Antimicrobial agents Flashcards
penicillins share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics with______,_____,_____,____.______ All are β-lactam compounds, so named because of their four-membered lactam ring.
cephalosporins, monobactams carbapenems, β-lactamase inhibitors PCMC
All penicillins have the basic structure _______ is attached to a β-lactam ring (B) that carries a secondary amino group (RNH–). Substituents can be attached to the amino group
thiazolidine ring
.Structural integrity of the _______ is essential for the biologic activity penicillin compounds.
6-aminopenicillanic acid nucleus
Hydrolysis of the β-lactam ring by ________ yields penicilloic acid, which lacks antibacterial activity.
bacterial β-lactamases
PENICILLIN
Substituents of the________________ determine the essential pharmacologic and antibacterial properties of the resulting molecules. Penicillins can be assigned to one of three groups.
6-aminopenicillanic acid moiety
Within each of these groupsPenicillin are compounds that are relatively stable to gastric acid and suitable for oral administration. The side chains of some representatives of each group, with a few distinguishing characteristics.
eg, penicillin V, dicloxacillin, and amoxicillin
These have greatest activity against gram-positive organisms, gram-negative cocci, and non- β-lactamase producing anaerobes.
However, they have little activity gainst gram-negative rods, and they are susceptible to
hydrolysis by β-lactamases.
Penicillins (eg, penicillin G)—
These
penicillins are resistant to staphylococcal β-lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods.
Antistaphylococcal penicillins (eg, nafcillin
— These drugs retain the antibacterial spectrum of penicillin and have improved activity against gram-negative organisms. Like penicillin, however, they are relatively
suceptible to hydrolysis by β-lactamases.
Extended-spectrum penicillins (ampicillin and the
antipseudomonal penicillins)
What is the MOA of Penicillin?
inhibits the bacterial cell growth by inhibiting the cell wall sybthesis
What is the MOA of Beta lactam antibiotics?
Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis.
Note: Beta lactam antibiotics bind to PBP which interferes transpeptidation reaction, halting the peptidoglycan synthesis and the cell dies.
Beta lactam antibiotics kill bacteria only when they are_________, _______.
actively growing and synthesizing cell wall
What is the enzyme that removes the terminal alanine in the process of forming cross-link which gives the cell wall its structural rigidity with nearby perptide?
PBP ( penicillin binding protein)
Resistance to penicillins and other B-lactams is due to one of four gen mechanisms:
- inactivation of antibiotic by B-lactamase
- modification of target PBPs
- impaired penetration of drug to target PBPs
- efflux
What is the most common resistance in the four general mechanism of it?
Beta lactamase production
Give examples of identified bacteria that produce B-lactamase that has relatively narrow in substrate specificity, preferring penicillin to cephalosporins?
Staphylococcus aureus
H. influenza
Eschericia coli
What are other B-lactamases?
Pseudomonas aeruginosa
Enterobacter sp.
What B-lactamase hydrolyze both the penicillins and cephalosporins?
ESBLs ( Extended spesctrum B-lactamase )
These are highly resistant to hydrolysis by penicillinases
and cephalosporinases, but they are hydrolyzed by
metallo-β lactamase and carbapenemases.
Carbapenems
__________ are the basis of methicillin resistance in
- *staphylococci** and of **penicillin resistance in pneumococci and
enterococci. **
Altered target PBPs
Note: These resistant organisms produce PBPs that have
low affinity for binding β-lactam antibiotics, and consequently,
they are not inhibited except at relatively high, often clinically
unachievable, drug concentrations.
Resistance due to impaired penetration of antibiotic to target
PBPs occurs only in ________ .
gram-negative species
Explanation: Because of their impermeable
outer cell wall membrane, which is absent in gram-positive
bacteria. Beta-lactam antibiotics cross the outer membrane and
enter gram-negative organisms via outer membrane protein
channels called porins. Absence of the proper channel or downregulation
of its production can greatly impair drug entry into the
cell.
Poor penetration alone is usually not sufficient to confer
resistance because enough antibiotic eventually enters the cell to
inhibit growth. However, this barrier can become important in the
presence of a β-lactamase, even a relatively inactive one, as long as
it can hydrolyze drug faster than it enters the cell.
Gram-negative
organisms also may produce an efflux pump, which consists of
cytoplasmic and periplasmic protein components that efficiently
transport some β-lactam antibiotics from the periplasm back
across the outer membrane.
These resistant organisms produce PBPs that have
low affinity for binding β-lactam antibiotics, and consequently,
they are not inhibited except at relatively high, often clinically
unachievable, drug concentrations.
Staphylococci
Enterococci
Pneumococci
Absorption of orally administered drug differs greatly for different
penicillins, depending in part on their _______ and ______.
acid stability
protein
binding.
Gastrointestinal absorption of ________ is erratic, so it is
not suitable for oral administration.
nafcillin
___________,__________ & ________ are acid-stable and relatively well absorbed, producing
serum concentrations in the range of 4–8 mcg/mL after a 500-mg
oral dose.
Dicloxacillin, ampicillin, and
amoxicillin
Absorption of_________ is impaired by food, and the drugs should be administered
at least 1–2 hours before or after a meal.
most oral penicillins (amoxicillin being
an exception)
Absorption of most oral penicillins except ___________ is impaired by food, and the drugs should be administered
at least 1–2 hours before or after a meal.
amoxicillin
Intravenous administration of _________ is preferred to the
intramuscular route because of irritation and local pain from intramuscular
injection of large doses.
penicillin G
_____________ generally
achieve lower free-drug concentrations in serum than less proteinbound
penicillins (eg, penicillin G or ampicillin). Protein binding
becomes clinically relevant when the protein-bound percentage is
approximately 95% or more.
Highly protein-bound penicillins (eg, nafcillin)
Areas where penicillin penetration is poor?
Eyes
Prostate
CNS
________ is primarily cleared by biliary excretion.
Nafcillin
________,_______ & _______are eliminated by both the kidney and
biliary excretion; no dosage adjustment is required for these drugs
in renal failure.
Oxacillin,
dicloxacillin, and cloxacillin
clearance of _______ is less efficient in the newborn, doses adjusted for weight alone result in higher systemic
concentrations for longer periods than in the adult.
penicillins
Blood
levels of all penicillins can be raised by simultaneous administration
of ________, 0.5 g (10 mg/kg in children) every 6 hours
orally, which impairs renal tubular secretion of weak acids such as
β-lactam compounds.
probenecid
_______ is a drug of choice for infections caused by streptococci,
meningococci, some enterococci, penicillin-susceptible pneumococci,
non-β-lactamase-producing staphylococci, Treponema
pallidum and certain other spirochetes, Clostridium species,
Actinomyces and certain other gram-positive rods, and non-β-
lactamase-producing gram-negative anaerobic organisms
Penicillin G
_______, the oral form of penicillin, is indicated only in
minor infections because of its relatively poor bioavailability, the
need for dosing four times a day, and its narrow antibacterial
spectrum. Amoxicillin (see below) is often used instead.
Penicillin V
_________ and________ for intramuscular
injection yield low but prolonged drug levels.
Benzathine penicillin and procaine penicillin G
A single intramuscular
injection of benzathine penicillin, 1.2 million units, is
effective treatment for ____________;
given intramuscularly once every 3–4 weeks, it prevents reinfection.
β-hemolytic streptococcal pharyngitis
Benzathine penicillin G, 2.4 million units intramuscularly
once a week for 1–3 weeks, is effective in the treatment of ________.
syphilis
___________, formerly a work horse for treating uncomplicated
pneumococcal pneumonia or gonorrhea, is rarely used
now because many strains are penicillin-resistant.
Procaine penicillin G
Because clearance of penicillins is less efficient in the____________, doses adjusted for weight alone result in higher systemic
concentrations for longer periods than in the adult
newborn
These semisynthetic_______ are indicated for infection by
β-lactamase-producing staphylococci, although penicillin susceptible
strains of streptococci and pneumococci are also susceptible
to these agents. However, for infections caused by methicillin-susceptible
and penicillin-resistant strains of staphylococci, these are considered
the drugs of choice.
penicillins ( Methycillin, Isoxazolyl penicillins, nafcillin)
An ________________,
0.25–0.5 g orally every 4–6 hours (15–25 mg/kg/d for children),
is suitable for treatment of mild to moderate localized staphylococcal
infections.All are relativelyacid-stable and have reasonable bioavailability.
However, food interferes with absorption, and the drugs
should be administered 1 hour before or after meals.
isoxazolyl penicillin such as oxacillin, cloxacillin, or dicloxacillin
For serious systemic staphylococcal infections, _______, 8–12 g/d, is given by intermittent intravenous infusion
of 1–2 g every 4–6 hours (50–100 mg/kg/d for children).
oxacillin or
nafcillin
These drugs have greater activity than penicillin against gramnegative
bacteria because of their enhanced ability to penetrate the
gram-negative outer membrane. Like penicillin G, they are inactivated
by many β lactamases.
Extended-Spectrum Penicillins (Aminopenicillins,
Carboxypenicillins, and Ureidopenicillins)
The aminopenicillins, ampicillin and amoxicillin, have nearly
identical spectrums of activity, but _____ is better absorbed
orally.
amoxicillin
_______
is given orally to treat urinary tract infections, sinusitis, otitis, and
lower respiratory tract infections.
Amoxacillin
_________& ______ are
the most active of the oral β-lactam antibiotics against pneumococci
with elevated MICs to penicillin and are the preferred
β-lactam antibiotics for treating infections suspected to be caused
by these strains.
Ampicillin and amoxicillin
___________ is effective for
shigellosis. Its use to treat uncomplicated salmonella gastroenteritis
is controversial because it may prolong the carrier state.
Ampicillin (but not amoxicillin)
________, at dosages of 4–12 g/d intravenously, is useful for
treating serious infections caused by susceptible organisms, including
anaerobes, enterococci, L monocytogenes , and β-lactamase negative
strains of gram-negative cocci and bacilli such as E coli , and
Salmonella sp.
Ampicillin
________ is not active against Klebsiella sp, Enterobacter
sp, P aeruginosa , Citrobacter sp, Serratia marcescens , indole-positive
proteus species,and othergram-negative aerobes that are
commonly encountered in hospital-acquired infections.
Ampicillin
_______ the first antipseudomonal carboxypenicillin, is
no longer used in the USA, as there are more active, better tolerated
alternatives.
Carbenicillin,
A carboxypenicillin with activity similar to that
of carbenicillin is ______. It is less active than ampicillin against
enterococci.
ticarcillin
The ureidopenicillins, ________, _______ &_______, are also active against selected gram-negative bacilli,
such as Klebsiella pneumoniae. Although supportive clinical data
are lacking for superiority of combination therapy over singledrug
therapy, because of the propensity of P aeruginosa to develop
resistance during treatment, an antipseudomonal penicillin is frequently
used in combination with an aminoglycoside or fluoroquinolone
for pseudomonal infections outside the urinary tract.
piperacillin, mezlocillin, and
azlocillin
Ampicillin, amoxicillin, ticarcillin, and piperacillin are also
available in combination with one of several β-lactamase inhibitors:
_______________
NOTE :The addition
of a β-lactamase inhibitor extends the activity of these penicillins
to include β-lactamase-producing strains of S aureus as well
as some β-lactamase-producing gram-negative bacteria (see Beta-
Lactamase Inhibitors).
clavulanic acid, sulbactam, or tazobactam.
The penicillins are generally well tolerated, and unfortunately, this
encourages their misuse and inappropriate use. Most of the serious
adverse effects are due to _______.
hypersensitivity.
All ______ are crosssensitizing
and cross-reacting
penicillins
The antigenic determinants are
degradation products of penicillins, particularly ______ and ______ to host protein.
penicilloic acid
and products of alkaline hydrolysis bound t
Allergic reactions to penicillins include:
anaphylactic shock (very rare—0.05% of recipients);
serum sickness-type reactions (now rare—urticaria,
fever,
joint swelling,
angioneurotic edema,
intense pruritus, and
respiratory compromise occurring 7–12 days after exposure); and a
variety of skin rashes.
Oral lesions, fever, interstitial nephritis (an
autoimmune reaction to a penicillin-protein complex), eosinophilia,
hemolytic anemia and other hematologic disturbances, and
vasculitis may also occur.
Most patients allergic to penicillins can
be treated with alternative drugs. However, if necessary (eg, treatment
of enterococcal endocarditis or neurosyphilis in a patient
with serious penicillin allergy), _______ can be accomplished
with__________
.
desensitization
gradually increasing doses of penicillin
In patients with renal failure, penicillin in high doses can cause
______.
seizures
Nafcillin is associated with _____;
oxacillin can cause ______; and
methicillin causes ________
neutropenia
hepatitis
interstitial nephritis (and is no longer used for this reason).
Large doses of penicillins given
orally may lead to ________________.
gastrointestinal upset, particularly nausea,
vomiting, and diarrhea.
_______ has been associated with
pseudomembranous colitis.
Secondary infections such as vaginal candidiasis may occur
Ampicillin
________ & __________ can cause skin
rashes that are not allergic in nature. These rashes frequently occur
when these are inappropriately prescribed for a viral
illness.
aminopenicillins :Ampicillin and amoxicillin
________ are similar to penicillins, but more stable to many bacterial β lactamases and therefore have a broader spectrum of activity.
However, strains of E coli and Klebsiella sp expressing
extended-spectrum β lactamases that can hydrolyze most this are a growing clinical concern.
Cephalosporins
Cephalosporins are not
active against _______ and _________ .
enterococci and L monocytogenes .
The nucleus of the cephalosporins, __________
( Figure 43–6 ), bears a close resemblance to 6-aminopenicillanic
acid. The intrinsic antimicrobial activity of natural
cephalosporins is low,buttheattachment of various R 1 and R 2
groups has yielded hundreds of potent compounds of low toxicity.
Note: These can be classified into four major groups or generations,
depending mainly on the spectrum of antimicrobial
activity.
7-aminocephalosporanic acid
First-generation cephalosporins include________. .
cefazolin,
cefadroxil,
cephalexin
cephalothin
cephapirin
cephradine
These
drugs are very active against gram-positive cocci, such as pneumococci,
streptococci, and staphylococci.Traditional cephalosporins are
not active against methicillin-resistant strains of staphylococci; however,
new compounds have been developed that have activity against
methicillin-resistant strains (see below). E coli, K pneumoniae ,
and Proteus mirabilis are often sensitive, but activity against
P aeruginosa , indole-positive proteus species, Enterobacter sp,
S marcescens , Citrobacter sp, and Acinetobacter sp is poor. Anaerobic
cocci (eg, peptococci, peptostreptococci) are usually sensitive, but
Bacteroides fragilis is not
First Gene Cephalosporins
__________is the only first-generation parenteral cephalosporin still
in general use. After an intravenous infusion of 1 g, the peak level
of 90–120 mcg/mL. The usual intravenous dosage of
for adults is 0.5–2 g intravenously every 8 hours.
It can also be administered intramuscularly. Excretion is
via the kidney, and dose adjustments must be made for impaired
renal function.
Cefazolin
These oral drugs may be used for the treatment of urinary tract infections
and staphylococcal or streptococcal infections, including
cellulitis or soft tissue abscess. However,
should not be relied on in serious systemic infections.
First Gen Cephalosporins
_______penetrates well into most tissues. It is a drug of
choice for surgical prophylaxis. It may also be a choice in
infections for which it is the least toxic drug (eg, penicillinaseproducing
E coli or K pneumoniae ) and in individuals with
staphylococcal or streptococcal infections who have a history of
penicillin allergyother than immediate hypersensitivity.It
does not penetrate the central nervous system and cannot be used
to treat meningitis. This is an alternative to an antistaphylococcal
penicillin for patients who are allergic to penicillin.
Cefazolin
This is a heterogeneous group with marked individual differencesin activity, pharmacokinetics, and toxicity.
In general, they
are active against organisms inhibited by first-generation drugs,but in addition they have extended gram-negative coverage.
Klebsiella sp (including those resistant to cephalothin) are usually
sensitive.
SECOND GENERATION CEPHALOSPORIN
____________________ 2nd generation of cephalosporin that are active against H influenzae but not against serratia or
B fragilis .
Cefamandole, cefuroxime, cefonicid, ceforanide, and
cefaclor
These second generation of drugs are ,________________ are
active against B fragilis and some serratia strains but are less active
against H influenzae .
** cefoxitin, cefmetazole, and cefotetan**
___________________ can be given
orally. The usual dosage for adults is 10–15 mg/kg/d in two to
four divided doses; children should be given 20–40 mg/kg/d up to
Cefaclor, cefuroxime axetil, cefprozil, and loracarbef
Except for ______, Cefaclor, cefuroxime axetil, cefprozil, and loracarbef are
not predictably active against penicillin-non-susceptible pneumococci
and should be used cautiously, if at all, to treat suspected or
proved pneumococcal infections.
cefuroxime axetil
The oral _____________ are active against
β-lactamase-producing H influenzae or Moraxella catarrhalis and have
been primarily used to treat sinusitis, otitis, and lower respiratory tract
infections, in which these organisms have an important role.
Because
of their activity against anaerobes (including many B fragilis strains),
cefoxitin, cefotetan, or cefmetazole can be used to treat mixed anaerobic
infections such as peritonitis, diverticulitis, and pelvic inflammatory
disease.
second-generation cephalosporins
__________ is used to treat community-acquired
pneumonia because it is active against β-lactamase-producing
H influenzae or K pneumoniae and some penicillin-non-susceptible
pneumococci. Although it crosses the blood-brain barrier, it
is less effective in treatment of meningitis than ceftriaxone or cefotaxime
and should not be used.
Cefuroxime
these drugs have
expanded gram-negative coverage, and some are able to cross the
blood-brain barrier. These are active against
Citrobacter , S marcescens , and Providencia (although resistance can
emerge during treatment of infections caused by these species due to
selection of mutants that constitutively produce cephalosporinase).
They are also effective against β-lactamase-producing strains of
haemophilus and neisseria.
Third-generation drugs
Among the third gen drugs these are the ______________ and _________ are the
only two drugs with useful activity against P aeruginosa.
Ceftazidime and cefoperazone
Like the
second-generation drugs, ___________ are
hydrolyzed by constitutively produced AmpC β lactamase, and
they are not reliably active against Enterobacter species. Serratia ,
Providencia , and Citrobacteralso produce a chromosomally
encoded cephalosporinase that, when constitutively expressed, can
confer resistance to these.
third-generation cephalosporins
_____ and _____ are active against B fragilis .
Ceftizoxime
and moxalactam
These 3rd generation of cephalosporins are oral agents possessing
similar activity
Cefixime, cefdinir, ceftibuten, and cefpodoxime proxetil
Note: except that cefixime and ceftibuten are much
less active against pneumococci and have poor activity against
S aureus .
___________
penetrate body fluids and tissues well and, with the exception
of cefoperazone and all oral cephalosporins, achieve levels in
the cerebrospinal fluid sufficient to inhibit most susceptible
pathogens.
The half-lives of these drugs and the necessary dosing intervals
vary greatly:
Third-generation cephalosporins
The excretion of ________ ( 3rd gen) is
mainly through the biliary tract, and no dosage adjustment is
required in renal insufficiency. The others are excreted by the kidney
and therefore require dosage adjustment in renal insufficiency.
cefoperazone and ceftriaxone
__________ are used to treat a wide variety of
serious infections caused by organisms that are resistant to most
other drugs.
Strains expressing extended-spectrum β lactamases,
however, are not susceptible.
Third-generation cephalosporins
_________
should be avoided in treatment of enterobacter infections—even
if the clinical isolate appears susceptible in vitro—because of
emergence of resistance.
Third-generation cephalosporins
________ and _____ are approved
for treatment of meningitis, including meningitis caused by pneumococci,
meningococci, H influenzae , and susceptible enteric
gram-negative rods,but not by L monocytogenes.
These are the most active cephalosporins against penicillinnon-
susceptible strains of pneumococci and are recommended for
empirical therapy of serious infections that may be caused by these
strains.
Ceftriaxone and cefotaxime
Other potential indications
include empirical therapy of sepsis of unknown cause in
both the immunocompetent and the immunocompromised
patient and treatment of infections for which a cephalosporin is
the least toxic drug available. In neutropenic, febrile immunocompromised
patients, _________ is often used in combination with
other antibiotics.
ceftazidime
__________ is an example of a so-called fourth-generation
cephalosporin. It is more resistant to hydrolysis by chromosomal
β lactamases (eg, those produced by Enterobacter ). However, like
the third-generation compounds, it is hydrolyzed by extendedspectrum
β lactamases. Cefepime has good activity against
P aeruginosa, Enterobacteriaceae , S aureus , and S pneumoniae . It
is highly active against Haemophilus and Neisseria sp.
It penetrates
well into cerebrospinal fluid. It is cleared by the kidneys and has
a half-life of 2 hours, and its pharmacokinetic properties are very
similar to those of ceftazidime. Unlike ceftazidime, however,
it has good activity against most penicillin-non-susceptible
strains of streptococci, and it is useful in treatment of enterobacter
infections.
Cefepime
___________are drugs with a monocyclic β-lactam ring. Their spectrum of activity is limited to aerobic
gram-negative rods (including P aeruginosa ). Unlike other β-lactam
antibiotics, they have no activity against gram-positive bacteria or
anaerobes.
Monobactams
____________is the only monobactam available in the
USA. It has structural similarities to ceftazidime; hence, its gramnegative
spectrumis similar to that of thethird-generation cephalosporins.
It is stable to many β lactamases with the notable
exceptions being AmpC β lactamasesandextended-spectrum
β lactamases.
It penetrates well into the cerebrospinal fluid.
It is given intravenously every 8 hours in a dose of
1–2 g, providing peak serum levels of 100 mcg/mL. The half-life
is 1–2 hours and is greatly prolonged in renal failure.
Penicillin-allergic patients tolerate this without reaction.
Occasional skin rashes and elevations of serum aminotransferases
occur during administration of this but major toxicity is
uncommon. In patients with a history of penicillin anaphylaxis, this
may be used to treat serious infections such as pneumonia,
meningitis, and sepsis caused by susceptible gram-negative pathogens.
Aztreonam
These substances resemble β-lactam molecules , but
they have very weak antibacterial action. They are potent inhibitors
of many but not all bacterial β lactamases and can protect hydrolyzable
penicillins from inactivation by these enzymes.
BETA-LACTAMASE INHIBITORS
(CLAVULANIC ACID, SULBACTAM,
& TAZOBACTAM)
These are most active against Ambler class A β lactamases
(plasmid-encoded transposable element [TEM] β lactamases in
particular), such as those produced by staphylococci, H influenzae,
N gonorrhoeae, salmonella, shigella, E coli , and K pneumoniae.
They
are not good inhibitors of class C β lactamases, which typically are
chromosomally encoded and inducible, produced by Enterobacter sp,
Citrobacter sp, S marcescens , and P aeruginosa, butthey do inhibit
chromosomal β lactamases of B fragilis and M catarrhalis .
B-lactamase inhibitors
( Clavulinic acid, Sulbactam, Tazobactam)
Note: The three inhibitors differ slightly with respect to pharmacology,
stability, potency, and activity, but these differences usually
are of little therapeutic significance.
____________ are
available only in fixed combinations with specific penicillins. The
antibacterial spectrum of the combination is determined by the
companion penicillin, not the β-lactamase inhibitor. (
Beta-lactamase inhibitors
Note: An inhibitor extends the spectrum of a penicillin provided
that the inactivity of the penicillin is due to destruction by
β lactamase and that the inhibitor is active against the β lactamase
that is produced
Thus, ampicillin-sulbactam is active against
β-lactamase-producing ______ and _____but not against
______, which produces a β lactamase that is not inhibited
by sulbactam.
S aureus
H influenzae
serratia
Note: Similarly, if a strain of P aeruginosa is resistant to
piperacillin, it is also resistant to piperacillin-tazobactam because
tazobactam does not inhibit the chromosomal β lactamase produced
by P aeruginosa .
The indications for____________
are empirical therapy for infections caused by a wide range
of potential pathogens in both immunocompromised and immunocompetent
patients and treatment of mixed aerobic and anaerobic
infections, such as intra-abdominal infections.
Doses are the
same as those used for the single agents except that the recommended
dosage of piperacillin in the piperacillin-tazobactam
combination is 3–4 g every 6 hours. Adjustments for renal insufficiency
are made based on the penicillin component.
penicillin-β-lactamase inhibitor combinations
The ______ are structurally related to β-lactam antibiotics
carbapenems
Note: Doripenem, ertapenem, imipenem , and
meropenem are licensed for use in the USA.
__________, the first
drug of this class ( carbapenems) , has a wide spectrum with good activity against
many gram-negative rods, including P aeruginosa , gram-positive organisms, and anaerobes.
It is resistant to most β lactamases but
not carbapenemases or metallo-β lactamases.
Imipenem
Enterococcus faecium ,
methicillin-resistant strains of staphylococci, Clostridium difficile ,
Burkholderia cepacia , and Stenotrophomonas maltophilia are resistant.
Imipenem is inactivated by _______ in renal
tubules, resulting in low urinary concentrations. Consequently, it
is administered together with an inhibitor of renal dehydropeptidase,
_____
, for clinical use.
dehydropeptidases
cilastatin
________ and _______ are
similar to imipenem but have slightly greater activity against
gram-negative aerobesandslightly lessactivityagainst grampositives.
They are not significantly degraded by renal dehydropeptidase
and do not require an inhibitor.
Doripenem and meropenem
____is a carbapenem that is less active
than the other carbapenems against P aeruginosa and Acinetobacter
species. It is not degraded by renal dehydropeptidase.
Ertapenem
Note: Intramuscular ertapenem is irritating, and for that reason the drug
is formulated with 1% lidocaine for administration by this route.
A ___________is indicated for infections caused by susceptible
organisms that are resistant to other available drugs, eg, P aeruginosa ,
and for treatment of mixed aerobic and anaerobic infections.
These are active against many penicillin-non-susceptible
strains of pneumococci. These are highly active in the
treatment of enterobacter infections because they are resistant to
destruction by the β lactamase produced by these organisms.
Clinical experience suggests that these are also the treatment
of choice for infections caused by extended-spectrum
β-lactamase-producing gram-negative bacteria..
carbapenem
Note:Carbapenems penetrate body tissues and fluids well, including
the cerebrospinal fluid. All are cleared renally, and the dose must be
reduced in patients with renal insufficiency
__________, with or without an aminoglycoside, may be effective
treatment for febrile neutropenic patients.
Imipenem, meropenem,
or doripenem
The most common adverse effects of carbapenems—which
tend to be more common with______—are nausea, vomiting,
diarrhea, skin rashes, and reactions at the infusion sites.
. Patients allergic to penicillins
may be allergic to carbapenems as well.
imipenem
Note: Excessive
levels of imipenem in patients with renal failure may lead to
seizures
Note: Meropenem, doripenem, and ertapenem are much less
likely to cause seizures than imipenem.
_____ is an antibiotic produced by Streptococcus orientalis
and Amycolatopsis orientalis. With the exception of Flavobacterium ,
it is active only against gram-positive bacteria.
Vancomycin
______ inhibits cell wall synthesis by binding firmly to the
D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide
. This inhibits the transglycosylase, preventing further
elongation of peptidoglycan and cross-linking. The peptidoglycan
is thus weakened, and the cell becomes susceptible to lysis.
The cell membrane is also damaged, which contributes to the
antibacterial effect.
Vancomycin
Resistance to vancomycin in enterococci is due to _________ in which the terminal D-Ala is replaced by D-lactate. This
results in the loss of a critical hydrogen bond that facilitates highaffinity
binding of vancomycin to its target and loss of activity.
.
.
modification
of the D-Ala-D-Ala binding site of the peptidoglycan building
block.
Note: This mechanism is also present in vancomycin-resistant S aureus
strains (MIC ≥ 16 mcg/mL), which have acquired the enterococcal
resistance determinants.
_______ is bactericidal for gram-positive bacteria in concentrations
of 0.5–10 mcg/mL.
Most pathogenic staphylococci, including
those producing β lactamase and those resistant to nafcillin and
methicillin, are killed by 2 mcg/mL or less. It kills
staphylococci relatively slowly and only if cells are actively dividing;
the rate is less than that of the penicillins both in vitro and in vivo.
It is synergistic in vitro with gentamicin and streptomycin
against Enterococcus faecium and Enterococcus faecalis strains that
do not exhibit high levels of aminoglycoside resistance.
Vancomycin
Vancomycin is poorly absorbed from the intestinal tract and is
administered orally only for the treatment of antibiotic-associated
colitis caused by ________ .
C difficile
Important indications for parenteral vancomycin are ________ and ____________
.
However, vancomycin is not as effective as an antistaphylococcal
penicillin for treatment of serious infections such as
endocarditis caused by methicillin-susceptible strains.
bloodstream
infections
endocarditis caused by methicillin-resistant staphylococci
Vancomycin
in combination with _____ is an alternative regimen for
treatment of enterococcal endocarditis in a patient with serious
penicillin allergy.
gentamicin
Vancomycin (in combination with _____,______and _____) is also recommended for treatment of
meningitis suspected or known to be caused by a penicillin-resistant
strain of pneumococcus (ie, penicillin MIC > 1 mcg/mL).
cefotaxime,
ceftriaxone, or rifampin
Oral vancomycin, 0.125–0.25 g every 6 hours, is used to treat
antibiotic-associated colitis caused by _______ . Because of the
emergence of vancomycin-resistant enterococci and the potential
selective pressure of oral vancomycin for these resistant organisms,
_______ had been preferred as initial therapy over the last
two decades. However, receipt of oral vancomycin does not appear
to be a significant risk factor for acquisition of vancomycinresistant
enterococci.
C difficile
metronidazole
Note: Additionally, recent clinical data suggest that
vancomycin is associated with a better clinical response than
metronidazole for more severe cases of C difficile colitis. Therefore,
oral vancomycin may be used as a first line treatment for severe
cases or for cases that fail to respond to metronidazole.
Ototoxicity is rare and nephrotoxicity uncommon with current
preparations. However, administration with another ototoxic or
nephrotoxic drug, such as an aminoglycoside, increases the risk of
these toxicities. Ototoxicity can be minimized by maintaining
peak serum concentrations below 60 mcg/mL. Among the more
Vancomycin
Among the more common reactions is the so-called “red man” or “red neck”
syndrome. This infusion-related flushing is caused by release of
histamine. It can be largely prevented by prolonging the infusion
period to 1–2 hours or pretreatment with an antihistamine such
as diphenhydramine.
Vancomycin
________ is a glycopeptide antibiotic that is very similar to
vancomycin in mechanism of action and antibacterial spectrum.
Unlike vancomycin, it can be given intramuscularly as well as
intravenously.
Teicoplanin
Note :Teicoplanin has a long half-life (45–70 hours), permitting
once-daily dosing. This drug is available in Europe but has
not been approved for use in the United States.
_______ is a semisynthetic lipoglycopeptide derived from
vancomycin. It is active versus gram-positive bacteria,
including strains with reduced susceptibility to vancomycin.
This has two mechanisms of action. Like vancomycin, It
**inhibits cell wall synthesis by binding to the D-Ala-D-Ala **terminus of peptidoglycan in the growing cell wall.
In addition, it
- *disrupts the bacterial cell membrane potential and increases membrane
permeability. ** T
Telavancin
Note: he half-life of telavancin is approximately
8 hours, which supports once-daily intravenous dosing. Telavancin
is approved for treatment of complicated skin and soft tissue infections
at a dose of 10 mg/kg IV daily. Unlike vancomycin therapy,
monitoring of serum telavancin levels is not required. Telavancin
is potentially teratogenic, so administration to pregnant women
must be avoided.
_____ is a semisynthetic lipoglycopeptide derived from
teicoplanin. It shares the same mechanism of action as
vancomycin and teicoplanin but has improved activity against
many gram-positive bacteria including methicillin-resistant and
vancomycin-intermediate S aureus. It is not active against most
strains of vancomycin-resistant enterococci.
Dalbavancin
Note :Dalbavancin has an
extremely long half-life of 6–11 days, which allows for onceweekly
intravenous administration. Development of dalbavancin
has been put on hold pending additional clinical trials.
______ is a novel cyclic lipopeptide fermentation product of
Streptomyces roseosporus . It was discovered decades
ago but has only recently been developed as the need for drugs active against resistant organisms has become more acute. Its spectrum
of activity is similar to that of vancomycin except that it is
more rapidly bactericidal in vitro and may be active against
vancomycin-resistant strains of enterococci and S aureus .
Note :known to bind to the cell membrane via calcium-dependent insertion
of its lipid tail. This results in depolarization of the cell membrane
with potassium efflux and rapid cell death
Daptomycin
It can cause myopathy, and creatine phosphokinase levels
should be monitored weekly. Pulmonary surfactant antagonizes
this, and it should not be used to treat pneumonia.
This can also cause an allergic pneumonitis in patients
receiving prolonged therapy (> 2 weeks). Treatment failures have
been reported in association with an increase in daptomycin MIC
for clinical isolates obtained during therapy, but the relation
between the increase in MIC and treatment failure is unclear at
this point. It is an effective alternative to vancomycin,
and its ultimate role continues to unfold.
daptomycin
_____, a stable salt of fosfomycin (phosphonomycin),
inhibits a very early stage of bacterial cell wall synthesis.
An analog of phosphoenolpyruvate, it is structurally
unrelated to any other antimicrobial agent. It inhibits the cytoplasmic
enzyme enolpyruvate transferase by covalently binding to the
cysteine residue of the active site and blocking the addition of
phosphoenolpyruvate to UDP-N-acetylglucosamine. This reaction
is the first step in the formation of UDP- N- acetylmuramic acid,
the precursor of N -acetylmuramic acid, which is found only in
bacterial cell walls. The drug is transported into the bacterial cell by
glycerophosphate or glucose 6-phosphate transport systems.
Fosfomycin trometamol
Note :Resistance is due to inadequate transport of drug into the cell.
Note : Fosfomycin is active against both gram-positive and gramnegative
organisms at concentrations ≥ 125 mcg/mL. Susceptibility
tests should be performed in growth medium supplemented with
glucose 6-phosphate to minimize false-positive indications of
resistance. In vitro synergism occurs when fosfomycin is combined
with β-lactam antibiotics, aminoglycosides, or fluoroquinolones.
Fosfomycin trometamol is available in both oral and parenteral
formulations.
The drug appears to be safe for use in pregnancy.
______ is a cyclic peptide mixture first obtained from the Tracy
strain of Bacillus subtilis in 1943.
It is **active against gram-positive **microorganisms. Bacitracin inhibits cell wall formation by interfering
with dephosphorylationin cycling of the lipid carrier that
transfers peptidoglycan subunits to the growing cell wall.
There is no cross-resistance between this and
other antimicrobial drugs.
Bacitracin
NOTE :Bacitracin is highly nephrotoxic when administered systemically
and is only used topically . Bacitracin is poorly
absorbed. Topical application results in local antibacterial activity
without systemic toxicity. Bacitracin, 500 units/g in an ointment
base (often combined with polymyxin or neomycin), is indicated
for the suppression of mixed bacterial flora in surface lesions of
the skin, in wounds, or on mucous membranes. Solutions of
bacitracin containing 100–200 units/mL in saline can be used for
irrigation of joints, wounds, or the pleural cavity.
Cycloserine is an antibiotic produced by Streptomyces orchidaceous.
It is water soluble and very unstable at acid pH. Cycloserine inhibits
many gram-positive and gram-negative organisms, but it is used
almost exclusively to treat tuberculosis caused by strains of
Mycobacterium tuberculosis resistant to first-line agents. Cycloserine is
a structural analog of D-alanine and inhibits the incorporation of
D-alanine into peptidoglycan pentapeptide by inhibiting alanine racemase,
which converts L-alanine to D-alanine, and D-alanyl- D-alanine
ligase ( Figure 43–5 ).
Cycloserine
Note : After ingestion of 0.25 g of cycloserine
blood levels reach 20–30 mcg/mL—sufficient to inhibit many
strains of mycobacteria and gram-negative bacteria. The drug is
widely distributed in tissues. Most of the drug is excreted in active
form into the urine. The dosage for treating tuberculosis is 0.5 to
1 g/d in two or three divided doses.
Cycloserine causes serious dose-related central nervous system
toxicity with headaches, tremors, acute psychosis, and convulsions.
If oral dosages are maintained below 0.75 g/d, such effects
can usually be avoided.
