Antimicrobial prophylaxis to prevent surgical site infections in a rural sub-Saharan hospital.

A prospective cohort study was performed to collect baseline data concerning surgical site infections (SSIs) and antimicrobial prophylaxis (AMP) in a remote sub-Saharan district hospital. The SSI rate of 22% was high. Most (88%) of the patients received prophylaxis after incision, and only 5% within the 30-min period before incision. Of all pathogens isolated from SSIs, 60% were resistant to the agent administered. The antibiotics given most frequently were chloramphenicol (60%), aminopenicillins (23%) and benzylpenicillin (15%). Staphylococcus aureus (36%), Escherichia coli (5%) and enterococci (4%) were the pathogens isolated most commonly from SSIs.

Anaemia during pregnancy in southern Tanzania.

Anaemia in pregnancy is associated with maternal morbidity and mortality and is a risk factor for low birth-weight. Of 507 pregnant women recruited in a community, cross-sectional study in southern Tanzania, 11% were severely anaemic (<8 g haemoglobin/dl). High malarial parasitaemia [odds ratio (OR)=2.3] and iron deficiency (OR=2.4) were independent determinants of anaemia. Never having been married (OR=2.9) was the most important socio-economic predictor of severe anaemia. A subject recruited in the late dry season was six times more likely to be severely anaemic than a subject recruited in the early dry season. Compared with the women who were not identified as severely anaemic, the women with severe anaemia were more likely to present at mother-and-child-health (MCH) clinics early in the pregnancy, to seek medical attention beyond the MCH clinics, and to report concerns about their own health. Pregnancy-related food taboos in the study area principally restrict the consumption of fish and meat. Effective anti-malaria and iron-supplementation interventions are available but are not currently in place; improvements in the mechanisms for the delivery of such interventions are urgently required. Additionally, opportunities for contacting the target groups beyond the clinic environment need to be developed.

Cholera outbreak in southern Tanzania: risk factors and patterns of transmission.

To identify risk factors and describe the pattern of spread of the 1997 cholera epidemic in a rural area (Ifakara) in southern Tanzania, we conducted a prospective hospital-based, matched case- control study, with analysis based on the first 180 cases and 360 matched controls. Bathing in the river, long distance to water source, and eating dried fish were significantly associated with risk for cholera. Toxigenic Vibrio cholerae O1, biotype El Tor, serotype Ogawa, was isolated in samples from Ifakara's main water source and patients' stools. DNA molecular analyses showed identical patterns for all isolates.

Diarrhea in children under 5 years of age from Ifakara, Tanzania: a case-control study.

A matched case-control study was conducted in the Maternal and Child Health Clinic (MCH) in Ifakara, Tanzania, during the rainy season in order to elucidate the risk factors for and etiology of diarrheal diseases in children under 5 years of age. Cases (103) and controls (206) were matched for sex and age group. Precoded questionnaires with demographic details, clinical history, and physical signs were completed. Stools samples were collected for bacterial, parasitological, and viral studies. A high number of siblings (odds ratio [OR], 0.86; P = 0.027), the number of siblings surviving (OR, 0.82; P = 0.007), the birth order (OR, 0.85; P = 0.018) and the distance from the house to the water source (OR, 0.33; P = 0.011) were associated with the risk of diarrhea. There were high rates of enteropathogen isolates in stool samples from children without diarrhea (52.23%). Shigella species were the only enteropathogen statistically related with diarrhea (OR, 2.90; P < 0.029). Enterotoxigenic, enteropathogenic, and enteroaggregative strains of Escherichia coli were not related with diarrhea, and neither were Giardia lamblia or Salmonella species.

Humoral immune responses during a malaria vaccine trial in Tanzanian infants.

The development of a malaria vaccine is a priority for improved and sustained malaria control. Optimal use of a vaccine in Africa will only be achieved if it can be delivered through the Expanded Programme of Immunization (EPI). We have completed a trial of the peptide vaccine SPf66 in Tanzanian infants, given alongside the EPI vaccines. This paper describes the humoral responses to SPf66 and the EPI vaccines. A total of 1207 infants were recruited into a two-arm, double-blind, individually randomized placebo-controlled trial of SPf66. The objectives of the trial were to determine the safety, immunogenicity and efficacy of SPf66 and to assess interactions with EPI vaccines when three doses of SPf66 were delivered alongside the EPI vaccines. Cross-sectional surveys were carried out to asses seroconversion rates to the EPI vaccines and the antibody response to SPf66 (NANP)50 and Plasmodium falciparum lysates. Seroconversion rates to EPI vaccines were high and no statistically significant differences in prevalence or titres were found between SPf66 and placebo recipients. IgG antibodies against SPf66 (NANP)50 and whole P. falciparum lysate were present in high titres in mothers of recruited children at the time of birth. Vaccination with SPf66 stimulated a good anti-SPf66 IgG response which declined to preimmunization levels by 2 years of age and which was not associated with protection against clinical malaria. The vaccine induced no IgG antibodies against (NANP)50 or P. falciparum lysates. SPf66 stimulated a humoral immune response when given to very young infants and did not interfere with seroconversion to EPI vaccines. The response to SPf66 was qualitatively different from that seen in older children, in whom SPf66 has been shown to be moderately efficacious. This difference raises concerns about the difficulties of immunizing very young infants who need to be targeted by antimalarial vaccination programs.

Antimicrobial resistance of diarrheagenic Escherichia coli isolated from children under the age of 5 years from Ifakara, Tanzania.

Diarrhea caused by multidrug-resistant bacteria is an important public health problem among children in developing countries. The prevalence and antimicrobial susceptibility of diarrheagenic Escherichia coli in 346 children under 5 years of age in Ifakara, Tanzania, were studied. Thirty-eight percent of the cases of diarrhea were due to multiresistant enterotoxigenic E. coli, enteroaggregative E. coli, or enteropathogenic E. coli. Strains of all three E. coli categories showed high-level resistance to ampicillin, tetracycline, co-trimoxazole, and chloramphenicol but were highly susceptible to quinolones. Guidelines for appropriate use of antibiotics in developing countries need updating.

Typing and characterization of mechanisms of resistance of Shigella spp. isolated from feces of children under 5 years of age from Ifakara, Tanzania.

Eighty-six strains of Shigella spp. were isolated during the dry season from stool samples of children under 5 years of age in Ifakara, Tanzania. The epidemiological relationship as well as the antimicrobial susceptibility and mechanisms of resistance to ampicillin, chloramphenicol, and co-trimoxazole were investigated. Four different epidemiological tools, pulsed-field gel electrophoresis (PFGE), repetitive extragenic palindromic (REP)-PCR, plasmid analysis, and antibiogram, were compared for typing Shigella strains. Seventy-eight (90%) strains were Shigella flexneri and were distributed into four groups, by either PFGE or REP-PCR, with 51, 17, 7, and 3 strains. The four strains of Shigella dysenteriae belonged to the same group, and the four strains of Shigella sonnei were distributed in two groups with three and one strain each. Plasmid analysis showed a high level of heterogeneity among strains belonging to the same PFGE group, while the antibiogram was less discriminative. REP-PCR provided an alternative, rapid, powerful genotyping method for Shigella spp. Overall, antimicrobial susceptibility testing showed a high level of resistance to ampicillin (81.8%), chloramphenicol (72.7%), tetracycline (96.9%), and co-trimoxazole (87.9%). Ampicillin resistance was related to an integron-borne OXA-1-type beta-lactamase in 85.1% of the cases and to a TEM-1-type beta-lactamase in the remaining 14.8%. Resistance to co-trimoxazole was due to the presence of a dhfr Ia gene in all groups except one of S. flexneri, where a dhfr VII gene was found within an integron. Chloramphenicol resistance was associated in every case with positive chloramphenicol acetyltransferase activity. All strains were susceptible to nalidixic acid, ciprofloxacin, ceftazidime, cefotaxime, and cefoxitin. Therefore, these antimicrobial agents may be good alternatives for the treatment of diarrhea caused by Shigella in Tanzania.

African children with malaria in an area of intense Plasmodium falciparum transmission: features on admission to the hospital and risk factors for death.

Malaria remains the most important parasitic cause of mortality in humans. Its presentation is thought to vary according to the intensity of Plasmodium falciparum transmission. However, detailed descriptions of presenting features and risk factors for death are only available from moderate transmission settings. Such descriptions help to improve case management and identify priority research areas. Standardized systematic procedures were used to collect clinical and laboratory data on 6,624 children admitted to hospital over a 1-year period in an intensely malarious part of Tanzania. Frequencies of signs and symptoms were calculated and their association with a fatal outcome was assessed using multivariate logistic regression. There were 72 deaths among 2,432 malaria cases (case fatality rate [CFR] = 3.0%); 44% of the cases and 54% of the deaths were in individuals less than 1 year of age. There was no association between level of parasitemia and CFR. Increased risk of dying was independently found in all children with hypoglycemia (odds ratio [OR] = 6.7, 95% confidence interval [CI] = 3.9-11.7), in children 1-7 months of age with tachypnea (OR = 8.8, 95% CI = 2.6-30.5) and dehydration (OR = 5.0, 95% CI = 1.9-14.2), and in children 8 months to 4 years of age with chest indrawing (OR = 4.7, 95% CI = 2.0-11.2) and inability to localize a painful stimulus (OR = 6.9, 95% CI = 2.9-16.5). Children in the bottom quartile of weight-for-age were more likely to die (OR = 2.1, 95% CI = 1.3-3.5). Eight percent of the malaria cases had severe anemia (packed cell volume < 15%) but 24% received a blood transfusion. The epidemiology of malaria disease may be more complex than previously thought. Improved case management in a wide variety of health facilities may result from adequate identification and treatment of dehydration and hypoglycemia. Transfusion-requiring anemia is a major problem and sustainable, effective preventive measures are urgently needed.

Evaluation of the SPf66 vaccine for malaria control when delivered through the EPI scheme in Tanzania.

BACKGROUND: Malaria control programmes need to protect young children, who bear the brunt of malaria disease and death in Africa. The development of a vaccine is a priority if improved and sustained malaria control is to be achieved. The best use of a vaccine in Africa will be achieved if it can be delivered through the expanded programme of immunization (EPI). We conducted a trial designed to evaluate the efficacy of SPf66 vaccine for malaria control when delivered through the EPI scheme in Tanzania. METHODS: The study was a two-arm, double blind, individually randomized placebo controlled trial involving 1207 infants. The primary objective of the trial was to estimate the efficacy of three doses of SPf66 given at 1, 2 and 7 months of age in preventing clinical episodes of malaria. These were documented through a health facility-based passive case detection system. RESULTS: Among 1207 randomized children, overall compliance for third dose was 91%. SPf66 was safe, immunogenic and did not interfere with the humoral immune responses to EPI vaccines. There were 294 children among SPf66 recipients and 288 among placebo recipients with at least one malaria episode, yielding a vaccine efficacy estimate of 2% (95% CI: -16, 16; P = 0.84). CONCLUSION: This has been the first trial of a malaria vaccine among very young infants. It provides information on the safety of peptide vaccines administered at this early age as well as their capacity to induce immune responses without negatively interacting with EPI vaccines. Given the modest protection previously documented in older age groups and the lack of efficacy in younger infants, this vaccine in its current alum-based formulation does not appear to have a role in malaria control in sub-Saharan Africa. The lack of efficacy found in this trial also raises concerns about potential difficulties of inducing protective immune responses against malaria through immunization in infants.

Safety in infants of SPf66, a synthetic malaria vaccine, delivered alongside the EPI.

The most likely mechanism to deliver a malaria vaccine in African countries is through the Expanded Program of Immunization (EPI). So far only SPf66, a multistage synthetic peptide, has shown any evidence of protection in Phase III field trials. In Tanzania, SPf66 reduced the risk of clinical malaria by 31% in children aged 1-5 years. In order to progress in the critical path of vaccine development and testing towards the implementation of a new vaccine in malaria control programs, we carried out a randomized double-blind placebo controlled efficacy trial of SPf66 when given alongside the EPI scheme. Monitoring of safety and reactogenicity during this trial included detailed clinical and laboratory assessments on 98 infants and assessment of adverse effects within 1 h of vaccination for all 1207 children vaccinated. Surveillance systems monitored attendances as outpatients, admissions to hospital and fatal events in the community. No serious adverse effects were detected more frequently amongst SPf66 recipients compared to placebo. This first assessment in very young infants of a synthetic vaccine provides evidence of a good safety profile.

Antibodies against Plasmodium falciparum vaccine candidates in infants in an area of intense and perennial transmission: relationships with clinical malaria and with entomological inoculation rates.

Serum immunoglobulin (Ig)G1, IgG3 and total IgG were assessed by immunoabsorbent assay in 198 infants from a Tanzanian village highly endemic for Plasmodium falciparum. Antibodies were measured against epitopes of the circumsporozoite protein (the repetitive epitope (NANP)50 and a construct of the flanking regions (CS27IC)), the malaria vaccine SPf66, and two constructs of the merozoite surface protein-1 (MSP-1), a 19-kDa fragment from the C-terminal domain (MSP-119) and an N-terminal fragment spanning blocks 1-6 (H6-p190 M-1/6-H6). IgG1 and total IgG titres showed similar age profiles, all decreasing for the first 2 months of life. Anti-(NANP)50 titres remained very low throughout the first year of life, while anti-CS27IC antibody appeared to peak around 7 months of age. Only a slight tendency to increase with age was observed for levels of the other antibodies studied. IgG3 titres except for H6-p190(1/6), were very low initially and remained very low throughout the first year of life. Clinical malaria incidence at the village dispensary was analysed prospectively in relation to antibody. No IgG1 or total IgG titre showed protective effects, but low IgG3 against p190(1/6) appeared to be a risk factor in some age groups. Given the large number of antibodies tested, this single indication of possible protection could merely be chance. There were no strong associations between antibody titres and entomologically assessed sporozoite exposure suggesting that transmission-reducing interventions may have little effect on antibody levels in such children.

Immune responses to Plasmodium falciparum antigens during a malaria vaccine trial in Tanzanian children.

Among Tanzanian children living in an area of intense and perennial malaria transmission, prevalence of naturally acquired IgG antibodies that recognize SPf66, NANP, p190 and a 19 kDa fragment of the merozoite surface protein-1 (MSP-1) is high and increases with age. This possibly reflects the high level of natural exposure of the children to P. falciparum. The prevalences of IgG antibodies that recognize the three putative merozoite derived sequences contained in the malaria vaccine SPf66 (83.1, 55.1 and 35.1) is low but also show some age dependence. Three doses of the SPf66 vaccine induce a strong IgG antibody response against both the SPf66 construct, NANP and the three individual peptides. Vaccination with SPf66 did not result in an increase of anti19 kDa fragment antibodies. This reflects the specificity of the humoral immune response induced by the SPf66 construct. Among vaccinated children, antibody titres against SPf66 decreased over time following the third dose. However, 18 months after the third dose, SPf66 recipients still had significantly higher IgG titres and stimulation indices of peripheral blood mononuclear cells (PBMC) than placebo recipients. Within the vaccine group, there is a trend for increasing anti-SPf66 IgG titre to be associated with decreasing risk of clinical malaria but this was not statistically significant. Results also show the difficulties of establishing whether antibody responses are related to protection in field trials in endemic areas.

Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants.

BACKGROUND: Malaria and anaemia, especially that due to iron deficiency, are two leading causes of morbidity worldwide. Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas. We undertook a randomised comparison of different strategies for control of anaemia and malaria in infants, including an assessment of the effect of iron supplementation on malaria susceptibility. METHODS: 832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October, 1995, were randomly assigned to group DI, receiving daily oral iron (2 mg/kg daily) plus weekly Deltaprim (3.125 mg pyrimethamine plus 25 mg dapsone); group IP, receiving iron plus weekly placebo; group DP, receiving daily placebo plus weekly Deltaprim; or group PP. supplementation was given from 8 to 24 weeks of age, and the weekly chemoprophylaxis from 8 to 48 weeks. The frequency of severe anaemia (packed-cell volume < 25%) and malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys. FINDINGS: The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron (0.62 vs 0.87 cases per person-year; protective efficacy 28.8% [95% CI 6.3-45.8). Iron supplementation had no effect on the frequency of malaria (0.87 vs 1.00 cases per person-year; protective efficacy 12.8% [-12.8 to 32.5]). The groups that received malaria prophylaxis had lower frequencies of both severe anaemia (0.45 vs 1.04 episodes per person-year; protective efficacy 57.3% [43.0-67.9]) and malaria (0.53 vs 1.34 episodes per person-year; protective efficacy 60.5% [48.2-69.9]) than the groups that did not receive prophylaxis. After the end of the intervention period, children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups (relative risks 2.2 [1.3-3.7] and 1.8 [1.3-2.6]). INTERPRETATION: Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity. Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria. Our findings support iron supplementation of infants to prevent iron-deficiency anaemia, even in malaria-endemic areas.

PIP: The impact of iron supplementation and malaria chemoprophylaxis was investigated in a double-blind, placebo-controlled study involving 832 infants born in a malaria-hyperendemic area of Tanzania in 1995. Infants were randomly assigned to receive daily oral iron (2 mg/kg) and weekly Deltaprim (3-125 mg pyrimethamine plus 25 mg dapsone), daily iron plus weekly placebo, or daily and weekly placebo. Daily supplementation was provided from 8 to 24 weeks of age, while weekly chemoprophylaxis was given from 8 to 48 weeks. The 2 groups that received iron supplementation had a lower frequency of severe anemia (packed cell volume under 25%) than those who received placebo (0.62 versus 0.87 cases per person-year; protective efficacy, 28.8%), but iron supplementation did not have a significant effect on malaria incidence (0.87 versus 1.00 cases per person-year; protective efficacy, 12.8%). Infants who received malaria prophylaxis had lower frequencies of both severe anemia (0.45 versus 1.04 episodes per person-year; protective efficacy, 57.3%) and malaria (0.53 versus 1.43 episodes per person-year; protective efficacy, 60.5%) than those who received placebo. However, after the end of the intervention period, children who had received malaria prophylaxis had higher rates of severe anemia and malaria than those in the non-chemoprophylaxis groups (relative risks, 2.2 and 1.8, respectively). These findings indicate that malaria chemoprophylaxis during the first year of life can impair the development of natural immunity, while iron supplementation effectively prevents severe anemia without increasing susceptibility to malaria.

MRP 8/14 as marker for Plasmodium falciparum-induced malaria episodes in individuals in a holoendemic area.

Presence of Plasmodium falciparum parasites in the peripheral blood of patients in a holoendemic area does not necessarily show that their illness is due to malaria. The aim of the present project was therefore to look for biological markers related to symptomatology or clinical events during a malaria episode. We focused our work on a complex of heterodimeric calcium-binding proteins secreted by stimulated neutrophils and monocytes, named MIF or myeloid-related proteins (MRP 8/14). In a longitudinal study including 51 adults from Ifakara, Tanzania (84.7% prevalence for P. falciparum in adults during the study), the level of MRP 8/14 in the serum was significantly related to the parasite load (Spearman correlation coefficient, 0.52; P < 0.0001). In the serum from children up to 6 years admitted at a health post the MRP 8/14 levels were closely related to parasitemia but also to fever episodes (Spearman correlation coefficients, 0.96 and 0.736; P < 0.0001 and P < 0.001, respectively). Although not specific to malaria, the measurement of MRP 8/14 could be an additional tool in assessing malaria-related morbidity.

The role of low level Plasmodium falciparum parasitaemia in anaemia among infants living in an area of intense and perennial transmission.

Children under one year of age in an area of intense and perennial Plasmodium falciparum transmission were followed up for one year to establish to what extent chronic, low parasitaemia was associated with severe anaemia. There was a significant increase in the prevalence of anaemia (PCV < or = 25%) with increase in parasite density. PCV levels were related not only to concurrent parasite density but also decreased with densities measured one month previously. At any point in time, the mean PCV level in infants with low parasitaemia (< 1000 parasites/microliter) was higher than that of infants with intermediate (1000-9999/microliter) and high parasite densities (> or 10000/microliter). After the age of 7 months, infants with low parasite densities tend to recover, probably as a result of developing immunity. At the age of 12 months, they have similar PCV levels to infants with no detectable parasitaemia by microscopy. The maintenance of low parasite density appears crucial to the survival of infants in malaria endemic areas. The findings suggest that interventions which lower parasite densities in areas of intense transmission reduce the development of severe malarial anaemia and thus malaria-related mortality and morbidity in infants.

Plasmodium falciparum malaria in the first year of life in an area of intense and perennial transmission.

A longitudinal study of Plasmodium falciparum malaria in infants in Idete village, south-eastern Tanzania, was conducted over a period of 14 months in order to determine the incidence of P. falciparum infection and clinical malaria in the first year of life. Of 1356 blood slides from cross-sectional surveys, 52.1% were positive for asexual stages of P. falciparum. There were marked increases in P. falciparum prevalence, parasite densities, overall fever incidence and the incidence of malaria fevers with age for the first 6 months of life. The average attack rate, estimated from a reversible catalytic model, was 0.029 per day with a slight increase with age but there was no initial period of protection against infection in neonates. Estimated average duration of infections was 64 days, with infections in older infants lasting much longer than those contracted during the first 2 months of life. These results support the hypotheses that the main effect of passively transferred maternal immunity to malaria is in the control of asexual stage parasites, and that the level of clinical immunity depends upon the extent of recent exposure to parasites. Infants as young as 4 months of age are at high risk of clinical attacks. Intervention programmes against malaria in areas of the highest transmission should therefore be designed to include this group.