Artikels

As penisillien aanvanklik bekendgestel is, was dit effektief teen alle gram positiewe eienskappe?

As penisillien aanvanklik bekendgestel is, was dit effektief teen alle gram positiewe eienskappe?


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

Ek probeer die geskiedenis van verset ondersoek. Hoe goed was penisillien toe dit die eerste keer verskyn? Was daar enige gram positiewe dinge wat dit nie kon kry nie?


Nee, dit sou nie teen alles effektief gewees het nie.

Byvoorbeeld, bakterieë met voldoende β-laktamase produksie sou bestand gewees het. Hierdie ensiem is ook baie oud en het ontwikkel a miljard jare terug. Alhoewel ek dus nie weet van enige spesie wat in sy geheel bestand was nie, individu weerstandbiedende bakterie bestaan voor die kliniese aanvaarding van penisillien. Dit is bewys in die Lederberg -eksperiment, wat getoon het dat daar weerstandbiedende bakterieë in 'n kolonie bestaan voor kontak met penisillien, in teenstelling met 'n mutasie daarna.

Wat is Dit is egter duidelik dat die doeltreffendheid van penisillien afbrekend was. As dit aanvanklik beskikbaar gestel is vir algemene antibakteriese gebruik, penisillien was ongelooflik effektief teen stafilokokke en streptokokke, twee baie vrugbare oorsake van infeksies. Dit het nie gehou nie - reeds in 1946 verskyn berigte oor penisillienbestande Staphylococcus aureus regoor die wêreld, en nou het die meeste bakteriestamme weerstandbiedend geword. Teen die 1960's het dit ontwikkel tot die plaag, bekend as MSRA.

Toe penisillien in 1944 bekendgestel is, was meer as 94% van die Staphylococcus aureus -isolate vatbaar; teen 1950 was die helfte weerstandig. Teen 1960 het baie hospitale uitbreek van virulente multi-weerstandige S. aureus.

- Livermore, David M. "Antibiotiese weerstand by stafilokokke." International Journal of Antimicrobial Agents 16 (2000): 3-10.


As penisillien aanvanklik bekendgestel is, was dit effektief teen alle gram positiewe eienskappe? - Geskiedenis

Bakteriële weerstand teen antibiotika (bladsy 1)

In die afgelope 60 jaar was antibiotika van kritieke belang in die stryd teen aansteeklike siektes wat deur bakterieë en ander mikrobes veroorsaak word. Antimikrobiese chemoterapie was 'n leidende oorsaak vir die dramatiese styging van die gemiddelde lewensverwagting in die twintigste eeu. Siekteveroorsakende mikrobes wat weerstand teen antibiotika-terapie geword het, is egter 'n toenemende probleem vir openbare gesondheid. Wondinfeksies, gonorree, tuberkulose, longontsteking, septisemie en oorinfeksies by kinders is slegs enkele van die siektes wat moeilik geword het om met antibiotika te behandel. Een deel van die probleem is dat bakterieë en ander mikrobes wat infeksies veroorsaak, merkwaardig veerkragtig is en verskeie maniere ontwikkel het om antibiotika en ander antimikrobiese middels te weerstaan. 'N Ander deel van die probleem is die toenemende gebruik en misbruik van bestaande antibiotika in menslike en veeartsenykundige medisyne en in die landbou.

In 1998, in die Verenigde State, is 80 miljoen voorskrifte van antibiotika vir menslike gebruik ingevul. Dit is gelykstaande aan 12 500 ton in een jaar. Dierlike en landbougebruik van antibiotika word by die menslike gebruik gevoeg. Landboupraktyke is verantwoordelik vir meer as 60% van die antibiotikaverbruik in die VSA, dus voeg dit 'n ekstra 18 000 ton per jaar by tot die antibiotiese las in die omgewing.

Tans is ongeveer 70 persent van die bakterieë wat infeksies in hospitale veroorsaak, bestand teen ten minste een van die medisyne wat die algemeenste vir die behandeling gebruik word. Sommige organismes is bestand teen alle goedgekeurde antibiotika en kan slegs behandel word met eksperimentele en moontlik giftige middels. 'N Onrusbarende toename in weerstand van bakterieë wat infeksies deur die gemeenskap veroorsaak, is ook gedokumenteer, veral by die stafilokokke en pneumokokke (Streptococcus pneumoniae), wat algemene oorsake van siektes en sterftes is. In 'n onlangse studie is bewys dat 25% van die gevalle van bakteriële longontsteking bestand is teen penisillien, en 'n bykomende 25% van die gevalle is weerstand teen meer as een antibiotika.

Mikrobiese ontwikkeling van weerstand, sowel as ekonomiese aansporings, het gelei tot navorsing en ontwikkeling in die soektog na nuwe antibiotika om te alle tye 'n poel effektiewe middels te handhaaf. Alhoewel die ontwikkeling van weerstandbiedende stamme onvermydelik is, het die slap manier waarop ons antibiotika toedien en gebruik, die proses baie vererger.

Tensy daar probleme met antibiotika -weerstandigheid opgemerk word en onmiddellik opgetree word om dit te voorkom, kan die samelewing gekonfronteer word met siektes wat voorheen behandel kan word, wat weer onbehandelbaar geword het, soos in die dae voordat antibiotika ontwikkel is.

Geskiedenis van antibiotika en die voorkoms van antibiotiese weerstand

Die eerste antibiotika, penisillien, is in 1929 deur sir Alexander Fleming ontdek, wat die remming van stafilokokke op 'n agarplaat waargeneem het, waargeneem het. Penicillium vorm. Fleming was op soek na moontlike antibakteriese verbindings. Hy het opgemerk dat 'n stuk van die vorm Penicillium notatum het gegroei op 'n bord met die bakterie Staphylococcus en dat daar rondom die vorm 'n sone was waar nr Staphylococcus kon groei. Na meer navorsing kon hy aantoon dat die kweekbouillon van die vorm die groei van die vorm voorkom Staphylococcus selfs wanneer dit tot 800 keer verdun word. Hy noem die aktiewe stof penisillien, maar kon dit nie afsonder nie.


In die middel van die bord is 'n kolonie van Penicillium notatum, 'n vorm wat penisillien produseer. Na die voorkoms van die vormkolonie, was die plaat bedek met 'n bakteriese kultuur van Micrococcus luteus wat 'n geel "grasperk" van groei vorm. 'N Sone van remming van bakteriegroei omring die swamkolonie waar penisillien in die medium versprei het. http://helios.bto.ed.ac.uk/bto/microbes/penicill.htm#Top

'N Paar jaar later, in 1939, ontwikkel Ernst Chain en Howard Florey 'n manier om penisillien te isoleer en gebruik dit om bakteriese infeksies tydens die Tweede Wêreldoorlog te behandel. Die nuwe middel het in 1946 klinies gebruik geword en 'n groot impak op die volksgesondheid gehad. Vir hierdie ontdekkings is Fleming, Chain en Florey in 1945 met die Nobelprys bekroon. Hulle ontdekking en ontwikkeling het 'n omwenteling in die moderne medisyne gemaak en die weg gebaan vir die ontwikkeling van baie meer natuurlike antibiotika.

Terwyl Fleming aan penisillien gewerk het, het Gerhard Domagk, 'n Duitse dokter, die ontdekking van 'n sintetiese molekule met antibakteriese eienskappe aangekondig. Hy noem die verbinding Prontosil, en dit word die eerste van 'n lang reeks sintetiese antibiotika wat sulfonamiede of sulfamiddels genoem word. Prontosil is in die 1930's bekendgestel vir kliniese gebruik en is gebruik om urienweginfeksies, longontsteking en ander toestande te bestry. Alhoewel sulfa -medisyne in baie gevalle nie so effektief is as natuurlike antibiotika nie, word dit tans wyd gebruik vir die behandeling van baie toestande. Gerhard Domagk ontvang die Nobelprys in 1939 vir sy ontdekking van Prontosil.

In 1946 word penisillien algemeen beskikbaar vir die behandeling van bakteriële infeksies, veral dié wat stafilokokke en streptokokke veroorsaak. Aanvanklik was die antibiotika effektief teen allerhande infeksies wat deur hierdie twee Gram-positiewe bakterieë veroorsaak word. Penisillien het 'n ongelooflike vermoë om hierdie bakteriese patogene dood te maak sonder om die gasheer te beskadig. Dit is belangrik om daarop te let dat 'n beduidende fraksie van alle menslike infeksies deur hierdie twee bakterieë veroorsaak word (dws keelontsteking, longontsteking, skarlakenkoors, septisemie, velinfeksies, wondinfeksies, ens.).

In die laat veertigerjare en vroeë vyftigerjare is nuwe antibiotika bekendgestel, waaronder streptomisien, chlooramfenikol en tetrasiklien, en die ouderdom van antibiotiese chemoterapie het tot stand gekom. Hierdie antibiotika was effektief teen die hele reeks bakteriële patogene, insluitend Gram-positiewe en Gram-negatiewe bakterieë, intrasellulêre parasiete en die tuberkulose-basil. Sintetiese antimikrobiese middels soos die "sulfa-middels" (sulfonamiede) en anti-tuberkulose-middels, soos para aminosalicylic acid (PAS) en isoniazid (INH), is ook in groter gebruik gebring.


BEGIN

Op 6 Augustus 1881 is Alexander Fleming gebore aan Hugh Fleming en Grace Stirling Morton in Lochfield Farm, Skotland. Fleming, wat aanvanklik in Skotland gestudeer het, verhuis uiteindelik met drie broers en 'n suster na Londen en voltooi sy jeugopleiding aan die Regent Street Polytechnic. Hy het nie onmiddellik na die mediese skool gegaan nie, maar hy het vier jaar in 'n skeepvaartkantoor gewerk. Toe sy oom John sterf, het hy sy broers en susters, niggies en nefies dieselfde deel van sy boedel toegestaan, en Fleming kon sy deel gebruik om 'n mediese opleiding te volg. In 1906 studeer hy met lof aan die St Mary ’s Medical School aan die Universiteit van Londen.


Gram positief teenoor gram negatiewe bakterieë en die stryd teen HAI

In formele beskrywings van die kiembestrydende magte van antibakteriese en biosiedprodukte word die terme "Gram-positief" en "Gram-negatief" gebruik as 'n manier om bakterieë te kategoriseer. Alhoewel daar na raming meer as 10 000 spesies bakterieë is, kan hulle in 'n paar nuttige kategorieë ingedeel word.

Een van die kategorieë het te doen met die struktuur van die selmembraan. Al die bekende bakterieë pas in een van twee kategorieë van selmembraanstruktuur: Gram-positief of Gram-negatief. Maar wat beteken dit?

Kom ons kyk eers waar 'Gram' vandaan kom. In hierdie geval verwys Gram - met 'n hoofletter G - na die Deense bakterioloog Hans Christian Gram. In 1884 het Gram 'n toets opgestel om vas te stel of 'n bakterie a peptidoglycan ('n maasagtige suikerlaag en aminosure) muur. In sy toets is 'n kleurstof aan die bakterieë bekendgestel. As die bakterieë 'n dik peptidoglycaanse selwand gehad het, het dit die kleurstof geabsorbeer en pers geword - dit is getoets positief vir peptidoglycan. As dit nie pers geword het nie, het dit getoets negatief vir peptidoglycan, wat beteken dat die peptidoglycan laag daarvan dun was. Namate hierdie metode aangeneem is, is die gevolglike kategorieë 'Gram -positief' en 'Gram -negatief' genoem. Hierdie metode van "Gram-kleuring" is nog steeds 'n wyd gebruikte, standaardmetode in mikrobiologie.

Nou kan ons kyk na 'n paar van die belangrikste verskille tussen Gram-positiewe en Gram-negatiewe bakterieë in die stryd teen HAI's. Die rede waarom EPA aanspraak maak op volksgesondheid, en gevolglik produkte, verduidelik dat toetsing beide Gram-positiewe en Gram-negatiewe bakterieë insluit, is dat hulle verskillende vlakke van weerstand teen reinigingsprodukte, verskillende reaksies op droë oppervlaktes en ander belangrike onderskeidings het.

Gram-positief bakterieë, die spesies met peptidoglycan buitenste lae, is makliker om dood te maak - hul dik peptidoglycan laag absorbeer antibiotika en skoonmaakprodukte maklik. Daarteenoor weerstaan ​​hul neefs met baie membraan hierdie indringing met hul meerlagige struktuur. Daarom moet infeksievoorkomingstegnieke verseker dat hulle die dik peptidoglycan-laag van die Gram-positiewe bakterieë kan oortree, maar ook deur die vele lae van die Gram-negatiewe bakterieë kan kom.

Hoe dun hulle peptidoglykaanlaag ook al is, Gram-negatiewe bakterieë word beskerm teen sekere fisiese aanvalle omdat hulle nie vreemde materiale absorbeer wat dit omring nie (insluitend Gram se pers kleurstof). Stel jou voor 'n ruimtetuig met 'n reeks sluise. Enige indringer sal deur hierdie sluise moet gaan voordat hy die skip binnekom. Dit is die geval met gram-negatiewe bakterieë. Hulle ekstra membraan stel hulle in staat om te beheer wat die binneste lugslot bereik, sodat hulle dreigemente in die spasie tussen die membrane (periplasmiese ruimte) kan afsluit of selfs verwyder voordat dit die sel self bereik.

Gevolglik word gram-negatiewe bakterieë nie vernietig deur sekere skoonmaakmiddels wat maklik Gram-positiewe bakterieë doodmaak nie. Terwyl dit dik is, absorbeer die membraan van die Gram-positiewe bakterieë vreemde materiale (Gram se kleurstof), selfs die wat giftig is vir die binnekant daarvan. Dit maak dit makliker om met sekere skoonmaakmiddels te vernietig. As gevolg hiervan word slegs sekere reinigingsmiddels goedgekeur om bakterieë uit te skakel - omdat dit moet doodmaak beide Gram-positiewe en gram-negatiewe bakterieë.

Gram-negatiewe bakterieë kan nie so lank as Gram-positiewe bakterieë op droë oppervlaktes oorleef nie (terwyl albei verbasend lank oorleef). Dit maak sekere spesies gevaarliker tussen roetine -skoonmaak, aangesien hulle op droë oppervlaktes kan oorleef en selfs vermeerder. Die lang oorlewingstyd van baie patogene beteken egter dat hospitale nuwe tegnologie moet gebruik om bakterieë tussen roetine skoon te maak.

Laastens is Gram-negatiewe bakterieë meer intrinsiek bestand teen antibiotika - hulle absorbeer nie die gifstof in hul binneste nie. Hulle vermoë om tradisionele antibiotika te weerstaan, maak dit gevaarliker in hospitale, waar pasiënte swakker is en bakterieë sterker is. Nuwe en baie duur antibiotika is ontwikkel om hierdie weerstandbiedende spesies te bestry, maar daar is nog steeds 'n paar superbekke (MDRO's) niks kan doodmaak. Die natuurlike verdediging van die gram-negatiewe bakterieë hou nie net hierdie antibiotika uit nie, sommige het selfs weerstand teen antibiotika wat hul binneste selliggame bereik.

Gram-positiewe en gram-negatiewe bakterieë bestaan ​​oral, maar hou unieke bedreigings in vir gehospitaliseerde pasiënte met 'n swak immuunstelsel. Gram-positiewe bakterieë veroorsaak geweldige probleme en is die fokus van baie uitroeiingspogings, maar intussen ontwikkel gram-negatiewe bakterieë gevaarlike weerstand en word dit deur die CDC geklassifiseer as 'n ernstiger bedreiging. Om hierdie rede is die behoefte aan nuwe tegnologieë wat bakterieë doodmaak, beide Gram-positief en Gram-negatief, noodsaaklik om hospitale vir almal veiliger te maak.

Nota van die redakteur: Hierdie pos is oorspronklik in Augustus 2015 gepubliseer en is opgedateer vir varsheid, akkuraatheid en omvattendheid.


Werkingsmeganisme

Die vier-ledige ring van beta-laktam-antibiotika gee hierdie verbindings 'n driedimensionele vorm wat die D-Ala-D-Ala peptiedterminus naboots wat as die natuurlike substraat vir transpeptidase aktiwiteit tydens selwand sintese dien (figuur 1). Soos geïllustreer in Figuur 2, inhibeer die noue binding van hierdie middels aan die transpeptidase -aktiewe plek selwand sintese, wat lei tot 'n verswakte selwand wat vatbaar is vir lysis tydens periodes van selgroei. Een van die belangrikste dryfkragte van sellysis is die einste hoë interne osmotiese druk teenwoordig in bakterieë, wat veroorsaak word deur die teenwoordigheid van 'n hoë konsentrasie proteïene en ander molekules wat groeiende bakterieë nodig het om te oorleef.

Figuur 2. Werkingsmeganisme van beta-laktam antibiotika. Top: By gebrek aan medisyne kataliseer transpeptidase-ensieme (ook bekend as Penicillin Binding Proteins PBP) in die selwand kruisverbindings tussen aangrensende glikankettings, wat die verwydering van 'n terminale D-alanienresidu uit een van die peptidoglycan-voorlopers behels (beklemtoon deur die gebreekte ovaal). Glikosyltransferases (GT), wat bestaan ​​as afsonderlike subeenhede, of nou verband hou met transpeptidases (bv. Soos die geval is met PBP-2), skep kovalente bindings tussen aangrensende suikermolekules NAM en NAG. Die netto resultaat van kovalente bindings tussen beide die peptied- en suikerkettings skep 'n stewige selwand wat die bakteriese sel beskerm teen osmotiese kragte wat andersins selbreuk kan veroorsaak. Onder: Betalaktam-antibiotika, wat penisilliene (Pen), kefalosporiene (Ceph), monobaktams (Mono) en carbapenems (Carba) insluit, het 'n strukturele ooreenkoms met die natuurlike D-Ala-D-Ala-substraat vir die transpeptidase en oefen hul remmende effekte uit. op die selwand sintese deur styf binding aan die aktiewe plek van die transpeptidase (PBP). NAG: N-asetielglukosamien NAM: N-asetielmuramiensuur. Struktuur van PBP aangepas by Mcstrother (Wikipedia Commons).

Glycopeptides is 'n "verskillende" klas selwand sintese inhibeerders

Glikopeptiede belemmer ook die sintese van selwande, maar verskil van beta -laktame (sien Glycopeptide Pharm) deurdat hulle:


Sifilis

Donkerveldondersoeke en toetse om op te spoor T. pallidum direk van letsel -ekssudaat of weefsel is die definitiewe metodes vir die diagnose van vroeë sifilis (395). Hoewel nee T. pallidum opsporingstoetse in die handel beskikbaar is, bied sommige laboratoriums plaaslik ontwikkelde en gevalideerde PCR -toetse vir die opsporing van T. pallidum DNA. 'N Vermoedelike diagnose van sifilis vereis dat twee toetse gebruik word: 'n nie-reponemale toets (dws Venereal Disease Research Laboratory [VDRL] of Rapid Plasma Reagin [RPR]) en 'n treponemale toets (dws fluorescerende treponemale teenliggaam geabsorbeerde [FTA-ABS] toetse, die T. pallidum passiewe deeltjie-agglutinasie [TP-PA] toets, verskillende ensiem-immunoassays [EIA's], chemiluminescentie-immunoassays, immunoblots of vinnige treponemale toetse). Alhoewel baie op treponemal gebaseerde toetse in die handel beskikbaar is, word slegs 'n paar goedgekeur vir gebruik in die Verenigde State. Die gebruik van slegs een tipe serologiese toets is onvoldoende vir diagnose en kan vals-negatiewe resultate tot gevolg hê by persone wat tydens primêre sifilis getoets word en vals-positiewe resultate by persone sonder sifilis. Vals-positiewe nie-reponemale toetsuitslae kan verband hou met verskillende mediese toestande en faktore wat nie met sifilis verband hou nie, insluitend ander infeksies (bv.395,396). Daarom moet persone met 'n reaktiewe nie -reponemale toets altyd 'n treponemale toets ontvang om die diagnose van sifilis te bevestig.

Nontreponemale toets teenliggaam titers kan korreleer met siekte aktiwiteit en word gebruik om die reaksie van die behandeling te volg. Uitslae moet kwantitatief gerapporteer word. 'N Viervoudige verandering in titer, gelykstaande aan 'n verandering van twee verdunnings (bv. Van 1:16 tot 1: 4 of van 1: 8 tot 1:32), word nodig geag om 'n klinies beduidende verskil tussen twee nie -reponemale toetsresultate wat verkry is, aan te toon gebruik dieselfde serologiese toets. Sekwensiële serologiese toetse by individuele pasiënte moet uitgevoer word met dieselfde toetsmetode (VDRL of RPR), verkieslik deur dieselfde laboratorium. Die VDRL en RPR is ewe geldige toetse, maar kwantitatiewe resultate van die twee toetse kan nie direk vergelyk word nie, omdat RPR -titers gereeld effens hoër is as VDRL -titers. Nontreponemale toetstitels neem gewoonlik af na behandeling en kan mettertyd nie -reaktief raak, maar by sommige persone kan nie -reponemale teenliggaampies vir 'n lang tydperk voortduur, 'n reaksie wat na verwys word as die & ldquoserofast -reaksie. & Rdquo Die meeste pasiënte wat reaktiewe treponemale toetse ondergaan, sal reaktief toetse vir die res van hul lewens, ongeag behandeling of siekte -aktiwiteit. Maar 15% en 25% van die pasiënte wat tydens die primêre stadium behandel is, keer na 2 en 3 jaar weer serologies nie -reaktief (397). Treponemal teenliggaam titers voorspel nie die reaksie van die behandeling nie en moet daarom nie vir hierdie doel gebruik word nie.

Sommige kliniese laboratoriums ondersoek monsters met behulp van treponemale toetse, tipies deur OIE- of chemiluminescentie -immuno -toetse (398,399). Hierdie omgekeerde siftingsalgoritme vir sifilistoetsing kan persone identifiseer wat voorheen behandel is vir sifilis, diegene met onbehandelde of onvolledig behandelde sifilis en persone met vals positiewe resultate wat met 'n lae waarskynlikheid van infeksie kan voorkom. Persone met 'n positiewe treponemale siftingstoets moet 'n standaard nie -reponemale toets met titer refleksief deur die laboratorium laat doen om besluite oor pasiëntbestuur te lei. As die nie -reponemale toets negatief is, moet die laboratorium 'n ander treponemale toets uitvoer (verkieslik een wat gebaseer is op ander antigene as die oorspronklike toets) om die resultate van die aanvanklike toets te bevestig. As 'n tweede treponemale toets positief is, benodig persone met 'n geskiedenis van vorige behandeling geen verdere behandeling nie, tensy seksuele geskiedenis die waarskynlikheid van herblootstelling aandui. In hierdie geval word 'n herhaalde, nie -reponemale toets in twee en vier weke aanbeveel om te evalueer vir vroeë infeksie. Diegene sonder 'n geskiedenis van behandeling vir sifilis moet behandeling aangebied word. Tensy die geskiedenis of resultate van 'n fisiese ondersoek 'n onlangse infeksie aandui, moet persone wat voorheen nie behandel is nie, behandel word vir laat latente sifilis. As die tweede treponemale toets negatief is en die epidemiologiese risiko en kliniese waarskynlikheid vir sifilis laag is, word verdere evaluering of behandeling nie aangedui nie. Twee studies toon aan dat hoë kwantitatiewe indekswaardes van treponemale EIA/CIA -toetse korreleer met TPPA -positiwiteit, maar die omvang van die optiese digtheidswaardes wissel tussen verskillende treponemale immuno -toetse, en die kliniese betekenis van hierdie bevindings vereis verdere ondersoek (400,401).

Vir die meeste mense met MIV -infeksie is serologiese toetse akkuraat en betroubaar vir die diagnose van sifilis en die reaksie van die pasiënt op die behandeling. Atipiese nie-reponemale serologiese toetsresultate (dws ongewoon hoog, buitengewoon laag of wisselende titers) kan egter voorkom ongeag die status van MIV-infeksie. As serologiese toetse nie ooreenstem met kliniese bevindings wat dui op vroeë sifilis nie, word vermoedelike behandeling aanbeveel vir persone met risikofaktore vir sifilis, en moet ander toetse (bv. Biopsie en PCR) oorweeg word.

Verdere toetse is nodig vir persone met kliniese tekens van neurosifilis (bv. Disfunksie van die kraniale senuwee, gehoor- of oftalmiese afwykings, breinvliesontsteking, beroerte, akute of chroniese veranderde geestestatus en verlies aan vibrasie). Laboratoriumtoetse is nuttig om die diagnose van neurosifilis te ondersteun, maar geen enkele toets kan in alle gevalle gebruik word om neurosifilis te diagnoseer nie. Die diagnose van neurosifilis hang af van 'n kombinasie van serebrospinale vloeistof (CSF) toetse (CSF seltelling of proteïen en 'n reaktiewe CSF-VDRL) in die teenwoordigheid van reaktiewe serologiese toetsuitslae en neurologiese tekens en simptome. CSF -laboratoriumafwykings kom algemeen voor by persone met vroeë sifilis en is van onbekende betekenis in die afwesigheid van neurologiese tekens of simptome (402). CSF-VDRL is hoogs spesifiek, maar ongevoelig. By 'n persoon met neurologiese tekens of simptome word 'n reaktiewe CSF-VDRL (in die afwesigheid van bloedbesmetting) beskou as die diagnose van neurosifilis. As CSF-VDRL negatief is ondanks die teenwoordigheid van kliniese tekens van neurosifilis, reaktiewe serologiese toetsuitslae en abnormale CSF-seltelling en/of proteïen, moet neurosifilis oorweeg word. In hierdie geval kan addisionele evaluering met behulp van FTA-ABS-toetsing op CSF geregverdig word. Die CSF FTA-ABS-toets is minder spesifiek vir neurosifilis as die CSF-VDRL, maar is baie sensitief. Neurosifilis is hoogs onwaarskynlik met 'n negatiewe CSF FTA-ABS-toets, veral onder persone met nie-spesifieke neurologiese tekens en simptome (403).

Onder mense met MIV -infeksie word die aantal CSF -leukosiete gewoonlik verhoog (& witbloedseltelling [WBC]/mm3). Die gebruik van 'n hoër afsny (& gt20 WBC/ mm 3) kan die spesifisiteit van neurosifilisdiagnose verbeter (404).

Behandeling

Penisillien G, wat parenteraal toegedien word, is die voorkeurmiddel vir die behandeling van persone in alle stadiums van sifilis. Die preparaat wat gebruik word (dws bensatien, waterige prokaïen of waterige kristallyne), dosis en duur van behandeling hang af van die stadium en kliniese manifestasies van die siekte. Behandeling vir laat latente sifilis en tersiêre sifilis verg 'n langer terapie, omdat organismes teoreties stadiger kan deel (die geldigheid van hierdie rasionaal is nie beoordeel nie). Persone met latente sifilis van onbekende duur is langer behandeling nodig om te verseker dat diegene wat nie sifilis binne die voorafgaande jaar opgedoen het nie, behoorlik behandel word.

Dit is belangrik om die geskikte penisillienpreparaat te kies T. pallidum kan op gesekwestreerde plekke (byvoorbeeld die SSS en waterige humor) woon, wat deur sommige vorme van penisillien swak verkry word. Kombinasies van bensatienpenisillien, prokaïenpenisillien en orale penisillienpreparate word nie as geskik geag vir die behandeling van sifilis nie. Verslae het aangedui dat praktisyns per ongeluk kombinasie benzathine-procaine penicillin (Bicillin C-R) voorgeskryf het in plaas van die standaard benzathine penicillin-produk (Bicillin L-A) wat wyd in die Verenigde State gebruik word. Praktisyns, aptekers en aankoopagente moet bewus wees van die soortgelyke name van hierdie twee produkte om te voorkom dat die onvanpaste kombinasie terapie vir die behandeling van sifilis (405).

Die effektiwiteit van penisillien vir die behandeling van sifilis is goed gevestig deur kliniese ervaring nog voordat die waarde van gerandomiseerde beheerde kliniese proewe erken is. Daarom is byna alle aanbevelings vir die behandeling van sifilis nie net gebaseer op kliniese toetse en waarnemingsstudies nie, maar ook op baie dekades se kliniese ervaring.

Spesiale oorwegings

Swangerskap

Parenterale penisillien G is die enigste terapie met gedokumenteerde doeltreffendheid vir sifilis tydens swangerskap. Swanger vroue met sifilis in enige stadium wat penisillienallergie rapporteer, moet ongevoelig wees en met penisillien behandel word (sien Bestuur van persone wat 'n geskiedenis van penisillienallergie het).

Jarisch-Herxheimer-reaksie

Die Jarisch-Herxheimer-reaksie is 'n akute koorsreaksie wat gereeld gepaard gaan met hoofpyn, myalgie, koors en ander simptome wat binne die eerste 24 uur na die aanvang van enige terapie vir sifilis kan voorkom. Pasiënte moet ingelig word oor hierdie moontlike newe -reaksie en hoe om dit te hanteer as dit voorkom. Die Jarisch-Herxheimer-reaksie kom die meeste voor by persone wat vroeë sifilis het, vermoedelik omdat bakteriese laste gedurende hierdie stadiums hoër is. Koorswerende middels kan gebruik word om simptome te bestuur, maar dit is nie bewys dat hierdie reaksie voorkom nie. Die Jarisch-Herxheimer-reaksie kan vroeë kraam veroorsaak of fetale nood by swanger vroue veroorsaak, maar dit moet nie die terapie voorkom of vertraag nie (sien Syfilis tydens swangerskap).

Bestuur van seksmaats

Seksuele oordrag van T. pallidum Daar word vermoed dat dit slegs voorkom as mukokutane sifilitiese letsels voorkom. Sulke manifestasies is ongewoon ná die eerste jaar van infeksie. Persone wat seksueel blootgestel word aan 'n persoon met primêre, sekondêre of vroeë latente sifilis, moet klinies en serologies geëvalueer word en behandel word volgens die volgende aanbevelings:

  • Persone wat seksueel kontak gehad het met 'n persoon wat binne 90 dae voor die diagnose 'n diagnose van primêre, sekondêre of vroeë latente sifilis ontvang, moet vermoedelik vir vroeë sifilis behandel word, selfs al is die serologiese toetsuitslae negatief.
  • Persone wat seksueel kontak gehad het met 'n persoon wat 'n diagnose kry van primêre, sekondêre of vroeë latente sifilis en gt90 dae voor die diagnose, moet vermoedelik vir vroeë sifilis behandel word indien serologiese toetsuitslae nie onmiddellik beskikbaar is nie en die geleentheid vir opvolging moontlik is onseker. As serologiese toetse negatief is, is geen behandeling nodig nie. As serologiese toetse positief is, moet die behandeling gebaseer wees op kliniese en serologiese evaluering en stadium van sifilis.
  • In sommige gebiede of bevolkingsgroepe met hoë sifilis, beveel gesondheidsdepartemente kennisgewing aan en vermoedelike behandeling van seksmaats van persone met laat latente sifilis met hoë nie -reponemale serologiese toetstitels (dws & gt1: 32), omdat hoë titers moontlik dui op vroeë sifilis. Hierdie vennote moet bestuur word asof die indeksgeval vroeë sifilis het.
  • Langtermyn seksmaats van persone wat laat latente sifilis het, moet klinies en serologies vir sifilis geëvalueer word en behandel word op grond van die evaluerings- en rsquos-bevindings.
  • Die volgende seksmaats van persone met sifilis word as 'n risiko vir infeksie beskou en moet vertroulik in kennis gestel word van die blootstelling en die behoefte aan evaluering: vennote wat seksueel kontak gehad het binne 1) 3 maande plus die duur van die simptome vir persone wat 'n diagnose van primêre sifilis, 2) 6 maande plus duur van simptome vir diegene met sekondêre sifilis, en 3) 1 jaar vir persone met vroeë latente sifilis.

Primêre en sekondêre sifilis

Behandeling

Parenterale penisillien G is effektief gebruik om kliniese resolusie te bereik (dws genesing van letsels en voorkoming van seksuele oordrag) en om laat gevolge te voorkom. Geen vergelykende proewe is egter uitgevoer om die keuse van 'n optimale penisillienregime te rig nie. Aansienlik minder data is beskikbaar vir nie -penisillien -behandelings.

Aanbevole regime vir volwassenes*

*Aanbevelings vir die behandeling van sifilis by persone met MIV -infeksie en swanger vroue word elders in hierdie verslag bespreek (sien Sifilis onder persone met MIV -infeksie en Sifilis tydens swangerskap).

Beskikbare data toon aan dat die gebruik van addisionele dosisse bensatienpenisillien G, amoksisillien of ander antibiotika nie die doeltreffendheid verhoog as dit gebruik word om primêre en sekondêre sifilis te behandel nie, ongeag die MIV -status (406,407).

Aanbevole regime vir babas en kinders
  • Benzatien penisillien G 50 000 eenhede/kg IM, tot 'n volwasse dosis van 2,4 miljoen eenhede in 'n enkele dosis

Babas en kinders in die ouderdom & gt1 maand wat 'n diagnose van sifilis kry, moet die geboorte- en moederlike mediese rekords nagegaan word om te bepaal of hulle aangebore of verworwe sifilis het (sien aangebore sifilis). Babas en kinders ouer as 1 maand met primêre en sekondêre sifilis moet deur 'n pediatriese spesialis in aansteeklike siektes bestuur word en geëvalueer word vir seksuele misbruik (bv. Deur konsultasie met kinderbeskermingsdienste) (sien seksuele aanranding of mishandeling van kinders).

Ander bestuursoorwegings

Alle persone met primêre en sekondêre sifilis moet getoets word vir MIV -infeksie. In geografiese gebiede waarin die voorkoms van MIV hoog is, moet persone met primêre of sekondêre sifilis binne drie maande weer vir akute MIV getoets word as die eerste MIV -toetsuitslag negatief was.

Persone met sifilis en simptome of tekens wat dui op neurologiese siektes (bv. Disfunksie van die kraniale senuwee, breinvliesontsteking, beroerte en gehoorverlies) of oftalmiese siekte (bv. Uveïtis, iritis, neuroretinitis en optiese neuritis) moet 'n evaluering hê wat CSF -analise insluit , oogspleetlamp oftalmologiese ondersoek en otologiese ondersoek. Behandeling moet gelei word deur die resultate van hierdie evaluering.

Invasie van CSF deur T. pallidum vergesel van CSF -laboratoriumafwykings kom algemeen voor by volwassenes met primêre of sekondêre sifilis (402). By gebrek aan kliniese neurologiese bevindings, ondersteun geen bewyse afwyking van die aanbevole behandelingsregime vir primêre en sekondêre sifilis nie. Simptomatiese neurosifilis ontwikkel slegs by 'n beperkte aantal persone na behandeling met die penisillienregime wat aanbeveel word vir primêre en sekondêre sifilis. Tensy daar dus kliniese tekens of simptome van neurologiese of oftalmiese betrokkenheid is, word roetine -CSF -analise nie aanbeveel vir persone wat primêre of sekondêre sifilis het nie.

Volg op

Kliniese en serologiese evaluering moet op 6 en 12 maande na die behandeling uitgevoer word, kan meer gereelde evaluering verstandig wees as die opvolging onseker is of as herhaalde infeksie kommerwekkend is. Serologiese reaksie (dit wil sê titer) moet vergelyk word met die titer ten tyde van die behandeling. However, assessing serologic response to treatment can be difficult, and definitive criteria for cure or failure have not been well established. In addition, nontreponemal test titers might decline more slowly for persons previously treated for syphilis (408,409).

Persons who have signs or symptoms that persist or recur and those with at least a fourfold increase in nontreponemal test titer persisting for >2 weeks likely experienced treatment failure or were re-infected. These persons should be retreated and reevaluated for HIV infection. Because treatment failure usually cannot be reliably distinguished from reinfection with T. pallidum, a CSF analysis also should be performed treatment should be guided by CSF findings.

Failure of nontreponemal test titers to decline fourfold within 6&ndash12 months after therapy for primary or secondary syphilis might be indicative of treatment failure. However, clinical trial data have demonstrated that 15%&ndash20% of persons with primary and secondary syphilis treated with the recommended therapy will not achieve the fourfold decline in nontreponemal titer used to define response at 1 year after treatment (406,409). Serologic response to treatment appears to be associated with several factors, including the person&rsquos stage of syphilis (earlier stages are more likely to decline fourfold and become negative) and initial nontreponemal antibody titers (lower titers are less likely to decline fourfold than higher titers) (409). Optimal management of persons who have less than a fourfold decline in titers after treatment of syphilis is unclear. At a minimum, these persons should receive additional clinical and serologic follow-up and be evaluated for HIV infection. If additional follow-up cannot be ensured, retreatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, CSF examination can be considered in such situations.

For retreatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended, unless CSF examination indicates that neurosyphilis is present (see Neurosyphilis). Serologic titers might not decline despite a negative CSF examination and a repeated course of therapy (410). In these circumstances, although the need for additional therapy or repeated CSF examinations is unclear, it is not generally recommended.

Management of Sex Partners

Special Considerations

Penicillin Allergy

Data to support use of alternatives to penicillin in the treatment of primary and secondary syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic persons who have primary or secondary syphilis. Regimens of doxycycline 100 mg orally twice daily for 14 days (411,412) and tetracycline (500 mg four times daily for 14 days) have been used for many years. Compliance is likely to be better with doxycycline than tetracycline, because tetracycline can cause gastrointestinal side effects and requires more frequent dosing. Although limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone (1&ndash2 g daily either IM or IV for 10&ndash14 days) is effective for treating primary and secondary syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined (413). Azithromycin as a single 2-g oral dose has been effective for treating primary and secondary syphilis in some populations (414-416). Maar, T. pallidum chromosomal mutations associated with azithromycin and other macrolide resistance and treatment failures have been documented in multiple geographical areas in the United States (417-419). Accordingly, azithromycin should not be used as first-line treatment for syphilis and should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be used in MSM, persons with HIV, or pregnant women. Careful clinical and serologic follow-up of persons receiving any alternative therapies is essential.

Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see Management of Persons Who Have a History of Penicillin Allergy).

Pregnancy

Pregnant women with primary or secondary syphilis who are allergic to penicillin should be desensitized and treated with penicillin. For more information, see Management of Persons Who Have a History of Penicillin Allergy and Syphilis During Pregnancy.

HIV Infection

Persons with HIV infection who have primary or secondary syphilis should be treated as those without HIV infection. For more information on treatment and management, see Syphilis in Persons with HIV infection.

Latent Syphilis

Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of primary, secondary, or tertiary disease. Persons who have latent syphilis and who acquired syphilis during the preceding year are classified as having early latent syphilis, a subset of latent syphilis. Persons can receive a diagnosis of early latent syphilis if, during the year preceding the diagnosis, they had 1) a documented seroconversion or a sustained (>2 week) fourfold or greater increase in nontreponemal test titers 2) unequivocal symptoms of primary or secondary syphilis or 3) a sex partner documented to have primary, secondary, or early latent syphilis. In addition, for persons with reactive nontreponemal and treponemal tests whose only possible exposure occurred during the previous 12 months, early latent syphilis can be assumed. In the absence of these conditions, an asymptomatic person should be considered to have latent syphilis. Nontreponemal serologic titers usually are higher early in the course of syphilis infection. However, early latent syphilis cannot be reliably diagnosed solely on the basis of nontreponemal titers. All persons with latent syphilis should have careful examination of all accessible mucosal surfaces (i.e., the oral cavity, perianal area, perineum and vagina in women, and underneath the foreskin in uncircumcised men) to evaluate for mucosal lesions.

Treatment

Because latent syphilis is not transmitted sexually, the objective of treating persons in this stage of disease is to prevent complications and transmission from a pregnant woman to her fetus. Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available to guide choice of specific regimens or duration.

Recommended Regimens for Adults*
Early Latent Syphilis

Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early latent syphilis do not enhance efficacy, regardless of HIV infection (406,407)

Late Latent Syphilis or Latent Syphilis of Unknown Duration
  • Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals

*Recommendations for treating syphilis in persons with HIV infection and pregnant women are discussed elsewhere in this report (see Syphilis in Persons with HIV infection and Syphilis During Pregnancy).

Recommended Regimens for Infants and Children
Early Latent Syphilis
  • Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose
Late Latent Syphilis
  • Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as 3 doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units)

Infants and children aged &ge1 month diagnosed with latent syphilis should be managed by a pediatric infectious-disease specialist and receive a CSF examination. In addition, birth and maternal medical records should be reviewed to assess whether these infants and children have congenital or acquired syphilis. For those with congenital syphilis, treatment should be undertaken as described in the congenital syphilis section in this document. Those with acquired latent syphilis should be evaluated for sexual abuse (e.g., through consultation with child protection services) (see Sexual Assault or Abuse of Children). These regimens are for penicillin nonallergic children who have acquired syphilis and who have normal CSF examination results.

Other Management Considerations

All persons who have latent syphilis should be tested for HIV infection. Persons who receive a diagnosis of latent syphilis and have neurologic signs and symptoms (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis or stroke) should be evaluated for neurosyphilis (see Neurosyphilis).

If a person misses a dose of penicillin in a course of weekly therapy for latent syphilis, the appropriate course of action is unclear. Clinical experience suggests that an interval of 10&ndash14 days between doses of benzathine penicillin for latent syphilis might be acceptable before restarting the sequence of injections (i.e., if dose 1 is given on day 0, dose 2 is administered between days 10 and 14). Pharmacologic considerations suggest that an interval of 7&ndash9 days between doses, if feasible, might be more optimal (420-422). Missed doses are not acceptable for pregnant women receiving therapy for latent syphilis (423). Pregnant women who miss any dose of therapy must repeat the full course of therapy.

Follow-Up

Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. A CSF examination should be performed if 1) a sustained (>2 weeks) fourfold increase or greater in titer is observed, 2) an initially high titer (&ge1:32) fails to decline at least fourfold within 12&ndash24 months of therapy, or 3) signs or symptoms attributable to syphilis develop. In such circumstances, patients with CSF abnormalities should be treated for neurosyphilis. If the CSF examination is negative, retreatment for latent syphilis should be administered. Serologic titers might fail to decline despite a negative CSF examination and a repeated course of therapy, especially if the initial nontreponemal titer is low (<1:8) in these circumstances, the need for additional therapy or repeated CSF examinations is unclear but is generally not recommended. Serologic and clinical monitoring should be offered along with a reevaluation for HIV infection.

Management of Sex Partners

Special Considerations

Penicillin Allergy

The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well documented. Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to antibiotics recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see Primary and Secondary Syphilis, Treatment). The only acceptable alternatives for the treatment of latent syphilis are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), each for 28 days. The efficacy of these alternative regimens in persons with HIV infection has not been well studied. These therapies should be used only in conjunction with close serologic and clinical follow-up, especially in persons with HIV infection. On the basis of biologic plausibility and pharmacologic properties, ceftriaxone might be effective for treating latent syphilis. However, the optimal dose and duration of ceftriaxone therapy have not been defined treatment decisions should be discussed in consultation with a specialist. Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see Management of Persons Who Have a History of Penicillin Allergy).

Pregnancy

Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin. For more information, see Management of Persons Who Have a History of Penicillin Allergy and Syphilis During Pregnancy.

HIV Infection

Persons with HIV infection with latent syphilis should be treated as persons who do not have HIV infection. For more information on treatment and management of latent syphilis, see Syphilis in Persons with HIV Infection.

Tertiary Syphilis

Tertiary syphilis refers to gummas and cardiovascular syphilis but not to neurosyphilis. Guidelines for all forms of neurosyphilis (e.g., early or late neurosyphilis) are discussed elsewhere in these recommendations (see Neurosyphilis). Persons who are not allergic to penicillin and have no evidence of neurosyphilis should be treated with the following regimen.

Recommended Regimen
Tertiary Syphilis with Normal CSF Examination
  • Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals

Other Management Considerations

All persons who have tertiary syphilis should be tested for HIV infection and should receive a CSF examination before therapy is initiated. Persons with CSF abnormalities should be treated with a neurosyphilis regimen. Some providers treat all persons who have cardiovascular syphilis with a neurosyphilis regimen. These persons should be managed in consultation with an infectious-disease specialist. Limited information is available concerning clinical response and follow-up of persons who have tertiary syphilis.

Management of Sex Partners

Special Considerations

Penicillin Allergy

Providers should ask patients about known allergies to penicillin. Any person allergic to penicillin should be treated in consultation with an infectious-disease specialist.

Pregnancy

Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin. For more information, see Management of Persons Who Have a History of Penicillin Allergy and Syphilis During Pregnancy.

HIV Infection

Persons with HIV infection who have tertiary syphilis should be treated as described for persons without HIV infection. For more information on the management of tertiary syphilis in persons with HIV infection, see Syphilis in Persons with HIV Infection.

Neurosyphilis

Treatment

CNS involvement can occur during any stage of syphilis, and CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurologic findings. No evidence exists to support variation from recommended treatment for syphilis at any stage for persons without clinical neurologic findings, with the exception of tertiary syphilis. If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis or stroke), a CSF examination should be performed.

Syphilitic uveitis or other ocular manifestations (e.g., neuroretinitis and optic neuritis) can be associated with neurosyphilis. A CSF examination should be performed in all instances of ocular syphilis, even in the absence of clinical neurologic findings. Ocular syphilis should be managed in collaboration with an ophthalmologist and according to the treatment and other recommendations for neurosyphilis, even if a CSF examination is normal. In instances of ocular syphilis and abnormal CSF test results, follow-up CSF examinations should be performed to assess treatment response.

Recommended Regimen
Neurosyphilis and Ocular Syphilis
  • Aqueous crystalline penicillin G 18&ndash24 million units per day, administered as 3&ndash4 million units IV every 4 hours or continuous infusion, for 10&ndash14 days

If compliance with therapy can be ensured, the following alternative regimen might be considered.

Alternative Regimen
  • Procaine penicillin G 2.4 million units IM once daily
    PLUS
  • Probenecid 500 mg orally four times a day, both for 10&ndash14 days

The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for latent syphilis. Therefore, benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

Other Management Considerations

The following are other considerations in the management of persons who have neurosyphilis:

  • All persons who have neurosyphilis should be tested for HIV.
  • Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven to be beneficial.

Follow-Up

If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to evaluate changes in the CSF-VDRL or CSF protein after therapy however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important (424,425). Leukocyte count is a sensitive measure of the effectiveness of therapy. If the cell count has not decreased after 6 months, or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered. Limited data suggest that in immunocompetent persons and persons with HIV infection on highly active antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters following neurosyphilis treatment (425).

Management of Sex Partners

Special Considerations

Penicillin Allergy

Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10&ndash14 days can be used as an alternative treatment for persons with neurosyphilis (426,427). Cross-sensitivity between ceftriaxone and penicillin can occur, but the risk for penicillin cross-reactivity between third-generation cephalosporins is negligible (428-431) (see Management of Persons Who Have a History of Penicillin Allergy). If concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, penicillin desensitization in consultation with a specialist is recommended. Other regimens have not been adequately evaluated for treatment of neurosyphilis.

Pregnancy

Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin. For more information, see Syphilis During Pregnancy.

HIV Infection

Persons with HIV infection who have neurosyphilis should be treated as described for persons without HIV infection. For more information on neurosyphilis, see Syphilis in Persons with HIV infection.

Persons with HIV Infection

Diagnostic Considerations

Interpretation of treponemal and nontreponemal serologic tests for persons with HIV infection is the same as for the HIV-uninfected patient. Although rare, unusual serologic responses have been observed among persons with HIV infection who have syphilis although most reports have involved post-treatment serologic titers that were higher than expected (high serofast) or fluctuated, false-negative serologic test results and delayed appearance of seroreactivity have also been reported (432).

When clinical findings are suggestive of syphilis but serologic tests are nonreactive or their interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, and PCR of lesion material) might be useful for diagnosis. Neurosyphilis should be considered in the differential diagnosis of neurologic signs and symptoms in persons with HIV infection.

Treatment

Persons with HIV infection who have early syphilis might be at increased risk for neurologic complications (433) and might have higher rates of serologic treatment failure with recommended regimens. The magnitude of these risks is not defined precisely, but is likely small. Although long-term (>1 year) comparative data are lacking, no treatment regimens for syphilis have been demonstrated to be more effective in preventing neurosyphilis in persons with HIV infection than the syphilis regimens recommended for persons without HIV infection (406). Careful follow-up after therapy is essential. The use of antiretroviral therapy as per current guidelines might improve clinical outcomes in persons with HIV infection and syphilis (425,434,435).

Primary and Secondary Syphilis among Persons with HIV Infection

Recommended Regimen

Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in primary and secondary syphilis do not result in enhanced efficacy (406,407).

Other Management Considerations

Most persons with HIV infection respond appropriately to the recommended benzathine penicillin treatment regimen for primary and secondary syphilis. CSF abnormalities (e.g., mononuclear pleocytosis and elevated protein levels) are common in persons with HIV infection, even in those without syphilis. The clinical and prognostic significance of such CSF laboratory abnormalities in persons with primary and secondary syphilis who lack neurologic symptoms is unknown. Certain studies have demonstrated that among persons with HIV infection and syphilis, CSF abnormalities are associated with a CD4 count of &le350 cells/mL and/or an RPR titer of &ge1:32 (404,436,437) however, CSF examination has not been associated with improved clinical outcomes in the absence of neurologic signs and symptoms. All persons with HIV infection and syphilis should have a careful neurologic exam (425,434,435).

Follow-Up

Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy those who meet the criteria for treatment failure (i.e., signs or symptoms that persist or recur or persons who have a sustained [>2 weeks] fourfold increase or greater in titer) should be managed in the same manner as HIV-negative patients (i.e., a CSF examination and retreatment guided by CSF findings). In addition, CSF examination and retreatment can be considered for persons whose nontreponemal test titers do not decrease fourfold within 12&ndash24 months of therapy. If CSF examination is normal, treatment with benzathine penicillin G administered as 2.4 million units IM each at weekly intervals for 3 weeks is recommended. Serologic titers might not decline despite a negative CSF examination and a repeated course of therapy (410). In these circumstances, the need for additional therapy or repeated CSF examinations is unclear, but is not generally recommended. Serologic and clinical monitoring should be provided.

Management of Sex Partners

Special Considerations

Penicillin Allergy

Persons with HIV infection who are penicillin-allergic and have primary or secondary syphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative persons. Persons with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Persons Who Have a History of Penicillin Allergy). The use of alternatives to penicillin has not been well studied in persons with HIV infection azithromycin is not recommended in persons with HIV infection and primary and secondary syphilis. Alternative therapies should be used only in conjunction with close serologic and clinical follow-up.

Latent Syphilis among Persons with HIV Infection

Recommended Regimen for Early Latent Syphilis
Recommended Regimen for Late Latent Syphilis

Other Management Considerations

All persons with HIV infection and syphilis should undergo a careful neurologic examination those with neurologic symptoms or signs should undergo immediate CSF examination. In the absence of neurologic symptoms, CSF examination has not been associated with improved clinical outcomes and therefore is not recommended.

Follow-Up

Patients should be evaluated clinically and serologically at 6, 12, 18, and 24 months after therapy. If, at any time, clinical symptoms develop or a sustained (>2 weeks) fourfold or greater rise in nontreponemal titers occurs, a CSF examination should be performed and treatment administered accordingly. If the nontreponemal titer does not decline fourfold after 24 months, CSF examination can be considered and treatment administered accordingly, although initial low titers (<1:8) might not decline. Even after retreatment, serologic titers might fail to decline. In these circumstances, the need for repeated CSF examination or additional therapy is unclear but is generally not recommended. Serologic and clinical monitoring should be provided.

Management of Sex Partners

Special Considerations

Penicillin Allergy

The efficacy of alternative nonpenicillin regimens in persons with HIV infection has not been well studied, and these therapies should be used only in conjunction with close serologic and clinical follow-up. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Persons Who Have a History of Penicillin Allergy).

Neurosyphilis among Persons with HIV Infection

All persons with HIV infection and syphilis should receive a careful neurologic examination. Persons with HIV infection and neurosyphilis should be treated according to the recommendations for HIV-negative persons with neurosyphilis (See Neurosyphilis).

Follow-Up

Persons with HIV infection and neurosyphilis should be managed according to the recommendations for HIV-negative persons with neurosyphilis (see Neurosyphilis). Limited data suggest that changes in CSF parameters might occur more slowly in persons with HIV infection, especially those with more advanced immunosuppression (424,434).

Management of Sex Partners

Special Considerations

Penicillin Allergy

Persons with HIV infection who are penicillin-allergic and have neurosyphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients with neurosyphilis (See Neurosyphilis). Several small observational studies conducted in persons with HIV infection with neurosyphilis suggest that ceftriaxone 1&ndash2 g IV daily for 10&ndash14 days might be effective as an alternate agent (438-440). The possibility of cross-sensitivity between ceftriaxone and penicillin exists, but the risk of penicillin cross-reactivity between third- generation cephalosporins is negligible (428-431)(see Management of Persons Who Have a History of Penicillin Allergy). If concern exists regarding the safety of ceftriaxone for a person with HIV infection and neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, penicillin desensitization in consultation with a specialist is recommended. Other regimens have not been adequately evaluated for treatment of neurosyphilis.


FORTUNATE CHOICES

Fleming did not intend to begin a career in research. While serving as a private in the London Scottish Regiment of the Territorial Army, he became a recognised marksman. Wishing to keep Fleming in St Mary’s to join its rifle club, the club’s captain convinced him to pursue a career in research rather than in surgery, as the latter choice would require him to leave the school. The captain introduced him to Sir Almroth Wright, a keen club member and a pioneer in immunology and vaccine research, who agreed to take Fleming under his wing. It was with this research group that Fleming stayed throughout his entire career.

When World War I broke out, Fleming served in the Army Medical Corps as a captain. During this time, he observed the death of many of his fellow soldiers, not always from wounds inflicted in battle, but from the ensuing infection that could not be controlled. The primary means to combat infection was antiseptics, which frequently did more harm than good. In an article he wrote during this time, Fleming discussed the presence of anaerobic bacteria in deep wounds, which proliferated despite antiseptics. Initially, his research was not accepted, but Fleming continued undaunted and in 1922, he discovered lysozyme, an enzyme with weak antibacterial properties. History tells us that, while infected with a cold, Fleming transferred some of his nasopharyngeal mucus onto a Petri dish. Not known for fastidious laboratory organisation, he placed the dish among the clutter at his desk and left it there, forgotten, for two weeks. In that time, numerous colonies of bacteria grew and proliferated. However, the area where the mucus had been inoculated remained clear. Upon further investigation, Fleming discovered the presence of a substance in the mucus that inhibited bacterial growth and he named it lysozyme. He also discovered lysozyme in tears, saliva, skin, hair and fingernails. He was soon able to isolate larger amounts of lysozyme from egg white, but in subsequent experiments found that this enzyme was effective against only a small number of non-harmful bacteria. Nevertheless, this would lay the groundwork for Fleming’s next great discovery.


G. M. R. has served in the speakers' bureau of and attended advisory board meetings organized by Janssen-Cilag. M. S. D. has received speaker honoraria from Bayer, Novartis, Pfizer and Wyeth, participated as a clinical investigator and as a data reviewer in a number of studies involving antibiotics mentioned in this article, and participated in advisory board meetings for Bayer, Janssen-Cilag, Novartis, Pfizer and Wyeth. R. S. K. has no relevant conflicts of interest to report. A. Q. and R. K. F. are full-time employees of Johnson & Johnson. J. M. L. is a full-time employee of Janssen-Cilag EMEA, a subsidiary of Johnson & Johnson. A. Q., R. K. F. and J. M. L. hold stock and options with Johnson & Johnson. E. L. is a full-time employee of Janssen Pharmaceutica, a subsidiary of Johnson & Johnson. I. M. is a full-time employee of Quotient Bioresearch, which was a paid consultant in regards to the conduct of this study Quotient Bioresearch also conducts research for other pharmaceutical companies. I. M. holds stocks and options in Quotient Bioresearch Ltd.

Editorial support for the development of this manuscript was provided by Philip Matthews, PhD, of PAREXEL MMS.


Glycopeptides

  • glycopeptides are produced in fermentation by various micro-organisms
  • prevent bacterial cell wall synthesis ( different mechanism to penicillin)
  • structure: glycosylated .. cyclic or polycyclic .. nonribosomal peptides
  • most include amino acids differing from the normal 20 in proteins, perhaps connected by bonds other than peptide or disulfide bonds
  • used against Gram-positive microorganisms
  • toxicity of early isolates ("Mississippi mud" - contained impurities) slowed down early development
  • the related compound avoparcin (animal "growth promoter" produced by Cyanamid) has stimulated development of resistance (not in USA, banned in Europe in 1997, recently dropped in Australia)
  • Vancomycin-resistant enterococci (VRE) emerged in the mid-1980s
  • Vancomycin-resistant Staphylococci emerged in the mid-1990s
  • Vancomycin and related compounds were considered as drugs of last resort for treating MRSA

Penicillin and Macrolides

Penicillin and Macrolides – The ANTIBIOTICS
Penicillin and Macrolides, each having different properties belong to the same group of medicine called ANTIBIOTICs. Antibiotics refer to the chemical substance secreted or produced by various species of micro-organisms which are capable of inhibiting or killing the bacteria. Antibiotics have enabled the effective treatment of infections including life threatening diseases ranging from respiratory diseases to sexually transmitted diseases (Rang et al.,2007). An antibiotic acts by either limiting or stopping the growth of bacteria. It accomplishes this by probably interfering with the cell wall of the bacteria while having minimal effect on the normal body cells. Classifying bacteria into classes helps in identifying the bacterial species and hence they are classified as gram positive bacteria and gram negative bacteria based upon their staining techniques. Penicillin is the oldest and the best known antibiotic. Basically, it is an antibiotic compound derived from the moulds Penicillium notatum and Penicillin chrysogenum and is active in opposition to gram positive bacteria and few gram negative bacteria. Penicillin turns out to have two rings fused together one being the β-lactam ring and the other Thiazolidine ring (Ref figure 1) ( β-Lactam Antibiotics: Penicillins). |

Figure 1: General Structure of Penicillin |

All Penicillins have the same fundamental structure, only the group R varies. Penicillin is generally classified as bio-synthetic and semi-synthetic. Bio-synthetic refers to the naturally occurring penicillin. These are the very first agents in the family of penicillin introduced for clinical use. They include Penicillin G, Penicillin V and Benzyl Penicillin. These prove to be effective against Gram positive bacteria like meningococcus and also prove useful in patients with oral-cavity infection. Certain chemical alterations in the structure of naturally occurring penicillin results in formation of semi-synthetic penicillins. For example, penicillin V is made by replacing the -CH2C6H5 group in natural penicillin G with -CH2OC6H5 group. The semi-synthetic class consists of Penicillinase-resistant penicillin and Aminopenicillins. The Penicillinase-resistant penicillin includes Cloxacillin, dicloxacillin, methicilin and Nagcillin while the Aminopenicillins consists of Ampicillin, Amoxocillin and Bacampicillin. Penicillinase-Resistant Penicillin provides a narrower antibacterial spectrum of activity than the natural ones. Aminopenicillins are known to be active against the gram negative bacteria like E. Coli and are used to treat mild infections like sinusitis and bronchitis. The further classified Extended Spectrum Penicillin provides additional action against the gram negative bacteria (Chain, 1945). Macrolides which are also anti bacterial antibiotics are often used in patients appearing sensitive to penicillin. These are bacteriostatic and work by inhibiting the synthesis of vital proteins in bacteria. The Macrolides were isolated from Streptomyces bacteria, and got their name because they have a macrocyclic lactone chemical structure, also called the macrolide ring. The macrolide molecules are made up of large-ring lactones to which one or more deoxy sugar(s) is attached. Also they can be 14/15/16 membered (refer table 1). Erythromycin is the best known medicine in this group. Newer members of the group, azithromycin and clarithyromycin, are particularly useful for their high level of lung penetration. Clarithromycin has been widely used to treat Helicobacter pylori infections, the cause of stomach ulcers (Chain, 1945). Table 1: Classification of Macrolides depending upon the size of their rings 14- membered ring | 15-membered ring | 16 membered ring |

Erthyomycin | Azithromycin | Josamycin |
Roxithromycin | | Spiramycin |
Clarithromycin | | Micomycin |
Dirthromycin | | |


Kyk die video: How To Convert Kilograms to Grams and Grams to Kilograms (Mei 2022).