Serious bacterial infections in newborn infants in developingcountriesDavid Osrin, Stefania Vergnano and Anthony Costello
The overwhelming majority of the world’s annual 4 million
The Millennium Development Goals include a reduc-
neonatal deaths occur in developing countries. This review
tion in child mortality by two-thirds between 1990 and
therefore briefly addresses the burden, aetiology, prevention
2015 . The number of children under 5 years of age
and management of serious neonatal bacterial infections in low-
that die each year is 10.8 million, making up 32% of
global deaths . Neonatal deaths account for about half
of these [3,4.] and two-thirds of infant deaths ,
Bacterial infection is the biggest cause of neonatal admissions
proportions which rise as post-neonatal mortality falls
to hospitals, and probably the biggest cause of morbidity in the
[4.,6]. Of the estimated 3.9 million annual neonatal
community, but its burden is unclear. The commonest serious
deaths [3,4.], 98% occur in developing countries .
infections involve bacteraemia, meningitis and respiratoryinfection, and case fatality rates may be as high as 45%. Key
This overview addresses the burden, aetiology, preven-
pathogens are Escherichia coli, Klebsiella species,
tion and management of serious neonatal bacterial
Staphylococcus aureus and Streptococcus pyogenes. The
infections in low-income countries. Malaria, tuberculosis,
incidence of neonatal infections with group B streptococcus is
HIV/AIDS and other viral or sexually transmitted
highly variable, as is the spectrum of antimicrobial resistance.
infections are not its focus. The rural, home-born
neonate remains relatively invisible to either research
Current areas of research include the rectification of
or health services and – despite the ﬁgures above – the
micronutrient deficiencies, neonatal skin care, appropriate
burden of neonatal mortality in low-income countries is
breastfeeding recommendations, cleansing of the birth canal,
barely quantiﬁed [8.]. Although a range of strategies for
and simplified methods of diagnosis of infection. Operational
prevention and management have been proposed, the
activities include the control of neonatal tetanus, the diagnosis
gaps between the conceptual bases of these strategies
and treatment of sexually transmitted infections, integrated
strategies for improving pregnancy, childbirth and neonatalsurvival, community-based management of acute respiratory
infections, and community-based management of neonatal
Most births in developing countries take place at home,as do most neonatal deaths. The major causes of death
are likely to be infections, preterm birth and birth
developing countries, essential newborn child care, neonatal
asphyxia . The incidence of neonatal bacterial illness
is unclear [9,10]. In major reviews by Stoll [11,12],hospital data suggested that infection was a cause of 4–
Curr Opin Infect Dis 17:217–224. # 2004 Lippincott Williams & Wilkins.
56% of neonatal deaths, and community data a ﬁgure of8–84% . These ﬁgures yielded an estimate of 1.5–
International Perinatal Care Unit, Centre for International Child Health, Institute of
2 million infection-related neonatal deaths per annum
Child Health, University College London, London, UK
[11,12]. World Health Organization (WHO) estimates
Correspondence to Dr David Osrin, International Perinatal Care Unit, Institute of Child
suggest that sepsis, pneumonia, tetanus and diarrhoea
Health, 30 Guilford Street, London WC1N 1EH, UK
Tel: +44(0) 207 905 2261; fax: +44(0) 207 404 2062; e-mail: email@example.com
Current Opinion in Infectious Diseases 2004, 17:217–224
The variability of these estimates underlines ﬁve issues.
(1) The invisibility of the neonatal period makes pick-up
rates variable. (2) There are difﬁculties in diagnosingneonatal infection and in disaggregating it from other
potential causes of death, and the clinical tools available
for diagnosis in poorer settings are limited. (3) The siteof research is important: hospital-based studies haveoften been conducted in tertiary units, may includehigher proportions of preterm infants, generally recruiturban participants of higher socioeconomic status, often
include more male infants, and tend to miss early
73 per 1000 live births, and the prevalence of low birth
neonatal illness and mortality. (4) All research in low-
weight was high (42%); 763 neonates were observed and
income countries faces the problems of workload,
17% developed clinical features suggestive of sepsis.
opportunity and consumable costs, and variations in
Although it is possible that the clinical ascription of
the quality of laboratory procedures. (5) These issues
sepsis was over-inclusive, the case fatality rate in infants
aside, there is likely to be a wide range of incidences and
in this category was 18.5%, even when the subjects were
case fatality rates across geographic, socioeconomic and
treated with oral antibiotics. The investigators noted that
no neonate was seen at a primary health centre, and thatif all who merited a visit had been seen, the primary
health-care system would have been overloaded.
bacterial infectionAttempts to measure morbidity are confused by the
selective nature of studies, particularly the recruitment
Reviewing 18 hospital-based studies in 1989, a WHO
of sick infants at health facilities . In a hospital-based
expert group concluded that the aetiology of commu-
study from Karachi, Pakistan, infection was the biggest
nity-acquired pneumonia – and, by implication, sepsis –
cause of hospitalization of newborn infants , and at a
in young infants in developing countries was unknown
district hospital in Kenya, where 95% of admissions were
. Subsequently, the WHO Young Infants Study
outborn, serious infections were the most common cause
Group attempted to describe pathogenic organisms in
of admission for infants under 2 months of age [15.]. In
young infants as close to community settings as possible.
their review of sepsis neonatorum of 1981, Siegel and
Four country sites were involved: a hospital in Addis
McCracken  suggested that the primary site of
Ababa, Ethiopia , a research institute in Alabang, the
invasion was most often the bloodstream, with spread to
Philippines , a base hospital in the eastern highlands
the meninges in 25–30% of cases. Other clinical entities
of Papua New Guinea , and two sites in the Gambia
included acute respiratory infection, diarrhoea, and
(a ﬁrst-level facility and a referral hospital) . Infants
omphalitis, itself associated with neonatal tetanus. In
were enrolled on presentation at under 3 months of age,
clinical series, congenital and neonatal pneumonias are
using a formalized sequence of assessment and investi-
often grouped with sepsis and meningitis because of the
gations; 8418 infants were triaged, 4552 enrolled, and
overlap in symptom constellations. The Kenyan study
[15.] looked at 432 early neonatal and 260 late neonataladmissions. Sepsis accounted for 30% of early neonatal
In the neonatal period, the commonest blood-culture
admissions, tetanus for 6%, and meningitis for 1%. In the
isolates were Staphylococcus aureus (23%), Streptococcus
late neonatal period, sepsis accounted for 60% of
pyogenes (20%), and Escherichia coli (18%). Cerebrospinal
admissions, tetanus for 7%, and meningitis for 4%
[15.]. Stoll’s reviews [11,12] put the global incidence
meningitis was predominantly caused by Gram-nega-
of neonatal sepsis at 5–6 per 1000 live births and that of
tive micro-organisms, and late neonatal meningitis was
meningitis at 0.7–1 (2.4–16 in South and South-East
caused by roughly equal numbers of Gram-negative
Asia, 6–21 in sub-Saharan Africa, and 1.8–12 in the
micro-organisms and Streptococcus pneumoniae, particularly
Middle East and North Africa) . Estimates of case
of serotype 2. This trend was supported by the tendency
fatality rates for neonatal infections range from 13% to
for post-neonatal meningitis to be dominated by Strep.
45% [11,12]. There is some evidence that infants
pneumoniae, which accounted for 43% of proven bacterial
delivered to poorer families at home have higher case
meningitis. There were differences between sites: Staph.
fatality rates, but this may also reﬂect later consultation
aureus was commoner in the Gambia (possibly the result
of a high prevalence of scabies), E. coli in Ethiopia ,Salmonella in the Philippines , and Strep. pyogenes in
Community-based studies are rare and vary in their
Papua New Guinea . At the same site, nasophar-
classiﬁcation of neonatal sepsis. In a prospective study of
yngeal aspirates were positive for Chlamydia trachomatis
329 births in rural Guatemala , infection was the
in 33% of severe pneumonias – an issue that requires
largest cause of morbidity and mortality. Mortality from
further study . Despite the investigators’ efforts, the
infectious illness was more common in the early neonatal
sampling frame was hospital-based, so the recruitment
period and in preterm and low-birth-weight infants,
pool would have omitted infants who did not present to
although the majority of illnesses occurred in term
a facility. This is true of almost all previous and
infants of normal birth weight. In Maharashtra, India,
subsequent studies, of which there have been many,
Bang and colleagues  employed village-based female
and of which a brief summary follows.
health workers to describe the burden of morbidities byusing a clinical algorithm. At the time, 95% of births took
There appears to be regional variation in the split
place at home, the infant mortality ratio in the area was
between Gram-positive and Gram-negative pathogens.
Serious infections in developing countries Osrin et al.
The split has been about even in studies from sub-
Saharan Africa, but Gram-negative micro-organisms have
Although it is not clear how much institutional spectra
been more common in Asian studies [11,25,26]. In all
of resistance are applicable to the community, institu-
series, the most common Gram-negative pathogens have
tional infection control presents its own problems .
been Klebsiella species and E. coli [15.,17,28–37]. It is
Degrees of resistance vary: some centres report low levels
quite likely that E. coli, a more common isolate in outborn
[28,54], while others report rapid increases in multidrug-
neonates and in vaginal swabs from women in rural areas
resistant neonatal infections [30,31,34,36,37,55]. In unu-
, reﬂects community patterns of colonization and
sual but worrying situations, ﬁrst-line therapy comprises
infection. Klebsiella species have often been isolated in
vancomycin and amikacin or a carbapenem .
hospital series and are often implicated in nurseryoutbreaks [39,40]. Other important pathogens have been
Reducing the burden of neonatal bacterial
found to be Pseudomonas and Enterobacter species. The
most common Gram-positive isolate has been found to be
The importance of neonatal survival in developing
Staph. aureus [17,28,31,33,34,36,37,41,42]. Studies from
countries has been addressed over the last decade by a
the Caribbean yield similar isolates, but show the effect of
number of reviews, working groups and alliances
nosocomial outbreaks of Pseudomonas infection  and a
[3,8.,11,56–62,63.,64]. The following list summarizes
rising incidence of neonatal sepsis associated with group
recommendations for the reduction of neonatal morbid-
ity and morbidity from bacterial infection. Theserecommendations
It is difﬁcult to generalize about the importance of group
sources [3,8.,11,56–62,63.,64], as well as from the
B streptococcal infection. Until recently, the limited role
WHO initiatives for Essential Newborn Care , the
of group B streptococcus in neonatal sepsis in developing
Mother–Baby Package  and the Integrated Manage-
countries was a point of discussion [11,25,26]. It
ment of Pregnancy and Childbirth .
accounted for less than 1% of infections in Asian studiesand about 8% in African studies, which is surprising in
view of the possibility that maternal colonization levels
appeared similar to those in high-income countries .
Gender equity and education for women.
In a 10-year retrospective series from a tertiary care
perinatal centre in Vellore, India, the incidence of
Political commitment to improving neonatal survival.
symptomatic early neonatal group B streptococcal bacter-
Improvements in general health and health care
aemia was as low as 0.17 per 1000 live births . The
Improved access to, and quality of, health services.
problem may be increasing, however [15.,42]. It is not
clear whether group B streptococcal sepsis runs, to some
Integration of health service and community activities,
extent, in parallel with the epidemiological transition, or
with the emphasis on community-based aspects of
whether there is a connection with clustering in hospital
births [47–49]. Regular monitoring of pathogens in
institutional centres is necessary in order to pick up
Improvements in mother and child health care
evolving patterns of infection. Identiﬁcation of rising
National strategy to reduce neonatal mortality.
rates of group B streptococcal infection allows screening
Surveillance of vital events and neonatal outcomes.
and response protocols to be put in place, in the absence
Reduced prevalence of low birth weight.
of which case fatality rates can be as high as 60% .
Integration of neonatal survival into existing safe-
motherhood and child-survival programmes.
Availability, quality and uptake of antenatal care.
Ampicillin and gentamicin are currently recommended as
ﬁrst-line antimicrobials [26,42,51], ampicillin replacing
the previous recommendation of penicillin . An
Knowledge of maternal and neonatal danger signs in
antistaphylococcal agent such as cloxacillin may be added
when scabies or pustular skin lesions are present, and a
Recognition, management and referral of maternal and
third-generation cephalosporin should be considered for
suspected meningitis. The emergence of resistant patho-
gens is a problem for both institutions and communities.
Rahman and colleagues  ably summarize the situation
Focused antenatal care, i.e. a limited number of visits
in many areas: lack of control of antibiotic use, little
with speciﬁc effective activities.
legislation on prescription, over-the-counter sale of
Antenatal micronutrient supplementation (the evi-
antibiotics, poor sanitary conditions, a lack of basic
dence for effects on neonatal infection are currently
facilities that would help hand-washing, and a lack of
Immunization: tetanus toxoid administration before
1% to 8%  among pregnant women attending for
and during antenatal care. Pneumococcal and
antenatal care, but estimates are more reliable in settings
Haemophilus inﬂuenzae type B vaccines are under
with higher antenatal care uptake. In a survey of 22
countries in sub-Saharan Africa, where antenatal care
Facility-based and community-based training of birth
attendance is around 72%, only 38% of attendees were
screened and treated for syphilis. This leaves over
Diagnosis and treatment of sexually transmitted and
1 million women untreated despite the existence of cost-
Planning for clean, safe delivery (‘birth preparedness’). Action to address infective complications: partography,
What models do we have for achieving some of the far-
limited vaginal examinations, antibiotic prophylaxis
reaching and ambitious changes recommended in the
above list? The success of the WHO strategy of
Clean delivery: skilled attendance, hand-washing, use
identiﬁcation and case management of acute respiratory
of clean delivery kit, clean cord cutting and
infection in the community is now clear. However, ﬁeld
activities exclude infants below the age of 2 months who
Neonatal care: essential training on newborn infant
should be referred for management in hospital [75,76]. A
care for health workers, support for breast-feeding,
meta-analysis of nine community-based trials of case
‘rooming in’ at facilities, identiﬁcation of preterm
management of pneumonia in preschool children in
and low-birth-weight infants, kangaroo mother care
developing countries (all but one in Asia, the other in
for low-birth-weight infants, prophylaxis against
Africa) yielded a summary estimate for reduction in all-
ophthalmia neonatorum, early immunization, post-
cause neonatal mortality of 27% (95% conﬁdence
partum maternal care linked with newborn care,
interval, 18–35%). The reduction in neonatal pneumonia
mortality was 42% (22–57%). Of particular interest was
Home-based diagnosis and treatment of neonatal
the ﬁnding that case management was successful in the
neonatal period, and that it allowed for a range ofactivities that did not necessarily require the use of
It is important to ensure that recommendations are
evidence-based. However, the history of the primaryhealth-care movement alerts us to an understandable
The Integrated Management of Childhood Illness
tendency to dwell on biomedical and technical aspects of
strategy of the WHO covers three areas: improving the
the agenda at the expense of the organizational, social
skills of health personnel in the prevention and
and political changes that it demands . There is a
treatment of childhood illness; improving health systems
wide gap between the requirements and our knowledge
to deliver quality care; and improving family and
of how to meet those needs at operational level. This is
community practices in relation to child health .
particularly true of community-based activities.
The activities of the Integrated Management of Child-hood Illness have so far excluded the infant under 2
An exception is the control of neonatal tetanus: despite
months of age, but neonatal guidelines are currently
setbacks that resulted in shifting of the target date to
being drawn up and adapted. Some of the studies
2005 , there has been steady progress towards the
mentioned in this review have been explicitly oriented
elimination of the infection . Incidence fell by about
towards this [15.,25,79.], and the ideal would be to
75% over the decade to 2000, at which point about
dovetail the Integrated Management of Childhood
200 000 cases were reported . Activities are currently
Illness work with the Integrated Management of
focused on 57 countries. The key strategies are
Pregnancy and Childbirth practice guide . The
promotion of clean deliveries (which has implications
emphasis of the activities of the Integrated Management
for other bacterial infections), surveillance and immuni-
of Childhood Illness so far has been on the tools and
zation. Routine tetanus toxoid immunization is augmen-
training of health personnel . This may lead to
ted by supplemental activities, a high-risk approach
improvements in quality that themselves encourage
involving immunization of all women of child-bearing
greater uptake of services, but there is a danger that
age (in speciﬁc areas) with three doses of tetanus toxoid.
health-system and community requirements will achieveless attention [81–83].
Diagnosis and treatment of sexually transmitted infec-tions is becoming a priority, especially with respect to
A trial of a community-based model designed to improve
the HIV pandemic. Syphilis infection is particularly
neonatal outcomes in rural Maharashtra, India, has had a
relevant to neonatal health, being responsible for
strong inﬂuence on current opinion . The non-
stillbirths, low birth weight, preterm delivery and
randomized trial involved 39 intervention and 47 control
congenital infection . Its prevalence ranges from
villages. In the ﬁrst year of activities, female village
Serious infections in developing countries Osrin et al.
health workers collected data and managed minor
low-birth-weight prevalence and an increase in labora-
illnesses and pneumonia in neonates. In the second
tory measures of maternal immunocompetence , but
year, they undertook case management of neonatal
the effects on bacterial infection are unclear.
illnesses, including the identiﬁcation and treatment ofpresumptive sepsis with intramuscular gentamicin and
oral cotrimoxazole. In the third year, health education for
A recent review explores the possibility that topical
mothers and grandmothers was added to the package.
application of natural vegetable oils might boost the
Sepsis was suggested by a combination of any two of
skin’s barrier properties. If this were the case, traditional
eight possible symptoms or signs, and hospital treatment
oil massage might be a means of reducing neonatal
was advised, home-based management being a second
infection, especially in preterm and small infants .
option. The study described a reduction in neonatal
Sunﬂower seed oil accelerated the recovery of mouse
sepsis mortality from 27.5 to 6.6 per 1000 live births.
epidermal barrier function and electron micrographic
There are some difﬁculties in interpretation and extra-
ultrastructure, whereas mustard oil – commonly applied
polation: (1) the non-random nature of the sample and its
in developing countries – was prone to a lack of purity,
reliance on two clusters; (2) the inclusiveness of the
and caused deterioration in barrier function.
clinical diagnostic criteria; (3) the stepwise introductionof a number of interventions; and (4) the reliance on a
cadre parallel to government staff. Nevertheless, it
A pooled analysis of data from three developing country
seems that locally trained workers can undertake case
studies (Brazil, Pakistan, and the Philippines) looked at
management of neonatal sepsis and administer paren-
the protective effect of breast-feeding against mortality
teral antibiotics safely, and efforts are underway to
from infectious disease. The pooled odds ratio for
systematize once-daily regimens and safe injection
infectious mortality associated with not breast-feeding
technology. The possibility of home-based care for
in the ﬁrst month of life was 5.8 (95% conﬁdence
neonatal illness has been raised, and the next steps are
interval, 3.4–9.8). Unfortunately, deaths in the ﬁrst week
modiﬁcation of the model, replication and expansion.
were excluded from the analysis . Breast-feedingrecommendations in countries with high HIV prevalence
are a subject of debate and current research. An example
A number of other issues relevant to neonatal bacterial
is the study from Kenya in which HIV-infected mothers
infection have seen research activity over the last few
were randomized to either exclusively breast-feed or
formula feed. On one hand, the breast-feeding groupshowed a higher rate of mother-to-child HIV transmis-
sion; on the other, by the time the infants were 2 years
A link between micronutrient deﬁciencies – either single
old the groups had comparable all-cause mortality
or multiple – and neonatal infection is plausible .
Although a number of studies are under way, we do notpresently have evidence that improvements in micro-
nutrient status, with the exception of vitamin A, would
A study from Malawi  showed a signiﬁcant reduction
lead to reductions in infection-speciﬁc morbidity or
in early neonatal infections, admissions and mortality
mortality . Vitamin A supplementation for children
when chlorhexidine was used to clean the birth canal at
aged over 6 months could reduce childhood mortality by
delivery. This simple, affordable intervention warrants
about one-quarter , at least part of this being
mediated by a reduction in infectious morbidity. However, supplementation for infants in the later
Prediction of neonatal bacterial infection
neonatal period has not been shown to reduce morbidity
A score-based or algorithmic system for identifying
 or mortality . It is possible that earlier
presumptive neonatal bacterial infection would be useful
intervention would be beneﬁcial: an Indonesian trial
given the difﬁculty of diagnosis [99–101]. In a hospital-
 in which most infants received supplements on the
based sample from Delhi, India, a respiratory rate of over
ﬁrst day of life showed a 64% reduction in infant
60 breaths/min was 88.3% sensitive and 6.3% speciﬁc for
mortality, and an Indian trial [91.] showed a promising
neonatal pneumonia; chest retractions were 93.2%
mortality reduction in the ﬁrst 3 months of life when
sensitive and 36.1% speciﬁc . The WHO Young
vitamin A supplements were given in the ﬁrst 48 h.
Infants Study used regression and receiver–operator
Unfortunately, we do not have evidence that supple-
modelling to generate a list of 14 historical factors and
mentation for mothers during pregnancy reduces neo-
signs that were independently predictive of severe
disease [79.]. The presence of any factor had a
controlled trial of multivitamin supplements for pregnant
sensitivity for severe disease of 87% and a speciﬁcity
HIV-infected women in Tanzania showed a reduction in
of 54%. A model involving nine factors had slightly lower
sensitivity but greater speciﬁcity, but further reductions
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