35861722 Multi Drug Resistant Tuberculosis

8/13/2019 35861722 Multi Drug Resistant Tuberculosis

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Multi-drug-resistant Tuberculosis

ulti-drug resistant tuberculosis(DR-TB) is defined asTB that is resistant at least to isoniazid (INH)and rifampicin

(RM)! the t"o most po"erful first-lineanti-TB drugs# Isolates

that are multipl$-resistant to an$ other combination of anti-TB

drugs but not to INH and RM are not classed as MDR-TB#

MDR-TB de%elops during treatment of full$-sensiti%e TB "hen the

course of antibiotics is interrupted and the le%els of drug in

the bod$ are insufficient to &ill ' of bacteria# This can

happen for a number of reasons* patients ma$ feel better and

halt their antibiotic course! drug supplies ma$ run out or

become scarce! or patients ma$ forget to ta&e their medication

from time to time# MDR-TB is spread from person to person as

readil$ as drug-sensiti%e TB and in the same manner#

+pidemiolog$

MDR-TB most commonl$ de%elops in the course of TB

treatment! and is most commonl$ due to doctors gi%ing

inappropriate treatment! or patients missing doses or failing to

complete their treatment# MDR-TB strains are often less fit andless transmissible! and outbrea&s occur more readil$ in people

"ith "ea&ened immune s$stems (e#g#! patients

"ith HI,)# utbrea&s among non.immunocompromised health$ people

do occur! but are less common# / '001 sur%e$ of 23 countries

found rates abo%e 4 in about a third of the countries sur%e$ed#

The highest rates "ere in the former 566R! the Baltic states!

/rgentina! India and 7hina! and "as associated "ith poor or

failing national tuberculosis control programmes#

It has been &no"n for man$ $ears that INH-resistant TB is

less %irulent in guinea pigs! and the epidemiological e%idence

is that MDR strains of TB do not dominate naturall$# / stud$ in

8os /ngeles found that onl$ 9 of cases of MDR-TB "ere

clustered# 8i&e"ise! the appearance of high rates of MDR-TB in

Ne" :or& cit$ in the earl$ '00s "as associated "ith the

e;plosion of /ID6in that area#
http://en.wikipedia.org/wiki/Tuberculosishttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/First-line_treatmenthttp://en.wikipedia.org/wiki/HIVhttp://en.wikipedia.org/wiki/AIDShttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/First-line_treatmenthttp://en.wikipedia.org/wiki/HIVhttp://en.wikipedia.org/wiki/AIDShttp://en.wikipedia.org/wiki/Tuberculosis


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Treatment of MDR-TB

5suall$! multidrug-resistant tuberculosis can be cured "ith long

treatments of second-line drugs! but these are more e;pensi%e than first-

linedrugs and ha%e more ad%erse effects# The treatment and prognosis of MDR-

TB are much more a&in to that for cancer than to that for infection# It has a

mortalit$ rate of up to orit$ of patients suffering from multi-drug resistant tuberculosis do

not recei%e treatment as the$ tend to li%e in underde%eloped countries or in

a state of po%ert$# Denial of treatment remains a difficult human rights

issue as the high cost of second-line medications often precludes indi%iduals

"ho cannot afford therap$#

Treatment courses are generall$ measured in months to $earsA MDR-TB ma$

re@uire surger$! and death rates remain high despite optimal treatment# That

said! good outcomes are still possible#

The treatment of MDR-TB must be underta&en b$ a ph$sician e;perienced in the

treatment of MDR-TB# Mortalit$ and morbidit$ in patients treated in non-

specialist centres is significantl$ inferior to those patients treated in

specialist centres#

In addition to the ob%ious ris&s (i#e#! &no"n e;posure to a patient "ith MDR-

TB)! ris& factors for MDR-TB include HI, infection! pre%ious incarceration!
http://en.wikipedia.org/wiki/First-line_treatmenthttp://en.wikipedia.org/wiki/First-line_treatmenthttp://en.wikipedia.org/wiki/First-line_treatmenthttp://en.wikipedia.org/wiki/First-line_treatment


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failed TB treatment! failure to respond to standard TB treatment! and relapse

follo"ing standard TB treatment#

Treatment of MDR-TB must be done on the basis of sensiti%it$ testing* it is

impossible to treat such patients "ithout this information# If treating a

patient "ith suspected MDR-TB! the patient should be started on 6HR+

(6treptom$cinCisonicotin$l H$drazineCRifampicinC+thambutolCp$rainamide)

CMECc$closerinepending the result of laborator$ sensiti%it$ testing# There

is e%idence that pre%ious therap$ "ith a drug for more than a month "as

associated "ith diminished efficac$ of that drug regardless of in %itrotests

indicating susceptibilit$! so! detailed &no"ledge of the treatment histor$ of

that patient is essential#

/ gene probe for rpoBis a%ailable in some countries and this ser%es as a

useful mar&er for MDR-TB! because isolated RM resistance is rare (e;cept

"hen patients ha%e a histor$ of being treated "ith rifampicin alone)# If the

results of a gene probe (rpoB) are &no"n to be positi%e! then it is

reasonable to omit RM and to use 6H+CMECc$closerine# The reason for

maintaining the patient on INH is that INH is so potent in treating TB that

it is foolish to omit it until there is microbiological proof that it is

ineffecti%e (e%en though isoniazid resistance so commonl$ occurs "ith

rifampicin resistance)#

=hen sensiti%ities are &no"n and the isolate is confirmed as resistant to

both INH and RM! fi%e drugs should be chosen in the follo"ing order (based

on &no"n sensiti%ities)*

an aminogl$coside(e#g#! ami&acin! &anam$cin) or pol$peptide antibiotic

(e#g#! capreom$cin)

/

+MB

a fluoro@uinolone* e#g#! mo;iflo;acin(ciproflo;acinshould no longer be

usedF'3G)A

rifabutin

c$closerine

a thioamide* prothionamideor ethionamide
http://en.wikipedia.org/wiki/Streptomycinhttp://en.wikipedia.org/wiki/INHhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Ethambutolhttp://en.wikipedia.org/wiki/Pyrazinamidehttp://en.wikipedia.org/wiki/Moxifloxacinhttp://en.wikipedia.org/wiki/Cycloserinehttp://en.wikipedia.org/wiki/RpoBhttp://en.wikipedia.org/wiki/Moxifloxacinhttp://en.wikipedia.org/wiki/Cycloserinehttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Amikacinhttp://en.wikipedia.org/wiki/Kanamycinhttp://en.wikipedia.org/wiki/Capreomycinhttp://en.wikipedia.org/wiki/Pyrazinamidehttp://en.wikipedia.org/wiki/Pyrazinamidehttp://en.wikipedia.org/wiki/Ethambutolhttp://en.wikipedia.org/wiki/Ethambutolhttp://en.wikipedia.org/wiki/Fluoroquinolonehttp://en.wikipedia.org/wiki/Moxifloxacinhttp://en.wikipedia.org/wiki/Ciprofloxacinhttp://en.wikipedia.org/wiki/Multi-drug-resistant_tuberculosis#cite_note-14http://en.wikipedia.org/wiki/Rifabutinhttp://en.wikipedia.org/wiki/Rifabutinhttp://en.wikipedia.org/wiki/Cycloserinehttp://en.wikipedia.org/wiki/Cycloserinehttp://en.wikipedia.org/wiki/Thioamidehttp://en.wikipedia.org/wiki/Prothionamidehttp://en.wikipedia.org/wiki/Ethionamidehttp://en.wikipedia.org/wiki/Streptomycinhttp://en.wikipedia.org/wiki/INHhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Ethambutolhttp://en.wikipedia.org/wiki/Pyrazinamidehttp://en.wikipedia.org/wiki/Moxifloxacinhttp://en.wikipedia.org/wiki/Cycloserinehttp://en.wikipedia.org/wiki/RpoBhttp://en.wikipedia.org/wiki/Moxifloxacinhttp://en.wikipedia.org/wiki/Cycloserinehttp://en.wikipedia.org/wiki/Aminoglycosidehttp://en.wikipedia.org/wiki/Amikacinhttp://en.wikipedia.org/wiki/Kanamycinhttp://en.wikipedia.org/wiki/Capreomycinhttp://en.wikipedia.org/wiki/Pyrazinamidehttp://en.wikipedia.org/wiki/Ethambutolhttp://en.wikipedia.org/wiki/Fluoroquinolonehttp://en.wikipedia.org/wiki/Moxifloxacinhttp://en.wikipedia.org/wiki/Ciprofloxacinhttp://en.wikipedia.org/wiki/Multi-drug-resistant_tuberculosis#cite_note-14http://en.wikipedia.org/wiki/Rifabutinhttp://en.wikipedia.org/wiki/Cycloserinehttp://en.wikipedia.org/wiki/Thioamidehttp://en.wikipedia.org/wiki/Prothionamidehttp://en.wikipedia.org/wiki/Ethionamide


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a macrolide* e#g#! clarithrom$cin

linezolid

high-dose INH(if lo"-le%el resistance)

interferon-

thioridazine

/mpicillin

Drugs are placed nearer the top of the list because the$ are more effecti%e

and less to;icA drugs are placed nearer the bottom of the list because the$are less effecti%e or more to;ic! or more difficult to obtain#

Resistance to one drug "ithin a class generall$ means resistance to all drugs

"ithin that class! but a notable e;ception is rifabutin* rifampicin-

resistance does not al"a$s mean rifabutin-resistance and the laborator$

should be as&ed to test for it# It is onl$ possible to use one drug "ithin

each drug class# If it is difficult finding fi%e drugs to treat then the

clinician can re@uest that high le%el INH-resistance be loo&ed for# If the

strain has onl$ lo" le%el INH-resistance (resistance at '# mg.l INH! but

sensiti%e at #4 mg.l INH)! then high dose INH can be used as part of the

regimen# =hen counting drugs! / and interferon count as zeroA that is to

sa$! "hen adding / to a four drug regimen! $ou must still choose another

drug to ma&e fi%e# It is not possible to use more than one in>ectable (6TM!

capreom$cin or ami&acin)! because the to;ic effect of these drugs is

additi%e* if possible! the aminogl$coside should be gi%en dail$ for a minimum

of three months (and perhaps thrice "ee&l$ thereafter)# 7iproflo;acin should

not be used in the treatment of tuberculosis if other fluoro@uinolones are

a%ailable#

There is no intermittent regimen %alidated for use in MDR-TB! but clinical

e;perience is that gi%ing in>ectable drugs for fi%e da$s a "ee& (because

there is no-one a%ailable to gi%e the drug at "ee&ends) does not seem to

result in inferior results# Directl$ obser%ed therap$ certainl$ helps to

impro%e outcomes in MDR-TB and should be considered an integral part of the

treatment of MDR-TB#
http://en.wikipedia.org/wiki/Aminosalicylic_acidhttp://en.wikipedia.org/wiki/Aminosalicylic_acidhttp://en.wikipedia.org/wiki/Macrolidehttp://en.wikipedia.org/wiki/Clarithromycinhttp://en.wikipedia.org/wiki/Linezolidhttp://en.wikipedia.org/wiki/Linezolidhttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Interferon-%CE%B3http://en.wikipedia.org/wiki/Interferon-%CE%B3http://en.wikipedia.org/wiki/Interferon-%CE%B3http://en.wikipedia.org/wiki/Interferon-%CE%B3http://en.wikipedia.org/wiki/Thioridazinehttp://en.wikipedia.org/wiki/Thioridazinehttp://en.wikipedia.org/wiki/Aminosalicylic_acidhttp://en.wikipedia.org/wiki/Macrolidehttp://en.wikipedia.org/wiki/Clarithromycinhttp://en.wikipedia.org/wiki/Linezolidhttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Interferon-%CE%B3http://en.wikipedia.org/wiki/Thioridazine


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Response to treatment must be obtained b$ repeated sputum cultures (monthl$

if possible)# Treatment for MDR-TB must be gi%en for a minimum of '< months

and cannot be stopped until the patient has been culture-negati%e for a

minimum of nine months# It is not unusual for patients "ith MDR-TB to be on

treatment for t"o $ears or more#

atients "ith MDR-TB should be isolated in negati%e-pressure rooms! if

possible# atients "ith MDR-TB should not be accommodated on the same "ard as

immunosuppressed patients (HI, infected patients! or patients on

immunosuppressi%e drugs)# 7areful monitoring of compliance "ith treatment is

crucial to the management of MDR-TB (and some ph$sicians insist on

hospitalisation if onl$ for this reason)# 6ome ph$sicians "ill insist that

these patients are isolated until their sputum is smear negati%e! or e%en

culture negati%e ("hich ma$ ta&e man$ months! or e%en $ears)# eeping these

patients in hospital for "ee&s (or months) on end ma$ be a practical or

ph$sical impossibilit$ and the final decision depends on the clinical

>udgement of the ph$sician treating that patient# The attending ph$sician

should ma&e full use of therapeutic drug monitoring (particularl$ of the

aminogl$cosides) both to monitor compliance and to a%oid to;ic effects#

6ome supplements ma$ be useful as ad>uncts in the treatment of tuberculosis!

but the for the purposes of counting drugs for MDR-TB! the$ count as zero (if

$ou alread$ ha%e four drugs in the regimen! it ma$ be beneficial to add

arginine or %itamin D or both! but $ou still need another drug to ma&e fi%e)#

arginine (peanuts are a good source)

,itamin D

The drugs listed belo" ha%e been used in desperation and it is uncertain

"hether the$ are effecti%e at all# The$ are used "hen it is not possible to

find fi%e drugs from the list abo%e#

imipenem

co-amo;icla%

clofazimine

prochlorperazine

metronidazole
http://en.wikipedia.org/wiki/Argininehttp://en.wikipedia.org/wiki/Argininehttp://en.wikipedia.org/wiki/Vitamin_Dhttp://en.wikipedia.org/wiki/Vitamin_Dhttp://en.wikipedia.org/wiki/Imipenemhttp://en.wikipedia.org/wiki/Imipenemhttp://en.wikipedia.org/wiki/Co-amoxiclavhttp://en.wikipedia.org/wiki/Co-amoxiclavhttp://en.wikipedia.org/wiki/Clofaziminehttp://en.wikipedia.org/wiki/Clofaziminehttp://en.wikipedia.org/wiki/Prochlorperazinehttp://en.wikipedia.org/wiki/Prochlorperazinehttp://en.wikipedia.org/wiki/Metronidazolehttp://en.wikipedia.org/wiki/Metronidazolehttp://en.wikipedia.org/wiki/Argininehttp://en.wikipedia.org/wiki/Vitamin_Dhttp://en.wikipedia.org/wiki/Imipenemhttp://en.wikipedia.org/wiki/Co-amoxiclavhttp://en.wikipedia.org/wiki/Clofaziminehttp://en.wikipedia.org/wiki/Prochlorperazinehttp://en.wikipedia.org/wiki/Metronidazole


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The follo"ing drugs are e;perimental compounds that are not commerciall$

a%ailable! but "hich ma$ be obtained from the manufacturer as part of a

clinical trial or on a compassionate basis# Their efficac$ and safet$ are

un&no"n*

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of DR-TB ma$ coincide "ith the institution of ne" policies to promote drug

compliance! such as DT6#

ne in three people in the "orld is infected "ith TB bacteria# nl$ "hen the

bacteria become acti%e do people become ill "ith TB# Bacteria become acti%e

as a result of an$thing that can reduce the persons immunit$! such as HI,!

ad%ancing age! or some medical conditions# TB can usuall$ be treated "ith a

course of four standard! or first-line! anti-TB drugs# If these drugs are

misused or mismanaged! multidrug-resistant TB (MDR-TB) can de%elop# MDR-TB

ta&es longer to treat "ith second-line drugs! "hich are more e;pensi%e and

ha%e more side-effects# DR-TB can de%elop "hen these second-line drugs are

also misused or mismanaged and therefore also become ineffecti%e#

DR-TB raises concerns of a future TB epidemic "ith restricted treatment

options! and >eopardizes the ma>or gains made in TB control and progress on

reducing TB deaths among people li%ing "ith HI,./ID6# It is therefore %ital

that TB control is managed properl$ and ne" tools de%eloped to pre%ent! treat

and diagnose the disease#

The true scale of DR-TB is un&no"n as man$ countries lac& the necessar$

e@uipment and capacit$ to accuratel$ diagnose it# It is estimated ho"e%er

that there are around ?! cases per $ear# /s of June 4

ha%e confirmed cases of DR-TB#

Definition

DR-TB is defined as TB that has de%eloped resistance to at

least rifampicinand isoniazid(resistance to these first line anti-TB drugs

defines Multi-drug-resistant tuberculosis! or MDR-TB)! as "ell as to an$

member of the @uinolonefamil$ and at least one of the follo"ing second-line

anti-TB in>ectable drugs* &anam$cin! capreom$cin! or ami&acin# This

definition of DR-TB "as agreed b$ the =Hlobal Tas& Eorce on DR-TB inctober 49# The earlier definition of DR-TB as MDR-TB that is also

resistant to three or more of the si; classes of second-line drugs! is no

longer used! but ma$ be referred to in older publications#

Transmission

8i&e other forms of TB! DR-TB is spread through the air# =hen a person "ith

infectious TB coughs! sneezes! tal&s or spits! the$ propel TB germs! &no"n
http://en.wikipedia.org/wiki/Directly_observed_treatmenthttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Multi-drug-resistant_tuberculosishttp://en.wikipedia.org/wiki/MDR-TBhttp://en.wikipedia.org/wiki/Quinolonehttp://en.wikipedia.org/wiki/Kanamycinhttp://en.wikipedia.org/wiki/Capreomycinhttp://en.wikipedia.org/wiki/Amikacinhttp://en.wikipedia.org/wiki/World_Health_Organizationhttp://en.wikipedia.org/wiki/Directly_observed_treatmenthttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Multi-drug-resistant_tuberculosishttp://en.wikipedia.org/wiki/MDR-TBhttp://en.wikipedia.org/wiki/Quinolonehttp://en.wikipedia.org/wiki/Kanamycinhttp://en.wikipedia.org/wiki/Capreomycinhttp://en.wikipedia.org/wiki/Amikacinhttp://en.wikipedia.org/wiki/World_Health_Organization


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as bacilli! into the air# / person needs onl$ to inhale a small number of

these to be infected# eople infected "ith TB bacilli "ill not necessaril$

become sic& "ith the disease# The immune s$stem"alls off the TB bacilli

"hich! protected b$ a thic& "a;$ coat! can lie dormant for $ears#

The spread of TB bacteria depends on factors such as the number and

concentration of infectious people in an$ one place together "ith the

presence of people "ith a higher ris& of being infected (such as those

"ith HI,./ID6)# The ris& of becoming infected increases the longer the time

that a pre%iousl$ uninfected person spends in the same room as the infectious

case# The ris& of spread increases "here there is a high concentration of TB

bacteria! such as can occur in closed en%ironments li&e o%ercro"ded houses!

hospitals or prisons# The ris& "ill be further increased if %entilation is

poor# The ris& of spread "ill be reduced and e%entuall$ eliminated if

infectious patients recei%e proper treatment#

Diagnosis

6uccessful diagnosis of DR-TB depends on the patients access to

@ualit$ health-care ser%ices# If TB bacteria are found in the sputum! the

diagnosis of TB can be made in a da$ or t"o! but this finding "ill not be

able to distinguish bet"een drug-susceptible and drug-resistant TB# To

e%aluate drug susceptibilit$! the bacteria need to be culti%ated and tested

in a suitable laborator$# Einal diagnosis in this "a$ for TB! and especiall$

for DR-TB! ma$ ta&e from 9 to '9 "ee&s#F1GTo reduce the time needed for

diagnosis! ne" tools for rapid TB diagnosis are urgentl$ needed#

Treatment

The principles of treatment for MDR-TB and for DR-TB are the same# Treatment

re@uires e;tensi%e chemotherap$for up to t"o $ears# 6econd-line drugs are

more to;ic than the standard anti-TB regimen and can cause a range of serious

side-effects including hepatitis! depression and hallucinations# atients are

often hospitalised for long periods! in isolation# In addition! second-line

drugs are e;tremel$ e;pensi%e compared "ith the cost of drugs for standard TB

treatment#
http://en.wikipedia.org/wiki/Bacteria#Morphologyhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/HIV/AIDShttp://en.wikipedia.org/wiki/Sputumhttp://en.wikipedia.org/wiki/Extensively_drug-resistant_tuberculosis#cite_note-6http://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Bacteria#Morphologyhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/HIV/AIDShttp://en.wikipedia.org/wiki/Sputumhttp://en.wikipedia.org/wiki/Extensively_drug-resistant_tuberculosis#cite_note-6http://en.wikipedia.org/wiki/Chemotherapy


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DR-TB is associated "ith a much higher mortalit$ rate than MDR-TB! because

of a reduced number of effecti%e treatment options# Despite earl$ fears that

this strain of TB "as untreatable! recent studies ha%e sho"n that DR-TB can

be treated through the use of aggressi%e regimens# / stud$ in the Toms&

oblast of Russia! reported that '? out of 40 (?


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most common and most infectious form of TB# The effect of B7 against DR-TB

"ould therefore li&el$ be %er$ limited# Ne" %accines are urgentl$ needed! and

=H and members of the 6top TB artnership are acti%el$ "or&ing on ne"

%accines#

DR-TB and HI,./ID6

TB is one of the most common infections in people li%ing "ith HI,./ID6# In

places "here DR-TB is most common! people li%ing "ith HI, are at greater

ris& of becoming infected "ith DR-TB! compared "ith people "ithout HI,!

because of their "ea&ened immunit$# If there are a lot of HI,-infected people

in these places! then there "ill be a strong lin& bet"een DR-TB and HI,#

Eortunatel$! in most of the places "ith high rates of HI,! DR-TB is not $et"idespread# Eor this reason! the ma>orit$ of people "ith HI, "ho de%elop TB

"ill ha%e drug-susceptible or ordinar$ TB! and can be treated "ith standard

first-line anti-TB drugs# Eor those "ith HI, infection! treatment "ith

antiretro%iral drugs "ill li&el$ reduce the ris& of becoming infected "ith

DR-TB! >ust as it does "ith ordinar$ TB#

/ research stud$ titled TB re%alence 6ur%e$ and +%aluation of /ccess to TB

7are in HI,-Infected and 5ninfected TB atients in /sembo and em! =estern

en$a! sa$s that HI,./ID6 is fueling large increases in TB incidence in

/frica! and a large proportion of cases are not diagnosed#

6$mptoms

6$mptoms of DR-TB are no different from ordinar$ or drug-susceptible TB* a

cough "ith thic&! cloud$ mucus (or sputum)! sometimes "ith blood! for more

than 4 "ee&sA fe%er! chills! and night s"eatsA fatigue and muscle "ea&nessA

"eight lossA and in some cases shortness of breath and chest pain# / person

"ith these s$mptoms does not necessaril$ ha%e DR-TB! but the$ should see

doctor for a chec&-up# TB patients "hose s$mptoms do not impro%e after a fe"

"ee&s of treatment "ith TB and are ta&ing treatment should inform their

clinician or nurse#
http://en.wikipedia.org/wiki/HIVhttp://en.wikipedia.org/wiki/AIDShttp://en.wikipedia.org/wiki/HIVhttp://en.wikipedia.org/wiki/AIDS

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35861722 Multi Drug Resistant Tuberculosis