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Background: Neonatal sepsis is one of the leading causes of neonatal morbidity and mortality in low- and middle-income countries. Blood culture positivity rates and antibiotic resistance pattern of neonatal sepsis differs across various regions. This study aims to identify clinical cofactors associated with blood culture-proven neonatal sepsis and in vitro resistance to first-line antibiotics (ampicillin and gentamicin) from cases originating in a tertiary healthcare center in Surabaya, Indonesia., Methods: A retrospective cohort study was conducted from January 2020 to August 2022 by utilizing secondary data collected from standardized electronic medical records. Microbiologic characteristics and associated factors were statistically analyzed using multivariable logistic regression., Results: Across 266 neonatal sepsis cases, 46.9% were culture-proven and 79.2% of confirmed sepsis were resistant to first-line antibiotics. The most common isolated pathogen is Klebsiella pneumoniae , followed by coagulase-negative Staphylococci , Acinetobacter baumannii and Enterobacter cloacae . Extremely preterm delivery [adjusted odds ratio (aOR): 5.813; 95% confidence interval (CI): 1.70-19.91] and late-onset sepsis (aOR: 9.165; 95% CI: 5.12-16.40) were associated with culture-proven neonatal sepsis. Increased odds of resistance to first-line antibiotics were identified in extremely preterm (<28 weeks) or very-preterm delivery (28 to <32 weeks) (aOR: 50.80; 95% CI: 1.66-1554.21 and aOR: 45.679; 95% CI: 3.22-647.46, respectively), cesarean section (aOR: 4.149; 95% CI: 1.04-16.53) and an absence of antenatal corticosteroid use (aOR: 0.233; 95% CI: 0.07-0.76)., Conclusions: The association between clinical cofactors with culture-proven sepsis and antibiotic resistance emphasizes the importance for clinicians to adjust empirical antibiotic regimens based on the local antibiogram and resource availability., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Late onset sepsis (LOS) in preterm infants is preceded by fecal volatile organic compound (VOC) alterations, suggesting an etiologic role of gut microbiota in LOS rather than being primarily caused by central venous catheters (CVC). To increase our knowledge about the involvement of the gut microbiota in LOS, we analyzed fecal samples from septic infants without a CVC., Methods: In this prospective multicenter study, fecal samples were collected daily from all infants born at ≤30 weeks gestation. Fecal VOC profiles up to 3 days prior to sepsis onset from infants with non-catheter-related LOS were compared with profiles from non-septic controls by means of High-Field Asymmetric Waveform Ion Mobility Spectrometry., Results: In total, 104 fecal samples were analyzed. Fecal VOC profiles allowed for discrimination between non-catheter-related LOS cases (n = 24) and matched controls (n = 25). Discriminative accuracy increased after focusing on center of origin (area under the curve, sensitivity, specificity; 0.95, 100%, 83%) and after focusing on LOS cases caused by Staphylococcus epidermidis (0.95, 100%, 78%), the most cultured pathogen (n = 11)., Conclusions: Fecal VOC profiles of preterm LOS infants without a CVC differed from matched controls underlining the increasing notion that aberrations in gut microbiota composition and activity may play a role in LOS etiology.

Background: The Aetiology of Neonatal Infection in South Asia (ANISA) study is being carried out at 5 sites across Bangladesh, India and Pakistan, generating in-depth information on etiologic agents in the community setting. Pregnancies are identified, births are registered and young infants are followed up to 59 days old with regular assessments for possible serious bacterial infection following a generic protocol. Specimens are collected from suspected cases. This article describes the challenges in implementing the generic ANISA protocol and modifications made to accommodate the Odisha site, India., Challenges: Primary challenges in implementing the protocol are the large geographic area, with a population of over 350,000, to be covered; assessing young infants at home and arranging timely transport of sick young infants to study hospitals for physician confirmation of illness; and specimen collection and treatment. A large workforce is deployed in a 3-tier system in the field, while clinical, microbiology, laboratory and data management teams collaborate dynamically. Mobile phones with text message capability, integration with the Odisha State government's health system, involvement of local communities and strict monitoring at different levels have been critical in addressing these challenges., Conclusion: This article describes the challenges and modalities adopted to collect complex and accurate data on etiology, timing of disease and associated factors for community-acquired neonatal infections. Attention to local culture and customs, training and employing community level workers and supervisors, involving existing government machinery, using technology (cell phones), and uninterrupted systematic monitoring are critical for implementing such complex protocols that aim to collect population-based data to drive policy.

Background: The Aetiology of Neonatal Infection in South Asia (ANISA) study is a population-based study with sites in Bangladesh, India and Pakistan. It aims to determine community-acquired incidence, etiology and associated risk factors for neonatal infections. Matiari, a rural site in Pakistan, was chosen for the study due to its high neonatal mortality rate and the presence of an established pregnancy and birth surveillance system. This article summarizes various challenges, remedial measures taken and lessons learned during the implementation of the ANISA study protocol in the unique rural setting of Matiari where the majority of births take place at home and accessibility to health care is limited., Challenges: Achieving and maintaining project targets of early registration of birth and collection of biological specimens in households have been challenging in Matiari. Capturing births of study subjects that occur outside the catchment areas and those taking place during public holidays and acquiring parental consent for specimen collection from healthy controls require extensive community mobilization. Contamination and power outages that affect the laboratory equipment are 2 of the major logistic challenges faced. We keep track of pregnancy outcomes through mobile phones and reimburse the costs for birth notifications to the caller. We created separate dedicated mobile teams that visit newborns outside the catchment area and carry out possible serious bacterial infection assessments. We also formed mobile teams for specimen collection from residences of newborns as there is no facility for specimen collection at this site. Our study personnel work on holidays and weekends to improve the study's performance. We nurture strong community liaison by employing staff from within the community. We train the study physicians on communication and counseling skills required for overcoming refusal for referral and specimen collection. The contamination rate is controlled by repeated training and supervision and extensive monitoring of phlebotomy activities. The majority of phlebotomy procedures are recorded on video in the field to provide feedback to phlebotomists for improving their performance., Conclusion: The contextual challenges faced in field implementation of the ANISA protocol in the rural setting of Matiari are unique. These challenges are being successfully addressed through hard work, strict monitoring and improvisation. This experience can be used for improving study performance in similar settings elsewhere.

Background: The Aetiology of Neonatal Infection in South Asia study is a major effort to determine the causes of community-acquired neonatal infections. It involves collecting epidemiological, clinical and laboratory data in 5 sites in 3 countries. The field and laboratory research operations are streamlined to maintain integrity and validity while operating in complex and variable environments. We developed a customized system for implementation of labeling and tracking biological specimen in both rural and urban community settings and integrated into all study laboratories. This report outlines the development and implementation of this harmonized system., Design: The system links and tracks specimens with study participants and results generated from laboratory tests. Each biological specimen and its aliquots are tracked through key steps of the protocol, from collection and transport through molecular testing and long-term storage., Conclusion: The labeling and tracking system allows for standardization and monitoring of laboratory processes and improves the accuracy of Aetiology of Neonatal Infection in South Asia data. Community-based scientific projects could greatly benefit by adopting this, or a similar, system for specimen tracking and data linkage.

Background: The Aetiology of Neonatal Infection in South Asia (ANISA) study takes advantage of text messaging technology to record information required for randomizing the study population into a control subcohort. The text message system is also used for monitoring various study activities., Methods: When a child-health worker registers a newborn in the study, she sends a text message to a database server containing the study identification number and newborn's age at the time of registration. For each possible serious bacterial infection case, a study physician also sends a text message to the same server with the age of the young infant at the time of illness assessment. Using this information, a computer-based algorithm randomizes the newborn into a control subcohort. Text messages are also sent to alert the study physicians and study supervisors of a possible serious bacterial infection case being referred to health-care facilities. Phlebotomists working at remote specimen collection sites send text messages to the site laboratory personnel before sending the specimens through porters., Discussion: Real-time data entry and monitoring are challenging for any population-based study conducted in remote areas. Our text messaging system provides an opportunity to overcome this barrier where availability of data entry facilities is limited.

Background: The Aetiology of Neonatal Infection in South Asia (ANISA) study aims to determine the population-based incidence, etiology, risk factors and antibiotic resistance profiles of community-acquired young infant infections in Bangladesh, India and Pakistan using community-based surveillance and standard newer diagnostic tests. The data generated will help plan preventive and treatment strategies to reduce neonatal and infant mortality in this region. The aim of this article is to describe the site-specific characteristics, challenges and solutions in implementing the ANISA protocol at the Vellore site, India., Challenges: Vellore joined the ANISA study 2 years after the sites in Bangladesh and Pakistan, and some challenges relate to the need for rapid implementation. The Vellore site differs primarily in the high rate of institutional deliveries, actively promoted by the Government of India's conditional cash transfer program. The Vellore site hospitals are regular care providers for the study population, which leads to very high rates of consent for enrollment and collection of samples. Keeping blood culture contamination rates low was a challenge the site team overcame by adhering strictly to the protocol. Issues related to incorporation of a large study into a busy clinical services laboratory were overcome by meticulously setting up algorithms related to receipt, processing and storage of samples., Conclusion: ANISA is a complex study, but the challenges in implementation have been largely resolved and documented.

Background: Despite the high rate of deaths in young infants (0-59 days) attributable to infections in resource-poor countries, data on bacterial and viral etiologies of community-acquired infections in this age group are limited. These data are needed to develop appropriate preventive strategies and suitable antibiotic treatment regimens for reducing the number of young infant deaths from infections. The Aetiology of Neonatal Infection in South Asia (ANISA) study is designed to generate these critical data and is being implemented in Bangladesh, India and Pakistan. The Sylhet site in Bangladesh was selected because neonatal mortality is high in this country and particularly in Sylhet District. In this article, we describe the contextual challenges in implementing the ANISA study in Sylhet, as well as the strategies developed by our team to address these challenges., Contextual Challenges: The major challenge in implementing the ANISA protocol in Sylhet is conducting the first postnatal visit within 24 hours of birth. This problem stems from several social, cultural and geographical characteristics of the study population and its demographic profile. In this area, most births take place at home, referral compliance for newborn illness to health facilities is low and the blood culture contamination rate is high. Community mobilization, cellphone-based birth notification by families, delivery of quality services at study hospitals and referral support to families in need were some of the strategies adopted by the Sylhet site team for overcoming these challenges during study implementation. Quality control in specimen collection, transportation and processing also plays a role in ensuring satisfactory performance., Conclusion: Our research team, with support from the ANISA coordination center, has successfully addressed these challenges and is implementing the study protocol while maintaining the high quality benchmark set by the coordination center.

Background: Aetiology of Neonatal Infection in South Asia (ANISA) is a multicenter study in Bangladesh, India and Pakistan exploring the incidence and etiology of neonatal infections. A periurban site in Karachi was selected for its representativeness of the general population in neonatal health indicators. An established demographic surveillance system and other infrastructure needed for conducting the study already existed at this site. ANISA presents a unique challenge because of the need to capture every birth outcome in the community within a few hours of delivery to reliably estimate the incidence and etiology of early-onset sepsis in a setting where home births and deaths are common., Contextual Challenges: Major challenges at the Karachi site are related to early birth reporting and newborn assessment for births outside the catchment areas, parental refusal to participate, diverse ethnicity of the population, collection of biological specimens from healthy controls, political instability and crime, power outages and blood culture contamination. Some of the remedial actions taken include prolonging working hours; developing counseling skills of field workers; hiring staff with different linguistic abilities from within the study community; liaising with health facilities, key community informants, Lady Health Workers and traditional birth attendants; hiring community mobilizers; enhancing community sensitization; developing contingency plans for field work interruptions and procuring backup generators. The specimen contamination rate has decreased through training, supervision and video monitoring of blood collection procedures with individualized counseling of phlebotomists., Conclusion: ANISA offers lessons for successful implementation of complex study protocols in areas of high child mortality and challenging social environments.

The multisite community-based study, Aetiology of Neonatal Infection in South Asia (ANISA), uses blood culture as the gold standard for identifying the etiology of neonatal infection. Considering the importance of this age-old diagnostic tool and the risk of contamination, ANISA has employed rigorous measures to prevent contamination at all stages of blood collection, processing and culture. Because contamination may still occur, an independent expert group evaluates the routinely collected clinical and laboratory data to determine whether a blood culture isolate is a contaminant or a true pathogen. This article describes the methodology used by ANISA to determine whether a blood culture isolate is likely to be a true pathogen or a contaminant in neonatal sepsis.

Background: The Aetiology of Neonatal Infection in South Asia (ANISA) study maintains operations in Bangladesh, India and Pakistan. We developed and deployed a multilayered monitoring system to measure performance indicators of field sites and laboratory operations. This system allows for real-time provision of feedback to study site teams and project stakeholders. The goal of this monitoring and evaluation system is to promote optimal performance and consistency in protocol application at all sites over the course of the study, thereby safeguarding the validity of project findings. This article describes each of the interdependent monitoring layers that were conceptualized, developed and employed by the ANISA coordination team., Methods: Layers of monitoring include site-level, central and database-related activities along with periodic site visitation. We provide a number of real-world examples of how feedback from the ANISA monitoring system directly informs a number of crucial decisions and course corrections during the project., Conclusion: The ANISA monitoring system represents a transparent, understandable and practical resource for development of project monitoring systems in complex multisite health research projects.