A systematic review of the clinical presentation, treatment and relapse characteristics of human Plasmodium ovale malaria

Additional file 1. Alphabetic list of included articles with overall quality of reporting and risk of bias assessment. -, not determined; overall risk of bias was declared “high” for case reports and case series; for applicable trials, overall risk of bias results from the detailed risk of bias assessment outlined in the Additional file 2; detailed completeness of reporting assessment is displayed in the Additional file 3

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

Pyronaridine–artesunate real-world safety, tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm, open-label, cohort event monitoring study

BACKGROUND In Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine-artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa. METHODS AND FINDINGS This single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine-artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine-artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine-artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated. CONCLUSIONS Pyronaridine-artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine-artesunate as an operationally useful addition to the management of acute uncomplicated malaria. TRIAL REGISTRATION ClinicalTrials.gov NCT03201770

Pathophysiology and treatment of non-falciparum and falciparum malaria

Die Diskrepanz zwischen Heilungsraten neuer Malariamedikamente in klinischen Studien und der Effektivität im Einsatz in der klinischen Routine erlangt immer mehr Wichtigkeit und gibt Anlass, Arzneimittelregimes aus neuen und komplexeren Blickwinkeln zu betrachten. Der Schwerpunkt der klinischen Forschung liegt nach wie vor auf der Effizienz medikamentöser Behandlungen, aber es zeigte sich, dass auch das effizienteste Medikament nicht die gewünschte Wirkung entfalten kann, wenn die Effektivität außer Acht gelassen wird. Probleme sind unter anderem Nichteinhaltung des Arzneiregimes oder Abbruch der Medikamenteneinnahme, sobald sich eine kurative Wirkung zeigt. Die Möglichkeit, die benötigte Dosis mit einer einzigen Gabe verabreichen zu können, bietet hier einen innovativen Lösungsansatz. Die gesamte Dosis könnte unter Aufsicht im Gesundheitszentrum verabreicht werden, ohne die Notwendigkeit weiterer Compliance von Seiten des Patienten. Ein Teil dieser Arbeit wurde der Evaluierung einer Kombination von Artefenomel und Piperaquinphosphat als Einzeldosistherapie für Malariapatienten in Sub-Sahara Afrika und Asien gewidmet. Der Schwerpunkt von Forschung und Entwicklung im Bereich der Malaria lag in den letzten Jahrzehnten insbesondere auf Monoinfektionen von Plasmodium falciparum und in geringerem Ausmaß von Plasmodium vivax, sowie auf klinischen Studien mit dem Ziel effiziente Medikamente gegen selbige Spezies zu finden. Plasmodium ovale spp. und Plasmodium malariae wurden auf verschiedenen Ebenen größtenteils ausgeschlossen. Obwohl diese Spezies eher selten auftreten und oft eine klinisch milde Verlaufsform mit niedriger Parasitendichte zeigen, können auch schwere Verlaufsformen bis hin zum Tod auftreten. Seit die molekulare Diagnostik ein verlässliches Mittel zur Erfassung niedriger Parasitämien und der Differenzierung zwischen den Parasitenspezies geworden ist stellte sich heraus, dass die Prävalenz von nicht-falciparum Malaria eine höhere ist als lange angenommen. Gleichzeitig birgt die Behandlung beider Spezies ihre Tücken, da beide zu einem späteren Wiederauftreten von Parasiten führen können, jedoch auf unterschiedlichen pathophysiologischen Mechanismen basierend. Klinische Studien als Basis für Behandlungsempfehlungen fehlen Großteils. Es gibt wenig rezente Behandlungsstudien, die Anzahl der eingeschlossenen Patienten ist klein und randomisierte kontrollierte klinische Studien fehlen. Inzwischen haben nicht-falciparum Spezies einen besonderen Stellenwert im Bereich der Malariaelimination eingenommen, da unbehandelte und nicht ausreichend behandelte Individuen als Reservoir für den Vektor dienen und somit zur anhaltenden Malariatransmission beitragen. Zusätzliche Herausforderungen für die Eliminationsanstrengungen birgt das vermutete Hypnozoitenreservoir von P. ovale spp., wissenschaftliche Evidenz für dieses Phänomen ist jedoch nur spärlich vorhanden. Der Schwerpunkt dieser Arbeit lag auf der Beleuchtung von Behandlungsmöglichkeiten, der klinischen Präsentation und dem Rezidivphänomen von P. ovale, sowie auf der Bewertung der Effizienz einer weit verbreiteten Artemisinin-Kombinationstherapie für P. ovale spp., P. malariae und Plasmodium-Mischinfektionen.In hand with current control and elimination efforts the efficacy-effectiveness gap of antimalarial treatments takes on a more and more important role and requires evaluating drug regimens from a new and more complex perspective. The emphasis of clinical research still remains on treatment efficacy but it has become apparent that the most efficacious drug cannot have the desired effect in real-world settings when “real-world-effectiveness” is left out of consideration. These problems include non-adherence to drug regimens and early interruption as soon as the drug shows a curative effect. Single dose treatment provides a potential solution to these challenges. The full curative dose can be administered under supervision at the health care centre and no further compliance from the patients side is subsequently needed. This thesis was partly devoted to the evaluation of a promising single dose antimalarial regimen. A combination of artefenomel and piperaquine phosphate was studied as single dose treatment in selected malaria infected patient populations in sub-Saharan Africa and Asia. During the last decades, research and development in the field of malaria has mainly focussed on Plasmodium falciparum mono-infections, on Plasmodium vivax and on clinical trials aiming at finding effective drugs against those species. Plasmodium ovale spp. and Plasmodium malariae have been largely left out on multiple levels. Although these species occur less frequently and disease caused by them is often of low parasitaemia and comparatively mild in clinical presentation, they have the potential to evoke severe disease and death. Since molecular methods have become a tool that enables detecting low parasite densities and reliably identifying malaria species, it increasingly becomes apparent that the prevalence of non-falciparum malaria is more pronounced than for long assumed. At the same time, the treatment of both species has its own challenges as they are capable of causing late reappearance of parasites, however, based on different pathophysiological mechanisms. Importantly, clinical trials as basis for species specific treatment recommendations are largely missing. Recent treatment studies are scarce, numbers of recruited patients are small and randomised controlled clinical trials are lacking. Nowadays, non-falciparum species have gained special importance in malaria elimination settings as untreated and insufficiently treated individuals contribute to the sustained transmission of malaria. Additionally, the presumed hypnozoite reservoir of P. ovale spp. may constitute a challenge for elimination efforts but scientific evidence for this phenomenon is scarce. The focus of this thesis was to shed light on treatment options, clinical presentation and the relapse phenomenon of P. ovale spp. as well as to evaluate treatment efficacy of a widely used artemisinin combination treatment in P. ovale spp. and P. malariae mono-infections, and mixed Plasmodium infections.submitted by Mirjam GrogerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2018OeBB(VLID)257773

Molecular evidence for relapse of an imported Plasmodium ovale wallikeri infection

Abstract Background Malaria caused by Plasmodium ovale spp. has been neglected by and large from research and has received only little scientific attention during the past decades. Ovale malaria is considered to feature relapses by liver hypnozoites although scientific evidence for this paradigm is scarce. Case presentation Here, the case of a 16-year-old male, who presented with fevers to the outpatient department in Vienna, Austria, after travelling to Uganda and Papua New Guinea is described. Infection with Plasmodium malariae was diagnosed by microscopy and the patient was treated accordingly with a full course of supervised artemether–lumefantrine. He was discharged in good clinical condition with a negative blood smear. One month after initial diagnosis, he returned complaining of fever. Thick blood smear was positive again for malaria parasites, which were confirmed as P. ovale wallikeri by PCR. Retrospective analysis revealed the identical Plasmodium spp. in the initial blood samples. Molecular analysis of various gene loci (nuclear porbp2, 18S rRNA and potra genes) gave identical results providing further evidence for relapse by an identical parasite genotype. Consecutively, the patient was retreated with artemether–lumefantrine and received a regimen of primaquine according to WHO guidelines. Conclusion Conclusive evidence for relapses with P. ovale spp. is rare. The presented case provides convincing confirmation for the relapse paradigm based on re-appearing parasitaemia following supervised treatment in a non-endemic region with a parasite strain of identical genotype

Parasitology Research / Intra-cystic concentrations of albendazole-sulphoxide in human cystic echinococcosis : a systematic review and analysis of individual patient data

Cystic echinococcosis (CE) is a widespread zoonosis caused by the species complex Echinococcus granulosus. Albendazole (ABZ)the first-line anthelminthic drug for medical treatment of CEis metabolized in vivo to the active derivative ABZ-sulphoxide (ABZ-SO). Target-site ABZ-SO concentrations in the hydatid cyst mediate the anthelminthic effect in CE. Primary outcome of this systematic review of individual patient data was the intra-cystic ABZ-SO concentration stratified by cyst size, location, calcification status and use of praziquantel. Studies reporting intra-cystic ABZ-SO concentrations in humans were identified by a systematic search. A pooled analysis of individual patient data was performed to assess intra-cystic concentrations. Pharmacokinetic data of 121 individual cysts were analysed. There was no correlation between plasma and intra-cystic ABZ-SO concentrations (rho = 0.03, p = 0.76). Intra-cystic drug concentrations were also not associated with sex and treatment duration. Use of praziquantel in combination with ABZ was associated with higher plasma (median 540 vs. 240 g/L; p = 0.04) but not intra-cystic ABZ-SO concentrations (median 220 vs. 199 g/L; p = 0.36). Relative drug concentrations in hepatic cysts were higher than in other cysts (0.8 vs. 0.4; p = 0.05). Intra-cystic concentrations were higher in calcified than non-calcified cysts (median 897 vs. 245 g/L; p = 0.03). There was a trend towards higher intra-cystic concentrations in smaller sized cysts ( = 17.2 g/L/cm; 95th CI, 35.9 to 1.6; p = 0.07). This study demonstrates that mean intra-cystic drug concentrations are similar to plasma concentrations on a population level. However, in individual patients plasma concentrations are not directly predictive for intra-cystic concentrations. The use of booster drugs was not associated with higher intra-cystic ABZ-SO concentrations in this analysis.(VLID)347877