Efficacy of linezolid on Treponema pallidum, the syphilis agent: A preclinical study.

BACKGROUND: Penicillin G, the current standard treatment for syphilis, has important drawbacks, but virtually no preclinical or clinical studies have been performed to identify viable alternatives. We tested, both in vitro and in vivo, three marketed antibiotics with adequate pharmacological properties to treat syphilis. METHODS: We used an in vitro culturing system of T. pallidum to perform drug susceptibility testing and applied quantitative PCR targeting the tp0574 gene to measure bacterial growth. To confirm in vivo efficacy, fifteen rabbits were infected intradermally with T. pallidum at eight sites each and randomly allocated to an experimental treatment (linezolid, moxifloxacin, clofazimine) or a control arm (benzathine penicillin G [BPG], untreated). The primary outcome was treatment efficacy defined as the time to lesion healing measured from the date of treatment start. Secondary outcomes were absence of treponemes or treponemal mRNA in injection sites, absence of seroconversion, and cerebrospinal fluid (CSF) abnormalities and negative rabbit infectivity tests (RIT). FINDINGS: Linezolid showed in vitro bactericidal activity at concentrations of 0.5 µg/mL or higher. When administered orally to experimentally infected rabbits, it induced healing of early lesions at a time similar to BPG (hazard ratio 3.84; 95% CI 2.05-7.17; p < 0.0001 compared to untreated controls). In linezolid-treated animals, dark-field microscopy and qPCR assessment showed no presence of treponemes after day 3 post-treatment start, serologic test did not convert to positive, CSF had no abnormalities, and RIT was negative. Moxifloxacin and clofazimine failed to inhibit bacterial growth in vitro and could not cure the infection in the rabbit model. INTERPRETATION: Linezolid, a low-cost oxazolidinone, has in vitro and in vivo activity against T. pallidum, with efficacy similar to BPG in treating treponemal lesions in the animal model. Our findings warrant further research to assess the efficacy of linezolid as an alternative to penicillin G to treat syphilis in human clinical trials. FUNDING: European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 850450).

Pathophysiology of Anemia in HIV-Infected Children Exposed to Malaria.

Anemia is a common condition in HIV-infected children; however, its pathophysiology and the contribution of frequent causes of anemia such as iron deficiency (ID) and malaria are poorly understood. We carried out an ancillary study on the effect of HIV on anemia as part of a case-control study on risk factors of anemia among Mozambican children aged 1-59 months with documented HIV status. Of them, 390 children were admitted to the hospital with anemia (hemoglobin [Hb] < 11 g/dL), whereas 272 children without anemia (Hb ≥ 11 g/dL) were recruited in the community. We assessed differences by HIV status in the presentation of anemia etiological factors and the effect of HIV infection on the association of each factor with anemia. Among the 99 HIV-infected and 563 uninfected children included, HIV-infected anemic children had an increased risk of undernutrition (P < 0.0001), Epstein-Barr virus infection (P < 0.0001), bacteremia (P = 0.0060), a decreased risk of malaria (P < 0.0001), and a similar risk of ID (P = 0.7371) compared with anemic-uninfected children. HIV-infected children were significantly less likely to have anemia associated with Plasmodium falciparum hyperparasitemia (P = 0.0444) and had a lower prevalence of parasitemia in the bone marrow (BM) (P < 0.0001) than anemic-uninfected children. Levels of BM erythropoiesis and dyserythropoiesis were comparable between groups. These findings suggest that the pathophysiology of anemia among HIV-infected malaria-exposed children is not related to HIV-specific effects. For unclear reasons, HIV-infected children had reduced risk of malaria infection, whereas ID prevalence was comparable in HIV-infected and uninfected children, suggesting that iron supplementation recommendations should not be different in HIV-infected children.

Overuse of diagnostic tools and medications in acute rhinosinusitis in Spain: a population-based study (the PROSINUS study).

OBJECTIVES: Acute rhinosinusitis (ARS) has a high incidence. Diagnosis is clinical, and evolution is mostly self-limited. The aim of this study was to describe the sociodemographic characteristics and use of diagnostic tools and medications in patients with ARS. DESIGN: This is a prospective observational study in real-life clinical practice. SETTING: Patients with clinical diagnosis of ARS (n=2610) were included from ear, nose and throat clinics in Spain. A second visit at resolution was done. PARTICIPANTS: Patients were classified according to the duration of symptoms: viral ARS (≤10 days), postviral ARS (>10 days, ≤12 weeks) and chronic rhinosinusitis (>12 weeks). MAIN OUTCOME MEASURES: Sociodemographic characteristics, symptoms, disease severity, quality of life (Sino-Nasal Outcome Test-16), used diagnostic tools and medications, and the management performed by primary care physicians (PCPs) and by otorhinolaryngologists (ORLs) were assessed. RESULTS: Of the patients 36% were classified as having viral ARS, 63% postviral ARS and 1% as chronic rhinosinusitis. Working in a poorly air-conditioned environment was a risk factor (OR: 2.26, 95% CI 1.27 to 4.04) in developing postviral ARS. A higher number of diagnostic tools (rhinoscopy/endoscopy: 80% vs 70%; plain X-ray: 70% vs 55%; CT scan: 22% vs 12%; P<0.0001) were performed in postviral than viral cases. PCPs performed more X-rays than ORLs (P<0.0001). Patients, more those with postviral than viral ARS, received a high number of medications (oral antibiotics: 76% vs 62%; intranasal corticosteroids: 54% vs 38%; antihistamines: 46% vs 31%; mucolytic: 48% vs 60%; P<0.0001). PCPs prescribed more antibiotics, antihistamines and mucolytics than ORLs (P<0.0068). More patients with postviral than viral ARS reported symptoms of potential complications (1.5% vs 0.4%; P=0.0603). Independently of prescribed medications, quality of life was more affected in patients with postviral (38.7±14.2 vs 36.0±15.3; P=0.0031) than those with viral ARS. ARS resolution was obtained after 6.04 (viral) and 16.55 (postviral) days, with intranasal corticosteroids being associated with longer (OR: 1.07, 95% 1.02 to 1.12) and phytotherapy with shorter (OR: 0.95, 95% CI 0.91 to 1.00) duration. CONCLUSIONS: There is a significant overuse of diagnostic tools and prescribed medications, predominantly oral antibiotics, by PCPs and ORLs, for viral and postviral ARS.

Anaemia in hospitalised preschool children from a rural area in Mozambique: a case control study in search for aetiological agents.

BACKGROUND: Young children bear the world's highest prevalence of anaemia, the majority of which is of multifactorial aetiology, which in turn hampers its successful prevention. Even moderate degrees of anaemia are associated with increased mortality and morbidity. Despite this evidence, there is a lack of effective preventive programs and absence of consensus in the safety of iron supplementation in malaria areas, which reflects the poor understanding of the contribution of different aetiologies to anaemia. In order to reduce the anaemia burden in the most vulnerable population, a study to determine the aetiology of anaemia among pre-school Mozambican children was performed. METHODS: We undertook a case-control study of 443 preschool hospitalized children with anaemia (haemoglobin concentration <11 g/dl) and 289 community controls without anaemia. Inclusion criteria were: age 1-59 months, no blood transfusion in the previous month, residence in the study area and signed informed consent. Both univariable and multivariable logistic regression analyses were performed to identify factors associated with anaemia and adjusted attributable fractions (AAF) were estimated when appropriate. RESULTS: Malaria (adjusted odds ratio (AOR) = 8.39, p < 0.0001; AAF = 37%), underweight (AOR = 8.10, p < 0.0001; AAF = 43%), prealbumin deficiency (AOR = 7.11, p < 0.0001; AAF = 77%), albumin deficiency (AOR = 4.29, p = 0.0012; AAF = 30%), HIV (AOR = 5.73, p = 0.0060; AAF = 18%), and iron deficiency (AOR = 4.05, p < 0.0001; AAF = 53%) were associated with anaemia. Vitamin A deficiency and α-thalassaemia were frequent (69% and 64%, respectively in cases) but not independently related to anaemia. Bacteraemia (odds ratio (OR) = 8.49, p = 0.004), Parvovirus-B19 (OR = 6.05, p = 0.017) and Epstein-Barr virus (OR = 2.10, p = 0.0015) infections were related to anaemia only in the unadjusted analysis. Neither vitamin B12 deficiency nor intestinal parasites were associated with anaemia. Folate deficiency was not observed. CONCLUSIONS: Undernutrition, iron deficiency, malaria, and HIV are main factors related to anaemia in hospitalised Mozambican preschool children. Effective programs and strategies for the prevention and management of these conditions need to be reinforced. Specifically, prevention of iron deficiency that accounted in this study for more than half of anaemia cases would have a high impact in reducing the burden of anaemia in children living under similar conditions. However this deficiency, a common preventable and treatable condition, remains neglected by the international public health community.

Challenges in the diagnosis of iron deficiency in children exposed to high prevalence of infections.

BACKGROUND: While WHO guidelines recommend iron supplements to only iron-deficient children in high infection pressure areas, these are rarely implemented. One of the reasons for this is the commonly held view that iron supplementation increases the susceptibility to some infectious diseases including malaria. Secondly, currently used markers to diagnose iron deficiency are also modified by infections. With the objective of improving iron deficiency diagnosis and thus, its management, we evaluated the performance of iron markers in children exposed to high infection pressure. METHODOLOGY/PRINCIPAL FINDINGS: Iron markers were compared to bone marrow findings in 180 anaemic children attending a rural hospital in southern Mozambique. Eighty percent (144/180) of the children had iron deficiency by bone marrow examination, 88% (155/176) had an inflammatory process, 66% (119/180) had moderate anaemia, 25% (45/180) severe anaemia and 9% (16/180) very severe anaemia. Mean cell haemoglobin concentration had a sensitivity of 51% and specificity of 71% for detecting iron deficiency. Soluble transferrin receptor (sTfR) and soluble transferrin receptor/log ferritin (TfR-F) index (adjusted by C reactive protein) showed the highest areas under the ROC curve (AUC(ROC)) (0.75 and 0.76, respectively), and were the most sensitive markers in detecting iron deficiency (83% and 75%, respectively), but with moderate specificities (50% and 56%, respectively). CONCLUSIONS/SIGNIFICANCE: Iron deficiency by bone marrow examination was extremely frequent in these children exposed to high prevalence of infections. However, even the best markers of bone marrow iron deficiency did not identify around a quarter of iron-deficient children. Tough not directly extrapolated to the community, these findings urge for more reliable, affordable and easy to measure iron indicators to reduce the burden of iron deficiency anaemia in resource-poor settings where it is most prevalent.

Challenges in the diagnosis of iron deficiency in children exposed to high prevalence of infections

Background: While WHO guidelines recommend iron supplements to only iron-deficient children in high infection pressure areas, these are rarely implemented. One of the reasons for this is the commonly held view that iron supplementation increases the susceptibility to some infectious diseases including malaria. Secondly, currently used markers to diagnose iron deficiency are also modified by infections. With the objective of improving iron deficiency diagnosis and thus, its management, we evaluated the performance of iron markers in children exposed to high infection pressure. Methodology/Principal Findings: Iron markers were compared to bone marrow findings in 180 anaemic children attending a rural hospital in southern Mozambique. Eighty percent (144/180) of the children had iron deficiency by bone marrow examination, 88% (155/176) had an inflammatory process, 66% (119/180) had moderate anaemia, 25% (45/180) severe anaemia and 9% (16/180) very severe anaemia. Mean cell haemoglobin concentration had a sensitivity of 51% and specificity of 71% for detecting iron deficiency. Soluble transferrin receptor (sTfR) and soluble transferrin receptor/log ferritin (TfR-F) index (adjusted by C reactive protein) showed the highest areas under the ROC curve (AUCROC) (0.75 and 0.76, respectively), and were the most sensitive markers in detecting iron deficiency (83% and 75%, respectively), but with moderate specificities (50% and 56%, respectively). Conclusions/Significance: Iron deficiency by bone marrow examination was extremely frequent in these children exposed to high prevalence of infections. However, even the best markers of bone marrow iron deficiency did not identify around a quarter of iron-deficient children. Tough not directly extrapolated to the community, these findings urge for more reliable, affordable and easy to measure iron indicators to reduce the burden of iron deficiency anaemia in resource-poor settings where it is most prevalent.

The effects of short-term iron supplementation on iron status in infants in malaria-endemic areas.

Iron deficiency and Plasmodium falciparum malaria are the two main causes of anemia in young children in region endemic for this disease. The impact on iron status of prophylactic oral iron supplementation (2 mg/kg/day from two to six months of age) and the duration of this effect were assessed in a group of 832 Tanzanian infants exposed to P. falciparum malaria. Iron parameters and red blood cell indices were assessed at 2, 5, 8, and 12 months of age. Infants who received iron supplements had a significantly lower prevalence of iron deficiency (P < 0.01 at 5 months and P < 0.001 at 8 and 12 months). Red blood cell indices (mean corpuscular volume, mean cell hemoglobin, and mean cell hemoglobin concentration) were increased in children receiving iron supplementation and they did not differ between those protected and unprotected against malaria. The prevalence of ferropenia was similar in children protected against malaria and in those who were not protected and did not receive iron supplements (34.7% versus 37.3% at 12 months of age). We concluded that iron supplementation between the ages of 2-6 months improves iron status at least up to 12 months of age. Malaria infection does not contribute to iron deficiency.

Awareness of the use of folic acid to prevent neural tube defects in a Mediterranean area.

OBJECTIVES: The risk of neural tube defects (NTDs) is decreased in women who take folic acid during the periconceptional period. The main objective of our study was to evaluate the awareness of the need for folic acid supplementation and also the actual intake during the periconceptional period to prevent neural tube defects in a Mediterranean area. STUDY DESIGN: A retrospective study was performed from 1 July to 30 November 2000. One thousand consecutive women who delivered in our hospital were interviewed during the immediate postpartum period about their knowledge of neural tube defects and folic acid intake before and during pregnancy. RESULTS: Most women (85.7%) referred not having been specifically informed about the need to take folic acid to prevent neural tube defects although approximately half of the women (50.6%) were in fact, aware of the need for folic acid intake. Eight percent (8.1%) of the women took folic acid before conception but only 6.9% did so during the effective period from 4 weeks before conception to 4 weeks after conception. Logistic regression analysis showed that awareness of the need to take folic acid together with having had preconceptional counselling and knowledge of NTDs were the strongest variables related to the fact of having taken folic acid during the correct period. CONCLUSIONS: Although the population is aware of the need to take folic acid, the real impact of the present recommendations is almost negligible. Information in primary care and preconceptional counselling to specifically inform patients about the need to take folic acid to prevent NTDs seem to be crucial to improve the final intake of folic acid during the protective period.