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Supplemental Paper MAI

  1. 1. JosephHelms The most commonnon-tuberculosismycobacteriathatcause pulmonaryinfectionsare Mycobacteriumavium complex, Mycobacteriumkansasii,andMycobacteriumabscessus (210).1 Non- tuberculosismycobacteriaare widelyknownforcausingpulmonaryinfections.Because pulmonary infectionsare mostcommonlycausedbythese strainsof non-tuberculosismycobacteriabacteria,the diagnosisandtreatmentof these infectionswillbe discussedhere.The mostrecentprimaryliterature discussingthe treatmentforM.avium complex, M.kansasii, andM.abscessus will alsobe discussed. Diagnosisandtreatmentof M.chelonae,M.fortuitum,M.genavense,M.gordonae,M.haemophilum, M. immunogenum,M.malmoense,M.marinum,M.mucogenicum,M.nonchromogenicum,M. scrofulaceum,M.simiae,M.smegmatis,M.szulgai,M.terrae complex,M.ulcerans, and M.xenopiare mentionedinthe 2007 ATS/IDSA guidelines,butwill notbe discussed,becausethese donotcause pulmonaryinfectionsascommonlyasthose thatwere previouslymentioned,andaccordingtothe 2007 ATS/IDSA Guidelines, becausethere’snotenoughinformationabouttheseinfectionstoknow if the diagnosticcriteriaapply (367,378).2 Accordingto the 2007 ATS/IDSA Guidelines“DiagnosticCriteriaof Nontuberculous Mycobacterial LungDisease”table, the diagnosisof nontuberculosismycobacteriuminfections are best usedto diagnose Mycobacteriumavium complex (MAC), M.kansasii,andM.abscessus.There isnot enoughknownaboutmostotherNTM infectionstoknow if the diagnosticcriteriaapply(367, 378).2 These testsare keyto the diagnosisof Mycobacteriumavium complex, Mycobacteriumkanasasii,and Mycobacteriumabscessus (367,378).2 In summary,these guidelinesare statingthatthere are both clinical andmicrobiological diagnosticcriteriaforthese infections (378-379).2 Accordingto Table 3, in the 2007 ATS/IDSA Guidelines,todiagnose anyof these infectionsusingclinical criteria,theremustbe an exclusionof otherdisease statesandthere mustbe nodulesorcavitiespresentonaCT Scan or chest radiograph.To diagnose anyof these infectionsusingmicrobiological criteria,there shouldbe two positive sputumcultures,orone positiveculture fromflushingof respiratorytract,or lungbiopsywitha positive culture.Expertsshouldbe consultedif there isaconcernfor spreadof the more uncommon typesof nontuberculosismycobacteriuminfections. Patientspecificfactorsshouldbe considered before initiatingtreatmentof these infections,because the agentsusedtotreatthese infections are not well tolerated(379).2 Mycobacteriumavium complexmayoccurin patientswithstructural lungdiseaseslike COPD (372).2 Accordingto the recommendation andtable 5, inthe 2007 ADS/IDSA Guidelines,there are regimensforthe treatmentof MACnodular/bronchiectaticdisease,andfibrocavitaryorsevere nodular/bronchiectaticdisease.The treatmentof MACnodularbronchiectaticdisease isclarithromycin 1000 mg dailyor azithromycin500 mg daily,rifampin600mg, and ethambutol 15mg/kg three timesa weekuntil otherunlessothersusceptibilitiesare identified. The treatmentof MACfibrocavitaryor severe nodular/bronciectacticdisease isclarithromycin500-1000 mg/dayor azithromycin250 mg/day, rifampin600 mg/day,and ethambutol 25mg/kg/day unlessothersusceptibilitiesare identified. Rifabutincanbe substitutedforrifampinandamikacinorstreptomycincanbe consideredasadd-on therapythree timesweekly.The goalsof therapyforpulmonarypatientswhohave M.avium complex are to remainat a lowrisk of the infectionoccurringagain andremain withoutsymptoms for12 months
  2. 2. (389, 394, 405).2 Drugsthat are usuallyusedtotreat tuberculosisare notusedtotreat these infections, because of resistance.2 Patientsare likelytreatedwiththisdrugcombinationdue tosusceptibility. Data in a retrospective cohortstudyshowedthatpatientswhohad nodularbronchiectasis causedby M.avium Complex whowere giventhree timesweeklytherapyof clarithromycinor azithromycin,rifampin,andethambutol comparedtothose whotookthe same therapyregimenonce daily,toleratedtherapybetter. However,the efficacyoutcomesintreatmentof the diseasewere not significantlydifferent.The evidence fromthisstudyprovidesfurtherevidencethatthere isnoextra benefitintreatingpatientswhohave M.avium Complex more frequentlythanthree timesweekly. 3 The retrospective cohortstudyisagood studydesignforthistrial,because itmaybe difficulttofindpatients to participate in a study whohave a disease of lowerincidence like M.avium complex (370).2 Because the drugs that are usuallyusedtotreat MAC are notwell tolerated,thisstudyprovidesfurtherevidence for the recommendationthatthe 2007 ATS/IDSA Guidelines make whichis three timesweeklytherapy for M.avium complex (389, 405).2 “The treatmentof fibrocavitatorypulmonaryinfectiondue toMycobacteriumaviumcomplex and Mycobacteriummalmoenseposesachallenge.Thisstudyassessedmicrobial,inflammatory, radiographic,andclinical outcomesforastandardized24-monthtriple-drugregime.Following treatmentcompletion,all patientshadfewersymptoms,experienceda reductioninsystemic inflammation,andhadnegative sputummycobacterial cultureresults (222)).”4 The patientswere given the standard of care optionsanddosages(rifampin450-600 mg/day,ethambutol 15mg/kg/day,and clarithromycin1000 mg/day) forcavitarydisease accordingtothe 2007 ATS/IDSA Guidelines (389).2 The studywas conductedinScotland,andthe treatmentinthisstudywaslikelycomparedtostatisticsof those takingthe usual treatmentof rifampicinandethambutol,withisoniazidasanadditional option witha durationof 2 yearsof treatment. The studyshowsthattreatmentswithclarithromycinare better toleratedandhave betterefficacy,thoughthe treatmentinthe study wasa longerdurationthanthe ATS/IDSA Guidelinesrecommend(394).2 Patientswhowere diagnosedwith M.aviumcomplexwere givenatwo or three drugregimenin an open-label,randomizedobservational study.The three drugregimenconsistedof clarithromycin, rifampin,andethambutol.The twodrugregimenconsistedof clarithromycinandethambutol. Approximatelyhalf of thesepatientswere treatedwiththe three drugregimen,andhalf were treated withthe two drugregimen.These patientsdidnothave HIV,whichmeanstheywere more likelytohave a pulmonarydisease.Rifampinmaydecrease the serumconcentrationsof clarithromycin,because clarithromycinisaCYP3A4 substrate of rifamycin derivatives,andrifampinisaCYP3A4 inducer.5,6 A lowerpercentage of patientsonthe twodrugregimendiscontinuedthe twodrugregimenthanthe percentage of patientswhodiscontinuedthe three drugregimen,andthe efficacyintreating M.avium complex wasnotclinicallydifferentbetweenthe groups.7 Becauserifampinhasalotof seriousadverse effects,andinteractswithclarithromycin,inthe future the evidence fromthisrecentstudycouldbe usedto create a newtreatmentoptionforpatientswhocannottolerate atriple drugregimen,though more trialsare needed. In a multi-drugtrial, M.avium complexpatientswere givenahigherdose of rifabutininaddition to othertreatmentsforMAC. Accordingtothe trial the followingadverse effectswere present,
  3. 3. “Rifabutin-relatedadverse eventsoccurredin77% of patients.Fifty-eightpercentof patientsrequireda dosage adjustmentordiscontinuance of rifabutintherapy.The mostcommonadverse eventwasa reductioninthe meantotal white bloodcell (WBC) count,whichdecreasedfrom8,600 ± 2,800/mm3 before treatmentto4,500 ± 2,100/mm3 duringtreatment(P= .0001). Althoughall patientshadsome decrease inWBC count,onlythree patients(12%) requiredadosage adjustmentforthisreason.Other commonadverse eventsincludedgastrointestinal symptoms(nausea,vomiting,ordiarrhea;42%) and abnormal liverenzyme levels(12%). Eightof 11 patients(73%) withgastrointestinal symptoms,including one patientwithabnormal liverenzyme levels,requiredarifabutin-dosage adjustment.The mostsevere adverse events,alwaysrequiringanadjustmentof therapy,were adiffusepolyarthralgiasyndrome (19%) andanterioruveitis(8%) (594).”8 Anterioruveitisisinflammationof the iris,whichseemstobe a concerningadverse effectsince thisisinthe headarea.Increasesinliverenzymeslevelsare also especiallyconcerning,because thismeansrifabutinislikelycausinghepatotoxicity. Giventhatrifabutin (a rifamycin derivative) hassignificantadverse effectsandthatin the observational studydiscussedin the previousparagraph thatpatientsexperiencedlessadverse effectswhentakenoff rifampin(a rifamycinderivative),itwouldseemthatmore researchneedstobe conductedtoassessif rifabutinisa necessarycomponentof treatmentforall patientswith M.avium complex.8 Accordingto the recommendationinthe 2007 ATS/IDSA guidelines,the standardof treatment and goal of therapy forM. kansasiiisrifampin600 mg/d (10 mgk/kg/day),isoniazid300 mg/d(5 mg/kg/day),andethambutol 15mg/kg/dayfor12 monthswithoutapositive sputumculture for M. kansasii.Pyridoxine 50mg/daymay alsobe includeddue todeficiencycausedbyisoniazid.2,5,6 The drugs that are used totreat tuberculosisare usuallyresistanttoMAC, butisoniazidisusedtotreat M. kansasii, whichisinteresting,because isoniazidisalsousedtotreattuberculosis.2 Accordingtothe guidelines, due to rifampinresistance,otherregimensfor M.kanasasii,include threedrugregimensthatinclude the followingantimicrobials:amikacin,streptomycin,ciprofloxacin,clarithromycin,ethambutol, rifabutin,andsulfonamides(377).2 However,the drugsthatare a part of the standard of treatmenthave lessthandesirable adverseeffects,soitwouldseemif intermittenttherapycouldbe anefficacious therapyforthese patients,thatthiswouldbe agood treatmentoption. Treatmentwithclarithromycinhasnotbeenstudiedextensivelyin M.kansasii.However,the treatmentof M.kansasiiwithclarithromycin wasassessed inaprospectivestudy.Patientswere given ethambutol,rifampin,andclarithromycinthree timesaweekuntil patientsexperiencednegative sputumculturesforM.kansasiiover12 months.As discussedinthistrial, clarithromycinactuallyhasa higherMIC in Mycobacteriumavium complex thanin M.kansasii.9 Thismeansthatnotas much clarithromycinisrequiredtoinhibitthe growthof M.kansasiiasis requiredtoinhibitthe growthof M. aviumcomplex.The patientsweregivenrifampin,clarithromycin,andethambutolthree timesaweek until patientsshowednegative sputumculturesof over12 months.The patientsinthe trial didnot experience anysignificantadverse effects.The strengthsof thistrial showedthatclarithromycinmaybe an efficaciousandwell-toleratedtherapyforthe treatmentof M.kansasii.While the trial showedthata significantamount of patientsexperiencedadecrease insputumculturespositive for M.kansasii,there were notany statistical testsperformedoranythat couldbe found.9 Accordingtothe 2007 ATS/IDSA Guidelines,clarithromycinmayinhibitthe growthof M.kansasii,butthere isnot currentlyenoughdata to suggestthisisa beneficialtreatmentoptionforpatients.2 However,becauseof the lackof side effects
  4. 4. and the susceptibilityof these bacteriatoclarithromycin,itwouldseemthatclinicaltrialsshouldbe conductedtoassessif clarithromycinwouldbe aviable treatmentoptionforthese patients.Mostof the drugsusedto treat mycobacteriumare notusuallyverywell-toleratedwhichopensthe doorformore studiesof thistreatmentforthisinfection. Perthe 2007 ATS/IDSA Guidelines, M.abscessus doesnothave aneffective pharmacological standardof care unlessgiveninconjunctionwithsurgery (406).2 Accordingto the recommendation in the 2007 ATS/IDSA guidelines,multi-drugregimensof chemotherapythat includeclarithromycin combinedwithsurgical resectionof the local infectedtissuesare the besttreatmentoptionforthese patients,asthisisthe bestknowntreatmentforcure of the disease (406).2 It wasnot discussedinthe literature whythere are notbetterknowntreatmentsforthisdisease.Muchlike the treatmentisnot well-definedforM.abscessus,the goalsof therapyforM.abscessus are notwell definedeither. Accordingto the guidelines,treatmentmayalsoinclude amikacin,cefoxitin,and imipenemrepeatedly or overmonths(406).2 The therapyovermonthscouldbe because there isnotreallyagiventimeline for howlongit takesfor patientstoexperienceaclinical cure of M. abscessus,sothe authorsdidnotwant to give a definiteamountof monthsthatpatientsshouldbe treatedwiththese otheragents.There is not an extensive amountof literature onthe treatmentof M.abscessus. The treatmentof these respiratoryinfectionsisextensive andrequiresahighlevel of monitoring and compliance.There are establishedstandardof treatmentsfor M.avium andM.kansasii,butstill no establishedtreatmentsforM.abscessus.However,thereappeartobe bettertoleratedtreatmentsfor M. avium andM. kansasiithatneedmore evidence before theycanbe usedtotreat patients. References: Others: 1. JohnsonMM, andOdell JA.Nontuberculousmycobacterial pulmonaryinfections.J.Thoracic Disease [Internet].2014 Mar [cited2016 Feb22]; 6(3): 210-220. Availablefrom: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949190/. 2. GriffithDE, AksamitT, Brown-ElliottBA,CatanzaroA,DaleyC,Gordin F,HollandSM, Horsburgh R, HuittG, LademarcoMF, IsemanM, OlivierK,RuossS,ReynCF,Wallace Jr. RJ,and WinthropK, and Mycobacterial DiseasesSubcommittee.Anofficial ATS/IDSAstatement:diagnosis, treatment,andpreventionof nontuberculousmycobacterialdiseases.AmJof Respirand Crit Care Med[Internet].2007 Jan [cited2016 Feb22]; 175(4): 367-416. Available from: http://www.atsjournals.org/doi/pdf/10.1164/rccm.200604-571ST. PrimaryLiterature: 3. JeongB-H, JeonK,Park HY, KimS-Y, Lee KS,Huh HJ, Ki C-S,Lee N-Y, ShinSJ, Daley CL,and Koh W-J.Intermittentantibiotictherapyfornodularbronchiectatic Mycobacterium aviumComplex lungdisease.ATSJournals:AmJof Respirand CritCare Med [Internet].2015 Jan 1 [cited2016 Feb22]; 191(1): 96-103. Available from:
  5. 5. http://www.atsjournals.org/doi/abs/10.1164/rccm.201408-1545OC?url_ver=Z39.88- 2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed#.Vsue9vkrLIV . 4. Murray MP, LaurensonIF,and Hill AT.Outcomesof a StandardizedTriple-DrugRegimenforthe Treatmentof NontuberculousMycobacterial PulmonaryInfection.OxfordJournals:ClinInfect Dis[Internet].2008 July [cited2016 Feb23]; 47(2): 222-224. Availablefrom: http://cid.oxfordjournals.org/content/47/2/222.full.pdf+html . Others: 5. Clinical Pharmacology.[Internet].Tampa(FL):Elsevier/GoldStandard;2016. [modified2016; cited2016 Feb22]. Available from: http://www.clinicalpharmacology- ip.com.portnoy.wingate.edu/default.aspx . 6. Facts and ComparisonsEanswers.[Internet].(Netherlands)AlphenaandenRijn.Wolters Kluwer.[modified2016; cited2016 Feb22]. Available from: http://online.factsandcomparisons.com/index.aspx. Primary Literature: 7. Miwa S,Shirai M, ToyoshimaM,Shirai T, Yasuda K, Yokomura K, Yamada T, Masuda M, Inui N, ChidaK, SudaT, and HayakawaH. Efficacyof clarithromycinandethambutol for Mycobacterium avium Complex pulmonarydisease.A preliminarystudy.Annalsof the AmericanThoracic Society[Internet].2014 Jan [cited2016 Feb22]; 11(1): 23-29. Available from: http://www.atsjournals.org/doi/full/10.1513/AnnalsATS.201308-266OC#.VsufzfkrLIV. 8. GriffithDE,Brown BA,Girard WM, and Wallace Jr. RJ.Adverse eventsassociatedwithhigh-dose rifabutininmacrolide-containingregimensforthe treatmentof Mycobacterium aviumComplex lungdisease.OxfordJournals:ClinInfectDis[Internet].1995 Apr 19 [cited2016 Feb22]; 21(3): 594-598. Available from:http://cid.oxfordjournals.org/content/21/3/594. 9. GriffithDE,Brown-ElliotBA,Wallace JrRJ.Thrice-weeklyclarithromycin-containingregimenfor treatmentof Mycobacteriumkansasiilungdisease:resultsof apreliminarystudy.Oxford Journals:ClinInfectDis [Internet].2003 Jun26 [cited2016 Feb22]; 37(9): 1178-1182. Available from:http://cid.oxfordjournals.org/content/37/9/1178.long .

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