Protein Synthesis Inhibitors Antibiotics. Manual of Clinical Microbiology, 11th Edition Clinical Microbiology Residency Program

1. Antibacterial Agents
Manual of Clinical Microbiology, 11th Edition
Done By: Dr. Abdullatif Al Rashed (Clinical Microbiology Resident)
To reach the intracellular
ribosomal binding targets,
an aerobic energy-
dependent process is
necessary to enable
successful penetration of
the inner cell membrane
by the aminoglycosides.
Thus,
Aminoglycosides
are
INACTIVE
against anaerobic
bacteria.
• Aminoglycosides and Aminocyclitols
Types:
Gentamicin
kanamycin
Neomycin
Streptomycin
Tobramycin
Mechanisms of Action:
They also cause misreading of the genetic code, with resultant production
of nonsense proteins.
The aminoglycoside-bound bacterial ribosomes then become unavailable for
translation of mRNA during protein synthesis, thereby leading to cell death
They are bactericidal agents that inhibit bacterial protein synthesis by
binding irreversibly to the bacterial 30S ribosomal subunit.

2. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
Spectrum of Activity:
• Aminoglycoside antibiotics are active primarily against aerobic Gram-negative bacilli and
S. aureus.
o In gram negatives, they are particularly potent against the Enterobacteriaceae, P.
aeruginosa, and Acinetobacter spp.
• Certain differences in antimicrobial spectra among the various aminoglycosides do exist:
Streptomycin
Used as a multidrug
regimen in the
treatment of M.
tuberculosis
if high-level
gentamicin is resistant
in enterococci (high
level streptomycin is
used here)
Treatment of
Francisella
tularensis, &
Yersinia pestis
Gentamicin
More potent against
Serratia spp than
tobramycin
combined with a
penicillin or
vancomycin for
synergy in treatment
of serious infections
due to
staphylococci,
enterococci, or
viridans streptococci
Tobramycin
More potent
against
P.aeruginosa than
Gentamycin
Amikacin
Used when
gentamicin and
tobramycin are
resistant
Active against many
drug-susceptible
Mycobacterium spp.
Spectinomycin
Was used for N.
gonorrhoeae in
patients with
penicillin or
cephalosporin
allergy and
contraindications to
fluoroquinolone
therapy

3. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
• Aminoglycosides are only moderately active against Haemophilus and Neisseria spp.
• Of the agents active against Bartonella spp., aminoglycosides are the only drugs
consistently bactericidal toward this group of organisms
Pharmacology:
o Gastrointestinal absorption of these agents is low.
o Aminoglycosides (IV adminstration) are freely distributed in the extracellular space
but penetrate poorly into the CSF, vitreous fluid, biliary tract, prostate, and
tracheobronchial secretions, even in the presence of inflammation.
o Excreted via the kidneys.
o Monitoring of serum aminoglycoside levels in impaired renal functions patients is
essential for providing adequate therapy and reducing toxicity.
Side effects:
o Nephrotoxicity, Risk factors of this side effect are:
§ Hypotension, prolonged duration of therapy, preexisting renal insufficiency,
and excessive trough serum aminoglycoside concentrations
o Auditory toxicity:
§ More frequently associated with kanamycin and amikacin.
§ Irreversible because of selective destruction of the hair cells in the cochlea.
o Vestibular toxicity:
§ More frequently associated with streptomycin, gentamicin, and tobramycin.
§ Irreversible because of selective destruction of the hair cells in the cochlea.
o Neuromuscular paralysis:
§ Reversible
§ Occur after rapid intravenous infusion of aminoglycosides.
§ Particularly seen in myasthenia gravis or in concurrent use of
succinylcholine during anesthesia.
o Local pain and allergic skin rashes.

4. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
• Tetracyclines and Glycylcyclines
Types:
Tetracyclines Agent
Glycylcyclines Agents
Mechanisms of Action:
• Tetracyclines and glycylcyclines enter bacteria by an energy-dependent process and bind
reversibly to the 30S ribosomal subunits, preventing the attachment of aminoacyl-tRNA to
the ribosomal acceptor A site in the RNA-ribosome complex.
Spectrum of Activity:
• In general, all tetracyclines have similar antimicrobial spectra, with activities against many
Gram-positive and Gram-negative bacteria, mycoplasmas, chlamydiae, rickettsiae, and
some protozoa.
• Susceptibility testing with tigecycline should be done using freshly prepared media or
media containing a biocatalytic oxygen-reducing reagent (e.g., Oxyrase), because the drug
is prone to oxidative degradation.
Drug Name Type
Tetracycline Short-Acting Drug
demeclocycline Intermediate-Acting Drug
doxycycline and Minocycline Long-Acting Drugs
Type
Tigecycline
Omadacycline (still not FDA approved)
Eravacycline (still not FDA approved)

5. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
Pharmacology:
• Tetracyclines are bacteriostatic and they are incompletely absorbed from the
gastrointestinal tract, but their absorption is improved in the fasting state.
• Ingestion of food, especially dairy products, and other substances, such as divalent and
trivalent cation containing antacids and iron preparations, impairs the absorption of these
drugs.
• Tissue penetration of these drugs is excellent, but levels in CSF are low even in the presence
of meningeal inflammation.
• Tetracyclines cross the placenta and into fetal bone and teeth. They are excreted in high
concentrations in human milk. Therefore, tetracyclines are not advised for pregnant or
lactating women.
• Tigecycline is administered as an IV formulation because of limited oral bioavailability.
• Tigecycline has a rapid and wide distribution into tissues, including bone. Penetration into
CSF in patients with or without meningitis is marginal.
Drug Active Against Inactive against
Tetracyclines S. aureus; S. pyogenes; S. pneumoniae;
Burkholderia pseudomallei; Brucella spp.;
Vibrio spp.; Mycobacterium marinum;
Nocardia spp.; Acinetobacter spp. and S.
maltophilia; C. trachomatis; U. urealyticu;
M. hominis; Treponema pallidum; B.
burgdorferi; Plasmodium falciparum;
Entamoeba histolytica; some anaerobes
• A percentage of E. coli isolates are now doxycycline
and minocycline resistant.
• Pseudomonads and many Enterobacteriaceae are
resistant.
• Most strains of Shigella and Salmonella spp. are
resistant.
• Resistance is prevalent among N. gonorrhoeae strains
Tigecycline Most staphylococci, including MRSA and
VISA; vancomycin susceptible and resistant
enterococci; Viridans group streptococci;
beta-hemolytic streptococci; MDR
pneumococci; Enterobacteriaceae; non
lactose fermenter Gram negatives; MDR A.
baumannii; S. maltophilia; H. influenzae;
M. catarrhalis; B.fragili; Clostridium spp.;
Prevotella spp.; Propionibacterium;
Fusobacterium; M. pneumonia; M.
hominis; C. pneumoniae; C. trachomatis;
M. abscessus; M. chelonae; members of the
M. fortuitum group,
• P. aeruginosa is resistant to tigecycline.
• Proteus, Morganella, and Providencia are resistant
• It is less active toward U. urealyticum and Legionella
spp.
• M. kansasii, M. marinum, and M. xenopi are less
susceptible to tigecycline.

6. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
Side effects:
Esophageal
ulcerations
Vomiting,
Diarrhea
Epigastric
distress
Nausea Pseudomembranous
colitis
Morbilliform
rashes
Photosensitivity
reactions
Pseudotumor
cerebri and
Vertigo (in
minocycline)
Aggravates
Renal
failure
Urticaria,
Anaphylaxis
In pedia,
Depression of bone
growth, permanent
discoloration of the
teeth, and enamel
hypoplasia
Fixed Drug
Eruptions,
• Macrolides:
Types:
• Erythromycin | Clarithromycin | Azithromycin.
Mechanisms of Action:
• They bind reversibly to the 23S rRNA of the 50S ribosomal subunits of susceptible
organisms, thereby blocking the translocation reaction of polypeptide chain elongation.
Spectrum of Activiy:
• Macrolides are relatively broad-spectrum antibiotics, with activity against Gram-positive
and some Gram-negative bacteria, mycoplasmas, chlamydiae, treponemes, and rickettsiae.
o Clarithromycin is the most active drug in this class against C. pneumoniae and
legionella.
o Clarithromycin is 2-to4-fold more potent than the other macrolides, and
azithromycin is less active than erythromycin against most staphylococci and
streptococci.
o Clarithromycin is widely considered the gold standard agent against atypical
mycobacteria.
o MRSA and many enterococci are resistant to all macrolides.
o They are active against Corynebacterium spp., L. monocytogenes, and Actinomyces
israelii
o H. influenzae and M. catarrhalis are more susceptible to azithromycin.
o All macrolides are equally potent against Bordetella pertussis and M. pneumoniae.
o Macrolides are active against Campylobacter spp., H. pylori, P. multocida, N.
meningitidis, and Borrelia burgdorferi.
They are Bacteriostatic agents but may be
bactericidal at high drug concentrations and
against a low inoculum of bacteria

7. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
o They are active against STD pathogens N. gonorrhoeae, Haemophilus ducreyi, C.
trachomatis, and U. urealyticum, but only azithromycin is active against
Mycoplasma hominis.
o Azithromycin as a 2-g dose is suggested as a possible third-line therapy in early-
syphilis patients who cannot tolerate penicillin G or doxycycline.
o Azithromycin is effective as an alternative to tetracyclines for the treatment of
genital chlamydial infections.
o The macrolides have good activity against anaerobic bacteria, except:
§ Have poor activity against Fusobacterium nucleatum, Clostridium
innocuum, and Lactobacillus spp.
o Clarithromycin and azithromycin have comparable activities against Toxoplasma
gondii and are alternative therapies for this organism
Pharmacology:
Side effects:
o Abdominal cramps, nausea, vomiting, and diarrhea, (MOST COMMON)
o Thrombophlebitis. (with IV erythromycin infusion)
o Hypersensitivity reactions.
o Cholestatic hepatitis.
o Reversible hearing loss.
o Pseudomembranous colitis. (RARE)
o Superinfection of the gastrointestinal tract or vagina with Candida spp. or Gram-
negative bacilli. (RARE)
o Erythromycin is a potent inhibitor of cytochrome P450 enzymes.
o Azithromycin increases risk of sudden cardiac death due to cardiac dysrhythmias.
Drug Pharmacology
Erythromycin 1) Available in various topical, parenteral, and oral
2) They penetrate poorly into the brain and CSF, but they do cross the placenta and are excreted in breast milk.
3) Metabolized by the liver and excreted primarily in the bile.
Clarithromycin 1) Available only in oral forms
2) They penetrate poorly into the brain and CSF, but they do cross the placenta and are excreted in breast milk.
3) Metabolized by the liver and excreted primarily in the bile.
4) Dosage adjustment is necessary with moderate to severe renal failure
Azithromycin 1) azithromycin is formulated for oral and intravenous administration.
2) They penetrate poorly into the brain and CSF, but they do cross the placenta and are excreted in breast milk.
3) Excreted largely unchanged in the bile.

8. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
potent activity
against
intracellular
bacteria
H. influenzae
M. catarrhalis
Enterococci
N
S. aureus and coagulase-
negative staph
negative staphylococci
Pediococcus,
Leuconostoc,
Stomatococcus, and
Rhodococcus equi
Potent activity against
respiratory pathogens Gram-positive bacilli
§ Azithromycin use may lead to potentially fatal irregular heart rhythms.
§ The risk is highest in patients with a history of cardiac dysrhythmias,
electrolyte abnormalities, or concurrent use of cardiac antiarrhythmic
medications.
• Ketolides:
Types:
Ketolides are semisynthetic derivatives of erythromycin A:
o Telithromycin:
§ The first and only ketolide currently approved for clinical use in the United
States.
o Cethromycin and Solithromycin:
§ Still not FDA approved.
Mechanism of Action:
Spectrum of Activity:
Also inhibit the formation of the 30S ribosomal unit
Like the macrolide antibiotics, ketolides inhibit bacterial protein synthesis in
susceptible organisms by binding to the bacterial 23S rRNA at domains II and V of
the peptidyltransferase site in 50S ribosomal subunit 47
They have poor activity against Gram-
negative bacilli, including the Entero-
bacteriaceae, Acinetobacter spp., P.
aeruginosa, and Borrelia burgdorferi

9. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
Pharmacology:
• Telithromycin is administered orally as a once-daily dose of 800 mg, with rapid
gastrointestinal absorption.
• The drug penetrates well into bronchopulmonary, tonsillar, and sinus tissues and into
middle ear fluid, and it is accumulated by polymorphonuclear neutrophils.
• Hepatic metabolism with elimination via feces (∼80%) is the main route of excretion,
and <15% of the administered dose is eliminated in urine.
• Dosage adjustments are not necessary in patients with renal or hepatic impairment.
Side effects:
o Hepatotoxicity and respiratory failure in myasthenia gravis.
o Diarrhea, nausea, vomiting, and dizziness.
o Elevation of serum transaminase levels.
o Lengthen of the QT interval when given with by CYP3A4 inhibitors, such as
the triazole antifungal agents.
• Lincosamides:
Types, Pharmacology and side effects:
Mechanism of Action:
• Lincosamides bind to the 50S ribosomal subunits of susceptible bacteria and prevent
elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing
protein synthesis.
• Clindamycin can be bactericidal or bacteriostatic, depending on the drug con-
centration, bacterial species, and inoculum of bacteria.
Type Pharmacology
Clindamycin
• Oral, topical and IV forms.
• Distributes well into bone, lungs, pleural fluid, and bile, but it penetrates poorly into
CSF, even in patients with meningitis.
• Crosses the placenta and enters fetal tissues.
• Clindamycin is actively concentrated in neutrophils and macrophages.
• Metabolized by the liver and excreted in an inactive form in the urine.
Lincomycin ----
Side effects: Clindamycin-associated diarrhea, Pseudomembranous colitis caused by toxin-producing C. difficile, skin
rashes, fever, and reversible elevation of serum transaminases, blocking neuromuscular transmission (RARE)

10. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
Spectrum of Activity:
• Clindamycin is one of the most potent activity against anaerobic bacteria
including:
o B. fragilis group, Fusobacterium, and Clostridium and others.
• Clindamycin is active against aerobic Gram-positive Cocci including:
o MSSA, S. pneumoniae, and group A and viridans group streptococci
o Community acquired MRSA strains often susceptible to clindamycin.
• Enterococci and all Enterobacteriaceae are uniformly resistant to the
lincosamides.
• Clindamycin is also effective in combination with pyrimethamine for
toxoplasma encephalitis and in combination with primaquine for Pneumocystis
jirovecii pneumonia.
• Clindamycin phosphate and benzoyl peroxide as a gel is used for the topical
treatment of acne vulgaris.
• Oxazolidinones:
Types, Pharmacology, Mechanism of Action and side effects:
Drug Name Pharmacology Mechanism of Action
Linezolid
• Linezolid is available in oral and parenteral
forms.
• The drug is metabolized primarily in the liver.
• It is well distributed in all body tissues,
including the CSF
• The drug is eliminated via the kidneys.
• No dose adjustment is necessary in patients
with renal insufficiency or mild to moderate
hepatic impairment,
• Oxazolidinones in general inhibit bacterial protein
synthesis by preventing the formation of a functional
initiation complex of tRNAfMet ribosome, mRNA,
initiation factors, and the ribosome.
• Linezolid binds to the domain V region of 23S rRNA in
the 50S ribosomal subunit, thereby distorting the binding
site for tRNAfMet and inhibiting the formation of a
functional 70S initiation complex, thus preventing
initiation of mRNA translation.
• Side effects:
• Diarrhea, headache, nausea (Most Common)
• Optic neuropathy, peripheral neuropathy, myelosuppression. (with prolonged use)

11. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
Spectrum of Activity:
• Linezolid is generally inactive against Gram-negative bacteria because of endogenous efflux
pumps present in these organisms.
• Linezolid is an important therapeutic option for skin and soft tissue infections, respiratory tract
infections and infections due to MRSA and vancomycin-resistant enterococci.
Linezolid activity against
staphylococci including MRSA, streptococci, and MDR
enterococci
Actinomyces spp., Bacillus cereus, Corynebacterium spp.,
Leuconostoc, Pediococcus, R. equi, L. monocytogenes
Clostridium spp., and Gram-positive anaerobic cocci
Mycobacterium spp. and Nocardia spp.

12. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
At therapeutic concentrations achievable in the serum, it can be bactericidal
against common meningeal pathogens, such as S. pneumoniae, N.
meningitidis, and H. influenzae
The drug is a bacteriostatic agent that inhibits protein synthesis by binding reversibly
to the peptidyltransferase component of the 50S ribosomal subunit and preventing the
transpeptidation process of peptide chain elongation.
• Chloramphenicol:
Mechanism of Action:
Pharmacology
• Chloramphenicol is available for topical, oral, or parenteral use.
• It diffuses well into many tissues and body fluids, including CSF, where levels are generally 30
to 50% of concentrations in serum even without meningeal inflammation.
• It crosses the placental barrier and is present in human milk.
• It is metabolized and inactivated by glucuronidation in the liver and excreted by the kidneys.
• Careful monitoring of serum chloramphenicol levels, maintaining peak concentrations in serum
in the therapeutic range of 10 to 20 μg/ml, is useful for ensuring therapeutic efficacy and
reduced toxicity.
• Dosage modification is not necessary in the presence of renal insufficiency.
Spectrum of Activity
• Chloramphenicol is active against many Gram-positive and Gram-negative bacteria,
chlamydiae, mycoplasmas, and rickettsiae.
• It is inactive against MRSA and methicillin-resistant S. epidermidis and is variably active
against enterococci.
• N. meningitidis, H. influenzae (ampicillin-resistant and -susceptible strains), and most
Enterobacteriaceae are susceptible.
• Its activities against Serratia and Enterobacter isolates are varied, and strains of Pseudomonas
spp. are usually resistant.

13. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
• Salmonellae, including Salmonella enterica serovar Typhi, are also susceptible, but resistant
isolates are being encountered.
• Chloramphenicol is active against anaerobic bacteria, including members of the B. fragilis
group.
• It is active against Rickettsia spp. and Coxiella burnetii.
Side effects:
o Bone marrow toxicity
o Gray baby syndrome:
§ Characterized by vomiting, abdominal distention, cyanosis,
hypothermia, and circulatory collapse,
§ May occur in premature infants and neonates treated with
chloramphenicol.
o Reversible optic neuritis. (with prolonged therapy)
o Hypersensitivity reactions, including skin rashes, drug fevers, and anaphylaxis.
o It potentiates the actions of warfarin, phenytoin, and oral hypoglycemic agents
by competitive inhibition of hepatic microsomal enzymes.

14. Antibacterial Agents Manual of Clinical Microbiology, 11th Edition
• Streptogramins:
Types, Pharmacology, Mechanism of Action and side effects
Spectrum of Activity
Streptogramins are active mainly against Gram-positive bacteria, Not active
against selected Gram-negative and anaerobic pathogens.
Quinupristin-Dalfopristin
Active Against Inactive Against
• MSSA, MRSA.
• Coagulase negative staphylococci.
• Streptococci.
• E. faecium. (including VRE)
• N. meningitidis, N. gonorrhoeae, M.
pneumoniae, C. pneumoniae.
• Legionella pneumophila, M. catarrhalis.
• H. influenzae.
• Anaerobic bacteria.
• E. faecalis is intrinsically
resistant.
• Enterobacteriaceae other nonfermenting Gram-
negative bacilli are resistant
Types Pharmacology Mechanism of Action
Group A
streptogramins
(pristinamycin
II and
pristinamycin
II)
-----------------
• The streptogramins exert a synergistic
bactericidal effect on susceptible organisms by
inhibiting bacterial protein synthesis.
• They enter bacterial cells via passive diffusion
and then bind specifically and irreversibly to the
50S subunits of the 70S bacterial ribosomes.
• Group A streptogramins prevent peptide bond
formation during the chain elongation step,
while group B components cause release of the
incomplete peptide chains from the 50S
ribosomal subunit
Group B
streptogramins
(Quinupristin-
Dalfopristin)
• Quinupristin-dalfopristin is administered intravenously,
with distribution into most tissues.
• Rapidly cleared from plasma via biliary excretion by
hepatic conjugation processes.
• Less than 20% of the drug is excreted in the urine.
• The drug does not cross a noninflamed blood-brain
barrier or placenta to any significant degree.
• Dosage adjustment is needed for patients with renal
insufficiency
Side Effects: Phlebitis at the site of intravenous infusion, Reversible arthralgias and myalgia (most common), Elevated levels
of serum transaminases, Itching, Burning, and Erythema of the face, neck, or upper body.