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. (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. “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. 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. 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 .
