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SHORT-TERM MALARIA REDUCTION BY SINGLE-DOSE AZITHROMYCIN DURING MDA FOR TRACHOMA, TANZANIA

Thursday, 19th of June 2014

SHORT-TERM MALARIA REDUCTION BY SINGLE-DOSE AZITHROMYCIN DURING MASS DRUG ADMINISTRATION FOR TRACHOMA, TANZANIA

Emerging Infectious Disease ISSN

Abstract below; full text, with figures, is at http://wwwnc.cdc.gov/eid/article/20/6/13-1302_article

EID journal

June 2014

Short-Term Malaria Reduction by Single-Dose Azithromycin during Mass Drug Administration for Trachoma, Tanzania

Stephen E. Schachterle1, George Mtove, Joshua P. Levens, Emily Clemens, Lirong Shi, Amrita Raj, J. Stephen Dumler, Beatriz Munoz, Shelia West, and David J. Sullivan 

Author affiliations: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA (S.E. Schachterle, L. Shi, A. Raj, D.J. Sullivan); National Institute for Medical Research, Ubwari, Tanzania (G. Mtove); Johns Hopkins University School of Medicine, Baltimore (J.P. Levens, E. Clemens, J.S. Dumler, B. Munoz, S. West)

Abstract

Single-dose mass drug administration of azithromycin (AZT) is underway to eliminate trachoma worldwide. Studies in Ethiopia showed a reduction in all-cause childhood deaths after administration. To examine the effect of single-dose AZ MDA on prevalent malaria infections in a large prospective cohort of children and parents in Dodoma Province, Tanzania, we quantified the temporal prevalence of malaria parasitemia by real-time PCR for 6 months after single-dose AZT. In the first month after treatment but not in subsequent months, Plasmodium falciparum infections were reduced by 73% (95% CI 43%–89%) in treatment versus control villages and differences remained significant (p = 0.00497) in multivariate models with village-level random effects. Genetic sequencing of P. falciparum ribosomal L4 protein showed no mutations associated with AZT resistance. AZT mass drug administration caused a transient, 1-month antimalarial effect without selecting for P. falciparum ribosomal L4 resistance mutations in a region with a 10-year history of treating trachoma with this drug.

Malaria can be treated or prevented with the broad-spectrum antimicrobial drugs tetracycline or azithromycin (AZT) (1). In vitro, AZT interferes with malarial parasite replication by targeting the unique apicoplast organelle of the parasite (1). AZT inhibits malarial parasite growth 10–fold every 48 hours, and the pharmacokinetics of AZT predict that it remains at concentrations high enough to limit parasite growth for >1 week (2). AZT might interfere with transmission by exoerythrocytic inhibition of parasite liver stages in humans and mice (3) and by interference with ookinete and sporozoite production in mosquitoes (4). Monotherapy with AZT is not typically used to treat malaria. However AZT is highly effective against Chlamydia trachomatis, the causative agent of trachoma, which causes blindness (5,6). Persons with malaria who live in trachoma-endemic regions may undergo repeated AZT therapy as part of the World Health Organization–sponsored global trachoma eradication program (7,8).

Data regarding the effects of AZ mass drug administration (MDA) on malaria are limited. In a cluster randomized trial in The Gambia, AZ MDA given in 3 doses (20 mg/kg) 7 days apart reduced malaria rates by half when measured at 1 time point in children 5–14 years of age (9). More recently, a 49% reduction in the odds of death (95% CI 29%–90%) was reported for children 1–9 years of age in an AZ MDA treatment group compared with controls in Ethiopia (10,11). Porco et al. suggested that reductions in malaria prevalence associated with AZT MDA might have contributed to observed decreases in overall deaths. (10).

For malaria treatment, a randomized clinical trial that compared AZT/artesunate with artemether/lumefantrine in Muheza, Tanzania, reported that the odds of treatment failure were 5 times greater (95% CI 3.3–11.4) in the group that received AZT/artesunate (12). The authors postulated that the AZT/artesunate showed treatment failure because MDA for trachoma in Tanzania could have led to localized Plasmodium spp. resistance to AZT (12). Plasmodium spp. drug resistance to AZT has not been documented in the field. However, in vitro selection for AZT resistance identified a G76V mutation among conserved active site amino acids at position 71–79 in P. falciparum apicoplast-encoded ribosomal protein L4 (PfRpL4) (PFC10_API0043) (1.) A Cochrane meta-analysis report stated that “azithromycin’s future for the treatment of malaria does not look promising” (13) and cited studies in which AZT, although well tolerated, was inferior to tetracycline for malaria prophylaxis (14–17).

In the current study, we evaluated malaria prevalence in a cohort of 2,053 children and adults in central Tanzania to examine the effect of single dose AZ MDA on prevalent malaria infections. We also searched for PfRpL4 mutations that might confer P. falciparum AZT resistance.