Antimycobacterials First-line drugs

2009 Mark Tuttle

Name Target
Organism
Mechanism Side effects Absortion !"cretion #esistance
ANT$%
T&'!#(&)OS
$S
-Mycobacterium
tubercolosis
-Other
Mycobacteria
- -Hepatotoxicity is a major concern
-Need to rule out hepatitis viruses and liver toxins
(including alcohol)
- - -Common i only
one drug is used
#ifamin
*#$+,
-'road%
sectrum
-!hould be used
in a coc"tail
#henever
possible in H$%-
associated
Mycobacterium
tuberculosis
inection
-&ctive against dividing and
semi-dormant
Mycobacterium
tuberculosis
-'acterio($-A)
-$nhibits 'N&-dependent
(N& polymerase in
bacterial cells by binding its
beta-subunit) prevents
transcription
-.eatoto"icity almost never seen #hen used
alone but *+,- ris" #hen used #ith $NH and .+.-
ris" #ith other
-/ruritis (itching) /0- rash in 12-
-/ermanent orange staining3 small amount
enters tears) saliva) and urine #ith staining o
contacts / clothing
-Se0ere immunologic reactions3 (are cause o
acute renal ailure) thrombocytopenia) hemolytic
anemia) thrombotic thrombocytopenia purpura
(445)+
6ach in 78+.- patients
-9ood CN!
penetration
since it is
lipophilic
-6xcreted in liver0bile
-/120 is induced by drug so
enhanced clearance over
time
- Oral contraceptives)
methadone) NN(4is)
#ararin
-:pregulates cytosolic drug-
metaboli;ing en;ymes
including glcuronosyl
transferase that
metaboli;es <idovudine
(&<4) = Chloramphenicol
-Can be used #ith 6aviren;
(NN(4$) most N(4$ NO4
&<4
-
$sonia3id
*$N.,
-T'%secific
-Mycobacterium
tuberculosis
$ncluded in all
regimens
-Can be used as
monotherapy or
55'-positive
persons in
absence o
ongoing disease
(latent)
-$nhibits mycolic acid synth
-'acterio($-A) against
actively-replicating bacteria
-Not very eective against
slo#ly-replicating
-.eatoto"icity (lo# ris" 78+*- i used alone but
ris" increases #ith age)
$ncrease i underlying disease but can be used i
stable
-+atal heatitis i in presence o clinical hepatitis
-/eriheral neuroathy- increase ris" in
nutritional deiciency) H$%) renal ailure)
pregnancy) breast eeding
-6specially in slo#-acetylators (psych disturbances
too)
-Many adverse reactions are reduced by daily
yrido"ine *4itamine '5,
-)uus%like syndrome3 *8- patients develop
&N&) .- develop lupus (stop drug)
-.yersensiti0ity) monoamine
(histamine0tyramine) poisoning ater cheeses and
beers generali;ed lushing
-9ood CN!
penetration
-6xcreted in urine as
unchanged and acetyl orm
-Need
catalase3peroxidas
e to transorm it to
active orm
-$ catalse gene
absent (katG) or
transport gene
mutated (inhA)
resistant
/yra3inami
de */6A,
-T'%secific -'acterioSTAT$( on
dormant 0 semi-dormant in
>phages or in acidic casous
oci
-7(idal on active-replicating
-NO acti0ity at
alkaline8neutral .
-Converted to pyra;inoic
acid by deaminase #hich
inhibits atty acid synthase
-The most heatoto"ic) #orst at high dose
.- ris" in absence o preexisting liver disease
-/olyarthralgia (non-gouty) ?8- o patients @
aspirin (x
-Asymtomatic hyeruricemia9 transient rash
Common but not problematic
-/hotosensiti0e dermatitis
Occasional
- -$nactivated by the liver
-6xcreted by the "idney
Monitoring needed in renal
disease
-M. bovis is resistant
since its deaminase
has single-base
mutation
!thambutol
*!M',
-T' : Some
others
-'acterioSTAT$(
-$nhibits
arabinosyltransferase
(needed or cell #all0outer
-NOT .!/ATOTO;$( @ sae to use #0liver
disease
-#etinobulbar neurotis #orst at high dose or
renal dis
- -Cleared by "idneys (dose
needs adjustment or renal
d)
-
layer arabinogalactan) -'ecrease in visual acuity
-'ecrease in red-green color discrimination
(Not advised in children #here vis testing cant be
done unless $NH0($F resistance is "no#n0li"ely)
-(utaneous reactions @ reAuire discontinuation in
8+B-
Antimycobacterials !econd-line drugs
2009 Mark Tuttle
Name Target Organism Mechanism Side effects Absortion !"cretion #esistance
Stretomyc
in
(&minoglycocid
e)
-Formerly used as a 4C
drug) no# 4C is resistant
-Mainly #or"s on
extracellular organisms
-&cts #ell in neutral and
al"aline environments
can be used #ith 5<&
(only #or"s at acid pH)
- -NOT .!/ATO;$(
-Neurotoxicity (especially CN %$$$)
-Ototoxic
-Circumoral parasthesias
-Not used in pregnancy to avoid etal
hearing loss
-Dess eective at
penetrating
inlammatory oci so
does not sterili;e
inections
- -Fairly common
Other !econd-line 'rugs3 (:sed #hen drug resistance is a problem)
4hiaceta;one p-aminosalicylic acid (5&C&) 6thionamide and prothionamide Capreomycin %iomycin
Cycloserine
FluorAuinolones (levoloxacin) moniloxacin) gatiloxacin) !treptomycin (&minoglycosides) &mi"acin Eanamycin
(&minoglycoside)
ANT$%)!/#OS< = Need multidrug therapy
-asone - -+olate inhibitor -$nflammatory reaction *!rythema
nodosum lerosum,
-Thalidomide (teratogenic) and
steroids
- - -
#ifamin - - - - - -
(lofa3imine - - - - - -
Others - - - - - -
ANT$% MYCOBACTERIUM AVIUM = in &$'!) Fe# anti-Mycobacterium tuberculosis drugs #or"
-&;ythromicin/ 6MC (/ Ciproloxacin) - - - - -
-Clarithromycin / 6MC / Ciproloxacin - - - - -
Nucleic Acid Synthesis $nhibitors
F*88G Mar" 4uttle
Name Target Organism Mechanism Side effects Absortion !"cretion
S&)+ONAM$-!S
-!ome stimulate
Rickettsia
gro#th
-(esistance is
becoming
#idespread
including E. coli
-9ram / and 9ram @
-Nocardia
-Chlamydia
-!ome proto;oa
-5oor activity against anaerobes
/yrimethamine%sulfonamide=
-4oxoplasmosis
-Malaria
-5yrimethamine is a dihydroolate reductase
inhibitor
!ulomamide alone is NO4 recommended in any
case #here systemic disease is being treated
(including uncomplicated :4$s)
-(educed toxicity
-H days 4M5-!MI is eAuivalent to B-.8 !MI
-. day 4M5-!MI - H days !MI
-Folate synth
inhibitor
-!tructural
analogue o
p-
aminoben;oic
acid (5&C&)
-$nhibits
dihydropteroa
te synthetase
in early step
o 4HF acid
synthesis
-
-&llergies
-5hotosensitivity
-Nausea and diarrhea
-Fever and s"in rashes) exoliative
dermatitis
-!teven-Johnson syndrome (7.-) @
&utoimmune #0 rashes
-Crystalluria) hematuria (drugs precipitate at
acid pH)
-Hematopoietic reactions
- Hemolytic anemia or aplastic anemia
- 9ranulocytopenia) thrombocytopenia)
leu"emoid (KCC L)
- $n late pregnancy
- Eernicterus (brain damage rom
jaundice)
- 5roblems in toxoplasmosis
treatment
Oral absorbable3
-has various hal-lie
Oral non-absorbable3
-!ulasala;ine
(used or ulcerative colitis)
4opical3
-!odium !ulacetamine
(ophthalmic @ trachoma)
-!ilver suladia;ine
-%aries) usually
urine
T#$M!T.O/#$M Trimethorim%sulfametho"a3ole *TM/%SM6,
-5rophylaxis against pneumocystis pneumonia in
H$%
-H days or uncomplicated :4$ (Cystitis) typically
caused by E. Coli
-Salmonella, Shigella, E. Coli, ibro cholera, but
Auinolones are usually the irst choice
-Folate synth
inhibitor
-'ihydroolate
reductase
inhibitor
Occasional (4rimethoprim by itsel)
-Megaloblastic anemia
-9ranulocytopenia
-Deu"openia
-&lso has the typical side eects o
!ulomamides #hen used in combination
-More severe toxicity in elderly) especially
#hen less good renal unction and #hen
treatment periods are long
-9ood absorption orally
-Dipid solubility enhances its
distribution
( M sulamethoxa;ole)
including C!F
-4M5-!M< .3B ratio reaches
.3*8 in plasma
-(oncentrates in rostatic
and 0aginal fluids
-Mainly in urine
>&$NO)ON!S - -$nterere #ith
'N& gyrase
and 'N&
topoisomeras
e $%
-Nausea @ vomiting @diarrhea
-!ome cause >%T inter0al rolongation
-May damage gro#ing cartilage (not
recommended or ppl under .N especially
in long-term use)
-6x+ 'onOt use or 5seudomonas in CF
-4endinitis @ rare in adults) main M B8
:sually &chilles) can lead to rupture
Oral administration
-:pta"e $ n habited up to N8-
by coadministration #ith &l
and Mg-containing antacids
-!ome inhibition by Ca and Fe
$% administration
-%ariable
+luoro?uinolo
ne
'erivative o
nalidixic acid
(#as or :4$)
-6xcellent against 9ram neg
-Dess activity against 9ram pos
-(4$s3 may need in combination #ith C-lactam or
severe pneumonia or !seudomonas
-9astrointestinal inection3 Shigella, (resistance)
Salmonella, E. coli, cholera, Campylobacter
-CacterioC$'&
D
-Have post-
antibiotic
eect
9enitourinary systems
-C-lactam resistant gonococcus (. dose)
-Cystitis (#here 4M5-!MI not useul)
-Complicated ascending :4$
-5rostatitis (drugs concentrate in prostate)
-5elvic $nlammatory 'isease (5$')
-%ariable
-:rine3
Oxaloxacin)
levoloxacin
(iroflo"acin -Cetter against 9ram pos - - -B8- urine
(& luoroAuinolone) -6specially or C. anthracis -B8- Diver orms
inactive
glucuronides
M!T#ON$-A6O)
!
*+lagil,
-Obligate anaerobic bacteria (Clostridium di""icille,
Gardnerella vaginallis)
-NO4 Actinomyces, !roprionibacteria
-&naerobic proto;oa (4richomonas) 9iardia)
6ntamoeba)
-5roduces ree
radicals #hich
ragment 'N&
-(eduction o
NO* group
-&ctivated by being reduced by erredoxin
-&erobic bact donOt have lo# enough redox
potential
-No net charge at phys pH
-6nters cells #ell) good
bioavail
-Can be given orally
-%ariable