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PHL 424
Antimicrobials
9th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Therapeutic Uses:
 Erythromycin is the drug of choice for treating persons with B. pertussis disease
and for postexposure prophylaxis of household members and close contacts
 Erythromycin is very effective in corynebacterial infections
 Erythromycin is useful as a penicillin substitute in penicillin-allergic individuals
with infections caused by streptococci or pneumococci
 Chlamydial infections can be treated effectively with any of the macrolides

During pregnancy, erythromycin is recommended as first-line therapy for
chlamydial urogenital infections
 A macrolide or tetracycline is the drug of choice for mycoplasma infections
 Clarithromycin 500 mg, in combination with omeprazole, 20 mg, and amoxicillin,
1 g, each administered twice daily for 10 to 14 days, is effective for treatment of
peptic ulcer disease caused by H. pylori
 Penicillin is the drug of choice for the prophylaxis of recurrences of rheumatic
fever. Erythromycin is an effective alternative for individuals who are allergic to
penicillin
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Side effects :
 Serious untoward effects are rarely caused by erythromycin

Among the allergic reactions observed are fever, eosinophilia and skin
eruptions, which may occur alone or in combination; each disappears shortly
after therapy is stopped
 Cholestatic hepatitis is the most striking side effect (fever, jaundice, impaired
liver function), probably as a hypersensitivity reaction
 Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral
administration (due to a direct stimulation of gut motility)
 Drug interactions:
 Erythromycin and clarithromycin can inhibit cytochrome P450 enzymes and
thus increase the serum concentrations of numerous drugs, including
theophylline, warfarin, cyclosporine, corticosteroids and digoxin

Azithromycin appears to be free of these drug interactions
Inhibitors of bacterial protein synthesis,
Clindamycin
 Clindamycin is a chlorine-substituted derivative of
lincomycin, an antibiotic produced by Streptomyces
lincolnensis
 Lincomycin, although structurally distinct,
resembles erythromycin in activity, but it is toxic and
no longer used
 MOA:
 Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the
aminoacyl translocation reaction (see MOA of macrolides)
 The binding site for clindamycin on the 50S subunit of the bacterial ribosome is
identical with that for erythromycin
 Although clindamycin, erythromycin and chloramphenicol are not structurally
related, they act at sites in close proximity, and binding by one of these antibiotics
to the ribosome may inhibit the interaction of the others

There are no clinical indications for the concurrent use of these antibiotics
Inhibitors of bacterial protein synthesis,
Clindamycin, contd.
 Antimicrobial actions:
 Clindamycin generally is similar to erythromycin in its in vitro activity against
susceptible strains of pneumococci and streptococci
Some strains of streptococci that are macrolide-resistant remain susceptible to
clindamycin
Clindamycin is more active than erythromycin or clarithromycin against anaerobic
bacteria
 Methicillin-susceptible strains of S. aureus usually are susceptible to clindamycin,
but MRSA are resistant
 Essentially all aerobic G-ve bacilli are resistant
 Resistance mechanisms:
1. Mutation of the ribosomal receptor site
2. Modification of the receptor by a constitutively expressed methylase
3. Enzymatic inactivation of clindamycin
4. G-ve aerobic species are intrinsically resistant because of poor permeability of the
outer membrane
 Resistance to clindamycin generally confers cross-resistance to macrolides
Inhibitors of bacterial protein synthesis,
Clindamycin, contd.
 Pharmacokinetics
 Clindamycin is nearly completely absorbed following oral administration. The
presence of food in the stomach does not reduce absorption significantly
 It penetrates well into most tissues, with brain and CSF (even when the meninges are
inflamed!) being important exceptions. It penetrates well into abscesses and is actively
taken up and concentrated by phagocytic cells
 The drug is about 90% protein-bound. It is metabolized by the liver, and both active drug
and active metabolites are excreted in bile
 Therapeutic Uses:
 Clindamycin is indicated in the treatment of serious infections due to susceptible
strains of streptococci, pneumococci and staphylococci
The high incidence of diarrhea and the occurrence of pseudomembranous colitis limit
its use to infections in which it is clearly superior to other agents
 It is effective topically (or orally) for acne vulgaris and bacterial vaginosis
 It is particularly valuable for the treatment of infections with anaerobes
 It has replaced penicillin as the drug of choice for treatment of lung abscess and
anaerobic lung and pleural space infections
Inhibitors of bacterial protein synthesis,
Clindamycin, contd.
 Side effects:
 Abdominal pain, pseudomembranous colitis, esophagitis, nausea, vomiting and
diarrhea
Antibiotic-associated colitis that has followed administration of clindamycin and other
drugs is caused by toxigenic C difficile. This potentially fatal complication must be
recognized promptly and treated with metronidazole (the preferred therapy)
 Skin rashes occur in approximately 10% of patients treated with clindamycin
 Impaired liver function (with or without jaundice) and neutropenia sometimes
occur
 It can inhibit neuromuscular transmission and may potentiate the effect of a
neuromuscular blocking agent administered concurrently
Inhibitors of bacterial protein synthesis,
Aminoglycosides
 Aminoglycosides are a group of bactericidal
antibiotics originally obtained from various
streptomyces species and sharing chemical,
antimicrobial, pharmacologic and toxic
characteristics
 The group includes streptomycin, neomycin,
kanamycin, amikacin, gentamicin, tobramycin
and others
 Streptomycin is the oldest and best-studied
of the aminoglycosides
 Gentamicin, tobramycin and amikacin are the
most widely employed aminoglycosides at
present
 Neomycin and kanamycin are now largely
limited to topical or oral use
Inhibitors of bacterial protein synthesis,
Aminoglycosides, MOA
 Aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer
membrane of G-ve bacteria to enter the periplasmic space. Their transport across the
cytoplasmic membrane depends on electron transport (membrane electrical potential is
required to drive permeation of these antibiotics)
 This transport is rate-limiting and can be inhibited by divalent cations (e.g., Ca2+ & Mg2+), a
reduction in pH and anaerobic conditions. The last two conditions impair the ability of the
bacteria to maintain the membrane potential, which is the driving force necessary for
transport. Thus the antimicrobial activity of aminoglycosides is reduced markedly in the
anaerobic environment of an abscess for example
Inhibitors of bacterial protein synthesis,
Aminoglycosides, MOA
 Once inside the cell, aminoglycoside binds to the 30S ribosomal subunit and interferes
with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start
codon (AUG) of mRNA, leading to accumulation of abnormal initiation complexes, socalled streptomycin monosomes, blocking further translation of the message
Inhibitors of bacterial protein synthesis,
Aminoglycosides, MOA
 Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to:
 premature termination of translation with detachment of the ribosomal complex and incompletely
synthesized protein (B)
 incorporation of incorrect amino acids (indicated by the X), resulting in the production of
abnormal or nonfunctional proteins (C)
 The resulting aberrant proteins may be inserted into the cell membrane, leading to altered
permeability and further stimulation of aminoglycoside transport. This leads to leakage of small
ions, followed by larger molecules and, eventually, by proteins from the bacterial cell. This
progressive disruption of the cell envelope, as well as other vital cell processes, may help to
explain the lethal action of aminoglycosides