Background
World Health Organization (WHO) estimates about 5 million neonatal deaths a year. Almost all deaths occur in developing countries; half of them in the African region [
1]. Septicemia is a common cause of infants' morbidity and mortality in developing countries [
1]. There is no pathognmonic features of neonatal sepsis [
2]; clinical presentation of neonatal sepsis can vary; in most studies symptoms include fever, difficult in breathing, tachycardia, malaise, difficult in feeding and lethargy [
1,
3,
4]. It is therefore important to carry out investigation to confirm neonatal sepsis in the setting of good laboratory facilities and services. In the study done in Kenya, difficult in feeding, unexplained pallor, cyanosis and unconsciousness were strongly associated with severe sepsis while fast breathing, nasal flaring, grunting and lethargy were found to be associated with moderate form of sepsis [
5]. WHO has made criteria for initial diagnosis of neonatal sepsis, but the sensitivity and specificity of clinical diagnosis can vary considerably [
1,
2,
6].
Prompt diagnosis and effective treatment is necessary to prevent deaths and complications due to septicemia. Physical signs and symptoms are useful in identifying infants and children with septicemia. These clinical characteristics can be good predictors for positive blood culture but they have limited specificity and sensitivity [7. 8]. Neonatal blood culture positive rate have been found to range from 25-54% [
5,
9‐
11]. Rapid immunological techniques like C-Reactive Proteins (CRP) assays may help in the diagnosis of septicemia; however they lack the capacity to detect specific pathogens and are not available in many centers in developing countries [
12]. Blood culture to isolate the offending pathogen remains the gold standard for definitive diagnosis of septicemia [
1,
12] but the results of blood culture takes hours to days, thus necessitating initial empirical treatment of suspected cases. Knowledge of predictors of positive blood culture and anti-microbial susceptibility pattern of common pathogens in a given area is essential in guiding local empirical choice of antibiotics [
12].
At Bugando Medical Centre (BMC) neonatal units' ampicillin and gentamicin are used as the first line empirical treatment, the decision of this regimen is based on research in different units in developed countries. The antimicrobial susceptibility may vary between units and there is increasing resistance rate of gram negative bacteria to ampicillin gentamicin and cefotaxime worldwide; this warrants the availability of local data [
13].
In Tanzania, as in other Sub-Saharan countries the epidemiology of neonatal sepsis has not been extensively studied and therefore to date most of empirical treatments have been formulated using data from developed countries [
1,
5]. Thus this study was done to determine the pattern of neonatal sepsis and the outcome at BMC, Mwanza Tanzania in order to generate local data that will be used for local policy formulation in managing neonatal sepsis. The predictors of positive blood culture and deaths established in the present study are useful to Pediatricians locally and in other centers for aggressive management of neonatal sepsis.
Discussion
This study at BMC neonatal unit shows the prevalence of neonatal sepsis among neonates admitted during study period is about 39%. These findings are consistent with reports from other developing countries and those done in other tertiary hospitals in Tanzania [
9‐
11]; but higher than those reported in developed countries [
1]. The variations between developed countries and developing countries are due to high quality of life and hospital services in developed countries [
1].
In this study the mortality rate of neonatal sepsis was 19% which is similar to that observed in other studies in East Africa region [
11,
12]; this can be explained by relative similar management practices and similar hospital services. Higher mortality rate was observed among neonates with early onset disease although the difference observed was not statistically significant. Among children suspected with neonatal sepsis using clinical criteria 49% were confirmed to have septicemia and no significant difference was observed among neonates with early or late onset sepsis. These findings are similar to those obtained in other studies in Africa which have been found to range from 25-54% [
9,
10,
18]. When the findings are compared to the study in Uganda [
11] in which proven sepsis was 37% among 293 neonates, the difference could be explained by stringent criteria used in the present study.
In the present study clinical characteristics such as inability to feed, cyanosis, lethargy and convulsion were found to be significantly associated with positive blood culture (p < 0.05) in both early and late onset neonatal sepsis, similar findings were observed in other studies [
11,
19]. Hypothermia, maternal fever, umbilical redness and jaundice were also found to be predictors of positive blood culture only among neonates with late onset sepsis whereas increased respiratory rate was significant predictor of positive blood in early onset disease only. These clinical signs and symptoms laid by WHO Young infants study group [
6] could be used in the areas of limited facilities to predict positive blood culture and initiation of proper empirical management.
As in other studies perinatal factors which were strongly found to predict positive blood culture in both early and late onset disease were PROM and meconium stained liquor [
19,
20]. Of neonates with late onset disease positive blood culture rate was significantly higher in those delivered at hospital (p = 0.006). This could partly be explained by type of organisms isolated, most of the isolates in the present study were multiply resistant, possibly hospital acquired infections. Place of delivery had no influence on positive blood culture among neonates with early onset sepsis. There was no control group in the present study and only neonates with blood culture drawn were included in the analysis; this could have caused selection bias in determining the predictors of positive blood culture.
Organisms which were found significantly causing septicaemia in PROM were
Escherichia coli,
Enterobacter spp,
Group B streptococci and
Klebsiella pneumoniae (p < 0.05), this could be due to the ascending infection from perineum and vagina. As in other studies [
2,
20,
21] these pathogens are commonly responsible for early onset disease and this was confirmed in the present study.
In contrast to other studies in developed countries [
22], gram negative bacteria formed majority of the isolates in our study.
Klebsiella pneumoniae was the commonest isolate recovered in the present study. The predominance of an organism causing septicemia in the unit can be due to selective pressure of antibiotics, this has been found to be true with neonatal septicemia due to
Klebsiella pneumoniae [
20]. In our study majority of
Klebsiella pneumoniae were resistant to multiple antibiotics with 49% of these isolates producing extended spectrum beta-lactamases (ESBL).
Escherichia coli were the second commonest gram negative bacteria with majority of them causing early neonatal sepsis and 45.5% were found to be ESBL producer. About 68% of
Klebsiella pneumoniae and
Escherichia coli isolates in the unit were resistant to gentamicin and 90% resistant to ampicillin. This poses challenge in the use of these first line drugs in the management of neonatal sepsis in our setting. In the unit the second choice of treatment is third generation cephalosporins of which more than 49% of gram negative isolates were found to be resistant. High resistance rate of third generation cephalosporins can be contributed by irrational use of these antibiotics in the unit; this can further be supported by low resistance rate of ciprofloxacin, the drug which is not commonly prescribed to neonates and there is no pharmacokinetic information to guide dosing of ciprofloxacin in infants [
4,
23]. About 95% of gram negative enteric bacteria were sensitive to meropenem similar findings have been reported elsewhere [
23]. This drug is expensive and not available in many centers in developing countries, this makes the management of neonatal sepsis due to multi-resistant gram negative bacteria to be difficult in these countries.
Staphylococcus aureus was the second common isolate in this study and the leading among gram positive isolates.
Staphylococcus aureus was significantly recovered in neonates from mothers without PROM (p < 0.05) and it was the commonest isolate in the late onset sepsis. About 28.1% of
Staphylococcus aureus were found to be MRSA and about 91% resistant to penicillin, similar observation was made by Mugalu
et al [
11]. The significant association of late onset disease and
Staphylococcus aureus septicaemia (p = 0.008), could partly be explained by the fact that these organisms are transferred to neonates from health care workers and relatives. In contrast to other studies [
1,
2], gram positive such as Group B Streptococci and
Listeria spp were not commonly isolated in this study. Only two blood cultures were positive for group B streptococci (1.3%) and these were found in early onset sepsis.
Listeria spp was isolated in 5 samples of which 3 were from early onset sepsis.
Different factors were found to contribute to increased mortality rate in the present study. As demonstrated in previous studies the outcome of sepsis is usually determined by duration of inflammatory response to the offending pathogens, with severe and worse outcome in the gram negative sepsis [
18,
24]. Factors which were significantly found to predict deaths in this study were being blood culture positive, isolation of gram negative bacteria, ESBL isolate and MRSA isolate. As in other studies gram negative sepsis has been associated with severe sepsis and increased mortality [
21,
23] and this was confirmed in our study. Routine report of laboratory results gram stain reaction could have significant influence in the management and outcome of the neonatal sepsis in our setting and other setting in developing countries. High mortality rate was observed among neonates infected with ESBL producing organisms in the present study [
21,
23]. In this study as in other few studies no significant difference was observed in mortality among neonates with early or late onset sepsis [
11,
23,
24]. Majority of neonates with multi-resistant organisms died within 72 hrs of initiation of antimicrobials. Relative good survival was demonstrated in neonates with sensitive organisms, more than 80% of them improved after 72 hrs of treatment, this has been reported elsewhere [
23,
25].
Currently there is no guideline to treat neonatal sepsis due ESBL isolates in most centers in the developing countries. In this study high dose of gentamicin in combination with high dose of cefotaxime was used, and in some cases ciprofloxacin was used. Survival rate was 47% among 36 cases, survival was better with ciprofloxacin; than cefotaxime+ gentamicin, twenty neonates survived of which 13/20 (65%) received ciprofloxacin.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
NK participated in collecting specimens, collecting clinical data, treating neonates and processing samples, ER participated in planning, data analysis and manuscript writing, SJ participated in microbiological analysis, DM participated in manuscript writing, SEM participated in design and execution of the work including microbiological procedures, data analysis, interpretation of data and preparation of the manuscript. All authors have read and approved the final manuscript.