Li et al. Treatment of early syphilis J Infect Dev Ctries 2014; 8(2):228-231.

Brief Original Article

Early syphilis: serological treatment response to doxycycline/tetracycline
versus benzathine penicillin

Jun Li, He-Yi Zheng

Department of Dermatology and Venereology, Peking Union Medical College Hospital, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beiing, China

Abstract
Introd!tion: "en#athine peni!illin $ is the treatment of !hoi!e for syphilis% &t do'y!y!line and tetra!y!line are
effe!ti(e se!ond-line treatments. The o&)e!ti(e of this stdy *as to assess the serolo+i!al response to treatment for
early syphilis *ith &en#athine peni!illin !ompared *ith do'y!y!line or tetra!y!line.
,ethodolo+y: -e e'amined rapid plasma re+ain (./.) serolo+i!al test reslts of all first-time early syphilis
patients in /e0in+ 1nion ,edi!al 2olle+e 3ospital &et*een 2000 and 2011% !omparin+ treatment *ith t*o doses of
peni!illin to 14-day !orse of oral do'y!y!line (100 m+ t*i!e daily) or oral tetra!y!line (400 m+ 4 times a day).
.eslts: 5f the 641 early syphilis !ases *ith a(aila&le treatment ot!ome data% 606 (74.48) re!ei(ed peni!illin and
34 (4.48) re!ei(ed do'y!y!line9tetra!y!line. ,ore than half (42.18) had se!ondary syphilis% 13.48 had primary
syphilis% and 34.48 had early latent syphilis. : statisti!ally similar serolo+i!al treatment s!!ess rate (p ; 0.14<)
*as o&ser(ed in peni!illin-treated patients 71.48 (4449606)% *hen !ompared *ith patients treated *ith
do'y!y!line9tetra!y!line 82.78 (27934).
2on!lsion: =o'y!y!line9tetra!y!line had a similar serolo+i!al treatment s!!ess rate *hen !ompared to peni!illin
in the treatment of early syphilis.

Key words: do'y!y!line; tetra!y!line; peni!illin; early syphilis; syphilis; 2hina

J Infect Dev Ctries 2014; 8(2):228-231. doi:10.38449)id!.3103

(.e!ei(ed 14 >eptem&er 2012 ? :!!epted 23 @ly 2013)

2opyri+ht A 2014 Li et al. This is an open-a!!ess arti!le distri&ted nder the 2reati(e 2ommons :ttri&tion Li!ense% *hi!h permits
nrestri!ted se% distri&tion% and reprod!tion in any medim% pro(ided the ori+inal *or0 is properly !ited.
Introduction
>yphilis is a spiro!hetal infe!tion *ith mltiple
manifestations. In re!ent years% syphilis has
reemer+ed as a si+nifi!ant p&li! health pro&lem
in many !ontries in!ldin+ 2hina. Bation*ide
sr(eillan!e data indi!ated that the in!iden!e rate
of syphilis in 2hina in 1773 *as 0.2 !ases per
100%000 persons% *hereas primary and se!ondary
syphilis alone represented 4.< !ases per 100%000
persons in 2004. The rate of !on+enital syphilis
!onsidera&ly in!reased *ith an a(era+e annal rise
of <1.78% from 0.01 !ases per 100%000 li(e &irths
in 1771 to 17.< !ases per 100%000 li(e &irths in
2004 C1D.

:!!ordin+ to nation*ide sr(eillan!e
data% there *ere 32<%433 ne* !ases of syphilis in
2hina in 2007 (24.< !ases per 100%000) C2%3D.
2ontrollin+ syphilis in(ol(es the early
re!o+nition and adeEate treatment of patients
*ith !lini!al and serolo+i!al e(iden!e of infe!tion
and mana+ement of all se'al partners. "en#athine
peni!illin $ has &een the treatment of !hoi!e for
early infe!tios syphilis (primary% se!ondary% and
early latent syphilis). In the a&sen!e of
!ontraindi!ations% do'y!y!line or tetra!y!line are
se!ond-line treatments !onsidered for patients
na&le to tolerate peni!illin aller+ies C4D.

3o*e(er%
there are limited stdies on the se of these
se!ond-line a+ents for early syphilis treatment C4-
11D.

-e !ond!ted a retrospe!ti(e !ohort stdy to
!ompare the serolo+i!al response rates of patients
*ith early syphilis treated *ith peni!illin and
patients aller+i! to peni!illin treated *ith
do'y!y!line9tetra!y!line.
=espite the !hallen+es in the interpretation of
serolo+i!al test reslts% !han+e in nontreponemal
titers is the most *idely sed !riterion for
e(alation of the response to syphilis treatment
C12-16D.

/atients *ith nontreponemal titers that
228
Li et al. Treatment of early syphilis J Infect Dev Ctries 2014; 8(2):228-231.
de!line 4-fold or more &y 6 months follo*in+
treatment are re+arded as ha(in+ an appropriate
serolo+i!al response% *hereas an in!rease in titer
*ithot reinfe!tion is indi!ati(e of treatment
failre C4D.

Methodology
Study subjects
=emo+raphi!% !lini!al% and la&oratory data of
<48 patients *ith syphilis *ere retrospe!ti(ely
analy#ed. 5f the <48 early syphilis !ases% 384
!ases had se!ondary syphilis% 78 !ases had
primary syphilis% and 264 !ases had early latent
syphilis. :ll syphiliti! !ases *ere otpatients *ho
(isited the se'ally transmitted disease (>T=)
!lini! of /e0in+ 1nion ,edi!al 2olle+e 3ospital%
2hina% &et*een =e!em&er 2000 and 2011. :ll
patients *ere dia+nosed *ith syphilis in different
sta+es a!!ordin+ to the national 2enters for
=isease 2ontrol dia+nosti! standard. :!!ordin+ to
national +idelines C1<D%

primary syphilis *as
defined as a !lini!ally !ompati&le !ase
!hara!teri#ed &y one or more !han!res and
in+inal lymphadenopathy% and la&oratory
!onfirmation of Treponema pallidm in !lini!al
spe!imens &y rapid plasma rea+in serolo+i!al test
(./.) and parti!le a++ltination assay for
anti&ody to Treponema pallidm (T//:)% and9or
FT::&s; se!ondary syphilis *as defined as a
!lini!ally !ompati&le !ase !hara!teri#ed &y
ma!lopaplar rash and% in many !ases%
lymphadenopathy% and la&oratory test
!onfirmation for the primary syphilis; early latent
syphilis *as defined as an asymptomati! !ase *ith
a possi&le history of infe!tion spported &y
rea!ti(e ./. and a rea!ti(e treponemal test% and
normal !ere&rospinal flid 2lini!ians from the
>T= of or Instittion as0 the patient the possi&le
infe!tion time: *hen initial infe!tion has o!!rred
*ithin the pre(ios 12 months% latent syphilis is
!lassified as early. The stdy *as appro(ed &y the
ethi!s !ommittee of the /e0in+ 1nion ,edi!al
2olle+e. 5ne hndred and se(en patients *ere
e'!lded &e!ase they *ere 3IG positi(e%
nonrea!ti(e ./. test at &aseline% they had past
episodes of syphilis% inadeEate follo*-p time to
determine serolo+i!al ot!ome of treatment
(patients lost to follo* p *ithin 6 months *ere
e'!lded).

Laboratory testing
For ml of &lood *as !olle!ted from ea!h
patient drin+ the first time they (isited or >T=
!lini!. Then% the &lood *as transported to the
la&oratory *here trained la&oratory personnel
performed ./. and T//: and9or FT:-:&s
(Hality !ontrol: >yphilis >erolo+y /rofi!ien!y
Testin+ >r(ey% La&oratory 2ode Bm&er 7700<<%
2enters for =isease 2ontrol and /re(ention
:tlanta% -orld 3ealth 5r+ani#ation). Ia!h test
*as performed &y la&oratory staff on sera
a!!ordin+ to manfa!trerJs instr!tions. The
patientJs syphilis sta+e *as assessed &ased on
physi!al e'amination and on serolo+y reslts
sin+ the !riteria des!ri&ed pre(iosly.
Treatment
:!!ordin+ to national +idelines C1<D%

patients
*ith early syphilis *ere treated *ith t*o doses of
&en#athine peni!illin% 2.4 million nits
intrams!lar ea!h% separated &y one *ee0.
/atients aller+i! to peni!illin *ere treated *ith
do'y!y!line% 100 m+ orally t*i!e a day for 14
days or tetra!y!line 400 m+ orally% 4 times a day
for 14 days. :s a rotine in or >T= !lini!% after
treatment% all the patients *ere as0ed to
periodi!ally re(ie* their !lini!al symptoms and
serm ./. titers e(ery 3 months. The primary
ot!ome *as response to therapy% determined on
the &asis of !han+es in ./. titers at 6 months
after treatment. >erolo+i!al treatment s!!ess *as
defined as either ne+ati(e ./. test reslts or a K
4-fold (2 diltions) de!rease in titer at 6 months. If
rapid plasma rea+in test titer *as 1:2% or 1:1 at
&aseline% a serofast sta&le serolo+y (i.e.% L 1
diltion from &aseline) at 6 months after treatment
initiation *as also !onsidered treatment s!!ess.
Treatment *as !onsidered to ha(e failed if none of
the a&o(e !onditions *ere met% in!ldin+ if the
rapid plasma rea+in test titer in!reased from
&aseline &y at least 4-fold &et*een month
1and month 6 C4D.

Data analysis

/earsonJs !hi-
sEared test *as sed to !ompare differen!es in
!ate+ori!al (aria&les and >tdentJs t-test for
normally distri&ted !ontinos (aria&les.
.eslts *ere !onsidered statisti!ally si+nifi!ant
at p M0.04.
Results
227
Li et al. Treatment of early syphilis J Infect Dev Ctries 2014; 8(2):228-231.
5f the 641 early syphilis !ases *ith a(aila&le
treatment ot!ome data% 606 (74.48) re!ei(ed
peni!illin and 34 (4.48) re!ei(ed
do'y!y!line9tetra!y!line. 5(erall% the mean a+e
of the patients in the stdy !ohort *as 34 years
of a+e (ran+ed &et*een14 and 80 years of a+e)%
s&)e!ts *ere mostly male (42.68). ,ore than
half (42.18) had se!ondary syphilis% 13.48 had
primary syphilis% and 34.48 had early latent
syphilis. There *as a similar distri&tion of
patient !hara!teristi!s in ea!h treatment +rop
(Ta&le 1). : statisti!ally similar (p ; 0.14<)
serolo+i!al treatment s!!ess rate *as o&ser(ed
in 71.48 (4449606) of peni!illin-treated patients
*hen !ompared *ith 82.78 (27934) of patients
treated *ith do'y!y!line9tetra!y!line.
iscussion
=o'y!y!line is a tetra!y!line deri(ati(e *ith
&etter oral &ioa(aila&ility% !on(enient t*i!e a
day dosin+% and fe*er +astrointestinal side
effe!ts. =o'y!y!line at a dosa+e of 100 m+
e(ery 12 hors is pharma!olo+i!ally eEi(alent
to tetra!y!line at 400 m+ e(ery 6 hors C18D.
The mean inhi&itory and &a!teri!idal
!on!entrations a+ainst treponemes are similar
for tetra!y!line and do'y!y!line C17-20D.

The
ma)or ad(anta+es of "en#athine peni!illin
treatment are its safety% effe!ti(eness% and the
fa(ora&le adheren!e to the *ee0ly dosin+
s!hedle of 1 to 3 *ee0s C21D. =isad(anta+es of
this re+imen in!lde the !ost% pain asso!iated
*ith intrams!lar in)e!tion% and the in!iden!e
of peni!illin aller+y in some patients. >e(eral
!hara!teristi!s of do'y!y!line or tetra!y!line
ma0e them attra!ti(e alternati(es to peni!illin%
in!ldin+ their oral rote of administration and
their pharma!olo+i! and pharma!o0ineti!
properties.
5ne of the 0ey findin+s of or stdy is that
serolo+i!al treatment s!!ess (in peni!illin
treated patients the rate *as 71.48 and
do'y!y!line9tetra!y!line treated patients it *as
82.68) *as not as hi+h as in pre(iosly
p&lished reports. : stdy &y Ghanem et al C8D
sin+ a retrospe!ti(e !hart re(ie* sho*ed +ood
response to do'y!y!line amon+ patients *ith
early syphilis from t*o >T= !lini!s in
"altimore. In that stdy% serolo+i!al treatment
s!!ess *as noted amon+ 67 of <3 (74.48)
patients treated *ith peni!illin% *hile 1008
amon+ 34 patients treated *ith do'y!y!line.
:nother stdy from 2anada &y ong et al C4D
sed a retrospe!ti(e stdy to assess the
serolo+i!al response to treatment of primary
syphilis *ith &en#athine peni!illin !ompared
*ith do'y!y!line or tetra!y!line. In that stdy%
of the total 444 primary syphilis !ases *ith
a(aila&le treatment ot!ome data% 420 (74.48)
re!ei(ed peni!illin and 24 (4.68) re!ei(ed
do'y!y!line9tetra!y!line. The serolo+i!al
treatment s!!ess rate *as 7<.48 in the
peni!illin +rop (4079420) and 1008 in the
do'y!y!line9tetra!y!line +rop (24924)% and not
si+nifi!antly different. 3o*e(er% In another
e'ample in Tan#ania% !iedner et al. sed a
similar 4-fold de!rease in rapid plasma rea+in
test titer to define serolo+i!al s!!ess and fond
serolo+i!al s!!ess rates of only appro'imately
808 *ith peni!illin at 6 months C22D. The &road
ran+e of treatment s!!ess may &e related to
(ariations in formlations and dosin+ of
peni!illin% in addition to the different methods
adopted &y ea!h stdy. 5(erall% or data% alon+
*ith these reports% pro(ide a &asis for the se of
do'y!y!line as an alternati(e therapeti! option
in the treatment of early syphilis.
A!nowledgements
Non+ s!ientifi! resear!h fnd of /e0in+ 1nion
,edi!al 2olle+e 3ospital
Re"erences
1. 2hen OH% Ohan+ $2% $on+ P=% Lin 2% $ao
P% Lian+ $@ (200<) >yphilis in 2hina: reslts of
a national sr(eillan!e pro+ramme. Lan!et 367:
132-138.
2. 102 B2>T= (2011). Ipidemiolo+i! reports
of syphilis and +onorrhea !ase reports in 2hina.
:(aila&le: http:99 ***.n!std!.or+9#'+l-
detail9#'+l-'')l.htm Last a!!essed 11 ,ay
2011.
3. @oseph = T!0er% Ne-/in+ Nin% "ao'i
-an+% Pian+->hen+ 2hen% ,yron > 2ohen
(2011) :n e'pandin+ syphilis epidemi! in
2hina: epidemiolo+y% &eha(ioral ris0 and
230
Li et al. Treatment of early syphilis J Infect Dev Ctries 2014; 8(2):228-231.
!ontrol strate+ies *ith a fo!s on lo*-tier
female se' *or0ers and men *ho ha(e se' *ith
men. >e' Transm Infe!t 8< >ppl 2: ii16-8.
4. 2enters for =isease 2ontrol and /re(ention
(2010) >e'ally transmitted diseases treatment
+idelines% 2010. ,or& ,ort -0ly .ep 48: 26-
34.
4. Tom -on+% :meeta I% /rith*ish =e(2008)
/rimary
>yphilis: >erolo+i!al Treatment .esponse to
=o'y!y!line9 Tetra!y!line (erss "en#athine
/eni!illin. The :meri!an @ornal of ,edi!ine
121: 703-708.
6. /somas Q2% "rn ,% 2asse :% :toi B%
.eynes @% Le ,oin+ G(2012) Iffi!a!y of
!eftria'one and do'y!y!line in the treatment of
early syphilis. ,ed ,al Infe!t 42: 14-17.
<. 5noda N (17<7) Therapeti! effe!t of oral
do'y!y!line on syphilis. "r @ Gener =is 44:
110-114.
8. $hanem Q$% Ir&eldin+ I@% 2hen+ --%
.ompalo :, (2006) =o'y!y!line !ompared
*ith &en#athine peni!illin for the treatment of
early syphilis. 2lin Infe!t =is 42: e44-e47.
7. 2nha ":% >i&ley 2,% .ist!!ia :,
(1782) =o'y!y!line. Ther =r+ ,onit 4: 114-
134.
10. Oenilman @,% .and >% "ardit!h /% .ompalo
:, (1773) :symptomati! nerosyphilis after
do'y!y!line therapy for early latent syphilis.
>e' Transm =is 20: 346-34<.
11. 3arshan G% @aya0mar - (1782)
=o'y!y!line in early syphilis: a lon+ term
follo* p.Indian @ =ermatol 2<: 117124.
12. 5*s-Idsei Q @r% Qos0i Q:% "allard .2
(2011) The tale of t*o serolo+i! tests to s!reen
for syphilis--treponemal and nontreponemal:
does the order matterR >e' Transm =is 38: 448-
446.
13. Fimara B@ (1780) Treatment of primary
and se!ondary syphilis. >erolo+i!al response.
@:,: 243: 2400-2402.
14. "ro*n >T% Oaidi :% Larsen >:% .eynolds
$3 (1784) >erolo+i!al response to syphilis
treatment. : ne* analysis of old data. @:,:
243: 1276-1277.
14. Larsen >:% >teiner ",% .dolph :3 (1774)
La&oratory dia+nosis and interpretation of tests
for syphilis. 2lin ,i!ro&iol .e( 8: 1-21.
16. .omano*s0i "% >therland .% Fi!0 $3%
,ooney =% Lo(e I@ (1771) >erolo+i! response
to treatment of infe!tios syphilis. :nn Intern
,ed 114: 1004-1007.
1<. >"T>9,53 (1776) Bational standard of the
/eopleJs .ep&li! of 2hina: dia+nosti! !riteria
and mana+ement of syphilis ($" 147<4-1774).
"ei)in+: >tandards /ress of 2hina.
18. >tandiford 3.2 (2004)Tetra!y!lines and
!hlorampheni!ol In: $.L. ,andell% ..$.
=o+las% @.I. "ennett (Ids.)% /rini!iples and
/ra!ti!e of Infe!tios =iseases (6th edition)%
Ilse(ier 2hr!hill Li(in+stone% /hiladelphia%
/: 346-3<3.
17. :&ramson I@% >mi&ert ., (17<1) >mi&ert
Inhi&ition of +ro*th of treponemes &y
antimi!ro&ial a+ents. "r @ Gener =is 4<: 40<-
412.
20. :&ramson I@% >mi&ert ., (17<1) >mi&ert
"a!teri!idal a!ti(ity of antimi!ro&ial a+ents for
treponemes. "r @ Gener =is 4<: 413-418.
21. Qaplan IL (2012) "en#athine peni!illin $: a
do!menta&ly important anti&ioti! in need of a
tne-pR /ediatr Infe!t =is @ 31: <26-8.
22. .iedner $% .si#o0a ,% Todd @% ,a&o0o L%
3oels!her ,% ,m&ando =% >am0y I% Lyamya
I% ,a&ey =% $ross0rth 3% 3ayes . (2004)
>in+le-dose a#ithromy!in (erss peni!illin $
&en#athine for the treatment of early syphilis. B
In+l @ ,ed 343: 1236-1244.

#orresponding author
3e-Ni Ohen+% ,=.
=epartment of =ermatolo+y and Genereolo+y%
/e0in+ 1nion ,edi!al 2olle+e 3ospital% 2hinese
:!ademy of ,edi!al >!ien!es and /e0in+ 1nion
,edi!al 2olle+e% "ei)in+ 100<30% 2hina. /hone:
86-010-67146372; Fa': 86-010-67146372;
I-mail: #hen+hy62Shotmail.!om


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