scholarly journals Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?

Parasitology ◽  
2011 ◽  
Vol 138 (12) ◽  
pp. 1459-1468 ◽  
Author(s):  
COLIN J. SUTHERLAND ◽  
HAMZA BABIKER ◽  
MARGARET J. MACKINNON ◽  
LISA RANFORD-CARTWRIGHT ◽  
BADRIA BABIKER EL SAYED
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Selective Pressure ◽  
Severe Disease ◽  
Preventive Therapy ◽  
Combination Regimen ◽  
First Line ◽  
Drug Pressure ◽  
Paediatric Malaria ◽  
Parasite Populations

SUMMARYArtemisinin-based combination therapy is exerting novel selective pressure upon populations of Plasmodium falciparum across Africa. Levels of resistance to non-artemisinin partner drugs differ among parasite populations, and so the artemisinins are not uniformly protected from developing resistance, already present in South East Asia. Here, we consider strategies for prolonging the period of high level efficacy of combination therapy for two particular endemicities common in Africa. Under high intensity transmission, two alternating first-line combinations, ideally with antagonistic selective effects on the parasite genome, are advocated for paediatric malaria cases. This leaves second-line and other therapies for adult cases, and for intermittent preventive therapy. The drug portfolio would be selected to protect the ‘premier’ combination regimen from selection for resistance, while maximising impact on severe disease and mortality in children. In endemic areas subject to low, seasonal transmission of Plasmodium falciparum, such a strategy may deliver little benefit, as children represent a minority of cases. Nevertheless, the deployment of other drug-based interventions in low transmission and highly seasonal areas, such as mass drug administration aimed to interrupt malaria transmission, or intermittent preventive therapy, does provide an opportunity to diversify drug pressure. We thus propose an integrated approach to drug deployment, which minimises direct selective pressure on parasite populations from any one drug component. This approach is suitable for qualitatively and quantitatively different burdens of malaria, and should be supported by a programme of routine surveillance for emerging resistance.

scholarly journals Beta Lactams plus Daptomycin Combination Therapy for Infective Endocarditis: An Italian National Survey (BADAS)

Antibiotics ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 56
Author(s):  
Silvia Corcione ◽  
Tommaso Lupia ◽  
Carlo Pallotto ◽  
Daniele Roberto Giacobbe ◽  
Ilaria De Benedetto ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Combination Therapy ◽  
National Survey ◽  
Severe Disease ◽  
Combination Regimen ◽  
Beta Lactams ◽  
First Line ◽  
Cross Sectional ◽  
Bacterial Killing ◽  
Feasible Option

Background: infective endocarditis (IE) remains a severe disease frequently encountered in clinical practice and often requiring interdisciplinary medical and surgical management. This national survey aims to describe the clinical prescribing habits of the use of daptomycin in the setting of IE and the possible role for combination therapy with beta-lactams. Methods: The study was a cross-sectional internet-based questionnaire survey on therapy with daptomycin. The questionnaire was designed with closed-ended questions and distributed using the SurveyMonkey® platform between October 2019 to December 2020. Results: 55 clinicians from twelve Italians regions joined the questionnaire. The survey reported use of daptomycin as first-line choice in 31.48% of cases and as the first-line anti-MRSA agent in 44.44%. The empiric use of daptomycin was stated in the high suspicion of MRSA rather than MSSA, enterococcal or streptococcal IE. The rationale of daptomycin for the empirical treatment of native and prosthetic valve IE was mostly the possibility of administering an aminoglycoside-sparing combination regimen, high bacterial killing rate and high clinical efficacy. Conclusions: In conclusion, in selected patients, daptomycin could be a feasible option for the treatment of infective endocarditis in line with data from the European registry of daptomycin.

scholarly journals In Vitro Monitoring of Plasmodium falciparum Drug Resistance in French Guiana: a Synopsis of Continuous Assessment from 1994 to 2005

2007 ◽  
Vol 52 (1) ◽  
pp. 288-298 ◽  
Author(s):  
Eric Legrand ◽  
Béatrice Volney ◽  
Jean-Baptiste Meynard ◽  
Odile Mercereau-Puijalon ◽  
Philippe Esterre
Keyword(s):  
Plasmodium Falciparum ◽  
French Guiana ◽  
Control Program ◽  
Drug Susceptibility ◽  
Warning Signs ◽  
Strongly Correlated ◽  
First Line ◽  
Drug Pressure ◽  
Line Drug

ABSTRACT Implemented as one arm of the malaria control program in French Guiana in the early 1990s, our laboratory has since established in vitro profiles for parasite drug susceptibility to a panel of eight antimalarials for more than 1,000 Plasmodium falciparum isolates from infected patients. The quinine-doxycycline combination was introduced in 1995 as the first-line drug treatment against uncomplicated P. falciparum malaria, replacing chloroquine, and the first-line drug combination was changed to the artemether-lumefantrine combination in 2002. Resistance to chloroquine declined 5 years after it was dropped in 1995 as the first-line drug, but unlike similar situations in Africa, there was a rapid halt to this decline. Doxycycline susceptibility substantially decreased from 2002 to 2005, suggesting parasite selection under quinine-doxycycline drug pressure. Susceptibility to mefloquine decreased from 1997 onward. Throughout the period from 1994 to 2005, most isolates were sensitive in vitro to quinine, amodiaquine, and atovaquone. Susceptibility to amodiaquine was strongly correlated with that to chloroquine and to a lesser extent with that to mefloquine and halofantrine. Susceptibilities to mefloquine and to halofantrine were also strongly correlated. There were two alerts issued for in vitro artemether resistance in the period from 2002 to 2003 and again in 2005, both of which could be associated with the presence of an S769N polymorphism in the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-type P. falciparum ATPase6 (PfATPase6) gene. Analysis of susceptibility to lumefantrine, conducted for the first time in 2005, indicates an alarming rate of elevated 50% inhibitory concentrations. In vitro monitoring of parasite drug susceptibility should be pursued to further document the consequences of specific drug policies on the local parasite population and, in particular, to establish profiles of susceptibility to individual components of drug combinations to provide early warning signs of emerging parasite resistance.

scholarly journals A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Satish K. Dhingra ◽  
Devasha Redhi ◽  
Jill M. Combrinck ◽  
Tomas Yeo ◽  
John Okombo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Partial Resistance ◽  
Selective Pressure ◽  
Chloroquine Resistance ◽  
Variant Form ◽  
Combination Therapies ◽  
First Line ◽  
Chloroquine Resistance Transporter ◽  
Biochemical Assays ◽  
Global Agenda

ABSTRACT Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance. Using heme fractionation assays, we demonstrate that PPQ causes a buildup of reactive free heme and inhibits the formation of chemically inert hemozoin crystals. Our data evoke inhibition of heme detoxification in the parasite’s acidic digestive vacuole as the primary mode of both the bis-aminoquinoline PPQ and the related 4-aminoquinoline CQ. Both drugs also inhibit hemoglobin proteolysis at elevated concentrations, suggesting an additional mode of action. Isogenic lines differing in their pfmdr1 copy number showed equivalent PPQ susceptibilities. We propose that mutations in PfCRT could contribute to a multifactorial basis of PPQ resistance in field isolates. IMPORTANCE The global agenda to eliminate malaria depends on the continued success of artemisinin-based combination therapies (ACTs), which target the asexual blood stages of the intracellular parasite Plasmodium. Partial resistance to artemisinin, however, is now established in Southeast Asia, exposing the partner drugs to increased selective pressure. Plasmodium falciparum resistance to the first-line partner piperaquine (PPQ) is now spreading rapidly in Cambodia, resulting in clinical treatment failures. Here, we report that a variant form of the Plasmodium falciparum chloroquine resistance transporter, harboring a C101F mutation edited into the chloroquine (CQ)-resistant Dd2 isoform prevalent in Asia, can confer PPQ resistance in cultured parasites. This was accompanied by a loss of CQ resistance. Biochemical assays showed that PPQ, like CQ, inhibits the detoxification of reactive heme that is formed by parasite-mediated catabolism of host hemoglobin. We propose that novel PfCRT variants emerging in the field could contribute to a multigenic basis of PPQ resistance. IMPORTANCE The global agenda to eliminate malaria depends on the continued success of artemisinin-based combination therapies (ACTs), which target the asexual blood stages of the intracellular parasite Plasmodium. Partial resistance to artemisinin, however, is now established in Southeast Asia, exposing the partner drugs to increased selective pressure. Plasmodium falciparum resistance to the first-line partner piperaquine (PPQ) is now spreading rapidly in Cambodia, resulting in clinical treatment failures. Here, we report that a variant form of the Plasmodium falciparum chloroquine resistance transporter, harboring a C101F mutation edited into the chloroquine (CQ)-resistant Dd2 isoform prevalent in Asia, can confer PPQ resistance in cultured parasites. This was accompanied by a loss of CQ resistance. Biochemical assays showed that PPQ, like CQ, inhibits the detoxification of reactive heme that is formed by parasite-mediated catabolism of host hemoglobin. We propose that novel PfCRT variants emerging in the field could contribute to a multigenic basis of PPQ resistance.

scholarly journals Decreased Prevalence of the Plasmodium Falciparum Pfcrt K76T and Pfmdr1 N86Y Mutations Post- Chloroquine Treatment Withdrawal in Katete District, Eastern Zambia

2021 ◽  
Author(s):  
Mulenga Chilumba Mwenda ◽  
Lungowe Sitali ◽  
Ilinca Ciubotariu ◽  
Moonga B Hawela ◽  
Busiku Hamainza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Complete Recovery ◽  
The Body ◽  
Chloroquine Resistance ◽  
Treatment Withdrawal ◽  
Combination Regimen ◽  
Drug Pressure ◽  
Length Polymorphisms ◽  
Chloroquine Treatment ◽  
First Choice

Abstract Background: In 2002, Zambia withdrew chloroquine as first line treatment for Plasmodium falciparum malaria due to increased treatment failure and world-wide spread of chloroquine resistance. The artemisinin combination regimen artemether-lumefantrine replaced chloroquine as first choice malaria treatment. The present study determined the prevalence of chloroquine resistance molecular markers in the malaria parasite Pfcrt and Pfmdr1 genes in Eastern Zambia at nine and thirteen years after the removal of drug pressure.Methods: We assayed by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) the prevalence of the genetic mutations, K76T on the Pfcrt gene and N86Y on the Pfmdr1 gene in samples collected from Katete District during drug therapeutic efficacy assessments conducted in 2012 and 2016.Results: A total of 204 P. falciparum positive samples from 2012 and 2016 were further analysed for Pfcrt K76T and Pfmdr1 N86Y. 112 P. falciparum infected samples collected in 2012 were successfully amplified for Pfcrt and Pfmdr1, while 69 (65.7%) and 72 (68.6%) samples from 2016 were successfully amplified for Pfcrt and Pfmdr1. In 2012, the prevalence of Pfcrt 76K was 97.3%, 76T was 1.8%, and 0.8% had both 76K and 76T codons. The prevalence of Pfmdr1 86N was 97.9% and 86Y was 2.1%. In the 2016 samples, the prevalence of the respective parasite genotypes was 100% Pfcrt 76K and Pfmdr1 86N.Conclusion: This study shows that there was a complete recovery of chloroquine-sensitive parasites by 2016 in Katete District, thirteen years following the withdrawal of CQ. These findings add to the body of evidence for a fitness cost in chloroquine-resistant P. falciparum in Zambia and elsewhere. Further studies are recommended to explore the feasibility of integration of the former best antimalarial in combination therapy in the future.

scholarly journals Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

2016 ◽  
Vol 60 (10) ◽  
pp. 5649-5654 ◽  
Author(s):  
Joaniter I. Nankabirwa ◽  
Melissa D. Conrad ◽  
Jennifer Legac ◽  
Stephen Tukwasibwe ◽  
Patrick Tumwebaze ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Sensitivity ◽  
Selective Pressure ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Drug Pressure ◽  
Content Type ◽  
The Past ◽  
The Impact ◽  
Selection Of

ABSTRACTDihydroartemisinin-piperaquine (DP) offers prolonged protection against malaria, but its impact onPlasmodium falciparumdrug sensitivity is uncertain. In a trial of intermittent preventive treatment in schoolchildren in Tororo, Uganda, in 2011 to 2012, monthly DP for 1 year decreased the incidence of malaria by 96% compared to placebo; DP once per school term offered protection primarily during the first month after therapy. To assess the impact of DP on selection of drug resistance, we compared the prevalence of key polymorphisms in isolates that emerged at different intervals after treatment with DP. Blood obtained monthly and at each episode of fever was assessed forP. falciparumparasitemia by microscopy. Samples from 160 symptomatic and 650 asymptomatic episodes of parasitemia were assessed at 4 loci (N86Y, Y184F, and D1246Y inpfmdr1and K76T inpfcrt) that modulate sensitivity to aminoquinoline antimalarials, utilizing a ligase detection reaction-fluorescent microsphere assay. Forpfmdr1N86Y andpfcrtK76T, but not the other studied polymorphisms, the prevalences of mutant genotypes were significantly greater in children who had received DP within the past 30 days than in those not treated within 60 days (86Y, 18.0% versus 8.3% [P= 0.03]; 76T, 96.0% versus 86.1% [P= 0.05]), suggesting selective pressure of DP. Full sequencing ofpfcrtin a subset of samples did not identify additional polymorphisms selected by DP. In summary, parasites that emerged soon after treatment with DP were more likely than parasites not under drug pressure to harborpfmdr1andpfcrtpolymorphisms associated with decreased sensitivity to aminoquinoline antimalarials. (This study has been registered at ClinicalTrials.gov under no. NCT01231880.)

scholarly journals Beyond a single pathway: combination therapy in pulmonary arterial hypertension

2016 ◽  
Vol 25 (142) ◽  
pp. 408-417 ◽  
Author(s):  
Olivier Sitbon ◽  
Sean Gaine
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Triple Therapy ◽  
Severe Disease ◽  
Dual Therapy ◽  
Disease Stage ◽  
Combination Regimen ◽  
Initial Regimen ◽  
Pulmonary Arterial

There is a strong rationale for combining therapies to simultaneously target three of the key pathways implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Evidence to support this strategy is growing, and a number of studies have demonstrated that combination therapy, administered as either a sequential or an initial regimen, can improve long-term outcomes in PAH. Dual combination therapy with a phosphodiesterase-5 inhibitor and an endothelin receptor antagonist is the most widely utilised combination regimen. However, some patients fail to achieve their treatment goals on dual therapy and may benefit from the addition of a third drug. The use of triple therapy in clinical practice was previously reserved for patients with severe disease due to the need for parenteral administration of prostanoids. Although triple therapy with parenteral prostanoids plays a key role in the management of severe PAH, the approval of oral therapies that target the prostacyclin pathway means that all three pathways can now be targeted with oral drugs at an earlier disease stage. Furthermore, there is evidence demonstrating that this approach can delay disease progression. Based on the evidence available, it is becoming increasingly clear that all PAH patients should be offered the benefits of combination therapy.

scholarly journals Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine Exert Inverse Selective Pressure on Plasmodium Falciparum Drug Sensitivity-Associated Haplotypes in Uganda

2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Aimee R. Taylor ◽  
Jennifer A. Flegg ◽  
Chris C. Holmes ◽  
Philippe J. Guérin ◽  
Carol H. Sibley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Selective Pressure ◽  
Frequency Estimation ◽  
Haplotype Frequency ◽  
Wild Type ◽  
Estimation Model ◽  
Drug Pressure ◽  
Prior Therapy ◽  
Haplotype Frequency Estimation ◽  
Combination Regimens

Abstract Background Altered sensitivity to multiple antimalarial drugs is mediated by polymorphisms in pfmdr1, which encodes the Plasmodium falciparum multidrug resistance transporter. In Africa the N86Y and D1246Y polymorphisms have been shown to be selected by treatment, with artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) selecting for wild-type and mutant alleles, respectively. However, there has been little study of pfmdr1 haplotypes, in part because haplotype analyses are complicated by multiclonal infections. Methods We fit a haplotype frequency estimation model, which accounts for multiclonal infections, to the polymorphic pfmdr1 N86Y, Y184F, and D1246Y alleles in samples from a longitudinal trial comparing AL and DP to treat uncomplicated P falciparum malaria in Tororo, Uganda from 2007 to 2012. We regressed estimates onto covariates of trial arm and selective drug pressure. Results Yearly trends showed increasing frequency estimates for haplotypes with wild type pfmdr1 N86 and D1246 alleles and decreasing frequency estimates for haplotypes with the mutant pfmdr1 86Y allele. Considering days since prior therapy, we saw evidence suggestive of selection by AL for haplotypes with N86 combined with 184F, D1246, or both, and against all haplotypes with 86Y, and evidence suggestive of selection by DP for 86Y only when combined with Y184 and 1246Y (haplotype YYY) and against haplotypes NFD and NYY. Conclusions Based on our model, AL selected several haplotypes containing N86, whereas DP selection was haplotype specific, demonstrating the importance of haplotype analyses. Inverse selective pressure of AL and DP on the complementary haplotypes NFD and YYY suggests that rotating artemisinin-based antimalarial combination regimens may be the best treatment option to prevent resistance selection.

scholarly journals Decreased prevalence of the Plasmodium falciparum Pfcrt K76T and Pfmdr1 and N86Y mutations post-chloroquine treatment withdrawal in Katete District, Eastern Zambia

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Mwenda C. Mulenga ◽  
Lungowe Sitali ◽  
Ilinca I. Ciubotariu ◽  
Moonga B. Hawela ◽  
Busiku Hamainza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Complete Recovery ◽  
The Body ◽  
Chloroquine Resistance ◽  
Treatment Withdrawal ◽  
Combination Regimen ◽  
Drug Pressure ◽  
Length Polymorphisms ◽  
Chloroquine Treatment ◽  
First Choice

Abstract Background In 2002, Zambia withdrew chloroquine as first-line treatment for Plasmodium falciparum malaria due to increased treatment failure and worldwide spread of chloroquine resistance. The artemisinin combination regimen, artemether–lumefantrine, replaced chloroquine (CQ) as first choice malaria treatment. The present study determined the prevalence of CQ resistance molecular markers in the Pfcrt and Pfmdr1 genes in Eastern Zambia at 9 and 13 years after the removal of drug pressure. Methods Samples collected from Katete District during the drug therapeutic efficacy assessments conducted in 2012 and 2016 were assayed by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) to determine the prevalence of genetic mutations, K76T on the Pfcrt gene and N86Y on the Pfmdr1 gene. A total of 204 P. falciparum-positive DBS samples collected at these two time points were further analysed. Results Among the samples analysed for Pfcrt K76T and Pfmdr1 N86Y in the present study, 112 (82.4%) P. falciparum-infected samples collected in 2012 were successfully amplified for Pfcrt and 94 (69.1%) for Pfmdr1, while 69 (65.7%) and 72 (68.6%) samples from 2016 were successfully amplified for Pfcrt and Pfmdr1, respectively. In 2012, the prevalence of Pfcrt 76K (sensitive) was 97.3%, 76T (resistant) was 1.8%, and 0.8% had both 76K and 76T codons (mixed). Similarly in 2012, the prevalence of Pfmdr1 86N (sensitive) was 97.9% and 86Y (resistant) was 2.1%. In the 2016 samples, the prevalence of the respective samples was 100% Pfcrt 76K and Pfmdr1 86N. Conclusion This study shows that there was a complete recovery of chloroquine-sensitive parasites by 2016 in Katete District, Eastern Zambia, 13 years following the withdrawal of CQ in the country. These findings add to the body of evidence for a fitness cost in CQ-resistant P. falciparum in Zambia and elsewhere. Further studies are recommended to monitor resistance countrywide and explore the feasibility of integration of the former best anti-malarial in combination therapy in the future.

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