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The Journal of Antimicrobial... Nov 2007A systematic review and meta-analysis of the effectiveness of atovaquone-proguanil (Malarone) as a chemoprophylactic agent against malaria. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
A systematic review and meta-analysis of the effectiveness of atovaquone-proguanil (Malarone) as a chemoprophylactic agent against malaria.
METHODS
The data sources searched for this study included Cochrane systematic reviews (on infectious diseases), MEDLINE and EMBASE, Web of Knowledge and Annals of Tropical Medicine. All unconfounded randomized controlled trials assessing the chemoprophylaxis against malaria with atovaquone-proguanil were included in the review. Data on study design, study sample, inclusion and exclusion criteria, allocation, blinding, primary and secondary study end points were all extracted by one reviewer and independently rechecked by the second reviewer.
RESULTS
In general, all 10 studies identified had excellent quality with total scores of >or=4 using the Jadad criteria. Ten controlled trials comprising 4,539 participants were included for this review. A meta-analysis of six of the ten studies found chemoprophylaxis with atovaquone-proguanil, with a prophylaxis efficacy of 95.8% (95% CI = 91.5-97.9), to be superior to placebo. It was also considered safe and better tolerated with fewer treatment-related adverse events that could lead to premature discontinuation of prophylaxis than in controls. Comparison with alternative chemoprophylaxis also showed atovaquone-proguanil to be better tolerated with fewer treatment-related self-reported adverse events (RR = 0.8234; 95% CI = 0.673164-1.01) or severe adverse events (RR = 0.6140; 95% CI = 0.420055-0.8975). Atovaquone-proguanil is well tolerated with no difference in non-compliance with placebo (RR = 0.8804; 95% CI = 0.6964-1.113; I(2) = 31.4%).
CONCLUSIONS
Evidence from this review shows that atovaquone-proguanil is highly efficacious as a prophylactic agent against malaria infection and is very well tolerated compared with other antimalarial agents.
Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria; Proguanil
PubMed: 17848375
DOI: 10.1093/jac/dkm337 -
The Journal of Antimicrobial... Mar 2018Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers. Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance.
METHODS
This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information.
RESULTS
Data suggest that atovaquone/proguanil treatment efficacy is 89%-98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%-26% for Plasmodium vivax malaria (from 1 study including 25 patients). The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM. Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent.
CONCLUSIONS
Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective. Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population. However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation.
Topics: Atovaquone; Drug Combinations; Drug Resistance, Multiple; Drug Therapy, Combination; Electron Transport Complex III; Humans; Malaria, Falciparum; Malaria, Vivax; Mutation; Plasmodium falciparum; Proguanil; Travel; Treatment Failure
PubMed: 29237012
DOI: 10.1093/jac/dkx431 -
Travel Medicine and Infectious Disease 2018We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the... (Review)
Review
BACKGROUND
We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the day of return from a malaria-endemic area instead of seven days after return as per currently recommended post-travel schedule.
METHODS
PubMed and Embase databases were searched to identify relevant studies. This PROSPERO-registered systematic review followed PRISMA guidelines. The search strategy included terms or synonyms relevant to AP combined with terms to identify articles relating to prophylactic use of AP and inhibitory and half-life properties of AP. Studies considered for inclusion were: randomized controlled trials, cohort studies, quasi-experimental studies, open-label trials, patient-control studies, cross-sectional studies; as well as case-series and non-clinical studies. Data on study design, characteristics of participants, interventions, and outcomes were extracted. Primary outcomes considered relevant were prophylactic efficacy and prolonged inhibitory activity and half-life properties of AP.
RESULTS
The initial search identified 1,482 publications, of which 40 were selected based on screening. Following full text review, 32 studies were included and categorized into two groups, namely studies in support of the current post-travel regimen (with a total of 2,866 subjects) and studies in support of an alternative regimen (with a total of 533 subjects).
CONCLUSION
There is limited direct and indirect evidence to suggest that an abbreviated post-travel regimen for AP may be effective. Proguanil, however, has a short half-life and is essential for the synergistic effect of the combination. Stopping AP early may result in mono-prophylaxis with atovaquone and possibly select for atovaquone-resistant parasites. Furthermore, the quality of the studies in support of the current post-travel regimen outweighs the quality of the studies in support of an alternative short, post-travel regimen, and the total sample size of the studies to support stopping AP early comprises a small percentage of the total sample size of the studies performed to establish the efficacy of the current AP regimen. Additional research is required - especially from studies evaluating impact on malaria parasitaemia and clinical illness and conducted among travellers in high malaria risk settings - before an abbreviated regimen can be recommended in current practice.
PROSPERO REGISTRATION NUMBER
CRD42017055244.
Topics: Antimalarials; Atovaquone; Drug Administration Schedule; Drug Combinations; Drug Synergism; Endemic Diseases; Humans; Malaria; Post-Exposure Prophylaxis; Proguanil; Travel; Travel-Related Illness
PubMed: 29242073
DOI: 10.1016/j.tmaid.2017.12.005 -
Travel Medicine and Infectious Disease 2019Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence...
BACKGROUND
Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence of adverse outcomes after atovaquone-proguanil (AP) exposure during pregnancy.
METHODS
Following PRISMA guidelines, the authors searched PubMed, MEDLINE, and the Malaria in Pregnancy Consortium Library to identify relevant literature including infant outcomes after exposure to atovaquone, proguanil, or AP in pregnancy. Two authors independently screened the titles, abstracts, and full texts, and extracted data into an EpiInfo database. Overall proportions and 95% confidence intervals of adverse outcomes were determined by pooling data across studies.
RESULTS
Of 455 records identified, 16 studies were included: ten AP studies and six proguanil studies. The overall proportions and 95% confidence intervals (CI) of adverse outcomes reported for the 446 women exposed to AP include miscarriage (8.08% CI: 5.07, 12.08%), stillbirth (1.05% CI: 0.03, 5.73%), early neonatal death (0% CI: 0, 7.4%), and congenital anomalies (2.56% CI: 1.28, 4.53%).
CONCLUSIONS
The limited available data suggest that outcomes following AP exposure during pregnancy are similar to expected rates in similar populations. AP may be a promising option for pregnant women, but further data are needed on its safety in pregnancy.
Topics: Abortion, Spontaneous; Antimalarials; Atovaquone; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant, Newborn; Malaria; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Proguanil; Stillbirth; Travel
PubMed: 30654041
DOI: 10.1016/j.tmaid.2019.01.008 -
Clinical Microbiology and Infection :... Jul 2024Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.
OBJECTIVES
To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis.
METHODS
DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023.
STUDY ELIGIBILITY CRITERIA
Comparative randomized controlled trials (RCTs).
PARTICIPANTS
PWH.
INTERVENTIONS
Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.
ASSESSMENT OF RISK OF BIAS
Cochrane risk-of-bias tool for RCTs 2.
METHODS OF DATA SYNTHESIS
Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed.
RESULTS
A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups.
CONCLUSIONS
TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
Topics: Humans; Pneumonia, Pneumocystis; Randomized Controlled Trials as Topic; Network Meta-Analysis; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumocystis carinii; HIV Infections; AIDS-Related Opportunistic Infections; Dapsone; Pentamidine; Atovaquone; Antifungal Agents; Treatment Outcome
PubMed: 38583518
DOI: 10.1016/j.cmi.2024.03.037 -
BMJ Clinical Evidence Jul 2010Malaria transmission occurs most frequently in environments with humidity greater than 60% and ambient temperature of 25 °C to 30 °C. Risks increase with longer... (Review)
Review
INTRODUCTION
Malaria transmission occurs most frequently in environments with humidity greater than 60% and ambient temperature of 25 °C to 30 °C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10 to 14 days but can be up to 18 months depending on the strain of parasite.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug preventive interventions in non-pregnant adult travellers? What are the effects of drug prophylaxis in non-pregnant adult travellers? What are the effects of antimalaria vaccines in adult and child travellers? What are the effects of antimalaria interventions in child travellers, pregnant travellers, and in airline pilots? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone-proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), dietary supplementation, doxycycline, electronic mosquito repellents, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vapourising mats, primaquine, pyrimethamine-dapsone, pyrimethamine-sulfadoxine, smoke, topical (skin-applied) insect repellents, and vaccines.
Topics: Antimalarials; Bedding and Linens; Chloroquine; Humans; Malaria; Mefloquine; Primaquine; Travel
PubMed: 21418669
DOI: No ID Found -
Travel Medicine and Infectious Disease 2017With increased international travel over the world the need for safe and effective chemoprophylaxis for malaria is as great as ever. The choice of regimen is difficult,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
With increased international travel over the world the need for safe and effective chemoprophylaxis for malaria is as great as ever. The choice of regimen is difficult, as effectiveness should be weighted against potential adverse effects. Although, some studies have reported high prophylactic efficacy of primaquine, there is no comprehensive evidence comparing its prophylactic effectiveness as well as toxicity. To fill the gap, this systematic review and meta-analysis study was carried out.
METHODS
Using MeSH terms, 756 records were detected through searching "Pubmed", "Embase","Web of Science"and "Cochrane" databases. From these,7 relevant full-text articles with 14 comparisons for final quantitative meta-analysis were included in our review. In order to make a comparison between the studies, Risk Ratios(RRs) and their 95% confidence intervals(CIs) were estimated.
RESULTS
Overall,74% reduction in the incidence of parasitaemia by primaquine versus other prophylactic regimens was estimated(RRoverall = 0.26, CI 95%:0.16-0.41--RRvivax = 0.16, CI 95%:0.07-0.36--RRfalciparum = 0.31, CI 95%:0.18-0.55). The incidence rate ratios for adverse effects showed no statistically significant difference between primaquine and control groups (p > 0.05).
CONCLUSIONS
For persons without G6PD deficiency, who are not pregnant, primaquine is the most effective presently available prophylactic for P. vivax malaria and comparable to such regimens as doxycycline, mefloquine and atovaquone-proguanil for the prevention of P. falciparum malaria.
Topics: Antibiotic Prophylaxis; Antimalarials; Humans; Malaria, Falciparum; Malaria, Vivax; Parasitemia; Plasmodium falciparum; Plasmodium vivax; Primaquine; Travel
PubMed: 28450185
DOI: 10.1016/j.tmaid.2017.04.005 -
Travel Medicine and Infectious Disease 2022Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for... (Review)
Review
Discontinuing atovaquone/proguanil prophylaxis ad-hoc post-exposure and during-travel dose-sparing prophylactic regimens against P. falciparum malaria: An update with pointers for future research.
BACKGROUND
Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for seven days post exposure. A systematic review by Savelkoel et al. summarised data up to 2017 on abbreviated AP regimens, and concluded that discontinuing AP upon return may be effective, although the available data was insufficient to modify current recommendations. The same applies to other studies evaluating during-travel dose-sparing regimens.
METHODS
A literature search in Pubmed and Embase was performed including search terms related to AP prophylaxis and pharmacokinetics to search for recent studies on abbreviated AP regimens published since 2017.
RESULTS
Since the 2017 review, no new studies assessing discontinuing AP ad-hoc post-exposure prophylaxis have been published. Two new studies were identified assessing other abbreviated AP regimens; one investigated a twice-weekly AP regimen in 32 travellers, and one a three-day AP course in therapeutic dose (1000/400 mg) prior to exposure in 215 travellers. No malaria cases were detected in the study participants adhering to these regimens.
CONCLUSIONS
Further research would be needed if the research question is considered of sufficient importance to facilitate evidence-based decision-making to modify current guidelines, as efficacy studies in travellers are fraught with confounders. We recommend human challenge trials to study abbreviated AP regimens pertaining to malaria chemoprophylaxis as they allow for rational, subject number, time- and cost-saving trial designs.
Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria; Malaria, Falciparum; Proguanil; Travel
PubMed: 35661741
DOI: 10.1016/j.tmaid.2022.102365 -
BMJ Clinical Evidence Nov 2007Malaria transmission occurs most frequently in environments with humidity over 60% and ambient temperature of 25-30 degrees C. Risks increase with longer visits and... (Review)
Review
INTRODUCTION
Malaria transmission occurs most frequently in environments with humidity over 60% and ambient temperature of 25-30 degrees C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10-14 days but can be up to 18 months depending on the strain of parasite.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug preventive interventions in adult travellers? What are the effects of drug prophylaxis in adult travellers? What are the effects of antimalaria vaccines in travellers? What are the effects of antimalaria interventions in child travellers, pregnant travellers, and in airline pilots? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acoustic buzzers, aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone-proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), doxycycline, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vaporising mats, primaquine, pyrimethamine-dapsone, pyrimethamine-sulfadoxine, smoke, topical (skin-applied) insect repellents, and vaccines.
Topics: Administration, Oral; Animals; Antimalarials; Bedding and Linens; Chloroquine; Humans; Insect Repellents; Insecticides; Malaria; Travel
PubMed: 19450348
DOI: No ID Found -
Parasitology Research Oct 2018Currently, there is no approved therapy that can eradicate Toxoplasma gondii tissue cysts, which are responsible for chronic infection. This systematic review was... (Review)
Review
Currently, there is no approved therapy that can eradicate Toxoplasma gondii tissue cysts, which are responsible for chronic infection. This systematic review was performed to assess drugs or compounds that can be used as anti-T. gondii tissue cysts in vitro and in vivo. English electronic databases (i.e., PubMed, Science Direct, Scopus, Google Scholar, and Web of Science) were systematically searched for articles published up to 2017. A total of 55 papers published from 1987 to 2017 were eligible for inclusion in this systematic review. Among the drugs, atovaquone and azithromycin were found effective after long-term inoculation into mice; however, clinical cases of resistance to these drugs have been reported. Also, FR235222, QUI-11, tanshinone IIA, and hydroxyzine were shown to be effective against Toxoplasma cysts, but their effectiveness in vivo remains unknown. Additionally, compound 32, endochin-like quinolones, miltefosine, and guanabenz can be used as effective antiparasitic with the unique ability to reduce brain tissue cysts in chronically infected mice. Importantly, these antimicrobial agents are significant criteria for drug candidates. Future studies should focus on the biology and drug susceptibility of the cyst form of T. gondii in chronic toxoplasmosis patients to find more effective strategies that have sterilizing activity for eliminating T. gondii tissue cysts from the host, preventing disease relapse and potentially shortening the required duration of drug administration. Graphical abstract.
Topics: Abietanes; Animals; Antiparasitic Agents; Atovaquone; Azithromycin; Brain; Cysts; Humans; Hydroxyzine; Mice; Peptides, Cyclic; Toxoplasma; Toxoplasmosis; Toxoplasmosis, Animal
PubMed: 30088074
DOI: 10.1007/s00436-018-6027-z