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Community-Acquired Bacteremia Among Children Admitted to a Rural Hospital in Mozambique

Sigaúque, Betuel MD*†‡; Roca, Anna MSc, PhD*‡; Mandomando, Inácio DVM*†‡; Morais, Luís DVM*; Quintó, Llorenç MPH; Sacarlal, Jahit MD, MPH*‡§; Macete, Eusébio MD, MPH, PhD*†; Nhamposa, Tacilta MD*†; Machevo, Sónia MD; Aide, Pedro MD*†‡; Bassat, Quique MD*‡; Bardají, Azucena MD, MSc*‡; Nhalungo, Delino MSc*; Soriano-Gabarró, Montse MD, MSc; Flannery, Brendan PhD; Menendez, Clara MD, PhD*‡; Levine, Myron M. MD, DTPH; Alonso, Pedro L. MD, MSc, PhD*‡

Author Information
The Pediatric Infectious Disease Journal: February 2009 - Volume 28 - Issue 2 - p 108-113
doi: 10.1097/INF.0b013e318187a87d
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Abstract

Africa suffers a disproportionate burden of global childhood mortality caused by infectious diseases.1 Early studies indicated the important contribution of bacterial infection to excess morbidity and mortality.2–5 Few health facilities in Africa have microbiologic laboratories to identify invasive bacterial infection. As a result, the clinical importance of bacterial infections and associated mortality is not often recognized. Data on etiologies that could inform prevention strategies are scarce throughout Africa, especially in rural areas where most Africans live.

Randomized controlled trials of conjugate vaccines against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (Pneumococcus) in African children uncovered the substantial vaccine-preventable burden of bacterial disease.6–9 Population-based surveillance coupled with systematic use of blood cultures among hospitalized children in rural Kenya10 and Gambia11 has changed current paradigms regarding leading causes of childhood mortality, elevating the importance of invasive bacterial infection, and need for improved case management and prevention.12 As shown in Kenya,10 HIV infection and malnutrition increase the incidence and severity of invasive bacterial infections, in particular, with pneumococcal infections. The epidemiology of invasive Hib disease is markedly different in countries that have already introduced Hib conjugate vaccines into their national expanded program on immunization.8

Mozambique is a malaria endemic country with high HIV prevalence. To determine the incidence of community-acquired bacteremia in Mozambican children before introduction of Hib conjugate vaccine in the country, we systematically collected and cultured blood samples from children <15 years of age admitted to a rural hospital in southern Mozambique from 2001 to 2006. We describe the public health burden and clinical characteristics of community-acquired bacteremia among hospitalized children in a rural area of Mozambique.

MATERIALS AND METHODS

Study Setting and Population

The study was conducted at the Manhiça district hospital, which is the referral health facility for Manhiça district, a rural area located 80 km north of Maputo in southern Mozambique. The climate of the area is subtropical with 2 distinct seasons: a warm and rainy season between November and April and a cool and dry season during the rest of the year. The mean annual rainfall between 2001 and 2006 was 1200 mm.

The district has an estimated population of 140,000 inhabitants. A full description of the geographic and sociodemographic characteristics of the study community has been presented elsewhere.13 There is perennial malaria transmission, mostly due to Plasmodium falciparum14,15 and high HIV prevalence (23.6%) among pregnant women attending the antenatal clinic.16 The Centro de Investigação em Saúde da Manhiça (CISM) has been running a continuous demographic surveillance system (DSS) in the area since 1996. The DSS population included 35,000 inhabitants in an area of 100km2,13,17 from 1996 until August 2002, when the study area was expanded to include 82,000 inhabitants. In 2002, approximately 17% were children <5 years of age and 26% were children 5–14 years of age.

The national expanded program on immunization calendar in Mozambique includes Bacillus Calmatte Guérin vaccination at birth, oral polio vaccine at birth, 8, 12, and 16 weeks, diphtheria-tetanus-whole cell pertussis-hepatitis B vaccine at 8, 12, and 16 weeks, and measles vaccine at 9 months.18 In 2003, approximately 180 children from the study area, aged 12–24 months (representing 1.6% of children younger than 24 months of age in Manhiça District), received 2 doses of 7-valent pneumococcal conjugate vaccine (Prevenar, Wyeth) and 1 dose of Hib conjugate vaccine (Hiberix, Glaxo-Smith Kline) as part of a malaria vaccine trial.19

The invasive bacterial surveillance system described in this study was included in several study protocols reviewed and approved by the Mozambican National Bioethics Committee and institutional review boards of Hospital Clinic of Barcelona, Spain, the US Centers for Disease Control and Prevention and the University of Maryland School of Medicine.

Patients and Clinical Management

The Manhiça district hospital is a 110-bed hospital with 36 pediatric beds. Since January 1997, the hospital and CISM have jointly operated round-the-clock surveillance of all pediatric visits at the outpatient department and of all hospital admissions.20 During the study period, trained clinical officers or clinicians recorded clinical signs and symptoms observed at admission using standard forms. A thick blood smear for malaria parasites determination was obtained by finger prick from children with axillary temperature ≥37.5°C or reported history of fever within the previous 24 hours. Respiratory rate observed for 1 minute was measured in awake, noncrying children using UNICEF chronometers. Dehydration was diagnosed based on clinical signs including skin turgor, mucosal dryness, sunken eyes, depressed fontanel (only for children <1 year of age), and state of alertness. Blood glucose was measured on admission by finger-prick using Accu-Check Glucometer (Roche). Packed red blood cell volume was also measured. Beginning in 2002, oxyhemoglobin saturation was measured using a digital pulsoximeter (Nellcor). When available, oxygen therapy was given to children with hemoglobin oxygen saturation <94% or according to clinical indication.

According to Mozambican national guidelines,21 empirical antimicrobial therapy was started on admission for children with suspected bacterial infection using parenteral chloramphenicol or a combination of penicillin plus gentamicin. Children <2 months of age and other children with clinical severe malnutrition were treated with ampicillin plus gentamicin. Antibiotic therapy was reassessed based on results of blood cultures. Ceftriaxone was used in cases of multiresistant (defined as resistance to 2 or more no related antibiotics). Blood transfusion was indicated when severe anemia was detected. Patients requiring transfusion were transferred to Maputo Central Hospital when blood supply was not available at Manhiça district hospital.

Bacteriologic Procedures

As part of routine clinical practice at Manhiça district hospital, a single venous blood specimen for bacterial culture was collected before hospital admission for all children <2 years of age and for children 2–14 years with axillary temperature ≥39°C or with any sign of severity,22 including severe clinical malnutrition (defined as kwashiorkor or/and marasmus). Given that more than 90% of admitted children over 2 years of age have any sign of severity, blood cultures were performed for all admitted children except for those with trauma. Approximately 1–3 mL of whole blood was immediately inoculated into 1 pediatric blood culture bottle (Pedibact; Becton-Dickinson, Franklin Lakes, NJ), which was incubated in an automatic BACTEC 9050 system (Becton-Dickinson) for 4 days. Positive blood cultures were examined by Gram stain and subcultured on blood agar, chocolate agar, or MacConkey agar plates according to Gram stain findings. Bacterial isolates were identified according to standard microbiologic procedures as described previously.23,24 Antibiotic susceptibility was determined by disk diffusion for sulfamethoxazole-trimethoprim (cotrimoxazole), chloramphenicol, oxacillin/ampicillin, gentamicin, and erythromycin according to the Clinical Laboratory Standards Institute guidelines.25 For Pneumococcus, penicillin minimum inhibitory concentrations were estimated for oxacillin-resistant strains using E-test strips (AB Biodisk, Solna, Sweden). Nontyphoidal Salmonella (NTS) ampicillin-resistant strains were tested against amoxicillin and clavulanic acid. Isolates with intermediate or full resistance are referred to as nonsusceptible.

Clinical Definitions

A case of community-acquired bacteremia was defined as isolation of pathogenic bacteria in blood from a hospitalized child <15 years of age. Coagulase-negative staphylococci, Corynebacterium spp, Bacillus spp, and Streptococcus viridans were considered contaminants. Fever was defined as axillary temperature ≥37.5°C or a history of fever within 24 hours of admission as reported by the mother/care taker of the child. Age groups were categorized as neonates (≤28 days), infants (29 days–11 months), young children (1–4 years), and older children (5–14 years).

Malaria infection was defined as any asexual parasites in blood smears after observation of 200 leukocytes.26 Anemia was classified as severe if packed red blood cell volume was <25% in neonates or <15% for other ages groups or nonsevere if between 25% and 42% in neonates or 15% and 32% for other ages. Severe malnutrition was defined as weight for age z-score 3 standard deviations or more below the mean27 according to US growth charts.28 Severe hypoglycemia was defined as blood glucose <2.2 mmol/L; 2.3–3.2 mmol/L glucose was classified as nonsevere. Case fatality rate (CFR) was calculated considering children with known outcome at discharge (death or discharged), excluding patients transferred to Maputo Central Hospital or absconded from the hospital.

Statistical Analysis

Questionnaires were double entered in FoxPro (version 2.6, Microsoft Corporation, Redmond, WA) at CISM, and discrepancies in data entry were resolved by referring to the original forms. Statistical analysis was performed using STATA software (version 9.0, STATA Corporation, College Station, TX). Proportions were compared using χ2 tests, and odds ratios and 95% confidence intervals were estimated using logistic regression. Wilcoxon rank-sum tests were used for nonparametric comparisons. Minimum incidence rates of bacteremia and 95% confidence intervals were calculated using Poisson log-likelihood, considering individual time at risk for children residing in the CISM study area excluding periods of migration. Person time was excluded during a lag period of 15 days after each episode of community-acquired bacteremia.

RESULTS

From May 1, 2001 to April 30, 2006, 23,686 children <15 years of age were admitted to the Manhiça district hospital and blood samples were collected for bacterial culture from 84% of these children (fig. 1). Blood stream infections were identified in 8% (1550/19,896) of hospital episodes. Prevalence of bacteremia was 16% (154/952) for hospitalized neonates, 8% (520/6829) for infants 29 days–11 months old, 7% (767/10,591) for children 1–4 years, and 7% (108/1523) for children 5–14 years (P < 0.001). Children <1 year of age accounted for 44% (674/1550) of bacterial isolates and 59% (916/1550) of bacterial isolates were recovered during the 6-month (November through April) rainy season. CFR for children hospitalized with bacteremia was 12% (162/1365) compared with 3% (625/19,539) for hospitalized children without bacteremia (P < 0.001). CFR for bacteremic children was 11% (15/141) for neonates, 13% (59/463) for infants, 11% (73/659) for children 1–4 years, and 15% (15/101) for those 5–14 years (P = 0.616). Children <1 year accounted for 47% (74/162) of deaths among children hospitalized with bacteremia. In addition, 39 (3%) of bacteremic children were transferred to the central Hospital in Maputo and 142 (9%) absconded from hospital. Most community-acquired bacteremia deaths occurred early in admission: 21% (33/162) within the first 24 hours and 24% (39/162) within the following 24 hours. Overall, 21% (162/788) of all deaths registered in Manhiça district hospital during the surveillance period occurred among children with bacteremia.

F1-6
FIGURE 1.:
Study profile. Bacteremia in children admitted to Manhiça hospital, from May 01, 2001 to April 30, 2006.

Pathogens Associated With Bacteremia

Table 1 shows the etiology of community-acquired bacteremia and CFR according to age groups. The most prevalent pathogens isolated from children with community-acquired bacteremia were NTS species; predominantly S. typhimurium 66% (263/401) and S. enteritidis 25% (101/401), followed by Pneumococcus, Staphylococcus aureus, Escherichia coli, and Haemophilus influenzae. The distribution of pathogens was different for neonates: S. aureus and group B Streptococcus were the most prevalent bacteria [42 (39%) and 35 (20%) of 154 bacteremia cases, respectively]. Among 154 community-acquired bacteremia cases in neonates, 43 (28%) occurred among newborns age ≤7 days.

T1-6
TABLE 1:
Bacterial Species Isolated From Children <15 Years of Age Admitted to Manhiça Hospital, According to Age Groups, 2001–2006

The median age for community-acquired bacteremia differed by pathogen: 10 days of age for group B Streptococcus, 5 months for Pseudomonas spp, 17 months for Pneumococcus, and 28 months for meningococcal bacteremia. Case fatality also varied by pathogen, from 6% for S. aureus to 63% for Klebsliella spp (Table 1). Among 162 deaths among bacteremic children, pneumococcus was isolated from 27%, NTS from 26%, and H. influenzae from 14%.

Incidence Rates of Community-Acquired Bacteremia

The incidence of community-acquired bacteremia was calculated among hospitalized children from the surveillance population. There were 622 episodes of community-acquired bacteremia among children <15 years of age living in the DSS area during the study period; 24 children had 2 episodes and 2 children had 3 episodes. Overall incidence was 425 cases per 100,000 child-years. Incidence of pneumococcal bacteremia was 108/100,000 child-years and of NTS was 120/100,000 child-years. Children <1 year of age had the highest incidence (Table 2).

T2-6
TABLE 2:
Incidence of Community-Acquired Bacteremia Among Admitted Children in Manhiça District, Stratified by Age Group

Clinical Characteristics of Children With Community-Acquired Bacteremia

Table 3 compares clinical characteristics of hospitalized children with (n = 1550) and without bacteremia (n = 15,804), excluding episodes for which bacterial contaminations were recovered. Factors associated with bacteremia in univariate analysis included younger age, severe malnutrition, IRR, dehydration, fever, and hypoglycemia. In the multivariate analysis (data not shown), the same variables remained independently associated with bacteremia, including severe anemia which was not significant in univariate analysis. The presence of malaria parasites was inversely associated with bacteremia. The most common admission diagnoses in children with community-acquired bacteremia were malaria (20%), anemia (19%) pneumonia (15%), bacterial sepsis (9%), malnutrition (8%), and acute diarrhea/gastroenteritis (5%). In cases of pneumococcal bacteremia, pneumonia (26%) was the most common diagnosis followed by malaria (17%) and anemia (16%). Of all patients with clinical malaria diagnosis 5% (705/13,544) had bacteremia.

T3-6
TABLE 3:
Comparison of Clinical Characteristics for Admitted Children <15 Years of Age With and Without Bacteremia at Admission to Manhiça Hospital, 2001–2006

Bacteremia and Malnutrition

The prevalence of severe malnutrition among children with bacteremia was high (23%), (Table 4). Admitted children with malnutrition (unadjusted analysis) had a higher risk of developing any bacteremia. Isolates showing statistically increased odds of bacteremia were Pneumococcus, E. coli, H. influenzae, and NTS.

T4-6
TABLE 4:
Odds Ratio for Community-Acquired Bacteremia in Admitted Children With Malnutrion

Antibiotic Susceptibility

Susceptibility of bacterial isolates to the antibiotics most commonly used in Mozambique is shown in Table 5. Pneumococcal isolates were predominantly susceptible to penicillin (89%, 289/326) and chloramphenicol (93%, 356/384), while 44% (158/360) were nonsusceptible to trimethoprim-sulfamethoxazole. No Pneumococcus was fully resistant to penicillin. H. influenzae, E. coli, and NTS displayed high rates of nonsusceptibility to most of antibiotics. Among NST isolates, 74% (300/395) were nonsusceptible to ampicillin, 66% (257/390) to trimethoprim-sulfamethoxazole, and 54% (206/384) to chloramphenicol. In addition, 38% (113/297) of NTS isolates were nonsusceptible to amoxicillin-clavulanic acid (data not shown). S. aureus isolates were 90% (163/182) nonsusceptible to ampicillin and 9% (15/176) to oxacilin.

T5-6
TABLE 5:
Antibiotic Susceptibility of Pathogens Associated With Community-Acquired Bacteremia Among Children <15 Years Admitted to Manhiça Hospital, 2001–2006

DISCUSSION

These results underscore the public health burden of community-acquired bacteremia among children admitted to a rural hospital in southern Mozambique, a malaria endemic area with high prevalence of HIV infection and malnutrition, adding to a growing base of evidence from Africa.10,11,29–31 Community-acquired bacteremia was extremely common. Overall, 1 in 10 hospital admissions and 1 in 5 in-hospital deaths occurred among bacteremic children. Approximately one-fifth of hospitalized neonates were bacteremic at admission. Importantly, neonates had almost 4 times an increased risk of bacteremia than older children. Incidence of community-acquired bacteremia and case fatality among hospitalized bacteremic children were extremely high among children <1 year of age.

The most predominant bacterial isolates among hospitalized children were NTS and Pneumococcus. These 2 pathogens, along with H. influenzae, were the most common causes of death. The relative importance of each pathogen changed with age; S. aureus was the most frequent among neonates, NTS among children aged 1–5 years, and Pneumococcus in children older than 5 years of age. The predominant etiologies found in our study are consistent with results from 2 other studies conducted in Africa10,32 before the implementation of Hib vaccination, although there seems to be geographic variation in the frequency and etiologies of bacteremia compared with other studies.30,33 CFR among hospitalized children with bacteremia was 4 times higher than mortality for hospitalized children without bacteremia.10,32 However, CFR in our study (12%) were lower than found in rural Kenya (28%)10 and urban Malawi (38%).32 If we assume that children with unknown outcome (including transferred or absconded from the hospital) had outcomes similar or worse than those with known outcome, case fatality would range from 10% to 22%. In the univariate analysis, CFR varied by etiologic agent but did not show significant variation by age. Three pathogens (Pneumococcus, NTS, and H. influenzae) were associated with more than two-thirds of all deaths among bacteremic children.

Severe malnutrition has been strongly associated with bacteremia in all population-based surveillance studies in Africa.10,30,32,34 Malnutrition prevalence was as high as 23% among our pediatric admissions with bacteremia, and was associated with a variety of pathogens. HIV testing was not part of routine clinical care at Manhiça district hospital during the study period, so the association between HIV-infection and bacteremia in this setting could not be evaluated. Among pregnant women attending the antenatal clinic in Manhiça, HIV prevalence was high, 23.6% between the years 2003 and 2005.16 As expected, malaria parasitemia was less frequent among children with bacteremia as the most prevalent clinical diagnostic for the rest of admissions is malaria. Still, almost half of the bacteremic admissions had malaria coinfection. The high prevalence of coinfection with bacterial pathogens and malaria parasites is important for proper inpatient clinical management.35

Resistance of the most prevalent bacterial pathogens to the most common antibiotics used in Mozambique raises concern about effectiveness of antibiotic treatment, particularly for cotrimoxazole. Many isolates of H. influenzae, NTS, and E. coli were resistant to all antibiotics tested. Implications of changing first line antibiotic treatment should be evaluated in Mozambique, including economic implications for the national health system.

Several factors should be considered when interpreting incidence estimates based on systematic use of blood cultures. Blood cultures have low sensitivity for bacterial infection. Follow-up blood cultures in patients with high fever may increase sensitivity, but only a single blood specimen was collected upon admission in this study. This might have higher implications in young infants to whom the sample collection is more difficult, and therefore, the amount of blood to be collected tends to be lower. Secondly, more than half of pediatric deaths in this community occur at home (Sacarlal et al, unpublished data). Because many children with severe or fatal bacterial infections may not present to hospital, incidence rates of community-acquired bacteremia in this study are minimal estimates.

The high incidence rates, antibiotic resistance, and mortality associated with community-acquired bacteremia in Mozambican children underscore the need for prevention. Existing vaccines against Hib and Pneumococcus disease could reduce the incidence of community-acquired bacteremia. Improvements in clinical management are also needed. Mozambique has been approved by the GAVI Alliance for support to introduce vaccination against Hib disease, and the introduction of pneumococcal conjugate vaccines would have an even higher impact in terms of prevention of disease burden and mortality.

ACKNOWLEDGMENTS

The authors thank Emili Letang, Madalena Ripinga, and Mariano Sitaúbe for their clinical and laboratory support. The authors also thank other clinicians and nursing staff from CISM and Manhiça district hospital for collecting and processing data, Anne Schuchat for her input, and Christopher Pell for editing in the initial versions of the manuscript. The authors finally thank the district health authorities for their collaboration in the research activities ongoing in the Manhiça district.

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Keywords:

community-acquired bacteremia; incidence; mortality; antibiotic-resistance; Mozambique

© 2009 Lippincott Williams & Wilkins, Inc.