• 1.

    Jelinek T, Schulte C, Behrens R, Grobusch MP, Coulaud JP, Bisoffi Z, Matteelli A, Clerinx J, Corachán M, Puente S, Gjørup I, Harms G, Kollaritsch H, Kotlowski A, Björkmann A, Delmont JP, Knobloch J, Nielsen LN, Cuadros J, Hatz C, Beran J, Schmid ML, Schulze M, Lopez-Velez R, Fleischer K, Kapaun A, McWhinney P, Kern P, Atougia J, Fry G, da Cunha S, Boecken G, 2002. Imported falciparum malaria in Europe: sentinel surveillance data from the European network on surveillance of imported infectious diseases. Clin Infect Dis 34: 572576.

    • Search Google Scholar
    • Export Citation
  • 2.

    Boccolini D, Romi R, D'Amato S, Pompa MG, Majori G, 2007. Sorveglianza della malaria in Italia e analisi della casistica del quinquennio 2002–2006. Giornale Italiano di Medicina Tropicale 12: 512.

    • Search Google Scholar
    • Export Citation
  • 3.

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366: 717725.

    • Search Google Scholar
    • Export Citation
  • 4.

    World Health Organization, 2010. Guidelines for the treatment of malaria, second edition. Available at: http://www.who.int/malaria/publications/atoz/9789241547925/en/index/html. Accessed May 8, 2010.

    • Search Google Scholar
    • Export Citation
  • 5.

    Jones KL, Donegan S, Lalloo DG, 2007. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 4: CD005967.

  • 6.

    Jelinek T, 2005. Intravenous artesunate recommended for patients with severe malaria: position statement from TropNetEurop. Euro Surveill 10: E0511245.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA, 2007. HPA Advisory Committee on Malaria Prevention in UK Travelers. UK malaria treatment guidelines. J Infect 54: 111121.

    • Search Google Scholar
    • Export Citation
  • 8.

    Rosenthal PJ, 2008. Artesunate for the treatment of severe falciparum malaria. N Engl J Med 358: 18291836.

  • 9.

    Mørch K, Strand Ø, Dunlop O, Berg A, Langeland N, Leiva RA, Longva JA, Sjursen H, Skrede S, Sundal J, Jensenius M, 2008. Severe malaria and artesunate treatment, Norway. Emerg Infect Dis 14: 18161818.

    • Search Google Scholar
    • Export Citation
  • 10.

    Studdert DM, Mello MM, Sage WM, DesRoches CM, Peugh J, Zapert K, Brennan TA, 2005. Defensive medicine among high-risk specialist physicians in a volatile malpractice environment. J Am Med Assoc 293: 26092617.

    • Search Google Scholar
    • Export Citation
  • 11.

    Newton PN, Chierakul W, Ruangveerayuth R, Silamut K, Teerapong P, Krudsood S, Looareesuwan S, White NJ, 2001. A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria. Trans R Soc Trop Med Hyg 95: 519523.

    • Search Google Scholar
    • Export Citation
  • 12.

    Zamidei L, Durval A, Bettocchi D, Luzzio MG, Bartoloni A, Consales G, 2010. Efficacy and safety of quinine-artesunate in an HIV-positive patient with severe falciparum malaria. Minerva Anestesiol 76: 6669.

    • Search Google Scholar
    • Export Citation
  • 13.

    Mascarello M, Allegranzi B, Angheben A, Anselmi M, Concia E, Laganà S, Manzoli L, Marocco S, Monteiro G, Bisoffi Z, 2008. Imported malaria in adults and children: epidemiological and clinical characteristics of 380 consecutive cases observed in Verona, Italy. J Travel Med 15: 229236.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Combined Intravenous Treatment with Artesunate and Quinine for Severe Malaria in Italy

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  • Clinica Malattie Infettive, Dipartimento Area Critica Medico-Chirurgica, Università degli Studi di Firenze, Firenze, Italy; SOD Malattie Infettive e Tropicali, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy; Istituto Malattie Infettive e Tropicali, Università di Brescia, Brescia, Italy; Dipartimento di Pediatria, Università di Firenze, Firenze, Italy; UO Malattie Infettive, Spedali Riuniti Livorno, Livorno, Italy

Severe imported malaria is an important problem in European countries, where approximately 8,000 cases of Plasmodium falciparum malaria are reported each year. Although the World Health Organization recommends intravenous artesunate (IVA) as the treatment of choice for severe malaria in areas of low transmission, it is rarely used in Europe, because it is not yet available as a drug manufactured under Good Manufacturing Practices. We report a series of eight imported severe falciparum malaria cases treated with IVA combined with intravenous quinine (IVQ). This combined therapy was found to be efficacious, safe, and well-tolerated. The only observed death occurred in a young man who presented 10 days after the onset of symptoms. IVA plus IVQ treatment seems to be an acceptable approach, because the legal risks in using an unlicensed drug for treating a severe malaria case denies the patient the possibility of being treated with the most effective regimen.

Introduction

Severe imported malaria is an important problem in Europe as well as in other nonendemic countries. Each year, approximately 10,000 cases of imported malaria are reported in European countries, with the number of Plasmodium falciparum malaria patients estimated to be as high as 8,000.1 In Italy, malaria is the most common imported infectious disease from the tropics, with about 600 cases reported each year and 1–4 deaths.2 Intravenous quinine (IVQ) is currently the first line drug approved for the treatment of severe malaria in Italy as well as in other European countries; however, another drug, IV artesunate (IVA), has been documented to be superior in reducing high parasite loads more rapidly and treating severe malaria more effectively.35 A large, multicenter randomized trial conducted in South and Southeast Asia documented a 34.7% reduction in all-cause mortality in patients with severe malaria with the use of IVA (15%) compared with IVQ (22%).3 In addition to being more effective than IVQ, IVA has been shown to be safer and simpler to administer. IVA is now recommended as the treatment of choice for severe malaria by the World Health Organization (WHO), and its use is strongly supported by the European Network on Imported Infectious Disease Surveillance (TropNetEurope) and the Advisory Committee on Malaria Prevention in United Kingdom Travelers.4,6,7 Although not licensed in the European Union, a Chinese non-Good Manufacturing Practice (GMP) product made by Guilin Pharmaceutical may be obtained from IDIS Pharma (www.idispharma.com). It is the same formulation used in the above-mentioned large clinical trial. In the United States, IVA manufactured under GMP standards may be obtained as an investigational drug from the Centers for Disease Control and Prevention (www.cdc.gov/malaria/features/artesunate_now_available.htm), and it is considered the appropriate therapy for severe malaria as long as it can be acquired promptly.8 In Europe, the use of IVA is currently limited to few specialist tropical-disease centers.7,9 The main barrier for the use of this drug is the unavailability of an IVA produced in accordance with GMP standards. In Italy, many physicians and pharmacists are opposed to the use of IVA in clinical practice considering that is not approved in our country or other European countries. This practice, that in the setting of defensive medicine falls in the so-called avoidance behavior that reflects physicians' efforts to distance themselves from sources of legal risk, is actually disallowing the most appropriate care for most of the patients with severe malaria.10 Taking into account this current behavior, a combination treatment approach, IVA plus IVQ, has been adopted in some Italian centers to treat severe malaria with the double aim to use the most effective drug (IVA) but at the same time, maintain the use of the IVQ in accordance with national guidelines. No additive effect was expected by the addition of IVQ to IVA, considering that the very fast parasite clearance of artesunate, resulting from its broad-spectrum parasiticidal activity, may not be accelerated by the slower-acting quinine.11 Drug-metabolism interactions are also unlikely in virtue of the different metabolic pathways of the two drugs. Quinine is metabolized by cytochrome P450 3A4, and artesunate is hydrolyzed to dihydroartemisinin; this cleared by glucuronidation.11

Case series

We report here a retrospective analysis of clinical and laboratory features of the first eight imported cases of P. falciparum severe malaria treated with the combination of IVA plus IVQ in the period of May 2008 to October 2009 (Table 1). All patients acquired malaria in West Africa. Five were children (one 1-year-old child, one 3-year-old child, two 6-year-old children, and one 7-year-old child) of African descent born in Italy that had visited relatives, and three were Italian adults working in Africa for a short period. One of the adults was HIV-positive, not on antiretroviral treatment, and reported as having a CD4 + lymphocyte count of 1,008/μL.12 Only two patients had received chemoprophylaxis, incomplete in both cases, with mefloquine. The patients' symptoms fulfilled up to five of the WHO criteria for severe malaria: six had impaired consciousness, two had pulmonary edema, six had severe anemia, three had jaundice, one had acute renal failure, two had hemoglobinuria, and eight had hyperparasitemia (Table 1). The time between the onset of symptoms and the start of therapy was 1–10 days. Parasitemia was estimated at 8% in one case and 10–20% in the other cases. Five patients were admitted to the intensive care unit for supportive treatment (mechanical ventilation in two cases). In all cases, treatment was started with IVA followed by IVQ, at the recommended dosages, after obtaining written informed consent. In three pediatric cases, the loading dose of quinine was not given. IVA was produced by Guilin Pharmaceutical Company, Guangxi, China. Side effects, attributed to quinine, were observed in four cases (two had cinchonism and two had hypoglycemia). The parasitemia fell below 1% after 24 hours in five of eight cases and within 48 hours in the other three cases. None of the patients received exchange transfusion. One patient died after 48 hours from the start of antimalarial treatment, despite the complete parasite clearance at 24 hours after the start of treatment. In this case, the diagnosis was very delayed (10 days after the onset of symptoms), and the treatment started when the patient was in coma. Treatment was switched to oral route in six cases (quinine, N = 4; arthemeter–lumefantrine, N = 2) within 3.6 days (mean). A case of recrudescence was observed 5 days after stopping antimalarial treatment (3 days of IVA plus IVQ followed by the standard six-dose regimen of arthemeter–lumefantrine). This episode was treated successfully with oral quinine and doxycycline. Molecular analysis to clarify the recrudescence episode is currently ongoing.

Table 1

Epidemiologic, clinical, and laboratory data from eight patients with severe falciparum malaria treated with combined intravenous artesunate and quinine, Italy, 2008–2009*

Patient no. (gender/ age in years)Reason for travelCountry of disease acquisitionWHO severe malaria criteriaDays from symptom onset to therapyInitial IV therapyFollow-on oral therapyParasitemia level (%)Stay in ICUSupportive careLength of hospital stay (days)
DrugDayDrugDayDay 012 hDay 1Day 2Day 3Day 4Day 5
1 (F/32)VolunteerMaliImpaired consciousness, severe anemia, hyperparasitemia9AS+Q1–3AR+L4–6100.5003Oxygen; blood transfusion20 (recrudescence at day 11)
2 (M/40)TourismIvory CoastImpaired consciousness, acute renal failure, jaundice, pulmonary edema, hyperparasitemia4AS+Q1–610180.10.10.005015Oxygen; mechanical ventilation; platelet transfusion25
3 (F/1)VRFNigeriaImpaired consciousness, severe anemia, hyperparasitemia9AS+Q1–4AR+L5–78100Blood transfusion7
4 (F/3)VRFBurkina FasoImpaired consciousness, severe anemia, jaundice, hemoglobinuria, hyperparasitemia2AS§+Q1–5Q6–91220111
5 (F/6)VRFBurkina FasoImpaired consciousness, severe anemia, hemoglobinuria, hyperparasitemia4AS+Q1–4Q5–81510.00402Blood transfusion14
6 (M/30)VolunteerGuinea BissauComa, pulmonary edema, hyperparasitemia10AS+Q1–215301Oxygen; mechanical ventilation2(exitus)
7 (M/6)VRFGhanaImpaired consciousness, severe anemia, jaundice, hyperparasitemia4AS+Q1–3Q4–8157302Platelet transfusion8
8 (M/7)VRFBurkina FasoSevere anemia, hyperparasitemia1AS+Q1–3Q4–720113007

WHO = World Health Organization; VFR = visiting friends and relatives; ICU = intensive care unit; AS = artesunate; Q = quinine; AR = arthemeter; L = lumefantrine; IV = intravenous.

The initial therapy was IV artesunate (2.4 mg/kg at time 0, 12, and 24 hours the first day and then one time daily) and IV quinine (a loading dose of 20 mg/kg followed by 10 mg/kg 3 times a day).

IV quinine was administered without a loading dose.

IV artesunate was administered only on the first day.

Discussion

Our case series was in large part represented by children who traveled to subSaharan Africa to visit relatives and friends (VRF), confirming that this population is a high-risk group for severe malaria and that there is a need for educational actions directed to immigrants traveling to VRF focusing on the risk of severe malaria.13

To the best of our knowledge, no published data are available about combined artesunate and quinine in the parenteral treatment of severe malaria, except for a study conducted by Newton and others11 in Thailand. This study, including uncomplicated and severe malaria, provided no benefit evidence from the addition of IVQ to IVA. IVA monotherapy is currently recognized as the treatment of choice for severe falciparum malaria in adults, and the addition of IVQ is considered unnecessary to avoid an increase in the incidence of adverse events.11 In this perspective, our findings cannot add anything about the augmented efficacy of the combined parenteral artesunate and quinine in the treatment of severe falciparum malaria. In our experience, the combined use of IVQ and IVA was found to be an efficacious and safe treatment for severe malaria. The only observed death occurred in a young man presenting 10 days after the onset of symptoms in an advanced state of illness with multiorgan involvement. No adverse events attributable to the combination therapy were observed. Additionally, our rationale for combining parenteral administration of the two antimalarials was not that of obtaining an augmented efficacy but that of offering an acceptable approach in settings where the fear of legal risks from the use of an unlicensed drug for treating severe malaria denies the patient the possibility of being treated with the most effective regimen. Considering that a commercial form of artesunate produced under GMP standards will probably not be available before 2011, although artesunate has received the Orphan Medicinal Drug Designation from the European Medicines Agency (www.emea.europa.eu/pdfs/human/comp/opinion/48693207en.pdf), this approach may represent a temporary solution that can contribute to the reduction of mortality from severe imported malaria in Europe.

  • 1.

    Jelinek T, Schulte C, Behrens R, Grobusch MP, Coulaud JP, Bisoffi Z, Matteelli A, Clerinx J, Corachán M, Puente S, Gjørup I, Harms G, Kollaritsch H, Kotlowski A, Björkmann A, Delmont JP, Knobloch J, Nielsen LN, Cuadros J, Hatz C, Beran J, Schmid ML, Schulze M, Lopez-Velez R, Fleischer K, Kapaun A, McWhinney P, Kern P, Atougia J, Fry G, da Cunha S, Boecken G, 2002. Imported falciparum malaria in Europe: sentinel surveillance data from the European network on surveillance of imported infectious diseases. Clin Infect Dis 34: 572576.

    • Search Google Scholar
    • Export Citation
  • 2.

    Boccolini D, Romi R, D'Amato S, Pompa MG, Majori G, 2007. Sorveglianza della malaria in Italia e analisi della casistica del quinquennio 2002–2006. Giornale Italiano di Medicina Tropicale 12: 512.

    • Search Google Scholar
    • Export Citation
  • 3.

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366: 717725.

    • Search Google Scholar
    • Export Citation
  • 4.

    World Health Organization, 2010. Guidelines for the treatment of malaria, second edition. Available at: http://www.who.int/malaria/publications/atoz/9789241547925/en/index/html. Accessed May 8, 2010.

    • Search Google Scholar
    • Export Citation
  • 5.

    Jones KL, Donegan S, Lalloo DG, 2007. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 4: CD005967.

  • 6.

    Jelinek T, 2005. Intravenous artesunate recommended for patients with severe malaria: position statement from TropNetEurop. Euro Surveill 10: E0511245.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA, 2007. HPA Advisory Committee on Malaria Prevention in UK Travelers. UK malaria treatment guidelines. J Infect 54: 111121.

    • Search Google Scholar
    • Export Citation
  • 8.

    Rosenthal PJ, 2008. Artesunate for the treatment of severe falciparum malaria. N Engl J Med 358: 18291836.

  • 9.

    Mørch K, Strand Ø, Dunlop O, Berg A, Langeland N, Leiva RA, Longva JA, Sjursen H, Skrede S, Sundal J, Jensenius M, 2008. Severe malaria and artesunate treatment, Norway. Emerg Infect Dis 14: 18161818.

    • Search Google Scholar
    • Export Citation
  • 10.

    Studdert DM, Mello MM, Sage WM, DesRoches CM, Peugh J, Zapert K, Brennan TA, 2005. Defensive medicine among high-risk specialist physicians in a volatile malpractice environment. J Am Med Assoc 293: 26092617.

    • Search Google Scholar
    • Export Citation
  • 11.

    Newton PN, Chierakul W, Ruangveerayuth R, Silamut K, Teerapong P, Krudsood S, Looareesuwan S, White NJ, 2001. A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria. Trans R Soc Trop Med Hyg 95: 519523.

    • Search Google Scholar
    • Export Citation
  • 12.

    Zamidei L, Durval A, Bettocchi D, Luzzio MG, Bartoloni A, Consales G, 2010. Efficacy and safety of quinine-artesunate in an HIV-positive patient with severe falciparum malaria. Minerva Anestesiol 76: 6669.

    • Search Google Scholar
    • Export Citation
  • 13.

    Mascarello M, Allegranzi B, Angheben A, Anselmi M, Concia E, Laganà S, Manzoli L, Marocco S, Monteiro G, Bisoffi Z, 2008. Imported malaria in adults and children: epidemiological and clinical characteristics of 380 consecutive cases observed in Verona, Italy. J Travel Med 15: 229236.

    • Search Google Scholar
    • Export Citation

Author Notes

*Address correspondence to Alessandro Bartoloni, Clinica Malattie Infettive, Università di Firenze, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy. E mail: bartoloni@unifi.it

Authors' addresses: Alessandro Bartoloni, Sara Veloci, and Lorenzo Zammarchi, Clinica Malattie Infettive, Università di Firenze Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy, E-mails: bartoloni@unifi.it, sara.veloci@gmail.com, and lorenzozammarchi@hotmail.it. Lina Tomasoni, Alessandro Pini, and Francesco Castelli, Istituto Malattie Infettive e Tropicali, Università di Brescia, Brescia, Italy, E-mails: l.tomasoni@infettivibrescia.it, alessandropini79@yahoo.it, and castelli@med.unibs.it. Filippo Bartalesi, SOD Malattie Infettive e Tropicali, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy, E-mail: bartalesif@aou-careggi.toscana.it. Luisa Galli, Dipartimento di Pediatria, Università degli Studi di Firenze, Firenze, Italy, E-mail: luisa.galli@unifi.it. Spartaco Sani, UO Malattie Infettive, Spedali Riuniti Livorno, Livorno, Italy, E-mail: spartacosani@virgilio.it.

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