Antibiotics 2018
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Antibiotics 2018

DisciplinaFarmacologia Farmacêutica503 materiais4.088 seguidores
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a	tissue	is	not	the	only	determinant	of	effectiveness	in	that
tissue.	For	example,	ceftriaxone	is	a	very	highly	protein-bound	drug,	and	5%
or	less	enters	into	the	CNS	in	patients	with	meningitis.	However,	large	doses
(2	g	twice	daily	in	adults)	of	ceftriaxone	can	be	given	safely	to	adults,
resulting	in	high	serum	levels	(peak	levels	of	around	200	mg/L).	In	addition,
the	minimum	inhibitory	concentration	(MIC)	to	ceftriaxone	for	organisms
usually	causing	meningitis	is	typically	very	low	(1	mg/L	or	less);	thus,	a
concentration	far	in	excess	of	the	organism\u2019s	MIC	can	be	obtained	(200	mg/L
×	5%	=	10	mg/L).	Also,	the	concentration\u2013time	curves	in	many	tissues	are
different	than	they	are	in	the	bloodstream\u2014more	like	rolling	hills	than	peaks
and	valleys	(think	Appalachians	versus	the	Rockies).
Patient	characteristics	may	also	significantly	influence	drug	distribution.	In
order	for	a	drug	to	distribute	to	a	tissue,	there	must	be	adequate	blood	flow
to	that	tissue.	Conditions	that	reduce	blood	flow	to	tissues,	either	locally
(e.g.,	peripheral	vascular	disease)	or	systemically	(septic	shock),	can	reduce
antibiotic	concentrations	at	the	site	of	infection.	Patients	with	severe
infections	can	develop	abscesses	or	areas	of	dead	and	devitalized	tissue;
distribution	of	antibiotics	into	these	\u201cprotected\u201d	sites	of	infection	can	be
significantly	impaired.	These	patients	are	perfect	setups	for	treatment	failure
and	development	of	resistance	and	highlight	the	importance	of	appropriate
surgical	management	of	infections	along	with	antibiotic	treatment.	Given	the
growing	problem	of	obesity,	another	important	consideration	is	the	extent
which	drugs	distribute	into	adipose	tissue.	Depending	on	the	characteristics
of	the	drug,	it	is	possible	to	underdose	patients	who	are	morbidly	obese	(if
the	drug	distributes	extensively	into	adipose	tissue	and	doses	for	standard
weights	are	used)	or	overdose	them	(if	a	higher	dose	is	used	because	of
obesity,	but	the	drug	does	not	distribute	well	into	excess	adipose	tissue).
Thus,	you	may	see	recommendations	for	antibiotic	dosing	based	on	total	or
actual	body	weight,	ideal	body	weight	(an	estimate	of	the	patient\u2019s	body
weight	without	their	excess	adipose	tissue),	or	adjusted	body	weight	(a	value
between	the	ideal	and	total	body	weight).	This	is	an	area	that	is	relatively
Finally,	it	is	important	to	note	that	with	few	exceptions,	microbiological
susceptibility	testing	does	not	account	for	distribution	and	is	based	on
achievable	bloodstream	concentrations.	For	example,	the	microbiology	lab
may	determine	that	an	organism	with	an	MIC	of	4	mg/L	is	considered
susceptible	to	a	drug	that	achieves	a	concentration	of	8	mg/L	in	the
bloodstream,	but	it	may	only	achieve	a	concentration	of	1	mg/L	in
cerebrospinal	fluid.	Thus,	that	drug	is	likely	to	work	for	a	bloodstream
infection	caused	by	the	organism,	but	would	fail	for	meningitis	where
cerebrospinal	fluid	concentrations	are	important.	Thus,	distribution	is	a	key
consideration	when	choosing	antibiotics.
Many	antibiotics	are	excreted	from	the	body,	either	in	the	urine	or	feces,	in
the	same	form	as	they	were	administered.	In	fact,	shortly	after	penicillin	was
developed	and	supplies	were	scarce,	doctors	used	to	collect	the	urine	of
patients	who	received	penicillin	and	recrystallize	the	drug	for	use	in	other
patients!	When	a	drug	is	excreted	unchanged,	it	can	reach	very	high
concentrations	in	the	area	in	which	it	is	eliminated,	making	it	potentially	more
effective	for	infections	in	those	systems	than	would	be	anticipated	based	on
blood	concentrations.	For	example,	the	concentrations	of	nitrofurantoin
achieved	in	the	blood	and	tissues	are	generally	inadequate	to	inhibit	bacterial
growth.	However,	it	is	removed	from	the	bloodstream	by	the	kidneys	and
accumulates	in	the	bladder	until	its,	ahem,	final	clearance.	The	concentrations
achieved	in	the	bladder	are	manyfold	higher	than	those	in	the	bloodstream,
making	nitrofurantoin	an	effective	drug	for	treatment	of	bladder
When	the	body	does	not	inactivate	the	drug,	an	important	consideration	is	to
appropriately	reduce	the	administered	dose	of	the	drug	if	there	is	damage	to
the	organ	responsible	for	excreting	the	drug.	The	most	common	example	of
this	for	antibiotics	is	the	need	to	reduce	the	doses	of	most	beta-lactams	for
patients	with	kidney	dysfunction	to	avoid	accumulation	of	toxic	levels	of	the
drug.	Practitioners	also	need	to	be	vigilant	to	increase	doses	if	patients	have
improving	renal	function	or	treatment	failure	may	occur.
Other	drugs	may	be	extensively	transformed	by	the	body	prior	to	their
excretion.	These	antibiotics	that	undergo	extensive	metabolism	are
considered	to	be	substrates	of	drug-metabolizing	enzymes.	They	have	the
potential	to	be	subject	to	clinically	important	drug	interactions,	as	other	drugs
may	interfere	with	the	enzymes	that	break	the	drugs	down.	Moreover,	certain
antibiotics	have	the	potential	to	influence	the	metabolism	of	other	drugs,
either	through	inhibition	of	those	enzymes	(leading	to	a	decrease	in
metabolism	of	the	other	drug)	or	induction	(leading	to	an	increase	in
metabolism	of	the	other	drug).	A	list	of	antibiotics	with	the	greatest	likelihood
of	clinically	significant	metabolic	drug	interactions	is	in	Table	3\u20133,	organized
by	whether	the	drug	is	a	substrate,	an	inhibitor,	or	an	inducer	(and	note	that
drugs	may	be	in	more	than	one	category).	Note	that	the	several	antibiotic
classes	are	particularly	prevalent:	macrolides,	azole	antifungals,
antituberculosis	drugs,	and	antiretrovirals	account	for	most	of	the	antibiotics
with	significant	drug	interactions.	Complex	drug	interactions	can	occur	with
these	drugs:	for	example,	the	antiretroviral	drug	etravirine	is	simultaneously	a
substrate,	an	inhibitor,	and	an	inducer	of	drug-metabolizing	enzymes!
TABLE	3\u20133	Examples	of	Antibiotics	with	Significant	Metabolic	Drug
Substrates Inhibitors Inducers
4:	Antibiotic	Pharmacodynamics
The	term	antibiotic	pharmacodynamics	refers	to	the	manner	in	which
antibiotics	interact	with	their	target	organisms	to	exert	their	effects:	Does	the
antibiotic	kill	the	organism	or	just	prevent	its	growth?	Is	it	better	to	give	a	high
dose	of	antibiotics	all	at	once	or	to	achieve	lower	concentrations	for	a	longer
time?	Clinicians	increasingly	recognize	such	considerations	as	important	in
maximizing	the	success	of	therapy,	especially	for	difficult-to-treat	infections
and	in	immunocompromised	patients.
Susceptibility	Testing
Typically,	one	judges	the	susceptibility	of	a	particular	organism	to	an
antibiotic	based	on	the	minimum	inhibitory	concentration	(MIC)	for	the
organism\u2013antibiotic	combination.	Classically,	the	microbiology	laboratory
determines	the	MIC	by	combining	a	standard	concentration	of	the	organism
that	the	patient	has	grown	with	increasing	concentrations	of	the	antibiotic.
Historically	this	was	done	in	test	tubes	(Figure	4\u20131),	but	today	it	is	done
more	commonly	on	microdilution	plates	or	with	automated	systems.	The
mixture	is	incubated	for	about	a	day,	and	the	laboratory	technician	examines
the	tubes	or	plates	(with	the	naked	eye	or	with	a	computer)	for	signs	of
cloudiness,	indicating	growth	of	the	organism.	The	mixture	with	the	lowest
concentration	of	antibiotic	where	there	is	no	visible	growth	is	deemed	to	be
the	MIC.	For	each	organism\u2013antibiotic	pair,	there	is	a	particular	cutoff	MIC
that	defines	susceptibility.	This	particular	MIC	is	called	the	breakpoint.	Table