Clinical effectiveness
Due to the short half-life of the first generation of macrolides, their use for anti-malarial treatment is limited. The best-studied antiplasmodial molecules include azithromycin, for which chemical modifications significantly increase the half-life, and clindamycin.
In this section, the clinical trials using azithromycin and those using clindamycin will be successively discussed.
Concerning azithromycin, its antiplasmodial action was first described in vitro at the beginning of the 90s [17, 37]. At the end of the 90s, the mass distribution of azithromycin through the World Health Organization (WHO) trachoma elimination programme was shown to reduce malarial parasitaemia [38]. Several studies concerning the antiparasitic properties of antibiotics showed the delayed action of the molecule [16, 27, 28]. Only one clinical multicentre study of azithromycin for the treatment of acute uncomplicated P. falciparum malaria was conducted in India on 15 participants. In this study, patients were randomly assigned to groups treated with either azithromycin or chloroquine alone, or azithromycin associated with chloroquine [3]. The resolution of parasitaemia was inadequate with monotherapy with either azithromycin or chloroquine, but combination therapy provided substantially improved clinical and parasitological outcomes. The delayed resolution of parasitaemia and the potential adverse effects that may occur with effective high doses [39] confirmed that this drug was unsuitable for monotherapy treatment by azithromycin. In addition, different associations were tested in vivo (Table 1).
Clinical trials of azithromycin plus other drug against P. falciparum malaria
Randomized controlled trial
Only trials with adequate dosing, i.e. clindamycin given at least twice daily are mentioned in this table
Pop population, A adult, C children, P pregnant women
aA artesunate, Ath arthemeter, C chloroquine, F fosmidomycin, Q quinine, SP sulfadoxine–pyriméthamine
The effects of associations, such as azithromycin–chloroquine and azithromycin–quinine, were additive on sensitive chloroquine strains and synergistic on resistant strains [40]. Other associations were examined, showing effectiveness, associating azithromycin with a rapidly acting schizonticidal compounds, such as lumefantrine or artemisinin [9, 41]. Two in vitro studies [40, 42] suggested that the dihydroartemisinin-azithromycin combination had antagonistic effects and should be avoided. An in vivo study conducted in Thailand [41], a geographic area with high levels of resistance to anti-malarial drugs, showed that azithromycin–artesunate, even when administered only once daily for 3 days, and azithromycin–quinine, administered three times daily, are safe and efficacious combination treatments for uncomplicated falciparum malaria. A randomized controlled trial performed in Tanzanian children did not support the use of azithromycin–artesunate as treatment for malaria; indeed, the 58 % parasitological failure rate observed after day 28 clearly showed that this treatment could not be an appropriate first line treatment for malaria [9]. One clinical trial conducted in Bangladesh performed on 152 patients suggested that this combination was an efficacious and well-tolerated treatment for patients with uncomplicated falciparum malaria compared with the artemether–lumefantrine combination [43]. This study did not consider the re-emergence of parasites in the peripheral blood as a failure of the treatment, although the mean time was 31.5 ± 5 days. Moreover, these authors did not distinguish the study group according to the age of the patients and mixed children and adults for the data integration.
The efficacy of the azithromycin–quinine combination was confirmed in 2006 [44] when 100 % of the patients were cured through high azithromycin regimens (combination of quinine with 1000 mg of azithromycin per day for 5 days or 1500 mg of azithromycin for 3 days).
A longitudinal trial comparing the effects of chloroquine as a monotherapy or in combination with other drugs, including azithromycin, on children with repeated malaria infections in Malawi demonstrated a high efficacy of the repeated administration of different regimens and showed a significantly higher haemoglobin concentration in children in the chloroquine–azithromycin group. This result might reflect the prevention or treatment of bacterial infections [10]. This combination, chloroquine–azithromycin was recently confirmed as highly efficient and well tolerated in African adults [11].
Another combination treatment comprising azithromycin with sulfadoxine–pyrimethamine was tested in pregnant women from Malawi [8]. Sulfadoxine–pyrimethamine has been adopted in many sub-Saharan Africa countries as the drug of choice for intermittent preventive therapy to reduce placental malaria and low-birth weight. The azithromycin–sulfadoxine–pyrimethamine combination might have several advantages: first, although the parasite clearance rate was slow compared with sulfadoxine–pyrimethamine–artesunate, the rate of recrudescence was low and markedly similar between the two groups. Secondly, azithromycin has an adequate safety profile, as this molecule has often been used in pregnant women to treat STIs. In contrast, there has been concern about the use of artemisinin derivatives during the first trimester based on animal studies [45]. Thirdly, azithromycin has a relatively long half-life compared with artesunate. The azithromycin–sulfadoxine–pyrimethamine combination protects the longer-acting drug (sulfadoxine–pyrimethamine) [8], by decreasing the probability of parasites encountering sub-therapeutic drug levels and promoting the development of resistance [46].
Despite these results, a review from the Cochrane Collaboration [39] concluded that the available evidence suggested that azithromycin was a weak anti-malarial with some appealing safety characteristics, and that azithromycin’s future for the treatment of malaria did not look promising.
Concerning lincosamides, clindamycin is a major antibiotic for the treatment of anaerobic bacterial infections [47]. This drug also presents antimicrobial activity against Plasmodium, Toxoplasma, Babesia and Pneumocystis spp. Moreover, clindamycin is the drug of choice for treatment against toxoplasmic chorioretinitis in newborns and one of the treatments recommended in the babesiosis with Babesia microti and B. divergens [48]. Associated with pyrimethamine or primaquine, clindamycin is a treatment of second intention against toxoplasmosis and pneumocystosis [49].
The antiplasmodial indication of clindamycin was managed according to various therapeutic regimens. The effectiveness of clindamycin in monotherapy in this indication was initially reported in 1975 [50]. The WHO repeated this protocol in several studies conducted on different continents, and several sightings have been reported (Table 2), including the effectiveness of clindamycin in monotherapy against malaria. This efficiency is however conditioned through treatment for 5 days, with twice-daily administration, as this molecule acts slowly. Clindamycin is well tolerated, and minor side effects have been reported during treatment. The occurrence of diarrhoea resulting from Clostridium difficile has often been reported after treatment with clindamycin, and this side effect might progress to pseudomembranous colitis, as a result of lengthy treatment with antibiotics [51]. The potential problem of severe diarrhoea, observed in patients receiving a prolonged and high dose of clindamycin therapy, is not observed with a low dose and short duration of therapy to treat malaria [52]. The WHO did not ultimately recommend clindamycin treatment when used alone as an anti-malarial treatment, as parasite clearance might be deleterious in cases of significant parasitaemia in fragile subjects (children and pregnant woman) [2]. However, clindamycin is now recommended for pregnant women in the first trimester with uncomplicated malaria, in association with quinine or artemisinin-based combination therapies or oral artesunate for 7 days.
Clinical trials of clindamycin monotherapy against P. falciparum malaria
A adults, C children
The combination of clindamycin with other rapidly acting drugs is essential for the optimization of treatment. Clinically documented associations essentially involve the combination of clindamycin with quinine or chloroquine.
Quinine, showing a rapid onset and short half-life, is the ideal partner. In vitro studies have also shown a synergistic effect when the two molecules are associated [7, 52]. The bioavailability of the two drugs, when co-administered, remains unchanged [53]. A methodology and satisfactory post-treatment follow-up in approximately ten clinical trials with a wide number of patients have been published (Table 3) [2]. The duration of combination therapy remains controversial. While most studies consider that the administration of quinine for at least 7 days and clindamycin for at least 5 days is needed, treatments conducted for 3 days in African studies were effective [52, 54]. Short-duration treatment is justified for obtaining adequate compliance and fear of side effects with quinine. Parasite clearance has been correlated with parasitaemia in children treated for 4 days [55, 56]. In areas of multidrug resistance, such as Thailand, 5–7 days are needed to cure malaria.
Clinical trials of clindamycin plus other drug against P. falciparum malaria
Randomized controlled trial
Only trials with adequate dosing, i.e. clindamycin given at least twice daily are mentioned in this table
Pop population, A adult, C children, P pregnant women
aC chloroquine, Q quinine, F fosmidomycin, A artesunate
The second well-studied combination is clindamycin with chloroquine. Plasmodium falciparum is highly resistant to chloroquine in most malarial regions. However, this drug is still widely used and remains a first-line treatment in Africa. The clindamycin–chloroquine combination has been studied in Gabon [52], where chloroquine resistance is markedly high. Clindamycin was administered every 12 h for 3 days, and success rates ranged from 70 % in children to 97 % in adults, depending on the study [57]. The success rate in children was estimated as 94 % with chloroquine administered at a dose of 45 versus 25 mg/kg. Although these findings favour the effectiveness of the combined administration of chloroquine with clindamycin for 3 days, this treatment has not been widely adopted in practice.
Fosmidomycin, a phosphonic acid derivative, is a new anti-malarial drug with a novel mechanism of action that inhibits the synthesis of isoprenoid in P. falciparum and suppresses the growth of multidrug-resistant strains in vitro [58]. Studies in Africa evaluating fosmidomycin as a monotherapeutic agent demonstrated that the drug is well tolerated in humans. A randomized, controlled, open-label study was conducted in 2003 in children to evaluate the efficacy and safety of treatment with fosmidomycin combined with clindamycin (30 and 5Â mg/kg body weight every 12Â h for 5Â days, respectively) compared with treatment with either fosmidomycin or clindamycin alone. The combined treatment with the two molecules was superior to that with either agent alone [6].
Since 2010, the WHO advocates artemisinin-based combination therapy (ACT) as the mainstay in combating drug-resistant malaria in Africa [59]. To prevent the emergence of resistant mutants, various drugs have been studied in combination with artemisinin derivatives, according to the underlying principle to combine artemisinins with drugs that have long plasma elimination half-lives. These treatments seems inappropriate for patients from areas with a high rate of malaria transmission because of the increased risk of drug-resistant mutants resulting from prolonged exposure to subtherapeutic levels of the slowly eliminated drug in the combination [7, 60, 61]. In the same way, combination therapy with drugs that have a rapid elimination time reduces the selection of resistant isolates [62]. The difficulty lies in choosing the ideal combination given the pharmacokinetic properties of the molecules used. One clinical trial combining artesunate with clindamycin for the treatment of uncomplicated P. falciparum malaria in Gabonese children was reported in 2005 [7]. In this trial, clindamycin was selected based on promising results from animal models, in vitro studies of P. falciparum and the use of sequential treatment with artesunate and clindamycin on Brazilian children [63]. An open-labelled, randomized, controlled clinical trial was performed to evaluate the efficacy and tolerance of oral artesunate-clindamycin therapy (2 and 7 mg/kg) administered twice daily for 3 days compared with a standard quinine–clindamycin regimen administered twice daily for 3 days to treat uncomplicated falciparum malaria in 100 children. The results showed that the artesunate-clindamycin combination was consistent with that of quinine–clindamycin with respect to the cure rates (87 versus 94 % at day 28 of follow up). The decreased fever and parasites clearance were significantly shorter in the artesunate-clindamycin treatment group. Based on the results of this study, clindamycin associated with artemisinin-based combination therapy is a candidate for studies in areas with a high rate of malaria transmission.
Another in vivo study was conducted to evaluate the efficacy and drug interactions of clindamycin in combination with other anti-malarial drugs in populations from endemic areas. Some artemisinin derivatives have been tested on mice, such as the novel semi-synthetic endoperoxide artemisone [64]. This compound is synthetized from dihydroartemisin in a one-step process and in combination with clindamycin, exhibited increased antiplasmodial activity, improved in vivo half-life, improved oral bioavailability and metabolic stability, and presented tolerance and no neurotoxicity in humans compared with artesunate. Because this drug is a good candidate, clinical studies must be performed to assess the effect of artemisone in combination with other anti-malarials. If macrolides and their derivatives have been considered as good candidates for the treatment of uncomplicated malaria, their pharmacokinetic properties make them inconsistent against malaria in monotherapy [39].