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Pediatric chronic osteomyelitis is a rare, debilitating condition lacking management guidelines. In a national survey of 162 pediatric infectious disease physicians through the Emerging Infections Network, tremendous variability in diagnostic approaches and management was noted, highlighting a need for a prospective study to better define the spectrum of pathogens and disease.

Treatment of pediatric AHO requires antibiotic/surgical management. Considerable clinical experience exists, but with current knowledge of antibiotic pharmacokinetics and pharmacodynamics, recommendations for dosages for old or new antibiotics should be based on current standards for drug development whenever possible.

BACKGROUND Community-acquired pneumonia (CAP) is common in pediatrics. More severe complicated CAP (cCAP) requires broad-spectrum empirical therapy. Cell-free plasma next-generation sequencing (cfNGS), a DNA-based diagnostic tool, could be used to guide therapy. We retrospectively compared the pathogen identification rate of cfNGS to that of standard culture methods and assessed the impact of cfNGS on antibiotic therapy in children hospitalized for cCAP. METHODS We conducted a retrospective review of children aged 3 months to 18 years hospitalized for cCAP with cfNGS results from January 24, 2018, to December 31, 2020. We compared the positivity rate of conventional microbiologic diagnostic testing with that of cfNGS and the impact on clinical management, including changes in antibiotic therapy. RESULTS We identified 46 hospitalized children with cCAP with cfNGS results. Of these children, 34 also had blood cultures (1 positive for pathogen; 3%) and 37 had pleural fluid cultures (10 positive for pathogen; 27%). Of the 46 children, positive cfNGS testing results were positive for pathogen in 45 (98%), with the causative pathogen identified in 41 (89%). cfNGS was the only method for pathogen identification in 32 children (70%). cfNGS results changed management in 36 (78%) of 46 children, with the antibiotic spectrum narrowed in 29 (81%). CONCLUSIONS cfNGS provided a higher diagnostic yield in our pediatric cCAP cohort compared with conventional diagnostic testing and affected management in 78% of children. Prospective studies are needed to better characterize the clinical outcome, cost-effectiveness, and antimicrobial stewardship benefits of cfNGS in pediatric cCAP.

Background Pediatric chronic osteomyelitis (COM) is an uncommon, poorly defined, debilitating disorder often requiring multiple surgeries and prolonged antibiotic courses. Serious long-term sequelae may occur. As accepted diagnostic criteria do not exist, assessments of disease incidence, medical/surgical approach to management and outcomes are lacking. Methods We created a 14-question web-based survey sent to 390 pediatric infectious disease (PID) physician members of the Emerging Infections Network of the Infectious Diseases Society of America. With no standard definition of COM, respondents were asked to conceptualize this disease as they would during routine clinical practice. Of the 148 (38%) survey respondents so far (Table 1), 126 (85%) reported caring for children with COM. We assessed provider characteristics, diagnostic approach, and site-standard surgical and antibiotic management (including oral and intravenous [IV] antimicrobial choice and duration). We performed descriptive statistics on survey results. Results Of the 126 respondents, most were >5 years post-fellowship training and nearly half reported managing 3-6 cases of COM per year (Table 2). Prolonged duration of symptoms (79%), normal inflammatory markers (45%), and abnormal plain films (44%) were the most common findings used for diagnosis; however, diagnostic criteria varied. The most common risk factor was orthopedic implants (44%). Management choices and duration are in Figure 1. Most treated with IV antibiotics for < 2 weeks (34%), continuing oral antibiotics for at least 3-6 months (55%). In COM with retained orthopedic implant, most physicians (48%) use oral therapy until implant removal. Considerations for transition from IV to oral antibiotics included improved physical examination (60%), inflammatory markers (52%), extent of disease (55%), causative organism (41%) and location of infection (38%). Though 85% reported being comfortable diagnosing and managing COM, practices varied widely. Reported approaches to surgical management (a), duration of IV antibiotics (b), and duration of oral antibiotics (c) in children with COM, and management of COM in patients with implanted hardware (d) Responses from 126 pediatric infectious diseases physician participating in an Emerging Infections Network survey regarding diagnosis and management of chronic osteomyelitis (COM). Figure 1a) missing data for 2 respondents; figure 1b) missing data for 5 respondents; figure 1c) missing data for 2 respondents; figure 1d) missing data for 9 respondents. COM: Chronic osteomyelitis; IV: intravenous; abx: antibiotics. Conclusion Pediatric COM is a complex infection. Formal diagnostic criteria and future prospective studies for medical/surgical management by pathogen/site of infection and presence of foreign material are needed to optimize care and outcomes. Disclosures Daniel Benjamin, Jr., MD PhD MPH, Allergan: Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant|Syneos Health: Advisor/Consultant.

Background In rural sub-Saharan Africa, thatch roofs are being replaced by metal roofs. Metal roofing, however, increases indoor temperatures above human comfort levels, and thus makes it more likely that residents will not use an insecticide-treated bed net (ITN) at night. Whether the colour of a metal roof affects indoor temperature and human comfort was assessed. Methods Two identical, experimental houses were constructed with metal roofs in rural Gambia. Roof types were: (1) original bare-metal, (2) painted with red oxide primer or (3) white gloss, to reflect solar radiation. Pairwise comparisons were run in six, five-night blocks during the malaria season 2018. Indoor climate was measured in each house and multivariate analysis used to compare indoor temperatures during the day and night. Results From 21.00 to 23.59 h, when most residents decide whether to use an ITN or not, the indoor temperature of a house with a bare metal roof was 31.5 °C (95% CI 31.2–31.8 °C), a red roof, 30.3 °C (95% CI 30.0–30.6) and a white roof, 29.8 °C (95% CI 29.4–30.1). During the same period, red-roofed houses were 1.23 °C cooler (95% CI 1.22–1.23) and white roofs 1.74 °C cooler (95% CI 1.70–1.79) than bare-metal roofed houses (p p p = 0.081), compared with the bare-metal roofed houses. Human comfort analysis showed that from 21.00 to 23.59 h houses with white roofs (comfortable for 87% time) were more comfortable than bare-metal roofed houses (comfortable for 13% time; odds ratio = 43.7, 95% CI 27.5–69.5, p Conclusions Houses with a white roof were consistently cooler and more comfortable than those with a bare metal roof. Painting the roofs of houses white is a cheap way of making a dwelling more comfortable for the occupants and could potentially increase bed net use in hot humid countries.

Pediatric community-acquired pneumonia in pre-school aged children is a common diagnosis, frequently treated with antibiotics although most often caused by viruses. An accurate assessment of treatment-related clinical outcomes is dependent on identifying the pathogen(s) and their susceptibility to treatment interventions.

Background Anthrax is a toxin-mediated zoonotic disease caused by Bacillus anthracis, with a worldwide distribution recognized for millennia. Bacillus anthracis is considered a potential biowarfare agent. Methods We completed a systematic review for clinical and demographic characteristics of adults and children hospitalized with anthrax (cutaneous, inhalation, ingestion, injection [from contaminated heroin], primary meningitis) abstracted from published case reports, case series, and line lists in English from 1880 through 2018, assessing treatment impact by type and severity of disease. We analyzed geographic distribution, route of infection, exposure to anthrax, and incubation period. Results Data on 764 adults and 167 children were reviewed. Most cases reported for 1880 through 1915 were from Europe; those for 1916 through 1950 were from North America; and from 1951 on, cases were from Asia. Cutaneous was the most common form of anthrax for all populations. Since 1960, adult anthrax mortality has ranged from 31% for cutaneous to 90% for primary meningitis. Median incubation periods ranged from 1 day (interquartile range [IQR], 0–4) for injection to 7 days (IQR, 4–9) for inhalation anthrax. Most patients with inhalation anthrax developed pleural effusions and more than half with ingestion anthrax developed ascites. Treatment and critical care advances have improved survival for those with systemic symptoms, from approximately 30% in those untreated to approximately 70% in those receiving antimicrobials or antiserum/antitoxin. Conclusions This review provides an improved evidence base for both clinical care of individual anthrax patients and public health planning for wide-area aerosol releases of B. anthracis spores.

Background Bacillus anthracis can cause anthrax and is a potential bioterrorism agent. The 2014 Centers for Disease Control and Prevention recommendations for medical countermeasures against anthrax were based on in vitro data and expert opinion. However, a century of previously uncompiled observational human data that often includes treatment and outcomes is available in the literature for analysis. Methods We reviewed treatment outcomes for patients hospitalized with anthrax. We stratified patients by meningitis status, route of infection, and systemic criteria, then analyzed survival by treatment type, including antimicrobials, antitoxin/antiserum, and steroids. Using logistic regression, we calculated odds ratios and 95% confidence intervals to compare survival between treatments. We also calculated hospital length of stay. Finally, we evaluated antimicrobial postexposure prophylaxis (PEPAbx) using data from a 1970 Russian-language article. Results We identified 965 anthrax patients reported from 1880 through 2018. After exclusions, 605 remained: 430 adults, 145 children, and 30 missing age. Survival was low for untreated patients and meningitis patients, regardless of treatment. Most patients with localized cutaneous or nonmeningitis systemic anthrax survived with 1 or more antimicrobials; patients with inhalation anthrax without meningitis fared better with at least 2. Bactericidal antimicrobials were effective for systemic anthrax; addition of a protein synthesis inhibitor(s) (PSI) to a bactericidal antimicrobial(s) did not improve survival. Likewise, addition of antitoxin/antiserum to antimicrobials did not improve survival. Mannitol improved survival for meningitis patients, but steroids did not. PEPAbx reduced risk of anthrax following exposure to B. anthracis. Conclusions Combination therapy appeared to be superior to monotherapy for inhalation anthrax without meningitis. For anthrax meningitis, neither monotherapy nor combination therapy were particularly effective; however, numbers were small. For localized cutaneous anthrax, monotherapy was sufficient. For B. anthracis exposures, PEPAbx was effective.

The neurological sequelae of Bacillus anthracis infection include a rapidly progressive fulminant meningoencephalitis frequently associated with intracranial hemorrhage, including subarachnoid and intracerebral hemorrhage. Higher mortality than other forms of bacterial meningitis suggests that antimicrobials and cardiopulmonary support alone may be insufficient and that strategies targeting the hemorrhage might improve outcomes. In this review, we describe the toxic role of intracranial hemorrhage in anthrax meningoencephalitis. We first examine the high incidence of intracranial hemorrhage in patients with anthrax meningoencephalitis. We then review common diseases that present with intracranial hemorrhage, including aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage, postulating applicability of established and potential neurointensive treatments to the multimodal management of hemorrhagic anthrax meningoencephalitis. Finally, we examine the therapeutic potential of minocycline, an antimicrobial that is effective against B. anthracis and that has been shown in preclinical studies to have neuroprotective properties, which thus might be repurposed for this historically fatal disease.

Measures to limit SARS-CoV-2 transmission in 2020 reduced other viral infections. Among 7 US children’s hospitals, invasive pneumococcal disease cumulative incidence decreased by 46% in 2020 vs 2017-2019. Limited droplet transmission of pneumococci and preceding viral pathogens may be responsible.

BACKGROUND: Limited data are available on the contemporary epidemiology, clinical management, and healthcare utilization for pediatric urinary tract infection (UTI) due to third generation cephalosporin-resistant Enterobacterales (G3CR) in the United States. OBJECTIVES: To describe the epidemiology, antimicrobial treatment and response, and healthcare utilization associated with G3CR UTI. METHODS: Multi-site, matched cohort-control study including children with G3CR UTI versus non-G3CR UTI. UTI was defined as per American Academy of Pediatrics guidelines, and G3CR as resistance to ceftriaxone, cefotaxime or ceftazidime. We collected data from the acute phase of illness to 6 months thereafter. RESULTS: Among 107 children with G3CR UTI and 206 non-G3CR UTI with documented assessment of response, the proportion with significant improvement on initial therapy was similar (52% vs 57%, odds ratio (OR) 0.81, 95% confidence interval (CI) 0.44-1.50). G3CR-patients were more frequently hospitalized at presentation (38% vs 17%, OR 3.03, 95% CI 1.77-5.19) and for longer duration (8d vs 4d, p-value=0.05). In the follow-up period, more G3CR-patients had urine cultures (75% vs 53%, OR 2.61, 95% CI 1.33-5.24), antimicrobial treatment for any indication (53% vs 29%, OR 2.82, 95% CI 1.47-5.39), and subspecialty consultation (23% vs 6%, OR 4.52, 95% CI 2.10-10.09). In multivariate analysis, prior systemic antimicrobial therapy remained a significant risk factor for G3CR UTI (adjusted OR 1.91, 95% CI 1.06-3.44). CONCLUSIONS: We did not observe a significant difference in response to therapy between G3CR and susceptible UTI, but subsequent healthcare utilization was significantly increased.

BACKGROUND Infections with Gram-positive bacteria, including acute bacterial skin and skin structure infections (ABSSSIs), are common in children. We describe a single-dose pharmacokinetics and safety study of tedizolid phosphate, a new oxazolidinone under investigation for the treatment of ABSSSIs in children, in hospitalized participants 2 to

BACKGROUND Tedizolid phosphate is an oxazolidinone prodrug approved in 2014 for treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs); however, efficacy has not previously been evaluated in children. This study compared the safety and efficacy of tedizolid (administered as tedizolid phosphate) with active antibacterial comparators for the treatment of ABSSSIs in adolescents. METHODS This was a randomized, assessor-blind, global phase 3 study of tedizolid versus active comparators for the treatment of Gram-positive ABSSSIs in adolescents (12 to

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500mg by 2-hour intravenous (IV) infusion every 8hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5mg/kg (maximum 2,000-500mg) q8h for those ≥6months to 18years old, and 40-10mg/kg q8h for those ≥3 to 6months old with creatinine clearance > 50mL/min/1.73 m2 .

Background We prospectively evaluated efficacy and safety of daptomycin versus active comparator in children with acute hematogenous osteomyelitis (AHO). Methods Randomized, controlled, double-blind, global, multicenter, phase 3 trial. Patients 1-17 years of age with suspected/confirmed AHO requiring hospitalization and intravenous therapy were randomized 1:1 to intravenous daptomycin (once-daily, age-adjusted doses) or comparator (vancomycin, nafcillin or equivalent) ≥4 days, followed by oral therapy (14-42 days total). Primary endpoint: protocol-defined clinical improvement by Day 5 in the modified intention-to-treat (MITT) population (confirmed AHO, ≥1 dose of study treatment); differences between study arms were evaluated using a prespecified 15% noninferiority margin for daptomycin. Results Seventy-three patients per arm received treatment. Pathogens were isolated from 62% of patients (83% methicillin-susceptible Staphylococcus aureus, 9% methicillin-resistant S. aureus [MRSA]). Clinical improvement by Day 5 was observed in 55/71 (78%) daptomycin- and 58/70 (83%) comparator-treated MITT patients (95% confidence interval [CI]: -19.4, 7.4). This difference was not statistically significant; however, daptomycin did not meet the prespecified 15% noninferiority margin, since the lower bound of the 95% CI extended below 15%. Overall, 82% of daptomycin and 87% of comparator patients achieved clinical cure at the test-of-cure visit (secondary endpoint). More comparator patients had treatment-emergent (63% vs. 46%) and treatment-related (18% vs. 7%) adverse events. Conclusions Differences between daptomycin and comparator for the primary endpoint were not statistically significant; however, prespecified noninferiority criteria for daptomycin were not met. With insufficient cases of confirmed MRSA, we could not evaluate daptomycin for MRSA AHO. Our nonvalidated protocol design yields valuable information for implementing future trials in AHO (ClinicalTrials.gov NCT01922011).

Background Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring. Methods and results This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. Conclusions The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy.

International audience; Aedes-transmitted diseases, especially dengue, are increasing throughout the world and the main preventive methods include vector control and the avoidance of mosquito bites. A simple Premise Condition Index (PCI) categorizing shade, house, and yard conditions was previously developed to help prioritize households or geographical areas where resources are limited. However, evidence about the accuracy of the PCI is mixed. The current study aimed to contribute to a better understanding of the relevance by collecting data from 2,400 premises at four time points over 1 year in Kampong Cham, Cambodia. Regression models were then used to identify associations between PCI and Aedes adult female mosquitoes and pupae. In addition, receiver operating characteristic curves were used to measure the ability of PCI to identify premises in the top quartile of mosquito abundance. The density of adult Aedes females was positively associated with PCI at the household (ratio of means = 1.16 per point on the PCI scale) and cluster level (ratio of means = 1.54). However, the number of Aedes pupae was negatively associated with PCI at the household level (rate ratio = 0.74) and did not have a statistically significant association at the cluster level. Receiver operating characteristic curves suggest the PCI score had "rather low accuracy" (area under the ROC curve = 0.52 and 0.54) at identifying top-quartile premises in terms of adult female Aedes and pupae, respectively. These results suggest that caution is warranted in the programmatic use of PCI in areas of similar geography and mosquito abundance.

Currently employed methods for qualifying population physiologically-based pharmacokinetic (Pop-PBPK) model predictions of continuous outcomes (e.g., concentration-time data) fail to account for within-subject correlations and the presence of residual error. In this study, we propose a new method for evaluating Pop-PBPK model predictions that account for such features. The approach focuses on deriving Pop-PBPK-specific normalized prediction distribution errors (NPDE), a metric that is commonly used for population pharmacokinetic model validation. We describe specific methodological steps for computing NPDE for Pop-PBPK models and define three measures for evaluating model performance: mean of NPDE, goodness-of-fit plots, and the magnitude of residual error. Utility of the proposed evaluation approach was demonstrated using two simulation-based study designs (positive and negative control studies) as well as pharmacokinetic data from a real-world clinical trial. For the positive-control simulation study, where observations and model simulations were generated under the same Pop-PBPK model, the NPDE-based approach denoted a congruency between model predictions and observed data (mean of NPDE = - 0.01). In contrast, for the negative-control simulation study, where model simulations and observed data were generated under different Pop-PBPK models, the NPDE-based method asserted that model simulations and observed data were incongruent (mean of NPDE = - 0.29). When employed to evaluate a previously developed clindamycin PBPK model against prospectively collected plasma concentration data from 29 children, the NPDE-based method qualified the model predictions as successful (mean of NPDE = 0). However, when pediatric subpopulations (e.g., infants) were evaluated, the approach revealed potential biases that should be explored.

Background Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring. Methods and results This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. Conclusions The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy.

BACKGROUND Clinical trials for antibiotics designed to treat hospital-acquired and ventilator-associated bacterial pneumonias (HABP/VABP) are hampered by making these diagnoses in a way that is acceptable to the United States Food and Drug Administration and consistent with standards of care. We examined laboratory and clinical features that might improve pediatric HABP/VABP trial efficiency by identifying risk factors predisposing children to HABP/VABP and describing the epidemiology of pediatric HABP/VABP. METHODS We prospectively reviewed the electronic medical records of patients

Background Mosquito-feeding assays that assess transmission of Plasmodium from man-to-mosquito typically use laboratory mosquito colonies. The microbiome and genetic background of local mosquitoes may be different and influence Plasmodium transmission efficiency. In order to interpret transmission studies to the local epidemiology, it is therefore crucial to understand the relationship between infectivity in laboratory-adapted and local mosquitoes. Methods We assessed infectivity of Plasmodium vivax-infected patients from Adama, Ethiopia, using laboratory-adapted (colony) and wild-caught (wild) mosquitoes raised from larval collections in paired feeding experiments. Feeding assays used 4–6 day-old female Anopheles arabiensis mosquitoes after starvation for 12 h (colony) and 18 h (wild). Oocyst development was assessed microscopically 7 days post-feeding. Wild mosquitoes were identified morphologically and confirmed by genotyping. Asexual parasites and gametocytes were quantified in donor blood by microscopy. Results In 36 paired experiments (25 P. vivax infections and 11 co-infections with P. falciparum), feeding efficiency was higher in colony (median: 62.5%; interquartile range, IQR: 47.0–79.0%) compared to wild mosquitoes (median: 27.8%; IQR: 17.0–38.0%; Z = 5.02; P < 0.001). Plasmodium vivax from infectious individuals (51.6%, 16/31) infected a median of 55.0% (IQR: 6.7–85.7%; range: 5.5–96.7%; n = 14) of the colony and 52.7% (IQR: 20.0–80.0%; range: 3.2–95.0%; n = 14) of the wild mosquitoes. A strong association (ρ(16) = 0.819; P < 0.001) was observed between the proportion of infected wild and colony mosquitoes. A positive association was detected between microscopically detected gametocytes and the proportion of infected colony (ρ(31) = 0.452; P = 0.011) and wild (ρ(31) = 0.386; P = 0.032) mosquitoes. Conclusions Infectivity assessments with colony and wild mosquitoes yielded similar infection results. This finding supports the use of colony mosquitoes for assessments of the infectious reservoir for malaria in this setting whilst acknowledging the importance of mosquito factors influencing sporogonic development of Plasmodium parasites.

Objective New treatments are needed for multidrug-resistant (MDR) gram-negative infections in neonates. Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination that has broad-spectrum activity against most common gram-negative bacteria, including MDR strains. We evaluated pharmacokinetics (PK) and safety of ceftolozane/tazobactam in term and premature neonates and young infants. Study Design This is a subgroup analysis of a phase 1, noncomparative, open-label, multicenter study that characterized the PK, safety, and tolerability of a single intravenous (IV) dose of ceftolozane/tazobactam in pediatric patients with proven/suspected gram-negative infection or receiving perioperative prophylaxis. Results Seven patients were enrolled in Group A (birth [7 days postnatal] to 32 weeks gestation) and six patients were enrolled in Group B (birth [7 days postnatal] to Conclusion Among term and premature neonates and young infants, PK was comparable to older children and ceftolozane/tazobactam was generally well tolerated. An adaptable and flexible study design is necessary for enrollment in neonatal PK trials.

Background In rural Burkina Faso, the primary malaria vector Anopheles gambiae sensu lato (s.l.) primarily feeds indoors at night. Identification of factors which influence mosquito house entry could lead to development of novel malaria vector control interventions. A study was therefore carried out to identify risk factors associated with house entry of An. gambiae s.l. in south-west Burkina Faso, an area of high insecticide resistance. Methods Mosquitoes were sampled monthly during the malaria transmission season using CDC light traps in 252 houses from 10 villages, each house sleeping at least one child aged five to 15 years old. Potential risk factors for house entry of An. gambiae s.l. were measured, including socio-economic status, caregiver’s education and occupation, number of people sleeping in the same part of the house as the child, use of anti-mosquito measures, house construction and fittings, proximity of anopheline aquatic habitats and presence of animals near the house. Mosquito counts were compared using a generalized linear mixed-effect model with negative binomial and log link function, adjusting for repeated collections. Results 20,929 mosquitoes were caught, of which 16,270 (77.7%) were An. gambiae s.l. Of the 6691 An. gambiae s.l. identified to species, 4101 (61.3%) were An. gambiae sensu stricto and 2590 (38.7%) Anopheles coluzzii. Having a metal-roof on the child’s sleeping space (IRR = 0.55, 95% CI 0.32–0.95, p = 0.03) was associated with fewer malaria vectors inside the home. Conclusion This study demonstrated that the rate of An. gambiae s.l. was 45% lower in sleeping spaces with a metal roof, compared to those with thatch roofs. Improvements in house construction, including installation of metal roofs, should be considered in endemic areas of Africa to reduce the burden of malaria.

Metagenomic next-generation sequencing is a promising tool for detecting pathogens that are difficult to isolate by traditional modalities, particularly in the diagnosis of complex infections in immunocompromised children. We describe a child with X-linked agammaglobulinemia and chronic abdominal pain diagnosed with a multiorganism infection (Helicobacter cinaedi, Campylobacter coli and Parainfluenza) identified by various diagnostic tools, including plasma metagenomic next-generation sequencing.

Dyslipidaemia in adolescence tracks into adulthood and is an important risk factor for cardiovascular disease. Little is known about the effects of environmental exposures and early-life exposure to infectious diseases common to tropical regions on lipids. In 1119 early adolescent participants in the Entebbe Mother and Baby Study, we used linear regression to examine whether prenatal, childhood or adolescent factors are associated with lipid levels. Reduced high-density lipoprotein (HDL) and elevated triglyceride levels were common (prevalence 31% and 14%, respectively), but elevated low-density lipoprotein (LDL) or total cholesterol (TC) were rare. Current malaria infection was associated with lower mean LDL (adjusted ß − 0.51; 95% CI − 0.81, − 0.21), HDL (adjusted ß − 0.40; 95% CI − 0.56, − 0.23), and TC levels (adjusted ß − 0.62; 95% CI − 0.97, − 0.27), but higher mean triglyceride levels (geometric mean ratio (GMR) 1.47; 95% CI 1.18–1.84). Early-life asymptomatic malaria was associated with modest reductions in HDL and TC. Body mass index (BMI) was positively associated with LDL, TC, and triglycerides. No associations with helminth infection were found. Our findings suggest that early-life factors have only marginal effects on the lipid profile. Current malaria infection and BMI are strongly associated with lipids and important to consider when trying to improve the lipid profile.

Background Osteoarticular infections (OAIs) are frequently encountered in children. Treatment may be guided by isolation of a pathogen; however, operative cultures are often negative. Metagenomic next-generation sequencing (mNGS) allows for broad and sensitive pathogen detection that is culture-independent. We sought to evaluate the diagnostic utility of mNGS in comparison to culture and usual care testing to detect pathogens in acute osteomyelitis and/or septic arthritis in children. Methods This was a single-site study to evaluate the use of mNGS in comparison to culture to detect pathogens in acute pediatric osteomyelitis and/or septic arthritis. Subjects admitted to a tertiary children’s hospital with suspected OAI were eligible for enrollment. We excluded subjects with bone or joint surgery within 30 days of admission or with chronic osteomyelitis. Operative samples were obtained at the surgeon’s discretion per standard care (fluid or tissue) and based on imaging and operative findings. We compared mNGS to culture and usual care testing (culture and polymerase chain reaction [PCR]) from the same site. Results We recruited 42 subjects over the enrollment period. mNGS of the operative samples identified a pathogen in 26 subjects compared to 19 subjects in whom culture identified a pathogen. In 4 subjects, mNGS identified a pathogen where combined usual care testing (culture and PCR) was negative. Positive predictive agreement and negative predictive agreement both were 93.0% for mNGS. Conclusions In this single-site prospective study of pediatric OAI, we demonstrated the diagnostic utility of mNGS testing in comparison to culture and usual care (culture and PCR) from operative specimens., We evaluate the utility of next-generation sequencing in comparison to operative culture to detect a pathogen in acute pediatric osteomyelitis and septic arthritis.

Background Malaria is transmitted through the bite of Plasmodium‐infected adult female Anopheles mosquitoes. Ivermectin, an anti‐parasitic drug, acts by killing mosquitoes that are exposed to the drug while feeding on the blood of people (known as blood feeds) who have ingested the drug. This effect on mosquitoes has been demonstrated by individual randomized trials. This effect has generated interest in using ivermectin as a tool for malaria control. Objectives To assess the effect of community administration of ivermectin on malaria transmission. Search methods We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation index ‐ expanded, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the National Institutes of Health (NIH) RePORTER database to 14 January 2021. We checked the reference lists of included studies for other potentially relevant studies, and contacted researchers working in the field for unpublished and ongoing trials. Selection criteria We included cluster‐randomized controlled trials (cRCTs) that compared ivermectin, as single or multiple doses, with a control treatment or placebo given to populations living in malaria‐endemic areas, in the context of mass drug administration. Primary outcomes were prevalence of malaria parasite infection and incidence of clinical malaria in the community. Data collection and analysis Two review authors independently extracted data on the number of events and the number of participants in each trial arm at the time of assessment. For rate data, we noted the total time at risk in each trial arm. To assess risk of bias, we used Cochrane's RoB 2 tool for cRCTs. We documented the method of data analysis, any adjustments for clustering or other covariates, and recorded the estimate of the intra‐cluster correlation (ICC) coefficient. We re‐analysed the trial data provided by the trial authors to adjust for cluster effects. We used a Poisson mixed‐effect model with small sample size correction, and a cluster‐level analysis using the linear weighted model to adequately adjust for clustering. Main results We included one cRCT and identified six ongoing trials. The included cRCT examined the incidence of malaria in eight villages in Burkina Faso, randomized to two arms. Both trial arms received a single dose of ivermectin 150 µg/kg to 200 µg/kg, together with a dose of albendazole. The villages in the intervention arm received an additional five doses of ivermectin, once every three weeks. Children were enrolled into an active cohort, in which they were repeatedly screened for malaria infection. The primary outcome was the cumulative incidence of uncomplicated malaria in a cohort of children aged five years and younger, over the 18‐week study. We judged the study to be at high risk of bias, as the analysis did not account for clustering or correlation between participants in the same village. The study did not demonstrate an effect of Ivermectin on the cumulative incidence of uncomplicated malaria in the cohort of children over the 18‐week study (risk ratio 0.86, 95% confidence interval (CI) 0.62 to 1.17; P = 0.2607; very low‐certainty evidence). Authors' conclusions We are uncertain whether community administration of ivermectin has an effect on malaria transmission, based on one trial published to date., Plain language summary Malaria control using ivermectin What is the aim of this review? The aim of this Cochrane Review was to find out if giving the drug ivermectin to entire communities could reduce malaria transmission. We examined all relevant studies to answer this question, and found one relevant study. Key messages It is not possible to say at this point if treating an entire community with ivermectin reduces malaria. Several research studies are in progress; we anticipate they will provide more answers in the future. What was studied in the review? Malaria is a disease transmitted to humans through the bite of mosquitoes infected with Plasmodium parasites. It results in nearly half a million deaths every year. Ivermectin is a drug that is given to whole communities to control the parasites that are responsible for elephantiasis and river blindness. It has been observed that ivermectin can kill mosquitoes when they feed on the blood of people who have taken this medication. Therefore, it is believed that by giving this drug to whole communities, it will kill many mosquitoes, and could reduce malaria transmission. In this review, we assessed whether treating entire communities with ivermectin would reduce malaria transmission. We looked for studies from different sources, and only included studies that took place in communities with malaria, and that randomly assigned groups of people to ivermectin or a control, which could be a placebo or standard community drug treatments. We wanted to know if the treatment influenced the occurrence of malaria in the community. What are the main results of the review? One study met the inclusion criteria. This study included eight villages in Burkina Faso, which were randomly assigned to receive ivermectin or a control. All villages received ivermectin, as part of the scheduled control of lymphatic filariasis. In addition, the treatment villages received five more doses of ivermectin, once every three weeks. The effect of ivermectin on malaria was measured in children younger than five years of age. In these children, the treatment did not show a notable difference in the presence of malaria between the treatment and control groups (very low‐certainty evidence). Therefore, it is not possible to say at this point if the treatment of entire communities with ivermectin has an effect on reducing malaria. Several studies are currently ongoing; we anticipate they will provide more answers in the future. How up‐to‐date is this review? We searched for studies published up to 14 January 2021.

Background Selectively targeting and treating malaria-infected individuals may further decrease parasite carriage in low-burden settings. Using a trans-disciplinary approach, a reactive treatment strategy to reduce Plasmodium falciparum prevalence in participating communities was co-developed and tested. Methods This is a 2-arm, open-label, cluster-randomized trial involving villages in Central Gambia during the 2017 and 2018 malaria transmission season. Villages were randomized in a 1:1 ratio using a minimizing algorithm. In the intervention arm, trained village health workers delivered a full course of pre-packed dihydroartemisinin-piperaquine to all residents of compounds where clinical cases were reported while in the control arm, compound residents were screened for infection at the time of the index case reporting. All index cases were treated following national guidelines. The primary endpoint was malaria prevalence, determined by molecular methods, at the end of the intervention period. Results The trial was carried out in 50 villages: 34 in 2017 and 16 additional villages in 2018. At the end of the 2018 transmission season, malaria prevalence was 0.8% (16/1924, range 0–4%) and 1.1% (20/1814, range 0–17%) in the intervention and control arms, respectively. The odds of malaria infection were 29% lower in the intervention than in the control arm after adjustment for age (OR 0.71, 95% CI 0.27–1.84, p = 0.48). Adherence to treatment was high, with 98% (964/979) of those treated completing the 3-day treatment. Over the course of the study, only 37 villages, 20 in the intervention and 17 in the control arm, reported at least one clinical case. The distribution of clinical cases by month in both transmission seasons was similar and the odds of new clinical malaria cases during the trial period did not vary between arms (OR 1.04, 95% CI 0.57–1.91, p = 0.893). All adverse events were classified as mild to moderate and resolved completely. Conclusion The systematic and timely administration of an anti-malarial treatment to residents of compounds with confirmed malaria cases did not significantly decrease malaria prevalence and incidence in communities where malaria prevalence was already low. Treatment coverage and adherence was very high. Results were strongly influenced by the lower-than-expected malaria prevalence, and by no clinical cases in villages with asymptomatic malaria-infected individuals. Trial registration: This study is registered with ClinicalTrials.gov, NCT02878200. Registered 25 August 2016. https://clinicaltrials.gov/ct2/show/NCT02878200.

Disseminated gonococcal infection (DGI) often manifests as gonococcal arthritis and may carry significant morbidity. However, diagnosis remains elusive due to limited sensitivity of available diagnostic tests. We used metagenomic next-generation sequencing to detect Neisseria gonorrhoeae from culture-negative joint aspirates of 2 patients with clinically diagnosed DGI.

Osteoarticular infections are one of the more common invasive bacterial infections encountered in children. There exist significant practice variations in both the diagnosis and treatment of such infections. However, the practice of transitioning from parenteral therapy to oral antibiotics has been well validated by several studies. For methicillin-sensitive Staphylococcus aureus (MSSA), cephalexin is often recommended. Prospective, controlled data regarding optimal dosing of cephalexin in pediatric osteomyelitis are not available. We sought to review our retrospective, uncontrolled data on four times daily (QID) versus three times daily (TID) dosing of cephalexin for pediatric osteoarticular infections. Children ≥1 month to

Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI.Hospitalized children (≥3 months to18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit.Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits.Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.

In The Gambia, metal-roof houses were hotter during the day than thatched-roof houses. After 24 h, the mortality of Anopheles gambiae, the principal African malaria vector, was 38% higher in metal-roof houses than thatched ones. During the day, mosquitoes in metal-roof houses moved from the hot roof to cooler places near the floor, where the temperature was still high, reaching 35 °C. In laboratory studies, at 35 °C few mosquitoes survived 10 days, the minimum period required for malaria parasite development. Analysis of epidemiological data showed there was less malaria and lower vector survival rates in Gambian villages with a higher proportion of metal roofs. Our findings are consistent with the hypothesis that the indoor climate of metal-roof houses, with higher temperatures and lower humidity, reduces survivorship of indoor-resting mosquitoes and may have contributed to the observed reduction in malaria burden in parts of sub-Saharan Africa.

Background Clinical guidelines recommend pneumococcal and tetanus vaccinations in patients with rheumatoid arthritis (RA). Baricitinib is an oral, selective Janus kinase (JAK) 1/JAK 2 inhibitor and is approved for the treatment of moderately to severely active RA in adults in over 50 countries including European countries, the USA, and Japan. This substudy evaluated pneumococcal conjugate and tetanus toxoid vaccine (TTV) responses in patients with RA receiving baricitinib. These vaccines elucidate predominantly T cell-dependent humoral antibody response. Methods Eligible RA patients receiving baricitinib 2 mg or 4 mg with or without concomitant methotrexate (MTX) were enrolled in a phase 3 long-term extension trial (RA-BEYOND; ClinicalTrials.gov, NCT01885078) in USA/Puerto Rico. Patients were vaccinated with 13-serotype pneumococcal conjugate vaccine (PCV-13) and TTV. Primary endpoints were the proportion of patients achieving a satisfactory humoral response for PCV-13 (≥ 2-fold increase in anti-pneumococcal antibody concentrations in ≥ 6 serotypes) and TTV (≥ 4-fold increase in anti-tetanus concentrations) at 5 weeks post-vaccination. Secondary endpoints included humoral responses at 12 weeks and functional responses of serotypes 4, 6B, 14, and 23F (twofold and fourfold increases in opsonic indexes at 5 and 12 weeks). Results Of 106 patients with a mean duration of RA of approximately 12 years, 80% were female, 30% were taking corticosteroids, and 89% (N = 94) were taking baricitinib plus MTX; most patients (97% PCV-13/96% TTV) completed the evaluations. Overall, 68% (95% CI 58.4, 76.2) of patients achieved a satisfactory response to PCV-13, 43% (34.0, 52.8) achieved a ≥ 4-fold increase in anti-tetanus concentrations, and 74% (64.2, 81.1) achieved a ≥ 2-fold increase. PCV-13 response was similar for patients taking corticosteroids (71%; 53.4, 83.9) vs those not (67%; 55.2, 76.5). The percentage of sera with a ≥ 2-fold increase in post-vaccination opsonic indexes at week 5 ranged from 47% (serotype 14) to 76% (serotype 6B). Through 12 weeks post-vaccination, seven patients (6.6%) reported injection-site events. There were no deaths during the substudy, and three patients experienced a serious adverse event. Conclusions Approximately two thirds of patients on long-term baricitinib achieved satisfactory humoral and functional responses to PCV-13 vaccination, while TTV responses were less robust. PCV-13 response was not diminished in those taking concomitant corticosteroids. Trial registration ClinicalTrials.gov, NCT01885078. Registered on 24 June 2013.

To identify the etiologies of viral myocarditis in children in the pre-coronavirus disease 2019 era.This was a retrospective review of all patients (age18 years) diagnosed with myocarditis and hospitalized at Rady Children's Hospital San Diego between 2000 and 2018.Twenty-nine patients met inclusion criteria. Of 28 (97%) patients who underwent testing for viruses, polymerase chain reaction was used in 24 of 28 (86% of cases), and 16 of 24 (67%) detected a virus. Pathogens were rhinovirus (6), influenza A/B (4), respiratory syncytial virus (RSV) (3), coronavirus (3), parvovirus B19 (2), adenovirus (2), and coxsackie B5 virus, enterovirus, and parainfluenza virus type 2 in one case each. Six (21%) patients had no pathogen detected but imaging and other laboratory test results were compatible with myocarditis. Age 0-2 years was associated with RSV, influenza A/B, coronavirus, and enteroviruses (P .001). Twenty-one patients (72%) experienced full clinical recovery. Three patients (10%) required venoarterial extracorporeal membrane oxygenation (VA-ECMO), and all 3 recovered. Three others (10%) required and underwent successful cardiac transplantation without complications. Two patients (7%) died 9-10 days after hospitalization (1 had RSV and 1 had influenza A/B). Two other patients presented with complete atrioventricular block; 1 case (rhinovirus) resolved spontaneously, and 1 (coronavirus) resolved after support with VA-ECMO. Age2 years, female sex, lower ejection fraction at admission, and greater initial and peak levels of brain natriuretic peptide were significant predictors of critical outcomes (use of VA-ECMO, listing for cardiac transplantation, and death).Viral nucleic acid-based testing revealed a wider spectrum of viruses that could be associated with myocarditis in children than previously reported and traditionally anticipated. A predilection of certain pathogens in the very young patients was observed. Whether the observed range of viral agents reflects an undercurrent of change in viral etiology or viral detection methods is unclear, but the wider spectrum of viral pathogens found underscores the usefulness of polymerase chain reaction testing to explore possible viral etiologies of myocarditis in children.

Inferring the transmission direction between linked individuals living with HIV provides unparalleled power to understand the epidemiology that determines transmission. Phylogenetic ancestral state reconstruction approaches infer the transmission direction by identifying the individual in whom the most recent common ancestor of the virus populations originated. However, these methods vary in their accuracy but it is unclear why. To evaluate the performance of phylogenetic ancestral state reconstruction, we inferred the transmission direction for 112 HIV transmission pairs where transmission direction was known and detailed additional information was available. We then fit a statistical model to evaluate the extent to which epidemiological, sampling, genetic and phylogenetic factors influenced the outcome of the inference. We repeated the analysis under real-life conditions with only routinely-collected data. We found that the inference of transmission direction depends principally on the topology class and branch length characteristics of the phylogeny. Under real-life conditions, the probability of identifying the correct transmission direction increases from 52%—when a monophyletic-monophyletic or paraphyletic-polyphyletic tree topology is observed, when the sample size in both partners is small and when the tip closest to the root does not agree with the state at the root—to 93% when a paraphyletic-monophyletic topology is observed, when the sample size is large and when the tip closest to the root agrees with root state. Our results suggest that discordance between previous studies in inferring the transmission direction can be explained by differences in key phylogenetic properties that arise due to different evolutionary, epidemiological and sampling processes.Significance StatementIdentifying the direction of infectious disease transmission between individuals provides unparalleled power to understand infectious disease epidemiology. With epidemiological and clinical information typically unable to distinguish the direction, phylogenetic analysis of pathogen sequence data is an alternative approach. However, when these phylogenetic methods have been implemented, their accuracy is highly variable, and the reasons for this discordance is unknown. Here we analyse sequence data from over 100 pairs of individuals for whom both the direction of transmission of HIV is known and detailed epidemiological and sampling information is available. We find that easily quantifiable phylogenetic characteristics discriminate whether a phylogenetically-inferred transmission direction is correct. Our analysis highlights that phylogenetic approaches are unsuitable for individual-level analysis such as forensic investigations.

In sub-Saharan Africa, cooler houses would increase the coverage of insecticide-treated bednets, the primary malaria control tool. We examined whether improved ventilation, using windows screened with netting, cools houses at night and reduces malaria mosquito house entry in The Gambia. Identical houses were constructed, with badly fitting doors the only mosquito entry points. Two men slept in each house and mosquitoes captured using light traps. First, temperature and mosquito density were compared in four houses with 0, 1, 2 and 3 screened windows. Second, carbon dioxide (CO2), a major mosquito attractant, was measured in houses with (i) no windows, (ii) screened windows and (iii) screened windows and screened doors. Computational fluid dynamic modelling captured the spatial movement of CO2. Increasing ventilation made houses cooler, more comfortable and reduced malaria mosquito house entry; with three windows reducing mosquito densities by 95% (95%CI = 90–98%). Screened windows and doors reduced the indoor temperature by 0.6°C (95%CI = 0.5–0.7°C), indoor CO2concentrations by 31% between 21.00 and 00.00 h and malaria mosquito entry by 76% (95%CI = 69–82%). Modelling shows screening reduces CO2plumes from houses. Under our experimental conditions, cross-ventilation not only reduced indoor temperature, but reduced the density of house-entering malaria mosquitoes, by weakening CO2plumes emanating from houses.

Most malaria infections in sub-Saharan Africa are acquired indoors, thus finding effective ways of preventing mosquito house entry should reduce transmission. Since most malaria mosquitoes fly less than 1 m from the ground, we tested whether raising buildings off the ground would prevent the entry of Anopheles gambiae , the principal African malaria vector, in rural Gambia. Nightly collections of mosquitoes were made using light traps from four inhabited experimental huts, each of which could be moved up or down. Mosquito house entry declined with increasing height, with a hut at 3 m reducing An. gambiae house entry by 84% when compared with huts on the ground. A propensity for malaria vectors to fly close to the ground and reduced levels of carbon dioxide, a major mosquito attractant, in elevated huts, may explain our findings. Raised buildings may help reduce malaria transmission in Africa.

Plasmodium falciparum gametocyte kinetics and infectivity may differ between chronic and incident infections. In the current study, we assess parasite kinetics and infectivity to mosquitoes among children (aged 5–10 years) from Burkina Faso with (a) incident infections following parasite clearance (n = 48) and (b) chronic asymptomatic infections (n = 60). In the incident infection cohort, 92% (44/48) of children develop symptoms within 35 days, compared to 23% (14/60) in the chronic cohort. All individuals with chronic infection carried gametocytes or developed them during follow-up, whereas only 35% (17/48) in the incident cohort produce gametocytes before becoming symptomatic and receiving treatment. Parasite multiplication rate (PMR) and the relative abundance of ap2-g and gexp-5 transcripts are positively associated with gametocyte production. Antibody responses are higher and PMR lower in chronic infections. The presence of symptoms and sexual stage immune responses are associated with reductions in gametocyte infectivity to mosquitoes. We observe that most incident infections require treatment before the density of mature gametocytes is sufficient to infect mosquitoes. In contrast, chronic, asymptomatic infections represent a significant source of mosquito infections. Our observations support the notion that malaria transmission reduction may be expedited by enhanced case management, involving both symptom-screening and infection detection., In this longitudinal study of an incident (new infections) and chronic (asymptomatic infections) cohort of Plasmodium falciparum infection in children in Burkina Faso, the authors show higher gametocyte production and mosquito infectivity in chronic infections.