Lippincott Chapter 39: Protein Synthesis Inhibitors

Question 1

Tetracyclines

Answer 1

Demeclocycline DECLOMYCIN
Doxycycline VIBRAMYCIN
Minocycline MINOCIN
Tetracycline

Question 2

GLYCYLCYCLINES

Answer 2

Tigecycline

Question 3

AMINOGLYCOSIDES

Answer 3

Amikacin
Gentamicin GARAMYCIN
Neomycin NEO-FRADIN
Streptomycin
Tobramycin TOBREX

Question 4

Macrolides/Ketolides

Answer 4

Azithromycin ZITHROMAX
Clarithromycin BIAXIN
Erythromycin
Telithromycin KETEK

Question 5

MACROCYCLIC

Answer 5

Fidaxomicin DIFICID

Question 6

LINCOSAMIDES

Answer 6

Clindamycin CLEOCIN

Question 7

OXAZOLIDINONES

Answer 7

Linezolid

Question 8

Others

Answer 8

Linezolid ZYVOX
Quinupristin/Dalfopristin SYNERCID

Question 9

Tetracyclines

Answer 9

Tetracyclines consist of four fused rings with a system of conjugated
double bonds. Substitutions on these rings alter the individual pharma-
cokinetics and spectrum of antimicrobial activity.
A. Mechanism of action
Tetracyclines enter susceptible organisms via passive diffusion and
also by an energy-dependent transport protein mechanism unique
to the bacterial inner cytoplasmic membrane. Tetracyclines concen-
trate intracellularly in susceptible organisms. The drugs bind revers-
ibly to the 30S subunit of the bacterial ribosome. This action prevents
binding of tRNA to the mRNA–ribosome complex, thereby inhibiting
bacterial protein synthesis (Figure 39.2).
B. Antibacterial spectrum
The tetracyclines are bacteriostatic antibiotics effective against a
wide variety of organisms, including gram-positive and gram-negative
bacteria, protozoa, spirochetes, mycobacteria, and atypical species
(Figure 39.3). They are commonly used in the treatment of acne and
Chlamydia infections (doxycycline).

C. Resistance
The most commonly encountered naturally occurring resistance to
tetracyclines is an efflux pump that expels drug out of the cell, thus
preventing intracellular accumulation. Other mechanisms of bacterial
resistance to tetracyclines include enzymatic inactivation of the drug
and production of bacterial proteins that prevent tetracyclines frombinding to the ribosome. Resistance to one tetracycline does not con-
fer universal resistance to all tetracyclines.
D. Pharmacokinetics
1. Absorption: Tetracyclines are adequately absorbed after oral
ingestion (Figure 39.4). Administration with dairy products or other
substances that contain divalent and trivalent cations (for example,
magnesium and aluminum antacids or iron supplements) decreases
absorption, particularly for tetracycline [tet-rah-SYE-kleen], due to
the formation of nonabsorbable chelates (Figure 39.5). Both doxy-
cycline [dox-i-SYE-kleen] and minocycline [min-oh-SYE-kleen] are
available as oral and intravenous (IV) preparations.
2. Distribution: The tetracyclines concentrate well in the bile, liver,
kidney, gingival fluid, and skin. Moreover, they bind to tissues
undergoing calcification (for example, teeth and bones) or to
tumors that have a high calcium content. Penetration into most
body fluids is adequate. Only minocycline and doxycycline achieve
therapeutic levels in the cerebrospinal fluid (CSF). Minocycline
also achieves high levels in saliva and tears, rendering it useful
in eradicating the meningococcal carrier state. All tetracyclines cross the placental barrier and concentrate in fetal bones and
dentition.
3. Elimination: Tetracycline and doxycycline are not hepatically
metabolized. Tetracycline is primarily eliminated unchanged in the
urine, whereas minocycline undergoes hepatic metabolism and is
eliminated to a lesser extent via the kidney. In renally compromised
patients, doxycycline is preferred, as it is primarily eliminated via
the bile into the feces.

Question 10

Tetracyclines adverse effects

Answer 10

1. Gastric discomfort: Epigastric distress commonly results from
   irritation of the gastric mucosa (Figure 39.6) and is often respon-
   sible for noncompliance with tetracyclines. Esophagitis may be
   minimized through coadministration with food (other than dairy
   products) or fluids and the use of capsules rather than tablets.
   [Note: Tetracycline should be taken on an empty stomach.]
2. Effects on calcified tissues: Deposition in the bone and primary
   dentition occurs during the calcification process in growing children.
   This may cause discoloration and hypoplasia of teeth and a tempo-
   rary stunting of growth. The use of tetracyclines is limited in pediatrics.
3. Hepatotoxicity: Rarely hepatotoxicity may occur with high doses,
   particularly in pregnant women and those with preexisting hepatic
   dysfunction or renal impairment.
4. Phototoxicity: Severe sunburn may occur in patients receiving a
   tetracycline who are exposed to sun or ultraviolet rays. This toxic-
   ity is encountered with any tetracycline, but more frequently with
   tetracycline and demeclocycline [dem-e-kloe-SYE-kleen]. Patients
   should be advised to wear adequate sun protection.
5. Vestibular dysfunction: Dizziness, vertigo, and tinnitus may occur
   particularly with minocycline, which concentrates in the endolymph
   of the ear and affects function. Doxycycline may also cause vestibu-
   lar dysfunction.
6. Pseudotumor cerebri: Benign, intracranial hypertension charac-
   terized by headache and blurred vision may occur rarely in adults.
   Although discontinuation of the drug reverses this condition, it is
   not clear whether permanent sequelae may occur.
7. Contraindications: The tetracyclines should not be used in preg-
   nant or breast-feeding women or in children less than 8 years of age.

Question 11

Tigecycline

Answer 11

Tigecycline [tye-ge-SYE-kleen], a derivative of minocycline, is the first
available member of the glycylcycline antimicrobial class. It is indicated
for the treatment of complicated skin and soft tissue infections, as well as
complicated intra-abdominal infections.
A. Mechanism of action
Tigecycline exhibits bacteriostatic action by reversibly binding to the
30S ribosomal subunit and inhibiting protein synthesis.

B. Antibacterial spectrum
Tigecycline exhibits broad-spectrum activity that includes methicillin-
resistant staphylococci (MRSA), multidrug-resistant streptococci,
vancomycin-resistant enterococci (VRE), extended-spectrum
β-lactamase–producing gram-negative bacteria, Acinetobacter bau-
mannii, and many anaerobic organisms. However, tigecycline is not
active against Morganella, Proteus, Providencia, or Pseudomonas
species.
C. Resistance
Tigecycline was developed to overcome the recent emergence of tet-
racycline class–resistant organisms that utilize efflux pumps and ribo-
somal protection to confer resistance. However, resistance is seen
and is primarily attributed to overexpression of efflux pumps.
D. Pharmacokinetics
Following IV infusion, tigecycline exhibits a large volume of distri-
bution. It penetrates tissues well but has low plasma concentra-
tions. Consequently, tigecycline is a poor option for bloodstream
infections. The primary route of elimination is biliary/fecal. No dos-
age adjustments are necessary for patients with renal impairment.
However, a dose reduction is recommended in severe hepatic
dysfunction.

Question 12

Tigecycline Adverse Effects

Answer 12

E. Adverse effects
Tigecycline is associated with significant nausea and vomiting.
Acute pancreatitis, including fatality, has been reported with therapy.
Elevations in liver enzymes and serum creatinine may also occur.
Other adverse effects are similar to those of the tetracyclines and
include photosensitivity, pseudotumor cerebri, discoloration of perma-
nent teeth when used during tooth development, and fetal harm when
administered in pregnancy. Tigecycline may decrease the clearance
of warfarin and increase prothrombin time. Therefore, the interna-
tional normalized ratio should be monitored closely when tigecycline
is coadministered with warfarin.

Question 13

Aminoglycosides

Answer 13

Aminoglycosides are used for the treatment of serious infections due to
aerobic gram-negative bacilli. However, their clinical utility is limited by seri-
ous toxicities. The term “aminoglycoside” stems from their structure—two
amino sugars joined by a glycosidic linkage to a central hexose nucleus.
Aminoglycosides are derived from either Streptomyces sp. (have -mycin
suffixes) or Micromonospora sp. (end in -micin).
A. Mechanism of action
Aminoglycosides diffuse through porin channels in the outer mem-
brane of susceptible organisms. These organisms also have an
oxygen-dependent system that transports the drug across the cyto-
plasmic membrane. Inside the cell, they bind the 30S ribosomal sub-
unit, where they interfere with assembly of the functional ribosomal
apparatus and/or cause the 30S subunit of the completed ribosome
to misread the genetic code (Figure 39.2). Antibiotics that disrupt
protein synthesis are generally bacteriostatic; however, aminoglyco-
sides are unique in that they are bactericidal. The bactericidal effect
of aminoglycosides is concentration dependent; that is, efficacy is
dependent on the maximum concentration (Cmax) of drug above the
minimum inhibitory concentration (MIC) of the organism. For amino-
glycosides, the target Cmax is eight to ten times the MIC. They also
exhibit a postantibiotic effect (PAE), which is continued bacterial sup-
pression after drug levels fall below the MIC. The larger the dose,
the longer the PAE. Because of these properties, extended interval
dosing (a single large dose given once daily) is now more commonly
utilized than divided daily doses. This reduces the risk of nephrotoxic-
ity and increases convenience.
B. Antibacterial spectrum
The aminoglycosides are effective for the majority of aerobic gram-
negative bacilli, including those that may be multidrug resistant,
such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and
Enterobacter sp. Additionally, aminoglycosides are often combined
with a β-lactam antibiotic to employ a synergistic effect, particularly
in the treatment of Enterococcus faecalis and Enterococcus faecium
infective endocarditis. Some therapeutic applications of four com-
monly used aminoglycosides—amikacin [am-i-KAY-sin], gentamicin
[jen-ta-MYE-sin], tobramycin [toe-bra-MYE-sin], and streptomycin
[strep-toe-MYE-sin]—are shown in Figure 39.7.
C. Resistance
Resistance to aminoglycosides occurs via: 1) efflux pumps, 2) decreased
uptake, and/or 3) modification and inactivation by plasmid-associated
synthesis of enzymes. Each of these enzymes has its own aminogly-
coside specificity; therefore, cross-resistance cannot be presumed.
[Note: Amikacin is less vulnerable to these enzymes than other anti-
biotics in this group.]
D. Pharmacokinetics
1. Absorption: The highly polar, polycationic structure of the amino-
glycosides prevents adequate absorption after oral administration.
Therefore, all aminoglycosides (except neomycin [nee-oh-MYE-
sin]) must be given parenterally to achieve adequate serum lev-
els (Figure 39.8). [Note: Neomycin is not given parenterally due to
severe nephrotoxicity. It is administered topically for skin infections
or orally for bowel preparation prior to colorectal surgery.]
2. Distribution: All the aminoglycosides have similar pharmacokinetic
properties. Due to their hydrophilicity, tissue concentrations may
be subtherapeutic, and penetration into most body fluids is vari-
able. [Note: Due to low distribution into fatty tissue, the aminoglyco-
sides are dosed based on lean body mass, not actual body weight.]
Concentrations in CSF are inadequate, even in the presence of
inflamed meninges. For central nervous system infections, the intra-
thecal (IT) route may be utilized. All aminoglycosides cross the pla-
cental barrier and may accumulate in fetal plasma and amniotic fluid.
3. Elimination: More than 90% of the parenteral aminoglycosides
are excreted unchanged in the urine (Figure 39.8). Accumulation
occurs in patients with renal dysfunction, and dose adjustments
are required.

Question 14

Aminoglycosides adverse effects

Answer 14

Adverse effects
Therapeutic drug monitoring of gentamicin, tobramycin, and amikacin
plasma levels is imperative to ensure adequacy of dosing and to mini-
mize dose-related toxicities (Figure 39.9). The elderly are particularly
susceptible to nephrotoxicity and ototoxicity.
1. Ototoxicity: Ototoxicity (vestibular and auditory) is directly related
to high peak plasma levels and the duration of treatment. The anti-
biotic accumulates in the endolymph and perilymph of the inner
ear. Deafness may be irreversible and has been known to affect
developing fetuses. Patients simultaneously receiving concomitant
ototoxic drugs, such as cisplatin or loop diuretics, are particularly
at risk. Vertigo (especially in patients receiving streptomycin) may
also occur.
2. Nephrotoxicity: Retention of the aminoglycosides by the proximal
tubular cells disrupts calcium-mediated transport processes. This
results in kidney damage ranging from mild, reversible renal impair-
ment to severe, potentially irreversible, acute tubular necrosis.
3. Neuromuscular paralysis: This adverse effect is associated with
a rapid increase in concentrations (for example, high doses infused
over a short period.) or concurrent administration with neuromus-
cular blockers. Patients with myasthenia gravis are particularly at
risk. Prompt administration of calcium gluconate or neostigmine
can reverse the block that causes neuromuscular paralysis.
4. Allergic reactions: Contact dermatitis is a common reaction to
topically applied neomycin.

Question 15

Macrolides and Ketolides

Answer 15

V. MACROLIDES AND KETOLIDES
The macrolides are a group of antibiotics with a macrocyclic lactone
structure to which one or more deoxy sugars are attached. Erythromycin
[er-ith-roe-MYE-sin] was the first of these drugs to find clinical applica-
tion, both as a drug of first choice and as an alternative to penicillin in
individuals with an allergy to β-lactam antibiotics. Clarithromycin [kla-
rith-roe-MYE-sin] (a methylated form of erythromycin) and azithromycin
[a-zith-roe-MYE-sin] (having a larger lactone ring) have some features in
common with, and others that improve upon, erythromycin. Telithromycin
[tel-ith-roe-MYE-sin], a semisynthetic derivative of erythromycin, is the
first “ketolide” antimicrobial agent. Ketolides and macrolides have similar
antimicrobial coverage. However, the ketolides are active against many
macrolide-resistant gram-positive strains.
A. Mechanism of action
The macrolides bind irreversibly to a site on the 50S subunit of
the bacterial ribosome, thus inhibiting translocation steps of protein
synthesis (Figure 39.2). They may also interfere with other steps,
such as transpeptidation. Generally considered to be bacterio-
static, they may be bactericidal at higher doses. Their binding site
is either identical to or in close proximity to that for clindamycin and
chloramphenicol.
B. Antibacterial spectrum
1. Erythromycin: This drug is effective against many of the same
organisms as penicillin G (Figure 39.10). Therefore, it may be used
in patients with penicillin allergy.
2. Clarithromycin: Clarithromycin has activity similar to erythromy-
cin, but it is also effective against Haemophilus influenzae. Its activ-
ity against intracellular pathogens, such as Chlamydia, Legionella,
Moraxella, Ureaplasma species and Helicobacter pylori, is higher
than that of erythromycin.
3. Azithromycin: Although less active against streptococci and staph-
ylococci than erythromycin, azithromycin is far more active against
respiratory infections due to H. influenzae and Moraxella catarrhalis.
Extensive use of azithromycin has resulted in growing Streptococcus
pneumoniae resistance. Azithromycin is the preferred therapy for
urethritis caused by Chlamydia trachomatis. Mycobacterium avium
is preferentially treated with a macrolide-containing regimen, includ-
ing clarithromycin or azithromycin4. Telithromycin: This drug has an antimicrobial spectrum similar
to that of azithromycin. Moreover, the structural modification within
ketolides neutralizes the most common resistance mechanisms
(methylase-mediated and efflux-mediated) that make macrolides
ineffective.
C. Resistance
Resistance to macrolides is associated with: 1) the inability of the
organism to take up the antibiotic, 2) the presence of efflux pumps, 3) a
decreased affinity of the 50S ribosomal subunit for the antibiotic, result-
ing from the methylation of an adenine in the 23S bacterial ribosomal
RNA in gram-positive organisms, and 4) the presence of plasmid-
associated erythromycin esterases in gram-negative organisms such
as Enterobacteriaceae. Resistance to erythromycin has been increas-
ing, thereby limiting its clinical use (particularly for S. pneumoniae).
Both clarithromycin and azithromycin share some cross-resistance
with erythromycin, but telithromycin may be effective against macrolide-
resistant organisms.
D. Pharmacokinetics
1. Administration: The erythromycin base is destroyed by gastric
acid. Thus, either enteric-coated tablets or esterified forms of the
antibiotic are administered. All are adequately absorbed upon oral
administration (Figure 39.11). Clarithromycin, azithromycin, and
telithromycin are stable in stomach acid and are readily absorbed.
Food interferes with the absorption of erythromycin and azithro-
mycin but can increase that of clarithromycin. Erythromycin and
azithromycin are available in IV formulations.
2. Distribution: Erythromycin distributes well to all body fluids except
the CSF. It is one of the few antibiotics that diffuses into prostatic
fluid, and it also accumulates in macrophages. All four drugs con-
centrate in the liver. Clarithromycin, azithromycin, and telithromy-
cin are widely distributed in the tissues. Azithromycin concentrates
in neutrophils, macrophages, and fibroblasts, and serum levels are
low. It has the longest half-life and the largest volume of distribution
of the four drugs (Figure 39.12).
3. Elimination: Erythromycin and telithromycin are extensively metabo-
lized hepatically. They inhibit the oxidation of a number of drugs through
their interaction with the cytochrome P450 system. Interference with
the metabolism of drugs, such as theophylline, statins, and numerous
antiepileptics, has been reported for clarithromycin.
4. Excretion: Erythromycin and azithromycin are primarily con-
centrated and excreted in the bile as active drugs (Figure 39.11).
Partial reabsorption occurs through the enterohepatic circulation.
In contrast, clarithromycin and its metabolites are eliminated by
the kidney as well as the liver. The dosage of this drug should be
adjusted in patients with renal impairment.

Question 16

Macrolides and Ketolides adverse effects

Answer 16

1. Gastric distress and motility: Gastric upset is the most com-
   mon adverse effect of the macrolides and may lead to poor patient compliance (especially with erythromycin). Clarithromycin and
   azithromycin seem to be better tolerated (Figure 39.13). Higher
   doses of erythromycin lead to smooth muscle contractions that
   result in the movement of gastric contents to the duodenum, an
   adverse effect sometimes used therapeutically for the treatment of
   gastroparesis or postoperative ileus.
2. Cholestatic jaundice: This side effect occurs especially with the
   estolate form (not used in the United States) of erythromycin; however,
   it has been reported with other formulations.
3. Ototoxicity: Transient deafness has been associated with eryth-
   romycin, especially at high dosages. Azithromycin has also been
   associated with irreversible sensorineural hearing loss.
4. Contraindications: Patients with hepatic dysfunction should be
   treated cautiously with erythromycin, telithromycin, or azithromy-
   cin, because these drugs accumulate in the liver. Severe hepato-
   toxicity with telithromycin has limited its use, given the availability
   of alternative therapies. Additionally, macrolides and ketolides may
   prolong the QTc
   interval and should be used with caution in those
   patients with proarrhythmic conditions or concomitant use of proar-
   rhythmic agents.
5. Drug interactions: Erythromycin, telithromycin, and clarithromy-
   cin inhibit the hepatic metabolism of a number of drugs, which can
   lead to toxic accumulation of these compounds (Figure 39.14). An
   interaction with digoxin may occur. In this case, the antibiotic elimi-
   nates a species of intestinal flora that ordinarily inactivates digoxin,
   thus leading to greater reabsorption of the drug from the entero-
   hepatic circulation.

Question 17

Fidaxomicin

Answer 17

Fidaxomicin [fye-DAX-oh-MYE-sin] is a macrocyclic antibiotic with a
structure similar to the macrolides; however, it has a unique mechanism
of action. Fidaxomicin acts on the sigma subunit of RNA polymerase,
thereby disrupting bacterial transcription, terminating protein synthe-
sis, and resulting in cell death in susceptible organisms. Fidaxomicin
has a very narrow spectrum of activity limited to gram-positive aer-
obes and anaerobes. While it possesses activity against staphylococci
and enterococci, it is used primarily for its bactericidal activity against
Clostridium difficile. Due to the unique target site, cross-resistance
with other antibiotic classes has not been documented. Following oral
administration, fidaxomicin has minimal systemic absorption and pri-
marily remains within the gastrointestinal tract. This is ideal for the
treatment of C. difficile infection, which occurs in the gut. This char-
acteristic also likely contributes to the low rate of adverse effects. The
most common adverse effects include nausea, vomiting, and abdomi-
nal pain. Hypersensitivity reactions including angioedema, dyspnea,
and pruritus have occurred. Fidaxomicin should be used with caution
in patients with a macrolide allergy, as they may be at increased risk
for hypersensitivity. Anemia and neutropenia have been observed
infrequently.

Question 18

Chloramphenicol

Answer 18

The use of chloramphenicol [klor-am-FEN-i-kole], a broad-spectrum antibi-
otic, is restricted to life-threatening infections for which no alternatives exist.
A. Mechanism of action
Chloramphenicol binds reversibly to the bacterial 50S ribosomal sub-
unit and inhibits protein synthesis at the peptidyl transferase reaction
(Figure 39.2). Due to some similarity of mammalian mitochondrial
ribosomes to those of bacteria, protein and ATP synthesis in these
organelles may be inhibited at high circulating chloramphenicol levels,
producing bone marrow toxicity. [Note: The oral formulation of chlor-
amphenicol was removed from the US market due to this toxicity.]
B. Antibacterial spectrum
Chloramphenicol is active against many types of microorganisms
including chlamydiae, rickettsiae, spirochetes, and anaerobes. The drug
is primarily bacteriostatic, but depending on the dose and organism, it
may be bactericidal.
C. Resistance
Resistance is conferred by the presence of enzymes that inactivate
chloramphenicol. Other mechanisms include decreased ability to
penetrate the organism and ribosomal binding site alterations.
D. Pharmacokinetics
Chloramphenicol is administered intravenously and is widely distrib-
uted throughout the body. It reaches therapeutic concentrations in the
CSF. Chloramphenicol primarily undergoes hepatic metabolism to an
inactive glucuronide, which is secreted by the renal tubule and elimi-
nated in the urine. Dose reductions are necessary in patients with
liver dysfunction or cirrhosis. It is also secreted into breast milk and
should be avoided in breastfeeding mothers.

Question 19

Chloramphenicol adverse effects

Answer 19

Adverse effects
1. Anemias: Patients may experience dose-related anemia, hemo-
lytic anemia (seen in patients with glucose-6-phosphate dehydro-
genase deficiency), and aplastic anemia. [Note: Aplastic anemia
is independent of dose and may occur after therapy has ceased.]
2. Gray baby syndrome: Neonates have a low capacity to gluc-
uronidate the antibiotic, and they have underdeveloped renal func-
tion. Therefore, neonates have a decreased ability to excrete the
drug, which accumulates to levels that interfere with the function
of mitochondrial ribosomes. This leads to poor feeding, depressed
breathing, cardiovascular collapse, cyanosis (hence the term “gray
baby”), and death. Adults who have received very high doses of
the drug can also exhibit this toxicity.
3. Drug interactions: Chloramphenicol inhibits some of the hepatic
mixed-function oxidases and, thus, blocks the metabolism of drugs
such as warfarin and phenytoin, thereby elevating their concentra-
tions and potentiating their effects.

Question 20

Clindamycin

Answer 20

Clindamycin [klin-da-MYE-sin] has a mechanism of action that is the
same as that of erythromycin. Clindamycin is used primarily in the treat-
ment of infections caused by gram-positive organisms, including MRSA
and streptococcus, and anaerobic bacteria. Resistance mechanisms
are the same as those for erythromycin, and cross-resistance has been
described. C. difficile is always resistant to clindamycin, and the utility of
clindamycin for gram-negative anaerobes (for example, Bacteroides sp.)
is decreasing due to increasing resistance. Clindamycin is available in
both IV and oral formulations, but use of the oral form is limited by gastro-
intestinal intolerance. It distributes well into all body fluids including bone,
but exhibits poor entry into the CSF. Clindamycin undergoes extensive
oxidative metabolism to inactive products and is primarily excreted into
the bile. Low urinary elimination limits its clinical utility for urinary tract
infections (Figure 39.15). Accumulation has been reported in patients
with either severe renal impairment or hepatic failure. In addition to skin
rashes, the most common adverse effect is diarrhea, which may rep-
resent a serious pseudomembranous colitis caused by overgrowth of
C. difficile. Oral administration of either metronidazole or vancomycin is
usually effective in the treatment of C. difficile.

Question 21

Quinupristin-Dalfopristin

Answer 21

Quinupristin/dalfopristin [KWIN-yoo-pris-tin/DAL-foh-pris-tin] is a mixture
of two streptogramins in a ratio of 30 to 70, respectively. Due to significant
adverse effects, the drug is normally reserved for the treatment of severe
vancomycin-resistant Enterococcus faecium (VRE) in the absence of
other therapeutic options.
A. Mechanism of action
Each component of this combination drug binds to a separate site
on the 50S bacterial ribosome. Dalfopristin disrupts elongation by
interfering with the addition of new amino acids to the peptide chain.
Quinupristin prevents elongation similar to the macrolides and causes
release of incomplete peptide chains. Thus, they synergistically inter-
rupt protein synthesis. The combination drug is bactericidal and has
a long PAE.
B. Antibacterial spectrum
The combination drug is active primarily against gram-positive cocci,
including those resistant to other antibiotics. Its primary use is in the
treatment of E. faecium infections, including VRE strains, for which it
is bacteriostatic. The drug is not effective against E. faecalis.
C. Resistance
Enzymatic processes commonly account for resistance to these agents.
For example, the presence of a ribosomal enzyme that methylates
the target bacterial 23S ribosomal RNA site can interfere in quinu-
pristin binding. In some cases, the enzymatic modification can change
the action from bactericidal to bacteriostatic. Plasmid-associated acetyltransferase inactivates dalfopristin. An active efflux pump can
also decrease levels of the antibiotics in bacteria.
D. Pharmacokinetics
Quinupristin/dalfopristin is injected intravenously (the drug is incom-
patible with a saline medium). The combination drug is particularly
useful for intracellular organisms (for example, VRE) due to its excel-
lent penetration of macrophages and neutrophils. Levels in the CSF
are low. Both compounds undergo hepatic metabolism, with excretion
mainly in the feces.

Question 22

Quinupristin-Dalfopristin adverse effects

Answer 22

Adverse effects
Venous irritation commonly occurs when quinupristin/dalfopristin
is administered through a peripheral rather than a central line.
Hyperbilirubinemia occurs in about 25% of patients, resulting from
a competition with the antibiotic for excretion. Arthralgia and myal-
gia have been reported when higher doses are used. Quinupristin/
dalfopristin inhibits the cytochrome P450 (CYP3A4) isoenzyme, and
concomitant administration with drugs that are metabolized by this
pathway may lead to toxicities.

Question 23

Linezolid

Answer 23

Linezolid [lih-NEH-zo-lid] is a synthetic oxazolidinone developed to
combat resistant gram-positive organisms, such as methicillin-resistant
Staphylococcus aureus, VRE, and penicillin-resistant streptococci.
A. Mechanism of action
Linezolid binds to the bacterial 23S ribosomal RNA of the 50S sub-
unit, thereby inhibiting the formation of the 70S initiation complex
(Figure 39.2).
B. Antibacterial spectrum
The antibacterial action of linezolid is directed primarily against gram-
positive organisms, such as staphylococci, streptococci, and entero-
cocci, as well as Corynebacterium species and Listeria monocytogenes
(Figure 39.16). It is also moderately active against Mycobacterium
tuberculosis and may be used against drug-resistant strains. However,
its main clinical use is against drug-resistant gram-positive organ-
isms. Like other agents that interfere with bacterial protein synthesis,
linezolid is bacteriostatic. However, it is bactericidal against strepto-
cocci. Linezolid is an alternative to daptomycin for infections caused
by VRE. Use of linezolid for the treatment of MRSA bacteremia is not
recommended.
C. Resistance
Resistance primarily occurs via reduced binding at the target site.
Reduced susceptibility and resistance have been reported in S. aureus
and Enterococcus sp. Cross-resistance with other protein synthesis
inhibitors does not occur.

D. Pharmacokinetics
Linezolid is completely absorbed after oral administration. An IV prepa-
ration is also available. The drug is widely distributed throughout the
body. Although the metabolic pathway of linezolid has not been fully
determined, it is known that it is metabolized via oxidation to two inac-
tive metabolites. The drug is excreted both by renal and nonrenal routes.
No dose adjustments are required for renal or hepatic dysfunction.

Question 24

Linezolid adverse effects

Answer 24

E. Adverse effects
The most common adverse effects are gastrointestinal upset, nausea,
diarrhea, headache, and rash. Thrombocytopenia has been reported,
mainly in patients taking the drug for longer than 10 days. Linezolid
possesses nonselective monoamine oxidase activity and may lead
to serotonin syndrome if given concomitantly with large quantities of
tyramine-containing foods, selective serotonin reuptake inhibitors, or
monoamine oxidase inhibitors. The condition is reversible when the
drug is discontinued. Irreversible peripheral neuropathies and optic
neuritis (causing blindness) have been associated with greater than
28 days of use, limiting utility for extended-duration treatments.

Question 25

Lyme disease

Answer 25

This is a spirochetal infection caused by
Borrelia burgdorferi. The disease is
transmitted by the bite of infected ticks.
Infection results in skin lesions, headache,
and fever, followed by meningoencephalitis
and, eventually, arthritis.
A bull’s-eye pattern rash with a red outer
ring, called erythema migrans is a hallmark
of Lyme disease
Doxycycline is one of the preferred
therapeutic options.

Question 26

Mycoplasma pneumoniae

Answer 26

Mycoplasma pneumoniae, or walking
pneumonia, is a common cause of
community-acquired pneumonia in young
adults and in people who live in close
connes, such as in military camps.
Treatment with a macrolide or doxycycline
is eective.

Question 27

Cholera

Answer 27

Cholera is caused by Vibrio cholerae
ingested in fecally contaminated food or
water.
The organism multiplies in the gastro-
intestinal tract, where it secretes an
enterotoxin that produces diarrhea.
Treatment includes doxycycline, which
reduces the number of intestinal vibrios,
and uid replacement

Question 28

CHLAMYDIAL INFECTIONS

Answer 28

Chlamydia trachomatis is the major cause
of sexually transmitted disease in the
United States. It causes nongonococcal
urethritis, pelvic inammatory disease,
and lymphogranuloma venereum.
Chlamydia psittaci causes psittacosis,
which usually takes the form of pneumonia.
Other clinical forms include hepatitis,
myocarditis, and coma.
Doxycycline or azithromycin is used to
treat chlamydial infections

Question 29

Rocky mountain spotted fever

Answer 29

This disease, caused by Rickettsia
rickettsii, is characterized by fever,
chills, and aches in bones and joints.
Response to tetracyclines is prompt if
the drug is started early in the disease
process