Antibiotics 2018
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Antibiotics 2018


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their	use	does	carry	risks.	They	can	adversely	affect	patients	by
eliciting	allergic	reactions,	causing	direct	toxicity,	or	altering	the	normal
bacterial	flora,	leading	to	superinfections	with	other	organisms.	Antibiotic	use
is	the	primary	driving	force	in	the	development	of	antibiotic	resistance,	which
can	affect	not	only	the	treated	patients	but	other	patients	by	transmission	of
resistant	organisms.	It	is	important	to	keep	in	mind	all	of	these	potential
adverse	consequences	when	using	antibiotics.
Antibiotic	Allergy
Through	formation	of	complexes	with	human	proteins,	antibiotics	can	trigger
immunologic	reactions.	These	reactions	may	manifest	immediately	(such	as
anaphylaxis	or	hives)	or	be	delayed	(rashes,	serum	sickness,	drug	fever).
Because	of	their	highly	reactive	chemical	structure	and	frequent	use,	beta-
lactam	drugs	are	the	most	notorious	group	of	drugs	for	causing	allergic
reactions.	It	is	difficult	to	determine	how	likely	it	is	that	a	patient	with	an
allergy	to	a	particular	antibiotic	agent	will	have	a	similar	reaction	to	another
agent	within	that	class.	While	some	(highly	debated)	estimates	of	the	degree
of	cross-reactivity	are	available	for	beta-lactam	drugs,	estimates	for	cross-
reactivity	within	other	classes	(e.g.,	between	fluoroquinolones)	are	essentially
nonexistent.	Because	labeling	a	patient	with	an	allergy	to	a	particular
antibiotic	can	limit	future	treatment	options	severely	and	possibly	lead	to	the
selection	of	inferior	drugs,	every	effort	should	be	made	to	clarify	the	exact
nature	of	a	reported	allergy.
Antibiotic	Toxicities
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Antibiotic	Toxicities
Despite	being	designed	to	affect	the	physiology	of	microorganisms	rather
than	humans,	antibiotics	can	have	direct	toxic	effects	on	patients.	In	some
cases,	this	is	an	extension	of	their	mechanism	of	action	when	selectivity	for
microorganisms	is	not	perfect.	For	example,	the	hematologic	adverse	effects
of	trimethoprim	stem	from	its	inhibition	of	folate	metabolism	in	humans,	which
is	also	its	mechanism	of	antibiotic	effect.	In	other	cases,	antibiotics	display
toxicity	through	unintended	physiologic	interactions,	such	as	when
vancomycin	stimulates	histamine	release,	leading	to	its	characteristic	red
man	syndrome.	Some	of	these	toxicities	may	be	dose	related	and	toxicity
often	occurs	when	doses	are	not	adjusted	properly	for	renal	dysfunction	and
thus	accumulate	to	a	toxic	level.	Proper	dosage	adjustment	can	reduce	the
risk	of	dose-related	toxicities.
Superinfection
The	human	body	is	colonized	by	a	variety	of	bacteria	and	fungi.	These
organisms	are	generally	considered	commensals,	in	that	they	benefit	from
living	on	or	in	the	body	but	do	not	cause	harm	(within	their	ecologic	niches).
Colonization	with	commensal	organisms	can	be	beneficial,	given	that	they
compete	with	and	crowd	out	more	pathogenic	organisms.	They	may	even
have	a	role	in	the	prevention	of	other	human	diseases.	When	administration
of	antibiotics	kills	off	the	commensal	flora,	pathogenic	drug-resistant
organisms	can	flourish	because	of	the	absence	of	competition.	This	is
considered	a	superinfection	(i.e.,	an	infection	on	top	of	another	infection).	For
example,	administration	of	antibiotics	can	lead	to	the	overgrowth	of	the
gastrointestinal	(GI)	pathogen	Clostridium	difficile,	which	is	clinically
resistant	to	most	antibiotics.	C.	difficile	can	cause	diarrhea	and	life-
threatening	bowel	inflammation.	Similarly,	administration	of	broad-spectrum
antibacterial	drugs	can	select	for	the	overgrowth	of	fungi,	most	commonly
yeasts	of	the	genus	Candida.	Disseminated	Candida	infections	carry	a	high
risk	of	death.	To	reduce	the	risk	of	the	impact	of	antibiotics	on	the
commensal	flora,	and	thus	the	likelihood	of	superinfection,	antibiotics	should
be	administered	only	to	patients	with	proven	or	probable	infections,	using	the
most	narrow-spectrum	agents	appropriate	to	the	infection	for	the	shortest
effective	duration.
Antibiotic	Resistance
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Antibiotic	Resistance
Thousands	of	studies	have	documented	the	relationship	between	antibiotic
use	and	resistance,	both	at	a	patient	level	(if	you	receive	an	antibiotic,	you
are	more	likely	to	become	infected	with	a	drug-resistant	organism)	and	a
society	level	(the	more	antibiotics	a	hospital,	region,	or	country	uses,	the
greater	the	antibiotic	resistance).	The	development	of	antibiotic	resistance
leads	to	a	vicious	spiral	where	resistance	necessitates	the	development	of
broader-spectrum	antibiotics,	leading	to	evolution	of	bacteria	resistant	to
those	new	antibiotics,	requiring	ever	broader-spectrum	drugs,	and	so	on.
This	is	particularly	problematic	because	antibiotic	development	has	slowed
down	greatly.	Although	we	can	see	clearly	the	broad	relationship	between
antibiotic	use	and	resistance,	many	of	the	details	of	this	relationship	are	not
clear.	Why	do	some	bacteria	develop	resistance	rapidly	and	others	never
develop	resistance?	What	is	the	proper	duration	of	treatment	to	maximize	the
chance	of	cure	and	minimize	the	risk	of	resistance?
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6:	Antibiotic	Resistance
Though	it	may	seem	that	the	antibiotic	era	was	introduced	in	the	1930s	with
the	sulfonamides	and	penicillin,	it	had	actually	started	millions	of	years	earlier.
Alexander	Fleming	only	discovered	one	of	the	weapons	of	a	war	going	on
underfoot\u2014literally,	under	our	feet.	In	the	soil	and	elsewhere,	microbes	are
locked	in	life-and-death	battles	for	dominance	over	each	other	for	the	limited
resources	they	have	access	to.	Among	their	weapons	are	antibiotics.
Causes	of	Antibiotic	Resistance
The	basic	cause	of	antibiotic	resistance	is	simple:	antibiotic	use.	Some
organisms	are	notorious	for	an	intrinsic	ability	to	express	multiple	types	of
resistance,	such	as	Acinetobacter	baumannii	or	Pseudomonas	aeruginosa.
Others	have	been	generally	treatable	for	many	years	and	are	only	recently
becoming	highly	drug-resistant	through	acquiring	new	resistance	elements,
such	as	Klebsiella	pneumoniae.	And	some	have	remained	highly	susceptible
to	\u201cold\u201d	antibiotics	ever	since	their	introduction,	such	as	Streptococcus
pyogenes	and	penicillin.
Where	Does	Antibiotic	Resistance	Come	From?
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Where	Does	Antibiotic	Resistance	Come	From?
In	any	species	of	bacteria,	antibiotic	resistance	needs	to	have	a	point	of
origin.	Resistance	can	emerge	in	the	organism	of	interest	through	random
mutations	to	the	antibiotic\u2019s	target	or	other	key	elements.	However,	it	is	more
common	that	a	given	species	of	bacteria	acquired	the	genes,	which	enable	a
mechanism	of	resistance,	from	another	species	of	bacteria	that	already	had
it	through	the	transfer	of	mobile	genetic	elements.	Bacteria	are	promiscuous
little	organisms	and	they	are	not	picky\u2014they	often	swap	genes	not	only
between	their	own	species,	but	different	species	and	even	genera.	There	are
several	ways	that	genes	are	transmitted	between	bacteria,	but	the	most
important	is	by	the	transmission	of	plasmids	via	conjugation.	Plasmids	are
loops	of	DNA	that	may	contain	multiple	genes	in	them	that	encode	for	various
processes	(including	antibiotic	resistance),	and	they	are	highly	portable.
Since	plasmids	can	contain	multiple	genes,	they	can	encode	for	multiple
types	of	resistance	that	are	not	related,	such	as	resistance	to	cephalosporins
via	the	production	of	a	beta-lactamase	and	resistance	to	fluoroquinolone	due
to	an	efflux	pump.	With	one	act	of	gene	swapping,	a	multiply-resistant
bacterial	strain	is	born.
Mechanisms	of	Antibiotic	Resistance
The	multiple	mechanisms	by	which	resistance	occurs	can	be	confusing,	but
here	we	are	going	to\u2014wait	for	it\u2014simplify	it	into	four	basic	mechanisms,
which	are	outlined	in	Figure	6\u20131.
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Figure	6\u20131	Mechanisms	of	Antibiotic	Resistance
Decreased	permeability	prevents	the	antibiotic	from	penetrating	the	bacterial
cell,	decreasing	the	intracellular	concentration	of	the	antibiotic.