Protein Synthesis Inhibitors
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1 Protein Synthesis Inhibitors Assistant Professor Dr. Naza M. Ali 11 Nov 2018 Lec 7
2 Aminoglycosides Are structurally related two amino sugars attached by glycosidic linkages. They are bactericidal Inhibitors of protein synthesis
3 Aminoglycosides that are derived from Streptomyces have -mycin suffixes, Streptomycin Tobramycin Kanamycin Spectinomycin Neomycin
4 Those derived from Micromonospora end in - micin. Gentamicin Gentamicin Amikacin
5 Mechanism of action Susceptible gram-negative organisms allow aminoglycosides to diffuse through porin channels in their outer membranes. These organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic membrane. They have minimal activity against anaerobic.
6 Inside the cell, it bind to the 30S ribosomal subunit & interfere with protein synthesis in at least 3 ways 1)They block the formation of initiation complex. 2)They cause misreading of the code on mrna template. 3)They inhibit translocation.
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8 Mechanisms of Resistance 1) Efflux pumps, 2) Decreased uptake, and/or 3) Modification and inactivation by plasmidassociated synthesis of enzymes.
9 Antibacterial Spectrum Are effective in combination for the empirical treatment of infections suspected of being due to aerobic gram-negative bacilli, including Pseudomonas aeruginosa. To achieve an additive or synergistic effect, are often combined with a β-lactam antibiotic, vancomycin, or a drug active against anaerobic bacteria. Aminoglycosides may only be used as monotherapy for UTIs.
10 Clinical Uses I. Gentamycin, Tobramycin, Amikacin are drugs for the treatment of serious infections caused by aerobic gram negative bacteria E.coli, Enterobacter species, Klebsiella pneumoniae Proteus, Providencia, Pseudomons aeruginosa & Serratia species. also have activity against strains of Haemophilus influenzae, Moraxella catarrhalis
11 II. Streptomycin is used in treatment of T.B, plague, and tularemia. III. Spectinomycin is administered IM as a single dose for treatment of gonorrhea.
12 Pharmacokinetics and Once-Daily Dosing Aminoglycosides are absorbed very poorly from GIT Aminoglycosides are administered IV or IM After IM aminoglycosides giving peak concentrations in blood within minutes.
13 Aminoglycosides are highly polar compounds that do not enter cells readily. In the presence of active inflammation, the CFS levels reach 20% of plasma levels, and in neonatal meningitis, the levels may be higher. Even after parenteral administration, concentrations of aminoglycosides are not high in most tissues except the renal cortex.
14 Aminoglycosides have been administered in two or three equally divided doses per day in patients with normal renal function. For two reasons have concentration-dependent killing have postantibiotic effect because of these properties, once-daily dosing with the aminoglycosides can be employed. This results in fewer toxicities and is less expensive to administer.
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16 More than 90% of the parenteral aminoglycosides are excreted unchanged in urine Accumulation occurs in patients with renal dysfunction, and dose adjustments are required. All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and amniotic fluid.
17 Adverse effects Patient factors like: old age, previous exposure to aminoglycosides, and liver disease, tend to predispose to adverse reactions. The elderly are particularly susceptible to nephrotoxicity and ototoxicity.
18 1. Ototoxicity: Directly related to high peak plasma levels & duration of treatment, Deafness may be irreversible, patients receiving another ototoxic drug Vertigo & loss of balance in patients receiving streptomycin 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 impairment to severe, irreversible, acute tubular necrosis
19 3. Neuromuscular paralysis Is associated with a rapid increase in concentrations (high doses infused over a short period.) or concurrent administration with neuromuscular blockers. Patients with myasthenia gravis are particularly at risk. 4. Allergic reactions Contact dermatitis is a common reaction to topically applied neomycin.
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21 A patient with a gunshot wound to the abdomen, which has resulted in spillage of intestinal contents, is brought to the emergency room. Which antibiotic would you select to effectively treat an infection due to Bacteroides fragilis? A. Aztreonam. B. Clindamycin. C. Gentamicin. D. Azithromycin. E. Doxycycline
22 A pregnant woman was hospitalized and catheterized with a Foley catheter. She developed a urinary tract infection caused by Pseudomonas aeruginosa and was treated with gentamicin. Which of the following adverse effects was a risk to the fetus when the woman was on gentamicin? A. Skeletal deformity. B. Hearing loss. C. Teratogenesis. D. Blindness. E. Mental retardation.
23 A 30-year-old pregnant female has cellulitis caused by MRSA. Which of the following antibiotics would be the most appropriate option for outpatient therapy? A. Doxycycline. B. Clindamycin. C. Quinupristin/dalfopristin. D. Tigecycline.
24 Children younger than 8 years of age should not receive tetracyclines because these agents: A. Cause rupture of tendons. B. Do not cross into the cerebrospinal fluid. C. Are not bactericidal. D. Deposit in tissues undergoing calcification. E. Can cause aplastic anemia.
25 A 46-year-old woman is in the intensive care unit for treatment of a vancomycin-resistant strain of Enterococcus faecium caused bacteremia. She is receiving five other medications. To limit the risk of drug interactions in this woman, which one of the following antibiotics should be used? A. Azithromycin. B. Clindamycin. C. Doxycycline. D. Linezolid. E. Quinupristin/dalfopristin.
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