CAT 11.

04 Bacterial Vaginosis Matthew Hollon, MD MPH 1

Clinically Appraised Topic Evidence-Based Medicine (November 2004) Theme: Therapy Clinical Bottom Line: 1 Metroni!a"ole P# an! PV are e$%all& e''ecti(e in treating )acterial (aginosis. C%re rates e*cee! +0, at one wee-. . /*0erimental an! o)ser(ational !ata s%ggest that there is no a ris- o' !is%l'iram reaction with metroni!a"ole 1 s%ch a reaction is %nli-el& at )est an! is )ase! onl& on case re0orts. 2see articles . an! 3 )elow . 3 Metroni!a"ole PV is o(er 10 times as e*0ensi(e as metroni!a"ole P#. Clinical 4cenario: .. &ear ol! woman otherwise health with rec%rrent )acterial (aginosis an! reg%lar %se o' alcohol. Clinical !"es ion: 5s metroni!a"ole PV as e''ecti(e as metroni!a"ole P# at re!%cing !%ration o' s&m0toms an! is there a nota)le !i''erence in ris- o' the !is%l'iram t&0e reaction6 Data)ases: P%)Me!, Clinical /(i!ence, Cochrane, T75P, Microme!e*, Dr%gstore.com. 4earch Terms: Bacterial Vaginosis 8Me4H9 an! Metroni!a"ole The 4t%!&2ies : 1 Hanson :M, Mc;regor :A, Hillier 4L, /schen)ach DA, <re%tner A<, ;alas- 7P, Martens M. Metroni!a"ole 'or )acterial (aginosis. A com0arison o' (aginal gel (s. oral thera0&. : 7e0ro! Me!. .000 =o(>4?211 :++@A@B. . Cilliams C4, Coo!coc- <7. Do ethanol an! metroni!a"ole interact to 0ro!%ce a !is%l'iramAli-e reaction6 Ann Pharmacother. .000 De)>342. :.??AE. 3 Visa0aa :P, Tillonen :4, <aiho(aara P4, 4alas0%ro MP. Lac- o' !is%l'iramAli-e reaction with metroni!a"ole an! ethanol. Ann Pharmacother. .00. :%n>3B2B :@E1A4. Comments: 1 Two s%mmaries o' the onl& s&stematic re(iew o' treatment o' )acterial (aginosis are 0ro(i!e! )elow. The 'irst an! less critical is 'rom Clinical /(i!ence. The secon! highlights the shortcomings o' the one s&stematic re(iew an! is 0%)lishe! in Cochrane. . The c%m%lati(e e(i!ence re(eals no maFor !i''erences 'or an& o' the treatment regimens highlighting the 0ossi)ilit& that in man& circ%mstances a signi'icant 0ortion o' the cases o' )acterial (aginosis ma& im0ro(e in!e0en!ent o' thera0&. 3 5n the most rele(ant an! c%rrent 7CT, 1 in . 0atient treate! with P# metroni!a"ole !e(elo0e! Ggastrointestinal com0laintsH while 1 in 3 0atients treate! with PV metroni!a"ole !e(elo0e! Ggastrointestinal com0laintsH.

CAT 11.04 Bacterial Vaginosis Matthew Hollon, MD MPH .

The /(i!ence: #) $CT: Me ronida%ole &or bac erial va'inosis( A comparison o& va'inal 'el vs( oral herapy( #B:/CT5V/: To com0are the e''icac& an! sa'et& o' 0.E?, metroni!a"ole (aginal gel with oral metroni!a"ole 'or the treatment o' )acterial (aginosis 2BV . 4TIDJ D/45;=: =on0regnant women with BV were enrolle! in a m%lticenter, ran!omi"e!, in(estigatorA)lin! treatment trial. Patients were ran!oml& assigne! to either 0.E?, metroni!a"ole (aginal gel 2? g twice !ail& 'or 'i(e !a&s or oral metroni!a"ole 2?00 mg twice !ail& 'or se(en !a&s . DollowA%0 (isits occ%rre! a00ro*imatel& two an! 'i(e wee-s a'ter initiation o' thera0&. 7/4ILT4: BV was clinicall& eliminate! at the 'irst 'ollowA%0 (isit in +3.E, 23BK43, @?, C5 E..3A@?.1, o' the intra(aginal gro%0 an! +?.1, 240K4E, @?, C5 E4.BA@?.B, o' the oral gro%0. At the 'inal (isit, BV was eliminate! in E0.E, 2.@K41, @?, C5 ?B.3A +?.1, o' the intra(aginal gro%0 an! E1.1, 23.K4?, @?, C5 ?E.4A+4.+, o' the oral gro%0. 4igni'icantl& more 0atients in the oral treatment gro%0 2?1.+, re0orte! gastrointestinal com0laints as com0are! to the intra(aginal treatment gro%0 23..E,, P L .04 . C#=CLI45#=: The e''icac& o' 0.E?, metroni!a"ole (aginal gel twice !ail& 'or 'i(e !a&s in treating BV was similar to that o' stan!ar! oral metroni!a"ole treatment an! was associate! with 'ewer gastrointestinal com0laints. 2) )rice da a &rom *r"'s ore(com: Me ronida%ole 4?;M t%)e 0.E?, cream Me ronida%ole -+0 able s able s ,00MM?@.@@ M@.@@

+) ."mmary o& .ys ema ic $evie/ &rom Clinical Evidence: #ral (ers%s intra(aginal anti)acterial treatment. Ce 'o%n! one s&stematic re(iew 2search !ate 1@@B, ? 7CTs com0aring oral an! intra(aginal 'orm%lations o' metroni!a"ole an! clin!am&cin,8149 an! one s%)se$%ent 7CT.81?9 Three 7CTs were con!%cte! in s&m0tomatic nonA0regnant women an! two were con!%cte! in s&m0tomatic an! as&m0tomatic nonA0regnant women.8149 There was no signi'icant !i''erence in c%m%lati(e c%re rates ?110 !a&s a'ter com0leting treatment 2+B, with oral metroni!a"ole ?00 mg twice !ail& 'or E !a&s ( +?, with clin!am&cin (aginal cream ? g at )e!time 'or E !a&s ( +1, 'or metroni!a"ole (aginal gel ? g twice !ail& 'or ? !a&s> P (al%es an! C5 not re0orte! .

CAT 11.04 Bacterial Vaginosis Matthew Hollon, MD MPH 3

Do%r wee-s a'ter com0leting treatment, the c%m%lati(e c%re rates were E+, 'or oral metroni!a"ole, +., 'or clin!am&cin (aginal cream, an! E1, 'or metroni!a"ole (aginal gel. The s%)se$%ent 7CT 23@@ women com0aring clin!am&cin (aginal cream (ers%s oral metroni!a"ole also 'o%n! no signi'icant !i''erence in c%re rates 2B+, 'or clin!am&cin cream ( BE, 'or oral metroni!a"ole> P L 0.+1 .81?9 Howe(er, a large n%m)er o' women were not incl%!e! in the e''icac& anal&sis, ma-ing inter0retation o' the res%lts !i''ic%lt 2res%lts re0orte! on .33 women, man& e*cl%sions 'or !i''erent reasons . 14. :oesoe' M7, 4chmi! ;P. Bacterial (aginosis: re(iew o' treatment o0tions an! 0otential clinical in!ications 'or thera0&. Clin Infect Dis 1@@@>.+2s%00l 1 :4?E1 4B?. 4earch !ate 1@@B> 0rimar& so%rces Me!line, han! searches o' te*t )oo-s a)o%t se*%all& transmitte! !iseases an! meeting a)stracts, an! contact with !r%g man%'act%rers. 1?. Paa(onen :, Mangioni C, Martin MA, et al. Vaginal clin!am&cin an! oral metroni!a"ole 'or )acterial (aginosis: a ran!omi"e! trial. Obstet Gynecol .000>@B:.?B1.B0

4) Abs rac &rom Ar icle ci ed in Clinical Evidence :oesoe' M7, 4chmi! ;P, Hillier 4L. Bacterial (aginosis: re(iew o' treatment o0tions an! 0otential clinical in!ications 'or thera0&. Di(ision o' 4TD Pre(ention, Centers 'or Disease Control an! Pre(ention, Atlanta, ;eorgia 30333, I4A. Ce re(iewe! !ata on the treatment o' )acterial (aginosis 0%)lishe! 'rom 1@@3 thro%gh 1@@B. Dor non0regnant women, we recommen! %se o' metroni!a"ole 2?00 mg orall& twice !ail& 'or E !a&s , clin!am&cin (aginal cream 2.,, once !ail& 'or E !a&s , or metroni!a"ole (aginal gel 20.E?,, twice !ail& 'or ? !a&s as the 0re'erre! treatment 'or )acterial (aginosis. Dor 0regnant highAris- women2women with a 0rior 0reterm )irth , the o)Fecti(e o' the treatment is to 0re(ent a!(erse o%tcomes o' 0regnanc&, in a!!ition to relie' o' s&m0toms. Th%s, s&stemic thera0& 'or 0ossi)le s%)clinical %00er tract in'ection as well as me!ication that has )een st%!ie! in 0regnant women are 0re'era)le. There'ore, we recommen! metroni!a"ole 2.?0 mg orall& three times a !a& 'or E !a&s . Dor 0regnant lowAris- women 2women witho%t a 0rior 0reterm )irth with s&m0tomatic !isease, the main o)Fecti(e o' the treatment is to relie(e s&m0toms. Ce recommen! metroni!a"ole 2.?0 mg orall& three times a !a& 'or E !a&s .

CAT 11.04 Bacterial Vaginosis Matthew Hollon, MD MPH 4

,) ."mmary o& Na ional 0eal h .ervice (-rea Bri ain) Economic Eval"a ion *a abase accessed hro"'h T$1) - N0. EE* abs rac #2220343 ;eneric metroni!a"ole, rather than Metrogel Vaginal, sho%l! )e %se! 'or the ro%tine treatment o' 0atients s%''ering 'rom )acterial (aginosis. This is )eca%se metroni!a"ole was o(er 13 times less costl& than Metrogel Vaginal,an! the e''ecti(eness !i! not !i''er statisticall& )etween the treatments. 4) Micromede5 M/T7#=5DAN#L/ 2Anon, 1@EB> 4toc-le&, 1@+3 CellAcontrolle! st%!ies ha(e not s%)stantiate! earl& re0orts o' a !is%l'iramAli-e reaction 'ollowing alcohol ingestion. 5n (itro st%!ies show that metroni!a"ole !oes inhi)it al!eh&!e !eh&!rogenase, )%t animal st%!ies ha(e not con'irme! this. A !o%)leA)lin! crosso(er st%!& 2;el!er O /!war!s, 1@B+ !i! not 'in! signi'icant e''ects o' the !r%g on )loo! 0ress%re, 0%lse rate, or a%tonomic si!e e''ects a'ter a challenge !rin-.

CAT 11.04 Bacterial Vaginosis Matthew Hollon, MD MPH ?

6) Abs rac : 7illiams C.8 7oodcoc9 :$( *o e hanol and me ronida%ole in erac o prod"ce a dis"l&iram-li9e reac ion; #B:/CT5V/: To o)tain an! e(al%ate e(i!ence a)o%t the s%00ose! !is%l'iramAli-e interaction )etween metroni!a"ole an! ethanol. DATA 4#I7C/4: M/DL5=/ search 'rom :an%ar& 1@B4 to :%ne 1@@@, %sing the terms metroni!a"ole, ethanol, an! !r%g reaction. DATA 4J=TH/454: The man%'act%rerPs warnings incl%!e a !is%l'iramAli-e reaction )etween metroni!a"ole an! ethanol. Howe(er, re(iew o' re0orts 0%)lishe! )etween 1@B@ an! 1@+. 0ro!%ce! no con(incing e(i!ence that this reaction e*ists. 4i* case re0orts in(ol(ing eight 0atients were e(al%ate!. C#=CLI45#=4: Do%r o' the eight cases were serio%s, incl%!ing one !eath, )%t the a%thors o' all the re0orts 0res%me! the metroni!a"oleAethanol reaction to )e an esta)lishe! 0harmacologic 'act. =one 0ro(i!e! e(i!ence that co%l! F%sti'& their concl%sions. 3) Abs rac <isapaa =)8 Tillonen =.8 :aihovaara ).8 .alasp"ro M)( >ac9 o& dis"l&iram-li9e reac ion /i h me ronida%ole and e hanol( BAC<;7#I=D: Metroni!a"ole, an e''ecti(e antianaero)ic agent, has )een re0orte! to ha(e a(ersi(e 0ro0erties when ingeste! with ethanol. This is tho%ght to )e !%e to the )loc-ing o' he0atic al!eh&!e !eh&!rogenase 2ALDH en"&me 'ollowe! )& the acc%m%lation o' acetal!eh&!e in the )loo!. Howe(er, )ase! on animal st%!ies an! on onl& 10 h%man case re0orts, the e*istence o' metroni!a"oleArelate! !is%l'iramAli-e reaction has recentl& )een $%estione!. #B:/CT5V/: To in(estigate the 0ossi)le !is%l'iramAli-e 0ro0erties o' metroni!a"ole an! ethanol in h%man (ol%nteers. M/TH#D4: #' 1. health& male (ol%nteers in this !o%)leA)lin! st%!&, oneAhal' recei(e! metroni!a"ole 'or ? !a&s an! the other hal' recei(e! 0lace)o. All (ol%nteers recei(e! ethanol 0.4 gK-g at the )eginning o' the st%!&. 7e0eate! )loo! sam0les were ta-en e(er& .0 min%tes 'or 4 ho%rs, an! )loo! acetal!eh&!e an! ethanol concentrations were !etermine!. Bloo! 0ress%re, heart rate, an! s-in tem0erat%re were also meas%re! e(er& .0 min%tes 'or o)Fecti(e signs o' a 0ossi)le !is%l'iramAli-e reaction. Vol%nteers also com0lete! a $%estionnaire 'oc%sing on the s%)Fecti(e signs o' !is%l'iramAli-e reaction. 7/4ILT4: Metroni!a"ole !i! not raise )loo! acetal!eh&!e or ha(e an& o)Fecti(e or s%)Fecti(e a!(erse e''ects when %se! together with ethanol. C#=CLI45#=4: This st%!& shows that metroni!a"ole !oes not ha(e an e''ect on )loo! acetal!eh&!e concentrations when ingeste! with ethanol an! !oes not ha(e an& o)Fecti(e or s%)Fecti(e !is%l'iramAli-e 0ro0erties. Howe(er, it is 0ossi)le that !is%l'iramAli-e reaction can occ%r in some s%)gro%0s an! )& other mechanisms than the inhi)ition o' he0atic ALDH. 2) Cochrane $evie/ o& . r"c "red Abs rac Bacterial (aginosis: re(iew o' treatment o0tions an! 0otential clinical in!ications 'or thera0& 24tr%ct%re! a)stract =H4 Centre 'or 7e(iews an! Dissemination #75;5=AL A7T5CL/ :oesoe' M 7, 4chmi! ; P. Bacterial (aginosis: re(iew o' treatment o0tions an! 0otential clinical in!ications 'or thera0&. Clinical 5n'ectio%s Diseases. 1@@?.

CAT 11.04 Bacterial Vaginosis Matthew Hollon, MD MPH B

.024%00lement 1 . 4E.A4E@. 7/C#7D 4TATI4 This recor! is a str%ct%re! a)stract written )& C7D re(iewers. The original has met a set o' $%alit& criteria. AITH#7P4 #B:/CT5V/ To re(iew the !ata on the treatment o' )acterial (aginosis 2BV 0%)lishe! 'rom1@+@ to 1@@.. TJP/ #D 5=T/7V/=T5#= Treatment. 4P/C5D5C 5=T/7V/=T5#=4 5=CLID/D 5= TH/ 7/V5/C Treatment o' )acterial (aginosis. 4&stemic 'orm%lations: Metroni!a"ole 2single !ose (s E !a& , Clin!am&cin. To0ical 'orm%lations: Metroni!a"ole 0essaries. Metroni!a"ole s0onge 21 !a& (s 3 !a& . PA7T5C5PA=T4 5=CLID/D 5= TH/ 7/V5/C Demales 0resenting with BV as s&m0tom, 0regnant women with BV, se*%al 0artners o' women with BV> as&m0tomatic 0atients in s%rgical settings. #ITC#M/4 A44/44/D 5= TH/ 7/V5/C C%re rates were assesse!. 4TIDJ D/45;=4 #D /VALIAT5#=4 5=CLID/D 5= TH/ 7/V5/C 7an!omise! controlle! trials 27CTs , controlle! trials or case st%!ies, total nL.?. CHAT 4#I7C/4 C/7/ 4/A7CH/D T# 5D/=T5DJ P75MA7J 4TID5/46 M/DL5=/ was searche! 'rom 1@+@ to 1@@., %sing the search terms P)acterial (aginosisP, PnonAs0eci'ic (aginosisP, Pclin!am&cinP, Pmetroni!a"oleP. 4earches o' )oo-s on se*%all& transmitte! !iseases 24TDs , a)stracts o' meetings were gatherere!, an! in'ormation 'rom !r%g man%'act%rers so%ght. #ther recent re(iews were in(estigate!. C75T/75A #= CH5CH TH/ VAL5D5TJ 2#7 QIAL5TJ #D 4TID5/4 CA4 A44/44/D Dor each article, the a%thors !isc%sse! the st%!& !esign 2e.g. 7CT or case st%!& , the st%!& 0o0%lation, their treatments, the o%tcome meas%res, the re0orte! 'in!ings an! the )iases in the st%!& !esign an! anal&sis. H#C C/7/ TH/ 5=CLI45#= C75T/75A APPL5/D6 The a%thors !o not state how the 0a0ers were selecte! 'or the re(iew, or how man& o' the a%thors 0er'orme! the selection. H#C C/7/ :ID;/M/=T4 #D VAL5D5TJ 2#7 QIAL5TJ MAD/6

CAT 11.04 Bacterial Vaginosis Matthew Hollon, MD MPH E

The a%thors !o not state how the 0a0ers were assesse! 'or (ali!it&, or how man& o' the a%thors 0er'orme! the (ali!it& assessment. H#C C/7/ TH/ DATA /RT7ACT/D D7#M P75MA7J 4TID5/46 The a%thors !o not state how the !ata were e*tracte! 'or the re(iew, or how man& o' the a%thors 0er'orme! the !ata e*traction. =IMB/7 #D 4TID5/4 5=CLID/D The n%m)er o' st%!ies incl%!e! is %nclear as st%!ies were com)ine! with those incl%!e! in an earlier re(iew 2Lossic- 1@@0 . =arrati(e s%mmar& o' ? st%!ies o' s&stemic 'orm%lations, + st%!ies o' to0ical 'orm%lations, 3 st%!ies o' treatment o' se* 0artners, 1 st%!& o' treatment !%ring 0regnanc&, 1 st%!& o' treatment 'or as&m0tomatic 0atients !%ring s%rger&. H#C C/7/ TH/ 4TID5/4 C#MB5=/D6 4t%!ies were com)ine! in a narrati(e re(iew with one s%mmar& ta)le 'or s&stemic metroni!a"ole regimens. The st%!ies i!enti'ie! are com)ine! with the a 0re(io%s re(iew )& Lossic- 21@@0 . The& also a00ear to reAanal&se st%!ies 'rom a metaAanal&sis )& L%goA Miro et al 21@@. )%t !o not 0resent these !ata clearl&. H#C C/7/ TH/ D5DD/7/=C/4 B/TC//= 4TID5/4 5=V/4T5;AT/D6 The a%thors !o not state how !i''erences )etween the st%!ies were in(estigate!. 7/4ILT4 #D TH/ 7/V5/C 4&stemic 'orm%lations: c%re rates 'or the s&stemic metroni!a"ole treatment range 'rom E0, to 100, 'or in!i(i!%al st%!ies, with a Pc%m%lati(eP c%re rate o' @., 2.@? o%t o' 3.. 0atients treate! 'or the EA!a& treatment regimen an! +E, 23B@ o%t o' 4.B 'or the single !ose regimen. The rela0se rate 'or the in!i(i!%al st%!ies range! 'rom 13,A44, 'or the EA !a& regimen an! 0A?3, 'or the single !ose. To0ical 'orm%lations: e(i!ence o' the e''icac& o' metroni!a"ole s0onges s%ggests 3A!a& s0onge to )e more e''icacio%s than the 1A!a& s0onge. The high !ose 21000mg 3A!a& s0onge was 'o%n! to ha(e a )etter c%re rate than the lower !ose 2.?0mg 3A!a& s0onge 2++, (s ?B, . The e''icac& o' metroni!a"ole 0essaries is less clear. The onl& 7CT e(al%ating this treatment 'o%n! a high c%re rate at one wee- 241 o%t o' 41 )%t the st%!& s%''ere! 'rom a high !ro0Ao%t rate an! E o%t o' 41 women e*0erience! local si!eAe''ects 2itching, )%rning or increase! (aginal !ischarge . Treatment o' se*%al 0artners: one st%!& re0orte! a signi'icantl& !i''erent c%re rate )etween women whose stea!& 0artners were treate! with metroni!a"ole com0are! to a 0lace)o. The remaining st%!ies 'o%n! no e''ect. The a%thors concl%!e that the P)estP !ata show no )ene'it. Treatment !%ring 0regnanc&: as metroni!a"ole is contrain!icate! !%ring the 'irst trimester o' 0regnanc&, clin!am&cin is the 0re'erre! treatment !%ring 0regnanc&. The one st%!& e(al%ating the e''ects o' clin!am&cin thera0& 'o%n! the treatment to )e sa'e an! wellAtolerate!.

CAT 11.04 Bacterial Vaginosis Matthew Hollon, MD MPH +

Treatment )e'ore s%rgical a)ortion: one 7CT 'o%n! a three'ol! re!%ction in the inci!ence o' 0ostAa)ortion 0el(ic in'lammator& !isease 2P5D in women with BV treate! with metroni!a"ole. Treatment o' as&mtomatic 0atients !%ring s%rger&: onl& one 7CT was i!enti'ie! which s%ggests that treatment o' as&m0tomatic 0atients with BV )e consi!ere! )e'ore 0er'orming s%rgical a)ortion 0roce!%res to 0re(ent P5D. CA4 A=J C#4T 5=D#7MAT5#= 7/P#7T/D6 =o. AITH#7P4 C#=CLI45#=4 The re(iew s%ggests that oral metroni!a"ole 2?00mg twice !ail& 'or E !a&s is the 0re'erre! treatment 'or )acterial (aginosis. #ther e''ecti(e 2)%t alternati(e treatment regimens incl%!e singleA!ose metroni!a"ole 2.g orall& , ., clin!am&cin (aginal cream 2once !ail& 'or E !a&s , 0.E?, metroni!a"ole (aginal gel 2twice !ail& 'or ? !a&s an! oral clin!am&cin 2300 mg twice !ail& 'or E !a&s . Data !o not s%00ort the 0ractice o' ro%tine treatment o' male se*%al 0artners o' in'ecte! 'emales. Treatment o' )acterial (aginosis !%ring 0regnanc& sho%l! 'oc%s on the elimination o' s&m0toms> !ata on a!(erse 0regnanc& o%tcomes 'or women with )acterial (aginosis remain ins%''icient to recommen! treatment o' as&m0tomatic 0atients. Be'ore 0er'orming s%rgical a)ortion, treatment o' )acterial (aginosis sho%l! )e consi!ere! to 0re(ent P5D. C7D C#MM/=TA7J This re(iew is not metho!ologicall& rigoro%s. There are a n%m)er o' inconsistencies in the 0resentation o' the re(iew> the a%thors claim to loo- at st%!ies a'ter 1@+@ )%t incl%!e 0reA1@+@ st%!ies in Ta)le 1. This ta)le also s%mmarises st%!ies incl%!e! in Lossic-Ps re(iew &et there is no e(i!ence that the Lossic- re(iew was s&stematic. The search strateg& 'or this re(iew is (er& limite!, th%s o0en to 0otential )ias. 5t relies hea(il& on the Lossic- re(iew 'or 0reA1@+@ st%!ies, 0ossi)l& intro!%cing )ias into the re(iew. The a%thors state the& ha(e incl%sion criteria 2i.e. some attem0t to assess $%alit& )%t !o not !e(elo0 them. 5t is %nclear how the a%thors reach their concl%sions as the st%!ies !o not a00ear to ha(e )een s&nthesise! in an& wa&. C7D !ata)ase n%m)er: DA7/A@?0+?