DHEAS levels also were related to increased hemoglobin levels, even after accounting for age and other determinants of hemoglobin level. These findings support the hypothesis that host pubertal development, independent of age and, by proxy, cumulative exposure, is necessary for maximal expression of resistance to malarial infection and morbidity, as assessed by hemoglobin level.

The impact of insecticide (permethrin)-treated bed nets (ITNs) on the health of adolescent schoolgirls was investigated during a community-based, randomized, controlled trial of ITNs in western Kenya. Two school-based cross-sectional surveys were conducted to determine the prevalence of malaria and anemia in 644 schoolgirls 12-18 years old in a rural area with intense perennial malaria transmission. In 12- and 13-year-old schoolgirls, ITNs were associated with a reduced prevalence of all cause anemia (hemoglobin level <12 g/dL, 16.9% versus 31.4%, adjusted odds ratio [OR] = 0.38, 95% confidence interval [CI] = 0.21, 0.69%) and a 0.34 g/dL (95% CI = 0.02, 0.66) increase in mean hemoglobin concentrations. No beneficial effect on all-cause anemia (adjusted OR = 0.79, 95% CI = 0.43, 1.45) or hemoglobin concentrations (difference in mean = 0.14 g/dL, 95% CI = -0.24, 0.53) was evident in older girls. In all age groups, no effect was found on malaria parasite prevalence or density, clinical malaria, all-cause morbidity, standard measures of nutritional status and growth, or the use of antimalarials and other medications. ITNs approximately halved the prevalence of mild anemia in young, school-attending, non-pregnant, adolescent girls, but had no impact in older girls or on other malaria-associated morbidity or nutritional status.