First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age.

BACKGROUND: While there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth. METHODS: Data were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site). RESULTS: Overall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether-lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13 (95% confidence interval (CI) 0.62-2.05, p-value 0.700) and 2.03 (95% CI 1.09-3.78, p-value 0.027), respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85 (95% CI 0.50-1.44, p-value 0.543) and 1.41 (95% CI 0.71-2.77, p-value 0.322), respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14 (95% CI 0.78-5.89, p-value 0.142) for LBW and 8.60 (95% CI 1.29-57.6, p-value 0.027) for SGA. The level of between sites heterogeneity was moderate to high. CONCLUSION: ACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether-lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy

Assessment of the safety of antimalarial drug use during early pregnancy (ASAP): protocol for a multicenter prospective cohort study in Burkina Faso, Kenya and Mozambique.

BACKGROUND: A major unresolved safety concern for malaria case management is the use of artemisinin combination therapies (ACTs) in the first trimester of pregnancy. There is a need for human data to inform policy makers and treatment guidelines on the safety of artemisinin combination therapies (ACT) when used during early pregnancy. METHODS: The overall goal of this paper is to describe the methods and implementation of a study aimed at developing surveillance systems for identifying exposures to antimalarials during early pregnancy and for monitoring pregnancy outcomes using health and demographic surveillance platforms. This was a multi-center prospective observational cohort study involving women at health and demographic surveillance sites in three countries in Africa: Burkina Faso, Kenya and Mozambique [(ClinicalTrials.gov Identifier: NCT01232530)]. The study was designed to identify pregnant women with artemisinin exposure in the first trimester and compare them to: 1) pregnant women without malaria, 2) pregnant women treated for malaria, but exposed to other antimalarials, and 3) pregnant women with malaria and treated with artemisinins in the 2nd or 3rd trimesters from the same settings. Pregnant women were recruited through community-based surveys and attendance at health facilities, including antenatal care clinics and followed until delivery. Data from the three sites will be pooled for analysis at the end of the study. Results are forthcoming. DISCUSSION: Despite few limitations, the methods described here are relevant to the development of sustainable pharmacovigilance systems for drugs used by pregnant women in the tropics using health and demographic surveillance sites to prospectively ascertain drug safety in early pregnancy. TRIAL REGISTRATION: NCT01232530

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

BACKGROUND: Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. METHODS AND FINDINGS: Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. CONCLUSIONS: Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. REVIEW REGISTRATION: PROSPERO CRD42015032371

A systematic review of epidemiology, risk factors, diagnosis, antifungal resistance, and management of invasive aspergillosis in Africa.

Invasive aspergillosis (IA) affects more than 300,000 people annually worldwide with a case fatality rate reaching 80%. However, in Africa despite the presence of risk factors for the development of IA, the burden of these fungal infections remained unknown. This systematic review aimed to update the available information on the epidemiology and the therapeutic management of IA in Africa. The published papers were systematically searched on major medical databases from September 20 to October 10, 2021. The list of references of eligible articles and the Google scholar database were also checked in order to search for possible eligible articles. Results were reported following the Preferred Reporting Items for Systematic and Meta-analyses (PRISMA) guidelines. The search yielded 1864 articles of which 29 met the inclusion criteria. This systematic review showed the existence of IA in Africa. The prevalence of IA can reach 27% with a fatality rate of more than 60%. The most common clinical form of IA found was invasive pulmonary aspergillosis. The main predisposing conditions identified were neutropenia, HIV/AIDS, renal transplant recipients, and renal failure. Aspergillus section Flavi and Nigri were the main Aspergillus species identified and Aspergillus section Fumigati was uncommon. The main management strategy for IA cases was to start antifungal therapy only after a failure of broad-spectrum antibiotic therapy. This review provided evidence of the existence of invasive aspergillosis in Africa and especially a high rate of undiagnosed invasive aspergillosis cases

First investigative study of azole-resistant aspergillus fumigatus in the environment in burkina faso

Azole-resistant Aspergillus fumigatus (ARAF) strains have been reported on all continents, however, limited data exist on these strains in Africa, while several factors, mainly environmental ones, suggest their presence on this continent. This study aimed to assess the environmental prevalence of ARAF strains in Burkina Faso, a country situated in the West African region where data on ARAF is non-existent. In total, 120 environmental samples (soil) were collected and analyzed. Samples were screened for resistance using three azole-containing agar plates; one without azole antifungal (growth control) and two supplemented with either itraconazole (4 mg/L) or voricona-zole (2 mg/L). The EUCAST susceptibility testing method was used to confirm the azole-resistant phenotype of A. fumigatus sensu-stricto isolates. Mutations in the cyp51A gene were determined by sequencing. Of the 120 samples, 51 positive samples showed growth of A. fumigatus isolates on control medium. One ARAF (2%; 1/51) isolate was found amongst A. fumigatus positive samples and harbored the F46Y/M172V/E427K cyp51A mutations. No TR34/L98H or TR46/Y121F/T289A mutations were observed. Our study described the first A. fumigatus isolate resistant to an azole antifun-gal in Burkina Faso.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Comparison of effectiveness of two different artemisininbased combination therapies in an area with high seasonal transmission of malaria in Burkina Faso

In Sahelian countries such as Burkina Faso, malaria transmission is seasonal with a high incidence of transmission during the rainy season. This study aimed to compare the effectiveness of the two recommended treatments (Artemether-Lumefantrine and Artesunate-Amodiaquine) for uncomplicated malaria in Burkina Faso regarding this seasonal variation of malaria transmission. This is part of a randomized open label trial comparing the effectiveness and safety of Artemether-Lumefantrine versus Artesunate-Amodiaquine according to routine practice in Nanoro. Patients with uncomplicated falciparum malaria were recruited all year round and followed-up for 28 days. To distinguish recrudescences from new infections, dried blood spots from day 0 and day of recurrent parasitaemia were used for nested-PCR genotyping of the polymorphic loci of the merozoite surface proteins 1 and 2. Seasonal influence was investigated by assessing the treatment outcomes according to the recruitment period of the patients. Two main groups (dry season versus rainy season) were defined following the seasonal characteristics of the study area. In Artemether- Lumefantrine group, the uncorrected cure rate was 76.5% in dry season versus 37.9% in rainy season. In Artesunate-Amodiaquine group, this was 93.3% and 57.1% during dry and rainy seasons, respectively. After PCR adjustment, the cure rate decreased from 85.9% in dry season to 75.0% in rainy season in Artemether-Lumefantrine group. In Artesunate-Amodiaquine group, it was 93.3% in dry season and 80.7% during the rainy season. During the rainy season around 50% of patients had a new malaria episode by Day 28. The cure rate of both Artemether-Lumefantrine and Artesunate-Amodiaquine treatments was higher in dry season compared to rainy season due to high incidence of reinfections during the rainy season. For this reason, in addition to the curative effect, the post-treatment prophylactic effect should be taken into account in the choice of antimalarial regimens

Performances of disk diffusion method for determining triazole susceptibility of Aspergillus species: Systematic review.

The therapeutic management of invasive aspergillosis should be guided by antifungal susceptibility testing (AFST). The disk diffusion (DD) method due to its simplicity and low cost could be an appropriate alternative to the reference methods (CLSI, EUCAST) which are not suitable for AFST in routine clinical microbiology laboratories, particularly in resource-constrained settings. This review summarizes the available data on the performance of the DD method in determining triazole susceptibility profile of Aspergillus species. The published articles on the performance of DD method for determining triazole susceptibility of Aspergillus spp. were systematically searched on major medical databases and Google Scholar. We identified 2725 articles of which 13 met the inclusion criteria. The overall average agreement value obtained between DD and CLSI broth microdilution (CLSI-BMD) methods for the itraconazole 10 µg disk (70.75%) was low especially when the medium used was not Mueller-Hinton (MH) agar. In contrast average agreement for the voriconazole 1 µg disk and the posaconazole 5 µg disk were > 94% regardless of media used. The correlation coefficient values between the DD and CLSI-BMD methods on MH agar were acceptable (≥ 0.71) for the itraconazole 10 µg disk and posaconazole 5 µg disk and good (≥ 0.80) for the voriconazole 1 and 10 µg disk. The reproducibility of the DD method regardless to the medium used was ≥ 82%. This systematic review shows that the disk diffusion method could be a real alternative for triazole antifungals susceptibility testing of Aspergillus spp

First detection of triazole-resistant aspergillus fumigatus harbouring the TR34/L98H Cyp51A mutation in Burkina Faso

International audienceBackground: Triazole-resistant Aspergillus fumigatus (TRAF) isolates are a growing public health problem with worldwide distribution. Epidemiological data on TRAF is limited in Africa, particularly in West Africa.Objectives: This study aimed to screen for the environmental presence of TRAF isolates in the indoor air of two hospitals in Burkina Faso.Materials and methods: Air samples were collected in wards housing patients at risk for invasive aspergillosis, namely infectious diseases ward, internal medicine ward, nephrology ward, pulmonology ward, medical emergency ward and paediatric ward. Sabouraud Dextrose Agar supplemented with triazoles was used to screen the suspected TRAF isolates and EUCAST method to confirm the resistance of suspected isolates. Sequencing of cyp51A gene was used to identify the resistance mechanism of confirmed TRAF isolates.Results: Of the 198 samples collected and analysed, 67 showed growth of A. fumigatus isolates. The prevalence of TRAF isolates was 3.23% (4/124). One TRAF isolate exhibited a pan-triazole resistance. Sequencing of cyp51A gene identified the TR34/L98H mutation for this pan-triazole resistant isolate. This study showed for the first time the circulation of the pan-azole resistant isolate harbouring the TR34/L98H mutation in Burkina Faso.Conclusions: These findings emphasise the need to map these TRAF isolates in all parts of Burkina Faso and to establish local and national continuous surveillance of environmental and clinical TRAF isolates in this country