Qco1703va.pdf

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 [1]. 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 [2]. Neonatal deaths account for about half of these [3,4.] and two-thirds of infant deaths [5], 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 [7].
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 [7]. 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% [11]. 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: d.osrin@ich.ucl.ac.uk 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 [14]. 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 [13], and at a in young infants in developing countries was unknown district hospital in Kenya, where 95% of admissions were [20]. 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 [16] suggested that the primary site of Ababa, Ethiopia [21], a research institute in Alabang, the invasion was most often the bloodstream, with spread to Philippines [22], a base hospital in the eastern highlands the meninges in 25–30% of cases. Other clinical entities of Papua New Guinea [23], and two sites in the Gambia included acute respiratory infection, diarrhoea, and (a first-level facility and a referral hospital) [24]. 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) [11]. 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 [21],Salmonella in the Philippines [22], and Strep. pyogenes in Community-based studies are rare and vary in their Papua New Guinea [23]. 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 [18], infection was the in 33% of severe pneumonias – an issue that requires largest cause of morbidity and mortality. Mortality from further study [27]. 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 [19] 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 [53].
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- [38], 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 [34].
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 [43] 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 [65], the of group B streptococcus in neonatal sepsis in developing Mother–Baby Package [66] and the Integrated Manage- countries was a point of discussion [11,25,26]. It ment of Pregnancy and Childbirth [67].
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 [11].
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 [46]. 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% [50].
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 [52]. 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 [36] 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% [73] 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 [68]. 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 [78].
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 [69], there has been steady progress towards the mentioned in this review have been explicitly oriented elimination of the infection [70]. 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 [71]. Activities are currently Illness work with the Integrated Management of focused on 57 countries. The key strategies are Pregnancy and Childbirth practice guide [67]. 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 [80]. 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 [84]. The non- stillbirths, low birth weight, preterm delivery and randomized trial involved 39 intervention and 47 control congenital infection [72]. 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 [93], 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 [94].
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 [95]. 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 [85].
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 [98] showed a significant reduction lead to reductions in infection-specific morbidity or in early neonatal infections, admissions and mortality mortality [86]. 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 [87], 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 [88] or mortality [89]. 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- [90] 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 [35]. 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 13 Bhutta Z. Neonatal bacterial infections in developing countries: strategies for prevention. Semin Neonatol 1999; 4:159–171.
in complexity were associated with losses of sensitivity.
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infants are seen and where infants are unselected so that This prospective observational study carried out in a Kenyan district hospital the model has to deal with populations in which the underlines the importance of the neonatal period to the burden of mortality, as wellas that of infection. The importance of Strep. pneumoniae in sepsis in young likelihood of serious illness is lower.
infants, noted in the WHO Young Infants Study, is supported.
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