Antibiotics 2018
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Antibiotics 2018


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4\u20131	provides	examples	of	how	breakpoints	differ	for	various
organism/pathogen	combinations	and	even	based	on	the	site	of	infection.
Note	that	just	because	an	antibiotic	has	the	lowest	MIC	for	a	pathogen	it
does	not	mean	it	is	the	best	choice\u2014different	antibiotics	achieve	different
concentrations	in	the	body	in	different	places.	Thus,	antibiotic	MICs	for	a
single	organism	generally	should	not	be	compared	across	different	drugs	in
selecting	therapy.
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Figure	4\u20131	Susceptibility	Testing	of	Antibiotics
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TABLE	4\u20131	Examples	of	Antibiotic	Susceptibility	Breakpoints
Organism	Antibiotics Susceptible
(Breakpoint)
Susceptible,
Dose-
Dependent
Intermediate Resistant
Escherichia	Coli
Ampicillin \u2264	8	mg/L \u2014 16	mg/L \u2265	32	mg/L
Cefepime \u2264	2	mg/L 4\u20138	mg/L \u2014 \u226516	mg/L
Levofloxacin \u2264	2	mg/L \u2014 4	mg/L \u2265	8	mg/L
Trimethoprim/sulfamethoxazole \u2264	2/38	mg/L \u2014 \u2014 \u2265	4/76
mg/L
Streptococcus	pneumoniae
Ampicillin \u2014 \u2014 \u2014 \u2014
Cefepime	(meningitis)
(Nonmeningeal)
\u2264	0.5	mg/L \u2014 1	mg/L \u22652	mg/L
\u2264	1	mg/L \u2014 2	mg/L \u2265	4	mg/L
Levofloxacin \u2264	2	mg/L \u2014 4	mg/L \u2265	8	mg/L
Trimethoprim/sulfamethoxazole \u2264	0.5/9.5	mg/L \u2014 1\u20132/19\u201338
mg/L
\u2265	4/76
mg/L
MIC	values	are	often	misinterpreted	by	clinicians	who	are	trying	to	choose
the	best	therapy	for	their	patients	but	may	inadvertently	ignore
pharmacokinetic	and	pharmacodynamic	differences	between	agents.	For
example,	in	Table	4\u20131,	note	that	the	breakpoint	for	levofloxacin	against
Escherichia	coli	is	2	mg/L	and	for	ampicillin	8	mg/L.	So	if	an	isolate	of	E.	coli
in	the	bloodstream	of	a	patient	has	an	MIC	of	1	mg/L	to	levofloxacin	but	2
mg/L	to	ampicillin,	it	does	not	mean	that	levofloxacin	is	a	better	choice	for
that	patient.	Levofloxacin	is	a	concentration-dependent	drug	that	is	typically
dosed	in	amounts	of	500\u2013750	mg	daily.	Ampicillin	is	a	time-dependent	drug
that	is	typically	dosed	as	1\u20132	g	every	4\u20136	hours.	The	much	higher
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concentrations	of	ampicillin	achieved	in	the	body	(due	to	higher	doses)	mean
that	organisms	with	a	higher	MIC	to	ampicillin	are	still	susceptible	to	it.	In
other	words,	the	two	numbers	are	not	directly	comparable.	In	fact,	if	the	MIC
was	8	mg/L	to	both	drugs,	the	organism	would	be	considered	resistant	to
levofloxacin	and	susceptible	to	ampicillin.
Also	note	in	Table	4\u20131	the	categories	of	\u201csusceptible,\u201d	\u201csusceptible,	dose-
dependent,\u201d	\u201cintermediate,\u201d	and	\u201cresistant.\u201d	\u201cSusceptible\u201d	and	\u201cresistant\u201d	are
self-explanatory,	but	what	do	the	other	terms	mean?	\u201cIntermediate\u201d	is	a
poorly	defined	range	where	successful	therapy	may	be	possible	in	some
circumstances,	such	as	when	the	drug	is	eliminated	renally	(for	a	urinary	tract
infection)	or	if	higher	dosing	is	given.	It	is	more	of	a	grey	area	made	to
separate	the	two	more	definitive	terms	than	a	scientifically	derived	definition.
\u201cSusceptible,	dose-dependent\u201d	is	just	what	it	sounds	like\u2014the	organism	may
be	susceptible	to	high	doses	of	the	drug,	but	is	likely	to	be	resistant	to	low
doses.	This	was	created	because	many	of	these	drugs	are	used	in	various
doses,	and	a	low	dose	of	cefepime	like	1	g	IV	q12h	may	be	enough	to	treat
an	E.	coli	infection	with	an	MIC	of	2	mg/L,	but	a	dose	like	2	g	IV	q12h	may
be	needed	if	the	MIC	is	4	mg/L.	These	may	all	sound	like	hard-and-fast
rules,	but	they	are	really	probabilities	of	how	most	patients	will	fare	when
faced	with	a	certain	bug\u2013drug	combination	for	their	infections.	Some	will
succeed	even	with	high	MICs,	and	some	will	fail	even	with	low	ones.
Finally,	be	aware	that	other	methods	of	susceptibility	testing	exist,	including
disk	diffusion	and	E-tests,	but	that	broth	dilution	methods	are	generally
considered	the	gold	standard.
Static	Versus	Cidal
At	the	MIC	the	antibiotic	is	inhibiting	growth,	but	it	may	or	may	not	actually	be
killing	the	organism.	Antibiotics	that	inhibit	growth	of	the	organism	without
killing	it	are	termed	bacteriostatic	(or	fungistatic	in	the	case	of	fungi).	If
antibiotics	are	removed,	the	organisms	can	begin	growing	again.	However,
bacteriostatic	antibiotics	are	usually	successful	in	treating	infections	because
they	allow	the	patient\u2019s	immune	system	to	\u201ccatch	up\u201d	and	kill	off	the
organisms.	Other	antibiotics	are	considered	bactericidal;	their	action	kills	the
organisms	without	any	help	from	the	immune	system.www.allmedicalbooks.com
For	most	infections,	outcomes	using	appropriate	bacteriostatic	versus
bactericidal	drugs	are	similar;	however,	for	certain	infections	bactericidal
drugs	are	preferred.	Such	infections	include	endocarditis,	meningitis,
infections	in	neutropenic	patients,	and	possibly	osteomyelitis.	The	immune
system	may	not	be	as	effective	in	fighting	these	infections	because	of	the
anatomic	location	or	the	immunosuppression	of	the	patient.	Bactericidal
activity	is	determined	by	taking	a	sample	of	the	broth	at	various
concentrations	and	below	and	spreading	the	broth	on	agar	plates	(Figure	4\u2013
1).	The	bacterial	colonies	on	the	plates	are	counted,	and	the	concentration
corresponding	to	a	99.9%	reduction	(3-log)	in	the	original	bacterial	inoculum
is	considered	to	be	the	minimum	bactericidal	concentration	(MBC).	When	the
MBC	is	four	times	or	less	than	the	MIC,	the	drug	is	considered	to	be
bactericidal;	if	the	MBC/MIC	ratio	is	greater	than	four,	it	is	considered
bacteriostatic.	MIC	testing	is	standard	in	most	laboratories;	MBC	testing	is
more	difficult	and	is	not	commonly	done	in	clinical	practice.	Table	4\u20132	lists
drugs	and	indicates	whether	they	are	generally	considered	bacteriostatic	or
bactericidal;	however,	it	should	be	noted	that	this	activity	can	vary	based	on
the	pathogen	being	treated,	the	achievable	dose,	and	the	growth	phase	of
the	organism.
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TABLE	4\u20132	Antibiotic	Pharmacodynamic	Parameters
Antibiotic	Class Cidal	or	Static Predictive	PK/PD	Parameter
Penicillins
Cephalosporins
Carbapenems
Monobactams
Bactericidal Time	>	MIC
Vancomycin Bactericidal	(slowly) AUC/MIC
Fluoroquinolones
Aminoglycosides
Metronidazole
Daptomycin
Bactericidal Peak:	MIC
Macrolides
Tetracyclines
Linezolid
Bacteriostatic AUC/MIC
Pharmacokinetic/Pharmacodynamic
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Pharmacokinetic/Pharmacodynamic
Relationships
Besides	differing	in	whether	they	kill	microorganisms	or	merely	inhibit	their
growth,	antibiotics	also	differ	in	how	they	manifest	their	effects	over	time.
Careful	studies	have	revealed	that	for	certain	antibiotics,	activity	against
microorganisms	correlates	with	the	duration	of	time	that	the	concentration	of
the	drug	remains	above	the	MIC	(time-dependent	activity).	For	other
antibiotics,	antibacterial	activity	correlates	not	with	the	time	above	the	MIC
but	with	the	ratio	of	the	peak	concentration	of	the	drug	to	the	MIC
(concentration-dependent	or	time-independent	activity).	For	some	antibiotics,
the	best	predictor	of	activity	is	the	ratio	of	the	area	under	the	concentration\u2013
time	curve	(AUC)	to	the	MIC.	Figure	4\u20132	illustrates	these
pharmacokinetic/pharmacodynamic	(PK/PD)	parameters	schematically,	and
Table	4\u20132	shows	which	parameter	is	most	predictive	of	efficacy	for	antibiotic
classes.	The	practical	implications	of	these	findings	are	in	the	design	of
antibiotic	dosing	schedules:	aminoglycosides	are	now	frequently	given	as	a
single	large	dose	daily	to	leverage	the	concentration-dependent	activity,	while
some	clinicians	are	administering	beta-lactam	drugs	such	as	ceftazidime	as
continuous	or	prolonged	infusions	because	of	their	time-dependent	activity.
As	target	values	for	these	parameters	that	predict	efficacy	are	found,	there
may	be	an	increase	in	the	individualization	of	dosing	of	antibiotics	to	achieve
these	target	values.
Figure	4\u20132	Pharmacokinetic/Pharmacodynamic	Relationships
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5:	Adverse	Consequences	of
Antibiotic	Use
Although	antibiotics	are	undoubtedly	one	of	the	most	beneficial	discoveries	of
science,