Medicines Q&As

Q&A 155.2b

How do you treat syphilis with parenteral benzylpenicillins?

Prepared by UK Medicines Information (UKMi) pharmacists for !" hea#thcare professiona#s $ate of p%b#ication& A%' 2(11

Background
"yphi#is is a systemic disease ca%sed by the spirochaete bacteria Treponema pallidum. It can be con'enita# (thro%'h mother to chi#d transmission d%rin' pre'nancy) or ac)%ired (thro%'h se* or b#ood transf%sion) (1). It ca%ses considerab#e morbidity and the presence of 'enita# %#cers in primary syphi#is increases the se*%a# transmission of !I+ (2). ,he c#inica# presentation of both ear#y and #ate syphi#is is di-erse and patients may present to a .ide ran'e of ser-ices and c#inicians inc#%din' /enera# Practitioners (2). It is c#assified in terms of disease sta'es0 primary1 secondary1 ear#y #atent1 #ate #atent and #ate symptomatic (or 2tertiary3) syphi#is (2). "ymptoms of a primary infection inc#%de %#cers or chancres at the infection site and symptoms of a secondary infection inc#%de s4in rashes1 m%coc%taneo%s #esions and #ymphadenopathy (5). 6atent infections #ac4 c#inica# manifestations and tertiary infections inc#%de cardiac1 ne%ro#o'ica# or ophtha#mic manifestations1 a%ditory abnorma#ities or '%mmato%s ('ran%#omato%s) #esions (5). "yphi#is remains a common infection .or#d.ide .ith an estimated 1(712 mi##ion ne. infections each year (2). "ince the #ate 188(s infectio%s ear#y syphi#is has re7emer'ed as an important disease in 9estern :%rope and the United Kin'dom (2).

Answer
Parentera# ben;y#penici##in (a#so 4no.n as penici##in /) is the preferred dr%' treatment for a## sta'es of syphi#is (5). Parentera# rather than ora# therapy has been the treatment of choice beca%se therapy is s%per-ised and bioa-ai#abi#ity is '%aranteed (<). Parentera# ben;y#penici##ins for the treatment of syphi#is inc#%de0 Benzathine benzylpenicillin1 a #on' actin' form of ben;y#penici##in administered by deep intram%sc%#ar in=ection (5). It is %s%a##y 'i-en as a sin'#e dose or .ee4#y for the treatment of syphi#is dependin' on the disease sta'e and '%ide#ines %sed (5) (<). It is %n#icensed in the UK1 the brand a-ai#ab#e at the time of .ritin' is :*tenci##ine> (?((1((( %nits1 1.2mi##ion %nits (MU) and 2.<MU) (5). Procaine benzylpenicillin1 a #on' actin' form of ben;y#penici##in administered by deep intram%sc%#ar in=ection (?). It is %s%a##y 'i-en once dai#y to treat syphi#is (?). It is %n#icensed in the UK and c%rrent#y a-ai#ab#e as the brand @armaproina> (?((1((( %nits and 1.2 MU) (?). Aqueous crystalline benzylpenicillin is administered by intra-eno%s in=ection for ne%rosyphi#is. It is short actin'1 .ith a ha#f7#ife of 5( min%tes1 so it is 'i-en e-ery fo%r ho%rs (A). It is #icensed in the UK for con'enita# syphi#is and ne%rosyphi#is. It is a-ai#ab#e as the brand Brystapen > (?((m' and 12((m') (A).

9hen administerin' ben;athine ben;y#penici##in1 if the -o#%me for administration is #ar'e1 the dose may be sp#it and 'i-en as t.o in=ections at separate sites (1). Cen;athine ben;y#penici##in intram%sc%#ar in=ection can be painf%#. A sma## st%dy in paediatrics has sho.n that this can be impro-ed by %sin' #idocaine 1D as the di#%ent b%t the tria# .as too sma## to be conc#%si-e (E). Practice may -ary from c#inic to c#inic so #oca# practice '%ide#ines sho%#d be chec4ed. Parentera# ben;y#penici##ins ha-e been %sed effecti-e#y for more than 5( years to treat syphi#is b%t no comparati-e tria#s ha-e been ade)%ate#y cond%cted to '%ide the se#ection of an optima# penici##in re'imen (5). As a res%#t1 there are many different '%ide#ines and the dose1 d%ration and preparation -aries bet.een them1 dependin' on the sta'e and c#inica# manifestations of disease. It is important to differentiate bet.een the -ario%s prod%cts (See table 1). Fther factors s%ch as c#inica# e*perience and #oca# a-ai#abi#ity of medicines a#so affect the choice of re'imen.

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Medicines Q&As
"tandard antisyphi#is therapy rare#y fai#s to c%re the disease1 and there doesn3t appear to be resistance (2). :ar#y sta'es of syphi#is are more infectio%s b%t respond better to treatment (1). A treponemicida# #e-e# of antimicrobia#s needs to be achie-ed in both the ser%m and cerebrospina# f#%id (B"@) to pro-ide effecti-e treatment for syphi#is (1). A penici##in #e-e# of 'reater than (.(1Em' per #itre is considered s%fficient1 and needs to be maintained for at #east A71( days in ear#y syphi#is (1). A #on'er d%ration of treatment is 'i-en in #ate syphi#is on the basis of more s#o.#y di-idin' treponemes (<). Table 1. osage regi!ens "or treating syphilis with parenteral benzylpenicillins

#uideline

$arly syphilis %pri!ary& secondary and early latent' +ntra!uscular Cen;athine ben;y#penici##in 2.< MU as a sin'#e dose Fr

(ate latent& cardio)ascular and gu!!atous syphilis +ntra!uscular Cen;athine ben;y#penici##in 2.< MU %nits .ee4#y for 5 doses in tota# Fr

*eurosyphilis

UK ationa# /%ide#ines on the Mana'ement of "yphi#is 2((E (CA"!! '%ide#ines ) (<)

+ntra!uscular Procaine ben;y#penici##in 1.EMU to 2.<MU dai#y p#%s probenecid 5((m' po )ds for 1A days Fr +ntra)enous A)%eo%s crysta##ine ben;y#penici##in 57<MU e-ery fo%r ho%rs for 1A days +ntra)enous A)%eo%s crysta##ine ben;y#penici##in 57<MU e-ery fo%r ho%rs or contin%o%s inf%sion for 1( G 1< days Fr1 +ntra!uscular Procaine ben;y#penici##in 2.<MU dai#y p#%s probenecid 5((m' po )ds for 1(71< days

+ntra!uscular Procaine ben;y#penici##in ?(( ((( %nits dai#y for 1( days

+ntra!uscular Procaine ben;y#penici##in ?(( ((( %nits dai#y for 1A days +ntra!uscular Cen;athine ben;y#penici##in 2.<MU .ee4#y for 5 doses in tota#

Bentre for $isease Bontro# and Pre-ention /%ide#ines (U"A) 2((? (5)

+ntra!uscular Cen;athine ben;y#penici##in 2.< MU as a sin'#e dose

9or#d !ea#th Fr'ani;ation /%ide#ines 2((5 (1)

+ntra!uscular Cen;athine ben;y#penci##in 2.<MU as a sin'#e dose Fr1 +ntra!uscular Procaine ben;y#penici##in 1.2MU dai#y for 1( days

+ntra!uscular Cen;athine ben;y#penici##in 2.<MU .ee4#y for 5 doses in tota# Fr1 +ntra!uscular Procaine ben;y#penici##in 1.2MU dai#y for 2( days

+ntra)enous A)%eo%s crysta##ine ben;y#penici##in 27<MU e-ery fo%r ho%rs for 1< days Fr1 +ntra!uscular Procaine ben;y#penici##in 1.2MU dai#y p#%s probenecid 5((m' po )ds for 1(71< days

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Medicines Q&As
Alternati)e non parenteral treat!ents and regi!ens "or penicillin allergic patients If patients ref%se parentera# treatment1 or if they are penici##in a##er'ic1 a#ternati-e re'imens may be so%'ht. ,here are s%bstantia##y fe.er c#inica# tria# data a-ai#ab#e for non7penici##in re'imens (5). Fra# do*ycyc#ine1 erythromycin and a;ithromycin ha-e been e-a#%ated (<). :rythromycin is the #east effecti-e and does not penetrate the B"@ or p#acenta# barrier .e## (<). $o*ycyc#ine has s%perceded the o#der tetracyc#ines (<). A;ithromycin has sho.n efficacy in ear#y syphi#is e)%i-a#ent to ben;athine ben;ypenici##in b%t there are concerns re'ardin' a;ithromycin treatment fai#%re .hich appears to be intrinsic macro#ide resistance in some strains of Treponema pallidum (<)(8). In sma## st%dies a n%mber of ceftria*one re'imens ha-e been sho.n to be effecti-e (<). ,reatment re'imens -ary accordin' to different '%ide#ines. ,he UK ationa# /%ide#ines on the Mana'ement of "yphi#is 2((E ad-ise (<)0 $arly syphilis& 1. $o*ycyc#ine 1((m' bd ora##y for 1< days 2. A;ithromycin 2' stat ora##y1 or a;ithromycin 5((m' dai#y for 1( days 5. :rythromycin 5((m' )ds ora##y for 1< days <. Beftria*one 5((m' IM dai#y for 1( days (if no anaphy#a*is to penici##in) 5. Amo*ici##in 5((m' )ds ora##y p#%s probenecid 5((m' )ds for 1< days (ate latent syphilis& 1. $o*ycyc#ine 1((m' bd ora##y for 2E days 2. Amo*ici##in 2' tds ora##y p#%s probenecid 5((m' )ds ora##y for 2E days *eurosyphilis& 1. $o*ycyc#ine 2((m' bd ora##y for 2E days 2. Amo*ici##in 2' tds ora##y p#%s probenecid 5((m' )ds ora##y for 2E days 5. Beftria*one 2' IM (.ith #idocaine as di#%ent) or I+ (.ith .ater for in=ections as di#%ent) for 1( to 1< days (if no anaphy#a*is to penici##in)

,eactions to treat!ent Patients sho%#d be .arned of possib#e reactions to treatments. ,hese inc#%de the Harisch7!er*heimer reaction1 or reactions to either procaine1 penici##in1 or both. a) Harisch7!er*heimer is an ac%te febri#e i##ness .ith headache1 mya#'ia1 chi##s and ri'ors %s%a##y occ%rrin' after the first dose of therapy and reso#-in' .ithin 2< ho%rs (<). It is most common in ear#y syphi#is b%t is %s%a##y not important %n#ess there is ne%ro#o'ica# or ophtha#mic in-o#-ement or in pre'nancy (<). It is %ncommon in #ate syphi#is b%t can potentia##y be #ife threatenin' if there is cardio#o'ica#Ine%ro#o'ica# in-o#-ement (<). b) A reaction to procaine is %s%a##y d%e to inad-ertent I+ in=ection of procaine ben;y#penici##in (<). It is characterised by fear of impendin' death and may ca%se ha##%cinations or fits immediate#y after in=ection and #astin' #ess than 2( min%tes (<). Ba#m and -erba# reass%rance is re)%ired and recta# dia;epam may be %sed if the patient is fittin' (<). Jemind prescribers and staff administerin' procaine ben;y#penici##in that it m%st be 'i-en by intram%sc%#ar in=ection. c) Anaphy#a*is may occ%r in patients .ho are a##er'ic to penici##in (<). A#.ays chec4 patient3s a##er'y stat%s prior to administration. Special considerations !I+ infected patients .ith ear#y syphi#is are more #i4e#y to ha-e m%#tip#e1 #ar'e and deep 'enita# %#cers and the ris4 of ne%ro#o'ica# comp#ications may be hi'her in !I+ positi-e patients .ith ear#y syphi#is (<). ,reatment sho%#d be appropriate for the sta'e of infection0 that is !I+ positi-e indi-id%a#s sho%#d be 'i-en the same treatment re'imens as !I+ ne'ati-e indi-id%a#s. "ome e*perts be#ie-e that !I+ patients .ith syphi#is sho%#d be treated as for ne%rosyphi#is to pre-ent the de-e#opment of ne%ro#o'ica# in-o#-ement1 b%t hard e-idence for this po#icy is #ac4in' (<) (1().

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Medicines Q&As
Su!!ary

Parentera# ben;y#penici##in (a#so 4no.n as penici##in /) is the preferred dr%' treatment for a## sta'es of syphi#is (5). ,he #on' actin' forms of ben;y#penici##in %sed to treat syphi#is are procaine ben;y#penici##in and ben;athine ben;y#penici##in. ,hey are administered by deep intram%sc%#ar in=ection (5) (?). Procaine ben;y#penici##in is %s%a##y 'i-en once dai#y in syphi#is .here as ben;athine ben;y#penici##in is 'i-en once .ee4#y or as a sin'#e dose. ,he dose1 d%ration and preparation -ary accordin' to the sta'e of disease and different '%ide#ines (See table 1). $arly syphilis- 2.<MU ben;athine ben;y#penici##in IM is recommended as a sin'#e dose (<) (1). A#ternati-e#y1 procaine ben;y#penci##in can be 'i-en at a dose of ?(( ((( %nits IM dai#y for 1( days accordin' to the UK ationa# /%ide#ines 2((E (<). (ate latent& cardio)ascular and gu!!atous syphilis- 2.<MU ben;athine ben;y#penici##in IM .ee4#y is recommended for 2 .ee4s (5 doses) (<) (1). A#ternati-e#y1 procaine ben;y#penici##in can be 'i-en at a dose of ?(( ((( %nits IM dai#y for 1A days accordin' to the UK ationa# /%ide#ines 2((E (<). A #on'er d%ration of treatment is 'i-en in #ate syphi#is than ear#y syphi#is on the basis of more s#o.#y di-idin' treponemes (<). *eurosyphilis- ,he UK ationa# /%ide#ines 2((E recommend 1.EMU to 2.<MU procaine ben;y#penici##in dai#y IM p#%s ora# probenecid 5((m' )ds for 1A days (<). A#ternati-e#y1 a)%eo%s crysta##ine ben;y#penici##in 5MU to <MU intra-eno%s#y e-ery fo%r ho%rs for 1A days can be %sed (<). Patients sho%#d be informed abo%t possib#e ad-erse reactions s%ch as the Harisch7 !er*heimer reaction1 a reaction to procaine1 or penici##in or both. A#ternati-e ora# antibiotics are a-ai#ab#e for penici##in a##er'ic patients1 and patients ref%sin' parentera# therapy. "pecia# consideration sho%#d be 'i-en to !I+7infected persons1 .ho ha-e a 'reater ris4 of ne%ro#o'ica# comp#ications (<)1 and #ate syphi#is may de-e#op more rapid#y in !I+ positi-e positi-e indi-id%a#s (1).

(i!itations ,his Q&A does not co-er treatment of syphi#is in pre'nancy and con'enita# syphi#is in ne.borns. Information can be fo%nd in c%rrent '%ide#ines. http&II....bashh.or'I'%ide#ines ....cdc.'o-IstdItreatmentI http&II.h)#ibdoc..ho.intIp%b#icationsI2((5I82<15<?2?5.pdf isclai!er Medicines Q&As are intended for hea#thcare professiona#s and ref#ect UK practice. :ach Q&A re#ates on#y to the c#inica# scenario described. Q&As are be#ie-ed to acc%rate#y ref#ect the medica# #iterat%re at the time of .ritin'. "ee e6M for f%## disc#aimer. ,e"erences 1. 9or#d !ea#th Fr'ani;ation /%ide#ines for the mana'ement of se*%a##y transmitted infections. /ene-a1 2((5. Accessed -ia http&II.h)#ibdoc..ho.intIp%b#icationsI2((5I82<15<?2?5.pdf on 11I(AI2((E 2. @rench P. "yphi#is. B#inica# re-ie.. CMH 2((A0 55<&1<571<A 5. Benters for $isease Bontro# and Pre-ention. "e*%a##y ,ransmitted $iseases ,reatment /%ide#ines 2(1(. MM9J 2(1(0 58(JJ712)&1711( <. B#inica# :ffecti-eness /ro%p. Critish Association for "e*%a# !ea#th and !I+. UK ationa# /%ide#ines on the Mana'ement of "yphi#is 2((E. Accessed -ia http&II....bashh.or'I'%ide#ines on (?I(AI11 5. "%mmary of Prod%ct Bharacteristics. :*tenci##ine. "anofi7a-entis @rance. 2((2. ,rans#ated for I$I" 6imited1 "%rrey1 K,15 E$C. ?. "%mmary of Prod%ct Bharacteristics. @armaproina. Jei' Hofre "A #aboratory1 Carce#ona1 "pain. 6ast re-ision of te*t1 March 2((1. ,rans#ated for I$I" 6imited1 "%rrey1 K,15 E$C.

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Medicines Q&As
A. "%mmary of Prod%ct Bharacteristics. Brystapen In=ection. Critannia Pharmace%tica#s 6imited. Accessed -ia http&II....emc.medicines.or'.%4 on (?I(AI2(11 ($ate of re-ision of te*t H%#y 2((E ) E. Amir H1 /inat "1 Bohen K!1 et a#. 6idocaine as a di#%ent for administration of ben;athine penici##in /. Paediatr Infect $is H. 188E Fct0 1A (1()&E8(75 8. Jiedner /1 J%si;o4a M1 ,odd H1 et a#. "in'#e7dose a;ithromycin -ers%s penici##in / ben;athine for the treatment of ear#y syphi#is. :HM 2((50 555&125?712<<1 1(. C#an4 6H1 Jompa#o AM1 :rbe#din' :H et a#. ,reatment of syphi#is in !I+7infected s%b=ects& a systematic re-ie. of the #iterat%re. "e* ,ransm Infect 2(110 EA& 871?

.uality Assurance
Prepared by Jan% A#i1 Medicines Information Pharmacist1 6ondon MI "er-ice ( orth.ic4 Par4)1 based on a pre-io%s Q&A .ritten by Baro#ine ,ay#or1 6MI". ate Prepared H%#y2(11 /hecked by A#e*andra $enby1 Je'iona# MI Mana'er1 6ondon MI "er-ice ( orth.ic4 Par4) ate o" check 2Eth H%#y 2(11 Search strategy :mbase (search strate'y L syphi#is Mpenici##in Mh%man since 2((E) Med#ine (se*%a##y transmitted diseases M penici##ins Mh%man M:n'#ish M intram%sc%#ar in=ections) In ho%se database G MI databan4 since (1I(1I2((E G 5 hits I$I" .or#d medicines Pharm#ine -ia e6M (ben;athine penici##in Mprocaine ben;y#penici##in) Chair-i /osrani1 "pecia#ist pharmacist !I+1 orth.ic4 Par4 !ospita#

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