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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Protein synthesis inhibitors such as doxycycline and clindamycin have been used to treat infections due to various plasmodial species. A recent review of chloroquine resistance in P. vivax was recently published, discussing the merits of alternative therapies to chloroquine.3 Data has accumulated that suggest that azithromycin may also have clinical utility in this setting. In a study of malaria prophylaxis, azithromycin was found to be > 98% effective in prevention of malaria due to P. vivax.4 Additionally, if azithromycin was found to be effective for treatment of P. vivax malaria, it might be considered a partner for other drugs active against P. vivax, given the interest in combination therapies for treatment of malaria. With these data as support, a clinical trial was undertaken to explore the role of a 3-day course of azithromycin for treatment of vivax malaria.
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MATERIALS AND METHODS |
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The institutional review board of each participating center reviewed and approved the protocol. Patients who met the inclusion and exclusion criteria subsequently provided witnessed, written informed consent in the local language. They then underwent a history and physical examination and subsequently were randomized to either azithromycin 1,000 mg q.d. x 3 days or chloroquine 600 mg q.d. each for 2 days and 300 mg on Day 3. In addition to active drug, patients were also provided matching placebos. Primaquine was provided at Days 7 through 20. Study drug was provided to sites in blocks of four. Sealed envelopes were available at each site to be opened only in the case of emergencies. The integrity of these envelopes was monitored periodically at each site. All parties remained blinded to treatment assignment.
Patients were hospitalized from the time of randomization. Peripheral blood smears and oral temperatures were obtained at baseline and every 8 hours. Patients were discharged when two consecutive blood smears were negative for parasites, returning for follow up visits at Days 7, 14, and 28 at which time a clinical examination and a quantitative parasite count was performed. Patients who the investigator felt were not responding to therapy were given alternative therapies at their discretion, including quinine and mefloquine.
The study was designed as a noninferiority trial, and the level of significance was 0.049, adjusted for an interim analysis. The two regimens would be considered equivalent if the lower limit on the difference in clinical response rates of the 95.1% confidence interval was greater than or equal to –10%. If the true success rates were the same for both treatments and as low as 95%, 200 subjects provides a probability of 0.845 of concluding that azithromycin is noninferior to chloroquine. Missing data were imputed by using the method of the last observation carried forward. Data were analyzed on a modified intent to treat basis, defined as including patients with a positive smear for malaria and a negative rapid test who were randomized into the study. The primary end point was clinical response, defined as resolution of fever, without relapse, at Day 7. Secondary end points included clinical response rate at Days 3, 14, and 28, parasitological response rate at Days 3, 7, 14, and 28, time to resolution of fever, and time to clearance of parasitemia. Parasite clearance times for 50% and 90% of the treated population (PC50, PC90) were also calculated for patients remaining on study therapy. Parasitologic failure was defined as RI (recrudescence after clearance of parasitemia); RII (reduction in parasitemia by > 75% of baseline without clearance); RIII (failure to reduce parasitemia to < 25% of baseline). A regression analysis was performed to assess the correlation between baseline parasitemia and time to parasite clearance.
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RESULTS |
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). By the Day 7 assessment, more patients given chloroquine had resolved their fever compared with those who received azithromycin [99% (101 of 102) versus 88% (87 of 97), respectively; 95.1% CI on the difference: –18, –4] (Table 2). An assessment of the resolution of fever by Day 3 revealed that the difference in clinical response was evident at that earlier timepoint (94% versus 74% for chloroquine and azithromycin treated patients, respectively).
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; Figure 1). The median time to clearance of parasitemia was 20 hours for patients receiving chloroquine compared with 55 hours for those getting azithromycin. The parasite clearance time for azithromycin and chloroquine treated subjects was proportional to the initial parasite count [correlation coefficients of 0.31 (P = 0.005) and 0.25 (P = 0.001), respectively].
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Patients were not provided primaquine until Day 7. By that time, fewer patients receiving chloroquine were seen to have gametocytes in their peripheral smear compared with those given azithromycin (0 of 99 versus 17 of 95, respectively; P < 0.001).
Significantly more adverse events were identified in patients receiving chloroquine compared with those receiving azithromycin (35 versus 15, respectively; P = 0.002) (Table 4). Gastrointestinal side effects were seen on both treatment arms but more frequently in those receiving chloroquine. Two patients receiving chloroquine discontinued treatment; one after development of a maculopapular rash, the other due to severe pruritus. The other two rashes, one maculopapular and one vesiculopapular, were mild in nature and self-limited.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Azithromycin was slower to resolve parasitemia. In parallel to these parasitologic findings, fever was slower to resolve in azithromycin-treated patients. While, in general, patients showed gradual reduction in their daily maximum temperature elevation, there may have been a tendency for investigators to switch treatment of patients not resolving their fever by Day 3, based on an anticipated rapid response to chloroquine. This slower resolution of fever and parasitemia was not unanticipated as clindamycin, another member of the macrolide/lincosamide family of antibiotics, has also been shown to resolve parasitemia more slowly than chloroquine.5–7 The reason for this slower resolution is not clear. The effects of interference with protein synthesis, possibly in the apicoplast, should be explored more fully.
As is demonstrated in Figure 1
, the rate of resolution of parasitemia, on average, was slower for patients treated with azithromycin. The reason for this delay in action is not clear but may be a result of the time it takes for the parasite to die after inhibition of protein synthesis. Partnering azithromycin for the first day or two with a more rapidly cidal agent may cause a faster parasitologic and symptomatic response and improve the overall treatment effect. These data also point out the difficulties with using the RI/RII/RIII nomenclature of parasitologic failure for slower acting drugs, as patients deemed RIII failures can go on to be cured.
There are two other published reports of an experience with azithromycin for the treatment of P. vivax infection. In the first, five patients with vivax malaria were initially cured but three of the five relapsed, suggesting that eradication of hypnozoites may not be possible with azithromycin.8 In the second experience, 16 patients were randomized to open-label azithromycin or other antibacterial agents, such as tetracycline, clindamycin, or doxycycline. Again, parasite clearance was noted in those treated with azithromycin but most patients relapsed within 28 days.6 Although similar parasite clearance times are reported, this study was smaller, did not use blinded therapy, did not provide primaquine, and used a 500-mg dose of azithromycin, half of the dose used in the current report. In both of these experiences, the initial cure rates through Day 7 are consistent with the results of this study.
This study has certain limitations. No conclusions can be drawn around the likelihood of late relapse on azithromycin compared with chloroquine as all patients received primaquine on Day 7 and the follow-up ended at Day 28. Studies to explore the activity of azithromycin on gametocytes are warranted. Also, this study was performed in only one geographic area. Conclusions about treatment effects in other regions will require studies from those areas.
In conclusion, azithromycin given as 1 g per day for 3 days resulted in an 88% clinical response rate by Day 7 but was not as active as chloroquine. Although it appeared to be better tolerated overall, the slower onset of action of azithromycin delayed the time to clinical improvement. These data provide support for further study of azithromycin to better define its role in the treatment of P. vivax malaria, either alone as second-line treatment or in combination with other active therapies.
Received January 12, 2005. Accepted for publication June 10, 2005.
Disclosure: Michael Dunne wishes to disclose that he is an employee of Pfizer Inc., the makers of azithromycin. This statement is being made in the interest of full disclosure and not because the author considers this to be a conflict of interest.
This study was presented to the American Society of Tropical Medicine and Hygiene, Atlanta, Georgia, November 2001.
Financial support: This study was funded by Pfizer Global Research and Development, Inc.
* Address correspondence to Michael W. Dunne, MD, Pfizer Global Research and Development, 50 Pequot Avenue, New London, CT 06320. E-mail: michael.w.dunne{at}pfizer.com 
Authors’ addresses: Michael W. Dunne, Pfizer Global Research and Development, 50 Pequot Avenue, New London, CT 06320, E-mail: michael.w.dunne{at}pfizer.com. Neeru Singh, Manmohan Shukla, C. Ushi Devi, and Tridibes Adak, Malaria Research Center, Jabalpur, India. Neena Valecha, Malaria Research Center, Delhi, India. Prabhash C. Bhattacharyya, Down Town Hospital, Guwahati, India. Kanta Patel, Baroda, India. Manoj Kumar Mohapatra, MKCG Medical College, Berhampur, India. Jitendra Lakhani, Pramukhrwami Medical College, Karamsad, India. Vas Dev, Malaria Research Center, Sonapur, India. Rajpal S. Yadav, Malaria Research Center, Nadiad, India. Chitra Lele and Kiran Patki, Pfizer, Inc., Mumbai, India.
Reprint requests: Michael W. Dunne, MD, Pfizer Global Research and Development, 50 Pequot Avenue, New London, CT 06320, Telephone: 860-732-3739, Fax: 860-715-9250, E-mail: michael.w.dunne{at}pfizer.com.
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