Recrudescence of imported falciparum malaria after quinine therapy: potential drug interaction with phenytoin

Quinine remains a reliable treatment for falciparum malaria in most parts of the world. We report recrudescence of imported Plasmodium falciparum malaria following quinine treatment in the context of concurrent phenytoin use. Supported by a subtherapeutic quinine level, we hypothesise that a drug interaction with phenytoin may compromise the efficacy of quinine in the treatment of malaria.     

Intravenous artesunate for severe malaria in travelers, Europe

Multicenter trials in Southeast Asia have shown better survival rates among patients with severe malaria, particularly those with high parasitemia levels, treated with intravenous (IV) artesunate than among those treated with quinine. In Europe, quinine is still the primary treatment for severe malaria. We conducted a retrospective analysis for 25 travelers with severe malaria who returned from malaria-endemic regions and were treated at 7 centers in Europe. All patients survived. Treatment with IV artesunate rapidly reduced parasitemia levels. In 6 patients at 5 treatment centers, a self-limiting episode of unexplained hemolysis occurred after reduction of parasitemia levels. Five patients required a blood transfusion. Patients with posttreatment hemolysis had received higher doses of IV artesunate than patients without hemolysis. IV artesunate was an effective alternative to quinine for treatment of malaria patients in Europe. Patients should be monitored for signs of hemolysis, especially after parasitologic cure.     

The metabolic effects of quinine in children with severe and complicated Plasmodium falciparum malaria in Dar es Salaam.

Quinine is widely used for the treatment of severe and complicated malaria, although resistant strains of Plasmodium falciparum may occur. The drug has been incriminated as a cause of hypoglycaemia in some malaria patients. To determine if quinine has untoward metabolic effects during treatment of severe and complicated malaria we have studied the effects of quinine on blood glucose and intermediary metabolites, serum insulin, C-peptide, plasma glucagon and non-esterified fatty acids in 97 children with severe malaria in Dar es Salaam. All patients responded clinically. No patient developed hypoglycaemia while on quinine therapy given as 10 mg/kg in 10 ml/kg of 5% dextrose infused over 4 h every 8 h. Endogenous insulin secretion, as reflected by C-peptide levels, increased after 4 h but insulin levels did not change significantly. Blood lactate, 3-hydroxybutyrate, plasma non-esterified fatty acids and plasma glucagon all fell appropriately during treatment. We conclude that quinine, when administered at the recommended dose and rate, does not disrupt blood glucose homeostasis, and is still the drug of choice for severe and complicated malaria in children.     

Intrarectal administration of quinine: an early treatment for severe malaria in children?

Delay for treatment of severe malaria is the cause of an important childhood mortality in Africa especially in rural zone when health facilities and accessibility are scarce. Intrarectal treatment is of particular interest in children as a non aggressive, painless and easy treatment. It can be used as early treatment and could decrease the lethality of severe malaria. We recently showed the kinetic profile, the optimal regimen and the clinical efficacy of intrarectal quinine (QIR) using Quinimax (Sanofi, Gentilly France) 20 mg/kg in solution with 2 ml of water. From 1994 to 1996 two open clinical trials were performed in Niger in children (2-15 years). QIR was compared with intraveinous infusion in cerebral malaria (n = 76) and with intramuscular quinine in severe malaria (n = 57). A three daily QIR administration (20 mg/kg followed by 15 mg/kg/8 h) was used in cerebral malaria; a two daily administration in severe malaria (30 mg/kg followed by 20 mg/kg/12 h). Symptomatic treatment was associated for hyperthermia, hypoglycemia, anemia and seizures. Results. In the cerebral malaria study 58 children presented a Blantyre coma score below 3. Four children in the IR group and 9 children in the infusion group died (P > 0.05). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 39.0 +/- 15.2 h and 37.1 +/- 16.5 h; return to consciousness 34.6 +/- 12.8 h and 33.0 +/- 14.1 h; decrease to 50% of the initial parasites count: 15.5 +/- 11.5 h and 13.8 +/- 10.0 h. Residual blood quinine concentrations at 48 hours were similar 7.4 +/- 3.7 mg/l and 7.2 +/- 2.9 mg/l. In the severe malaria study, the mortality was 0 and 7.6% in the QIR and IM group respectively (P > 0.005). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 38.7 +/- 22.8 h and 38.6 +/- 22.2 h; return to consciousness 26.8 +/- 13.9 h and 27.6 +/- 9.9 h for the 16 children in coma. The evolution under QIR treatment was also similar with that described with the other quinine routes. QIR allows an efficious treatment particularly when correct infusion cannot be performed. The efficacy, the simplicity and the good tolerance of QIR are of major concern to decrease the mortality of severe malaria due to delay for treatment and to decrease the side-effects due to intramuscular administrations of quinine in Africa.     

Clinical-parasitological response and in-vitro sensitivity of Plasmodium vivax to chloroquine and quinine on the western border of Thailand

This study was conducted during 2002-2004 at Mae Sot District, on the Thai-Myanmar border, an area of multidrug-resistant Plasmodium falciparum malaria. Sixty-two patients with P. vivax malaria were included in the study. All were randomized into two groups to receive a 3-day regimen of chloroquine or a 3-day regimen of quinine. Primaquine was given to patients in both groups for the elimination of hepatic stages. Results from the present study suggest that the standard regimen of chloroquine and a 3-day course of quinine at the dose regimens under investigation were very effective and well tolerated for the treatment of P. vivax malaria in this area. All patients responded well to both drug regimens; the cure rates with chloroquine or quinine, when given concurrently with the tissue schizontocidal drug primaquine, were virtually 100% within 28 days of follow-up. No significant correlations between parasite clearance time (PCT) or fever clearance time (FCT) and inhibitory concentration 50 (IC50) were found. Patients who had PCT < or = 24 h and those with PCT >24 h had comparable IC50 to chloroquine (alone and plus primaquine) and quinine, as well as similar concentrations of chloroquine/desethylchloroquine (in blood) or quinine (in plasma) at the investigated time points.     

Epidemiological and clinical aspects of blackwater fever among African children suffering frequent malaria attacks

Blackwater fever (BWF), one of the commonest causes of death of Europeans living in Africa at the beginning of the twentieth century, but rarely diagnosed since the 1950s, is related to Plasmodium falciparum malaria but there is considerable debate and controversy about its aetiology. From 1990 to 2000, the whole population of Dielmo, a village in Senegal, was involved in a prospective study of malaria. Three cases of BWF occurred in 3 children aged 4, 7 and 10 years, belonging to a subgroup of children who suffered malaria attacks every 4 to 6 weeks over many years, who had received repeated quinine treatment. The spread of chloroquine resistance, by increasing the use of more toxic alternative drugs, may expose endemic populations to a high incidence of severe side effects of antimalarials.     

A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria.

In some areas clinicians have combined parenteral artesunate and quinine in the belief that the 2 drugs would be additive or synergistic in severe malaria. A randomized comparison of the effectiveness of intravenous (i.v.) artesunate versus i.v. artesunate and i.v. quinine together on parasite clearance was conducted in 1998/99 amongst 69 patients with uncomplicated and severe Plasmodium falciparum malaria in western Thailand. The parasite clearance time did not differ significantly between the 2 treatment groups (P = 0.12), but adverse events were significantly more frequent in the artesunate plus quinine group (P = 0.05). Quinine did not have a significant antipyretic effect and artesunate did not affect the electrocardiographic QTc interval. There is no benefit evident from combining parenteral administration of these 2 antimalarial drugs in the acute phase of treatment.     

Severe Plasmodium knowlesi Malaria in a Tertiary Care Hospital, Sabah, Malaysia

The simian parasite Plasmodium knowlesi causes severe human malaria; the optimal treatment remains unknown. We describe the clinical features, disease spectrum, and response to antimalarial chemotherapy, including artemether-lumefantrine and artesunate, in patients with P. knowlesi malaria diagnosed by PCR during December 2007–November 2009 at a tertiary care hospital in Sabah, Malaysia. Fifty-six patients had PCR-confirmed P. knowlesi monoinfection and clinical records available for review. Twenty-two (39%) had severe malaria; of these, 6 (27%) died. Thirteen (59%) had respiratory distress; 12 (55%), acute renal failure; and 12, shock. None experienced coma. Patients with uncomplicated disease received chloroquine, quinine, or artemether-lumefantrine, and those with severe disease received intravenous quinine or artesunate. Parasite clearance times were 1–2 days shorter with either artemether-lumefantrine or artesunate treatment. P. knowlesi is a major cause of severe and fatal malaria in Sabah. Artemisinin derivatives rapidly clear parasitemia and are efficacious in treating uncomplicated and severe knowlesi malaria.     

The safety and kinetics of intramuscular quinine in Malawian children with moderately severe falciparum malaria

The safety and kinetics of intramuscular quinine (10 mg salt/kg every 8 h for 3 doses) were assessed in Malawian children suffering from uncomplicated falciparum malaria, who were unable to take oral antimalarial drugs. Treatment was completed with oral pyrimethamine-sulfadoxine. The mean (+/- SD) peak plasma quinine concentration after the first injection was 9.0 (+/- 2.3) micrograms/ml, at 1.1 (+/- 0.7) h. Mean plasma concentrations increased further after the second and third doses to a maximum of 11.5 (+/- 2.6) micrograms/ml at 16.1 (+/- 3.2) h. No hypotension, hypoglycaemia or electrocardiographic abnormalities developed during quinine treatment. These results provide further evidence for the safety of intramuscular quinine in children with moderately severe malaria. Plasma concentrations of alpha 1-acid glycoprotein (AGP) were higher, and the degree of protein binding of quinine was greater, in acute malaria than in convalescence. There was a significant correlation between AGP concentration and the fraction of plasma quinine bound to plasma protein. These findings suggest a role for AGP in the binding of quinine in plasma in vivo and are of interest since unbound quinine is responsible for both the efficacy and toxicity of the drug.     

Quinine-Resistant Malaria in Traveler Returning from Senegal, 2007

We describe clinical and parasitologic features of in vivo and in vitro Plasmodium falciparum resistance to quinine in a nonimmune traveler who returned to France from Senegal in 2007 with severe imported malaria. Clinical quinine failure was associated with a 50% inhibitory concentration of 829 nmol/L. Increased vigilance is required during treatment follow-up.     

Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria.

Seventy-nine comatose cerebral malaria patients given standard supportive treatment were randomized to receive specific antimalarial chemotherapy of intravenous quinine, intravenous artesunate, or artemisinin suppositories. Artesunate and artemisinin reduced peripheral asexual parasitaemia significantly more rapidly than quinine (90% clearance time 16 h, 18.9 h and 34.5 h respectively), but did not significantly reduce the duration of coma or mortality. The rapid lowering of peripheral parasitaemia may not ameliorate complications already present. These results demonstrate that artemisinin suppositories are as effective as artesunate and quinine given intravenously, and have economic and practical advantages for the treatment of severe malaria in areas remote from major medical centres. However, large numbers of patients will need to be studied if differences in mortality between the 3 treatment groups are to be demonstrated.     

Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa

Objective

To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets.

Methods

The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted.

Findings

The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7–65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7–69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively.

Conclusion

Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.     

Three newly registered drugs in the Netherlands for the treatment and chemoprophylaxis of malaria: atovaquone-proguanil,artemether-lumefantrine and artemotil

Three new antimalarial drugs have recently been registered in the Netherlands: atovaquone-proguanil, artemether-lumefantrine and artemotil. These drugs are effective against parasites with multiple resistance. Atovaquone-proguanil and artemether-lumefantrine seem in practice to be equivalent for the treatment of non-severe Plasmodium falciparum infections for respectively persons of more than 11 kg and persons aged 12 years and older (35 kg). Artemotil (intramuscular injection) is registered for the treatment of severe malaria in children up to 17 years of age. Atovaquone-proguanil is also registered for prophylactic use in adults. The intravenous administration of quinine is preferable in the case of seriously ill patients. In patients with non-severe malaria for whom parenteral treatment is indicated, artemotil is a good alternative for quinine.     

A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria

We conducted a meta-analysis using individual patient data from randomized controlled trials comparing artemether and quinine in severe falciparum malaria. Eleven trials were identified, of which 8 were clearly randomized. Original individual patient data on 1919 patients were obtained from 7 trials, representing 85% of the patients in the original 11 studies. Overall there were 136 deaths among the 961 patients treated with artemether, compared with 164 in the 958 treated with quinine [14% vs 17%, odds ratio (95% confidence interval) 0.8 (0.62 to 1.02), P = 0.08]. There were no differences between the 2 treatment groups in coma recovery or fever clearance times, or the development of neurological sequelae. However, the combined 'adverse outcome' of either death or neurological sequelae was significantly less common in the artemether group [odds ratio (95% CI) 0.77 (0.62 to 0.96), P = 0.02], and treatment with artemether was associated with significantly faster parasite clearance [hazard ratio (95% CI) 0.62 (0.56 to 0.69), P < 0.001]. In subgroup analyses artemether was associated with a significantly lower mortality than quinine in adults with multisystem failure. In the treatment of severe falciparum malaria artemether is at least as effective as quinine in terms of mortality and superior to quinine in terms of overall serious adverse events. There was no evidence of clinical neurotoxicity or any other major side-effects associated with its use.     

Hypoglycaemia in severe falciparum malaria

The incidence of hypoglycaemia and the role of quinine in its causation was assessed in 46 patients with severe Plasmodium falciparum malaria. Plasma glucose and immunoreactive insulin were estimated before, during and after quinine therapy. In 5 patients the plasma glucose was in the hypoglycaemic range, the lowest value being 0.67 mmol/litre (12 mg/dl) in a pregnant patient. Most of the remaining patients showed a significant fall in plasma glucose (P less than 0.05), but not to the hypoglycaemic range, and an increase in plasma insulin after quinine (P less than 0.01). A good correlation was found between these changes (r = 0.79, P less than 0.01). Patients with severe P. falciparum malaria, particularly those on quinine therapy, should be watched carefully for developing hypoglycaemia.     

Antimalarial drugs and their ways to use in the African milieu

In the tropical African environment, malaria is both a major public health problem and a problem of socioeconomic development. It is caused by various agents, the most virulent and only lethal one of which is Plasmodium falciparum. This parasite is controlled by the appropriate use of antimalarial drugs and methods of individual and collective protection. The principal drugs used to treat bouts of malaria without vomiting caused by P. falciparum are amino-4-quinoleines, essentially chloroquine. This is based on the level of resistance of P. falciparum to drugs in most African countries, particularly those of Central and West Africa. Malawi is the only country of southern Africa to have replaced chloroquine by sulfadoxine-pyrimethamine for this indication, in 1993. In cases of bouts of benign malaria with vomiting, but that are not serious, and severe malaria caused by P. falciparum (suspected or confirmed) with or without drug resistance, quinine should be given intravenously for at least three days. Once the patient regains consciouness or the digestive problems cease, quinine treatment should be given orally for 5 to 7 days. Sulfadoxine-pyrimethamine can be given as an alternative to quinine. The other antimalarial drugs currently on the African market (halofantrine, mefloquine, artemisinine and its derivatives) are often used inappropriately and should be used only in exceptional cases of severe bouts of complicated P. falciparum malaria, with suspected or confirmed resistance to amino-4-quinoleines. Individual protection against the Anopheles mosquito, the principal vector of malaria in Africa, is based largely on the use of mosquito nets impregnated with pyrethroid insecticide and the use of aerosols. Collective protection involves essentially environment-based measures.     

Comparison of intramuscular sulfadoxine-pyrimethamine and intramuscular quinine for the treatment of falciparum malaria in children

The efficacy of intramuscular (i.m.) sulfadoxine-pyrimethamine (sulfadoxine 25 mg/kg plus pyrimethamine 1.25 mg/kg in a single dose; n = 48) was compared with that of i.m. quinine (10 mg/kg 8-hourly for at least 3 d followed by oral quinine to complete 7 d; n = 54) in children with severe malaria without life-threatening complications in Maputo Central Hospital, Mozambique, in 1989. Mean parasite clearance time and mean fever clearance time were 55.4 h and 48.1 h, respectively, in the sulfadozine-pyrimethamine group, and 60.7 h and 54 h in the quinine group. Seven cases in the sulfadoxine-pyrimethamine group were RII/RIII resistant compared with none in the quinine group, but parasite reduction during the first 48 h was no slower in the resistant cases than in the 7 poorest responders to quinine. Blood sugar levels were slightly, but not significantly, lower in the quinine group. On day 7, leucocyte counts were significantly lower in the sulfadoxine-pyrimethamine group, but within the normal range. It is concluded that a single dose of sulfadoxine-pyrimethamine may be useful for the treatment of complicated malaria at health care units without facilities for admission, or if transferral is necessary after start of treatment.     

Quinine pharmacokinetics in cerebral malaria: predicted plasma concentrations after rapid intravenous loading using a two-compartment model

To investigate the toxic potential of rapid intravenous quinine administration in severe malaria, the pharmacokinetic properties of low-dose quinine dihydrochloride injection (4 mg/kg body weight, equivalent to 3.3 mg base/kg) followed one hour later by infusion of 16 mg/kg over 3 h were studied in 7 patients with cerebral malaria. Plasma quinine concentrations closely followed a bi-exponential decline. Both the volumes of the central compartment (mean +/- SD: 0.17 +/- 0.10 litre/kg) and total volumes of distribution (0.74 +/- 0.30 litre/kg) were significantly smaller than those previously reported for healthy subjects. Based on the derived pharmacokinetic parameters, predicted plasma quinine concentrations following intravenous injection of the standard therapeutic dose (10 mg salt/kg) over 10-20 min are potentially toxic in severe malaria. Further reductions in administration time would produce disproportionately higher plasma quinine concentrations, especially as the distribution half-time (2.3 +/- 3.2 min) is approached. A theoretical regimen designed to achieve therapeutic, non-toxic plasma quinine concentrations promptly would be 7.0 mg quinine dihydrochloride/kg over 30 min. A subsequent maintenance infusion of 10 mg/kg over 4 h would allow for drug elimination and acute changes in pharmacokinetic parameters due to resuscitation and rehydration.     

The pharmacokinetic properties of intramuscular quinine in Gambian children with severe falciparum malaria

Plasma quinine concentrations were measured in 21 Gambian children with severe falciparum malaria after intramuscular administration of a 20 mg (salt) per kg loading dose of quinine dihydrochloride followed by 10 mg/kg at 12 h intervals. Quinine was well absorbed reaching mean peak concentrations of 15.6 (standard deviation [SD] 4.5) mg/litre in a median time of 3 h (range 1-6 h). A one compartment model was fitted to the plasma concentration-time profile. The mean estimated systemic clearance (Cl/F) was 0.89 (SD 0.81) ml/kg/min and the mean elimination half life was 18.8 (SD 8.0) h. Two patients, one of whom died, had low plasma quinine levels which remained below 10 mg/litre. Mean peak and trough plasma concentrations after subsequent intramuscular doses ranged between 11.1 and 15.1 mg/litre. In most cases this dose regimen provided a satisfactory profile of blood concentrations for the treatment of severe malaria in children.     

Quinine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan

An observational clinical trial was conducted in New Halfa, eastern Sudan, in November and December 2003. Sixty-two patients with uncomplicated Plasmodium falciparum malaria were treated with oral quinine (10 mg/kg thrice daily for 7 d); 47 (76%) of these patients were followed-up to day 28, and 5 (10.6%) of them appeared to have late treatment failures. The parasitological failures were early R1 in two (4.3%) patients and late R1 in three (6.4%) patients. The reappearance of parasites in three of these five patients were true recrudescences rather than a re-infection, based on genetic evidence. The present results and those of earlier investigations indicate that the response to quinine in this area may be faltering.