Azithromycin and chloroquine dosage
An interim analysis was planned after 32 participants with falciparum malaria had completed treatment. Statistical analyses. Analyses for both stages of the study were performed on the basis of both the group of intent-totreat participants and the group of evaluable participants; the results presented here are for the evaluable group and are similar to those for the intent-to-treat group. When data were missing, either data from the previous visit were substituted in the case of the analysis of the intent-to-visit group or data available within the visit window were substituted in the case of the analysis of the evaluable group.
Participants who received antimalarial medication because of treatment failure were, from that point forward, considered as representing cases of treatment failure. The primary statistical test for assessing the equivalence of azithromycin versus chloroquine was a 2-sided CIs for the difference in clinical response at days 3, 7, 14, and 28 were calculated by use of the exact method of Mehta and Patel rather than by normal approximation to the binomial.
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To account for the interim analysis, an adjustment of 0. Study-design modification after the interim analysis. When the interim analysis revealed inadequate therapeutic response, the protocol was amended so that all future participants with falciparum malaria would be treated, in an open-label fashion, with combination therapy in which the doses of azithromycin and chloroquine were the same as those used in monotherapy Figure 1.
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A total of 32 participants, half from Vadodara and half from Guwahati, were enrolled in the double-blind portion of the study. The baseline demographic characteristics of the participants randomized to each of the 2 monotherapy regimens were similar table 1. Figure 2 shows parasite counts during the course of treatment. The median time at resolution of parasitemia was 57 h and 96 h for monotherapy with chloroquine and azithromycin, respectively. As a consequence, monotherapy for participants infected with falciparum malaria was discontinued, and the protocol was amended to allow them to be treated with the combination of azithromycin and chloroquine.
Resolution of parasitemia. Values shown are mean parasite counts in evaluable participants during the first 8h of the day indicated.
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Combination therapy. The demographic characteristics of these participants were similar to those of the initial cohort, with the exception of baseline parasitemia table 1. Figure 2 shows the parasite counts during the course of treatment. Through day 28, no participant had a recrudescence of infection.
The median time to resolution of parasitemia was 36 h. More than half of the participants receiving either azithromycin or chloroquine in the double-blind, monotherapy phase of the trial reported treatment-related adverse events. The results of this clinical trial are notable for 3 reasons. Second, chloroquine, at its standard dose, achieved, at the 4 sites in India, a lower cure rate at day 28 than would be expected for treatment of fully sensitive organisms. Third, the results demonstrate that combination therapy with both azithromycin and chloroquine, at the same doses that had been used in mono-therapy, could achieve clinical success at acceptable rates.
This degree of chloroquine resistance is consistent with that in the Asian subcontinent in general. Resolution of parasitemia during the first 7 days was slower for monotherapy with azithromycin figure 2. Clindamycin, another inhibitor of protein synthesis, has been found to produce a similarly delayed resolution of parasitemia; the antimalarial effect of clindamycin has not been firmly established, but it has been shown to act on plasmodial 70S ribosome-specific protein synthesis [ 8 ].
Although azithromycin is known to target the bacterial ribosome and is presumed to target the plasmodial ribosome, the latter activity has not been established. Alternatively, the organism may have previously synthesized enough protein to allow for at least 1 additional cycle of replication before parasiticidal effects could be demonstrated. Interestingly, interference with the apicomplexan plastid—perhaps, in this case, through the inhibition of plastid-specific ribosomal protein—has resulted in the phenomenon of delayed cell death [ 9 ].
A precedent exists for expecting enhanced activity from combination therapy with a protein synthesis inhibitor and a 4-aminoquinoline. Three small clinical trials have reported improvements in clinical efficacy when clindamycin is used in combination with either chloroquine or quinine [ 10—12 ]. The clinical efficacy of the combination of azithromycin and chloroquine is supported by in vitro data demonstrating synergy between these 2 drugs. This in vitro synergy appears to be most pronounced in organisms that are isolated from regions where higher levels of clinical chloroquine resistance have been identified [ 13 ]; if this is the case, then these findings parallel those observed for verapamil [ 14 ], which is suspected to interfere with the modified pfcrt -gene product associated with chloroquine resistance [ 15 , 16 ]; however, it has not been determined whether azithromycin similarly interferes with the pfcrt -gene product.
It is also possible that azithromycin inhibits the function of other compensatory mutations in the resistant parasite, thereby impairing the fitness of the resistant organism. Alternatively, because azithromycin is also a weak base, it may, like chloroquine, raise the pH of the digestive vacuole, thereby preventing the organism from managing accumulated hematin.
In light of the small sample size used in the monotherapy phase of the present study, it is difficult to compare the adverse-event rates of the monotherapy regimens versus those of the open-label, combination-therapy regimen.
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The rates and types of adverse events reported for the combination therapy are, however, consistent with the known side effects of these drugs, were essentially mild, and did not require discontinuation of therapy. There are a number of limitations in the present study.
The baseline parasite counts observed in the combination-therapy regimen were lower than those in the monotherapy regimens, which may have occurred because a greater proportion of the enrollment in the combination-therapy regimen occurred during the dry season. However, in an analysis of 14 participants treated with the combination therapy who had some of the highest baseline parasite counts, the initial resolution of parasitemia was similar to that observed in the monotherapy regimen with chloroquine data not shown.
Because different strains of P. Whether combination therapy with azithromycin and chloroquine will result in similar outcomes in other geographic areas—specifically, in regions where category RII and RIII resistance predominate—remains to be determined. The recent experience in Thailand, where azithromycin was used in combination with quinine, another 4-aminoquinoline that has demonstrated similar in vitro synergy with azithromycin, is encouraging in this regard [ 17 ].
If the findings of the present study are reproducible, then the combination therapy of azithromycin and chloroquine may be a promising alternative for the treatment of malaria in regions with chloroquine resistance. Azithromycin and chloroquine are both considered to be safe for children, and the results seen when azithromycin has been used to treat pregnant women have been encouraging [ 18 ]. The once-daily, 3-day therapy regimen would be simple to administer and builds on the extensive experience with chloroquine therapy.
In addition, azithromycin and chloroquine are widely available in regions where malaria is endemic—and their currently defined prices in these countries make combination therapy with them a potentially cost-effective alternative. Although the discovery of new chemical entities with activity against plasmodia remains a priority, this combination therapy may prolong the useful life of chloroquine until such new entities are available for clinical use.
In summary, monotherapy with azithromycin should not be used to treat falciparum malaria; however, in India, combination therapy with azithromycin and chloroquine has been demonstrated to have clinical efficacy in a region of category RI chloroquine resistance, at a rate consistent with historical rates of efficacy for chloroquine alone. Additional clinical studies to confirm these findings will be an important step toward defining this combination therapy as an alternative regimen for treatment of falciparum malaria in areas where there is chloroquine resistance.
We are indebted to the participants who participated in this trial, without whom this study would not have been possible; to Neelakshi Mahanta, Mallika Nath, Rupjyoti Talukdar, Bhalendu Vaishnav, Sucheta Lakhani, Jaya Pathak, Kasinath Padhiary, Ganeswar Sethi, and Usha Pillai, for their assistance in management of participants' care and in laboratory measurements; to Rupesh Patki, Richa Chandra, Juanita Brown, Chandrashekar Potkar, and Veena Jaguste, for their diligence and attention to the quality of the data; and to Drew Lewis and Cindy McCoig, for their assistance in the preparation of the manuscript.
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Volume Article Contents Abstract. Oxford Academic. Google Scholar. Neeru Singh. Manmohan Shukla. Neena Valecha. Vas Dev.
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Kanta Patel. Vadodara a. Manoj K. Jitendra Lakhani.