Management of Newborn Infections During Inpatient Care · to commonly used antibiotics is emerging and constitutes an important problem worldwide. The impact of antibiotic use on

DO NO HARM TECHNICAL BRIEF

Management of Newborn Infections During Inpatient Care

Why is management of newborn infections during inpatient care important?A newborn infection is defined as an infection (evidenced by clinical and/or microbiologic criteria) occurring within the first 4 weeks of life and includes sepsis, bacteremia, pneumonia, meningitis, omphalitis, skin infections, urinary tract infections, tetanus, and diarrhea. Newborns, particularly preterm and low birth weight babies, may be born in the setting of high exposure to pathogens that can breach skin and mucosal barriers, and newborns are more susceptible to severe infections because their immature immune systems lack antigenic experience and are less able to control and recover from infection by potential pathogens.3 Preterm and low birth weight babies are also more exposed to organisms due to their greater dependency on care providers and the necessity of invasive therapies (i.e. intravenous access, intubation, nasogastric feeding), with inpatient care posing a significant exposure risk to more virulent pathogens.4

An estimated 6.9 million newborns in South Asia and sub-Saharan Africa required treatment for possible serious bacterial infection in 2012. Studies have indicated that the rate of neonatal infections in low and middle-income countries is 3 to 20 times higher than in resource-rich countries, with an alarming rate of antibiotic-resistant infections.5 The estimates of the incidence of newborn infections in lower- and middle-income countries range from 5.5 infections per 1,000 live births by positive blood culture to 170 infections per 1,000 live births using clinical diagnosis.6 An additional number of newborns die in the community before a blood culture or clinical diagnosis is made. It is estimated that more than 80% of infection-related deaths in newborns could be avoided if the coverage and quality of currently available preventive measures and effective interventions improved.7

How are newborn infections acquired? Newborn infections can originate from exposures to bacterial, viral, or more rarely to fungal organisms in utero, during labor and delivery, or in the postnatal period. Infections may be transmitted vertically from the mother or horizontally from caregivers and the environment. Exposures to pathogenic organisms can occur in the postnatal period via contact with organisms on the hands of caregivers, health care workers, family and community members, or contact with infected materials or equipment. Hospital-acquired infections can result from exposure to infected medical equipment/commodities such as incubators, oxygen delivery systems, feeding tubes, monitors, towels or wraps, and invasive procedures and in-dwelling medical devices such as intubation, urinary catheterization, and intravenous lines.

How can poor management of newborn infection cause harm? The risk of death from infection is high, even in the inpatient setting. Sick newborns often present with nonspecific clinical signs such as difficulty feeding, lethargy or irritability, and temperature instability; these signs may also be associated with prematurity. Newborn infections are difficult to identify and diagnose and disease progression occurs quickly, requiring extreme vigilance by providers, caregivers, and parents.8 Delays in recognition and treatment may lead to death and significant morbidity, including neurodevelopmental impairment. Severe invasive infections can result in an immunologic inflammatory response syndrome known as sepsis, which causes

dysfunction of and damage to organ systems including the circulatory and nervous systems, brain, kidneys, and other organs, and often leads to severe disability or death.While harms associated with delayed recognition or treatment of newborn infections can be serious, there may be harmful consequences of increased exposure to antibiotics. Newborns receiving antibiotics are often separated from the parents, making bonding and breastfeeding challenging. Because of the challenges differentiating serious bacterial infections from other newborn syndromes, and the severity of the consequences of failing to treat a true infection, antibiotics are prescribed liberally for suspected infection in newborns. There are issues of unnecessary exposure to antibiotics due to unregulated dispensing by drug sellers/pharmacist/chemists, and by clinicians with low thresholds for prescribing antibiotic therapy. Early antibiotic exposures cause changes to the newborn microbiome, resulting in long term sequelae including increased risk of asthma and allergy, gastro-intestinal disturbances and diarrhea. Importantly, early and prolonged exposures can result in increased risk of antibiotic-resistant infection. Necrotizing enterocolitis, late-onset sepsis, and death have all been associated with prolonged antibiotic exposure in newborns.9,10 Inappropriate prolonged antibiotic use also leads to longer hospitalizations, often at a substantial cost.11

What are the current evidence-based best practices? Prevention measuresElements of essential newborn care have been demonstrated to reduce the risk of infection. Such care practices include hand hygiene, appropriate umbilical cord care, as well as early and continued breastfeeding. Intrapartum and in-hospital hand hygiene has been shown to significantly reduce the risk of nosocomial infections in a variety of low-resource settings,12,13,14 with improved mortality and outcomes. A recent review reported the application of a 4% chlorhexidine solution to the umbilical stump of an infant born in the community resulted in a 12% reduction in neonatal mortality and 50% reduction in omphalitis, though the effect was not seen for infants born in hospital settings.15 An exclusive human milk diet has been associated with a reduced risk of serious infections in preterm/low birth weight infants compared to formula diet.16 The use of probiotics in very low birth weight infants has been investigated, reducing the risk of late-onset sepsis, necrotizing enterocolitis, and all-cause mortality.17

Current approach to management of newborn infectionsClinical manifestations of newborn infections range from subclinical infection to severe manifestations of focal or systemic disease, with symptoms often nonspecific and affecting feeding, breathing, temperature, and alertness patterns of the newborn. Clinical manifestations are influenced by timing of exposure, immune status of the infant, and the virulence of the causative agent.

Newborn sepsis can be classified as early onset or late onset:

• Early onset sepsis refers to bacteremia acquired either before or duringdelivery (vertical acquisition), manifesting within the first week of life.

• Late onset sepsis refers to bacteremia acquired after delivery fromnosocomial or community sources (horizontal acquisition), manifestingbetween 7 and 28 days of life.

Diagnosis of newborn serious bacterial infectionsSerious bacterial infections can be identified by clinical assessment, either biochemically (with biomarkers) or microbiologically. Limited availability of

Every year, 15 million newborns are born preterm1 and many are born with life-threatening conditions that require hospitalization. Premature infants are at higher risk of serious infections than infants born at term. Infections account for 14% of the annual 2.5 million newborn deaths,2 resulting in an estimated 355,000 annual deaths worldwide. Prompt diagnosis of serious bacterial infection and initiation of antibiotics as well as appropriate supportive therapy are critical for newborns, and any delays can worsen outcomes. However, resistance to commonly used antibiotics is emerging and constitutes an important problem worldwide. The impact of antibiotic use on the establishment of a healthy newborn microbiome also poses concerns. Effectively scaled prevention measures and improved diagnostic tools to tailor precise treatment of serious infection are needed.

microbiological diagnostic testing in LMICs is a major barrier to safe antibiotic use and shortening courses of treatment. In settings where families with sick young infants do not accept or cannot access more advanced care, diagnosis in outpatient settings by an appropriately trained health worker based on the signs of presumed serious bacterial infection.18

Currently available diagnostic tests have significant barriers in their use and interpretation. The actual impact of diagnostics depends on the availability, cost, time to result, and both negative and positive predictive value of the test, as well as the availability, uptake, and effectiveness of the treatment based on the test results. BiomarkersAt this time, there is no accepted biomarker for use in low and middle income countries. The availability, cost, rapidity of results, sensitivity, specificity, predictive value, and the interpretation of results pose challenges for the widespread use of biomarkers. Small studies have described hundreds of biomarkers associated with severe neonatal infections. Biomarkers, alone or in combination, have been used to identify newborn infections: procalcitonin (PCT), C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), interferon-g (IFN-g), interleukin-6 (IL-6), interleukin (IL-8).19 The majority of these studies have evaluated biomarkers in combination with C-reactive protein (CRP); already in widespread clinical use for the diagnosis of infection. As an acute-phase reactant, CRP alone is less useful in the earliest phases of severe neonatal infection because it does not peak until 12 to 24 hours after infection and can also be triggered by a non-infectious insult, such as trauma.20

MicrobiologyVariation in the causal agents and microbiome/flora are significant factors to consider with prevention, screening, and treatment protocols for newborns in lower- and middle-income countries. In Africa and Asia, Klebsiella and Escherichia coli are the most common causal organisms for early neonatal sepsis. Women with group B Streptococcus (GBS) colonization increase the risk of early neonatal GBS infection. Gram-negative organisms account for twice as many cases of newborn infection than gram positives in Africa and Asia, which is thought to be attributable to post-delivery exposure. Few reliable epidemiologic data are available from lower- and middle-income countries about the incidence of life-threatening, pregnancy-related infections and their microbial etiology,21 due to the very limited availability of microbiological diagnostic testing in LMICs. In a 2016 study from South Asia, the percentage of newborn deaths following suspected newborn infections due to bacteria was 13.8%, 11.8% were due to viruses, and 74% of deaths occurred unknown infection etiology or with no infection.22 Less than 10% of blood cultures from inpatient newborns with suspected serious bacterial infection in lower- and middle-income countries are positive.23 Additional considerations in investigating causal agents are bacterial versus viral. Especially for late-onset sepsis, viral etiologies may be considered, including human simplex virus (HSV), cytomegalovirus (CMV), HIV, or respiratory syncytial virus (RSV) or similar respiratory viruses. Clinical clues to a viral infection, though not specific, may include hematologic disturbances including low platelet counts and the presence of elevated liver enzymes in addition to physical exam findings.Use of antibioticsFor newborns with possible risk factors for infection, routine practice is to initiate broad-spectrum antibiotics after obtaining samples for cultures (blood, urine, cerebral spinal fluid as appropriate) and await culture results. Current evidence has suggested no benefits from prolonging the course beyond 36 to 48 hours of antibiotics if the blood cultures remain negative. If cultures return positive, antibiotics should be changed to the narrowest spectrum possible.24

In low resource settings bacterial culture is rarely available, and antibiotic recommendations are based on empiric management. Recent trials have demonstrated that simplified antibiotic courses, including oral amoxicillin with or without injectable gentamicin depending on severity of the clinical presentation, are equally efficacious as the reference course of injectable penicillin plus gentamicin in newborns with serious bacterial infections (excluding critically ill newborns) when referral was not feasible25 and patient safety with good adherence can be assured.If viral causes are suspected, prolonged exposure to antibiotics would be of little use, and antiviral therapy should be included. Acyclovir would be recommended for suspected HSV infection, while other antivirals maybe considered for HIV. There is not clear evidence for use of other antivirals against RSV, late-onset CMV (with exception being congenital CMV), or other viruses.Widespread use of broad-spectrum antibiotics as first-line drugs present many problems. For many oral and injectable antibiotics regimens, the duration and dose have not been optimized. Selection of antibiotic, dose and duration are not optimized because cultures, sensitivities, biomarkers and drug levels are generally not available. There are many potential side effects (see above harm section) that may result particularly from broad-spectrum antibiotic use, most notably the development of highly resistant strains of bacteria associated with high mortality.

What are the current WHO recommendations for the management of newborn infections during inpatient care?Current WHO recommendations and guidelines for the management of newborn infections are found across numerous documents. Sexually transmitted infections For prevention of vertical transmission of newborn infections, WHO recommends that all women receive screening and treatment for syphilis, Chlamydia trachomatis, Neisseria gonorrhoeae, and Herpes Simplex Virus Type 2 (HSV-2).26,27,28 Screening for Hepatitis B and C is recommended only in specific contexts and among high-risk women. Prevention of mother-to-child transmission programs in pregnancy, during delivery, and in the postnatal period in settings with a high burden of HIV could substantially reduce the probability that HIV-exposed newborns will acquire HIV infection via vertical transmission.20 In 2017, 1% or more of antenatal care attendees in 37 of 83 reporting countries were diagnosed with syphilis. Prevention, screening and treatment of maternal peripartum infection The prevention and treatment of peripartum infections addresses a primary cause of infection in newborns and prevents severe morbidity in women. Prophylactic intrapartum antibiotics are recommended for women with premature (or pre-labor) rupture of membranes. Women with intraamniotic infections including chorioamnionitis and endometritis should be treated with antibiotics.29

Prophylactic newborn antibiotics for high-risk newbornsProphylactic newborn antibiotics may prevent infection in newborns born to women with premature rupture of the membranes, obstructed or prolonged labor (over 18 hours), chorioamnionitis, or GBS colonization. In addition, infants with meconium-stained amniotic fluid or meconium aspiration, and those with suspected infection or who are at especially high risk of infection due to prematurity or low birth weight in combination with maternal risk factors for infection.28,30,31,32 However, there is debate about the relative benefit of such

treatment in light of growing antibiotic resistant infections, a paucity of data on the most appropriate/effective antibiotic regimens, a growing body of literature on the consequences of antibiotic exposure on the individual, including microbiome disturbances and chronic inflammatory illnesses, and the additional resource requirements of extended hospitalizations for antibiotic administration in low-resource settings.33,34,35,36

Localized and serious bacterial infections The WHO recommends oral antimicrobial therapy and home-based care for young infants with a localized infection, and follow-up by a trained health worker to evaluate status after 2 days.37 For newborns with suspected or confirmed serious bacterial infection, the recommendation is for admission to a referral-level facility and intramuscular or parenteral combination antimicrobial therapy of gentamicin, and ampicillin or penicillin as first-line treatment, or intravenous cloxacillin and gentamicin if staphylococcus infection is suspected.38,39 Simplified outpatient antibiotic therapy of injectable gentamicin plus oral amoxicillin is recommended when inpatient referral-level care at a higher-level facility is not feasible or not accepted, with close observation and follow-up by a trained health worker to assess clinical status.40

Malaria and tuberculosis WHO recommendations use of long-lasting insecticidal nets (LLINs), and intermittent preventive therapy for infants (IPTi) in areas of moderate to high transmission in sub-Saharan Africa; and prompt diagnosis and treatment of malaria infections.41 Congenital infection by vertical transmission of TB occurs late in pregnancy by transplacental transmission through umbilical veins; or aspiration and swallowing of infected amniotic fluid in utero or intrapartum. In newborns diagnosed of TB, a horizontal spread in the postpartum period by droplet or ingestion from mother or undiagnosed family member is most common.42

System requirements for prevention and management of newborn infections during inpatient careInfection prevention and control Although smaller babies are more vulnerable, they require the same infection prevention measures as all inpatient newborns, notably in the special care and intensive care units.4 Diligent infection prevention measures in the delivery room and postnatal wards can significantly reduce the incidence of infection and affect the nature of the infecting organisms.4 Fundamental components of infection prevention include (i) commodities/supplies for infection prevention, including capacity building, motivation and supervision for proper hand washing; (ii) adequate space to minimize crowding with only one baby per cot or incubator; and (iii) adequate, routine cleaning of surfaces and reprocessing of re-usable items with heat, appropriate disinfectants and/or sterilants.4

Antimicrobial resistanceThe emergence of antimicrobial resistance threatens to slow or halt progress in reductions in morbidity and mortality. As circulating pathogens increasingly become resistant to commonly available antibiotics, the efficacy of currently recommended treatment approaches is threatened. WHO warns that the many new antibiotics under development will be insufficient to address the growing number of resistant pathogens, especially multidrug-resistant tuberculosis and resistant gram-negative pathogens.43,44

Infection prevention and disease control strategies, appropriate and judicious use of antibiotics, development of new antibiotic agents and other novel therapies, and improved antimicrobial resistance surveillance are required urgently to address this issue globally.45

Vaccination against infectious diseases with high rates of antimicrobial resistance, such as typhoid, is another WHO priority strategy to address the growing threat of antimicrobial resistance.There are multiple causes of irrational use of medicines, and in particular antibiotics. A context-specific system change is needed as different countries have widely differing health care. Multiple global recommendations have been made to promote rational use of antibiotics and other medicines46 including 2 recent World Health Assembly resolutions47,48 and a regional resolution.49


An estimated 6.9 million newborns in South Asia and sub-Saharan Africa required treatment for possible serious bacterial infection in 2012. Studies have indicated that the rate of neonatal infections in low and middle-income countries is 3 to 20 times higher than in resource-rich countries, with an alarming rate of antibiotic-resistant infections.5

The estimates of the incidence of newborn infections in lower- and middle-income countries range from 5.5 infections per 1,000 live births by positive blood culture to 170 infections per 1,000 live births using clinical diagnosis.6 An additional number of newborns die in the community before a blood culture or clinical diagnosis is made. It is estimated that more than 80% of infection-related deaths in newborns could be avoided if the coverage and quality of currently available preventive measures and effective interventions improved.7




What are the current evidence-based best practices? Prevention measuresElements of essential newborn care have been demonstrated to reduce the risk of infection. Such care practices include hand hygiene, appropriate umbilical cord care, as well as early and continued breastfeeding. Intrapartum and in-hospital hand hygiene has been shown to significantly reduce the risk of nosocomial infections in a variety of low-resource settings,12,13,14 with improved mortality and outcomes. A recent review reported the application of a 4% chlorhexidine solution to the umbilical stump of an infant born in the community resulted in a 12% reduction in neonatal mortality and 50% reduction in omphalitis, though the effect was not seen for infants born in hospital settings.15 An exclusive human milk diet has been associated with a reduced risk of serious infections in preterm/low birthweight infants compared to formula diet.16 The use of probiotics in very low birthweight infants has been investigated, reducing the risk of late-onset sepsis, necrotizing enterocolitis, and all-cause mortality.17



• Early onset sepsis refers to bacteremia acquired either before or during delivery (vertical acquisition), manifesting within the first week of life.

• Late onset sepsis refers to bacteremia acquired after delivery from nosocomial or community sources (horizontal acquisition), manifesting between 7 and 28 days of life.



2

Table 1: Evidence-based clinical approaches and activities for the prevention, detection, management and referral of newborn infections

Approach

Prevention • Infection control practices including hand hygiene; propersterilization of medical equipment; and clean water andhygienic disposal of waste in the community and in themedical facility

• Clean cord care, chlorhexidine cord cleansing ifappropriate, and clean postnatal practices

• Breast feeding• Interventions to prevent hypothermia: drying, head

covering, skin-to-skin contact, and delayed bathing• Limit use of invasive procedures/venipuncture• Avoiding cot and incubator sharing• Appropriate inpatient admission and duration• Maternal vaccines (Tetanus, influenza, hepatitis B)• Screening and treatment of maternal infections• Reduce occurrence and severity of preterm birth• Pro/prebiotics

Activity

Detection • Biomarkers: Culture-independent diagnostics (serialmeasurements of CRP) and in combination with otherbiomarkers

• Microbiology: Culture methods

Management • Special newborn care or neonatal intensive care• Algorithmic case management of neonatal sepsis,

including injectable and oral antibiotics, andhospital-based care

• Antimicrobial resistance and antibiotic stewardshipincluding judicious use, appropriate selection and durationof antibiotic

Referral to appropriate facility

• Timely referral to appropriate facility for care, withappropriate pre-referral care

• Provide adequate care of the sick newborn duringtransport without separation from family members

• If referral to inpatient care not possible, combinationinjectable and oral antibiotics for 7 days in select settings

microbiological diagnostic testing in LMICs is a major barrier to safe antibiotic use and shortening courses of treatment. In settings where families with sick young infants do not accept or cannot access more advanced care, diagnosis in outpatient settings by an appropriately trained health worker is based on the signs of presumed serious bacterial infection.18 Currently available diagnostic tests have significant barriers in their use and interpretation. The actual impact of diagnostics depends on the availability, cost, time to result, and both negative and positive predictive value of the test, as well as the availability, uptake, and effectiveness of the treatment based on the test results. BiomarkersAt this time, there is no accepted biomarker for use in low and middle income countries. The availability, cost, rapidity of results, sensitivity, specificity, predictive value, and the interpretation of results pose challenges for the widespread use of biomarkers. Small studies have described hundreds of biomarkers associated with severe neonatal infections. Biomarkers, alone or in combination, have been used to identify newborn infections: procalcitonin (PCT), C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), interferon-g (IFN-g), interleukin-6 (IL-6), interleukin (IL-8).19 The majority of these studies have evaluated biomarkers in combination with C-reactive protein (CRP); already in widespread clinical use for the diagnosis of infection. As an acute-phase reactant, CRP alone is less useful in the earliest phases of severe neonatal infection because it does not peak until 12 to 24 hours after infection and can also be triggered by a non-infectious insult, such as trauma.20

MicrobiologyVariation in the causal agents and microbiome/flora are significant factors to consider with prevention, screening, and treatment protocols for newborns in lower- and middle-income countries. In Africa and Asia, Klebsiella and Escherichia coli are the most common causal organisms for early neonatal sepsis. Women with group B Streptococcus (GBS) colonization increase the risk of early neonatal GBS infection. Gram-negative organisms account for twice as many cases of newborn infection than gram positives in Africa and Asia, which is thought to be attributable to post-delivery exposure. Few reliable epidemiologic data are available from lower- and middle-income countries about the incidence of life-threatening, pregnancy-related infections and their microbial etiology,21 due to the very limited availability of microbiological diagnostic testing in LMICs. In a 2016 study from South Asia, the percentage of newborn deaths following suspected newborn infections due to bacteria was 13.8%, 11.8% were due to viruses, and 74% of deaths occurred unknown infection etiology or with no infection.22 Less than 10% of blood cultures from inpatient newborns with suspected serious bacterial infection in lower- and middle-income countries are positive.23 Additional considerations in investigating causal agents are bacterial versus viral. Especially for late-onset sepsis, viral etiologies may be considered, including human simplex virus (HSV), cytomegalovirus (CMV), HIV, or respiratory syncytial virus (RSV) or similar respiratory viruses. Clinical clues to a viral infection, though not specific, may include hematologic disturbances including low platelet counts and the presence of elevated liver enzymes in addition to physical exam findings.Use of antibioticsFor newborns with possible risk factors for infection, routine practice is to initiate broad-spectrum antibiotics after obtaining samples for cultures (blood, urine, cerebral spinal fluid as appropriate) and await culture results. Current evidence has suggested no benefits from prolonging the course beyond 36 to 48 hours of antibiotics if the blood cultures remain negative. If cultures return positive, antibiotics should be changed to the narrowest spectrum possible.24 In low resource settings bacterial culture is rarely available, and antibiotic recommendations are based on empiric management. Recent trials have demonstrated that simplified antibiotic courses, including oral amoxicillin with or without injectable gentamicin depending on severity of the clinical presentation, are equally efficacious as the reference course of injectable penicillin plus gentamicin in newborns with serious bacterial infections (excluding critically ill newborns) when referral was not feasible25 and patient safety with good adherence can be assured.If viral causes are suspected, prolonged exposure to antibiotics would be of little use, and antiviral therapy should be included. Acyclovir would be recommended for suspected HSV infection, while other antivirals maybe considered for HIV. There is not clear evidence for use of other antivirals against RSV, late-onset CMV (with exception being congenital CMV), or other viruses.Widespread use of broad-spectrum antibiotics as first-line drugs present many problems. For many oral and injectable antibiotics regimens, the duration and dose have not been optimized. Selection of antibiotic, dose and duration are not optimized because cultures, sensitivities, biomarkers and drug levels are generally not available. There are many potential side effects (see above harm section) that may result particularly from broad-spectrum antibiotic use, most notably the development of highly resistant strains of bacteria associated with high mortality.





Malaria and tuberculosis WHO recommendations use of long-lasting insecticidal nets (LLINs), and intermittent preventive therapy for infants (IPTi) in areas of moderate to high transmission in sub-Saharan Africa; and prompt diagnosis and treatment of malaria infections.41 Congenital infection by vertical transmission of TB occurs late in pregnancy by transplacental transmission through umbilical veins; or aspiration and swallowing of infected amniotic fluid in utero or intrapartum. In newborns diagnosed of TB, a horizontal spread in the postpartum period by droplet or ingestion from mother or undiagnosed family member is most common.42


Antimicrobial resistanceThe emergence of antimicrobial resistance threatens to slow or halt progress in reductions in morbidity and mortality. As circulating pathogens increasingly become resistant to commonly available antibiotics, the efficacy of currently recommended treatment approaches is threatened. WHO warns that the many new antibiotics under development will be insufficient to address the growing number of resistant pathogens, especially multidrug-resistant tuberculosis and resistant gram-negative pathogens.43,44

Infection prevention and disease control strategies, appropriate and judicious use of antibiotics, development of new antibiotic agents and other novel therapies, and improved antimicrobial resistance surveillance are required urgently to address this issue globally.45

Vaccination against infectious diseases with high rates of antimicrobial resistance, such as typhoid, is another WHO priority strategy to address the growing threat of antimicrobial resistance.There are multiple causes of irrational use of medicines, and in particular antibiotics. A context-specific system change is needed as different countries have widely differing health care. Multiple global recommendations have been made to promote rational use of antibiotics and other medicines46 including 2 recent World Health Assembly resolutions47,48 and a regional resolution.49


An estimated 6.9 million newborns in South Asia and sub-Saharan Africa required treatment for possible serious bacterial infection in 2012. Studies have indicated that the rate of neonatal infections in low and middle-income countries is 3 to 20 times higher than in resource-rich countries, with an alarming rate of antibiotic-resistant infections.5

The estimates of the incidence of newborn infections in lower- and middle-income countries range from 5.5 infections per 1,000 live births by positive blood culture to 170 infections per 1,000 live births using clinical diagnosis.6 An additional number of newborns die in the community before a blood culture or clinical diagnosis is made. It is estimated that more than 80% of infection-related deaths in newborns could be avoided if the coverage and quality of currently available preventive measures and effective interventions improved.7




What are the current evidence-based best practices? Prevention measuresElements of essential newborn care have been demonstrated to reduce the risk of infection. Such care practices include hand hygiene, appropriate umbilical cord care, as well as early and continued breastfeeding. Intrapartum and in-hospital hand hygiene has been shown to significantly reduce the risk of nosocomial infections in a variety of low-resource settings,12,13,14 with improved mortality and outcomes. A recent review reported the application of a 4% chlorhexidine solution to the umbilical stump of an infant born in the community resulted in a 12% reduction in neonatal mortality and 50% reduction in omphalitis, though the effect was not seen for infants born in hospital settings.15 An exclusive human milk diet has been associated with a reduced risk of serious infections in preterm/low birthweight infants compared to formula diet.16 The use of probiotics in very low birthweight infants has been investigated, reducing the risk of late-onset sepsis, necrotizing enterocolitis, and all-cause mortality.17



• Early onset sepsis refers to bacteremia acquired either before or during delivery (vertical acquisition), manifesting within the first week of life.

• Late onset sepsis refers to bacteremia acquired after delivery from nosocomial or community sources (horizontal acquisition), manifesting between 7 and 28 days of life.



3

How do we tackle antimicrobial resistance?• Disease control and infection prevention strategies• Vaccination of mothers• Narrow spectrum treatments with diagnostics• Antibiotic stewardship including guidelines for clinical use of

suitable antibiotics• New drugs• Repurposing and/or phenotypic reversion of older drugs• Testing of antibiotic combinations• Therapeutic antibodies

What actions can be taken to improve the management of newborn infections during inpatient care?Core actions needed by key stakeholders to ensure quality management of newborn infections

Policy Makers • Establish/strengthen newborn health committee in facilities with

representatives from key stakeholders and professional bodies• Ensure integration with other programs such as newborn infection

prevention and control, water, sanitation and hygiene (WASH), antimicrobial resistance and stewardship, and maternal health

• Develop suitable indicators for national and subnational and additionalindicators for hospitals admitting small/sick babies

• Develop standards, guidelines, and teaching aides; and establish policiesfor competency-based in-service and preservice training

Program Planners/Implementers• Establish a unit-wide training curriculum for best practices• Adapt indicators to monitor newborn outcomes and evaluate progress• Promote partnership across health care unit

Facility Managers/Administrators/Leaders• Create policies, procedures, and infrastructure that affirm infection

prevention and control practices• Make an explicit commitment to support quality inpatient care that

includes the prevention and management of newborn infections• Develop feedback loops so that newborn outcomes are regularly monitored,

reported, and acted upon• Provide handwashing stations and space for all health care providers and

parents to provide care for their newborn during hospitalization

Health Care Providers (physicians, nurses, midwives, ancillary staff)• Embrace antimicrobial resistance and antibiotic stewardship• Infuse evidence-based clinical approaches in routine medical and nursing

practice, foster interdisciplinary newborn care teams, and participate inquality improvement initiatives

• Educate family members on the unique contribution that they play in thecare of their newborn; train family members on the importance of theirinvolvement in hand-hygiene, and infection control practices

• Implement best infection prevention and infection management practices• At discharge, counsel families on newborn care and infection prevention

practices at home, and to recognize danger signs that triggerappropriate early care seeking

Families• Stay engaged and informed about infection prevention and care practices

while the newborn is in an inpatient setting, in follow-up care, or at home • Inform parents that the antibiotics may not be essential for newborns

during sickness, unless recommended by doctors/trained health workers• Seek medical advice and treatment from qualified professionals

AcknowledgementsThe Do No Harm Technical Series was prepared by a team led by editors James A. Litch (Every Preemie—SCALE/Global Alliance to Prevent Prematurity and Stillbirth), Judith Robb-McCord (Every Preemie—SCALE/Project Concern International) and Lily Kak (USAID). We would like to acknowledge the development of this brief by James A. Litch (Every Preemie–SCALE/GAPPS), Krystle M. Perez (University of Washington/GAPPS), and Gillian Levine (GAPPS). Expert reviews were provided by Rajiv Bahl (World Health Organization), Neelam Bhardwaj (UNFPA), Rachel A. Bishop (Peace Health), Tedbabe Degefie Hailegebriel (UNICEF), Troy Jacobs (USAID/Washington), Indira Narayanan (Georgetown University), Susan Niermeyer (USAID/Washington and University of Colorado School of Medicine), Shamim Quazi (World Health Organization), Pavani Ram (USAID/Washington and University of Buffalo), Judith Robb-McCord (Every Preemie–SCALE/Project Concern International), Samir Kumar Saha (Dhaka Shishu Hospital), Steve Wall (Saving Newborn Lives/Save the Children), Patrice White (Every Preemie–SCALE/American College of Nurse-Midwives).

microbiological diagnostic testing in LMICs is a major barrier to safe antibiotic use and shortening courses of treatment. In settings where families with sick young infants do not accept or cannot access more advanced care, diagnosis in outpatient settings by an appropriately trained health worker based on the signs of presumed serious bacterial infection.18

Currently available diagnostic tests have significant barriers in their use and interpretation. The actual impact of diagnostics depends on the availability, cost, time to result, and both negative and positive predictive value of the test, as well as the availability, uptake, and effectiveness of the treatment based on the test results. BiomarkersAt this time, there is no accepted biomarker for use in low and middle income countries. The availability, cost, rapidity of results, sensitivity, specificity, predictive value, and the interpretation of results pose challenges for the widespread use of biomarkers. Small studies have described hundreds of biomarkers associated with severe neonatal infections. Biomarkers, alone or in combination, have been used to identify newborn infections: procalcitonin (PCT), C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), interferon-g (IFN-g), interleukin-6 (IL-6), interleukin (IL-8).19 The majority of these studies have evaluated biomarkers in combination with C-reactive protein (CRP); already in widespread clinical use for the diagnosis of infection. As an acute-phase reactant, CRP alone is less useful in the earliest phases of severe neonatal infection because it does not peak until 12 to 24 hours after infection and can also be triggered by a non-infectious insult, such as trauma.20

MicrobiologyVariation in the causal agents and microbiome/flora are significant factors to consider with prevention, screening, and treatment protocols for newborns in lower- and middle-income countries. In Africa and Asia, Klebsiella and Escherichia coli are the most common causal organisms for early neonatal sepsis. Women with group B Streptococcus (GBS) colonization increase the risk of early neonatal GBS infection. Gram-negative organisms account for twice as many cases of newborn infection than gram positives in Africa and Asia, which is thought to be attributable to post-delivery exposure. Few reliable epidemiologic data are available from lower- and middle-income countries about the incidence of life-threatening, pregnancy-related infections and their microbial etiology,21 due to the very limited availability of microbiological diagnostic testing in LMICs. In a 2016 study from South Asia, the percentage of newborn deaths following suspected newborn infections due to bacteria was 13.8%, 11.8% were due to viruses, and 74% of deaths occurred unknown infection etiology or with no infection.22 Less than 10% of blood cultures from inpatient newborns with suspected serious bacterial infection in lower- and middle-income countries are positive.23 Additional considerations in investigating causal agents are bacterial versus viral. Especially for late-onset sepsis, viral etiologies may be considered, including human simplex virus (HSV), cytomegalovirus (CMV), HIV, or respiratory syncytial virus (RSV) or similar respiratory viruses. Clinical clues to a viral infection, though not specific, may include hematologic disturbances including low platelet counts and the presence of elevated liver enzymes in addition to physical exam findings.Use of antibioticsFor newborns with possible risk factors for infection, routine practice is to initiate broad-spectrum antibiotics after obtaining samples for cultures (blood, urine, cerebral spinal fluid as appropriate) and await culture results. Current evidence has suggested no benefits from prolonging the course beyond 36 to 48 hours of antibiotics if the blood cultures remain negative. If cultures return positive, antibiotics should be changed to the narrowest spectrum possible.24

In low resource settings bacterial culture is rarely available, and antibiotic recommendations are based on empiric management. Recent trials have demonstrated that simplified antibiotic courses, including oral amoxicillin with or without injectable gentamicin depending on severity of the clinical presentation, are equally efficacious as the reference course of injectable penicillin plus gentamicin in newborns with serious bacterial infections (excluding critically ill newborns) when referral was not feasible25 and patient safety with good adherence can be assured.If viral causes are suspected, prolonged exposure to antibiotics would be of little use, and antiviral therapy should be included. Acyclovir would be recommended for suspected HSV infection, while other antivirals maybe considered for HIV. There is not clear evidence for use of other antivirals against RSV, late-onset CMV (with exception being congenital CMV), or other viruses.Widespread use of broad-spectrum antibiotics as first-line drugs present many problems. For many oral and injectable antibiotics regimens, the duration and dose have not been optimized. Selection of antibiotic, dose and duration are not optimized because cultures, sensitivities, biomarkers and drug levels are generally not available. There are many potential side effects (see above harm section) that may result particularly from broad-spectrum antibiotic use, most notably the development of highly resistant strains of bacteria associated with high mortality.





Malaria and tuberculosis WHO recommends use of long-lasting insecticidal nets (LLINs), and intermittent preventive therapy for infants (IPTi) in areas of moderate to high transmission in sub-Saharan Africa; and prompt diagnosis and treatment of malaria infections.41 Congenital infection by vertical transmission of TB occurs late in pregnancy by transplacental transmission through umbilical veins; or aspiration and swallowing of infected amniotic fluid in utero or intrapartum. In newborns diagnosed with TB, a horizontal spread in the postpartum period by droplet or ingestion from mother or undiagnosed family member is most common.42


Antimicrobial resistanceThe emergence of antimicrobial resistance threatens to slow or halt progress in reductions in morbidity and mortality. As circulating pathogens increasingly become resistant to commonly available antibiotics, the efficacy of currently recommended treatment approaches is threatened. WHO warns that the many new antibiotics under development will be insufficient to address the growing number of resistant pathogens, especially multidrug-resistant tuberculosis and resistant gram-negative pathogens.43,44 Infection prevention and disease control strategies, appropriate and judicious use of antibiotics, development of new antibiotic agents and other novel therapies, and improved antimicrobial resistance surveillance are required urgently to address this issue globally.45 Vaccination against infectious diseases with high rates of antimicrobial resistance, such as typhoid, is another WHO priority strategy to address the growing threat of antimicrobial resistance.There are multiple causes of irrational use of medicines, and in particular antibiotics. A context-specific system change is needed as different countries have widely differing health care. Multiple global recommendations have been made to promote rational use of antibiotics and other medicines46 including 2 recent World Health Assembly resolutions47,48 and a regional resolution.49

References1 Chawanpaiboon S, Vogel JP, Moller A, Alkema L. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health. 2019;7:e37-46. doi: 10.1016/S2214-109X(18)30451-02 Hug L, Alexander M, You D, et al. National, regional, and global levels and trends in neonatal mortality between 1990 and 2017, with scenario-based projections to 2030: a systematic analysis. Lancet Glob Health. 2019;7:e710-20. doi: 10.1016/S2214-109X(19)30163-93 Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin Perinatol. 2010;37(2):307-337. doi: 10.1016/j.-clp.2010.04.001 4 Narayanan I, Litch JA, Ram P. Safe and Effective Infection Prevention for Inpatient Care of Newborns. In Litch JA, Robb-McCord J, Kak L (eds). Do No Harm Technical Brief Series. USAID, PCI, Global Alliance to Prevent Prematurity and Stillbirth, American College of Nurse-Midwives; 2017. http://www.everypree-mie.org/wpcontent/uploads/2017/06/InfectionPrevention_6.14.17.pdf5 Seale AC, Blencowe H, Manu AA, et al. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14(8):731-741. doi: 10.1016/S1473-3099(14)70804-76 Thaver D, Zaidi AK. Burden of neonatal infections in developing countries: a review of evidence from community-based studies. Pediatr Infect Dis J. 2009;28:S3–9. doi: 10.1097/INF.0b013e31819587557 Bhutta ZA, Das JK, Bahl R, et al. Can available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost? Lancet. 2014;384(9940):347-370. doi: 10.1016/S0140-6736(14)60792-38 Polin RA, Watterberg K, Benitz W, Eichenwald E. The conundrum of early-onset sepsis. Pediatrics. 2014;133(6):1122-1123. doi:10.1542/peds.2014-03609 Esaiassen E, Fjalstad JW, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1858-1870. doi: 10.1093/-jac/dkx088 10 Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016;28(2):141-149. doi: 10.1097/MOP.0000000000000338 11 Ranjeva SL, Warf BC, Schiff SJ. Economic burden of neonatal sepsis in sub-Saharan Africa. BMJ Glob Health2018;3:e000347. doi:10.1136/bm-jgh-2017-00034712 Salama MF, Jamal WY, Mousa HA, Al-Abdulghani KA, Rotimi VO. The effect of hand hygiene compliance on hospital-acquired infections in an ICU setting in a Kuwaiti teaching hospital. J Infect Public Health. 2013;6(1):27-34. doi: 10.1016/j.jiph.2012.09.01413 Al Kuwaiti A. Impact of a multicomponent hand hygiene intervention strategy in reducing infection rates at a university hospital in Saudi Arabia. Interv Med Appl Sci. 2017;9(3):137-143. doi: 10.1556/1646.9.2017.2414 Tyagi M, Hanson C, Schellenberg J, Chamarty S, Singh S. Hand hygiene in hospitals: an observational study in hospitals from two southern states of India. BMC Public Health. 2018;18(1):1299. doi: 10.1186/s12889-018-6219-615 Sinha A, Sazawal S, Pradhan A, Ramji S, Opiyo N. Chlorhexidine skin or cord care for prevention of mortality and infections in neonates. Cochrane Database Syst Rev. 2015;3:CD007835. doi: 10.1002/14651858.CD007835.pub216 Corpeleijn WE, Kouwenhoven SM, Paap MC. Intake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. Neonatology. 2012;102(4):276-81. doi: 10.1159/00034133517 Dermyshi E, Wang Y, Yan C, et al. The "golden age" of probiotics: a systematic review and meta-analysis of randomized and observational studies in preterm infants. Neonatology. 2017;112(1):9-23. doi: 10.1159/00045466818 World Health Organization (WHO). WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience. Geneva: WHO; 2016. https://apps.who.int/iris/bit-stream/handle/10665/250796/9789241549912-eng.pdf?sequence=119 Wagner TA, Gravett CA, Healy S, et al. Emerging biomarkers for the diagnosis of severe neonatal infections applicable to low-resource settings. J Glob Health. 2011;1(2):210-223. http://www.jogh.org/documents/issue201102/-JGH2-10_A5_Wagner.pdf20 Franz AR, Bauer K, Schalk A, et al. Measurement of interleukin 8 in combination with C-reactive protein reduced unnecessary antibiotic therapy in newborn infants: a multicenter, randomized, controlled trial. Pediatrics. 2004;114(1):1-8.21 Gravett CA, Gravett MG, Martin ET, et al. Serious and life-threatening pregnan-cy-related infections: opportunities to reduce the global burden. PLoS Med. 2012;9(10):e1001324. doi: 10.1371/journal.pmed.1001324.22 Saha SK, El Arifeen S, Schrag SJ. Aetiology of Neonatal Infection in South Asia (ANISA): an initiative to identify appropriate program priorities to save newborns. Pediatr Infect Dis J. 2016;35(5)(suppl 1):S6-S8. doi: 10.1097/INF.000000000000109923 Blackburn RM, Muller-Pebody B, Planche T, et al. Neonatal sepsis--many blood samples, few positive cultures: implications for improving antibiotic prescribing. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F487-F488. doi: 10.1136/archdis-child-2012-30226124 Vergnano S, Sharland M, Kazembe P, Mwansambo C, Heath P. Neonatal sepsis: an international perspective. Arch Dis Child Fetal Neonatal Ed. 2005;90(3):F220-F224. doi: 10.1136/adc.2002.02286325 African Neonatal Sepsis Trial (AFRINEST) group, Tshefu A, Lokangaka A, et al. Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised,

open-label, equivalence trail. Lancet. 2015;385(9979):1767-1776. doi: 10.1016/S0140-6736(14)62284-426 World Health Organization (WHO). WHO Guideline on Syphilis Screening and Treatment for Pregnant Women. Geneva: WHO; 2017. https://apps.who.int/iris/bit-stream/handle/10665/259003/9789241550093-eng.pdf?sequence=127 World Health Organization (WHO). WHO Guidelines for the Treatment of Chlamydia trachomatis. Geneva: WHO; 2016. https://apps.who.int/iris/bit-stream/handle/10665/246165/9789241549714-eng.pdf?sequence=128 World Health Organization (WHO). WHO Guidelines for the Treatment of Neisseria gonorrhoeae. Geneva: WHO; 2016. https://apps.who.int/iris/bitstream/han-dle/10665/246114/9789241549691-eng.pdf?sequence=129 World Health Organization (WHO). WHO Recommendations for Prevention and Treatment of Maternal Peripartum Infections. Geneva: WHO; 2015. https://apps.who.int/iris/bitstream/han-dle/10665/186171/9789241549363_eng.pdf?sequence=130 World Health Organization (WHO). WHO recommendation on intrapartum antibiotic administration to women with group B Streptococcus (GBS) colonization for prevention of early neonatal GBS infection. Geneva: WHO; 2015.31 World Health Organization (WHO). WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Geneva: WHO; 2015. https://apps.who.int/iris/bit-stream/handle/10665/183037/9789241508988_eng.pdf?sequence=132 World Health Organization (WHO). Recommendations for Management of Common Childhood Conditions: Evidence for Technical Update of Pocket Book Recommendations: Newborn Conditions, Dysentery, Pneumonia, Oxygen Use and Delivery, Common Causes of Fever, Severe Acute Malnutrition and Supportive Care. Geneva: WHO; 2012. https://apps.who.int/iris/bitstream/han-dle/10665/44774/9789241502825_eng.pdf;jsessionid=9CB0B83093F8096737A7313FF9D0E4C5?sequence=133 Simioni J, Hutton EK, Gunn E, et al. A comparison of intestinal microbiota in a population of low-risk infants exposed and not exposed to intrapartum antibiotics: The Baby & Microbiota of the Intestine cohort study protocol. BMC Pediatr. 2016;16(1):183. doi: 10.1186/s12887-016-0724-534 Hirsch AG, Pollak J, Glass TA, et al. Early-life antibiotic use and subsequent diagnosis of food allergy and allergic diseases. Clin Exp Allergy. 2017;47(2):236-244. doi: 10.1111/cea.1280735 Pitter G, Ludvigsson JF, Romor P, et al. Antibiotic exposure in the first year of life and later treated asthma, a population based birth cohort study of 143,000 children. Eur J Epidemiol. 2016;31(1):85-94. doi: 10.1007/s10654-015-0038-136 Carstens LE, Westerbeek EA, van Zwol A, van Elburg RM. Neonatal antibiotics in preterm infants and allergic disorders later in life. Pediatr Allergy Immunol. 2016;27(7):759-764. doi: 10.1111/pai.1261437 World Health Organization (WHO). Integrated Management of Childhood Illness: Distance Learning Course. Module 2: The Sick Young Infant. Geneva: WHO; 2014. https://apps.who.int/iris/bitstream/han-dle/10665/104772/9789241506823_Module-2_eng.pdf?sequence=438 World Health Organization (WHO). Pocket Book of Hospital Care for Children. Guidelines for the Management of Common Childhood Illnesses. 2nd ed. Geneva: WHO; 2013. https://apps.who.int/iris/bitstream/han-dle/10665/81170/9789241548373_eng.pdf?sequence=1 39 World Health Organization (WHO). Integrated Management of Childhood Illness Chart Booklet. Geneva: WHO; 2014. https://apps.who.int/iris/bitstream/han-dle/10665/104772/9789241506823_Chartbook_eng.pdf?sequence=1640 World Health Organization (WHO). Guideline: Managing Possible Serious Bacterial Infection in Young Infants When Referral Is Not Feasible. Geneva: WHO; 2015. https://apps.who.int/iris/bitstream/han-dle/10665/181426/9789241509268_eng.pdf?sequence=141 World Health Organization (WHO). Guidelines for the Treatment of Malaria. 3rd ed. Geneva: WHO, 2015. https://www.who.int/malaria/publications/a-toz/9789241549127/en/42 World Health Organization (WHO). Treatment of Tuberculosis Guidelines. 4th ed. Geneva: WHO; 2010. https://www.who.int/tb/publica-tions/2010/9789241547833/en/43 World Health Organization (WHO). Antibacterial Agents in Clinical Development: An Analysis of the Antibacterial Clinical Development Pipeline, Including Tuberculosis. Geneva: WHO; 2017. http://apps.who.int/iris/bit-stream/10665/258965/1/WHO-EMP-IAU-2017.11-eng.pdf?ua=144 World Health Organization (WHO). Antimicrobial Resistance: Global Report on Surveillance. Geneva: WHO; 2014. http://www.who.int/drugresistance/documents/-surveillancereport/en45 World Health Organization (WHO). Global Action Plan on Antimicrobial Resistance. Geneva: WHO; 2015. http://www.wpro.who.int/entity/drug_resis-tance/resources/global_action_plan_eng.pdf46 World Health Organization (WHO). WHO Global Strategy for Containment of Antimicrobial Resistance. 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New Delhi: WHO SEARO; 2010. https://apps.who.int/iris/bitstream/handle/10665/128408/-sea-rc63-r4.pdf?sequence=1&isAllowed=y


4

What actions can be taken to improve the management of newborn infections during inpatient care?Core actions needed by key stakeholders to ensure quality management of newborn infections

Policy Makers • Establish/strengthen newborn health committee in facilities with

representatives from key stakeholders and professional bodies• Ensure integration with other programs such as newborn infection

prevention and control, water, sanitation and hygiene (WASH), antimicrobial resistance and stewardship, and maternal health

• Develop suitable indicators for national and subnational and additional indicators for hospitals admitting small/sick babies

• Develop standards, guidelines, and teaching aides; and establish policies for competency-based in-service and preservice training

Program Planners/Implementers• Establish a unit-wide training curriculum for best practices• Adapt indicators to monitor newborn outcomes and evaluate progress• Promote partnership across health care unit

Facility Managers/Administrators/Leaders• Create policies, procedures, and infrastructure that affirm infection

prevention and control practices• Make an explicit commitment to support quality inpatient care that

includes the prevention and management of newborn infections• Develop feedback loops so that newborn outcomes are regularly monitored,

reported, and acted upon• Provide handwashing stations and space for all health care providers and

parents to provide care for their newborn during hospitalization

Health Care Providers (physicians, nurses, midwives, ancillary staff)• Embrace antimicrobial resistance and antibiotic stewardship• Infuse evidence-based clinical approaches in routine medical and nursing

practice, foster interdisciplinary newborn care teams, and participate in quality improvement initiatives

• Educate family members on the unique contribution that they play in the care of their newborn; train family members on the importance of their involvement in hand-hygiene, and infection control practices

• Implement best infection prevention and infection management practices• At discharge, counsel families on newborn care and infection prevention

practices at home, and to recognize danger sign that trigger appropriate early care seeking

Families• Stay engaged and informed about infection prevention and care practices

while the newborn is in an inpatient setting, in follow-up care, or at home • Inform parents that the antibiotics may not be essential for newborns

during sickness, unless recommended by doctors/trained health workers• Seek medical advice and treatment from qualified professionals

AcknowledgementsThe Do No Harm Technical Series was prepared by a team led by editors James A. Litch (Every Preemie—SCALE/Global Alliance to Prevent Prematurity and Stillbirth), Judith Robb-McCord (Every Preemie—SCALE/Project Concern International) and Lily Kak (USAID). We would like to acknowledge the development of this brief by James A. Litch (Every Preemie–SCALE/GAPPS), Krystle M. Perez (University of Washington/GAPPS), and Gillian Levine (GAPPS). Expert reviews were provided by Rajiv Bahl (World Health Organization), Neelam Bhardwaj (UNFPA), Rachel A. Bishop (Peace Health), Tedbabe Degefie Hailegebriel (UNICEF), Troy Jacobs (USAID/Washington), Indira Narayanan (Georgetown University), Susan Niermeyer (USAID/Washington and University of Colorado School of Medicine), Shamim Quazi (World Health Organization), Pavani Ram (USAID/Washington and University of Buffalo), Judith Robb-McCord (Every Preemie–SCALE/Project Concern International), Samir Kumar Saha (Dhaka Shishu Hospital), Steve Wall (Saving Newborn Lives/Save the Children), Patrice White (Every Preemie–SCALE/American College of Nurse-Midwives).

References1 Chawanpaiboon S, Vogel JP, Moller A, Alkema L. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health. 2019;7:e37-46. doi: 10.1016/S2214-109X(18)30451-02 Hug L, Alexander M, You D, et al. National, regional, and global levels and trends in neonatal mortality between 1990 and 2017, with scenario-based projections to 2030: a systematic analysis. Lancet Glob Health. 2019;7:e710-20. doi: 10.1016/S2214-109X(19)30163-93 Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin Perinatol. 2010;37(2):307-337. doi: 10.1016/j.-clp.2010.04.001 4 Narayanan I, Litch JA, Ram P. Safe and Effective Infection Prevention for Inpatient Care of Newborns. In Litch JA, Robb-McCord J, Kak L (eds). Do No Harm Technical Brief Series. USAID, PCI, Global Alliance to Prevent Prematurity and Stillbirth, American College of Nurse-Midwives; 2017. http://www.everypree-mie.org/wpcontent/uploads/2017/06/InfectionPrevention_6.14.17.pdf5 Seale AC, Blencowe H, Manu AA, et al. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14(8):731-741. doi: 10.1016/S1473-3099(14)70804-76 Thaver D, Zaidi AK. Burden of neonatal infections in developing countries: a review of evidence from community-based studies. Pediatr Infect Dis J. 2009;28:S3–9. doi: 10.1097/INF.0b013e31819587557 Bhutta ZA, Das JK, Bahl R, et al. Can available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost? Lancet. 2014;384(9940):347-370. doi: 10.1016/S0140-6736(14)60792-38 Polin RA, Watterberg K, Benitz W, Eichenwald E. The conundrum of early-onset sepsis. Pediatrics. 2014;133(6):1122-1123. doi:10.1542/peds.2014-03609 Esaiassen E, Fjalstad JW, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1858-1870. doi: 10.1093/-jac/dkx088 10 Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016;28(2):141-149. doi: 10.1097/MOP.0000000000000338 11 Ranjeva SL, Warf BC, Schiff SJ. Economic burden of neonatal sepsis in sub-Saharan Africa. BMJ Glob Health2018;3:e000347. doi:10.1136/bm-jgh-2017-00034712 Salama MF, Jamal WY, Mousa HA, Al-Abdulghani KA, Rotimi VO. The effect of hand hygiene compliance on hospital-acquired infections in an ICU setting in a Kuwaiti teaching hospital. J Infect Public Health. 2013;6(1):27-34. doi: 10.1016/j.jiph.2012.09.01413 Al Kuwaiti A. Impact of a multicomponent hand hygiene intervention strategy in reducing infection rates at a university hospital in Saudi Arabia. Interv Med Appl Sci. 2017;9(3):137-143. doi: 10.1556/1646.9.2017.2414 Tyagi M, Hanson C, Schellenberg J, Chamarty S, Singh S. Hand hygiene in hospitals: an observational study in hospitals from two southern states of India. BMC Public Health. 2018;18(1):1299. doi: 10.1186/s12889-018-6219-615 Sinha A, Sazawal S, Pradhan A, Ramji S, Opiyo N. Chlorhexidine skin or cord care for prevention of mortality and infections in neonates. Cochrane Database Syst Rev. 2015;3:CD007835. doi: 10.1002/14651858.CD007835.pub216 Corpeleijn WE, Kouwenhoven SM, Paap MC. Intake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. Neonatology. 2012;102(4):276-81. doi: 10.1159/00034133517 Dermyshi E, Wang Y, Yan C, et al. The "golden age" of probiotics: a systematic review and meta-analysis of randomized and observational studies in preterm infants. Neonatology. 2017;112(1):9-23. doi: 10.1159/00045466818 World Health Organization (WHO). WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience. Geneva: WHO; 2016. https://apps.who.int/iris/bit-stream/handle/10665/250796/9789241549912-eng.pdf?sequence=119 Wagner TA, Gravett CA, Healy S, et al. Emerging biomarkers for the diagnosis of severe neonatal infections applicable to low-resource settings. J Glob Health. 2011;1(2):210-223. http://www.jogh.org/documents/issue201102/-JGH2-10_A5_Wagner.pdf20 Franz AR, Bauer K, Schalk A, et al. Measurement of interleukin 8 in combination with C-reactive protein reduced unnecessary antibiotic therapy in newborn infants: a multicenter, randomized, controlled trial. Pediatrics. 2004;114(1):1-8.21 Gravett CA, Gravett MG, Martin ET, et al. Serious and life-threatening pregnan-cy-related infections: opportunities to reduce the global burden. PLoS Med. 2012;9(10):e1001324. doi: 10.1371/journal.pmed.1001324.22 Saha SK, El Arifeen S, Schrag SJ. Aetiology of Neonatal Infection in South Asia (ANISA): an initiative to identify appropriate program priorities to save newborns. Pediatr Infect Dis J. 2016;35(5)(suppl 1):S6-S8. doi: 10.1097/INF.000000000000109923 Blackburn RM, Muller-Pebody B, Planche T, et al. Neonatal sepsis--many blood samples, few positive cultures: implications for improving antibiotic prescribing. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F487-F488. doi: 10.1136/archdis-child-2012-30226124 Vergnano S, Sharland M, Kazembe P, Mwansambo C, Heath P. Neonatal sepsis: an international perspective. Arch Dis Child Fetal Neonatal Ed. 2005;90(3):F220-F224. doi: 10.1136/adc.2002.02286325 African Neonatal Sepsis Trial (AFRINEST) group, Tshefu A, Lokangaka A, et al. Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised,

open-label, equivalence trail. Lancet. 2015;385(9979):1767-1776. doi: 10.1016/S0140-6736(14)62284-426 World Health Organization (WHO). WHO Guideline on Syphilis Screening and Treatment for Pregnant Women. Geneva: WHO; 2017. https://apps.who.int/iris/bit-stream/handle/10665/259003/9789241550093-eng.pdf?sequence=127 World Health Organization (WHO). WHO Guidelines for the Treatment of Chlamydia trachomatis. Geneva: WHO; 2016. https://apps.who.int/iris/bit-stream/handle/10665/246165/9789241549714-eng.pdf?sequence=128 World Health Organization (WHO). WHO Guidelines for the Treatment of Neisseria gonorrhoeae. Geneva: WHO; 2016. https://apps.who.int/iris/bitstream/han-dle/10665/246114/9789241549691-eng.pdf?sequence=129 World Health Organization (WHO). WHO Recommendations for Prevention and Treatment of Maternal Peripartum Infections. Geneva: WHO; 2015. https://apps.who.int/iris/bitstream/han-dle/10665/186171/9789241549363_eng.pdf?sequence=130 World Health Organization (WHO). 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A comparison of intestinal microbiota in a population of low-risk infants exposed and not exposed to intrapartum antibiotics: The Baby & Microbiota of the Intestine cohort study protocol. BMC Pediatr. 2016;16(1):183. doi: 10.1186/s12887-016-0724-534 Hirsch AG, Pollak J, Glass TA, et al. Early-life antibiotic use and subsequent diagnosis of food allergy and allergic diseases. Clin Exp Allergy. 2017;47(2):236-244. doi: 10.1111/cea.1280735 Pitter G, Ludvigsson JF, Romor P, et al. Antibiotic exposure in the first year of life and later treated asthma, a population based birth cohort study of 143,000 children. Eur J Epidemiol. 2016;31(1):85-94. doi: 10.1007/s10654-015-0038-136 Carstens LE, Westerbeek EA, van Zwol A, van Elburg RM. Neonatal antibiotics in preterm infants and allergic disorders later in life. Pediatr Allergy Immunol. 2016;27(7):759-764. doi: 10.1111/pai.1261437 World Health Organization (WHO). Integrated Management of Childhood Illness: Distance Learning Course. 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Management of Newborn Infections During Inpatient Care · to commonly used antibiotics is emerging and constitutes an important problem worldwide. The impact of antibiotic use on