Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial

doi:10.1016/S0140-6736(09)60323-8

The Lancet

Volume 373, Issue 9669, 28 March–3 April 2009, Pages 1111-1118

https://doi.org/10.1016/S0140-6736(09)60323-8 Get rights and content

Summary

Background

Trachoma-control programmes distribute oral azithromycin to treat the ocular strains of chlamydia that cause the disease and to control infection. Theoretically, elimination of infection is feasible if untreated individuals receive an indirect protective effect from living in repeatedly treated communities, which is similar to herd protection in vaccine programmes. We assessed indirect protection against trachoma with mass azithromycin distributions.

Methods

In a cluster randomised trial, 24 subkebeles (government-defined units) in Amhara, Ethiopia, were randomised, with use of a simple random sample, to distribution four times per year of single-dose oral azithromycin to children aged 1–10 years (12 subkebeles, 4764 children), or to delayed treatment until after the study (control; 12 subkebeles, 6014 children). We compared the prevalence of ocular chlamydial infection in untreated individuals 11 years and older between baseline and 12 months in the treated subkebeles, and at 12 months between the treated and control subkebeles. Health-care and laboratory personnel were blinded to study group. Analysis was intention to treat. The study is registered with clinicaltrials.gov, number NCT00322972.

Findings

At 12 months, 637 children aged 1–10 years and 561 adults and children aged 11 years and older were analysed in the children-treated group, and 618 and 550, respectively, in the control group. The mean prevalence of infection in children decreased from 48·4% (95% CI 42·9–53·9) to 3·6% (0·8–6·4) after four mass treatments. At 12 months, the mean prevalence of infection in the untreated age group (≥11 years) was 47% (95% CI 33–57) less than baseline (p=0·002), and 35% (95% CI 1–57) less than that in untreated communities (p=0·04).

Interpretation

Frequent treatment of children, who are a core group for transmission of trachoma, could eventually eliminate infection from the entire community. Herd protection is offered by repeated mass antibiotic treatments, providing a strategy for elimination of a bacterial disease when an effective vaccine is unavailable.

Funding

National Institutes of Health.

Introduction

One mass distribution of oral azithromycin substantially reduces the prevalence of ocular chlamydial infection in a community.1, 2, 3 Unfortunately, infection returns over the subsequent 6–24 months in severely affected areas, so repeated treatment is almost certainly necessary.3, 4, 5 However, even repeated distributions cannot completely eliminate infection. Mathematical models of other diseases have shown that antimicrobial use can lead to the elimination of an infectious disease, even when treatments are imperfect and not universally available.⁶ Models specifically of trachoma control suggest that infection can be locally eliminated with repeated community-wide antibiotic distributions, even in severely affected areas.3, 7, 8, 9, 10

Treatment of everyone in the community is expensive and time consuming, and most individuals are typically not infected. Theoretically, treatment that is targeted to a core group of individuals could eventually lead to elimination in the entire community.¹¹ Mathematical models suggest that children are a core group for the transmission of trachoma.¹⁰ To test this notion, we assessed whether intensive treatment of children in communities in the Goncha woreda (district) of the Amhara region, Ethiopia, reduced the prevalence of ocular chlamydial infection in older individuals who were not treated. Thus we examined whether repeated mass antibiotics would induce an effect similar to the so-called herd protection seen in vaccine programmes.¹⁰

Section snippets

Study setting and design

Between May, 2006, and May, 2007, we undertook a cluster randomised trial in communities of the Goncha Seso Enesie woreda of the Amhara Region of northern Ethiopia. We selected and collected data for 72 contiguous subkebeles—a government-defined unit which in this area of Ethiopia typically contains four to five state teams (roughly 1400 individuals). A state team consists of about 50 households with 275 individuals, and for simplicity is termed as a community in this report. All subkebeles

Results

Figure 1 shows the trial profile. Of the 4764 children aged 1–10 years in the 12 subkebeles assigned to the children-treated group, 3547 received allocated intervention at baseline. 34 children in the control group were mistakenly treated at baseline, but their communities were still included as contols. Of the 5108 children allocated to the mass-treatment group (in 12 subkebeles), 4522 received intervention at baseline. Table 1 shows the pretreatment characteristics of the three study groups

Discussion

In this study, treatment of children decreased infection in untreated older children and adults, showing a form of herd protection from a mass antibiotic campaign. Treatment of children four times per year compared favourably with WHO's present recommendation of yearly mass treatment for all individuals in the community. Children treated four times per year were far less likely to be infected at 12 months than were those residing in communities in which everyone received one mass treatment.

References (34)

SK West et al.
Infection with Chlamydia trachomatis after mass treatment of a trachoma hyperendemic community in Tanzania: a longitudinal study
Lancet
(2005)
WP Glezen
Herd protection against influenza
J Clin Virol
(2006)
AW Solomon et al.
Strategies for control of trachoma: observational study with quantitative PCR
Lancet
(2003)
PM Emerson et al.
Transmission ecology of the fly Musca sorbens, a putative vector of trachoma
Trans R Soc Trop Med Hyg
(2000)
J Schachter et al.
Azithromycin in control of trachoma
Lancet
(1999)
AW Solomon et al.
Mass treatment with single-dose azithromycin for trachoma
N Engl J Med
(2004)
M Melese et al.
Feasibility of eliminating ocular Chlamydia trachomatis with repeat mass antibiotic treatments
JAMA
(2004)
JD Chidambaram et al.
Effect of a single mass antibiotic distribution on the prevalence of infectious trachoma
JAMA
(2006)
R Anderson et al.
Infectious diseases of humans: dynamics and control
(1991)
KJ Ray et al.
A rationale for continuing mass antibiotic distributions for trachoma
BMC Infect Dis
(2007)

DA Gill et al.

Complete elimination is a difficult goal for trachoma programs in severely affected communities

Clin Infect Dis

(2008)

M Melese et al.

Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma

JAMA

(2008)

T Lietman et al.

Global elimination of trachoma: how frequently should we administer mass chemotherapy?

Nat Med

(1999)

J Jacquez et al.

Core groups and R₀s for subgroups in heterogeneous SIS and SI models

B Thylefors et al.

A simple system for the assessment of trachoma and its complications

Bull World Health Organ

(1987)

CA Gaydos et al.

Evaluation of dry and wet transported intravaginal swabs in detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections in female soldiers by PCR

J Clin Microbiol

(2002)

RW Peeling et al.

Pooling of urine specimens for PCR testing: a cost saving strategy for Chlamydia trachomatis control programmes

Sex Transm Infect

(1998)

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Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years.
In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2–5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1–59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov, NCT02414399.
Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64–1·29, p=0·58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95–2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78–1·76, p=0·44).
We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period.
Eunice Kennedy Shriver National Institute of Child Health & Human Development.
Frequency of Mass Azithromycin Distribution for Ocular Chlamydia in a Trachoma Endemic Region of Ethiopia: A Cluster Randomized Trial
2020, American Journal of Ophthalmology
Citation Excerpt :
The TANA study randomized a common pool of 72 sentinel communities from 72 subkebeles to 1 of 6 trachoma treatment strategies. Although the communities were paired into 3 primary analyses,18,20,21 the randomization from a common pool allows secondary comparisons between any of the arms. In particular, we can assess whether increasing frequency of mass distribution of azithromycin results in lower chlamydia prevalence.
Annual mass azithromycin distribution significantly reduces the prevalence of ocular Chlamydia trachomatis, the causative organism of trachoma. However, in some areas a decade or more of treatment has not controlled infection. Here, we compared multiple treatment arms from a community-randomized trial to evaluate whether increasing frequency of azithromycin distribution decreases prevalence in the short term.
Seventy-two communities in Goncha Siso Enesie woreda in the Amhara region of Northern Ethiopia were randomized to 1 of 6 azithromycin distribution strategies: (1) delayed, (2) annual, (3) biannual, (4) quarterly to children only, (5) biennial, or (6) biennial plus latrine promotion. We analyzed data from the 60 communities in the delayed, annual, biannual, quarterly, and biennial distribution arms at the 12-month study visit. Communities in the annual and biennial distribution arm were combined, as they each had a single distribution before any 12-month retreatment. We assessed the effect of increased frequency of azithromycin distribution on ocular chlamydia prevalence.
Ocular chlamydia prevalence was significantly different across azithromycin distribution frequency in children (P < .0001) and adults (P < .0001), with lower prevalence associated with higher frequency. Among children, quarterly azithromycin distribution led to a significantly greater reduction in ocular chlamydia prevalence than the World Health Organization–recommended annual treatment prevalence (mean difference −11.4%, 95% confidence interval −19.5 to −3.3%, P = .007).
Increased frequency of azithromycin distribution leads to decreased ocular chlamydia prevalence over a short-term period. In some regions with high levels of ocular chlamydia prevalence, additional azithromycin distributions may help achieve local elimination of infection.
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Targeted malaria elimination interventions reduce Plasmodium falciparum infections up to 3 kilometers away
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Targeted Mass Azithromycin Distribution for Trachoma: A Community-Randomized Trial (TANA II)
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ArticlesAssessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study setting and design

Results

Discussion

Lancet

J Clin Virol

Lancet

Trans R Soc Trop Med Hyg

Azithromycin in control of trachoma

Lancet

Mass treatment with single-dose azithromycin for trachoma

N Engl J Med

Feasibility of eliminating ocular Chlamydia trachomatis with repeat mass antibiotic treatments

JAMA

Effect of a single mass antibiotic distribution on the prevalence of infectious trachoma

JAMA

Infectious diseases of humans: dynamics and control

A rationale for continuing mass antibiotic distributions for trachoma

BMC Infect Dis

Complete elimination is a difficult goal for trachoma programs in severely affected communities

Clin Infect Dis

Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma

JAMA

Global elimination of trachoma: how frequently should we administer mass chemotherapy?

Nat Med

Core groups and R0s for subgroups in heterogeneous SIS and SI models

A simple system for the assessment of trachoma and its complications

Bull World Health Organ

Evaluation of dry and wet transported intravaginal swabs in detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections in female soldiers by PCR

J Clin Microbiol

Pooling of urine specimens for PCR testing: a cost saving strategy for Chlamydia trachomatis control programmes

Sex Transm Infect

Articles
Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial

Core groups and R₀s for subgroups in heterogeneous SIS and SI models