Antibacterial Drugs

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Chapter 35  Antibacterial Drugs

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Bacterial Cell Wall: Sites of Antibacterial Action

Bacterial cell wall structure

Gram-negative Bacterial Membrane Structure
Gram-negative Cell Membrane Model
  • Gram-negative bacteria are surrounded by two membranes.
  • The outer membrane functions as an efficient permeability barrier containing lipopolysaccharides (LPS) and porins.

[graphic: Linda M. Stannard used with permission]

Cell Membrane

 

Peptidoglycan

Cytoplasmic Membrane

 

Gram-positive Bacterial Membrane Structure
Gram-positive Membrane
  • The lipid bilayer cell membrane of most of the Gram-positive bacteria is covered by a porous peptidoglycan layer

[graphic: Linda M. Stannard used with permission]

Peptidoglycan Layers

 

 

Cytoplasmic Membrane

 

Multiple sites of inhibition by antibacterial agents

 
Gram-negative Cell Membrane Model
  • Gram-negative bacteria are surrounded by two membranes.
  • The outer membrane functions as an efficient permeability barrier containing lipopolysaccharides (LPS) and porins.

[ graphic: Linda M. Stannard used with permission]

Cell Membrane
PBP: Penicillin Binding Protein: Site of Penicillin Action

Peptidoglycan

Cytoplasmic Membrane

 

Gram-positive Membrane
  • The lipid bilayer cell membrane of most of the Gram-positive bacteria is covered by a porous peptidoglycan layer

[graphic: Linda M. Stannard used with permission]

Peptidoglycan Layers
 
Penicillin-binding Protein (PBP): Site of Penicillin action

Cytoplasmic Membrane

 

 

 

Inhibitors of Cell-Wall Synthesis

Penicillin G
  •  Overview:
    • Penicillin G is bacteriocidal for sensitive strains, that is the agent itself can kill the bacteria as opposed to arrest growth (bacteriostatic)
    •  The principal mechanism for penicillin bacteriocidal action is inhibition of cell wall synthesis with penicillin primarily affecting gram-positive organisms.  Furthermore, for both the penicillins and cephalosporins bacteriocidal activity is dependent on actively growing bacteria which will be actively synthesizing new cell walls.
    • Penicillin is relatively nontoxic.

Disadvantages of Penicillin G

  •  Disadvantages of penicillin G include the possibility of hypersensitivity reactions, a relatively short duration of action, and acid lability.
  •  Particularly important concerns with the penicillins is sensitivity to -lactamases (penicillinases) which will limit effectiveness as well as their general lack of effectiveness against gram-negative organisms.
  • Not all penicillins exhibit acid lability. Acid stable penicillins include: carbenicillin (Geocillin),  ampicillin (Principen, Omnipen), floxacillin, nafcillin (Nafcil, Unipen), dicloxacillin (Dynapen), oxacillin (generic) and penicillin V.

Broad Spectrum Penicillins

  • Penicillins which are beta-lactamase resistant (penicillinase resistant) as well as antipseudamonal* in their spectrum of action include: ampicillin (Principen, Omnipen), * piperacillin (Pipracil),*mezlocillin (Mezlin), *carbenicillin (Geocillin), amoxicillin (Amoxil Polymox), and *ticarcillin (Ticar).

 

 

Penicillin Structural Features and Requirements for Antibacterial Activity
  • Penicillins have similar structures: a thiazolidine ring (A) atached to a -lactam ring (B).

  • Substituents are attached to the amino group (R). Moieties A and B together constitute the 6-aminopennicillanic acid nucleus required for antibacterial activity.

  • Cleaving the -lactam ring by penicillinases (-lactamases) results in loss of antibacterial properties.

  • Penicillins may also be inactivated by amidases.

  • Static figure (left top): Nitrogen atoms are red, sulfur light blue-green and oxygen atoms are green.

  • 3D interactive figure (left, bottom) atoms are identified.

 

 

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.

Penicillin Binding Proteins (PBPs)
  • Penicillin-binding Proteins (PBPs) catalyze an important step in bacterial cell wall synthesis [a transpeptidase reaction which removes a terminal alanine in a crosslinking reaction with a nearby peptide].
  • One mechanism of penicillin antibacterial action is through binding to these proteins, thereby inhibiting their activity.

Mechanisms by which bacteria develop resistance to -Lactams is through alteration of penicillin-binding proteins (PBPs)

  • Resistance to beta-lactam antibiotics may be acquired either by mutation of existing PBP genes or, more importantly, by acquiring new PBP genes (e.g. staphlococcal resistance to methicillin) or by acquiring new "pieces" of PBP genes (e.g. pneumococcal, gonococcal and meningococcal resistance).

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.

Spectrum: Penicillins
Penicillins (Penicillin G): Activity Profile: Effective Against:

Gram Positive Organisms

Gram-negative cocci

Non--lactamase producing anaerobes

Antistaphylococcal penicillins (nafcillin (Nafcil, Unipen)) are -lactamase resistant:

Effective Against:

Staphylococci

Streptococci

Extended Spectrum Agents (nafcillin (Nafcil, Unipen)); penicillinase sensitive: Effective Against:

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.

Resistance: -Lactams
  • Most common among several mechanisms by which bacteria develop resistance to -Lactam antibiotics is by elaboration of the enzyme -lactamase, which hydrolyzes the -lactam ring.
  •  -lactamase genes may be found in both gram-positive and gram-negative bactera.
  • Clavulanic acid and sulbactam, by binding to some -lactamases, can lessen resistance.
  • A second mechanism by which bacteria develop resistance to -Lactams is through alteration of penicillin-binding proteins (PBPs):
    •  either by mutation of existing PBP genes or, more importantly, by acquiring new PBP genes (e.g. staphlococcal resistance to methicillin) or by acquiring new "pieces" of PBP genes (e.g. pneumococcal, gonococcal and meningococcal resistance)
  • A third mechanism seen in gram-negative bacteria is due to alteration of genes that specify outer membrane proteins (porins) and reduce permeability to penicillins. (e.g. resistance of Enterbacteriaceae to some cephalosporins and that of Pseudomonas spp. to ureidopenicillins)
  • Multiple resistance mechanisms may be found in the same bacterial cell.

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 -Lactamase Resistant Penicillins

 Adverse Reactions to Penicillins

  • The most common adverse reaction to penicillins are classified as hypersensitivity reactions.  Furthermore, penicillins are the most common cause of drug allergy.
  •  Hypersensitivity reactions from most common to least* are as follows:
    1. macropapular rash
    2. urticarial rash
    3. fever
    4. bronchospasm
    5. vasculitis
    6. serum sickness
    7. exfoliative dermatitis
    8. Stevens-Johnson syndrome
    9. anaphylaxis

*Overall incidences is estimated to be between 0.7% to 10%.

  • The most serious hypersensitivity reactions caused by penicillin are angioedema and anaphylaxis. 
    • Angioedema is characterized by significant swelling of lips, tongue, face and periorbital tissues.
  •  Anaphylaxis places the patient in the most immediate danger and may manifest as sudden, severe hypotension and death.

Mandell, G.L. and Petri, W. A. Antimicrobial Agents: Penicillins, Cephalosporins, and other -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)

 

 

Clinical Use: -Lactams

note: all penicillins (excepting semisynthetic, penicillinase-resistant antistaphylococcal agents) can be hydrolyzed by -lactamases enzymes and will not be efficacious against bacterial strains that produce this enzyme.

Clinical Uses-Penicillins:

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.

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.

Clinical Use: Cephalosporins

Overview
  • Cephalosporins are similar to penicillins in terms of mechanism of action, chemical structure, and toxicities.
  • By targeting bacterial cell wall transpeptidases and penicillin binding proteins (PBPs), cephalosporins cause cells wall lysis, which is the basis of bacteriocidal activity for susceptible bacteria.
  • Although many (most) bacteria contain PBPs, cephalosporin antibiotics are not effective against all bacteria as a result of resistance.  

 

Cephalosporins and their Spectrum of Pharmacological Action
  1. First-generation agents (Cephalothin and cefazolin): exhibit good activity against gram-positive bacteria, but less activity against gram negative organisms.
    • Most gram-positive cocci are susceptible to first-generation cephalosporins-(not including enterococci and methicillin-resistant staph)
    • Most oral cavity anaerobes are sensitive.  However, the B. fragilis group is resistant.
    • Good activity against Moraxella catarrhalis, E. coli, K. pneumoniae and Proteus mirabilis.
  2. Second-generation agents include. cefoxitin (Mefoxin), cefotetan (Cefotan), cefmetazole(Zefazone)).
    • Second-generation drugs exhibit somewhat enhanced activity against gram negative organisms, but much less enhancement compared to third generation agents.
  3. Third-generation agents: (e.g. cefotaxime (Claforan), ceftriaxone (Rocephin), ceftazidime (Fortax, Taxidime, Tazicef)):
    • Third-generation cephalosporins are less active than First generation agents against gram-positive cocci
    • However, these drugs are much more active against Enterobacteriaceae, including those that produce -lactamase.
  4. Fourth-generation agents (e.g. cefepime (Maxipime)):
    • Fourth generation cephalosporins are generally similar to third generation drugs, although the fourth generation drugs exhibit increased resistance to beta-lactamase-producing bacteria.

 

Interlude:  Microorganisms

1Bacteriodes fragilis 

  • B. fragilis  is probably the most important of all anaerobes based on the likelihood of occurrence in clinical settings as well as because of its resistance to many antibiotics.
  • Bacteriodes fragilis is classified as a gram-negative Bacillus exhibiting rounded ends and are usually encapsulated.
  • Review: gram-negative aerobic bacilli are responsible for numerous infection types ranging from oral to bone infections.  Pathological manifestations include participation in pathologic processes such as periodontal disease and colon cancer.  Gram-negative bacteria release enzymes such as neuraminidase and collagenase which facilitate organism tissue penetration.
    • Anaerobic infections include: bite infections, oral or dental infections, empyema, lung abscess, aspiration pneumonia, post-abortion infections, appendicitis, diverticulitis, septic thrombophlebitis, and septicemia which may be associated with diabetes, cancer, "negative" blood cultures and corticosteroids.

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

E . coli

Klebsiella pneumoniae

Serratia (a, left)  Image credit: Shirley Owens and Catherine McGowan, Microbe Zoo
Project, Comm Tech Lab, Michigan State University. Serratia (b, right) EuroMech 422 Pattern Formation by Swimming Micro-Organisms http://www.amsta.leeds.ac.uk/Euromech422/

 

Proteus

http://www.laboratoria.khv.ru/std/gallery_std2/proteus.htm

  • 2In the clinical laboratory setting, E . coli (Escherichia coli) is probably the most commonly isolated organism.  E . coli is a member of the group of pathogens called coliform bacilli which include these genera  Escherichia, Enterobacter, Citrobacter, Klebsiella, and Serratia.  Additionally, Proteus is a member of this group.  Many of these organisms are normally found in the gastrointestinal tract, thereby being considered normal flora.
    • Infections:
      • Enteric infections -- E . coli is a major contributor to infections, especially in the developing countries, as a major enteric (intestinal) pathogen.
      • Nosocomial infections (hospital acquired infections) are frequently (frequency = 29%  in United States) due to Coliform and Proteus bacilli. These organisms are frequently responsible for urinary tract infections (46%) and infections associated with surgical sites (24%).  E . coli is the most prominent nosocomial pathogen.
      • Community-acquired infections:
        • As noted above for nosocomial infections come E . coli is prominent as a cause of urinary tract infection's in the community acquired environment.  Urinary tract infections include prostatitis and pyelonephritis.  Other common pathogens responsible for urinary tract infection's include Proteus, Klebsiella, and Enterobacter.  Proteus mirabilis is the most likely cause of infection-related kidney stones.  Klebsiella pneumoniae  causes severe pneumonia.

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

 

3Moraxella catarrhalis

  • 3Moraxella cattarrhalis, a gram-negative bacteria often found in normal human upper respiratory tract flora, are similar in appearance to Neisseria cells .  Occasionally, Moraxella cattarrhalis may cause significant lung disease such as pneumonia and acute bronchitis as well as important systemic infections including meningitis and endocarditis.  In both children and adults, this organism may be commonly responsible for otitis media, sinusitis, and conjunctivitis. (Moraxella cattarrhalis may cause as many as 20% of otitis media presentations)
    • Moraxella cattarrhalis may be responsible for lower respiratory tract infection in those adults who have chronic lung disease.
    • This organism is often found in the normal flora and children (frequency = 40%-50%).
    • Moraxella cattarrhalis can cause symptoms that are very similar, nearly indistinguishable from those caused by gonococci, so the differential assessment is quite important.  Also, many Moraxella cattarrhalis strains elaborate beta-lactamase making them resistance too many beta-lactam antibiotics.

3 Stephen A. Morse "Neisseria, Moraxella, Kingella, and Eikenella" in Medical Microbiology (4th edition) edited by Samuel Baron, M.D., The University of Texas Medical Branch, http://gsbs.utmb.edu/microbook/ch014.htm &Volk WA, Gebhardt BM, Hammarskjold M-L, et al, eds. Essentials of Medical Microbiology, 5th ed. Philadelphia, PA: Lippincott-Raven; 1996. & GlaxoSmithKline, 2001 (Augmentin use), http://www.augmentin.com/1_1_3.asp

 

Organisms susceptible to Cephalosporins
  • First Generation: Cefazolin (Ancef):  Streptococci (except for penicillin-resistant strains)
  • First Generation: Cefazolin (Ancef):  Staphylococcus aureus (except for methicillin-resistant strains)
  • Second Generation: Cefuroxime (Ceftin), Cefaclor (Ceclor):  Klebsiella, Haemophilus influenzae, E.coli, Moraxella catarrhalis and Proteus mirabilis 
  • Third-generation: Cefotaxime (Claforan), Ceftriaxone (Rocephin), Ceftazidime (Ceptaz):  Enterobacteriaceae, Pseudomonas aeruginosa, Serratia, Neisseria gonorrhoeae; activity for Staph. aureus and Strept. pyogenes similar to first generation agents. 

Streptococci

 

"Streptococci can survive within pus in a chronic abscess cavity where they are protected from other mechanisms for disposal of bacteria, e.g. macrophages, opsonising antibodies, complement and, of course, theraputically administered antibiotics.(Gram stain)." courtesy of-Department of Pathology, University of Birmingham, U.K.  

  • First generation: cefazolin (Ancef, Defzol) 

 

Staphylococcus aureus 

photo credit: Kenneth Todar University of Wisconsin Department of Bacteriology

  • Staphylococci causes many different infections ranging from superficial skin lesions (boils) to deep infections including osteomyelitis and endocarditis. 
  •  Staphylococcus aureus is a significant contributor to nosocomial infections, food poisoning (enterotoxins), and toxic shock syndrome secondary to superantigen release into the bloodstream.

3 Timothy Foster "Staphylococcus" in Medical Microbiology (4th edition) edited by Samuel Baron, M.D., The University of Texas Medical Branch, http://gsbs.utmb.edu/microbook/ch012.htm

  • First Generation: Cefazolin (Ancef)
  • Third-generation: Cefotaxime (Claforan); Ceftriaxone (Rocephin); Ceftazidime (Ceptaz)
  • Cefotaxime (Claforan)

 

Mandell, G.L. and Petri, W. A. Antimicrobial Agents: Penicillins, Cephalosporins, and other -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

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

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

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:

 

 Specific Third Generation Cephalosporin Drugs

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:

 

Fourth Generation

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 -lactam containing antibacterials

Aztreonam (Azactan) 

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

Effective in treating these infections:
urinary tract lower respiratory tract bones joints skin

intra-abdominal

 

gynecological mixed infections endocarditis bacterial septicemia

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

Most effective against plasmid-encoded beta-lactamases including those produced by:
  • staphylococci
  • H. influenzae
  • N. gonorrhoeae
  • Salmonella
  • Shigella
  • E. coli
  • K. pneumoniae

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

Bacitracin

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

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

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

Robertson, D.B, and Maibach, H.I. Dermatologic Pharmacology , in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p 1000.

 

Mechanistic Comparisons: Membrane Active Agents vs. Inhibitors of Cell-Wall Synthesis

Polymixin B

  •  Polymixins (polymixin E): basic peptides which are amphipathic (containing lipophilic and lipophobic groups)

  •  Disrupt bacterial cell membranes through strong interactions with phospholipid components.

Inhibitors of Cell Wall Synthesis

  • Penicillin-binding Proteins (PBPs) catalyze an important step in bacterial cell wall synthesis [a transpeptidase reaction which removes a terminal alanine in a crosslinking reaction with a nearby peptide].

  • One mechanism of penicillin antibacterial action is through binding to these proteins, thereby inhibiting their activity.

 

Inhibitors of protein synthesis (IPS)

Aminoglycosides

Mechanisms of action for aminoglycosides

Chloramphenicol: (Chloromycetin)

Macroclides/Clindamycin:

Tetracycline:

 

Susceptibility Differences between bacterial and mammalian cells

 

Aminoglycosides:

 

Most ototoxic-----------------------------Most toxic to the vestibular system
  • neomycin
  • kanamycin
  • amikacin
  • neomycin
  • tobramycin
  • gentamicin

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

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.

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.

 

Tetracyclines, macrolides, chloramphenicol, clindamycin, spectinomycin

 

Inhibitors of folate-dependent pathways
  • Production and use of folate derivatives in bacterial systems
    • Certain microbes require p-aminobenzoic acid (PABA) in order to synthesize dihydrofolic acid which is required to produce purines and ultimately nucleic acids.
    • Sulfonamides,chemical analogs of PABA, are competitive inhibitors of dihydropteroate synthetase.
    •  Sulfonamides therefore are reversible inhibitors of folic acid synthesis and bacterostatic not bacteriocidal.

 

Sulfonamides
  • Introduction to sulfonamide pharmacology
  •  Mechanism of action of sulfonamides
    • Certain microbes require p-aminobenzoic acid (PABA) in order to synthesize dihydrofolic acid which is required to produce purines and ultimately nucleic acids.
    •   Sulfonamides,chemical analogs of PABA, are competitive inhibitors of dihydropteroate synthetase.
    • Sulfonamides therefore are reversible inhibitors of folic acid synthesis and bacterostatic not bacteriocidal.

 

Trimethoprim
  • Trimethoprim (generic) mechanism of action

    • Trimethoprim is an inhibitor of bacterial dihydrofolic acid reductase.

    • Pyrimethamine (Daraprim) is an excellent inhibitor of dihydrofolic acid reductase in protozoa

    • These reductases are required for the synthesis of purines and hence DNA.

    • Inhibition of these enzymes are responsible for bacteriostatic and bacteriocidal activities.

    • When trimethoprim or pyrimethamine is combined with sulfonamides (sulfamethoxazole) there is sequential blocking of the biosynthetic pathway leading to drug synergism and enhanced antimicrobial activity. (see figure below)

    • Resistance to trimethoprim: usually by plasmid encoded trimethoprim-resistant dihydrofolate reductases.

    • Trimethoprim typically used orally often in combination with sulfamethoxazole, a sulfonamide with a similar half-life.

  • Clinical Uses

    • Oral trimethoprim: Acute urinary tract infections

    • Oral trimethoprim-sulfamethoxazole (Bactrim) combination: Pneumocystis carinii pneumonia, shigellosis,systemic Salmonella infection, some nontuberculous mycobacterial infections.

    • Respiratory tract pathogens: pneumococcus, Haemophilus, Moraxella catarrhalis, Klebsiella pneumoniae

    • By I.V. administration trimethoprim - sulfamethoxazole: agent of choice for moderately severe to severe infections with Pneumocystis carinii pneumonia, especially in patients with HIV. May be used for gram-negative sepsis

  • Adverse effects

    • Trimethoprim adverse effects referable to antifolate properties: megaloblastic anemia, leukopenia granulocytopenia (avoided by coadminstration of folinic acid)
    • Combination of Trimethoprim-Sulfamethoxazole cause in addition, sulfonamide side effects--nausea, vomiting,vasculitis, renal damage.
    •  AIDS patients being treated for pneumocystis pneumonia have a high frequency of adverse reactions, particularly fever, rash, leukopenia diarrhea.

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.

DNA gyrase inhibitors
  • DNA gyrase inhibitors:  The function of DNA gyrases, and the effects of their inhibition; clinical uses of quinolones and fluoroquinolones; adverse effects and potential drug-drug interaction for quinolones

Antimycobacterial agents

Drugs to Treat Mycobacterial Infections

Mechanisms of Actions of Antimycobacterial Agents

 

Chambers, H.F. and Jawetz, E.Antimycobacterical Drugs ,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, pp. 770 - 773

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