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The polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and polymyxin B are that isolates of Pseudomonas aeruginosa , Acinetobacter baumannii , and Enterobacteriaceae are considered susceptible at MIC values of ≤2 mg/liter. These recommendations are contingent upon dosing and testing strategies that are described in this commentary.

Background In Cambodia dengue vector control activities are focused on larviciding with temephos and pyrethroid based adulticide sprays to which Aedes have been shown to be increasingly resistant. A cluster randomized trial assessed the impact of using biological control tools (guppy fish, pyriproxyfen (PPF), and Communication for Behavioral Impact (COMBI) activities in combination), which would be used in a value comparison to traditional chemical control tools. Given these new intervention methods, a qualitative assessment was designed in order to represent the quality of understanding, acceptance, and implementation by participants. Methodology/Principal findings A total of 103 participants in 12 Focus Group Discussions (FGDs) and nine In-Depth Interviews (IDIs) were included in the study. The majority of participants in intervention villages (50 out of 80) preferred guppy fish over other vector control methods due to ease of use and rearing, quick reproduction and propensity to eat larvae. A substantial number of participants (11 out of 40) in intervention villages with PPF favored it due to long-lasting effectiveness, lack of smell and easy maintenance. Participants showed high demand for both interventions and were willing to pay between 100–500 riel (0.03–0.13 USD). Nearly all participants perceived that the interventions resulted in a reduction in Aedes mosquitos (both adults and immatures) and dengue cases. The presence of larvae in the water despite the use of PPF was a source of concern for some participants, although this was overcome in some cases with proper health education through health volunteers. Interpersonal communication through health volunteers was the most favorite method of transmitting prevention messages. Conclusions/Significance The community led COMBI strategy resulted in high acceptance and perceived effectiveness of the interventions in target villages. Health volunteers are an effective and accepted channel of communication to engage communities, disseminate information and promote behavioral change at the household and community level. If shown effective through corresponding entomological surveys, the interventions should be continued and further strengthened to ensure they are accessible, available and affordable., Author summary Dengue is one of the most rapidly spreading mosquito-borne viral diseases in the world and is caused by bites of infected Aedes mosquitoes. Dengue infection is a systemic and dynamic disease with a wide clinical spectrum that includes both severe and non-severe manifestations. In some cases dengue can lead to death. Cambodia has one of the highest per-capita incidence rates. Without a cure or routinely available vaccine, dengue control relies largely on reduction and avoidance mosquitoes. In Cambodia dengue mosquito control activities are focused on larviciding with temephos and pyrethroid based adulticide sprays to which Aedes have been shown to be increasingly resistant. The current qualitative study was designed to better understand the community acceptance and perceptions of biological controls that would overcome insecticide resistance for consideration in dengue control strategies for the future. Two control methods were deployed in different size water containers: (1) guppy fish to predate mosquito larvae in large containers, and (2) a slow-release larvicide (pyriproxyfen) product in small containers. A total of 103 people participated in 12 FGDs and nine IDIs. Both methods were generally seen positively. The advantages of guppy fish were their ease of use and rearing, and evident propensity to eat larvae. The advantages of pyriproxyfen was its long-lasting effectiveness, lack of smell, and easy maintenance. Interpersonal communication through health volunteers was the most preferred method of transmitting prevention messages. Both mosquito control interventions should be considered in future projects in Cambodia.

IntroductionArtemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria. Its efficacy has been extensively assessed in clinical trials. In routine healthcare settings, however, its effectiveness can be diminished by delayed access to treatment and poor adherence. As well as affecting clinical outcomes, these factors can lead to increased transmission, which is the focus of this study.MethodsWe extend a within-host model of P. falciparum to include gametocytes, the parasite forms responsible for onward transmission. The model includes a pharmacokinetic–pharmacodynamic model of AL, calibrated against both immature and mature gametocytes using individual-level patient data, to estimate the impact that delayed access and imperfect adherence to treatment can have on onward transmission of the parasite to mosquitoes.ResultsUsing survey data from seven African countries to determine the time taken to acquire antimalarials following fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-fold, compared with patients treated after 24 hours. Realistic adherence behaviour, based on data from a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold, compared with a perfectly-adherent cohort. This was driven largely by increased rates of treatment failure leading to chronic infection, rather than prolonged gametocytaemia in patients who have slower, but still successful, clearance of parasites after imperfect adherence to treatment. Our model estimated that the mean infectivity of untreated infections was 29–51 times higher than that of treated infections (assuming perfect drug adherence), underlining the importance of improving treatment coverage.ConclusionUsing mathematical modelling, we quantify how delayed treatment and non-adherent treatment can increase transmission compared with prompt effective treatment. We also highlight that transmission from the large proportion of infections which never receive treatment is substantially higher than those treated.

Objective To evaluate augmented renal clearance (ARC) using aminoglycoside clearance (CLAMINO24h) derived from pharmacokinetic (PK) modelling. Methods A retrospective study at two paediatric hospitals of patients who received tobramycin or gentamicin from 1999 to 2016 was conducted. Compartmental PK models were constructed using the Pmetrics package, and Bayesian posteriors were used to estimate CLAMINO24h. ARC was defined as a CLAMINO24h of ≥130 mL/min/1.73 m2. Risk factors for ARC were identified using multivariate logistic regression. Results The final population model was fitted to 275 aminoglycoside serum concentrations. Overall clearance (L/h) was=CL0 × (TBW/70)0.75 × AGEH/(TMH + AGEH) + CL1 (0.5/SCr), where TBW is total body weight, H is the Hill coefficient, TM is a maturation term and SCr is serum creatinine. Median CLAMINO24h in those with versus without ARC was 157.36 and 93.42 mL/min/1.73 m2, respectively (P Conclusions ARC was observed in one of every five patients. Sepsis, increasing age and low SCr were associated with ARC. Increased clearance was associated with an attenuation of AUC24h in this population. Future studies are needed to define optimal dosing in paediatric patients with ARC.

This statement updates the recommendations of the American Academy of Pediatrics for the routine use of influenza vaccines and antiviral medications in the prevention and treatment of influenza in children during the 2019–2020 season. The American Academy of Pediatrics continues to recommend routine influenza immunization of all children without medical contraindications, starting at 6 months of age. Any licensed, recommended, age-appropriate vaccine available can be administered, without preference of one product or formulation over another. Antiviral treatment of influenza with any licensed, recommended, age-appropriate influenza antiviral medication continues to be recommended for children with suspected or confirmed influenza, particularly those who are hospitalized, have severe or progressive disease, or have underlying conditions that increase their risk of complications of influenza.

Summary Background Child growth faltering persists in sub-Saharan Africa despite the scale-up of nutrition, water, and sanitation interventions over the past 2 decades. High temperatures have been hypothesised to contribute to child growth faltering via an adaptive response to heat, reduced appetite, and the energetic cost of thermoregulation. We did a cross-sectional study to assess whether child growth faltering is related to environmental temperature in sub-Saharan Africa. Methods Data were extracted from 52 Demographic and Heath Surveys, dating from 2003 to 2016, that recorded anthropometric data in children aged 0–5 years, and were linked with remotely sensed monthly mean daytime land surface temperature for 2000–16. The odds of stunting (low height-for-age), wasting (low weight-for-height), and underweight (low weight-for-age) relative to monthly mean daytime land surface temperature were determined using multivariable logistic regression. Findings The study population comprised 656 107 children resident in 373 012 households. Monthly mean daytime land surface temperature above 35°C was associated with increases in the odds of wasting (odds ratio 1·27, 95% CI 1·16–1·38; p

IntroductionA large proportion of malaria-infected individuals in endemic areas do not experience symptoms that prompt treatment-seeking. These asymptomatically infected individuals may retain their infections for many months during which sexual-stage parasites (gametocytes) are produced that may be transmissible to mosquitoes. Reductions in malaria transmission could be achieved by detecting and treating these infections early. This study assesses the impact of enhanced community case management (CCM) and monthly screening and treatment (MSAT) on the prevalence and transmissibility of malaria infections.Methods and analysisThis cluster-randomised trial will take place in Sapone, an area of intense, highly seasonal malaria in Burkina Faso. In total, 180 compounds will be randomised to one of three interventions: arm 1 - current standard of care with passively monitored malaria infections; arm 2 - standard of care plus enhanced CCM, comprising active weekly screening for fever, and detection and treatment of infections in fever positive individuals using conventional rapid diagnostic tests (RDTs); or arm 3 - standard of care and enhanced CCM, plus MSAT using RDTs. The study will be conducted over approximately 18 months covering two high-transmission seasons and the intervening dry season. The recruitment strategy aims to ensure that overall transmission and force of infection is not affected so we are able to continuously evaluate the impact of interventions in the context of ongoing intense malaria transmission. The main objectives of the study are to determine the impact of enhanced CCM and MSAT on the prevalence and density of parasitaemia and gametocytaemia and the transmissibility of infections. This will be achieved by molecular detection of infections in all study participants during start and end season cross-sectional surveys and routine sampling of malaria-positive individuals to assess their infectiousness to mosquitoes.Ethics and disseminationThe study has been reviewed and approved by the London School of Hygiene and Tropical Medicine (LSHTM) (Review number: 14724) and The Centre National de Recherche et de Formation sur le Paludisme institutional review board (IRB) (Deliberation N° 2018/000002/MS/SG/CNRFP/CIB) and Burkina Faso national medical ethics committees (Deliberation N° 2018-01-010).Findings of the study will be shared with the community via local opinion leaders and community meetings. Results may also be shared through conferences, seminars, reports, theses and peer-reviewed publications; disease occurrence data and study outcomes will be shared with the Ministry of Health. Data will be published in an online digital repository.Trial registration numberNCT03705624.

BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed in the United States in 2010. We describe invasive pneumococcal disease (IPD) in children at 8 children’s hospitals in the US from 2014 to 2017. METHODS: Children with IPD occurring from 2014 to 2017 were identified from a prospective study. Demographic and clinical data, including results of any immune evaluation along with the number and dates of previous pneumococcal conjugate vaccines administered, were recorded on case report forms. Isolate serotypes were determined in a central laboratory. Pneumococcal conjugate vaccine doses were counted if IPD occurred ≥2 weeks after a dose. RESULTS: PCV13 serotypes accounted for 23.9% (115 out of 482) of IPD isolates from 2014 to 2017. Serotypes 3, 19A, and 19F accounted for 91% of PCV13 serotypes. The most common non-PCV13 serotypes were 35B, 23B, 33F, and 22F. An underlying condition was significantly (P < .0001) more common in children with IPD due to non-PCV13 serotypes (200 out of 367, 54.5%) than for children with PCV13 serotypes (27 out of 115, 23.5%). An immune evaluation was undertaken in 28 children who received ≥2 PCV13 doses before IPD caused by a PCV13 serotype. Only 1 was found to have an immunodeficiency. CONCLUSIONS: PCV13 serotypes (especially serotypes 3, 19A, and 19F) continue to account for nearly a quarter of IPD in US children 4 to 7 years after PCV13 was introduced. Underlying conditions are more common in children with non-PCV13 serotype IPD. Immune evaluations in otherwise healthy children with PCV13 serotype IPD despite receiving ≥2 PCV13 doses did not identify an immunodeficiency.

Almost 1.2 billion long-lasting insecticidal nets (LLINs) have been procured for malaria control. Institutional buyers often assume that World Health Organization (WHO) prequalified LLINs are functionally identical with a three-year lifespan. We measured the lifespans of three LLIN products, and calculated their cost-per-year of functional life, through a randomised double-blinded prospective evaluation among 3,420 study households in Tanzania using WHO-recommended methods. Primary outcome was LLIN functional survival (LLINs present in serviceable condition). Secondary outcomes were 1) bioefficacy and chemical content (residual insecticidal activity) and 2) protective efficacy for volunteers sleeping under LLINs (bite reduction and mosquitoes killed). LLIN median functional survival was significantly different: 2·0 years for Olyset, 2·5 years for PermaNet and 2·6 years for NetProtect. Functional survival was affected by accumulation of holes resulting in users discarding nets. Protective efficacy also significantly differed between products as they aged. The longer-lived nets were 20% cheaper than the shorter-lived product.

Background The Gambia has successfully reduced malaria transmission. The human reservoir of infection could further decrease if malaria-infected individuals could be identified by highly sensitive, field-based, diagnostic tools and then treated. Methods A cross-sectional survey was done at the peak of the 2017 malaria season in 47 Gambian villages. From each village, 100 residents were randomly selected for finger-prick blood samples to detect Plasmodium falciparum infections using highly sensitive rapid diagnostic tests (HS-RDT) and PCR. The sensitivity and specificity of the HS-RDT were estimated (assuming PCR as the gold standard) across varying transmission intensities and in different age groups. A deterministic, age-structured, dynamic model of malaria transmission was used to estimate the impact of mass testing and treatment (MTAT) with HS-RDT in four different scenarios of malaria prevalence by PCR: 5, 15, 30, and 60%, and with seasonal transmission. The impact was compared both to MTAT with conventional RDT and mass drug administration (MDA). Results Malaria prevalence by HS-RDT was 15% (570/3798; 95% CI 13.9–16.1). The HS-RDT sensitivity and specificity were 38.4% (191/497, 95% CI 34.2–42.71) and 88.5% (2922/3301; 95% CI 87.4–89.6), respectively. Sensitivity was the highest (50.9%, 95% CI 43.3–58.5%) in high prevalence villages (20–50% by PCR). The model predicted that in very low transmission areas (≤ 5%), three monthly rounds of MTAT with HS-RDT, starting towards the end of the dry season and testing 65 or 85% of the population for 2 consecutive years, would avert 62 or 78% of malaria cases (over 2 years), respectively. The effect of the intervention would be lower in a moderate transmission setting. In all settings, MDA would be superior to MTAT with HS-RDT which would be superior to MTAT with conventional RDT. Conclusion The HS-RDT’s field sensitivity was modest and varied by transmission intensity. In low to very low transmission areas, three monthly rounds per year of MTAT with HS-RDT at 85% coverage for 2 consecutive years would reduce malaria prevalence to such low levels that additional strategies may achieve elimination. The model prediction would need to be confirmed by cluster-randomized trials.

BackgroundIn 2017, 2.5 million newborns died, mainly from prematurity, infections, and intrapartum events. Preventing these deaths requires health systems to provide routine and emergency care at birth, and quality inpatient care for small and sick newborns. Defined levels of emergency obstetric care (EmOC) and standardised measurement of "signal functions" has improved tracking of maternal care in low- and middle-income countries (LMICs). Levels of newborn care, particularly for small and sick newborns, and associated signal functions are still not consistently defined or tracked.MethodsBetween November 2016-November 2017, we conducted an online survey of professionals working in maternal and newborn health. We asked respondents to categorise 18 clinical care interventions that could act as potential signal functions for small and sick newborns to 3 levels of care they thought were appropriate for health systems in LMICs to provide: "routine care at birth", "special care" and "intensive care". We calculated the percentage of respondents that classified each intervention at each level of care and stratified responses to look at variation by respondent characteristics.ResultsSix interventions were classified to specific levels by more than 50% of respondents as "routine care at birth," three interventions as "special care" and one as "intensive care". Eight interventions were borderline between these care levels. Responses were more consistent for interventions with relevant WHO clinical care guidelines while more variation in respondents' classification was observed in complex interventions that lack standards or guidelines. Respondents with experience in lower-income settings were more likely to assign a higher level of care for more complex interventions.ConclusionsResults were consistent with known challenges of scaling up inpatient care in lower-income settings and underline the importance of comprehensive guidelines and standards for inpatient care. Further work is needed to develop a shortlist of newborn signal functions aligned with emergency obstetric care levels to track universal health coverage for mothers and their newborns.

Community-acquired pneumonia (CAP) is a common cause of pediatric hospital admission. Empiric antibiotic therapy for hospitalized children with serious CAP now targets the most likely pathogen(s), including those that may demonstrate significant antibiotic resistance. Cell-free plasma next-generation sequencing (CFPNGS) was first made available for Pediatric Infectious Diseases physicians in June 1, 2017, to supplement standard-of-care diagnostic techniques. A retrospective chart review was performed for children hospitalized with CAP between June 1, 2017, and January 22, 2018, to evaluate the impact of CFPNGS. We identified 15 hospitalized children with CAP without other underlying medical conditions for whom CFPNGS was performed. CFPNGS identified a pathogen in 13 of 15 (86%) children compared with 47% for those using standard culture and PCR-based methods alone. Changes in antibiotic management were made in 7 of 15 (47%) of children as a result of CFPNGS.

Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to

BACKGROUND: Ivermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms. METHODS: We invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150–200 μg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov, number NCT02509481. FINDINGS: Eight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 [49%] males and 1379 [51%] females; median age 15 years [IQR 6–34]), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference −0·49 [95% CI −0·79 to −0·21], p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events [3%] among 1447 participants in the intervention group vs 24 events [2%] among 1265 in the control group; risk ratio 1·63 [1·01 to 2·67]; risk difference 1·21 [0·04 to 2·38], p=0·060), and no adverse reactions were reported. INTERPRETATION: Frequently repeated mass administrations of ivermectin during the malaria transmission season can reduce malaria episodes among children without significantly increasing harms in the populace. FUNDING: Bill & Melinda Gates Foundation.

H. influenzaecauses common and sometimes severe pediatric disease including chronic obstructive respiratory disease, otitis media, and infections of the central nervous system. Serotype b strains, with a b-type capsule, have been the historical cause of invasive disease, and the introduction of a serotype b-specific vaccine has led to their decline. However, unencapsulated or non-b-typeH. influenzaeinfections are not prevented by the vaccine and appear to be increasing in frequency. Here we report two pediatric cases of severe central nervous systemH. influenzaeinfection presenting to the same hospital in San Diego, California during the same week in January 2016. Due to good vaccine coverage in this part of the world,H. influenzaecases are normally rare and seeing two cases in the same week was unexpected. We thus suspected a recent transmission chain, and possible local outbreak. To test this hypothesis, we isolated and sequenced whole genomes from each patient and placed them in a phylogenetic tree spanning the known diversity ofH. influenzae. Surprisingly, we found that the two isolates (H1 and H2) belonged to distantly related lineages, suggesting two independent transmission events and ruling out a local outbreak. Despite being distantly related, H1 and H2 belong to two different lineages that appear to engage in frequent horizontal gene transfer (HGT), suggesting overlapping ecological niches. Together, our comparative genomic analysis supports a scenario in which an f-type ancestor of H2 arrived in North America around 2011 and acquired an a-type capsule by recombination (HGT) with a recent ancestor of H1. Therefore, as in other bacterial pathogens, capsule switching by HGT may be an important evolutionary mechanism of vaccine evasion inH. influenzae.OUTCOMETwo cases of severe central nervous systemH. influenzaeinfection occurred during the same week in the same hospital in San Diego, California – a region where such infections are usually very rare due to vaccine coverage. We thus suspected a local outbreak of anH. influenzaeclone not covered by the vaccine. Using whole genome sequencing and phylogenetic analysis of two isolates (H1 and H2, one from each patient), we found that they were distantly related, rapidly ruling out a local outbreak and suggesting independent transmission events. This result highlights the potential for rapid global spread of non-vaccineH. influenzaestrains. In this case, both H1 and H2 both encoded a-type capsules, whereas the vaccine targets b-type capsules. We also present comparative genomic evidence that a recent f-type ancestor of H2 acquired an a-type capsule locus from a recent ancestor of H1, and that this horizontal gene transfer (HGT) event likely happened in the past decade in North America, but probably not in the San Diego hospital. These results highlight the potential importance of HGT in the capsule locus in allowingH. influenzaeto escape vaccine coverage.DATA SUMMARYH. influenzaeH1 and H2 genome sequences have been deposited in NCBI under BioProject PRJNA534512.CONFLICT OF INTEREST STATEMENTThe authors declare that they have no conflict of interest to report.

Background Insecticide-treated net (ITN) durability, measured through physical integrity and bioefficacy, must be accurately assessed in order to plan the timely replacement of worn out nets and guide procurement of longer-lasting, cost-effective nets. World Health Organization (WHO) guidance advises that new intervention class ITNs be assessed 3 years after distribution, in experimental huts. In order to obtain information on whole-net efficacy cost-effectively and with adequate replication, a new bioassay, the Ifakara Ambient Chamber Test (I-ACT), a semi-field whole net assay baited with human host, was compared to established WHO durability testing methods. Methods Two experiments were conducted using pyrethroid-susceptible female adult Anopheles gambiae sensu stricto comparing bioefficacy of Olyset®, PermaNet® 2.0 and NetProtect® evaluated by I-ACT and WHO cone and tunnel tests. In total, 432 nets (144/brand) were evaluated using I-ACT and cone test. Olyset® nets (132/144) that did not meet the WHO cone test threshold criteria (≥ 80% mortality or ≥ 95% knockdown) were evaluated using tunnel tests with threshold criteria of ≥ 80% mortality or ≥ 90% feeding inhibition for WHO tunnel and I-ACT. Pass rate of nets tested by WHO combined standard WHO bioassays (cone/tunnel tests) was compared to pass in I-ACT only by net brand and time after distribution. Results Overall, more nets passed WHO threshold criteria when tested with I-ACT than with standard WHO bioassays 92% vs 69%, (OR: 4.1, 95% CI 3.5–4.7, p

Background Innovative and cost-effective strategies that clear asymptomatic malaria infections are required to reach malaria elimination goals, but remain a challenge. This mixed methods study explored people’s attitudes towards the reactive treatment of compound contacts of malaria cases with a 3-day course of dihydroartemisinin-piperaquine (DHAP), the socio-cultural representations of asymptomatic infections, and more specifically their treatment. Methods Prior to the start of the intervention, a sequential mixed method study was carried out. Qualitative data collection involved in-depth interviews and participant observations (including informal conversations) with key informants from the trial communities and the trial staff. Quantitative data were derived from a pre-trial cross-sectional survey on health literacy and health-seeking behaviour among randomly selected members of the study communities. Results In the pre-trial cross-sectional survey, 73% of respondents reported that malaria could be hidden in the body without symptoms. Whilst this may be interpreted as people’s comprehension of asymptomatic malaria, qualitative data indicated that informants had different interpretations of asymptomatic disease than the biomedical model. It was described as: (i) a minor illness that does not prevent people carrying out daily activities; (ii) an illness that oscillates between symptomatic and asymptomatic phases; and, (iii) a condition where disease agents are present in the body but remain hidden, without signs and symptoms, until something triggers their manifestation. Furthermore, this form of hidden malaria was reported to be most present in those living in the same compound with a malaria case (71%). Conclusion Treating asymptomatic malaria with pharmaceuticals was considered acceptable. However, people felt uncertain to take treatment without screening for malaria first, largely due to the lack of symptoms. Knowledge of asymptomatic malaria was not a strong re-inforcement for treatment adherence. In this study, the pre-intervention active engagement of communities existed of having people co-design accurate information messages about their personal risk of malaria, which increased their trust in expert knowledge and thus proved essential for the successful implementation of the community-based intervention.

Background Plasmodium falciparum transmission depends on mature gametocytes that can be ingested by mosquitoes taking a blood meal on human skin. Although gametocyte skin sequestration has long been hypothesized as important contributor to efficient malaria transmission, this has never been formally tested. Methods In naturally infected gametocyte carriers from Burkina Faso, we assessed infectivity to mosquitoes by direct skin feeding and membrane feeding. We directly quantified male and female gametocytes and asexual parasites in finger-prick and venous blood samples, skin biopsy samples, and in of mosquitoes that fed on venous blood or directly on skin. Gametocytes were visualized in skin tissue with confocal microscopy. Results Although more mosquitoes became infected when feeding directly on skin then when feeding on venous blood (odds ratio, 2.01; 95% confidence interval, 1.21–3.33; P = .007), concentrations of gametocytes were not higher in the subdermal skin vasculature than in other blood compartments; only sparse gametocytes were observed in skin tissue. Discussion Our data strongly suggest that there is no significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes and can be used to target and monitor malaria elimination initiatives., Plasmodium falciparum gametocyte skin sequestration has long been hypothesized but never formally tested. We observed no evidence for higher gametocyte densities in skin tissue of naturally infected gametocyte carriers or blood meals of mosquitoes feeding on their skin.

Background: Almost 1.2 billion long lasting insecticidal nets (LLINs) have been procured for malaria control. World Health Organization (WHO) prequalifies LLINs that remain adequately insecticidal three years after deployment. Institutional buyers often assume that prequalified LLINs are functionally identical with a three-year lifespan. We measured the lifespans of three LLIN products, and calculated their cost per year of functional life, to explore whether using such data for LLIN procurement could lead to more cost-effective product selection. Methods: A randomised double-blinded prospective evaluation of three pyrethroid LLIN products was conducted in 2013 to 2016 among 3,420 study households in Tanzania using WHO-recommended methods. Primary outcome was LLIN functional survival (LLINs present in serviceable condition). Secondary outcomes were 1) bioefficacy and chemical content (residual insecticidal activity) and 2) protective efficacy for volunteers sleeping under the LLINs (bite reduction and mosquitoes killed). Findings: LLIN median functional survival was significantly different: 2·0 years for Olyset, 2·5 years for PermaNet and 2·6 years for NetProtect. Functional survival was affected by accumulation of holes resulting in users discarding nets. Protective efficacy also significantly differed between products as they aged. Equivalent annual cost varied between $1·2 and $1·5 USD, assuming that each net was priced identically at $3. The longer-lived nets were 20% cheaper than the shorter-lived product. Interpretation: LLIN functional survival is less than three years, and differs substantially between products. These differences strongly influence LLIN cost-effectiveness, and cannot be ignored by LLIN buyers who care about value for money. Funding Statement: The research was made possible by the Research Council of Norway through the ABCDR Project no. 220757. Sarah Moore was funded by awards from IVCC and Notre Dame OPP1081737. Declaration of Interests: Sarah Moore, William Kisinza, Olivier Pigeon and Jason Moore conduct product evaluations for a number of vector control product manufacturers. The other authors declare that they have no competing interests. Ethics Approval Statement: Ethical approval was granted from ethical review committees at London School of Hygiene & Tropical Medicine (6333/A443), Ifakara Health Institute (IHI/IRB/AMM/ No: 07- 2014) and the Tanzanian National Institute for Medical Research (NIMR/HQ/R.8c/Vol. I/285).

Contains fulltext : 208938.pdf (Publisher’s version ) (Open Access) Gametocyte density and sex ratio can predict the proportion of mosquitoes that will become infected after feeding on blood of patients receiving nongametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects.

Author(s): Arrieta, Antonio C; Sung, Lillian; Bradley, John S; Zwaan, C Michel; Gates, Davis; Waskin, Hetty; Carmelitano, Patricia; Groll, Andreas H; Lehrnbecher, Thomas; Mangin, Eric; Joshi, Amita; Kartsonis, Nicholas A; Walsh, Thomas J; Paschke, Amanda | Abstract: BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to l18 years; AG2, 2 to l7 years; and AG3, 3 months to l2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS:The percentage of subjects meeting the PK target was l90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to l7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to l18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to l18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION:The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01716234.

Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes., Naturally acquired antibodies may inhibit Plasmodium survival in mosquitoes, alter malaria transmission dynamics, and form the basis for transmission-blocking vaccines. Here, using sera from malaria-exposed individuals, Stone et al. reveal novel antibody correlates of transmission-reducing activity.

Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes.

X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the BTK gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the Pseudomonas aeruginosa PAO1 genome. The patient was diagnosed with XLA and pseudomonal sepsis.

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to 90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to

Background The broad-spectrum cephalosporin ceftaroline, a metabolite of the prodrug ceftaroline fosamil, has shown in vitro activity against clinical isolates from pediatric patients. Methods This multicenter, randomized, observer-blinded, active-controlled study (NCT01669980) assessed the safety and effectiveness of ceftaroline fosamil compared with ceftriaxone plus vancomycin in patients between 2 months and 17 years of age with complicated community-acquired bacterial pneumonia. Patients were randomized 3:1 (stratified by age cohort) to receive either ceftaroline fosamil or ceftriaxone plus vancomycin (comparator) as intravenous therapy for ≥3 days. Patients who met specific study criteria on or after Study Day 4 were permitted to switch to an oral study drug. Safety assessments were treatment-emergent adverse events, and the effectiveness of treatment was assessed by clinical and microbiologic outcomes. Results The median duration of intravenous treatment was 9.0 (range, 3.0-19.0) days in the ceftaroline fosamil group (N=30) and 7.5 (5.0-13.0) days in the comparator group (N=10). At least one treatment-emergent adverse event was experienced by 12/30 patients (40%) in the ceftaroline fosamil group and 8/10 (80%) in the comparator group; most treatment-emergent adverse events in both groups were mild to moderate in intensity. Clinical response rates in the modified intent-to-treat population were 52% (15/29 patients) in the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively. Conclusions Ceftaroline fosamil was well tolerated and showed similar clinical response rates to ceftriaxone plus vancomycin in pediatric patients with complicated community-acquired bacterial pneumonia.

Community-acquired bacterial pneumonia (CABP) remains a major infection among children, despite the use of pneumococcal vaccination. Ceftaroline fosamil is a broad-spectrum cephalosporin antibiotic with activity against many bacteria, including Streptococcus pneumoniae (both penicillin-nonsusceptible and multidrug-resistant strains) and Staphylococcus aureus (including methicillin-resistant S. aureus). This article describes the safety, tolerability, and effectiveness of ceftaroline fosamil in the treatment of pediatric patients hospitalized with CABP, from a randomized, active-controlled, observer-blinded clinical study (registration number NCT01530763).Pediatric patients were stratified into 4 age cohorts and randomized (3:1) to receive either intravenous ceftaroline fosamil or ceftriaxone, with optional oral switch for a total treatment duration of 5-14 days. Enrollment was planned for 160 patients. Data collected included demographics, infection characteristics and pathogens. Treatment-emergent adverse events, clinical outcomes, and microbiologic responses were assessed.Ceftaroline fosamil was well tolerated. Similar percentages of patients in the ceftaroline fosamil (55/121; 45%) and ceftriaxone (18/39; 46%) groups reported treatment-emergent adverse events. Coombs seroconversion was observed in 17% of patients in the ceftaroline fosamil group; however, no evidence of hemolytic anemia or hemolysis was found. No deaths were reported during the study. Ceftaroline fosamil had similar effectiveness to ceftriaxone, with high clinical cure rates at test-of-cure in the modified intent-to-treat population (94/107; 88% and 32/36; 89%, respectively). Three documented S. aureus infections were successfully treated in the ceftaroline group, including one caused by methicillin-resistant S. aureus.The results of this study suggest that ceftaroline fosamil may be an important treatment option for pediatric patients hospitalized with CABP.

Background Dengue is the most rapidly spreading arboviral disease in the world. The current lack of fully protective vaccines and clinical therapeutics creates an urgent need to identify more effective means of controlling Aedes mosquitos, principally Aedes aegypti, as the main vector of dengue. Pyriproxyfen (PPF) is an increasingly used hormone analogue that prevents juvenile Aedes mosquitoes from becoming adults and being incapable of transmitting dengue. The objectives of the review were to (1) Determine the effect of PPF on endpoints including percentage inhibition of emergence to adulthood, larval mortality, and resistance ratios; and (2) Determine the different uses, strengths, and limitations of PPF in control of Aedes. A systematic search was applied to Pubmed, EMBASE, Web of Science, LILACS, Global Health, and the Cochrane database of Systematic Reviews. Out of 1,369 records, 90 studies met the inclusion criteria. Nearly all fit in one of the following four categories 1) Efficacy of granules, 2) Auto-dissemination/horizontal transfer, 3) use of ultra-low volume thermal fogging (ULV), thermal fogging (TF), or fumigant technologies, and 4) assessing mosquito resistance. PPF granules had consistently efficacious results of 90–100% inhibition of emergence for up to 90 days. The evidence is less robust but promising regarding PPF dust for auto-dissemination and the use of PPF in ULV, TF and fumigants. Several studies also found that while mosquito populations were still susceptible to PPF, the lethal concentrations increased among temephos-resistant mosquitoes compared to reference strains. The evidence is strong that PPF does increase immature mortality and adult inhibition in settings represented in the included studies, however future research should focus on areas where there is less evidence (e.g. auto-dissemination, sprays) and new use cases for PPF. A better understanding of the biological mechanisms of cross-resistance between PPF, temephos, and other insecticides will allow control programs to make better informed decisions., Author summary Many important diseases are spread by Aedes mosquitoes including dengue, chikungunya, Zika, and yellow fever. Dengue cases are increasing worldwide and there is a lack of effective vaccines and therapeutics. Additionally, mosquitoes have become resistant to commonly used insecticides. Pyriproxyfen (PPF) is an insecticide that prevents juvenile Aedes mosquitoes from becoming adults. The objective of this review was to determine the effect of PFF on percentage inhibition of emergence to adulthood, larval mortality, and resistance ratios and determine different use cases, strengths, and limitations. A systematic search was applied to scholarly databases where 67 full text articles met the inclusion criteria. Nearly all included studies fit in four categories, 1) granules, 2) auto-dissemination, 3) ultra-low volume spray, thermal fogging, and fumigant formulations, and 4) mosquito resistance. While mosquito populations were still susceptible to PPF, the concentrations needed to kill a majority of mosquitoes increased among those resistant to temephos (a commonly used insecticide). The evidence is strong that PPF granules do increase immature mortality and adult inhibition, however evidence for other forms and uses is still weak or could be increased. Better understanding of the cross-resistance between PPF, temephos, and other insecticides will allow control teams to make better informed decisions.

Summary Introduction Unprecedented improvements in housing are occurring across much of rural sub-Saharan Africa, but the consequences of these changes on malaria transmission remain poorly explored. We examined how different typologies of rural housing affect mosquito house entry and indoor climate. Methods Five typologies of mud-block houses were constructed in rural Gambia: four were traditional designs with poorly fitted doors and one was a novel design with gable windows to improve ventilation. In each house, one male volunteer slept under a bednet and mosquitoes were collected indoors with a light trap. Typologies were rotated between houses weekly. Indoor conditions were monitored with data loggers and the perceived comfort of sleepers recorded with questionnaires. We used pyschrometric modelling to quantify the comfort of the indoor climate using the logger data. Primary measurements were mean number of Anopheles gambiae and mean temperature for each house typology. Findings In thatched-roofed houses, closing the eaves reduced A gambiae house entry by 94% (95% CI 89–97) but increased the temperature compared with thatched-roofed houses with open eaves. In houses with closed eaves, those with metal roofs had more A gambiae, were hotter (1·5°C hotter [95% CI 1·3–1·7]) between 2100h and 2300 h, and had 25% higher concentrations of carbon dioxide (211·1 ppm higher [117·8–304·6]) than those with thatched roofs. In metal-roofed houses with closed eaves, mosquito house entry was reduced by 96% (91–98) by well fitted screened doors. Improved ventilation of metal-roofed houses made them as cool as thatched houses with open eaves. Metal-roofed houses with closed eaves were considered more uncomfortable than thatched ones with closed eaves. In metal-roofed houses, ventilated houses were more comfortable than unventilated houses before midnight, when people retired to bed. Interpretation Closing the eaves reduced vector entry in thatched houses but increased entry in metal-roofed houses. Metal-roofed houses with closed eaves were, however, protected against malaria vectors by well fitted screened doors and were made comfortable by increasing ventilation. House designs that exclude mosquitoes and are comfortable to live in should be a priority in sub-Saharan Africa. Funding Sir Halley Stewart Trust, Global Clinical Trials, and Global Challenges Research Fund.

Despite compelling evidence that modern housing protects against malaria, houses in endemic areas are still commonly porous to mosquitoes. The protective efficacy of four prototype screened doors and two windows designs against mosquito house entry, their impact on indoor climate, as well as their use, durability and acceptability was assessed in a Gambian village. A baseline survey collected data on all the houses and discrete household units, each consisting of a front and back room, were selected and randomly allocated to the study arms. Each prototype self-closing screened door and window was installed in six and 12 units, respectively, with six unaltered units serving as controls. All prototype doors reduced the number of house-entering mosquitoes by 59–77% in comparison with the control houses. The indoor climate of houses with screened doors was similar to control houses. Seventy-nine percentage of door openings at night occurred from dusk to midnight, when malaria vectors begin entering houses. Ten weeks after installation the doors and windows were in good condition, although 38% of doors did not fully self-close and latch (snap shut). The new doors and windows were popular with residents. The prototype door with perforated concertinaed screening was the best performing door because it reduced mosquito entry, remained fully functional, and was preferred by the villagers. Screened doors and windows may be useful tools for reducing vector exposure and keeping areas malaria-free after elimination, when investment in routine vector control becomes difficult to maintain.

These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009, prior to the 2009 H1N1 influenza pandemic. This document addresses new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza. It is intended for use by primary care clinicians, obstetricians, emergency medicine providers, hospitalists, laboratorians, and infectious disease specialists, as well as other clinicians managing patients with suspected or laboratory-confirmed influenza. The guidelines consider the care of children and adults, including special populations such as pregnant and postpartum women and immunocompromised patients.

Solithromycin is a novel fluoroketolide antibiotic which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age, 6 years [age range, 4 days to 17 years]) were administered intravenous (i.v.) or oral (capsules or suspension) solithromycin (i.v., 6 to 8 mg/kg of body weight; capsules/suspension, 14 to 16 mg/kg on days 1 and 7 to 15 mg/kg on days 2 to 5). PK samples were collected after the first and multidose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (n = 13; median age, 16 years [age range, 12 to 17 years]) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and postmenstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg i.v. daily and oral dosing of 20 mg/kg on day 1 (800-mg adult maximum) followed by 10 mg/kg on days 2 to 5 (400-mg adult maximum) would achieve a pediatric solithromycin exposure consistent with the exposures observed in adults. Seventy-six treatment-emergent adverse events (TEAEs) were reported in 40 subjects. Diarrhea (6 subjects) and infusion site pain or phlebitis (3 subjects) were the most frequently reported adverse events related to treatment. Two subjects experienced TEAEs of increased hepatic enzymes that were deemed not to be related to the study treatment. (The phase 1 pediatric studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01966055 and NCT02268279.).

Background Insecticide resistance threatens malaria control in sub-Saharan Africa. Knockdown resistance to pyrethroids and organochlorines in Anopheles gambiae sensu lato (s.l.) is commonly caused by mutations in the gene encoding a voltage-gated sodium channel which is the target site for the insecticide. The study aimed to examine risk factors for knockdown resistance in An. gambiae s.l. and its relationship with malaria infection in children in rural Gambia. Point mutations at the Vgsc-1014 locus, were measured in An. gambiae s.l. during a 2-year trial. Cross-sectional surveys were conducted at the end of the transmission season to measure malaria infection in children aged 6 months–14 years. Results Whilst few Anopheles arabiensis and Anopheles coluzzii had Vgsc-1014 mutations, the proportion of An. gambiae sensu stricto (s.s.) mosquitoes homozygous for the Vgsc-1014F mutation increased from 64.8 to 90.9% during the study. The Vgsc-1014S or 1014F mutation was 80% higher in 2011 compared to 2010, and 27% higher in the villages with indoor residual spraying compared to those without. An increase in the proportion of An. gambiae s.l. mosquitoes with homozygous Vgsc-1014F mutations and an increase in the proportion of An. gambiae s.s. in a cluster were each associated with increased childhood malaria infection. Homozygous Vgsc-1014F mutations were, however, most common in An. gambiae s.s. and almost reached saturation during the study meaning that the two variables were colinear. Conclusions As a result of colinearity between homozygous Vgsc-1014F mutations and An. gambiae s.s., it was not possible to determine whether insecticide resistance or species composition increased the risk of childhood malaria infection. Electronic supplementary material The online version of this article (10.1186/s12936-018-2348-8) contains supplementary material, which is available to authorized users.

Influenza virus can cause severe or life-threatening infection in children. This review provides an update on antiviral medications available to treat and prevent influenza in both healthy children and children with underlying medical conditions, and recommendations on their appropriate use in the outpatient and inpatient settings.Despite the significant morbidity and mortality associated with influenza infection, a large number of children hospitalized with influenza do not receive specific antiviral treatment with a neuraminidase inhibitor. Although the effectiveness of this intervention has been debated, several recent observational studies have shown the potential benefits conferred by early antiviral treatment. Oral oseltamivir and inhaled zanamivir remain the best studied antiviral agents for influenza treatment and prevention. In addition, the US Food and Drug Administration recently approved peramivir, a novel neuraminidase inhibitor available for intravenous administration.Children with suspected or documented influenza infection benefit from early antiviral treatment with neuraminidase inhibitors that can shorten illness duration, decrease symptom severity, and lower the risk of complications leading to hospitalization and death. Unless contraindicated, all hospitalized children, children with underlying medical conditions, and those with severe or progressive symptoms of influenza should receive specific antiviral treatment for influenza with a neuraminidase inhibitor. Additionally, antiviral treatment of influenza-infected children in the outpatient setting should be strongly considered.

Understanding the importance of gametocyte density on human-to-mosquito transmission is of immediate relevance to malaria control. Previous work (Churcher et al., 2013) indicated a complex relationship between gametocyte density and mosquito infection. Here we use data from 148 feeding experiments on naturally infected gametocyte carriers to show that the relationship is much simpler and depends on both female and male parasite density. The proportion of mosquitoes infected is primarily determined by the density of female gametocytes though transmission from low gametocyte densities may be impeded by a lack of male parasites. Improved precision of gametocyte quantification simplifies the shape of the relationship with infection increasing rapidly before plateauing at higher densities. The mean number of oocysts per mosquito rises quickly with gametocyte density but continues to increase across densities examined. The work highlights the importance of measuring both female and male gametocyte density when estimating the human reservoir of infection.

Objective The aim of this study was to use a sampling-based approach to obtain estimates of retention in HIV care before initiation of antiretroviral treatment (ART), corrected for outcomes in patients who were lost according to clinic registers. Design Retrospective cohort study of HIV-positive individuals not yet eligible for ART (CD4 >500). Setting Three urban and three rural HIV care clinics in Uganda; information was extracted from the clinic registers for all patients who had registered for pre-ART care between January and August 2015. Participants A random sample of patients who were lost according to the clinic registers (>3 months late to scheduled visit) was traced to ascertain their outcomes. Outcome measures The proportion of patients lost from care was estimated using a competing risks approach, first based on the information in the clinic records alone and then using inverse probability weights to incorporate the results from tracing. Cox regression was used to determine factors associated with loss from care. Results Of 1153 patients registered for pre-ART care (68% women, median age 29 years, median CD4 count 645 cells/µL), 307 (27%) were lost according to clinic records. Among these, 195 (63%) were selected for tracing; outcomes were ascertained in 118 (61%). Seven patients (6%) had died, 40 (34%) were in care elsewhere and 71 (60%) were out of care. Loss from care at 9 months was 30.2% (95% CI 27.3% to 33.5%). After incorporating outcomes from tracing, loss from care decreased to 18.5% (95% CI 13.8% to 23.6%). Conclusion Estimates of loss from HIV care may be too high if based on routine clinic data alone. A sampling-based approach is a feasible way of obtaining more accurate estimates of retention, accounting for transfers to other clinics.

An urgent need exists to develop new antibacterial drugs for children. We conducted research with investigators of pediatric antibacterial drug trials to identify facilitators and barriers in the conduct of these trials. Seventy-three investigators completed an online survey assessing the importance of 15 facilitators (grouped in 5 topical categories) and the severity of 36 barriers (grouped in 6 topical categories) to implementing pediatric antibacterial drug trials. Analysis focused on the identification of key factors that facilitate the successful implementation of pediatric antibacterial drug trials and the key barriers to implementation. Almost all investigators identified two factors as very important facilitators: having site personnel for enrollment and having adequate funding. Other top factors were related to staffing. Among the barriers, factors related to parent concerns and consent were prominent, particularly obtaining parental consent when there was disagreement between parents, concerns about the number of blood draws, and concerns about the number of invasive procedures. Having overly narrow eligibility criteria was also identified as a major barrier. The survey findings suggest three areas in which to focus efforts to help facilitate ongoing drug development: (1) improving engagement with parents of children who may be eligible to enroll in a pediatric antibacterial drug trial, (2) broadening inclusion criteria to allow more participants to enroll, and (3) ensuring adequate staffing and establishing sustainable financial strategies, such as funding pediatric trial networks. The pediatric antibacterial drug trials enterprise is likely to benefit from focused efforts by all stakeholders to remove barriers and enhance facilitation.

Despite legislation to stimulate pediatric drug development through clinical trials, enrolling children in trials continues to be challenging. Non-investigator (those who have never served as a clinical trial investigator) providers are essential to recruitment of pediatric patients, but little is known regarding the specific barriers that limit pediatric providers from participating in and referring their patients to clinical trials. We conducted an online survey of pediatric providers from a wide variety of practice types across the United States to evaluate their attitudes and awareness of pediatric clinical trials. Using a 4-point Likert scale, providers described their perception of potential barriers to their practice serving as a site for pediatric clinical trials. Of the 136 providers surveyed, 52/136 (38%) had previously referred a pediatric patient to a trial, and only 17/136 (12%) had ever been an investigator for a pediatric trial. Lack of awareness of existing pediatric trials was a major barrier to patient referral by providers, in addition to consideration of trial risks, distance to the site, and time needed to discuss trial participation with parents. Overall, providers perceived greater challenges related to parental concerns and parent or child logistical barriers than study implementation and ethics or regulatory barriers as barriers to their practice serving as a trial site. Providers who had previously been an investigator for a pediatric trial were less likely to be concerned with potential barriers than non-investigators. Understanding the barriers that limit pediatric providers from collaboration or inhibit their participation is key to designing effective interventions to optimize pediatric trial participation.

Enrollment of children into pediatric clinical trials remains challenging. More effective strategies to improve recruitment of children into trials are needed. This study used in-depth qualitative interviews with parents who were approached to enroll their children in a clinical trial in order to gain an understanding of the barriers to pediatric clinical trial participation. Twenty-four parents whose children had been offered the opportunity to participate in a clinical trial were interviewed: 19 whose children had participated in at least 1 clinical trial and 5 who had declined participation in any trial. Each study aspect, from the initial explanation of the study to the end of the study, can affect the willingness of parents to consent to the proposed study and future studies. Establishing trust, appropriate timing, a transparent discussion of risks and benefits oriented to the layperson, and providing motivation for children to participate were key factors that impacted parents' decisions. In order for clinical trial accrual to be successful, parents' priorities and considerations must be a central focus, beginning with initial trial design. The recommendations from the parents who participated in this study can be used to support budget allocations that ensure adequate training of study staff and improved staffing on nights and weekends. Studies of parent responses in outpatient settings and additional inpatient settings will provide valuable information on the consent process from the child's and parent's perspectives. Further studies are needed to explore whether implementation of such strategies will result in improved recruitment for pediatric clinical trials.

Background Whilst there have been substantial reductions in malaria transmission over the past decade, in many countries in West and Central Africa the malaria burden remains high. Monitoring and evaluation of malaria transmission trends and intervention strategies are key elements for malaria control programmes. This study uses a time series of annual malaria indicator surveys to track the progress of malaria control in Bioko Island, Equatorial Guinea, over a 13 year period of intensive interventions. Malaria infection and haemoglobin were measured annually in children (1 to 14 years) in cross-sectional household surveys from 2004 to 2016 in 18 sentinel sites across the island. Trends in transmission patterns were assessed and the impact of the vector control interventions (net use and spray coverage) was evaluated. Results Between 2004 and 2016 approximately 106,500 individual tests for parasitaemia were conducted using rapid diagnostic tests. Although spray coverage remained relatively high (> 70%) over the time period, reported net usage was generally below 40%. Parasite prevalence reduced from 43.3 to 10.5% between 2004 and 2016. The prevalence of moderate to severe anaemia in children aged 1–5 years reduced from 14.9 to 1.6%. Impact in individual sites ranged from 57 to 100% reductions in parasite prevalence between 2004 and 2016. Sleeping under a net and living in a house that had been sprayed in the past 12 months were independently protective against infection (OR = 0.69 [95%CI 0.61–0.80] and OR = 0.87 [95% CI 0.78–0.97], respectively), whilst recent travel to the mainland increased the odds of infection nearly fourfold (OR = 3.94 [95%CI 2.79–5.56]). Conclusion Island-wide interventions have resulted in a substantial reduction in malaria transmission on Bioko Island. This unique time series of 13 consecutive annual malaria indicator surveys clearly demonstrates the long-term effectiveness of the sustained use of two vector control interventions, indoor residual spraying and LLINs, and the value of comprehensive and sustained surveillance. Despite considerable success in reducing the burden on the island, malaria is still endemic, with populations in some areas remaining at high risk of infection. Electronic supplementary material The online version of this article (10.1186/s12936-018-2213-9) contains supplementary material, which is available to authorized users.

Background Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes (ClinicalTrials.gov, NCT02836002). Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. Findings Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). Conclusions The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. Funding PATH Malaria Vaccine Initiative (MVI), eLife digest The parasite that causes malaria, named Plasmodium falciparum, has a life cycle that involves both humans and mosquitoes. Starting in the saliva of female Anopheles mosquitoes, it enters a person’s bloodstream when the insects feed. It then moves to the person’s liver, where it infects liver cells and matures into a stage known as schizonts. The schizonts then divide to form thousands of so-called merozoites, which burst out of the liver cells and into the bloodstream. The merozoites infect red blood cells, producing more schizonts and yet more merozoites, which continue the infection. To complete its life cycle, the parasite must return to a mosquito. Some of the parasites in the person’s blood transform into male and female cells called gametocytes that are taken up by a mosquito when it feeds on that person. Inside the mosquito, male and female parasites reproduce to create the next generation of parasites. The new parasites then move to the mosquito’s salivary glands, ready to begin another infection. Stopping the parasite being transmitted from humans to mosquitoes will stop the spread of malaria in the population. Yet it has proven difficult to study this part of the life cycle from natural infections. Here, Reuling et al. report a new method for generating gametocytes in human volunteers that will enable closer study of the biology of malaria transmission. The method is developed using the Controlled Human Malaria Infection (CHMI) model. Healthy volunteers without a history of malaria are bitten by mosquitoes infected with malaria parasites. Shortly afterwards, the volunteers are given a drug treatment to control and reduce their symptoms. The gametocytes form during this phase of the infection. At the end of the experiment, all the volunteers receive a final treatment that completely cures the infection. Reuling et al. recruited 16 volunteers and assigned them to four groups at random. Each group received a different drug regime. Roughly a week after the mosquito bites, all participants showed malaria parasites in their blood, and between 8.5 and 12 days later, mature gametocytes started to appear. This early appearance suggests that the parasites start to transform into gametocytes when they first emerge from the liver. The experiment also revealed that female gametocytes stay in the blood for a longer period than their male counterparts. These results are proof of principle for a new way to investigate malaria infection. The new model provides a controlled method for studying P. falciparum gametocytes in people. In the future, it could help to test the impact of drugs and vaccines on gametocytes. Understanding more about these parasites’ biology could lead to treatments that block malaria transmission.

Background The Government of Tanzania is the main source of long-lasting insecticidal nets (LLINs) for its population. Mosquito nets (treated and untreated) are also available in the commercial market. To sustain investments and health gains in the fight against malaria, it is important for the National Malaria Control Programme to monitor LLIN coverage especially in the years between mass distributions and to understand what households do if their free nets are deemed unusable. The aim of this paper was to assess standard LLIN indicators by wealth status in Tanzania in 2013, 2 years after the last mass campaign in 2011, and extend the analysis to untreated nets (UTNs) to investigate how households adapt when nets are not continuously distributed. Methods Between October–December 2013, a household survey was conducted in 3398 households in eight districts in Tanzania. Using the Roll Back Malaria indicators, the study analysed: (1) household net ownership; (2) access to nets; (3) population net use and (4) net use:access ratio. Outcomes were calculated for LLINs and UTNs. Results were analysed by socio-economic quintiles and by district. Results Only three of the eight districts had household LLIN ownership of more than 80%. In 2013, less than a quarter of the households had one LLIN for every two people and only half of the population had access to an LLIN. Only the wealthier quintiles increased their net ownership and access to levels above 80% through the addition of UTNs. Overall net use of the population was low (LLINs: 32.8%; UTNs: 9.5%) and net use:access ratio was below target level (LLINs: 0.66; UTN: 0.50). Both measures varied significantly by district. Conclusions Two years after the last mass campaign, the percentage of households or population with access to LLINs was low. These findings indicate the average rate at which households in Tanzania lose their nets is higher than the rate at which they acquire new nets. The wealthiest households topped up their household net ownership with UTNs. Efforts to make LLINs available through commercial markets should be promoted, so those who can afford to buy nets purchase LLINs rather than UTNs. Net use was low around 40% and mostly explained by lack of access to nets. However, the use:access ratio was poor in Mbozi and Kahama districts warranting further investigations to understand other barriers to net use. Electronic supplementary material The online version of this article (10.1186/s12936-018-2247-z) contains supplementary material, which is available to authorized users.

Antimicrobial agents are essential in the therapy of bacterial infections. The approach to antimicrobial therapy is outlined in Chapter 289 (Principles of Anti-Infective Therapy), providing the clinician with an overview of the selection of agents based on the characteristics of infected children with respect to their pathogens and antibiotic susceptibilities, sites of infection, drug absorption, distribution and elimination, comorbidities, and a consideration of the benefits versus the risks of antimicrobial therapy. In this chapter, the agents themselves are discussed, providing a background on mechanism of action, spectrum of antibacterial activity, antibiotic resistance, and current clinical use. A more detailed discussion for specific infections is found in each chapter describing that infection. An in-depth discussion of antibiotic resistance and the ways to detect resistance is presented in Chapter 291. Pharmacokinetic-pharmacodynamic basis of optimal antibiotic therapy is discussed in Chapter 292. Table 292-1 provides a summary of the pharmacokinetics, tissue distribution, metabolism, and excretion of commonly used antimicrobial agents within each of the antibiotic classes. Table 292-2 provides the spectrum of activity of each antibiotic. Appendices 292-1 and 292-2 provide dosages of antibiotics.