Endemic infectious diseases in pregnant women in central African Gabon: Epidemiology and Evaluation of new Interventions

Malaria is one of the most important infectious diseases with high morbidity rates particularly in young children and in pregnant women in Sub-Saharan Africa. Intermittent preventive treatment in pregnancy (IPTp) is an effective way to reduce morbidity of malaria in pregnancy and to reduce neonatal morbidity. Sulphadoxine/pyrimethamine (SP) is the recommended drug for IPTp in sub-Saharan Africa. Because of increasing resistance against SP there is a need to develop alternative drugs to replace SP for IPTp. Among the most promising candidate drugs in clinical development are mefloquine and azithromycin. Besides their antimalarial activity, these antimalarial drugs show significant antibacterial activity when given as IPTp. This antibacterial activity may offer several additional public health benefits when used as IPTp in pregnant women. These drugs may– besides protecting from malaria in pregnancy - treat and prevent often undetected sexually transmitted diseases (STDs) and urinary tract infections (UTIs). In this thesis, three studies are presented focusing on infectious diseases highly prevalent in sub-Saharan Africa. In the first study, the activity of mefloquine and azithromycin was assessed in vitro in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy. Results of this study demonstrated that SP was highly active against Staphylococcus aureus and Streptococcus pneumoniae. All tested Gram-positive bacteria, except Enterococcus faecalis, were sensitive to azithromycin. Additionally, azithromycin was active against Neisseria gonorrhoeae. Mefloquine showed good activity against pneumococci but lower in vitro activity against all other tested pathogens. These data indicate that the use of azithromycin may be associated with most collateral benefit in curing and preventing concomitant bacterial infections. In the second study the impact of routine IPTp with mefloquine (MQ) and SP on Streptococcus agalactiae (GBS) was evaluated. GBS is an important cause of early neonatal infections leading to considerable morbidity and mortality. In this nested randomized controlled clinical trial GBS colonization rates in pregnant women were assessed. The overall prevalence of recto-vaginal GBS colonization was comparable to published findings in industrialized countries. Demographic characteristics showed significant association between GBS colonization and literacy. No difference of maternal GBS colonization was observed between SP- and MQ-IPTp regimes. This finding indicates that SP-IPTp was not superior to MQ-IPTp in preventing GBS colonization in pregnant women in Gabon. In another analysis of the above described IPTp study, the prevalence of human herpes virus 8 (HHV-8) infections was assessed in Gabon. HHV-8 infection is associated with Karposi-sarcoma, Castleman disease and other malignant conditions and is known to be highly prevalent in Central Africa. In this sero-epidemiological study it was shown that 39% of pregnant women were seropositive for HHV-8 infections. Among 35% of seropositive women, real time PCR showed one pregnant women with detectable viraemia in peripheral blood. In analysis of cord blood samples of sero-positive women, no vertical transmission of HHV-8 was observed. Finally, a pharmacokinetic analysis of albendazole for the treatment of extra-hepatic echinococcosis is presented. Echinococcosis is highly prevalent in sub-Saharan Africa and medical treatment is one option in resource limited settings. Here the ability of albendazole and its active metabolite albendazole sulphoxide to penetrate into Echinococcus granulosus cysts of patients with non-liver cysts was investigated. Analysis of two patients with lung and soft tissue cysts demonstrated a satisfactory penetration of albendazole sulphoxide into Echinococcus cysts. These data underline the usefulness of albendazole therapy in extra-hepatic cystic echinococcosis

Anti-bacterial activity of intermittent preventive treatment of malaria in pregnancy: comparative in vitro study of sulphadoxine-pyrimethamine, mefloquine, and azithromycin

<p>Abstract</p> <p>Background</p> <p>Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine (SP) is recommended for the prevention of malaria in pregnancy in sub-Saharan Africa. Increasing drug resistance necessitates the urgent evaluation of alternative drugs. Currently, the most promising candidates in clinical development are mefloquine and azithromycin. Besides the anti-malarial activity, SP is also a potent antibiotic and incurs significant anti-microbial activity when given as IPTp - though systematic clinical evaluation of this action is still lacking.</p> <p>Methods</p> <p>In this study, the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay.</p> <p>Results</p> <p>SP was highly active against <it>Staphylococcus aureus </it>and <it>Streptococcus pneumoniae</it>. All tested Gram-positive bacteria, except <it>Enterococcus faecalis</it>, were sensitive to azithromycin. Additionally, azithromycin was active against <it>Neisseria gonorrhoeae</it>. Mefloquine showed good activity against pneumococci but lower <it>in vitro </it>action against all other tested pathogens.</p> <p>Conclusion</p> <p>These data indicate important differences in the spectrum of anti-bacterial activity for the evaluated anti-malarial drugs. Given the large scale use of IPTp in Africa, the need for prospective clinical trials evaluating the impact of antibiotic activity of anti-malarials on maternal and foetal health and on the risk of promoting specific drug resistance of bacterial pathogens is discussed.</p

Prospective evaluation of artemether-lumefantrine for the treatment of non-falciparum and mixed-species malaria in Gabon

Background: The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence. Methods: This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon. Results: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n = 38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study. Conclusions: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon. Trial Registration: ClinicalTrials.gov Identifier: NCT0072577

Streptococcus agalactiae Serotype Distribution and Antimicrobial Susceptibility in Pregnant Women in Gabon, Central Africa

Neonatal invasive disease due to Streptococcus agalactiae is life threatening and preventive strategies suitable for resource limited settings are urgently needed. Protective coverage of vaccine candidates based on capsular epitopes will relate to local epidemiology of S. agalactiae serotypes and successful management of critical infections depends on timely therapy with effective antibiotics. This is the first report on serotype distribution and antimicrobial susceptibility of S. agalactiae in pregnant women from a Central African region. Serotypes V, III, and Ib accounted for 88/109 (81%) serotypes and all isolates were susceptible to penicillin and clindamycin while 13% showed intermediate susceptibility to erythromycin

Loa loa Infection in Pregnant Women, Gabon

Loa loa, the African eye worm, is a filarial pathogen of Central African rainforest regions. As of 2013, it had affected an estimated 2–3 million persons in Central Africa (1,2). Adult worm migrations in humans may intermittently cause Calabar swelling, and microfilariae are commonly found in blood and body fluids. Loiasis is a chronic infection persisting for many years; a considerable proportion of women in loiasis-endemic regions are infected during gestation. To date, the epidemiology of loiasis in pregnant women has not been investigated, and the effects of loiasis on maternal and fetal health outcomes are unknown. We investigated the epidemiology of loiasis in a cohort of pregnant women participating in a drug trial for preventing malaria during pregnancy

Prospective evaluation of artemether-lumefantrine for the treatment of non-falciparum and mixed-species malaria in Gabon

Abstract Background The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence. Methods This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon. Results Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n = 38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study. Conclusions This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon. Trial Registration ClinicalTrials.gov Identifier: NCT00725777</p

Streptococcus agalactiae Serotype Distribution and Antimicrobial Susceptibility in Pregnant Women in Gabon, Central Africa

Neonatal invasive disease due to Streptococcus agalactiae is life threatening and preventive strategies suitable for resource limited settings are urgently needed. Protective coverage of vaccine candidates based on capsular epitopes will relate to local epidemiology of S. agalactiae serotypes and successful management of critical infections depends on timely therapy with effective antibiotics. This is the first report on serotype distribution and antimicrobial susceptibility of S. agalactiae in pregnant women from a Central African region. Serotypes V, III, and Ib accounted for 88/109 (81%) serotypes and all isolates were susceptible to penicillin and clindamycin while 13% showed intermediate susceptibility to erythromycin