Chapter 35 Antibacterial Drugs
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Bacterial cell wall structure
Multiple sites of inhibition by antibacterial agents
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Inhibitors of Cell-Wall Synthesis
Disadvantages of Penicillin G
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Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 724.
Mechanisms by which bacteria develop resistance to ß-Lactams is through alteration of penicillin-binding proteins (PBPs)
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Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 725.; Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859.
Penicillins (Penicillin G): Activity Profile: Effective Against: |
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Gram
Positive Organisms Gram-negative cocci Non-ß-lactamase producing anaerobes |
Antistaphylococcal
penicillins (nafcillin (Nafcil, Unipen)) are ß-lactamase
resistant: Effective Against: |
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Staphylococci Streptococci |
Extended Spectrum Agents (nafcillin (Nafcil, Unipen)); penicillinase sensitive: Effective Against: |
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Antibacterial
Spectrum of Penicillins Better activity against gram-negative organisms |
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 862-863; Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 724.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859. |
Acid and ß-Lactamase Resistant Penicillins
Acid Stable Penicillins include Carbenicillin, Indanyl, ampicillin (Principen, Omnipen), *nafcillin (Nafcil, Unipen), * dicloxacillin (Dynapen),*Cloxacillin (Cloxapen), oxacillin (generic), Penicillin V (Pen-Vee K, Veetids). [*: ß-lactamase (Penicillinase resistant)]
*Overall incidences is estimated to be between 0.7% to 10%.
Mandell, G.L. and Petri, W. A. Antimicrobial Agents: Penicillins, Cephalosporins, and other ß-Lactam Antibiotics.,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1086-1088) |
note: all penicillins (excepting semisynthetic, penicillinase-resistant antistaphylococcal agents) can be hydrolyzed by ß-lactamases enzymes and will not be efficacious against bacterial strains that produce this enzyme. |
Penicillin (Penicillin G) Effective Against: Staphylococci-non beta-lactamase producing, streptococci non-beta-lactamase producing, Bacillus anthracis, enterococci, Meningococci, Actinomyces, Spirochetes, Clostridium, Gram-positive rods.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 728.
As noted earlier penicillins may be sensitive to beta-lactamase producing bacteria. Those penicillins resistant to beta-lactamase producing staphylococcal strains include: methicillin (Staphcillin), nafcillin (Nafcil, Unipen) and certain isoxazolyl penicillins such as oxacillin (generic), cloxacillin (Cloxapen), and dicloxacillin (Dynapen)
Clinical Indications for penicillins resistant to beta-lactamase producing staphylococcal strains.
The primary indication would of course the infection by beta-lactamase producing staphylococcal organisms. However, other susceptible bacteria include penicillins susceptible strains of streptococci and pneumococci. These drugs however all are enacted against enterococci, anaerobic bacteria, gram-negative cocci and rods.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 729.
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1 Sydney M. Finegold "Anaerobic Gram-Negative Bacilli" in Medical Microbiology (4th edition) edited by Samuel Baron, M.D., The University of Texas Medical Branch, http://gsbs.utmb.edu/microbook/ch020.htm Klebsiella pneumoniae Serratia (a, left) Image credit: Shirley Owens and Catherine McGowan, Microbe Zoo
http://www.laboratoria.khv.ru/std/gallery_std2/proteus.htm
2 M. Neal Buentzel "Escherichia, Klebsiella, Enterobacter, Serratia, Citrobacter, and Proteus" in Medical Microbiology (4th edition) edited by Samuel Baron, M.D., The University of Texas Medical Branch, http://gsbs.utmb.edu/microbook/ch026.htm
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Mandell, G.L. and Petri, W. A. Antimicrobial Agents: Penicillins, Cephalosporins, and other ß-Lactam Antibiotics.,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1089-1092
More about Cephalosporins
First Generation Cephalosporins are rarely a drug of choice. However, these agents are very active against gram-positive cocci, but are not active against methicillin (Staphcillin)-resistant isolates of staphylococci. First-generation agents are excreted by glomerular filtration and tubular secretion which may be blocked by probenecid (Benemid).
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 732-733.
Second Generation Cephalosporins exhibit activity against gram-positive cocci with an extended gram-negative spectrum compared to first-generation agents. Second generation drugs are active against beta-lactamase producing H.influenzae. Furthermore, good activity is exhibited against anaerobes which is a particularly useful characteristic in mixed infections such as peritonitis.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 734.
Third Generation Cephalosporins are generally more active against gram-negative organisms (except for the drug cefoperazone (Cefobid)). Some members of this group have enhanced ability to cross the blood-brain barrier.
Third-generation drugs tend to exhibit activity against Citrobacter, Serratia marcescens and Providencia and ß-lactamase producing Haemophilus and Neisseria.
Third generation cephalosporins are effective in treating a large variety of infections resistant to many other drugs
Ceftriaxone (Rocephin) and and cefixime (Suprax) are first-line antibiotics for treating gonorrhea.
Third generation agents cross the blood brain barrier and are effective in treating menningitis caused by pneumococci, meningococci, H. influenzae and susceptible gram negative rods (not by Listeria monocytogenes)
Ceftriaxone (Rocephin) and cefotaxime (Claforan) are the most active cephalosporins against penicillin-resistant pneumococci.
Third generation agents may not be effective in treating menningitis caused by highly penicillin-resistant strains and treatment may require addition of vancomycin (Vancocin) or rifampin (Rimactane)
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 734-735.
Specific First Generation Cephalosporin Drugs
First generation cephalosporins include: cephalexin (Keflex), cephradine (Velosef), cephalothin (Keflin), cefadroxil (Duricef, Ultracef),and cephapirin (Cefadyl)
First generation cephalosporins are administered orally an exhibit a fairly broad spectrum of action while being relatively nontoxic.
These agents appear suitable for treatment of urinary tract infections (UTI), cellulitis or soft tissue abscess.
Oral cephalosporins not indicated for serious systemic infections.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 734.
Specific Second Generation Cephalosporin Drugs
Review & Overview: Second Generation Cephalosporins
Second generation agents are active against gram-positive cocci an exhibit an extended gram-negative spectrum compared to first generation drugs.
Second generation drugs are generally effective against beta-lactamase reducing H.influenzae.
They exhibit good activity against anaerobes and are effective in mixed-infections, as an example, peritonitis.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 734
Examples of second generation cephalosporins:
Cefaclor (Ceclor), cefamandole (Mandol), cefaclor (Ceclor), and cefonicid (Monocid).
Cefuroxime (Zinacef, Ceftin) is effective in community-acquired pneumonia or take your leave the causative organism may be beta-lactamase producing H.influenzae or Klebsiella pneumoniae. Cefuroxime (Zinacef, Ceftin) is the only second-generation drug across the blood-brain barrier, although third-generation agents such as ceftriaxone (Rocephin) or cefotaxime (Claforan) or more effective in managing meningitis.
Cefprozil (Cefzil) ceforanide (Precef).
Cefmetazole (Zefazone) cefotetan (Cefotan) and Cefoxitin (Mefoxin) are effective in mixed anaerobic infections due to activity against anaerobes (e.g. B. fragilis)
Specific Third Generation Cephalosporin Drugs
Review & Overview: Third Generation Cephalosporins
Generally, third-generation drugs are more active against gram-negative microbes (except cefoperazone) and exhibit enhanced ability (in some cases) to traverse the blood brain barrier.
These agents areActive against Citrobacter, Serratia marcescens and Providencia and ß-lactamase producing Haemophilus and Neisseria.
Third generation cephalosporins are effective in treating a large variety of infections resistant to many other drugs.
Ceftriaxone (Rocephin) and and cefixime (Suprax) are first-line antibiotics for treating gonorrhea.
Third generation agents cross the blood brain barrier and are effective in treating menningitis--caused by pneumococci, meningococci, H. influenzae and susceptible gram negative rods (not by Listeria monocytogenes)
Ceftriaxone (Rocephin) and cefotaxime (Claforan) most active cephalosporins against penicillin-resistant pneumococci.
Third generation agents may not be effective in treating menningitis caused by highly penicillin-resistant strains and treatment may require addition of vancomycin (Vancocin) or rifampin (Rimactane)
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 734-735.
Examples of third generation cephalosporins:
Ceftazidime, Cefoperazone are effective against P. aeruginosa. (Third-generation cephalosporins are hydrolyzed by enterobacter chromosomal ß-lactamase)
Cefotaxime (Claforan)
Ceftizoxime (Cefizox)
Ceftriaxone, Cefixime
Drugs of choice in treatment of gonorrhea since many isolates of N gonorrhoeae are penicillin resistant
Proxetil
Cefibute
Moxalactam
Cefepime, although classified as a fourth-generation agent, exhibits many properties of third-generation cephalosporins. Cefepime (Maxipime) is somewhat more resistant to hydrolysis by beta-lactamases and exhibits activity against certain beta-lactamases which inactivate many third-generation drugs.
Cefepime (Maxipime) exhibits activity against most penicillin-resistant strains of streptococci and has been considered effective in management of Enterobacter infections. At this agent also exhibits effectiveness against Staphylococcus aureus, Staphylococcus pneumoniae, Enterobacteriaceae and P. aeruginosa.
Generally, cefepime (Maxipime) may be considered clinically comparable to most third-generation cephalosporins.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 732-736;Chambers, H.F., Beta-Lactam Antibiotics & Other Inhibitors of Cell Wall Synthesis in Basic and Clinical Pharmacology, (Katzung, B. G., ed), Appleton-Lange, 2001, p. 766.
Other ß-lactam containing antibacterials
Aztreonam (Azactan)
Aztreonam (Azactan) is a synthetic monobactam antibiotic, having a moncyclic, rather than a bicyclic nucleus.
This agent inhibits synthesis of bacterial cell wall by high-affinity binding to penicillin-binding protein (PBP3 ) which is found primarily in aerobic, Gram-negative microbes.
Aztreonam (Azactan) is highly resistant to ß-lactamases.
Spectrum of activity includes aerobic, Gram-negative bacterial and is similar in activity to aminoglycosides without causing ototoxicity or nephrotoxicity.
Aztreonam (Azactan) is effective in treating Gram-negative urinary tract infections, lower respiratory tract, skin, intraabdominal, gynecologic infections and septicemia.
This drug may be used in combination with other antibiotics which are active against Gram-positive microbes and anaerobes in mixed infections.
Contraindications for Aztreonam (Azactan): safe use during pregnancy (category B), in nursing women, infants and children has not established.
Cautious use: hypersensitivity history to penicillin, cephalosporins; impaired renal or liver function.
Aztreonam (Azactan) exhibits activity against Hemophilus influenzae, Pseudomonas aeruginosa, Neisseria gonorrhoeae and Enterobacteriacea including most isolates of E . coli, Enterobacter, Klebsiella, Proteus, Providencia, Shigella, Salmonella, and Serratia.
Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 166-167.
Imipenem Premaxin, Meropenem
- Combination of imipenem, a ß-lactam antibiotic, and cilastin which inhibits dipeptidase enzyme degradation of imipenem. Without cilastin renal dehydropeptidases inactivate the drug which results in low urinary tract concentrations.
Imipenem inhibits bacterial cell wall mucopeptide synthesis and is bacteriocidal.
very wide spectrum among the ß-lactams, providing good coverage of gram-negative rods, gram-positive bacteria, and anaerobes.
ß-lactamase resistant.
Not Effective in treating: Enterococcus faecium, methicillin-resistant strains of staphylococci, Claostridium difficile, Burkholderia cepacia and Stenotrophomonas maltophilia.
Synergistic actions with aminoglycoside antibiotics against some strains of Pseudomonas aeruginosa. Combination with an aminoglycoside is recommended because of Pseudomonas rapidly develops resistance to imipenem.
Agent of choice for treating Enterobacter infections.
Meropenem has somewhat great antibacterial effects against gram-negative aerobes and slightly less activity against gram-positive organisms.
Meropenem is less seizure producing compared to imipenem.
Effective in treating these infections: urinary tract lower respiratory tract bones joints skin intra-abdominal
gynecological mixed infections endocarditis bacterial septicemia
Contraindications:
Contraindicated: hypersensitive patients
safe use in pregnancy (category C) or in children <12 not established.
Caution use: nursing mothers
Cautious use: patient with CNS disorders including seizures, brain lesions; renal impairment
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 737..;Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 614-615.
Clavulanic acid, Sulbactam, Tazobactam
Clavulanic acid, sulbactam and tazobactam are potent inhibitors of many bacterial ß-lactamases.
These agents are given together with hydrolyzable penicillins to protect them from inactivation.
Most effective against plasmid-encoded beta-lactamases including those produced by:
- staphylococci
- H. influenzae
- N. gonorrhoeae
- Salmonella
- Shigella
- E. coli
- K. pneumoniae
Not effective inhibitors of inducible chromosomal ß-lactamases which are produced by Enterobacter, Citrobacter, Serratia, Pseudomonas.
These similar drugs are given in fixed combination with specific penicillins which determines the antibacterial spectrum.
The ß-lactamase inhibitors can extend the spectrum of an antibiotic, e.g. ampicillin in combination with sulbactam is effective against ß-lactamase producing S. aureus and H. influenzae.
Effectiveness is dependent upon the variant of ß-lactamase enzyme produced.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 736-737.
Other Inhibitors of Cell-Wall Synthesis
Vancomycin
Vancomycin, a glycopeptide, is active only against gram-positive bacteria, especially staphylococci {one exception is that it is active against Flavobacterium}
Vacomycin is an inhibitor of bacterial cell wall synthesis by preventing peptidoglycan elongation and cross-linking.
Critical resistance to the antibacterial action of vancomycin is due to a modification of its peptidoglycan binding site, a modification that reduces binding affinity.
Vancomycin is bacteriocidal for gram-positive bacteria including ß-lactamase producing staphylococci and those resistant to nafcillin and methicillin.
Vancomycin kills only dividing cells and relatively slowly.
Vancomycin acts synergistically with gentamicin and streptomycin (aminoglycosides) against E. faecium and E. faecalis isolates not resistant to aminoglycosides.
Major Clinical Use
Sepsis
Endocarditis due to methicillin resistant staphylococci
note:Methicillin-susceptible Staph isolates would be more effectively treated with methicillin than vancomycin.
Treatment alternative enterococcal endocarditis.: Vancomycin with gentamycin: for patient allergic to penicillin.
Vancomycin incombination with cefotaxime, ceftriaxone or rifampim: appropriate for treatment of mennigitis when the suspected infecting agent is thought/known to be highly penicillin resistant.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 737-739.
Bacitracin
Bacitracin is a cyclic peptide mixture that is active against gram-positive microbes.
Bacitracin inhibits cell wall formation by interfering with peptidoglycan transfer to the developing cell wall and exhibits no cross-resistance between bacitracin and other antimicrobials.
Due to systemic toxicity, bacitracin is limited to topical use.
Major Clinical Use
Alone or in combination with polymyxin or neomycin: treatment of mixed skin, wound or mucous membrane infections.
Adverse Effects
Significant nephrotoxicity with systemic administration
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 739.
Cycloserine
Cycloserine, a structural analog of D-alanine, inhibits both Gram-positive and Gram-negative bacteria.
Mechanism of action is inhibition of D-alanine incorporation into peptidoglycan by inhibiting alanine racemase (which converts L-alanine to D-alanine) and D-alanyl-D-analanine ligase
Major Clinical Use
Used almost exclusively for treating tuberculosis caused by M. tuberculosis isolates resistant to primary drugs.
Adverse Effects
CNS toxicity at higher than clinical doses
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 739-740
Membrane-Active Agents
Mechanisms of action of polymixin and gramicidin antibacterial action & Clinical uses of these agents
Polymixins
Polymixins (polymixin E) are amphipathic (containing lipophilic and lipophobic groups) basic peptides which exhibit activity against gram-negative bacteria.
They are bacteriocidal for many gram-negative rods including Pseudomonas.
Polymixins disrupt bacterial cell membranes through strong interactions with phospholipid components.
Gram-positive bacteria, Proteus, Neisseria are resistant to polymixins.
Polymixin B sulfate used topically for treatment of external otitis and corneal ulcers due to Pseudomonas aeruginosa.
Systemic use of polymixins not recommended becasue of poor tissue distribution, significant nephrotoxicity and neurotoxicity and the availability of more effective other antibacterial drugs.
Polymixin E is active against:
Pseudomonas aeruginosa
Escherichia coli
Enterobacter
Klebsiella
Clinical Applications of Polymixin B
Skin, mucous membrane, eye and ear infections (for sensitive organism).
For example, external otitis (Pseudomonas) or corneal ulcers (Pseudomonas aeruginosa
Sometimes used by aerosol as an adjunct to other antibiotics in difficult cases of Pseudomonas pneumonia.
Chambers, H.F.and Hadley, W. K. Micellaneous Antimicrobial Agents: Disinfectants, Antiseptics adn Sterilants, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, pp 803-804
Robertson, D.B, and Maibach, H.I. Dermatologic Pharmacology , in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p 1000
Kapusnik-Uner, J.E., Sande, M.A. and Chambers,J.F. Antimicrobial agents: Tetracyclines, Chloramphenicol, Erythromycine, and Miscellaneous Antibacterial Agents, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.1143-1144.
Gramicidin
Gramicidin: peptide antibiotic which alters membrane permeability-effective against gram-positive organisms
Gramicidin may be used in combination with neomycin, polymyxin B or both.
Available only for topical usage
Systemic toxicity
Gramicidin Active Against:
Streptococci
Pneumococci
Staphylococci
Most anaerobic cocci
Neisseriae
tetanus bacilli
diphtheria bacilli
Robertson, D.B, and Maibach, H.I. Dermatologic Pharmacology , in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p 1000.
Polymixin B
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Inhibitors of Cell Wall Synthesis
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Inhibitors of protein synthesis (IPS)
Rationale for targeting of bacterial protein synthesis
Relationships between mechanism and therapeutic/adverse effects
Mechanisms of action for aminoglycosides
Chloramphenicol: (Chloromycetin)
Chloramphenicol, macrolides, and clindamycin (Cleocin) bind to bacterial ribosomal RNA (50S subunit of 70S ribosomal RNA)
Chloramphenicol blocks binding of charged tRNA to its binding site on the ribosomal RNA-mRNA complex.
As a result, transpeptidation cannot occur and the peptide is not transfered to the amino acid acceptor.
Protein synthesis stops.!
Macrolides and clindamycin (Cleocin) block movement of peptidyl tRNA from acceptor to donor site.
As a result, the next, incoming tRNA cannot bind to the still occupied acceptor site.
Protein synthesis stops.!
Tetracycline binds to 40S ribosomal RNA, blocking association of amino acid-charged tRNA with its acceptor site on the ribosomal mRNA complex.
Protein synthesis stops.!
Susceptibility Differences between bacterial and mammalian cells
Mammalian 80S ribosomal RNA does not bind chloramphenicol.
However, mammalian mitochondrial ribosomal RNA (70S) does bind chloramphenicol.
Chloramphenicol (Chloromycetin) dose-related bone marrow suppression may be due to drug's effect on mitochondrial ribosomes
Tetracycline inhibits mammalian cell protein synthesis, but an active efflux system may prevent intracellular drug concentrations from reaching toxic levels.
Protein synthesis inhibition is probably due to binding to 30S ribosomal proteins.
Detailed analysis of streptomycin suggest three specific protein synthesis inhibition mechanisms:
interference with "initiation complex" of peptide formation
causing misreading of mRNA which results in incorrect amino acid incorporation
promotion of polysomal dissociation into nonfunctional monosome. These combined effects, occurring at the same time, are probably responsibile for aminoglycoside bacteriocidal properties.
Spectrum of activity and clinical uses
Aminoglycosides: gram-negative enteric bacteria especially if the microbe is suspected to be a drug-resistant isolate or sepsis may be present.
Nearly always used in combination with a ß-lactam to extend coverage to possibly gram-positive microbes.
Aminoglycosides and ß-lactams are synergistic.
Penicillin-aminoglycoside combinations:
bacteriocidal in enterococcal endocarditis reduces therapy duration for viridans streptococcal and staphylococcal endocarditis
Classic adverse effects of aminoglycosides
Aminoglycosides are ototoxic and nephrotoxic.
Aminoglycoside in patients receiving a loop diuretic (furosemide) or other nephrotoxic antibiotics (vancomycin (Vancocin) or amphotericin B (Fungizone)) worsens renal toxicity.
Ototoxicity manifests as: tinnitus, high-frequency hearing loss or as vestibular damage: vertigo ataxia.
Reduced creating clearance and increasing serum creatinine are associated with aminoglycoside-induced renal toxicity. First indications of aminoglycoside renal toxicity may be increased "trough" drug concentrations, reflecting decreasing renal drug clearance.
Very high aminoglycoside doses produce neuromuscular blockade (paralysis) which is reversible in early stages by calcium infusion or by neostigmine.
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Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, pp. 753-754
Specific drugs
Streptomycin
Streptomycin: main use: second-line treatment for tuberculosis
Used only in combination with other antimicrobials (otherwise rapid emergence of resistance)
In combination with oral tetracycline, i.m. streptomycin may be used in treating:
plague
tularemia,
bucellosis.
In combination with penicillin:
treatment for enterococcal endocarditis
viridans streptococcal endocarditis (two-week regimen)
Adverse Reactions
fever
rash (hypersensitivity)
Most serious toxic effect: vestibular toxicity which tends to be irreversible.
treptomycin administration during pregnancy may result in deafness in the newborn.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 754.
Gentamicin (Garamycin):
Gentamicin (Garamycin): effective against gram-positive and gram-negative microbes
Active alone but shows synergism with ß-lactam antimicrobials in managing
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No activity against anaerobes.
Primary clinical use: Treatment of severe gram-negative bacterial infections (sepsis/pneumonia) when the bacteria is likely resistant to other antibiotics.
The combination of gentamicin and a cephalosporin or penicillin may be life-saving in the immunocompromised patient.
Gentamicin + penicillin G: viridans streptococcal endocarditis
Gentamicin + nafcillin (Nafcil, Unipen) in some cases of staphylococcal endocarditis.
Gentamicin should not be used as a single agent due to rapid development of resistance.
Aminoglycosides should not be used as single therapy in pneumonia due to poor tissue penetration.
Nephrotoxicity: requires serum gentamicin monitoring if administration exceeds a few days.
Adverse Reactions
Nephrotoxicity
Deafness
Vestibular toxicity which tends to be irreversible.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 755.
Tobramycin (Nebcin)
Antibacterial spectrum of action similar to gentamicin.
Some cross-resistance possible
Nearly identical pharmacokinetic profile
Similar antimicrobial spectum to gentamicin.
Adverse Reactions
Nephrotoxicity
Deafness
Vestibular toxicity which tends to be irreversible.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 756-758.
Amikacin (Amikin)
Amikacin: semisynthetic derivative of kanamycin, but less toxic.
Amikacin may be used against microbes resistant to:
gentamicin or tobramycin because it is resistant to enzymes which inactivate those agents.
Often effective in treating multi-drug resistant strains of Mycobacterium tuberculosis.
Kanamycin resistant isolates are likely to exhibit cross-resistance to amikacin.
Amikacin (Amikin) is ototoxic (auditory component especially) and nephrotoxic, as are all aminoglycosides.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 758.
Kanamycin & Neomycin
Kanamycin & Neomycin: Active against gram-positive, gram-negative and some mycobacteria.
Pseudomonas and streptococci: resistant
Mechanisms of action and resistance follow that of other aminoglycosides.
Cross-resistance between these agents and kanamycin and neomycin
Neomycin: topical and oral use only due to toxicity associated with parenteral administration.
Neomycin use: given prior to elective bowel surgery, reducing aerobic bowel flora.
Ototoxicity (auditory) and nephrotoxicity.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 758-759.
Spectinomycin (Trobicin)
Spectinomycin: structurally-related to aminoglycosides.
Used almost exclusively to treat gonorrhea resistant to other drugs or if the patient is allergic to penicillin.
No cross-resistance between spectinomycin and other drugs used to treat gonorrhea
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 759.
The dependency of therapeutic and toxic effects on pharmacokinetics
Aminoglycosides are poorly absorbed from the G.I. tract
Most of the oral dose is excreted directly. Aminoglycosides are usually administered intravenously (i.v).
Highly polar molecules, aminoglycosides do not penetrate the CNS or eye.
In menningitis with attendant inflammation, cerebral spinal fluid levels may reach 20% of plasma concentration.
Higher concentration requires directly intrathecal or intraventricular administration.
Tissue drug levels are generally low, except in the renal cortex.
Renal aminoglycosides clearance rates are directly proportion to creatinine clearance rates.
Many factors (age, gender) influence the relationship between serum creatinine levels and creatinine clearance. Reliance on estimated creatinine clearance is appropriate in determining aminoglycoside dosage in a patient.
In renal insufficiency, care must be used to avoid toxicity due to drug accumulation.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 753.
Development of resistance to aminoglycosides
Most common mechanism of resistance is antibiotic inactivation by enzyme-mediated covalent modification which results in phosphate, adenyl or acetyl group transfer.
Aminoglycoside-modifying enzymes are plasmid localized.
The modified antibiotic is also less active because of decreased transport & decreased binding to the ribosomal target site
Aminoglycoside-modifying enzymes have been found in both gram-negative and gram-positive bacteria.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 752.
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Chambers, H.F. and Jawetz, E.Sulfonamides,Trimethoprim, and Quinolones,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 761-763. |
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Drugs to Treat Mycobacterial Infections
Mycobacterial infections are a therapeutic challenge
Slow growth characteristic results in relative resistance to antibiotic therapy. Antibiotic activity is usually directly depend on the rate of cell division
Many mycobacterial organisms are intracellular (residing in macrophages, for example)
Single drug treatment of mycobacterial infections readily promotes development of resistance
Combination therapy over an extended period of time is required for effective treatment.
Mycobacterial infections include those caused by Mycobacterium tuberculosis, M bovis, atypical myocacterial infections, and M. leprae (leprosy)
First line of drugs in order of preference:
Isoniazid (INH)
Rifampin (Rimactane)
Pyrazinamide
Ethambutol
spectinomycin (Trobicin)
Second Line Drugs
Amikacin (Amikin)
Aminosalicylic Acid
Capreomycin
Ciprofloxacin (Cipro)
Clofazimine
Cycloserine
Ethionamide
Ofloxacin (Floxin)
Rifabutin (Mycobutin)
Mechanisms of Actions of Antimycobacterial Agents
Overview:
Isoniazid (INH) is the most active for treatment of tuberculosis.
INH inhibits mycolic acid synthesis, an essential part of mycobacterial cell walls.
Given alone, INH administration selects out resistant mutants which necessitates additional agents.
At present (1997) about 10% of tuberculosis isolates are INH resistant. INH is well absorbed after oral administration.
Hepatic metabolism by acetylation is influenced by genetic predisposition to fast- or slow acetylation. Dosage adjustments may be required INH metabolites are renally excreted.
Clinical Aspects:
Single-drug use: prevention of active tuberculosis in M. tuberculosis infected individuals who have not developed active disease.
Very young children who are seropositive within two years following a negative skin test and HIV-infected and AIDS patients are candidates for INH preventative treatment.
Single drug: INH treatment is also indicated as a preventative for individuals who have been in close contact with individuals who have active pulmonary tuberculosis.
Adverse Effects
Fever, skin rash.
Toxicity: INH-induced hepatitis--most frequent major toxic effect (1% incidence, age-dependent with older patients at higher risk and younger patients at much reduced risk).
Peripheral neuropathy which is reduced by pyridoxine supplimentation
Chambers, H.F. and Jawetz, E.Antimycobacterical Drugs ,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, pp. 770 - 773
Rifampin (Rimactane)
Overview:
Rifampin is a semisynthetic derivative of rifamycin.
Rifampin is active against gram-positive and gram-negative cocci, some enteric organisms, mycobacteria and Chlamydia.
Rifampin binds selectively to bacterial DNA-dependent RNA polymerase thus inhibiting RNA synthesis.
Rifampin is bacteriocidal for myobacteria.
Clinical Uses
Rifampin co-administered with isoniazid or ethambutol to treat myobacterial infections.
Rifampin in combination with a sulfone (dapsone) is used to treat leprosy.
Rifampin is a substitute for INH tuberculosis prophylaxis.
Other Uses: Prophylaxis for Haemophilus influenzae type children contact
Rifampin with another agent to eradicate staphylococci
Combination therapy for serious staphylococcal infections including osteomyelitis and prosthetic valve endocarditis.
Rifampin in combination with ceftriaxone or vancomycin to treat meningitis caused by highly penicillin-resistant pneumococcal isolates
Adverse Effects
Harmless orange coloration to urine, sweat, tears.
Occasional effects: rash, nephritis, thrombocytopenia, flu-like symptoms depending on dosing intervals
Rifampin microsomal P450 induction increases the metabolism of many drugs
Clinical Uses of Antibacterials (for management of gram positive organisms)