Antibiotics 2018
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Antibiotics 2018


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and	have	excellent	activity	against	Candida,	but	they
all	suffer	from	the	same	pharmacokinetic	setback:	lack	of	an	oral	formulation.
They	have	considerably	fewer	drug	interactions	than	azoles,	are	safer	than
polyenes,	and	have	great	activity	against	fluconazole-resistant	yeasts.
Mechanism	of	Action
Echinocandins	inhibit	beta-1,3-D-glucan	synthase,	the	enzyme	responsible	for
the	production	of	beta-1,3-D-glucan,	a	vital	component	of	the	cell	wall	of
many	fungi.	They	are	only	active	against	fungi	that	are	dependent	this	type	of
glucan.
Spectrum
Good:	Candida	albicans,	Candida	glabrata,	Candida	lusitaniae,	Candida
parapsilosis,	Candida	tropicalis,	Candida	krusei,	Aspergillus	species
Moderate:	Candida	parapsilosis,	some	dimorphic	fungi,	Mucorales	(in
combination	with	amphotericin	B)
Poor:	most	non-Aspergillus	molds,	Cryptococcus	neoformans
Adverse	Effects
Echinocandins	have	an	excellent	safety	profile.	They	can	cause	mild
histamine-mediated	infusion-related	reactions,	but	these	are	not	common	and
can	be	ameliorated	by	slowing	the	infusion	rate.	Hepatotoxicity	is	also
possible	with	any	of	these	agents,	but	this	is	not	common.
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Important	Facts
Differences	among	the	echinocandins	are	minor	and	mostly
pharmacokinetic.	Caspofungin	and	micafungin	are	eliminated	hepatically
by	noncytochrome	P450	metabolism,	while	anidulafungin	degrades	in	the
plasma	and	avoids	hepatic	metabolism.	Despite	this	unique	method	of
elimination,	it	is	not	completely	devoid	of	hepatotoxicity.
Echinocandins	have	excellent	fungicidal	activity	against	Candida,	but
against	Aspergillus	species	they	exhibit	activity	that	is	neither	classically
cidal	nor	static.	Instead,	they	cause	aberrant,	nonfunctional	hyphae	to	be
formed	by	the	actively	growing	mold.
The	echinocandins	are	only	modestly	active	against	molds,	but	do	appear
to	substantially	enhance	the	effects	of	other	antifungals	against	these
pathogens.	A	randomized	controlled	trial	of	voriconazole	with	or	without
anidulafungin	in	invasive	aspergillosis	showed	a	trend	toward	reduced
mortality	among	patients	receiving	combination	therapy	(the	difference
was	not	statistically	significant\u2014p	=	0.07\u2014but	given	the	low	toxicity	of
echinocandins	many	clinicians	refuse	to	submit	to	the	tyranny	of	the	p-
value	and	advocate	for	the	use	of	this	combination	therapy).	The
echinocandins	may	also	enhance	the	efficacy	of	liposomal	amphotericin	B
against	Mucorales	infections,	based	on	in	vitro	and	limited	clinical	data.
Though	drug	interactions	with	the	echinocandins	are	minor,	you	should	be
aware	of	some	of	them,	particularly	with	caspofungin	and	micafungin.	Be
careful	when	you	use	them	with	the	immunosuppressants	cyclosporine
(caspofungin)	and	sirolimus	(micafungin).
What	They\u2019re	Good	For
Echinocandins	are	drugs	of	choice	for	invasive	candidiasis,	particularly	in
patients	who	are	clinically	unstable	or	if	there	is	a	risk	the	infection	is	caused
by	an	azole-resistant	species.	They	are	also	useful	in	the	treatment	of
invasive	aspergillosis	but	do	not	have	the	level	of	supporting	data	that
voriconazole	and	the	polyenes	do	for	this	indication.	All	of	them	are	used	for
esophageal	candidiasis,	and	some	are	used	in	prophylaxis	or	empiric	therapy
of	fungal	infections	in	neutropenic	patients.	Some	clinicians	will	add	an
echinocandin	to	voriconazole	(for	Aspergillus	infections)	or	an	amphotericin	B
formulation	(versus	Mucorales)	in	an	attempt	to	increase	likelihood	of	cure	for
these	infections. www.allmedicalbooks.com
Don\u2019t	Forget!
Echinocandins	are	great	drugs	for	invasive	candidiasis,	but	they	are	not
cheap	and	IV	therapy	can	be	inconvenient.	After	beginning	empiric	therapy
with	an	echinocandin,	consider	transitioning	your	patient	to	fluconazole	if	he
or	she	has	a	susceptible	strain	of	Candida	and	no	contraindication	to
fluconazole.
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PART	5:	Antiviral	Drugs
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33:	Antiviral	Drugs
Introduction	to	Antiviral	Drugs
The	term	virus	has	interesting	meanings	in	popular	culture:	it	is	commonly
used	to	describe	something	that	has	or	can	spread	quickly	from	person	to
person,	such	as	a	computer	virus	or	a	\u201cviral\u201d	video,	a	video	that	gains	quick
popularity	through	Internet	or	e-mail	sharing.	This	usage	represents	a	basic
understanding	of	the	high	transmissibility	of	many	respiratory	viruses,	such	as
influenza	and	the	rhinoviruses	that	cause	the	common	cold.	However,	many
less-understood	viruses,	particularly	those	that	cause	chronic	disease,	can
be	confusing.
The	world	of	viruses	is	very	different	from	that	of	prokaryotes	and
eukaryotes.	Viruses	are	dependent	on	cells	to	replicate	and	cannot
perpetuate	without	them.	They	are	considerably	smaller	than	eukaryotes	and
even	much	smaller	than	most	prokaryotes,	though	they	vary	widely	in	size
(see	Figure	1\u20132).	They	are	relatively	simple	organisms	compared	with
prokaryotes	or	eukaryotes,	but	they	outnumber	all	other	life	forms	on	earth.
Scientists	have	debated	for	many	years	about	whether	viruses	are	life	forms
or	not,	and	no	clear	consensus	yet	exists.	The	understanding	of	how	they
interact	with	and	shape	the	existence	of	living	cells,	however,	has	increased
greatly	since	they	were	described	by	Louis	Pasteur	in	the	late	nineteenth
century.
An	in-depth	discussion	of	the	structure	of	viruses	is	beyond	the	scope	of	this
text,	but	a	basic	understanding	of	viruses	will	help	you	understand	the	actions
of	antiviral	drugs.	Viruses	are	highly	diverse,	though	nearly	all	of	them	share
a	few	common	characteristics.	Many	are	covered	by	a	viral	envelope	as	their
outmost	layer,	composed	of	elements	of	the	host	cell	membrane,
endoplasmic	reticulum,	or	nuclear	envelope.	This	layer	covers	the	capsid,	a
shell	composed	of	identical	building	blocks	of	capsomeres.	The	capsid
protects	the	viral	nucleic	acid,	which	is	either	DNA	or	RNA	but	not	both	(as	in
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cells).	The	DNA	or	RNA	can	be	either	single-	or	double-stranded.	Finally,
many	viruses	contain	enzymes	that	catalyze	reactions	that	lead	to	their
replication	or	cell	entry.	Viruses	cannot	synthesize	their	own	components	to
replicate\u2014they	are	dependent	on	host	cellular	processes	for	all	synthetic
functions.	Individual	complete	particles	of	virus	are	termed	virions.
The	specific	steps	of	the	viral	life	cycle	differ	from	virus	to	virus,	but	they
follow	the	same	basic	pathway.	Viruses	spread	from	host	to	host	through
various	means,	some	through	direct	inhalation,	some	through	direct	fluid
exchange,	some	through	vectors	such	as	mosquitoes.	Once	a	virus	reaches
its	target	cell,	it	has	to	penetrate	the	cell	membrane.	Specific	receptors	on
the	cell	and	viral	surfaces	often	facilitate	this	process.	The	virus	then	uncoats
and	releases	its	genetic	information	from	the	capsule	into	the	host	cell.	The
host	cell	reads	the	genetic	material	and	begins	to	translate	it	into	viral
proteins.	How	exactly	this	proceeds	depends	on	the	form	in	which	the	genetic
material	exists	in	the	virus.	In	some	cases,	the	genetic	material	is	encoded
as	RNA.	For	some	RNA	viruses,	host	cell	ribosomes	translate	the	RNA	into
proteins.	In	the	group	of	viruses	known	as	retroviruses,	the	RNA	genetic
material	is	first	translated	into	DNA	(via	an	enzyme	known	as	reverse
transcriptase)	before	integrating	into	the	host	genome.	For	these	viruses	or
those	viruses	whose	genome	is	already	encoded	as	DNA,	transcription	into
messenger	RNA	occurs,	followed	by	translation	into	protein.	Once	the	pieces
of	the	puzzle	are	built,	the	viral	enzymes	assemble	them	into	complete	virions
and	they	are	finally	released	from	the	cell.	The	available	antiviral	drugs	are
aimed	at	various	steps	in	this	cycle.	Some	are	aimed	at	specific	receptors
against	specific	viruses	(such	as	influenza),	and	some	are	aimed	at	more
general	steps	to	attack	multiple	viruses.
The	pharmacotherapy	of	viral	infections	is	different	from	that	of	bacterial
infections.