Articles

Single-dose azithromycin versus benzathine benzylpenicillin

for treatment of yaws in children in Papua New Guinea:
an open-label, non-inferiority, randomised trial
Oriol Mitj, Russell Hays, Anthony Ipai, Moses Penias, Raymond Paru, David Fagaho, Elisa de Lazzari, Quique Bassat

Summary
Lancet 2012; 379: 34247
Published Online
January 11, 2012
DOI:10.1016/S01406736(11)61624-3
See Comment page 295
Lihir Medical Centre
International SOS, Newcrest
Mining, Lihir Island,
Papua New Guinea (O Mitj MD,
R Hays MD, A Ipai HEO,
M Penias HEO, R Paru BSc,
D Fagaho BSc); and Barcelona
Centre for International Health
Research, Hospital Clinic,
University of Barcelona,
Barcelona, Spain (O Mitj MD,
E de Lazzari MSc, Q Bassat PhD)
Correspondence to:
Dr Oriol Mitj, Department of
Medicine, Lihir Medical Center,
PO Box 34, Lihir Island, NIP,
Papua New Guinea
[email protected]

Background Yawsan endemic treponematosis and, as such, a neglected tropical diseaseis re-emerging in children
in rural, tropical areas. Oral azithromycin is eective for syphilis. We assessed the ecacy of azithromycin compared
with intramuscular long-acting penicillin to treat patients with yaws.
Methods We did an open-label, non-inferiority, randomised trial at Lihir Medical Centre, Papua New Guinea, between
Sept 1, 2010, and Feb 1, 2011. Children aged 6 months to 15 years with a serologically conrmed diagnosis of yaws
were randomly allocated, by a computer-generated randomisation sequence, to receive either one 30 mg/kg oral dose
of azithromycin or an intramuscular injection of 50 000 units per kg benzathine benzylpenicillin. Investigators were
masked to group assignment. The primary endpoint was treatment ecacy, with cure rate dened serologically as a
decrease in rapid plasma reagin titre of at least two dilutions by 6 months after treatment, and, in participants with
primary ulcers, also by epithelialisation of lesions within 2 weeks. Non-inferiority was shown if the upper limit of the
two-sided 95% CI for the dierence in rates was lower than 10%. The primary analysis was per protocol. This trial is
registered with ClinicalTrials.gov, number NCT01382004.
Findings We allocated 124 patients to the azithromycin group and 126 to the benzathine benzylpenicillin group. In the
per-protocol analysis, after 6 months of follow-up, 106 (96%) of 110 patients in the azithromycin group were cured,
compared with 105 (93%) of 113 in the benzathine benzylpenicillin group (treatment dierence 34%; 95% CI
93 to 24), thus meeting prespecied criteria for non-inferiority. The number of drug-related adverse events (all
mild or moderate) was similar in both treatment groups (ten [8%] in the azithromycin group vs eight [7%] in the
benzathine benzylpenicillin group).
Interpretation A single oral dose of azithromycin is non-inferior to benzathine benzylpenicillin and avoids the need
for injection equipment and medically trained personnel. A change to the simpler azithromycin treatment regimen
could enable yaws elimination through mass drug administration programmes.
Funding International SOS and Newcrest Mining.

Introduction
Yawsan endemic treponematosis and, as such, a
neglected tropical diseaseis re-emerging. 40 years after
a worldwide control programme almost eradicated the
disease, it has re-emerged in children in poor, rural, and
marginalised populations in parts of Africa, Asia, and
South America. Yaws is caused by Treponema pallidum
subsp pertenue, and aects mainly skin, bones, and
cartilage. The disease has a natural history in primary,
secondary, and tertiary stages. Unless diagnosed and
treated at an early stage, yaws can become a chronic,
relapsing disease, and can lead to severe deforming bone
lesions in the long term.1
Between 1952, and 1964, WHO and UNICEF led a
worldwide campaign to control and eventually eradicate
yaws and other endemic treponematoses.2 Yaws became
the second disease targeted for eradication, after
smallpox. Control programmes were established in
46 countries and, by the end of 1964, the number of cases
had reduced by 95%, from 50 million to 25 million.
However, control eorts were gradually abandoned in
342

most countries3 and the disease re-emerged in the late

1970s, prompting the adoption of WHOs assembly
resolution 3858.4 According to the last estimate by WHO
in 1995, more than 500 000 children were still aected in
Africa, Asia, and South America.5
Penicillin remains the drug of choice to treat endemic
treponematoses.6,7 WHO guidelines recommend one
intramuscular injection of long-acting benzathine
benzylpenicillin at a dose of 12 MU for adults and
06 MU for children;8 however, other guidelines recommend higher doses.9 This treatment is eective and has
several advantages, as described for venereal syphilis.10
Although this treatment is cheap and well tolerated, it
has drawbacks, including the operational and logistical
diculties related to treatment with drug injection, the
potential risk of transmission of blood-borne pathogens
with unsafe injection practices, the pain related to deep
intramuscular injection of a large volume (4 mL), and a
high rate of self-reported allergy to penicillin.
Oral phenoxymethylpenicillin for 710 days (50 mg/kg
daily in four doses; maximum dose 300 mg four times a
www.thelancet.com Vol 379 January 28, 2012

Articles

day) was eective in a yaws control programme.11 Such a

regimen overcomes the disadvantages of intramuscular
drug administration, but poor adherence to a multiday
treatment regimen is a risk. In pilot studies of the potential
of oral, single-dose treatment against several infectious
disorders, azithromycina macrolide antibiotic with a
long half-life in tissueseemed to be a valuable drug
against Chlamydia trachomatis,12 Neisseria gonorrhoeae,13 and
Haemophilus ducreyi14 infections. Promising results were
also reported from a large-scale study10 done in Tanzania,
with two regimens to treat early syphilis: one oral dose
(2 g) of azithromycin and one intramuscular dose of
benzathine benzylpenicillin 24 MU. A multicentre trial15
in North America and Madagascar had similar ndings.
The immediate-release formulation of azithromycin
given in one oral dose of 30 mg per kg of bodyweight has
been approved and widely used to treat acute otitis media
in children since 2001.16,17 The product is available as an
oral tablet or as syrup, which is easier to administer to
very young children.
We assessed the ecacy of a single oral dose of
azithromycin compared with the standard single
intramuscular dose of benzathine benzylpenicillin to
treat yaws.

Methods
Study setting and patients
We undertook a prospective, open-label, non-inferiority,
randomised controlled trial at Lihir Medical Centre in
Papua New Guinea between Sept 1, 2010, and
Feb 24, 2011. The Lihir islands are geographically
remote, and despite being host to a major gold-mining
operation since 1995, the living conditions and sanitation
remain basic in most areas. Yaws is still a substantial
cause of morbidity in Papua New Guinea.18,19 Monthly
reports for monitoring several indicators of infectious
diseases and maternal and child health are being
collected via forms from hospitals, health centres, and
aid posts throughout the country. The national health
department estimated the number of yaws cases to be
17 000 nationwide in 2003, and 23 000 in 2008, of which
5000 were in New Ireland province, where Lihir Island
is located, and another 5000 in the neighbouring
province of West New Britain (unpublished).
All patients examined in the outpatient medical
department and suspected to have primary-stage or
secondary-stage yaws were assessed for possible inclusion
in the study. Eligible patients were children aged 6 months
to 15 years with a rapid plasma reagin titre of at least 1 in
16 and a reactive T pallidum haemagglutination test.
Exclusion criteria were known allergy to penicillin or
macrolide antibiotics, use of antibiotics active against
T pallidum during the preceding month, and known or
suspected coexisting diseases for which additional
antibiotic treatment with drugs eective against T pallidum
would be needed (use of quinolones, sulphonamides,
trimethoprim, and metronidazole was allowed).
www.thelancet.com Vol 379 January 28, 2012

A diagnosis of yaws chancre (primary stage) was

established by dermatological examination on the
basis of chronic (symptomatic for >2 weeks), painless,
atraumatic ulcers with raised margins. Criteria for the
diagnosis of secondary yaws included the presence
of one or more of: multiple hyperkeratotic papules;
polyarthralgia; or bone pain and swelling aecting the
ngers or toes, forearm, tibia, or bula. When an overlap
between the stages occurred (ie, primary lesion
persisting after the appearance of secondary yaws
symptoms) we classied the case as secondary stage.
The study was approved by the National Medical
Research Advisory Committee of the Papua New Guinea
Ministry of Health. All patients, or their parents,
provided signed informed consent.

Randomisation and masking

Eligible participants were randomly assigned, by use of a
computer-generated random-numbers list, to receive
either 30 mg/kg (maximum 2 g) azithromycin orally or
50 000 units per kg (maximum 24 MU) benzathine
benzylpenicillin by intramuscular injection. Randomisation was done in permuted blocks of four and in a
1:1 ratio. The allocation was concealed from investigators
by use of opaque, sealed, and sequentially numbered
envelopes that were opened after the study team had
decided to enrol a patient. Laboratory technicians were
unaware of participants treatment allocation, treatment
response, and previous rapid plasma reagin results at all
times. All participants received directly observed treatment, but masking of patients was not possible for
logistical reasons.

Procedures
The primary endpoint was serological cure, dened as
a decrease in the rapid plasma reagin titre by at least
two dilutions at the 6-month follow-up examination,
compared with the titre at time of treatment. For ulcers,
improvement of lesions in 2 weeks after treatment was
also needed. Secondary endpoints were the individual
components of the primary endpoint, cure rate 3 months
after treatment, and cure rates according to stage of yaws,
rapid plasma reagin titre at treatment, and history of
household exposure.
To guarantee timely follow-up of participants, we
implemented a community-based follow-up strategy.
A eld team, consisting of a physician, a laboratory
technician, and a local health worker, located patients
twice a week (for follow-up visit) at their residence by
tracking detailed locator information. All participants
were re-examined 2 weeks after treatment to assess
clinical resolution. Photographic documentation of skin
lesions was obtained at diagnosis and at the 14-day followup visit for comparison over time. Patients with
worsening ulcers were retreated with benzathine
benzylpenicillin (at the same dose). We assessed all
participants at 3 months and 6 months after treatment. A
343

Articles

Statistical analysis
255 patients enrolled
5 ineligible
3 declined to participate
2 allergic to benzathine
benzylpenicillin
250 patients underwent
randomisation

124 assigned azithromycin

126 assigned benzathine

benzylpenicillin

12 lost to follow-up
2 adverse events

13 lost to
follow-up

110 completed

113 completed

Figure 1: Trial prole

Azithromycin Benzathine benzylpenicillin

(n=124)
(n=126)
Age (years)

92 (37)

84 (33)

Male sex

54 (44%)

59 (47%)

Exposure*

26 (21%)

20 (16%)

Primary stage

50 (40%)

56 (44%)

Secondary stage

74 (60%)

70 (56%)

Persisting ulcer

18 (15%)

15 (12%)

Secondary skin lesions

16 (13%)

11 (9%)

Arthralgias

68 (55%)

64 (51%)

Bone swelling or pain

12 (10%)

10 (8%)

Clinical presentation

RPR titre at treatment

1 in 32

47 (38%)

60 (48%)

1 in 64

77 (62%)

66 (52%)

Data are mean (SD) or number (%). RPR=rapid plasma regain. *Household
exposure to other children with open skin ulcers during the previous 3 months.

Table 1: Baseline characteristics of the intention-to-treat population

5 mL blood sample was obtained at each follow-up visit

for serological analysis for T pallidum. All rapid plasma
reagin tests were done in duplicate by two independent
trained technicians at the Lihir Medical Centre
microbiology department, and tests were done a third
time in cases of discrepant results.
Safety assessments included documentation of immediate adverse events and patient-reported adverse events.
So that immediate reactions could be recorded and
treated, patients stayed at the health centre for 30 min
after treatment. Patient-reported adverse events were
assessed at the 2 week examination. Patients (or their
parents or guardians) were explicitly asked about pain at
site of injection, rash, fever, vomiting, diarrhoea, and
stomach pain.
344

This study was based on the notion that azithromycin

would be non-inferior to benzathine benzylpenicillin
for the primary ecacy outcome, with use of a prespecied non-inferiority margin; the upper limit of the
95% CI for the dierence in cure rates between groups
would not exceed 10%. We calculated that a sample size
of 242 patients (121 per group) would give a power of
80% to test the hypothesis of non-inferiority. This
sample size accounted for an expected ecacy of
benzathine benzylpenicillin of 95%,11,20 a non-inferiority
margin of 10%, and a one-sided type 1 error rate of 005,
with the assumption that 10% of participants would be
lost to follow-up.
We selected the per-protocol population for the primary
analysis. This population included all patients who
underwent randomisation and who completed the study
procedures to month 6. We also did a supporting analysis
with the intention-to-treat (missing equals failure)
population, which included all eligible patients, and in
which patients with missing data were regarded as having
treatment failure.
For analysis of the primary endpoint (cure rate at
6 months), we estimated two-sided 95% CIs for the
dierence in cure proportions between the benzathine
benzylpenicillin group and the azithromycin group
according to Altman and colleagues method.21 We used
the same method to analyse secondary binary endpoints.
We did additional post-hoc analyses to assess the
consistency of treatment eects in subgroups dened
according to disease stage, rapid plasma reagin titre, and
household exposure, with Fishers exact test. To compare
baseline characteristics and adverse events between the
treatment groups, we used two-sided t and Fishers exact
tests with a signicance level of 005. We did all statistical
analyses with Stata (version 11.1).
This study is registered with ClinicalTrials.gov, number
NCT01382004.

Role of the funding source

The sponsor of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report. All authors had full access to all the
data in the study and had nal responsibility for the
decision to submit for publication.

Results
Figure 1 shows the trial prole. 250 patients with
serologically conrmed yaws were randomly assigned
to receive either azithromycin or benzathine benzylpenicillin. Baseline clinical and serological characteristics
of the two treatment groups were similar (table 1). Mean
age of the participants was 88 years (SD 36; range
8 months to 15 years). 42% of patients had primary yaws
(table 1). The rapid plasma reagin titre was less than 1 in
32 in 107 (43%) participants and 1 in 64 or more in
143 (57%; table 1).
www.thelancet.com Vol 379 January 28, 2012

Articles

25 (10%) of the 250 participants could not be traced: ten

(4%) of these children could not be located for any
follow-up visit and 15 (6%) were lost after the rst followup visit. We could not locate seven (3%) participants
because they provided an invalid address, and 18 (7%)
were originally from the study area but moved elsewhere
during follow-up. Two patients did not complete follow
up because of adverse events related to drug administration. The remaining 223 patients constituted the perprotocol population.
Adverse events in the rst 14 days of treatment
were reported by ten (8%) of 119 patients interviewed in
the azithromycin group, and by eight (7%) of 121 in
the benzathine benzylpenicillin group. Of participants
given azithromycin, six (5%) reported nausea, two (2%)
stomach pain, and two (2%) vomiting within 30 min of
taking the drug. We classed the two patients who vomited
as having had treatment failure in the intention-totreat analyses, and they were retreated with benzathine
benzylpenicillin. In patients given benzathine benzylpenicillin administration-related adverse eects were the
most common. Six (5%) patients in the benzathine
benzylpenicillin group reported persistent injection-site
pain, despite use of lidocaine 1% as a diluent, and two
(2%) had an injection-related abscess. No serious adverse
events were reported during treatment or for the entire
follow-up period.
129 participants with ulcers (in primary or secondary
stage) were re-examined 2 weeks after treatment; the
ulcers had resolved in 51 (40%) and were healing in
70 (54%; gure 2). The rates of healing did not dier
signicantly between the two treatment groups (data not
shown). We classed the remaining eight (6%) patients
(four in the azithromycin group and four in the
benzathine benzylpenicillin group) as having clinical
treatment failure.
In both the per-protocol and intention-to-treat
analyses the criteria for non-inferiority were met for the
composite primary endpoint of serological cure at
6 months and clinical healing of ulcers. In the perprotocol analysis, 106 of 110 patients assigned
azithromycin were cured at 6 months compared with
105 of 113 patients in the benzathine benzylpenicillin
group (risk dierence 34%, 95% CI 93 to 24;
table 2). Incidence of the individual components of the
primary endpoint and intermediate cure rates did not
dier signicantly between groups (table 2). In the
intention-to-treat population, 106 of 124 patients
assigned azithromycin and 105 of 126 patients assigned
benzathine benzylpenicillin met the criteria for the
primary endpoint (22%, 111 to 68; table 2).
In subgroup analyses, the cure rates at 6 months
according to yaws stage, rapid plasma reagin titre at
treatment, and household exposure did not dier
signicantly between treatments in the per-protocol
population (table 3). No participant in either treatment
group had recurrent clinical signs of yaws or serological
www.thelancet.com Vol 379 January 28, 2012

5 cm

5 cm

Figure 2: Ulcers in patients with primary-stage or secondary-stage yaws who were re-examined 2 weeks
after treatment
(A, B) Red, moist, bedded, 5 cm ulcer on the left leg of a 9-year-old patient with primary yaws. (C, D) Partially
epithelialised tumour 2 weeks after treatment with azithromycin.
Azithromycin %
(95% CI)

Risk dierence %
Benzathine
benzylpenicillin % (95% CI)
(95% CI)

Primary population (PP) analysis (n=223)*

Primary endpoint: cure at 6 months
Cure at 3 months

964% (910986) 929% (867964) 34% (93 to 24)

800% (716864) 805% (723868)

Serologically dened cure at 6 months

Clinical cure of ulcers 14 days after treatment

100% (965100)

05% (99 to 109)

963% (903988) 37% (72 to 01)

964% (913986) 965% (910986)

01% (48 to 50)

Secondary population (ITT) analysis (n=250)

Primary endpoint: cure at 6 months

855% (782906) 833% (759888)

Cure at 3 months

710% (625782) 722% (634797)

22% (111 to 68)

13% (99 to 124)

Serologically dened cure at 6 months

883% (814929) 861% (788911)

23% (107 to 61)

Clinical cure of ulcers 14 days after treatment

854% (782906) 865% (795914)

10% (76 to 96)

PP=per protocol. ITT=intention to treat. *Including only patients with complete follow-up and study endpoint.
Including all randomised patients; we regarded patients with missing data as having treatment failure.

Table 2: Incidence of clinical endpoints

Azithromycin %
(95% CI)

Benzathine
Risk dierence %
benzylpenicillin % (95% CI) (95% CI)

Cure at 6 months by yaws stage

Primary
Secondary

909% (788964)
100% (945100)

891% (782949)

18% (137 to 100)

966% (883991)

34% (81 to 12)

929% (830972)

71% (139 to -04)

930% (833972)

14% (99 to 70)

Cure at 6 months by RPR titre at treatment

1 in 32
1 in 64

100% (908100)
944% (866-978)

Cure at 6 months by household exposure

Positive
Negative

100% (851100)
955% (889985)

100% (816100)
920% (850959)

35% (103 to 34)

Data are for the per-protocol analysis. RPR=rapid plasma reagin.

Table 3: Subgroup analysis of the primary endpoint at 6 months

345

Articles

evidence of recurrence during the 6-month followup period.

Discussion
Our ndings show that azithromycin was non-inferior to
benzathine benzylpenicillin for the primary composite
endpoint of serological cure at 6 months and healing of
ulcers. Furthermore, the two treatment groups had
similar rates of cure at 3 month follow-up and in
subgroups dened according to demographic and
biological characteristics. These results add to previous
evidence of the suitability of use of a single dose of a drug
such as azithromycin to treat various infectious diseases
(panel). Rates of serologically dened cure at 6 months
were substantially higher than expected for both
treatments, which validates our non-inferiority hypothesis
for the estimated penicillin cure rate. All participants had
a lower rapid plasmin reagin titre at 6 months than at
3 months, including 150 (67%) patients who
seroconverted. Additionally, we did not identify any
clinical or serological relapse after cure at 6 month followup. The azithromycin regimen did not resolve active
primary lesions in four patients. However, in the three
cases of failure that could be investigated, an
immunoperoxidase stain from a skin biopsy specimen
was negative for spirochaetes; therefore, we could not
conrm the biological treatment failure.
Azithromycin was well tolerated and no major adverse
eects occurred. Of participants who were treated with
azithromycin and interviewed, 8% reported mild to
moderate side-eects that were mainly gastrointestinal.
Only two children vomited within 30 min of oral
azithromycin administration, thus negligible drug
absorption would have occurred. These children were
then re-treated with benzathine benzylpenicillin. The
small number of participants vomiting after administration emphasises the suitability of azithromycin for
mass treatment programmes.
Our study had several limitations. First, diagnostic
criteria for inclusion in the study of primary lesions
did not include a microbiological test (eg, darkeld
microscopy); therefore, the non-healing ulcers could have
had post-treatment infection by other pathogens.
However, darkeld microscopy is rarely used to diagnose
treponemal infections because rapid serological tests are
available. Second, the imprecise denition of serological
cure, which could lead to overestimations in true rates of
cure, is a major issue aecting all research on the
treatment of treponematoses. Because laboratory technicians in this study were unaware of participants
treatment assignments, this drawback should not have
biased the comparison of cure rates between the groups.
Third, 6 months of follow-up might not be sucient to
assess the results after antibiotic treatment for yaws. Four
participants in the benzathine benzylpenicillin group did
not achieve serological cure. This nding could represent
a slower than usual decline in non-treponemal test titres
346

Panel: Research in context

Systematic review
We searched PubMed from Jan 1, 1952, to Aug 1, 2010, with
the terms yaws, Treponema pallidum, penicillin, and
azithromycin. We searched for trials that assessed the
ecacy and safety of single-dose oral azithromycin to treat
infectious diseases in adults and children. We identied two
randomised controlled trials,10,12 which showed the ecacy of
oral azithromycin for the treatment of treponemal disease
(syphilis) in adults. However, we did not identify any study
that explored yaws treatment with azithromycin. We
searched only publications written in English.
Interpretation
Our results provide substantial evidence of the non-inferiority
of a single oral-dose of azithromycin compared with the
standard recommended therapybenzathine
benzylpenicillinfor treatment of yaws. This nding
represents a potentially useful advance in yaws control.

after treatment, rather than a true penicillin-resistant

infection. Finally, because our trial design required
patients to meet certain prespecied criteria, and because
the study was done in one centre, our ndings might not
be generalisable to all children with yaws.
Two important reasons for caution with use of
azithromycin are the sustained success of benzathine
benzylpenicillin treatment for yaws, and the emergence
of azithromycin-resistant T pallidum. Clinical treatment
failure with penicillin has been reported for yaws,20
although, because in-vitro culture for T pallidum has not
been achieved,22 penicillin resistance has not been proven
by microbiological methods. Moreover, in countries such
as Papua New Guinea, cases of reinfection are occurring,
which suggests increased tolerance of some T pallidum
subsp pertenue strains to penicillin treatment.23 Azithromycin resistance in the non-venereal treponemes
has not been investigated, but resistance in the syphilis
treponeme is geographically clusteredeg, more than
95% resistance in Shanghai versus 0% in Madagascar.24,25
In areas where mutations have been found (eg, Seattle,
USA) the frequency of resistance has increased substantially in the past 10 years.26 Use of azithromycin in
the Lihir Island community to treat other infections has
been scarce, which might explain why we did not
encounter a substantial problem with resistance in our
study since there had been very little selective pressure.
Nonetheless, T pallidum subsp pertenue, seems to have
two of the genes encoding 23S ribosomal RNA where the
mutation that confers high-level resistance to macrolides
is located, as does T pallidum subsp pallidum.27 Thus,
close monitoring for potential treatment failure should
be considered in future studies of azithromycin.
With yaws re-emerging, treatment with an eective drug
that can be easily administered on a large scale is the
www.thelancet.com Vol 379 January 28, 2012

Articles

preferred method for treatment, prevention, and,

eventually, elimination worldwide. Elimination programmes need to take account of all epidemiological,
biological, and pharmacological factors, and the practical
considerations of a mass campaign to deliver and
administer drugs in isolated and under-resourced
communities. The potential for treatment of yaws with an
oral, single-dose drug has been explored in this context.
Azithromycin overcomes the major logistical and medical
disadvantages of the present regimen: it avoids the need
for injection equipment and medically trained personnel,
which can be scarce in countries with few health resources;
it prevents all the injection-related risks and side-eects;
and it can be safely administered to individuals with
penicillin allergy (1% in our trial population). Although we
did not formally assess the relative costs related to drug
acquisition and administration, low-cost generic preparations of azithromycin are widely available and the
treatment could therefore be highly cost eective.
Our ndings provide clear evidence that one high dose
of azithromycin is non-inferior to benzathine benzylpenicillin for treatment of yaws. If further studies
conrm our ndings (a similar trial is in progress in
Ghana, West Africa (Kwakye-Maclean C, Ga West
Municipal Heath Directorate, personal communication),
the next step is to attempt elimination and possibly
eradication of the disease in the remaining endemic
countries with mass drug administration programmes
under WHOs leadership.
Contributors
OM conceived and designed the study. OM, RH, AI, MP, and RP
contributed to the recruitment, clinical care, and follow-up of patients.
OM, EdL, and QB analysed and managed the data. DF did all laboratory
tests. OM, RH, and QB wrote the article.
Conicts of interest
We declare that we have no conicts of interest.
Acknowledgments
The study was funded by International SOS (Australasia) Pty and
Newcrest Mining. We thank the eld teams for clinical follow-up and
specimen collection, laboratory sta of Lihir Medical Centre for serology
work, Kingsley Asiedu and Joan-Ramon Laporte for reviewing the
manuscript and providing valuable comments, and Maria de Ros Villar
for image editing.
References
1
Meheus A. Non-venereal treponematoses. Medicine 2005; 33: 8284.
2
Guthe T, Willcox RR. Treponematoses: a world problem.
WHO Chron 1954; 8: 37113.
3
Antal GM, Causse G. The control of endemic treponematoses.
Rev Infect Dis 1985; 7 (suppl 2): S22026.
4
WHO. Resolutions and decisions: WHA31.58 control of endemic
treponematoses. May 24, 1978. www.who.int/neglected_diseases/
mediacentre/WHA_31.58_Eng.pdf (accessed Nov 21, 2011).
5
WHO. Recent news from WHO. Bull World Health Organ 2007;
85: 74.
6
WHO Scientic Group. Treponemal infections. Technical Report
Series No 674. Geneva: World Health Organization, 1982.

www.thelancet.com Vol 379 January 28, 2012

7
8
9

10

11

12

13

14

15

16

17

18
19
20

21

22
23
24

25

26

27

Antal GM, Lukehart SA, Meheus AZ. The endemic treponematoses.

Microbes Infect 2002; 4: 8394.
WHO. Yaws: a forgotten disease. January, 2007. http://www.who.int/
mediacentre/factsheets/fs316/en/ (accessed Nov 21, 2011).
Meheus AZ, Narain JP, Asiedu KB. Endemic treponematoses.
In: Cohen J, Powderly SM, Opal WG, eds. Infectious diseases,
3rd edn. London: Elsevier (in press).
Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin
versus penicillin G benzathine for the treatment of early syphilis.
N Engl J Med 2005; 353: 123644.
Scolnik D, Aronson L, Lovinsky R, et al. Ecacy of a targeted, oral
penicillin-based yaws control program among children living in
rural South America. Clin Infect Dis 2003; 36: 123238.
Martin DH, Mroczkowski TF, Dalu ZA, et al. A controlled trial of
a single dose of azithromycin for the treatment of chlamydial
urethritis and cervicitis. The Azithromycin for Chlamydial
Infections Study Group. N Engl J Med 1992; 327: 92125.
Handseld HH, Dalu ZA, Martin DH, Douglas JM Jr, McCarty JM,
Schlossberg D. Multicenter trial of single-dose azithromycin vs
ceftriaxone in the treatment of uncomplicated gonorrhea.
Sex Transm Dis 1994; 21: 10711.
Martin DH, Sargent SJ, Wendel GD Jr, McCormack WM, Spier NA,
Johnson RB. Comparison of azithromycin and ceftriaxone for the
treatment of chancroid. Clin Infect Dis 1995; 21: 40914.
Hook EW 3rd, Behets F, Van Damme K, et al. A phase III
equivalence trial of azithromycin versus benzathine penicillin
for treatment of early syphilis. J Infect Dis 2010; 201: 172935.
US Food and Drug Administration. Brieng document for
zithromax accelerated dosing; treatment of acute otitis media.
Nov 7, 2001. www.fda.gov/downloads/advisorycommittees/
committeesmeetingmaterials/drugs/anti-infectivedrugsadvisory
committee/ucm209921.pdf (accessed Nov 21, 2011).
Dunne MW, Khurana C, Mohs AA, et al Ecacy of single-dose
azithromycin in treatment of acute otitis media in children after
a baseline tympanocentesis. Antimicrob Agents Chemother 2003;
47: 266365.
Talwat E. Papua New Guinea yaws problems assessed.
Southeast Asian J Trop Med Public Health 1986; 17 (suppl 4): 5965.
Manning LA, Ogle GD. Yaws in the periurban settlements of
Port Moresby, Papua New Guinea. P N G Med J 2002; 45: 20612.
Backhouse JL, Hudson BJ, Hamilton PA, Nestero SI. Failure of
penicillin treatment of yaws on Karkar Island, Papua New Guinea.
Am J Trop Med Hyg 1998; 59: 38892.
Altman DG, Gore SM, Gardner MJ, Pocock SJ. Statistical guidelines
for contributors to medical journals. In: Altman DG, Machin D,
Bryant TN, Gardner MJ, eds. Statistics with condence: condence
intervals and statistical guidelines, 2nd edn. London: BMJ Books,
2000: 17190.
Stamm LV. Global challenge of antibiotic-resistant Treponema
pallidum. Antimicrob Agents Chemother 2010; 54: 58389.
Mitj O, Hays R, Ipai A, et al. Outcome predictors in
treatment of yaws. Emerg Infect Dis 2011; 17: 108385.
Martin IE, Gu W, Yang Y, Tsang RS. Macrolide resistance and
molecular types of Treponema pallidum causing primary syphilis
in Shanghai, China. Clin Infect Dis 2009; 49: 51521.
Van Damme K, Behets F, Ravelomanana N, et al. Evaluation of
azithromycin resistance in Treponema pallidum specimens from
Madagascar. Sex Transm Dis 2009; 36: 77576.
Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in
Treponema pallidum in the United States and Ireland. N Engl J Med
2004; 351: 15458.
Stamm LV, Bergen HL. A point mutation associated with bacterial
macrolide resistance is present in both 23s rRNA genes of an
erythromycin-resistant Treponema pallidum clinical isolate.
Antimicrob Agents Chemother 2000; 44: 80607.

347

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.