Pharmacology 3: Protein Synthesis Inhibitors Part 2 PDF

Pharmacology 3 Protein synthesis inhibitors Part 2: Aminoglycosides & Spectinomycin Dr. Lina Tamimi  Aminoglycosides Aminoglycosides are used for the treatment of serious infections due to aerobic g-ve bacilli. utility is limited...

Pharmacology 3 Protein synthesis inhibitors Part 2: Aminoglycosides & Spectinomycin Dr. Lina Tamimi  Aminoglycosides Aminoglycosides are used for the treatment of serious infections due to aerobic g-ve bacilli. utility is limited by serious toxicities. 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). Aminoglycoside structure 1- hexose ring: streptidine (in streptomycin) various amino sugars are attached by glycosidic linkages. 2- hexose ring : deoxystreptamine (in other aminoglycosides)  Agents: Streptomycin Neomycin The drugs described Kanamycin in this chapter are Amikacin bactericidal inhibitors of Gentamicin protein synthesis Tobramycin that interfere with Sisomicin ribosomal Netilmicin function. plazomicin others. Mechanism of action diffuse through porin channels organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic membrane  Inside the cell, they bind the 30S ribosomal subunit, IRREVERSABLY where they : 1- interfere with assembly of the and/or functional ribosomal apparatus 2- cause the 30S subunit of the completed ribosome to misread the genetic code 30S-subunit ribosomal proteins synthesis is inhibited by aminoglycosides in at least three ways:- (1) interference with the initiation complex of peptide formation. (2) misreading of mRNA. (3) breakup of polysomes into nonfunctional monosomes.  Antibiotics that disrupt protein synthesis are generally bacteriostatic aminoglycosides are unique …………… irreversible bactericidal. bactericidal effect is concentration dependent dependent on Cmax of drug above MIC of the organism the target Cmax is 8X to 10X times the MIC.  They also exhibit a post antibiotic effect (PAE), which is continued bacterial suppression after drug levels fall below the MIC. Because of these properties a single large dose given once daily is now more commonly utilized than divided daily doses risk of nephrotoxicity and convenience.  Against/spectrum majority of aerobic g-ve bacilli, including those that may be multidrug resistant, such as: Pseudomonas aeruginosa Klebsiella pneumoniae Enterobacter sp. aminoglycosides are often combined with a β-lactam antibiotic to employ a synergistic effect particularly in the treatment of :infective endocarditis Enterococcus faecalis Enterococcus faecium Low extracellular pH and anaerobic conditions inhibit transport by reducing the gradient. Transport may be enhanced by cell wall-active drugs such as penicillin or vancomycin; this enhancement may be the basis of the synergism of those antibiotics with aminoglycosides Typical therapeutic applications of aminoglycosides Copyright © 2015 Wolters Kluwer All Rights Reserved Resistance Resistance to aminoglycosides occurs via: 1) efflux pumps 2) ↓ uptake : porins and/or 3) modification and inactivation by plasmid-associated synthesis of enzymes that destroy aminoglycosides Each of these enzymes has its own aminoglycoside specificity; therefore, cross-resistance cannot be presumed. Pharmacokinetics 1. Absorption: The highly polar structure of the aminoglycosides prevents adequate absorption after oral administration All aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum levels  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. Once daily dosing has potential practical advantages Aminoglycosides are usually administered intravenously as Infusion After intramuscular injection aminoglycosides peak concentrations in blood are within 30–90 minutes. Once-daily : aminoglycoside dosing is safe and effective. If the creatinine clearance is > 60 mL/min a single daily dose of : 5–7 mg/kg of gentamicin or tobramycin is recommended 15 mg/kg for amikacin For patients with creatinine clearance < 60 mL/min traditional dosing is recommended. (see the last slide) 2. Distribution:  All the aminoglycosides have similar PK properties  Due to their hydrophilicity, tissue concentrations may be subtherapeutic, and penetration into most body fluids is variable.  Note: Due to low distribution into fatty tissue the aminoglycosides are dosed based on lean body mass, not actual body weight. CSF: Concentrations in are inadequate, even in the presence of inflamed meninges. CNS : infections, the intrathecal (IT) route may be utilized. Placenta: All aminoglycosides cross the placental 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.  Accumulation occurs in patients with renal dysfunction, and dose adjustments are required.  Traditionally, aminoglycosides have been administered in two or three equally divided doses per day in patients with normal renal function.  However, administration of the entire daily dose in a single injection may be preferred in many clinical situations. adverse effects Therapeutic drug monitoring of plasma levels : Gentamicin Tobramycin Amikacin is imperative to : 1- ensure adequacy of dosing 2- to minimize dose-related toxicities. 1- Ototoxicity: vestibular and auditory deafness may be irreversible affect developing foetus Vertigo (especially in patients receiving streptomycin) may also occur. Streptomycin and gentamicin are the most vestibulotoxic 2- Nephrotoxicity: kidney damage ranging from : mild reversible renal impairment to severe, potentially irreversible, acute tubular necrosis. The elderly, and in the setting of renal insufficiency are particularly susceptible to nephrotoxicity and ototoxicity. Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (eg, vancomycin or amphotericin B) can potentiate nephrotoxicity and should be avoided if possible. Neomycin, tobramycin, and gentamicin are the most nephrotoxic. 3. Allergic reactions: Contact dermatitis (itchy rash) is a common reaction to topically applied neomycin. 4. Neuromuscular paralysis: This adverse effect is associated with : 1. a rapid increase in concentrations (for example, high doses infused over a short period.) 2. concurrent administration with neuromuscular blockers. Patients with myasthenia gravis are particularly at risk. Prompt administration of : calcium gluconate or neostigmine (Ach-esterase Inh.) can reverse the block that causes neuromuscular paralysis. Therefore, aminoglycosides are contraindicated in myasthenia gravis disease Administration and fate of aminoglycosides Copyright © 2015 Wolters Kluwer All Rights Reserved Clinical uses Aminoglycosides are mostly used against gram-negative enteric bacteria……….. especially when: 1- the isolate may be drug-resistant 2- when there is suspicion of sepsis. They are almost always used in combination with a β-lactam antibiotic ???? 1- to extend coverage to include potential gram-positive pathogens 2- to take advantage of the synergism between these two classes of drugs.  Combination with Penicillin Tobramycin and gentamicin are almost always used in combination with a βlactam to extend empiric coverage and to take advantage of the potential synergy Bactericidal activity in treatment of: -enterococcal endocarditis -viridans streptococcal (Dental infections) -staphylococcal endocarditis. -osteomyelitis  Combination with antimycobacterial they are used for treatment of : drug-resistant infections ……. Mycobacterium tuberculosis Or other mycobacteria streptomycin + amikacin For Brucellosis caused by Brucella species: used in combination with doxycycline: gentamicin + doxycycline Other uses For Pseudomonas: Amikacin > tobramycin > gentamicin. For Klebsiella: amikacin = gentamicin > tobramycin Empiric use The most frequent clinical use of aminoglycosides (most commonly in combination is empiric therapy with other antibacterial agents). Once an organism has been identified and its susceptibilities determined to alternate agents aminoglycosides are usually discontinued in favor of less toxic antibiotics to complete a treatment course.  Monotherapy There are few indications for monotherapy with systemic aminoglycosides Tularemia caused by Francisella tularensis: Streptomycin and Gentamicin are first-line agents. Plague caused by Yersinia Pestis: Streptomycin and Gentamicin are first-line agents, although other options may be used in patients who cannot tolerate aminoglycosides. SPECTINOMYCIN Spectinomycin is: an aminocyclitol antibiotic structurally related to aminoglycosides. It lacks amino sugars and glycosidic bonds.  Spectinomycin is active in vitro against: many Gram-positive Gram-negative organisms but it is used almost solely as: alternative treatment for drug-resistant Gonorrhea Gonorrhea in penicillin-allergic patients.  SUMMARY Aminoglycosides bind to the 30s site ribosomal RNA disrupt bacterial peptide elongation which is usually bactericidal against susceptible aerobic gram-negative Microbiologic activity is pH-dependent: acidic environments, like those found in the lung and bronchial secretions may decrease the antimicrobial effect.  Gentamicin and Tobramycin are the most widely used drugs Amikacin is generally reserved for pathogens resistant to Gentamicin and Tobramycin Streptomycin has limited uses (Enterococcus, tuberculosis, and plague). Aminoglycosides are most frequently used in combination with another antibacterial agent for empiric therapy. Combination therapy with Gentamicin is frequently used. Netilmicin : shares many characteristics with Gentamicin and Tobramycin may be active against some Gentamicin-resistant and Tobramycin-resistant Bacteria Neomycin is generally limited to topical and oral use due to toxicity associated with parenteral use and higher resistance After oral administration, the susceptible intestinal flora is suppressed Neomycin, kanamycin, and Paromomycin have similar pharmacologic properties Kanamycin use is limited to treatment of multi-drug resistant Tuberculosis Paromomycin has been shown to be effective against visceral leishmaniasis