trimethoprim--sulfamethoxazole-drug-combination and Malnutrition

Undernutrition in childhood is estimated to cause 3.1 million child deaths annually through a potentiating effect on common infectious diseases, such as pneumonia and diarrhea. In turn, overt and subclinical infections, and inflammation, especially in the gut, alter nutrient intake, absorption, secretion, diversion, catabolism, and expenditure.. A narrative overview of the current understanding of infections, inflammation, and antimicrobials in relation to childhood malnutrition.. Searches for pivotal papers were conducted using PUBMED 1966-January 2013; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field.. Although the epidemiological evidence for increased susceptibility to life-threatening infections associated with malnutrition is strong, we are only just beginning to understand some of the mechanisms involved. Nutritional status and growth are strongly influenced by environmental enteric dysfunction (EED), which is common among children in developing countries, and by alterations in the gut microbiome. As yet, there are no proven interventions against EED. Antibiotics have long been used as growth promoters in animals. Trials of antibiotics have shown striking efficacy on mortality and on growth in children with uncomplicated severe acute malnutrition (SAM) or HIV infection. Antibiotics act directly by preventing infections and may act indirectly by reducing subclinical infections and inflammation. We describe an ongoing multicenter, randomized, placebo-controlled trial of daily cotrimoxazole prophylaxis to prevent death in children recovering from complicated SAM. Secondary outcomes include growth, frequency and etiology of infections, immune activation and function, the gut microbiome, and antimicrobial resistance. The trial is expected to be reported in mid-2014.. As well as improving nutritional intake, new case management strategies need to address infection, inflammation, and microbiota and assess health outcomes rather than only anthropometry.

Topics: Animals; Anti-Infective Agents; Child, Preschool; Humans; Infant; Infection Control; Infections; Inflammation; Intestines; Kenya; Malnutrition; Microbiota; Nutritional Status; Randomized Controlled Trials as Topic; Trimethoprim, Sulfamethoxazole Drug Combination

To evaluate the prognostic value of selected laboratory and growth markers on the short-term risk of mortality in untreated HIV-infected children in resource-limited settings.. A meta-analysis of individual longitudinal data on children aged 12 months onwards from 10 studies (nine African, one Brazilian in the 3Cs4kids collaboration).. The risk of death within 12 months based on age and the most recent measurements of laboratory and growth markers was estimated using Poisson regression models, adjusted for cotrimoxazole prophylaxis use and study effects.. A total of 2510 children contributed 357 deaths during 3769 child-years-at-risk, with 81% follow-up occurring after start of cotrimoxazole. At first measurement, median age was 4.0 years (interquartile range, 2.2-7.0 years), median CD4% was 15% and weight-for-age z-score -1.9. CD4% and CD4 cell count were the strongest predictors of mortality, followed by weight-for-age and haemoglobin. After adjusting for these markers, the effects of total lymphocyte count and BMI-for-age were relatively small. Young children who were both severely malnourished and anaemic had high mortality regardless of CD4 values, particularly those aged 1-2 years. By contrast, high CD4% or CD4 cell count values predicted low mortality level amongst either children older than 5 years or those younger with neither severe malnutrition nor anaemia.. CD4 measurements are the most important indicator of mortality and wider access to affordable tests is needed in resource-limited settings. Evaluation of antiretroviral initiation in children also needs to consider weight-for-age and haemoglobin. Prevention and treatment of malnutrition and anaemia is integral to HIV paediatric care and could improve survival.

Topics: Africa; Anemia; Anti-Retroviral Agents; Biomarkers; Brazil; CD4 Lymphocyte Count; Child; Child Mortality; Child, Preschool; Hemoglobins; HIV; HIV Infections; Humans; Malnutrition; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Weight Loss

Childhood malnutrition affects physiology and development. It increases infection rates, which may not present clinical signs in severe cases. The World Health Organization recommends prophylactic treatment with cotrimoxazole (SXT) and nutritional recovery to overcome this issue. This treatment is controversial, since evidence of a reduction in morbidity and mortality is not a consensus and could induce the development of antibiotic-resistant bacteria. Moreover, the impact of using this wide-spectrum antibiotic on gut microbiota in a critical period of development, and weakness is unknown. To understand how SXT prophylaxis could affect gut microbiota in undernutrition, we induced protein-energy undernutrition (PEU) in weaning C57BL/6 mice for three weeks and treated animals with SXT for two weeks. Using 16S rRNA gene sequencing, we compared the taxonomic composition and metabolic pathways of control mice, animals submitted to undernutrition (UND), treated with SXT, or undernourished and SXT treated (UND + SXT). We identified that UND mice had a significant increase in predicted pathways related to metabolic syndromes later in life. The prophylactic SXT treatment alone resulted in a significant loss in community richness and beta diversity. Furthermore, we identified the reduction of three genera in SXT treated mice, including the butyrate producers

Topics: Animals; Anti-Bacterial Agents; Dysbiosis; Malnutrition; Mice; Mice, Inbred C57BL; RNA, Ribosomal, 16S; Trimethoprim, Sulfamethoxazole Drug Combination

We describe tuberculosis (TB) disease among antiretroviral treatment (ART) eligible children living with HIV (CLHIV) in South Africa to highlight TB prevention opportunities.. In our secondary analysis among 0- to 12-year-old ART-eligible CLHIV in five Eastern Cape Province health facilities from 2012 to 2015, prevalent TB occurred 90 days before or after enrollment; incident TB occurred >90 days after enrollment. Characteristics associated with TB were assessed using logistic and Cox proportional hazards regression with generalized estimating equations.. Of 397 enrolled children, 114 (28.7%) had prevalent TB. Higher-income proxy [adjusted odds ratio (aOR) 1.8 [95% confidence interval (CI) 1.3-2.6] for the highest, 1.6 (95% CI 1.6-1.7) for intermediate]; CD4+ cell count <350 cells/µl [aOR 1.6 (95% CI 1.1-2.2)]; and malnutrition [aOR 1.6 (95% CI 1.1-2.6)] were associated with prevalent TB. Incident TB was 5.2 per 100 person-years and was associated with delayed ART initiation [hazard ratio (HR) 4.7 (95% CI 2.3-9.4)], malnutrition [HR 1.8 (95% CI 1.1-2.7)] and absence of cotrimoxazole [HR 2.3 (95% CI 1.0-4.9)]. Among 362 children with data, 8.6% received TB preventive treatment.. Among these CLHIV, prevalent and incident TB were common. Early ART, cotrimoxazole and addressing malnutrition may prevent TB in these children.. We describe tuberculosis (TB) in children living with HIV (CLHIV) eligible for HIV treatment in South Africa to highlight opportunities to prevent TB.. We analyzed additional data from our original study of CLHIV who were 0–12 years old and due to start HIV treatment in five health facilities in Eastern Cape Province from 2012 to 2015 and assessed characteristics associated with existing and new TB.. Of 397 enrolled children, 114 (28.7%) had existing TB. Children with a higher measure of household income had higher odds of existing TB. CD4+ cell count <350 cells/µl and malnutrition were also associated with existing TB. There were 5.2 new cases of TB for every 100 child-years. New TB was 4.7 times more likely for children with delayed HIV treatment start, 1.8 times more likely for children with malnutrition and 2.3 times more likely for children who did not get cotrimoxazole. Among 362 children with data, 8.6% received treatment to prevent TB.. Among these CLHIV, existing and new TB were common. Early HIV treatment, cotrimoxazole and addressing malnutrition may prevent TB in these children.

Topics: Anti-Retroviral Agents; CD4 Lymphocyte Count; Child; Child, Preschool; HIV Infections; Humans; Incidence; Infant; Infant, Newborn; Malnutrition; Prevalence; South Africa; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis

Severe malnutrition is a complex condition that increases susceptibility to infections. Thus, drugs are extensively used in malnutrition cases. In the present study, we assessed the mutagenic effects of combined trimethoprim and sulfamethoxazole (TMP-SMX) treatment in undernourished (UN) and well-nourished (WN) rats. Six-week-old UN and WN Han-Wistar rats were treated with TMP-SMX at a daily dose of 10 mg/kg/d TMP and 50 mg/kg/d SMX for 5 or 10 days. Blood was collected from the tail vein one day before (day -1) and 15, 30, and 45 days after TMP-SMX administration. The Pig-a mutant frequencies (MFs) in peripheral blood reticulocytes (RETs) and erythrocytes (RBCs) were measured through flow cytometry. Severe malnutrition increased the basal MFs in RETs (RET CD59-) and RBC (RBCs CD59-). These findings support the hypothesis that severe malnutrition is mutagenic even in the absence of exposure to an exogenous mutagen. UN and WN rats treated for 5 or 10 consecutive days with TMP-SMX had significantly increased and sustained Pig-a mutant frequencies, demonstrating the mutagenic effects of this drug.

Topics: Animals; Erythrocytes; Flow Cytometry; Malnutrition; Membrane Proteins; Mutagenicity Tests; Rats; Rats, Wistar; Reticulocytes; Trimethoprim, Sulfamethoxazole Drug Combination

Early mortality and morbidity remain high in children initiating antiretroviral therapy (ART), especially in sub-Saharan Africa. Many children still present with advanced human immunodeficiency virus (HIV) disease. Tuberculosis, pneumonia, and severe bacterial infections are the main causes of hospital admission in HIV-infected children. In contrast to adults with advanced HIV disease, cryptococcal disease is not common in childhood, although there is a peak in infancy and adolescence. Interventions such as TB screening in symptomatic children, and isoniazid and cotrimoxazole prophylaxis should be implemented. There is evidence suggesting that rapid initiation (within 1 week) of ART in children with severe malnutrition or those with advanced HIV disease admitted to hospital is not beneficial and should be delayed until their condition has been stabilized. Research informing the prevention of severe bacterial infections, the management of pediatric immune reconstitution inflammatory syndrome, and other potential strategies to decrease morbidity and mortality in HIV-infected children are urgently needed.

Topics: Adolescent; Africa South of the Sahara; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bacterial Infections; Child; Child, Hospitalized; Child, Preschool; HIV Infections; Humans; Infant; Isoniazid; Malnutrition; Mass Screening; Morbidity; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis

Information on antiretroviral therapy (ART) use in HIV-infected children with severe malnutrition (SM) is lacking. We investigated long-term ART outcomes in this population.. Children enrolled in the TREAT Asia Pediatric HIV Observational Database who had SM (weight-for-height or body mass index-for-age Z score less than -3) at ART initiation were analyzed. Generalized estimating equations were used to investigate poor weight recovery (weight-for-age Z score less than -3) and poor CD4% recovery (CD4% <25), and competing risk regression was used to analyze mortality and toxicity-associated treatment modification.. Three hundred fifty-five (11.9%) of 2993 children starting ART had SM. Their median weight-for-age Z score increased from -5.6 at ART initiation to -2.3 after 36 months. Not using trimethoprim-sulfamethoxazole prophylaxis at baseline was associated with poor weight recovery [odds ratio: 2.49 vs. using; 95% confidence interval (CI): 1.66-3.74; P < 0.001]. Median CD4% increased from 3.0 at ART initiation to 27.2 after 36 months, and 56 (15.3%) children died during follow-up. More profound SM was associated with poor CD4% recovery (odds ratio: 1.78 for Z score less than -4.5 vs. -3.5 to less than -3.0; 95% CI: 1.08-2.92; P = 0.023) and mortality (hazard ratio: 2.57 for Z score less than -4.5 vs. -3.5 to less than -3.0; 95% CI: 1.24-5.33; P = 0.011). Twenty-two toxicity-associated ART modifications occurred at a rate of 2.4 per 100 patient-years, and rates did not differ by malnutrition severity.. Trimethoprim-sulfamethoxazole prophylaxis is important for the recovery of weight-for-age in severely malnourished children starting ART. The extent of SM does not impede weight-for-age recovery or antiretroviral tolerability, but CD4% response is compromised in children with a very low weight-for-height/body mass index-for-age Z score, which may contribute to their high rate of mortality.

Topics: Adolescent; Anti-Bacterial Agents; Anti-Retroviral Agents; Antibiotic Prophylaxis; Antiretroviral Therapy, Highly Active; Asia; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Infant; Male; Malnutrition; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

To identify risk factors for loss to follow-up (LTFU) in an HIV-infected pediatric population in Dar es Salaam, Tanzania, between 2004 and 2011.. Longitudinal analysis of 6236 HIV-infected children.. We conducted a prospective cohort study of 6236 pediatric patients enrolled in care and treatment in Dar es Salaam from October 2004 to September 2011. LTFU was defined as missing a clinic visit for >90 days for patients on ART and for >180 days for patients in care and monitoring. The relationship of baseline and time-varying characteristics to the risk of LTFU was examined using a Cox proportional hazards model.. A total of 2130 children (34%) were LTFU over a median follow-up of 16.7 months (interquartile range, 3.4-36.9). Factors independently associated with a higher risk of LTFU were age ≤2 years (relative risk [RR] = 1.59, 95% CI: 1.40 to 1.80), diarrhea at enrollment (RR = 1.20, 95% CI: 1.03 to 1.41), a low mid-upper arm circumference for age (RR = 1.20, CI: 1.05 to 1.37), eating protein-rich foods ≤3 times a week (RR = 1.39, 95% CI: 1.05 to 1.90), taking cotrimoxazole (RR = 1.39, 95% CI: 1.06 to 1.81), initiating onto antiretrovirals (RR = 1.37, 95% CI: 1.17 to 1.61), receiving treatment at a hospital instead of a local facility (RR = 1.39, 95% CI: 1.06 to 1.41), and starting treatment in 2006 or later (RR = 1.10, 95% CI: 1.04 to 1.16).. Health workers should be aware of pediatric patients who are at a greatest risk of LTFU, such as younger and undernourished patients, so that they can proactively counsel families about the importance of visit adherence. Findings support decentralization of HIV care to local facilities as opposed to hospitals.

Topics: Anti-HIV Agents; Child; Child Nutritional Physiological Phenomena; Child, Preschool; Dietary Proteins; Female; HIV Infections; Humans; Lost to Follow-Up; Male; Malnutrition; Risk Factors; Tanzania; Trimethoprim, Sulfamethoxazole Drug Combination

There is limited information available regarding the etiology of gastrointestinal infections in Burkina Faso. The aim of this study was to investigate the prevalence and epidemiology of enteric pathogens causing gastroenteritis in young children, with a focus on rotavirus, and to investigate the levels of malnutrition and other clinical factors in association with the severity of diarrhea.. A prospective study was undertaken from May 2009 to March 2010, covering the rainy and dry seasons, at the Saint Camille Medical Center in Ouagadougou, Burkina Faso. A total of 309 children less than 5 years of age with diarrhea were enrolled and examined for rotavirus, bacterial, and parasitic infections, as well as clinico-epidemiological aspects.. At least one enteropathogen was detected in 57.9% (n=179) of the children. Of these, 32.4% had rotavirus infections, 16.8% bacterial infections (enteropathogenic Escherichia coli 9.7%, Shigella spp 5.8%, and Salmonella spp 2.3%), and 18.8% parasitic infections (Giardia lamblia 11.3%, Trichomonas intestinalis 6.8%, Entamoeba histolytica/dispar 1.3%). During the cold dry period from December 2009 to February 2010, we observed a large increase in diarrhea cases, which was mainly attributed to rotavirus infections, as 63.8% of these diarrhea cases were positive for rotavirus. In contrast, no rotavirus infection was observed during the rainy season (June-September 2009), when the frequency of parasitic infections was high. Rotavirus and parasitic infections were age-related, with rotavirus being more prevalent in young children (<12 months) and parasites more common in older children (>12 months), while bacteria were equally prevalent among all age groups. Rotavirus infections exhibited more severe symptoms compared to bacteria and parasites, and were associated with fever, vomiting, and severe dehydration. Malnutrition, especially acute malnutrition (wasting), was significantly associated with more severe symptoms in rotavirus-induced diarrhea. The undernourished children also exhibited a prolonged duration of diarrheal episodes.. This study demonstrates rotavirus as the main etiological agent in pediatric diarrhea in Burkina Faso, and further shows the great severity of rotavirus-induced diarrhea in undernourished children in Burkina Faso.

Topics: Age Factors; Anti-Infective Agents; Bacterial Infections; Burkina Faso; Child, Preschool; Diarrhea; Drug Resistance, Bacterial; Female; Gastroenteritis; Humans; Infant; Male; Malnutrition; Parasitic Diseases; Prevalence; Rotavirus Infections; Seasons; Trimethoprim, Sulfamethoxazole Drug Combination

The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is a widely used drug. In spite of this, there are few reports on its genotoxicity, and the results are controversial. Severe malnutrition is a complex condition that increases the susceptibility to infections. Consequently, drugs are extensively used in malnutrition cases. Experimental animal models have been widely used to study the effects of malnutrition. Neonatal rats were experimentally malnourished (UN) during lactation. The UN rats weighed 51.1% less than the well-nourished (WN) controls and had lower concentrations of serum protein and blood lipids. The micronucleus (MN) assay is useful for detecting chromosome damage induced by nutritional deficiencies. In vivo rodent MN assays have been widely used to screen genotoxic agents. In this study, we have evaluated the frequency of spontaneous and TMP-SMX-induced micronuclei in the peripheral blood of weanling (21 days of age) rats using a flow cytometric analysis technique. The spontaneous frequency of micronucleated reticulocytes (MN-RETs) was 2.7 times greater in the UN rats than in the WN rats. In rats that were not treated with TMP-SMX, the percentage of reticulocytes was significantly lower (41.1%) in the UN rats than the WN controls. A therapeutic dose of TMP-SMX (80 mg/kg (TMP), 400 mg/kg (SMX) for 48 hr) increased MN-RETs in the WN and in the UN rats. The data demonstrate the genotoxic effect of this drug. The results indicate that severe protein-calorie restriction and drug treatment enhance DNA damage in rat peripheral blood reticulocytes, potentially increasing the risk of negative effects on health.

Topics: Animals; Animals, Newborn; Dose-Response Relationship, Drug; Female; Flow Cytometry; Male; Malnutrition; Micronuclei, Chromosome-Defective; Micronucleus Tests; Mutagens; Rats; Rats, Wistar; Reticulocytes; Trimethoprim, Sulfamethoxazole Drug Combination; Weaning

This study shows the effect that severe malnourishment has on the kinetics of antibiotic penetration in tissues. A total of 104 male Wistar rats, 21 days old, were randomly divided into eight groups. Five groups of experimental rats were severely malnourished (SM) and three further groups were considered well-nourished control groups (WN). A single dose of trimethoprim-sulfamethoxazole (TMP-SMX) was administered intraperitoneally. Blood samples were taken by heart puncture and five organs were extracted 0-24 h after the administration of the drug. HPLC was used to assess the amount of trimethoprim and sulfamethoxazole in fluids. The elimination half-life for trimethoprim from plasma was longer in SM rats with a median of 3.15 h; in WN rats, it was 0.390 h. Clearance was slower in SM rats: 646.72 mL microg(-1) h(-1) vs 3036.38 mL microg(-1) h(-1) in WN rats (P < 0.05). Tissue penetration was much higher for trimethoprim, with penetration indexes of 0.80-5.66 in WN rats, compared with 0.35-2.14 in SM rats. In the case of sulfamethoxazole, penetration indexes were 0.029-1.13 for WN and 0.075-0.657 for SM rats. Similarly, the penetration ratio to muscle and heart tissue was lower in SM rats. However, penetration to kidney, lung, liver and spleen was greater in SM rats. It is evident that severe SM decreases the capacity of trimethoprim more importantly than sulfamethoxazole biotransformation.

Topics: Animals; Anti-Infective Agents; Chromatography, High Pressure Liquid; Dietary Proteins; Drug Administration Schedule; Injections, Intraperitoneal; Kidney; Liver; Lung; Male; Malnutrition; Rats; Rats, Wistar; Spleen; Trimethoprim, Sulfamethoxazole Drug Combination