Inhibitors of

Bacterial Ribosomal
Actions

Romeo Calubaquib, MD
Therapeutic Overview
Aminoglycosides
• Inhibit gram-negative aerobes
• Narrow therapeutic index
• Toxicities to patient can be serious, renal, otic
• Pharmacokinetics are an important
consideration
• Plasmid-mediated resistance is a problem
Tetracyclines
• Broad spectrum of organisms are inhibited

Chloramphenicol
• Kills major meningitis pathogens
• Serious toxicity inpatients

Macrolides
• Inhibit mycoplasma, chlamydia, legionella
• Inhibit gram0positive organisms
Ketolides
• Inhibit respiratory pathogens
• Active against penicillin and Macrolide resistant
S. pneumoniae

Clindamycin
• Inhibits gram-positive cocci and anaerobic
species
• Clostridium difficile-associated diarrhea and
colitis
Streptogramins
• Inhibit gram-positive organisms
• Active against VRE

Oxazolidinones
• Inhibit gram-positive organisms
• Active against VRE
• The Aminoglycosides are effective primarily
against gram-negative organisms; although they
are used less commonly because of their
toxicity, they remain important for treatment of
selected infections
* they are effective against aerobic gram-
negative bacteria and are often used in
combination with other classes of antibiotics but
are ineffective against anaerobic organisms
• The ribosome-binding sites for Macrolides such
as erythromycin, Azithromycin, Clarithromycin,
and Clindamycin are on the same 50S subunit
(S represents the sedimentation parameter), but
the structures of the drugs and the spectrum of
activities differ considerably
• Tetracyclines bind to the 30S ribosomal subunit
and are effective against aerobic and anaerobic
gram-positive and gram-negative organisms.
Given their wide spectrum activity, Tetracyclines
remain widely used for treatment of bacterial,
chlamydial, rickettsial and mycoplasmal
infections, although the development of bacterial
resistance has reduced their efficacy against
some pathogens
Therapeutic uses of Tetracyclines
Drug of choice
rickettsial diseases: rocky mountain spotted fever, typhus, scrub
typhus,Q fever
Ehrlichiosis, Mycoplasma pneumoniae, Chlamydia pneumoniae
Chlamydia psittaci, Lyme disease ( Borrelia burgdorferi)
Relapsing fever caused by borrelia organisms, bruceliosis
Alternative agent
Plague, pelvic inflammatory disease
As treatment of syndromes
Acne: low doseoral or topical
Bacterial exacerbations of bronchitis
Malabsorption syndrome resulting from bowel bacterial overgrowth
• Chloramphenicol was widely used at one time
but serious side effects have limited the
applications for which the drug is used in the
United States
• Erythromycin, however, is relatively safe and
widely used, especially for treatment of
infections in children
Therapeutic Uses of Erythromycin
Drug of Choice
Mycoplasma Pneumoniae
Group A streptococcal upper respiratory tract infection(penicillin-allergic
patient)
Legionella infection
Bordetella pertussis, campylobacter jejuni, ureaplasma urealyticum,
bartonella henselae, corynebacterium diphteriae
Alternative Agent
Lyme disease, chlamydia infection
As treatment of syndromes
Bacterial bronchitis, otitis media (withsulfonamide), acne, topical
Prophylaxis
Endocarditis (penicillin-allergic patient), largebowel surgery, oral surgery
• Clindamycin displays antimicrobial activity
somewhat similar to that of erythromycin. The
two differ structurally, however, with Clindamycin
displaying extensive anaerobic activity while
having no activity for atypical respiratory
pathogens
• The Ketolides represent a new class of
antibiotics within the macrolide-lincosamide-
streptogramin B family. Ketolides are semi
synthetic derivatives of erythromycin that inhibit
protein synthesis via interaction with the
50Sribosomal subunit. Activity against
Macrolide-resistant respiratory tract pathogens
is maintained in Ketolides, which also
demonstrate excellent activity against atypical
respiratory pathogens. Therefore, Ketolides may
provide an additional treatment option for lower
respiratory tract infections
• The streptogramins and oxazolidinones are
newer classes of antibiotics that were developed
primarily for the treatment of gram-positive
organisms and often have activity against
organisms that are resistant to β-lactams and
glycopeptides. Both inhibit protein synthesis, but
their structures and mechanisms of action are
different. These drugs represent important
agents for the treatment of multi-drug resistant
gram-positive infections, but prudent use will be
important to prevent the development of
resistance to these agents
• Mupirocin, which interferes with tRNA synthesis,
is a topical agent primarily used to treat
cutaneous streptococcal and staphylococcal
infection
Bacterial Ribosomal binding and Resulting overall effect on bacterial
viability

Drugs Subunit it Binds to

Aminoglycosides 30S, 50S, 30S/50Sinterface
Chloramphenicol 50S
Clindamycin 50S
Erythromycin 50S
Ketolides 50S
Streptogramins 50S
Oxazolidinones 50S
Mupirocin Leu tRNA
Spectinomycin 30S
tetracyclines 30S
Aminoglycosides
• Aminoglycosides consists of amino sugars
linked through glycosidic bonds to an
aminocyclitol. The particular amino sugars and
specific locations of the amino groups
distinguish the compounds and are important for
their antimicrobial effects and toxicity.
Gentamycin consists of a mixture of three
species with little difference in activities
• The Aminoglycosides exert a concentration
dependent bactericidal action by entering the
bacterial cell and inhibiting protein synthesis. The
overall process consists of two main steps:
1. transport through the bacterial cell wall and
cytoplasmic membrane
2. binding to ribosomal sites, thus inhibiting protein
synthesis
• The Aminoglycosides are more effective against
aerobic gram-negative than against gram-positive
bacteria. These drugs can cross the more complex
cell membrane structures of the gram-negative
bacteria
• Aminoglycosides bind to several ribosomal sites
of the 30S and 50S subunits of the bacterial
ribosome. Streptomycin, the most thoroughly
studied, binds to the 30S subunit, although this
can be altered by mutation of particular amino
acids
• Binding of Aminoglycosides interferes with
protein synthesis in two ways:
1. it restricts polysome formation
2. it causes mRNA to be misread
• Aminoglycosides also demonstrate a prolonged
post antibiotic effect, in which suppression of
bacterial growth continues after the serum
concentration falls below the minimal inhibitory
concentration (MIC)
• Synergistic killing has been demonstrated when
Aminoglycosides are combined with cell wall
active agents (e.g. β-lactams, glycopeptides)
• Bacterial resistance to Aminoglycosides occurs
and results from:
1. altered ribosomes
2. inadequate transport within the cell
3. enzymatic modification of drug
Spectinomycins
• Spectinomycin acts by binding to 30S ribosome
subunit and inhibiting a translocation step,
perhaps by interfering with movement of mRNA
along the 30S subunit
• Resistance to this drug stems from the transfer
of a plasmid directing synthesis of an enzyme
that acetylates the compound or changes amino
acids in the S5 protein of the 30Ssubunit
Tetracyclines
• They act by binding to 30S ribosomes, thereby
preventing attachment of the aminoacyl-tRNA to
its receptor site. This binding prevents the
addition of amino acids to the peptide chain being
synthesized. Differences in activity of individual
Tetracyclines are related to their solubility in lipid
membranes of the bacteria
• These drugs enter the cytoplasm of gram-positive
bacteria by an energy-dependent process, but in
gram-negative organisms, they pass through the
outer membrane by diffusion through the porins
• Because minocycline and Doxycycline are more
lipophilic, they can enter gram-negative cells
through the outer lipid membrane and through
the porins. Once in the periplasmic space, the
Tetracyclines are transported across the inner
cytoplasmic membrane by a protein-carrier
system
• There are several mechanisms of resistance to
Tetracyclines. The most common mechanism,
found in both gram-positive and gram-negative
bacteria, is plasmid or tranposon mediated and
involves decreased intracellular accumulation of
the drug and increased transport of the drug out
of the bacterial cell
* drug efflux occurs as a result of the action of a
new protein, probably induced by the drug
A second mechanism appears to be alteration of
outer membrane proteins resulting from
mutations in chromosomal genes
In a third mechanism, the ribosomal binding site
is protected as a result of the presence of a
plasmid-generated protein that binds to the
ribosome
• Resistance to one tetracycline usually implies to
all these compounds. However, some
staphylococci and some bacteroides species are
resistant to tetracycline but susceptible to
minocycline and Doxycycline because of the
lipophilicity of these latter agents. New
Tetracyclines, the glycylcyclines have been
developed that inhibit bacteria previously
resistant to all commercially available
Tetracyclines but are not yet available for clinical
use
Chloramphenicol, Macrolides, and Clindamycin

• Are discussed as a group because they bind to

the same site or sites on the ribosomal 50S
subunit
• They bind to bacterial 70S ribosomes but not to
the 80S ribosomes of mammalian cells. Bacterial
resistance is observed for all of these agents
• Chloramphenicol prevents addition of new
amino acids to growing peptide chains by
interfering with binding of the amino acid-acyl-
tRNA complex to the 50S subunit, preventing
formation of a peptide bond; it displays primarily
bacteriostatic activity but is bactericidal for
selected pathogens including Streptococcus
pneumoniae, Neisseria menigitidis and
haemophilus influenzae
• Macrolides and Clindamycin bind to the same
ribosomal site, causing competitive inhibition of
the activity of chloramphenicol (antagonism),
and should not be used concurrently
• Most resistance to chloramphenicol is caused by
chloramphenicol acetyltransferase. This enzyme
catalyzes acetylation of the hydroxy groups of
chloramphenicol, which makes it unable to bind
to the 50S subunit. Less common mechanisms
of resistance stem from alterations in cell wall
permeability or ribosomal proteins
• Erythromycin reversibly binds to 50S ribosomal
subunits causing disassociation of peptidyl
transfer RNA from the ribosome and interference
with peptide elongation. The newer Macrolides
Azithromycin, Clarithromycin and dirithromycin
bind to the same site. Erythromycin inhibits the
binding of chloramphenicol to 50S ribosomes,
but chloramphenicol does not inhibit
erythromycin binding. The activity of Macrolides
is primarily bacteriostatic, but bactericidal activity
is observed for certain organisms
• Bacterial resistance to Macrolides occurs by
several mechanisms, some of which also confer
resistance to Clindamycin and Streptogramins
type B
• The most problematic forms of resistance arise
either from alteration of ribosomal binding sites or
drug efflux
a. Alteration of ribosomal binding sites occurs via a
plasmid encoded enzyme that methylates the
50Sribosomal subunit
b. Efflux systems represent another prominent
mechanism of Macrolide resistance; this type of
resistance is associated with mef genes and does
not confer resistance to Clindamycin or
Streptogramin B. For these resistance types,
complete cross-resistance exists between
erythromycin, Clarithromycin and Azithromycin
Ketolides
• A semisynthetic derivative of erythromycin, are
part of the macrolide-lincosamide-streptogramin
B (MLSB) family of antimicrobials
• Similar to Macrolides, Ketolides inhibit protein
synthesis at the 50S ribosomal subunit.
However, Ketolides demonstrate a higher
binding affinity.
• Are primarily bacteriostatic but demonstrate
bactericidal activity against some pathogens,
including S. pneumoniae and H. influenzae
Streptogramins
• Are family of compounds derived from
Streptomyces pristinaespiralis whose members
are classified into groups A and B based upon
structure
• For clinical use, two Streptogramins,
Quinupristin from group B and dalfopristin from
group A, are combined as Quinupristin-
dalfopristin in a 30:70 mixture
Oxazolidinones

• Inhibit protein synthesis by binding to the 50S

ribosomal subunit and preventing formation of
the initiation complex
• Linezolid is bacteriostatic, with activity primarily
directed against gram-positive organisms,
including those resistant to other antibiotics
• The development of resistance to Linezolid in
gram-positive organisms has been relatively
limited. Although uncommon, resistance has
been observed in vancomycin-resistant
enterococci and methicillin-resistant S. aureus
Mupirocin
• A topical agent, previously known as
pseudomonic acid, that inhibit gram-positive and
some gram-negative bacteria by binding to
isoleucyltRNA synthetase, preventing isoleucine
incorporation into bacterial proteins
• Mupirocin has been shown to eliminate the
nasal carriage of methicillin-resistant
staphylococci
Pharmacokinetics
Aminoglycosides
• Are not absorbed after oral or rectal
administration, except after oral use in newborns
with necrotizing enterocolitis. If there is renal
impairment, even the small amount of drug
absorbed by the oral route may accumulate and
cause toxicity in adults
• Peak plasma concentrations occur in 30 to 60
minutes after IM injection, with plasma
concentrations comparable to those achieved
after 30-minute infusion. Absorption from the IM
site of injection is decreased in patients in
shock, and thus IM route is rarely used to treat
life-threatening infections
• Concentrations of Aminoglycosides in CSF after
IM or IV administration are inadequate for
treatment of gram-negative meningitis.
Intrathecal administration into the lumbar space
produces inadequate intraventricular
concentrations, whereas intraventricular
instillation yields high concentration in both
areas. Subconjunctival injection produces high
aqueous fluid concentrations but inadequate
intravitreal concentrations
Spectinomycin
• Is not absorbed from the GI tract and therefore
is administered IM. Elimination is primarily by
glomerular filtration with 85% to 90% removed in
24 hours
Tetracyclines
• Some tetracyclines are incompletely absorbed,
while others are well absorbed when
administered orally, but all attain adequate
plasma and tissue concentrations. Minocycline
and doxycycline are the most completely
absorbed and chlortetracycline the least.
Absorption is favored during fasting because
tetracyclines form complexes with divalent
metals, including calcium, magnesium,
aluminum and iron.
Absorption of some Tetracyclines is decreased
when they are ingested with milk products,
antacids or iron preparations. However, food
does not interfere with absorption of minocycline
or Doxycycline and absorption is not reduced by
H2 receptor blockers
• The Tetracyclines are widely distributed in body
compartments. High concentrations are found in
liver, kidney, bile, bronchial epithelium and
breast milk. These drugs can also enter pleural,
peritoneal, synovial, and sinus fluids; cross the
placenta; and enter phagocytic cells. Penetration
into the CSF is poor and increases only
minimally in the setting of meningeal
inflammation; however minocycline achieves
therapeutic concentrations in brain tissue
• Tetracyclines do not bind to formed bone but are
incorporated into calcifying tissue and into the
dentin and enamel of unerupted teeth
Chloramphenicol
• Is well absorbed from the GI tract with peak
plasma concentrations reached about 2 hours
after ingestion
• It is also available as an inactive palmitate, most
of which is hydrolyzed by pancreatic lipases in
the duodenum, with subsequent absorption of
the active compound. Parenterally administered
chloramphenicol is available as a succinate
ester, which must be hydrolyzed to the active
compound by esterases in the liver, lungs and
kidney. The succinate should not be given IM
because the plasma concentrations are
unpredictable
• Because it is highly lipid soluble,
chloramphenicol is well distributed throughout
the body and enters pleural, ascitic, synovial,
eye, abscess and CSF and lung, liver, and brain
tissues. About 90% of a dose of chloramphenicol
is conjugated in the liver to an inactive and non
toxic glucuronide that is filtered by the kidney.
The normal plasma half-life is prolonged in
patients with hepatic disease but not in patients
with renal disease.
Erythromycin
• In its free base form is inactivated by acid.
Therefore it is administered orally with an enteric
coating that dissolves in the duodenum. Even in
the absence of food, which delays absorption,
peak plasma concentrations are difficult to
predict. Ester forms of erythromycin are
available to help overcome this problem.
Lactobionate and gluceptate, water soluble
forms of the drug, are available for IV
administrations
• Erythromycin is well distributed and produces
therapeutic concentrations in tonsillar tissue,
middle ear fluid and lung. It enters prostatic fluid,
where it reaches concentrations about one third
those in plasma. It does not diffuse well into
brain or CSF. Erythromycin crosses the placenta
and is found in breast milk, with high
concentrations also observed in liver and bile. It
achieves high concentrations in alveolar
macrophages and neutrophils
Azithromycin
• Is stable in response to acid, as compared with
erythromycin. About 37% of a dose is absorbed,
but this is greatly reduced in the presence of
food. Serum concentrations are low because of
its rapid distribution in tissues. Therapeutic
concentrations are reached in lung, genital
tissues and liver.
Azithromycin is highly concentrated in
phagocytic cells, macrophages, and fibroblasts,
from which it is slowly released. The prolonged
tissue half-life with Azithromycin allows for
shorter durations of therapy. The presence of
bacteria causes the drug to b releasedfrom
neutrophils
Clarithromycin
• Is about 55%absorbed by the oral route and is
widely distributed to lung, liver and soft tissues.
Concentrations in phagocytic cells are about nine
fold greater than those in serum. The drug is
metabolized to a 14-hydroxy derivative, which has
antibacterial activity greater than that of the parent
compound. About 30% of drug is excreted and the
remainder in feces. The half-lives of
Clarithromycin and its active metabolite are
increased in patients with declining renal function
but are not appreciably affected by hepatic
disease
Clindamycin
• Is well absorbed from the GI tract, although
absorption is delayed but not decreased in the
presence of food. Mean peak plasma
concentrations occur within 1 hour. Clindamycin
is available as a palmitate ester, which is rapidly
hydrolyzed to free drug and also available as a
phosphate ester, with the latter used for IM
administration
• Distribution is widespread, with Clindamycin
entering most body compartments and achieving
adequate concentrations in lung, liver, bone and
abscesses. It enters CSF and brain tissue, but
the concentrations are inadequate to treat
meningitis and should not be relied on to treat
brain infections except toxoplasmosis. This drug
enters polymorphonuclear leukocytes and
alveolar macrophages and crosses the placenta
Ketolides
• After oral administration, Telithromycin is well
absorbed ; however, 33% undergoes first-pass
metabolism in the liver, with 57% reaching the
systemic circulation. Absorption is not affected
by food. Telithromycin achieves high intracellular
concentrations, particularly within neutrophils
and alveolar macrophages and has extensive
penetration into respiratory and tonsillar tissues.
Metabolism occurs in the liver, with elimination
primarily in feces, and a smaller portion in urine.
Telithromycin inhibits cytochrome P450activity,
which can lead to drug interactions. Dosing does
not require modification in patients with hepatic
or renal impairment
Streptogramins
• Quinupristin and dalfopristin are water-soluble
derivatives of pristinamycin that are only
available for parenteral use. After intravenous
administration, Quinupristin-dalfopristin rapidly
achieves a wide tissue distribution but does not
have significant CSF penetration and does not
cross the placenta. High concentrations are
found in macrophages
Quinupristin-dalfopristin is metabolized in the
liver and eliminated primarily through biliary
excretion into feces. In addition, a small fraction
is excreted by the urinary system unchanged.
Dose adjustment is not required for either
hepatic or renal impairment
Oxazolidinones
Linezolid undergoes rapid and complete absorption
after oral administration, and although this is
slower when taken with food, over all
bioavailability is not affected. Linezolid penetrates
into muscle, bone, alveolar cells, and CSF; in a
small number of patients with gram-positive bone
and joint infections, intra bone tissue
concentrations of linezolid were found to be
below the MIC90 for the tested pathogens, while
joint and periarticular tissue concentrations were
twice the MIC90
Additional studies are needed to fully define
Linezolid tissue distribution. Metabolism of
Linezolid occurs by non-enzymatic oxidation
throughout the body, with the majority of
unchanged Linezolid and its primary metabolites
eliminated by urinary excretion. Dose
adjustment is not required for either mild and
moderate hepatic impairment or for renal
insufficiency. Accumulation of metabolites does
occur in renal insufficiency, but the clinical
significance is unknown
Erythromycin, Azithromycin, Clarithromycin,
and Dirithromycin
Therapeutic uses of erythromycin
Drug of choice
Mycoplasma pneumoniae, group A streptococcal URTI(penicillin-
allergic patient), legionella infection, bordetella pertussis,
campylobacter jejuni, ureaplasma urealyticum, bartonella henselae,
corynebacterium diphtheriae
Alternative Agent
Lyme disease, chlamydia infection
As Treatment of Syndromes
Bacterial bronchitis, otitis media (with sulfonamides), acne topical
Prophylaxis
Endocarditis (penicillin-allergic patient), large bowel surgery, oral
surgery
• The Macrolides, erythromycin, Azithromycin,
Clarithromycin and dirithromycin are active
primarily against gram-positive species such as
staphylococci and streptococci but also inhibit
some gram-positive bacilli. Chlamydiae, M.
pneumoniae, ureaplasma urealyticum,
legionella, corynebacterium diphtheriae,
bordetella species, campylobacter jejuni and
most oral anaerobic species are inhibited. Most
aerobic gram-negative bacilli are resistant,
though Azithromycin inhibits salmonella
• Both Azithromycin and Clarithromycin inhibit H.
influenzae but of all the Macrolides,
Azithromycin is most effective. Azithromycin and
Clarithromycin both have activity against
mycobacterium avium complex and
mycobacterium chelonae, although
Clarithromycin is more effective against the
latter. Both agents also have important activity
against helicobacter pylori
• Dirithromycin, the Macrolide most recently
approved, is generally similar to erythromycin in
it spectrum of antibacterial activity
• Erythromycin and other Macrolides are used as
an alternative to penicillin particularly in children
and especially in those with streptococcal
pharyngitis, erysipelas, scarlet fever, cutaneous
streptococcal infections and pneumococcal
pneumonia. However, levels of Macrolide
resistance in S. pneumoniae and S. pyogenes
continue to increase making therapy with
Macrolides increasingly problematic
• Despite increasing resistance, Macrolides
continue to be used widely in combination with
β-lactams in treatment of CAP because of their
excellent activity against atypical respiratory
pathogens. Although Macrolides can cure S.
aureus infections, the high frequency of resistance
does not make them an initial choice for therapy.
Azithromycin is useful for treating STD, including
ones caused by Chlamydiae(potential for
treatment with a single 1-gram dose that
significantly increases compliance), and
erythromycin can be used to treat chlamydial
pneumonia of the newborn
Trachoma can be effectively treated with a
single dose of Azithromycin. Recent data also
support the use of Azithromycin for the treatment
of travelers diarrhea. Erythromycin is also useful
for eradicating the carrier state diphtheria and
may shorten the course of pertussis if
administered early. Clarithromycin and
Azithromycin are useful in both preventing and
treating M. avium complex infections in patients
with AIDS.
Bacillary angiomatosis in patients with AIDS has
also been successfully treated with
erythromycin. Erythromycin can be used to
prevent bacterial endocarditis in penicillin-
allergic patient with rheumatic fever
Clindamycin
• Inhibits many anaerobes and most gram-positive
cocci but not enterococci or the aerobic gram-
negative bacteria haemophilus, mycoplasma,
and chlamydia. The occurrence of serious
diarrhea, including pseudo membranous colitis
from clostridium difficile, in patients taking
Clindamycin limits its use to specific conditions.
Clindamycin is useful for anaerobic
pleuropulmonary and odontogenic infections.
 It is appropriate therapy for intra abdominal or
gynecological infections in which bacteroides
organisms are likely pathogens, although
increased levels of Clindamycin resistance in
bacteroides species are increasingly common.
Clindamycin should not be used for brain
abscess if anaerobic species are anticipated
• Clindamycin is an alternative to penicillin and
may be preferable in certain situations in which
β-lactamase-producing bacteroides organisms
are present. Clindamycin is also an alternative to
penicillinase-resistant penicillins in the treatment
of staphylococcal infections but is usually not
preferred to a Cephalosporins or vancomycin
and should not be used for treatment of
endocarditis. Clindamycin may be useful for
some methicillin-resistant S. aureus infections
but inducible Clindamycin resistance may occur
in isolates resistant to erythromycin
 For severe group a streptococcal infections or
toxic shock syndrome, Clindamycin is often used
in combination with penicillin to limit bacterial
growth and reduce toxin production
• In AIDS patients with sulfonamide allergy or
intolerance, Clindamycin represents an
important component of alternative combination
treatments for central nervous system
toxoplasmosis or pneumocystis carinii
pneumonia
Ketolides
• Telithromycin displays excellent activity against
most of the pathogens causing CAP, including
atypical intracellular pathogens. Potent in vitro
activity against S. pneumoniae, H. influenzae,
moraxella catarrhalis, mycoplasma pneumoniae,
chlamydia pneumoniae and legionella
pneumophila has been demonstrated.
Telithromycin retains activity against most
penicillin-resistant and Macrolide-resistant S.
Pneumoniae regardless of Macrolide resistance
phenotype
Clinically, Telithromycin represents an additional
treatment option for CAP, acute exacerbations of
chronic bronchitis and acute sinusitis. Given its
activity against drug-resistant pneumococci,
Telithromycin may prove to be useful in the
treatment of CAP in areas with high levels of
penicillin and Macrolide resistance. Efforts to
limit overuse will be important to prevent
development of Telithromycin resistance
 Streptogramins
• Quinupristin-dalfopristin primarily inhibits the
growth of gram-positive organisms and has limited
activity against gram-negative respiratory
pathogens. Enterobacteriaceae, acinetobacter and
pseudomonas are inherently resistant to
Quinupristin-dalfopristin. Activity is demonstrated
against methicillin-susceptible and MRSA,
coagulase-negative staphylococci, vancomycin-
susceptible and resistant E. faecium, penicillin-
resistant S. pneumoniae, viridans streptococci and
S. pyogenes. Quinupristin-dalfopristin has
extremely limited activity against E. faecalis
because of an intrinsic efflux pump
• Is approved for use in the treatment of adults
with serious vancomycin-resistant E. faecium
infections and for skin and soft tissue infections
caused by methicillin-susceptible S. aureus or S.
pyogenes. It has activity against MRSA and has
been used on a limited basis for treatment of
MRSA infections that are poorly responsive to
glycopeptides; however, treatment of MRSA
infections with Quinupristin-dalfopristin is not an
FDA-approved indication
Oxazolidinones

• Displays activity against many gram-positive

pathogens, including those resistant to standard
used antibiotics; these include methicillin-
susceptible and methicillin-resistant S. aureus,
penicillin and macrolide-susceptible or
macrolide-resistant S.pneumoniae, S pyogenes
and vancomycin-susceptible or vancomycin-
resistant E. faecium and E. faecalis
Activity against aerobic gram-negative
organisms is limited. Linezolid also has activity
against mycobacteria, including mycobacterium
tuberculosis, M. avium complex and rapidly
growing mycobacteria
• Clinical indications approved for use in the U.S.
include treatment of vancomycin-resistant
enterococcal infection caused by S. aureus or
streptococci, and hospital or community
acquired pneumonia caused S. aureus or S.
pneumonia. Since linezolid is bacteriostatic,its
use for S. aureus infections associated with
bacteremia should be avoided unless alternative
agents for treatment are not available or
additional data become available to support its
use in this setting
• Currently, the primary role for linezolid is in the
treatment of VRE infections, in step-down to oral
therapy for MRSA skin and soft tissue infections
and for treatment of MRSA infections in patients
with glycopeptides intolerance or allergy; linezolid
may also be useful for treating S aureus infections
caused by isolates with reduced glycopeptides
susceptibility if the isolates are linezolid
susceptible.prudent use of linezolid should be
emphasized to avoid development of resistance;
routine use for infections caused by pathogens
susceptible to other available antibiotics should be
avoided
• Given its activity against M. tuberculosis,
linezolid may prove effective as an adjunctive
therapy in the treatment of multi-drug resistant
tuberculosis. However, further study is needed
to better define the role and efficacy of linezolid
in this setting
 Side Effects, Clinical Problems and Toxicity

Clinical Problems
Aminoglycosides
• Nephrotoxicity, vestibular toxicity, neuromuscular
blockade (infrequent)
• Tetracyclines
• Binding to bone and teeth: can be serious in
infants or children under 8 years of age and
during pregnancy; gastrointestinal tract upsets;
hepatic and renal dysfunction, vaginal candidiasis;
vertigo (minocycline); photosensitivity
Other drugs
Chloramphenicol: major hematological effects can
be fatal (aplastic anemia, bone marrow
suppression); gray baby syndrome if
glucuronidation process not well developed ( for
Chloramphenicol elimination);drug interactions
with other agents that are metabolized; optic
neuritis may result
Erythromycin: relatively safe; mild GIT
disturbances; infrequent Hepatotoxicity; drug
interaction with Theophylline (metabolism);
deafness with high doses
Clindamycin: pseudomembranous colitis;
serious rash (rare)
Telithromycin: well tolerated; inhibits cytochrome
P450 with potential for drug interactions
Quinupristin-dalfopristin: venous irritation when
given by peripheral vein; myalgias and
arthralgias; inhibits cytochrome P450 with
potential for drug interactions
Linezolid: well tolerated; gastrointestinal
complaints; thrombocytopenia; peripheral
neuropathy
Aminoglycosides

• It can produce serious side effects, with

vestibular, cochlear and renal toxicities the
most important and most common
Renal toxicity
• Reversible renal impairment develops in 55 to
25% of patients receiving an aminoglycoside for
more than 3 days. The impairment can progress
to severe renal insufficiency in a small number of
patients, but it is usually reversible. In the renal
cortex, aminoglycosides are transported across
the luminal brush border of proximal tubular cells
by binding to phosphatidyllinositol in the
cytoplasmic membrane and undergo
internalization by pinocytosis. The agents fuse
with and ultimately are trapped in the lysosomes
• Mutilamellar structures, called myeloid bodies
also accumulate in the lysosomes and
phosphatidylinositol-specfic phosphalipases are
then inhibited. These enzymes are important in
prostaglandin synthesis and the initial decrease
in Glomerular filtration that occurs in response to
aminoglycoside toxicity may result from inhibition
of vasodilatory prostaglandins. Aminoglycosides
also inhibit sphingomyelinases and adenosine
triphosphatases and alter mitochondria and
ribosomes in proximal tubular cells
• The initial manifestation of aminoglycoside renal
toxicity is an increased excretion of brush border
enzymes such as β-d-glucosaminidase,alanine,
aminopeptidase and alkaline phosphatase.
However, it is not clinically useful to monitor
excretion of these enzymes, because fever and
other factors cause similar changes. Of greater
clinical significance is the decrease in renal
concentrating, ability, proteinuria and the
appearance of casts in the urine, followed by a
reduction in the Glomerular filtration rate and a
rise in the serum creatinine concentration
• The risk factors of renal toxicity are not completely
understood despite extensive study. Toxicity
correlates with the amount of drug given and
duration of administration, but older age, female
sex, concomitant liver disease and concomitant
hypotension appear to favor the development of
toxicity. Co administration of Aminoglycosides with
vancomycin, cisplatin, cyclosporine or
amphotericin B is associated with increased renal
toxicity, as is volume depletion. Additionally, the
risk of Nephrotoxicity is higher when
Aminoglycosides are administered in two or three
divided doses compared to a single daily dose.
• Aminoglycosides themselves differ in their
Nephrotoxic potential. Neomycin is the most
Nephrotoxic and streptomycin is the least.
However, clinical trials comparing the
Nephrotoxicity of the other agents have yield
contradictory results
• Because tubules can regenerate, renal function
usually returns to normal after the drug is
cleared. A few patients whose renal function
does not return to pre treatment values require
dialysis
Ototoxicity
• Aminoglycosides can damage either or both the
cochlear and vestibular systems. Aminoglycoside-
induced ototoxicity is usually irreversible. Although
the exact frequency is unknown, some damage
probably occurs in 5% to25% of patients,
depending on the underlying auditory status and
duration of therapy
• Cochlear toxicity is a result of the destruction of
hair cells of the organ of Corti particularly the
outer hair cells in the basal turn, accompanied by
subsequent retrograde degeneration of the
auditory nerves
• Aminoglycosides also damage hair cells of the
ampullar cristae, leading to vestibular
dysfunction and vertigo. In addition,
Aminoglycosides accumulate in perilymph and
endolymph and inhibit ionic transport, the cause
of cochlear cell damage. The drug accumulates
when plasma concentrations are high for
prolonged periods, and ototoxicity is probably
enhanced by persistently elevated plasma
concentrations. Single daily high dose therapy
produces less ototoxicity
• The amount of auditory or vestibular function
loss correlates with the amount of hair cell
damage. Repeated courses of therapy continue
to cause damage to more hair cells.
Concomitant use of loop diuretics, such as
furosemide, is thought to increase the risk of
ototoxicity. The incidence of vestibular toxicity is
highest for patients who receive four weeks of
therapy or longer
• Clinical signs of auditory problems such as
tinnitus, or a sensation of fullness in the ears are
not reliable predictors of this toxicity. The initial
hearing loss is of high frequencies outside the
voice range; thus toxicity will not be recognized
unless hearing tests are performed. Eventually
the loss of hearing may progress into the
auditory range. For patients receiving prolonged
courses of Aminoglycosides, serial high
frequency audiometric testing should be
undertaken
• Vestibular toxicity is usually preceded by
headache, nausea, emesis, and vertigo, so
patients who are ill often have difficulty
identifying the onset of vestibular toxicity. These
patients may go through a series of stages from
acute to chronic symptoms that are apparent
only on standing, or the patients may achieve a
compensatory state in which they use visual
cues to adjust for the loss of vestibular function
Tetracyclines

• Although usually well tolerated, Tetracyclines

may produce adverse effects ranging from minor
to life threatening. Allergy to a tetracycline
precludes its further use. Photosensitization with
a rash is a toxic rather than allergic effect and is
most often seen in patients receiving
Demeclocycline or Doxycycline
• Effects on bone and teeth preclude the use of
tetracycline in children less than eight years of age
because a permanent brown yellow discoloration
of teeth will develop in 80%. The effect is
permanent and the enamel is hypoplastic. The
effects on bone and teeth may also result from
maternal use of Tetracyclines during pregnancy.
Thus, pregnant women should not take
Tetracyclines. Tetracyclines cause dose-dependent
GIT disturbances, including epigastric burning,
nausea and vomiting. Esophageal ulcers have also
been reported. Pancreatitis is rarely observed
• Hepatic toxicity is encountered most often in
conjunction with parenteral use but can also occur
with oral administration. Tetracyclines also
aggravate existing renal dysfunction
• Demeclocycline can cause nephrogenic diabetes
insipidus, leading to its use for the treatment of
chronic inappropriate anti-diuretic hormone
secretion. Other side effects include minocycline-
produced vertigo, particularly in women. Super
infection caused by an over growth of other
bacteria, particularly oral and vaginal candidiasis,
frequently occurs after the use of tetracyclines
Chloramphenicol

• Produces serious side effects attributed to its

action on mitochondrial membrane enzymes,
cytochrome Oxidases and adenosine
triphosphatases. Because of these adverse
effects, Chloramphenicol has limited clinical
uses, primarily when no alternative treatment is
suitable
• Its hematological effects are the most important
and regular monitoring of CBC should be
performed in patients receiving chloramphenicol.
Aplastic anemia occurs in 1:25,000 to 1:40,000
patients, with a high death rate in those in whom
an aplastic state develops or who progress to
leukemia. Aplastic anemia is usually not dose-
dependent and most often occurs weeks to
months after therapy is completed but can occur
concurrently with therapy
• A second important hematological side effect
is reversible bone marrow suppression. This
form of toxicity usually develops during
therapy, is dose-dependent and is reversible.
It is manifested by either anemia,
thrombocytopenia and leukopenia or a
combination of these
• A combination known as the gray baby
syndrome also is encountered in infants given
Chloramphenicol. This syndrome of pallor,
cyanosis, abdominal distention, vomiting and
circulatory collapse, resulting in approximately a
50% mortality rate, develops in neonates with
excessively high plasma concentration of drug.
High concentrations result from inadequate
glucuronidation and failure to excrete the drug
by the kidneys
Children less than one month of age should
receive only low doses of Chloramphenicol,
though in over dose situations excess drug can
be removed by hemoperfusion over a bed of
charcoal. Chloramphenicol also can produce
optic neutritis in children; GI side effects
including nausea, vomiting and diarrhea and
hypersensitivity rashes
• Chloramphenicol inhibits hepatic cytochrome
P450 enzymes, thereby prolonging the half-
life of phenytoin, tolbutamide, and other
drugs; barbiturates on the other hand,
decrease the half-life of Chloramphenicol
Macrolides

• Erythromycin is one of the safest antibiotics,

with GI side effects characterized by epigastric
pain, abdominal cramps, nausea and emesis
representing the most common side effects.
Intravenous administration may be associated
with thrombophlebitis. Cholestatic hepatitis
may occur in patients receiving estolate
preparations of erythromycin, usually beginning
10 to20 days into treatment and characterized
by jaundice, fever, leukocytosis, and
eosinophilia
The problem rapidly abates once drug
administration is stopped. Erythromycin at high
doses can cause reversible transient deafness.
Rarely, erythromycin use has been associated
with polymorphic ventricular tachycardia
(Torsade de pointes). Erythromycin stimulates
GI motility by acting as a motilin receptor
agonist leading to enhanced gastric emptying.
Thus, erythromycin can be used to improve
gastric motility in patients with gastroparesis.
• Erythromycin also inhibits the cytochrome P450
system, which can lead to significant drug-drug
interactions. Erythromycin prolongs the half-life of
theophylline, and this can lead to theophylline
toxicity. It also inhibits the metabolism of
carbamazepines, cyclosporine, corticosteroids,
warfarin and digoxin
• Azithromycin is generally well tolerated and has
fewer GI side effects than erythromycin. Because it
does not interfere with cytochrome P450 enzymes,
it does not have same drug-drug interactions
• Clarithromycin is similarly well tolerated,
although the incidence of intolerance caused by
GI side effects is greater than for Azithromycin
but less than for erythromycin. Clarithromycin
also inhibits cytochromeP450 and may cause
increased serum concentrations of other drugs
• Like erythromycin, dirithromycin can also cause
GI side effects. It does not interfere with
cytochrome P450 metabolism
Clindamycin
• Diarrhea may occur in up to 20% of patients
treated with Clindamycin
• The most important adverse effect of
Clindamycin is pseudomembranous
enterocolitis, estimated to occur 3% to 5% of
patients. Pseudomembranous colitis is caused
by the toxin produced by clostridium difficile. It is
characterized by diarrhea, abdominal pain, and
fever with diarrhea beginning either during or
after drug therapy. Orally administered
vancomycin or metronidazole may be needed
Ketolides
• Overall, Ketolides are well tolerated, with diarrhea
and nausea being the most commonly reported
side effects. Like erythromycin, Telithromycin
inhibits cytochrome P450 activity but does not
form complexes with cytochrome P450, which may
lead to fewer drug-drug interactions. concomitant
administration of Telithromycin with drugs known
to prolong the QTc interval, such as midazolam or
class IA or IIIA antiarrythmics should be avoided.
The potential for increased levels of cyclosporine
exists requiring diligent monitoring of cyclosporine
levels
Streptogramins

• Local inflammation, pain, and thrombophlebitis

at the infusion site may occur with quinupristin-
dalfopristin administration, particularly when
infused via a peripheral vein. Therefore,
administration usually requires central venous
access. In non comparative trials, myalgia and
arthralgia were encountered in up to 13% of
patients administered Quinupristin-dalfopristin,
but these occurred with lower frequency in
comparative trials
• Quinupristin-dalfopristin inhibits cytochrome
P450 activity creating the potential for significant
drug-drug interactions. concomitant use of
quinupristin-dalfopristin and drugs known to
prolong the QTc interval should be avoided
Oxazolidinones

• Linezolid is generally well tolerated, with the

most common side effects related to GI
complaints, including nausea and diarrhea,
headache, rash and altered taste may also
occur. Thrombocytopenia often occurring with
therapy duration greater than 2 weeks is the
most problematic side effect. The mechanism
may be related in part to reversible
myelosuppression.
Platelet counts usually normalize after Linezolid
is discontinued. Linezolid use may also be
associated with anemia. CBC should be
monitored at least weekly in patients receiving
Linezolid. Additionally, peripheral neuropathy
may develop necessitating discontinuation of
therapy
• Linezolid may interact with serotonergic agents,
resulting in an increased risk of serotonin
syndrome when administered with serotogenic
agents. Weak and reversible inhibition of
monoamine oxidase occurs with Linezolid use.
Therefore, patients taking Linezolid should avoid
eating large quantities of food with high tyramine
content