Signature: Med SCI Monit, 2003; 9111): P1136-I42 PMID: 14586290

Received: 2003 05 93

Macrolide therapy of chronic Lyme Disease

Accepted: 2003.08 27 Published: 2003 TI03

Sam T. Donta

I

I Background:

Boston Linlvenliy Medical Center, Boston, MA, US A

Source of support: none

h h ~ m l i d eantibiotin are highly active in sirm against B.burgdbferi, but have limited eiflicacy in thc treanncnr of patient%with Lyine lliseasc. As maci-olidcs are lcss active at a low pH, their p o o ~clinical activity miglit be d u e lo localkation of burrelia to a n acidic endosorne, anrl rheir activity improved by alkaliniration of tbai n,rnpartrnmt with hydruxychloroquil~e.

Material/Methods:

25.5 patiei~uwith a multi-symptom complex lypical ofrrhiul~icL y n ~ ediseilsr, ic fdtipe, musculoskeletal pain, altri neuruco~nitivedysiunction and with serrilogic reactivity aEainsL B./>,crgdud>ri were treated with a n~acrolideantibiotic (eg c4aritlirnnryciri)anti hydroxychlort> rp~ine.

ResuRs:

Eighty 41. oCpatieilts had reti-reported i~npruvemmtol509L or more at die end nTY ~ninilhr. Mcr 2 manths or treatment, 20'h ondu~:redat Lhe Universiry 6f Calznecticuc Health (:cmsr; Ll-insc irom 19Y'L1!?97 includcd Izhl Capture Assays arid Wcstern Blots (ISM, IgG) conducted by RllliNl~i-tliAmcricaii Laboratories. Both laboratories have iigid qrrality co~ltrolproxrarns and have p a r t i c i p ~ t r lill rl~rrvaluatir~nof laboua~iiry tc%ts lor Lyme Uisease ill]. T47este1-h Blots were con.;irlcred to be posilive if therc were one 01- mure reactions to proteins specific t b l3i~i.rdinbllrgdo+~n:~ l;e PSkd, ?Ikd, 34kd,J7kaervatioi~ inight apply t o t h c trcatmciit of pacients with chronic Lyme Iliseasc using niacroltde antibiolics. Tlris reporr details the experience wlth 235 paiirrtcs wilo u7crctrcated ~vitlithe cmibinatlon n i a maa.olidc atltihiotic and l~vrli-nxvchlorotruilie.

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rivice daily, and a nlacrolide a~~rihiotic (clarillimmycin 500 mg tivice daily, mithromycin 250-500 sirx daily, or ei'ythronrycin 500 rng three rimes daily). 'lile treatment was continued until patients' symptoms were wsolvcd or improved. In those whose sympriimr corrlpleiely resolved, treatment was generally n>niinued for 1 more nlonth. I n those whose sympto~nsware improved, hut nor rt-;olx,ed, fieatment was genenlly wntinucd la-1-2 rriure months before slopping ur changing therapies. In those w h o railed rreaLment, the therapy was continued s r n being jutiged a for a lninimuin o f 9 ~ n u ~ l t hprior trcaunent faiiirrc. A il.eatment cure was definer1 as the ahrence nfwmpturns lor i or mose sears fbllowii~pcessation o i ihefapk u~arkediixpmve&en~.was de&ed as havirle rrcovercd 75% nr more ofi,~.evionsnurmai iu~lcrivn as assessed hy the paiieni. l'alicn~rU ~ ~ O S C S ~ I I I ~ ~ O I ~ ~ S rvsolvtd conioletelr. lhr, the entl ol. trcatmenr h u who ~ suhscguently iiad >,elapsingsympiolns after therapy was but disconiinued were coiisidcrrd ~narkedlv , imvrm~ed. . not cured; these patients usually relapsed withiii 2-8 ~veelisk,ni>u:i~igthc~dpy.

Product lfivabga11on

MedScl Mom1i4003,gal, Pi136 142

Table i.Westem blotvs EIA In Ule Uiagnosisoi chmnlc LYMEdiseas~ W.W.rn

EIA

M+G+

hl",

M+G-

WG+

MG-

Positiue149] 28 (57%)* 7 (14%). 11 (22%)* 3 (6%)' Negativei142J 28 (20%) 49 (35%) 18 (12%) 47 (33%) N u m b e r of patients (% ot total! wRh ~osffwe (+) or lieoattve (-1 semlountests byEik (Enzyme lmmunoassay)OrWestern Blot (M=lgM G=lgG)

contrast, IgG reactions were noted 117 79% of FIA-posinve paucnts and 32% of EIA-negatwe patients. 4 compdnbon of trcatmcnt outcomes acco~d~ilq to aerologic riactivity Is shown in Table 2. There we8.e no significant differences in treatment outcomes betwsrn d ~ o s ewhose Wc-ntern BIots or El& were uositive compared tu those who %,ereseronegatve

Age and gender a n d outcomes Table 2. Western blbtvsElA In the dmgnosis ofchronic LYMEdlsease ElA

cure

Iml)rovement

Failute

Western blot M+G+ 1 (2%) 52 (82%) 10 (16%) 4 (6%) 55 (76%) 13 (18%) MAG3 (9%) M-GA 23 (64%) 10 (27%) 3 (6%) M- G11 (20%) 41 (74%) 'Number oi pataflenls 1% oftotal)with posltlve (T) or negaiim (-)serolog!cfesls by EIA (Enzyme lmmunoassay) or WE wresternBlot, M=IQM G-106) who viere cured. ~mpmued,or \who laded treatmsn

Table 3 Gender vs oulcome in the traatmeniof chronlc LYME disease. Cure

lmprovemenl

Failure

.

--.-

Male 3 (5%)* 48 (80%) 10116%) Femate 8 (5%) 126 (75%) 34 (20%) Numbcr ol palontr 1% 01 totol] who were cured Improved, or falea treatment

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Table 4. Piror symptom duration vs treatment outcome in chrona LYME disease, PriorSxdnralim

Cure

Improvement

Pallure

cf yr 3 (9%)* 30 (85%) 2 (6%) 1 4 yr 4 (6%) 51-J9%! 10 (15%) >3 yr 4 (3%) 93 (72%) 33 ((25%) 'Numbsiof oatlenls 1% oflotal) who wera cured improved, nifalted treatment

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Patlcnts ranged in age from 15 to 78 (medlan of 41); 73% bete females. There were no d~SSeiencesm treatment outcomes accordmi: to ape (data not shuiun) or aendrr (Table 3) Prior symptoni duration and ouimmc Patients whose sylnptofirs had been pt-esent for idow than one year had more failures (15-25% 5s, 6%) than patients with symptoms for less than one year (Table 4). Patients with symptonls longer t l ~ a n3 years tared poorer than those with symptonrs lo? eillrer 1-3 years or less. than 1year. The prior dul-ation or sympronis was d s o d i ~ w t i yc o w Inted wiih thelime tc onset nlan? imptoversenl, i.c, the liingsr the prior duration 01 symprorns, tlie lorigcr thc interval of tirne before any signs ar iniprrrueinrnt were noted (Table 5). Compared to parien1.s wlime symptoms were prcscrlt h ~ Ira s than one ycdl, nro1.e than 50% of imiicnts with symptoms 01lnn$ev duxa~iunnoted no inrprovcmcnt until ac least 1 weeks n l d ~ e t a p yhad rinpscd. Almost 30% of patients with rylnpioms longer than thrcc ycars had no improvemrnl. lrtitil 6 accks or mure into treatment. Figure 1 shows the degree orimprovelamt XI 2 xiionthr arid 3 n~onth.ilollowing the iniiiation of ilrc.rapy. By 2 months, the niean improveinent. wa5 5(!-75% rtrirh only one-Lifih of pdtiens Seeiinl: aiarkrdly improved (75-1 00%): by 3 months, QC,% or patjenL? were rna~kedly irnpruvcd.

Type of m c r o l i d e and outcome Thcrc were no tfifkrenr'er in n~~lrbrne among the tliree dilferent macralide antil~ioricsused F a b l r 6). T h e lhilure rate ranged Tiom 12%.iu 21%, and the cure rate 4'X to 12%.

Semlogical reactivities a n d outconles Duration of treatment and outcome

A total 01 235 patients were crcatcd with a rnac'i.olide antibiotic 101- one or more months. Table I shows a comparison or their enzyme imniunoassdys (EIA) and Wesiein 1mmunoblot.s. Overall, 75% were posilive b y XI.& or TVesle~mDlnt 'rlie EIA was i>fisitive in 26% ol' p"ienis, wiri ihr 54Zestern RLlt was o s i t i v c in 74%. Wlrcrras ihe IlIA rvas positive in fi'A of parierits with a negaivc Walerrl ITlot, ilre EIA was negative. in 67% i>i paticnta ii'llose Westel-TInltit u,as positive. Of positive Western Bloti.'IgM reactivity was found in 71% oi EIApositive pdticnts and 55% of oiEIPi-negative patienrs: in

I1a!iri,ts were trratcd For ar little as 1 111on!6 or as ]arts as Id months, with a median of ti mnnrlis. >lost patients wcre hcatcd for hettreen 1 m ~ r 8l Imrmlis, The durauoii d l treatment r e q u ~ r e dril prticlucr s~istaincdimprouznient ~vzscorreiated ulitl~:he i>~-itisduration 01' smiuz toms (data not sliown). Some pdtiei>island difficulty tote~aiingliydroxyrhlnrorlu;ne, cithcr because o i tliarrliea or skin hyperwnsitiuity reactions. No one had aiig optic ach~eves~gnlficantmprovement in most patientq wnh chion~cI.vme Diseax. The most lmoortant deteimlndnt of treamerit duration and outcome appears to b e the dnrariun of symptoms prior to therapy ('Fables 4,5). Improvett~entfrequently did not even begin until after se\beral weeks of therdpy, especially in patiella who had rymptonts for mure than a few years. This slow rate of imorovement m i ~ hbe t related to %heslorv rater of rnetah. o1i.irn and mulwic'ation (if any) oTB.bu~~do$mi[42]. The actual duration of treatment needed to erect cure or mawinni~ninrpriiver~irnthas yet to be determined, hut in our oliservatioi~sthus Far appear to be clocer to 12-18 months ol'iliempy. This dilration of treatment should not bc surprising ivhen considering che long d m i i o n s or ~ i ~ w a p y needed to control other chronic idections sucl, x q ruherri~liuis,sonre funsat diseases, leprosy, n d (1leva 1431. ~

The rewlts oi'rhcse and previous studies h a emphasize the need lor better diagnostic tools, as well as therapeutic approaches. The existing re~c!mrnendation oS a twotiered approach for the diagnosis of Lyme Disease, beginning wid1 a screening ETA, fullowed by a Western Blot (351, bas hccn challengcil, and accumulating evidence sup~xor!~ cbc V~CII' thzt this approach lalls short of' the As w i ~ hrhc pl-ior rcsults that sl~oivedthat 1errZ:ycline desircd goal of a reliable tcst to support or refute the clinwar ~lfectivein resolving symptonis assuciatcd wit11 DC i : crite1-ia).These findings suggest that mtiar-llititis, but were subseque~ril?sliown 10 liave chroiiic hndy responses ate not the best correlates oidiseasz preyJ.ymc Disease, d e ~ n e dno h e n r f i ~ liilnt 115o x e w e o r actisit?*,consistent with what might he rtxper~rd in iiuracellular inlection. ~

T h e IiyliOrhesis t h a ~I . ~ m eDiseasr is a n intrsccllular ini'ection rlranvs support ilixr~what ifi known about the

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iUtllousi~dir resolis wich both Qtracycline and macmtide thel-spies s u g ~ e s tthat paucnts with chronic [.ymc

Med SciMonq 2003; Q(11): PM-142

Donta Si-lrlaomlide thmw of LymeDiease

Disease have marked improvement with these treatments, and that these approaches are relatively simple and inexpensive, conrrolled clinical trials cunlparing lung--term with short-term therapy are needed to validate or refute these observations. Recently, acnnh-olled trial one month of IV ceftriaxooe Eo~owed by tx$comonths of oral doxycycline neatmen1 wiih placebo treatments railed to slnw obvious differei~crs hnwecn the two g ~ o u p s1441. These results are consistent with both the lailure of ceitriaxone to a d q o a t e b intrace]lulnr reservoirs or organisms and either too small a dose or too short a duration u f dozycyline imatnient, and/or high prorein binding of' doxycyclioe compared LO tetracycline; these issues h.dre also heen previously addressed [1.5]. Additional trratmcnt trials, taking inro act:i>uni pl~drmacologiccunsidcrahons nr diffment arrtiliioclc~and obseroathns made in this L ~ I G1 rI5 . 1 1 1 .< i < ~ i ' , ~ .I..~LI;II1 c I., . ~ I U I1r1 . . I : . I . c I I ~ ~.c~E ; . 11111 'i i . I . n I 1 : 1 1 a l ~ r l l , l I. I ( T I C : T \ : ~ I \ !rc moi: cifcctive in the treal~nen!:o f c h ~ n ~ 1.yine ic Discase, ~

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REWREEIGES: I. Slecre AC, &arenlitgbnXH, C~allJ E a el: The clrly lt+"idl umni icsl~rjonrwFLyn~cd a c ; r s e . ~ n nLn~einMcd, 1983: 0'): iG-82 2. k d c i 1IS+,I1,C;el!>erht, and Krallsc 1'1: l[;ii.ly I.y,nc direarc: ;i 110like iUneu wirholdi C! yiiremanii:?aas:i~tiIiarricr, 1092: 41: 15-!I

4. Eallon B and Nicldr J k Lyli~cdiscass: a neir,.nji9yd*irtvicillmms AXIJ Prycli, 1014; 141: 1571-83 a. kciil;er Ax, nelaney I!, t'l'Nz.iil 'I: ;#nilMiyov E: I n d a l l a l i ~ nol' nooluiman pri!,iaLes ivilh ihe NbO sliain ofBoi~rUriiiuiiiloif&lcrd\ ro a nrodci o i l ynle neurohuriclioris iairhiui LO t h e kiimun itirc;lsc. N F ~ I I o I o ~14!ii;45: ~. lS5-iZ.12

la. I-eGnJM, NclsonJh seg;eiriJ.er all I n v i m i u e p r i b l i i k s of Barrella burtdorjd lo I I nntrmicmbial agents. h t i m i c r o b Agenu

Chemother, 1993: 37: 1444.6 19. KoIino Y, ~ ~ s h i d H,SUX,ZT. n. a n d ~ ~ gcompararlire ~ . ~ : ilamd colinc6croiclarithromyciu, a oew m n r r ~ ~ i aannbiodc, c 'lliromydn in raw. .hrinlio_ob. k c n o chcinothpi. 198% 33: 751.6 2" hiau~inM.Be?>oliel.AM, Hongiand P, andRarmlrD;Phqolyro~oonal alkaiinitabon and the barrericidel efio aianiibiotic*: h e Coxleila burnedipuradignJ InfenDir, 1992: 166: 1097.102 81. $ h a d i d NA p m P r ~ ~ , ~ oeL,~sleere i ~*c, i K~ a , P ~~ ~ d: ~ c r ?he long-term dinical outcomes afLyrne Disease. 4nn i n ~ e r nMed, 1991; 121: 560.7 22. hsch ES. Bujat Dl, Wa hI.ctal: Lyme Direare: aninferrioui and ix0aiinfeclious ryndxnbramr.] Rheum, 1994:ZI: 45401 23. D o n u $1':Lyne Disease: A clinioxl challenge. j Spim & Z c k nib. i!lY5:2:d4.1 24. Dm,la T:.r lrCraslence.rufchrBnicLy c.Cu,Teni Trcarmcor Opiionr i n lnferrioils niicnses, 2001; a: 261-2

zandlcr)i

45. r b r i l a ST: F l i q m n ~ improirr l rhceiliracy b l n * a m i i d e a i i i ~ i u t i c s in l h c r r e a r > n e n i o I I . ~ mD~i w ~ s r .18g4:VIInrernatianai ~ J P . C : C L C C * T . 1.11:. h ~ : f i l n. I i , I $8.. :I 1:. \ r s < n o ro::~C, I . r I I . . I . I. . : -!, \ . I ! 10 ? # # . , .r ~.('C,!.:?.;.s hl .?#:,I. Gcmnmny,i\hsirac~ PI43 28. Slt~rgill-KorryrliS, SFlllesinger PI*, Chakiaborly Pcld: l a r k o i aridificatio~iin hlyrol~aclr,riiinlplilgosomer produced by cxchliion oirheresirular proton-ATParc. Science 1494; P63: 678-81

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28. Xisrenbci:~ LG, h l d ~ n a niQl:, and Srhlcsinpr PH: Hisloplasna rspsuli~xmllir~odulaic$the rtidirieaiioo orphagolywroriier. J E r p Mrd, 1993; 177: liiU5-I 1 eg, rrendlickfl, &l.lal.kh.hamHi, azirl Crnlrmnn All: lnllibition of ~~liiigosomc-lya~sorne liisian in olawopliagcr hp rul~d~lei.rri~;~cu_ni vil-lilcnr Urucclla alxnlia. J Clin hlicruliiol, 1'185; 4G:332-5 SO, nr'inzen Rh; Scuimorc Mn, Rockc? DD, nnd Hacksl.irL i DiF6:rmiiri snirriirtion with endoryuc and caocytir paihwayi::

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36. Kalirh b, Mcl-lug11 T,. Giaoq*ilri J, ri a!: Pmblscnc~oflinmutin. globi&nM or immuna~lobulinG antibnrly responses to narnlln ining~l~~fen 10-20 years aflei acrivr Lyme dkezac. Clin i ~ ~ f rnir. r~. Ponl:13: 780.5 37. Prvac-hlur~rV, WcbcrI(, Pr8ccrInV.ei al: 3urviv;ii oi8anciin h?mgJo>feti>nancibioiicdly m a r e d patienw with L y m liorrcliorls. Illfenion. l!l89; 17: 6 B#. F ~ ~ ~ c - V, M paater u ~ ~ liw. ~ c sliegel H, r., RI: I;~TS an iris biopsy. J Clin Nerirn.O~lilil~aim, lLl9'i:li: 155-61 1 I : ,'.I irlr I ~ I. # 1.1 t ~ ~ : ~ r ~ ~ ~ 2 ~ : : ~ . ~ t c ~ . l . , , I I . 2 , .,.,-..I. ,