Antibiotics 2018
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Antibiotics 2018

DisciplinaFarmacologia Farmacêutica520 materiais4.133 seguidores
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Arabinogalactan	and
peptidoglycan	are	polysaccharide	components	of	the	cell	wall,	but	the
peptidoglycan	is	not	accessible	to	beta-lactam	antibiotics,	and	they	are
poorly	active.	Figure	23\u20131	shows	the	basic	structure	of	mycobacteria.
Figure	23\u20131	Mycobacterial	Cell	Wall
The	pharmacotherapy	of	mycobacterial	disease	is	complex.	Combinations	of
drugs	are	always	given	for	patients	with	active	disease	to	minimize	the
development	of	resistance	and	shorten	the	duration	of	therapy.	These
combinations	frequently	have	pharmacokinetic	drug	interactions	with	both
each	other	and	other	medications	that	the	patient	is	on	(in	part	because
immunocompromised	patients	are	particularly	vulnerable	to	mycobacterial
disease	and	they	tend	to	be	on	drugs	with	many	interactions).	Because
mycobacteria	grow	slowly,	standard	susceptibility	testing	takes	weeks
instead	of	days	to	perform,	so	empiric	regimens	are	often	given	for	extended
durations.	For	tuberculosis,	the	standard	of	care	for	patients	with	active
infections	is	to	start	with	a	four-drug	regimen,	so	compliance	and	careful
watching	for	drug	interactions	are	important.
First-line	drugs	for	tuberculosis	and	Mycobacterium	avium\u2013intracellulare
complex	(MAC)	are	discussed	in	this	section.	Many	second-line	drugs	are
available	for	tuberculosis;	however,	because	the	treatment	of	multidrug-
resistant	tuberculosis	(MDR-TB)	requires	the	management	of	an	infectious
diseases	specialist,	we	omit	them	from	this	text\u2014there	is	nothing	\u201csimplified\u201d
about	MDR-TB.	The	following	antimycobacterial	drugs	are	listed	in	the
antibacterial	chapters:	fluoroquinolones	(moxifloxacin	is	particularly	active),
macrolides,	and	aminoglycosides.	It	is	particularly	important	to	know	the
toxicities	of	the	first-line	agents	for	tuberculosis,	because	they	each	have	a
characteristic	one.	You	can	expect	questions	about	these	characteristics	to
pop-up	on	a	lot	of	exams,	both	in	school	and	for	licensure.
24:	Rifamycins
Agents:	rifampin	(aka	rifampicin),	rifabutin,
rifapentine,	rifaximin	(not	used	for	mycobacterial
The	rifamycins	are	cornerstones	of	therapy	for	both	tuberculosis	and	MAC.
They	are	protein	synthesis	inhibitors	that	inhibit	transcription	of	DNA	to
bacterial	messenger	RNA.	Rifampin	(or	rifampicin,	as	it	is	known	in	European
literature)	is	one	of	the	two	most	important	drugs	in	tuberculosis
pharmacotherapy.	The	rifamycins	are	potent	inducers	of	the	cytochrome
P450	system,	and	patients	receiving	them	should	always	be	screened	for
drug	interactions.	In	addition	to	their	activity	against	mycobacteria,	rifamycins
are	active	against	many	\u201ctypical\u201d	bacteria	as	well	and	are	sometimes	added
to	other	therapies,	particularly	to	treat	difficult	MRSA	infections.
Mechanism	of	Action
Rifamycins	are	protein	synthesis	inhibitors	that	work	by	inhibiting	RNA
polymerase,	preventing	transcription	by	blocking	the	production	of
messenger	RNA.	This	separates	them	from	other	protein	synthesis	inhibitors,
which	inhibit	translation.
Good:	most	mycobacteria
Moderate:	Staphylococcus,	Acinetobacter,	Enterobacteriaceae
Poor:	\u201ctypical\u201d	bacteria	as	monotherapy,	some	very	rare	mycobacteria
Adverse	Effects
Adverse	Effects
Rifamycins	are	generally	well-tolerated	drugs	that	are	most	notorious	for
their	potent	CYP450-inducing	effects.	Their	potent	induction	of	metabolism
can	lead	to	subtherapeutic	concentrations	of	other	drugs	that	can	manifest
with	devastating	clinical	consequences,	such	as	loss	of	seizure	control
(anticonvulsants)	or	organ	rejection	(antirejection	agents).	Rifampin
characteristically	colors	secretions	(urine,	tears,	etc.)	orange-red	and	can
actually	stain	contact	lenses,	which	should	not	be	worn	during	rifampin
therapy.	Otherwise,	this	effect	is	nonpermanent	and	not	harmful,	which
patients	appreciate	knowing.	Rifamycins	can	also	cause	hepatotoxicity.	Other
side	effects	include	rash,	nausea,	vomiting,	and	hypersensitivity	(often	fever).
Important	Facts
Important	Facts
Rifampin	is	a	drug	of	choice	for	tuberculosis,	while	rifabutin	is	a	drug	of
choice	for	MAC,	although	both	drugs	have	activity	against	both
pathogens.	MAC	infections	are	most	common	in	patients	with	HIV,	who
are	often	taking	antiretroviral	therapy	that	is	metabolized	by	CYP450.
Because	rifabutin	has	somewhat	less-potent	CYP450-inducing	effects
than	rifampin,	it	is	more	commonly	used	in	MAC	infections	to	minimize	the
impact	of	drug	interactions	in	this	population.
Rifampin	(or	rifabutin)	is	one	of	the	two	most	important	drugs	in	the
treatment	of	tuberculosis	(the	other	being	isoniazid).	If	an	isolate	of
Mycobacterium	tuberculosis	is	rifampin-resistant,	then	the	likelihood	of
successful	pharmacotherapy	is	lower	and	more	complicated	regimens
must	be	used	for	a	longer	duration.
All	systemic	rifamycins	induce	CYP450	enzymes	and	can	induce	the
metabolism	of	drugs	through	other	hepatic	pathways	as	well.	Always
screen	for	drug	interactions	when	starting	a	rifamycin.
Rifabutin	induces	CYP450	metabolism	less	potently	than	rifampin	does,
but	it	is	still	a	potent	inducer	and	requires	careful	review	of	potential
consequences	of	its	interaction	on	a	patient\u2019s	drug	regimen.
Rifapentine	is	a	second-line	drug	that	is	given	once	weekly.	It	shares
susceptibility	with	rifampin	and	rifabutin,	meaning	that	if	an	isolate	is
resistant	to	one	drug,	it	is	resistant	to	all	of	them.	Recent	guidelines
recommend	it	in	combination	with	isoniazid	as	a	once-weekly	therapy	for
latent	tuberculosis.
Rifaximin	is	a	nonabsorbed	rifamycin	used	only	in	the	treatment	or
prevention	of	GI	conditions.	It	is	not	used	for	mycobacterial	diseases	and
is	listed	here	only	for	completeness.
Rifamycins	should	not	be	used	as	monotherapy	for	treatment	of	active
tuberculosis,	but	rifampin	can	be	used	as	monotherapy	to	treat	latent
tuberculosis	infection.
What	They\u2019re	Good	For
Treatment	of	active	tuberculosis	and	MAC,	in	combination	with	other	agents;
latent	tuberculosis;	and	selected	bacterial	infections	(most	notably	bacterial
infections	involving	prosthetic	material\u2014such	as	an	artificial	hip	or	heart	valve
\u2014in	combination	with	standard	antibacterials)
Don\u2019t	Forget!
Ensure	that	patients	are	informed	that	their	urine	and	other	secretions	may
turn	orange	or	red.	That\u2019s	a	surprise	that	most	people	don\u2019t	want	and	could
lead	to	completely	unnecessary	Emergency	Room	visits!
25:	Isoniazid
Agent:	isoniazid
Isoniazid	is	active	only	against	Mycobacterium	tuberculosis	and	the	related
Mycobacterium	kansasii,	but	it	is	one	of	the	two	most	important	drugs	in
tuberculosis	pharmacotherapy	(the	other	being	rifampin),	being	effective
against	both	actively	growing	and	dormant	mycobacteria.	It	is	used	in	the
treatment	of	both	active	and	latent	tuberculosis.
Mechanism	of	Action
Isoniazid	prevents	the	synthesis	of	mycolic	acids	in	the	cell	wall	by	inhibiting
enzymes	that	catalyze	their	production.
Active	only	against	M.	tuberculosis	and	M.	kansasii.
Adverse	Effects
Like	several	other	tuberculosis	medications,	hepatotoxicity	is	a	concern.
Many	patients	will	experience	asymptomatic	elevations	in	liver	transaminases
early	in	therapy.	In	most	cases,	these	will	resolve	on	their	own	and	the
patient	can	complete	treatment.	However,	if	the	enzyme	levels	are	many
times	the	upper	limit	of	normal	and/or	the	patient	experience	symptoms	of
hepatitis	(nausea,	abdominal	pain,	jaundice),	the	drug	needs	to	be	stopped	to
prevent	severe	liver	damage.	Isoniazid\u2019s	other	characteristic	adverse	reaction
is	peripheral	neuropathy.	This	can	be	prevented	by	administering	pyridoxine
(vitamin	B ),	which	is	recommended	for	patients	at	risk	for	developing
neuropathy	(e.g.,	diabetics,	pregnant	women,	alcohol	abusers).	Other
neurotoxicities	that	are	less