In several settings, oral quinine continues to be used as treatment for uncomplicated malaria, a practice mainly resulting from frequent stock-outs of the recommended ACT [26
]. Previous studies of the effectiveness and efficacy of quinine for uncomplicated malaria showed mixed results (Table ). The majority of these studies were conducted in settings with reported declining efficacy of quinine in Southeast Asia and South America. Earlier studies in these regions, using varying dosing regimens, showed cure rates ranging from 76% to 98%. The lower cure rates were mainly observed with shorter regimens (3 days) and higher cure rates when the drug was combined with sulphadoxine-pyrimethamine, tetracycline or clindamycin [29
]. Similar findings were reported in Vietnam, where a three-day course of quinine plus artesunate had a cure rate of only 50%, compared to a five-day course, which had a cure rate of 76%[35
]. Studies in Southeast Asia using quinine monotherapy for 7 days showed cure rates of 85-87% [29
], which is similar to what was observed over 15 years earlier [36
], (Table ).
Summary of studies of quinine for the treatment of uncomplicated malaria
Moreover, the addition of either tetracycline or clindamycin to quinine in the Thai study improved cure rates to 98% and 100% respectively and also delayed the appearance of Plasmodium vivax
infection, suggesting additional activity against this species [33
In Africa, studies evaluating three-day quinine treatment regimens have usually found unacceptably high failure rates [37
], with recurrent infections at day 28 post-treatment experienced in 30% - 50% of patients[37
]. However most of these studies did not perform PCR analyses to distinguish between recrudescence and re-infection, leading to possible underestimation of efficacy. In interpreting these results, the malaria transmission intensity at the study sites needs to be taken into consideration, as high treatment failure rates in high transmission settings may be due to a high risk of new infections. Additional PCR unadjusted studies that have evaluated five-day regimens of quinine have found recurrent infection rates on day 7 between 4% and 7% [40
] and day 14 treatment failure rates of 0 to 5% (Table ) [41
]. In Equatorial Guinea, five-day courses of quinine were associated with day 14 PCR unadjusted failure rates as high as 22%. These latter results prompted a change in the quinine treatment regimen for this region to a 7 day course, with subsequent significant decrease in treatment failure rates to 3%-5.5% [43
]. This study also reported that treatment failure rates with quinine remained stable over the five-year period of surveillance.
Even with seven-day treatment durations, evaluations of different quinine dosage regimens have revealed interesting trends. Doses of 10 mg/kg/day given twice daily for 7 days were associated with day 28 treatment failure rates as high as 30%[37
]. Increasing the quinine dosage to 15 mg/kg/day or 20 mg/kg/day improved treatment outcomes, with failure rates ranging from 8% to 14%[37
], although potential increases in toxicity with higher dosages are a concern. The treatment regimen currently recommended in sub-Saharan Africa is 10 mg/kg of the base given 8 hourly for 7 days. This regimen was associated with a lower rate of recurrent infections on day 28 (6.3%) compared to the 10 mg/kg twice daily regimen (16.1%)[44
The advent of ACT has provided important new therapeutic options for the management of uncomplicated malaria in regions with high prevalence of multi-drug resistant malaria. A few available trials have shown superiority of ACT over quinine in the management of uncomplicated malaria [32
]. In Brazil, patients treated with artemether-lumefantrine (AL) had significantly faster parasite clearance times when compared to those treated with quinine+doxycycline [46
]. Considering the extensive available data, quinine should not be used to treat uncomplicated malaria when ACT is available [27
]. ACT has the advantages of simplicity of dosing, which promotes adherence to therapy when compared with the seven-day treatment courses of quinine [32
], better tolerance and decreased risks of serious toxicity.
Nevertheless, despite their scale up in Africa, the cost and availability of ACT in the public sector remains a major challenge. In 2008, ACT coverage in the public sector in high-burden African countries was only 42%[47
]. Similarly, a survey carried out during the same year in seven African countries showed that the percentage of fever cases in children < 5 years treated with ACT was only 16% [47
]. The sustainability of ACT supplies in resource limited settings therefore presents a huge problem, with stock-outs consistently occurring in health facilities [48
]. Quinine, on the other hand, is a relatively cheap drug and often the only available option, rendering its rapid withdrawal for uncomplicated malaria cases risky. The best approach in these settings would be to proactively identify solutions to ACT stock-outs and maintain quinine as a fall-back drug only in case of ACT stock-outs. Additionally, improving quinine treatment outcomes by combining it with antibiotics, such as tetracycline or clindamycin [49
], could be investigated and promoted. More recently, combinations of quinine and newer antibiotics with shorter treatment regimens that would improve adherence to therapy as well as minimize related adverse events have been evaluated. One such combination is that with azithromycin which is of particular interest, as the drugs act synergistically [52
]. This combination offers promise for use especially in pregnant women and children < 8 years, since, unlike tetracyclines, both drugs are safe in these groups. A study in Thailand showed comparable efficacy in the treatment of multidrug resistant malaria, with cure rates of 100%, for a seven-day course of quinine+doxycycline and a three-day course of quinine+azithromycin [49
]. These drug combinations will need further evaluation to confirm these findings and may offer a solution to the compliance problems associated with seven-day courses of quinine.