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Chapter 35 Antibacterial Drugs

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• Bacterial Cell Wall: Sites of Antibacterial Action

• Inhibitors of Cell-WallSynthesis,e.g.

○ Penicillins

○

Cephalosporins○ Vancomycin

(Vancocin)

• Membrane-Active Agents,e.g.

○ polymixin

○ gramicidin

• Inhibitors of ProteinSynthesis, e.g.,

○ Tetracyclines,

macrolides,chloramphenicol,clindamycin,spectinomycin

• Inhibitors of Folate-Dependent Pathways

○ Sulfonamides

• DNA-Gyrase Inhibitors, e.g.,

○ Ciprofloxacin

(Cipro)/ofloxacin

(Floxin)• Antimycobacterial Agents, e.g.

○ Isoniazid (INH),

Rifampin,Pyrazinamide,Ethambutol(Myambutol)l,

• Management of vancomycin(Vancocin)-resistant Enterococcusfaecium (VREF)

• Drugs for Surgical Prophylaxis

○ Overview

○

Cardiac Surgery○ Gastrointestinal Disease

○ Gynecologic/obstetric

○ Genitourinary

○ Head and Neck

○ Neurosurgery

○ Ophthalmic

○ Orthopedic

○

Thoracic(noncardiac)○ Vascular

• Drugs for Treating SexuallyTransmitted Infections

○ Chlamydia

○ Gonorrhea

○ Epididymitis

○ Pelvic Inflammatory Disease

○ Vaginal Infections

○ Syphilis

○ Chancroid

○ Genital Herpes

○ Pediculosis & Scabies

○ Genital Warts & human

papillomavirus (HPV)

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Streptomycin

• Clinical Use of AntibacterialDrugs

• Drugs of Choice for treating:

○ Pneumonia

○ Meningitis

○ Sepsis Syndrome

○ Urinary Tract Infection

infection

• Linezolid (Zyvox): new antibioticfor treatment of infection due tovancomycin (Vancocin)-resistantEnterococcus faecium

Bacterial Cell Wall: Sites of Antibacterial Action

Bacterial cell wall structure

Gram-negative Bacterial Membrane StructureGram-negative CellMembrane Model

• Gram-negative bacteria aresurrounded bytwo membranes.

• The outer membranefunctions as anefficient

permeability barrier containinglipopolysaccharides (LPS) and porins.

[graphic: © Linda M.Stannard used with permission]

Cell Membrane

Peptidoglycan

CytoplasmicMembrane

Gram-positive Bacterial Membrane Structure

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Gram-positiveMembrane

• The lipid bilayer cellmembrane of

most of theGram-positive bacteria iscovered by a porous peptidoglycanlayer

[graphic: © Linda M.Stannard used with permission]

Peptidoglycan Layers

CytoplasmicMembrane

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Multiple sites of inhibition by antibacterial agents

Gram-negative CellMembrane Model

• Gram-negative bacteria are

surrounded bytwo membranes.

• The outer membranefunctions as anefficient permeability barrier containinglipopolysaccharides (LPS) and

porins.[ graphic: ©Linda M.Stannard used with permission]

Cell Membrane

PBP: PenicillinBindingProtein: Site of PenicillinAction

Peptidoglycan

Cytoplasmic

Membrane



Gram-positiveMembrane

• The lipid bilayer cell membrane of most of the Gram-

positive bacteriais covered by a porous peptidoglycanlayer

[graphic: ©Linda M.Stannard used with permission]

PeptidoglycanLayers

Penicillin-binding Protein

(PBP): Site of Penicillinaction

CytoplasmicMembrane

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 affectinggram-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 hypersensitivityreactions, a relatively short duration of action, and acid lability.

• Particularly important concerns with the penicillins is sensitivity to ß-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) andpenicillin 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).

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Penicillin Structural Features and Requirements for Antibacterial Activity

• Penicillins havesimilar structures: athiazolidine ring(A) atached to a ß-lactam ring (B).

• Substituents areattached to theamino group (R).Moieties A and Btogether constitutethe 6-aminopennicillanicacid nucleusrequired for antibacterialactivity.

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

• Penicillins may also be inactivated byamidases.

• Static figure (left

top): Nitrogenatoms are red,sulfur light blue-green and oxygenatoms are green.

• 3D interactivefigure (left, bottom)atoms are



identified.

Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell WallSynthesis,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 cellwall synthesis [a transpeptidase reaction which removes a terminal alanine in acrosslinking 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 ß-Lactams is throughalteration 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 PBPgenes (e.g. pneumococcal, gonococcal and meningococcal resistance).

Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell WallSynthesis,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, InHarrison'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 (HealthProfessions Division), 1998, p. 859.

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Spectrum: Penicillins

Penicillins (Penicillin G): ActivityProfile: Effective Against:

Gram Positive Organisms

Gram-negative cocci

Non-ß-lactamase producinganaerobes

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

Effective Against:

Staphylococci

Streptococci



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

Antibacterial Spectrum of Penicillins

Better activity against gram-negativeorganisms

Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison'sPrinciples 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.

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Resistance: ß-Lactams• Most common among several mechanisms by which bacteria develop

resistance to ß-Lactam antibiotics is by elaboration of the enzyme ß-lactamase, which hydrolyzes the ß-lactam ring.

• ß-lactamase genes may be found in both gram-positive and gram-negative bactera.

• Clavulanic acid and sulbactam, by binding to some ß-lactamases, canlessen resistance.

• A second mechanism by which bacteria develop resistance to ß-Lactams isthrough alteration of penicillin-binding proteins (PBPs):

○ either by mutation of existing PBP genes or, more importantly, byacquiring 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 genesthat specify outer membrane proteins (porins) and reduce permeability to penicillins. (e.g. resistance of Enterbacteriaceae to some cephalosporins andthat of Pseudomonas spp. to ureidopenicillins)

• Multiple resistance mechanisms may be found in the samebacterial cell.

Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, InHarrison'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)]

Adverse Reactions to Penicillins

• The most common adverse reaction to penicillins are classified ashypersensitivity reactions. Furthermore, penicillins are the most commoncause 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 andmay manifest as sudden, severe hypotension and death.

Mandell, G.L. and Petri, W. A. Antimicrobial Agents: Penicillins, Cephalosporins, andother 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, andGilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1086-1088)

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Clinical Use: ß-Lactams

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.

Clinical Uses-Penicillins:

• 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.


• As noted earlier penicillins may be sensitive to beta-lactamase producing bacteria. Thosepenicillins resistant to beta-lactamase producing staphylococcal strains include:methicillin (Staphcillin), nafcillin (Nafcil, Unipen) and certain isoxazolyl penicillinssuch as oxacillin (generic), cloxacillin (Cloxapen), and dicloxacillin (Dynapen)

○ Clinical Indications for penicillins resistant to beta-lactamase producingstaphylococcal strains.

The primary indication would of course the infection by beta-lactamase producing staphylococcal organisms. However, other susceptible bacteriainclude penicillins susceptible strains of streptococci and pneumococci.These drugs however all are enacted against enterococci, anaerobic bacteria, gram-negative cocci and rods.


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 activityagainst gram-positive bacteria, but less activity against gram negativeorganisms.



○ Most gram-positive cocci are susceptible to first-generation

cephalosporins-(not including enterococci and methicillin-resistantstaph)

○ 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 thirdgeneration agents.

3. Third-generation agents: (e.g. cefotaxime (Claforan), ceftriaxone(Rocephin), ceftazidime (Fortax, Taxidime, Tazicef)):

○ Third-generation cephalosporins are less active than First generationagents against gram-positive cocci

○ However, these drugs are much more active against

Enterobacteriaceae, including those that produce ß-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 increasedresistance to beta-lactamase-producing bacteria.

Interlude: Microorganisms

1Bacteriodes fragilis



• B. fragilis is probably the most important of all anaerobes based on thelikelihood of occurrence in clinical settings as well as because of itsresistance to many antibiotics.

• Bacteriodes fragilis is classified as a gram-negative Bacillus exhibiting roundedends and are usually encapsulated.

• Review: gram-negative aerobic bacilli are responsible for numerous infectiontypes ranging from oral to bone infections. Pathological manifestations include participation in pathologic processes such as periodontal disease and coloncancer. Gram-negative bacteria release enzymes such as neuraminidase andcollagenase 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 septicemiawhich may be associated with diabetes, cancer, "negative" bloodcultures 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

http://gsbs.utmb.edu/microbook/ch020.htm




Klebsiella pneumoniae

Serratia (a, left) Image credit: Shirley Owens and Catherine McGowan, Microbe ZooProject, Comm Tech Lab, Michigan State University. Serratia (b, right) EuroMech



422 Pattern Formation by Swimming Micro-Organismshttp://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 themost 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 amember of this group. Many of these organisms are normally found in thegastrointestinal 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) arefrequently (frequency = 29% in United States) due to Coliformand Proteus bacilli. These organisms are frequently responsiblefor urinary tract infections (46%) and infections associated withsurgical 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 thecommunity acquired environment. Urinary tractinfections include prostatitis and pyelonephritis. Other common pathogens responsible for urinary tractinfection's include Proteus, Klebsiella, and Enterobacter.Proteus mirabilis is the most likely cause of infection-related kidney stones. Klebsiella pneumoniae causessevere pneumonia.

http://www.amsta.leeds.ac.uk/Euromech422/


http://www.amsta.leeds.ac.uk/Euromech422/




2 M. Neal Buentzel "Escherichia, Klebsiella, Enterobacter, Serratia, Citrobacter, andProteus" in Medical Microbiology (4th edition) edited by Samuel Baron, M.D., TheUniversity of Texas Medical Branch, http://gsbs.utmb.edu/microbook/ch026.htm

3Moraxella catarrhalis

•3 Moraxella cattarrhalis , a gram-negative bacteria often found in normal humanupper 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 infectionsincluding meningitis and endocarditis. In both children and adults, thisorganism may be commonly responsible for otitis media, sinusitis, andconjunctivitis. (Moraxella cattarrhalis may cause as many as 20% of otitismedia 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 differentialassessment is quite important. Also, many Moraxella cattarrhalisstrains elaborate beta-lactamase making them resistance too many beta-lactam antibiotics.

3 Stephen A. Morse "Neisseria, Moraxella, Kingella, and Eikenella" in MedicalMicrobiology (4th edition) edited by Samuel Baron, M.D., The University of TexasMedical 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 (Augmentinuse), http://www.augmentin.com/1_1_3.asp

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Organisms susceptible to Cephalosporins




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• First Generation: Cefazolin (Ancef): Streptococci (except for penicillin-resistant strains)

• First Generation: Cefazolin (Ancef): Staphylococcus aureus (except formethicillin-resistant strains)

•

Second Generation : Cefuroxime (Ceftin), Cefaclor (Ceclor): Klebsiella,Haemophilus influenzae, E.coli, Moraxella catarrhalis and Proteusmirabilis

• 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 achronic abscess cavity where they are protected from other mechanisms for disposal of bacteria, e.g. macrophages,opsonising antibodies, complement and, of course, theraputically administeredantibiotics.(Gram stain)." courtesy of-Department of Pathology, University of Birmingham, U.K.

• Firstgeneration:cefazolin(Ancef,Defzol)

Staphylococcus aureus • FirstGeneration:Cefazolin(Ancef)

• Third-generation:



photo credit: Kenneth Todar University of Wisconsin Department of Bacteriology

• Staphylococci causes many

different infections ranging fromsuperficial skin lesions (boils) todeep infections includingosteomyelitis and endocarditis.

• Staphylococcus aureus is asignificant contributor tonosocomial infections, food poisoning (enterotoxins), and toxicshock syndrome secondary tosuperantigen release into the bloodstream.

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

Cefotaxime(Claforan);Ceftriaxo

ne(Rocephin);Ceftazidime(Ceptaz)

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

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More about Cephalosporins

• First Generation Cephalosporins are rarely a drug of choice. However, these agentsare 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 Basicand 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. Secondgeneration drugs are active against beta-lactamase producing H.influenzae. Furthermore,good activity is exhibited against anaerobes which is a particularly useful characteristic inmixed infections such as peritonitis.

Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basicand Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 734.

• Third Generation Cephalosporins are generally more active against gram-negativeorganisms (except for the drug cefoperazone (Cefobid)). Some members of this grouphave 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 susceptiblegram 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)


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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 Basicand 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 Basicand 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 takeyour leave the causative organism may be beta-lactamase producing H.influenzae or Klebsiella pneumoniae. Cefuroxime (Zinacef, Ceftin) is the only second-generation drugacross 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 inmixed 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. influenzaeand 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)


Examples of third generation cephalosporins:

• Ceftazidime, Cefoperazone are effective against P. aeruginosa. ( Third-generationcephalosporins 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

○ Ceftriaxone (Rocephin)/cefixime should not be used to treat Enterobacter

infections due to the likelihood of resistance emergence.

• Proxetil

• Cefibute

• Moxalactam

Fourth Generation

• Cefepime, although classified as a fourth-generation agent, exhibits many properties of third-generation cephalosporins. Cefepime (Maxipime) is somewhat more resistant tohydrolysis by beta-lactamases and exhibits activity against certain beta-lactamases whichinactivate 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 Basicand 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 ClinicalPharmacology, (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 inactivity to aminoglycosides without causing ototoxicity or nephrotoxicity.

• Aztreonam (Azactan) is effective in treating Gram-negative urinary tractinfections, lower respiratory tract, skin, intraabdominal, gynecologic infectionsand 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 renalor liver function.

• Aztreonam (Azactan) exhibits activity against Hemophilus influenzae,Pseudomonas aeruginosa, Neisseria gonorrhoeae and Enterobacteriacea includingmost 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 NursingImplications Appleton & Lange, 1995, pp. 166-167.

Imipenem Premaxin, Meropenem

• Combination of imipenem, a ß-lactam antibiotic, and cilastin which inhibitsdipeptidase enzyme degradation of imipenem. Without cilastin renaldehydropeptidases inactivate the drug which results in low urinary tractconcentrations.

• 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 andStenotrophomonas 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 tractlower

respiratorytract

bones joints skin

intra-abdominal

gynecologicalmixed

infectionsendocarditis

bacterialsepticemia

• 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 Basicand 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 bacterialß-lactamases.

• These agents are given together with hydrolyzable penicillins to protect themfrom 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 penicillinswhich 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 enzymeproduced.


Other Inhibitors of Cell-Wall Synthesis

Vancomycin

• Vancomycin, a glycopeptide, is active only against gram-positive bacteria, especiallystaphylococci {one exception is that it is active against Flavobacterium}

• Vacomycin is an inhibitor of bacterial cell wall synthesis by preventing peptidoglycanelongation 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 producingstaphylococci 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/knownto be highly penicillin resistant.

Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents inBasic 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 thedeveloping 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 Basicand 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 byinhibiting 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 Basicand Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 739-740

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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 dueto 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 (Pseudomonasaeruginosa

○ 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 ClinicalPharmacology,(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 andGillman'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 againstgram-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 ClinicalPharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p 1000.

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

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 whichremoves a terminal alanine in acrosslinking reaction with a nearby peptide].

• One mechanism of penicillinantibacterial action is through binding to these proteins, therebyinhibiting their activity.

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Inhibitors of protein synthesis (IPS)

• Rationale for targeting of bacterial protein synthesis

• Relationships between mechanism and therapeutic/adverse effects

Aminoglycosides

Mechanisms of action for aminoglycosides

Chloramphenicol: (Chloromycetin)

•

Chloramphenicol, macrolides, and clindamycin (Cleocin) bind to bacterial ribosomalRNA (50S subunit of 70S ribosomal RNA)

• Chloramphenicol blocks binding of charged tRNA to its binding site on the ribosomalRNA-mRNA complex.

• As a result, transpeptidation cannot occur and the peptide is not transfered to the aminoacid acceptor.

• Protein synthesis stops.!



Macroclides/Clindamycin:

• 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:

• Tetracycline binds to 40S ribosomal RNA, blocking association of amino acid-chargedtRNA 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 todrug'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.

Aminoglycosides:

• Protein synthesis inhibition is probably due to binding to 30S ribosomal proteins.

• Detailed analysis of streptomycin suggest three specific protein synthesis inhibitionmechanisms:

1. interference with "initiation complex" of peptide formation

2. causing misreading of mRNA which results in incorrect amino acid incorporation

3. promotion of polysomal dissociation into nonfunctional monosome. Thesecombined 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



treptomycin administration during pregnancy may result in deafness in thenewborn.

Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basicand 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

○ Pseudomonas

○ Proteus

○ Enterobacter

○ Klebsiella

○ Serratia

○ Stenotrophomonas

○ Other gram-negative rods

○ 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.


• 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 Basicand 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 whichinactivate 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 Basicand 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 Basicand 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 Basicand 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 isappropriate in determining aminoglycoside dosage in a patient.

○ In renal insufficiency, care must be used to avoid toxicity due to drug

accumulation.


• Development of resistance to aminoglycosides

○ Most common mechanism of resistance is antibiotic inactivation by enzyme-

mediated covalent modification which results in phosphate, adenyl or acetylgroup 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'sPrinciples 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.




Tetracyclines, macrolides, chloramphenicol, clindamycin, spectinomycin

• Spectrum of activity and clinical uses

• Specific indications for use

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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 andultimately nucleic acids.

○ Sulfonamides,chemical analogs of PABA, are competitive inhibitors of

dihydropteroate synthetase.

○ Sulfonamides therefore are reversible inhibitors of folic acid synthesisand 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.

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○ When trimethoprim or pyrimethamine is combined with sulfonamides

(sulfamethoxazole) there is sequential blocking of the biosynthetic pathway leading to drug synergism and enhanced antimicrobialactivity. (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 Salmonellainfection, 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 Pneumocystiscarinii 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 bycoadminstration 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, leukopeniadiarrhea.

Chambers, H.F. and Jawetz, E.Sulfonamides,Trimethoprim, and Quinolones,in Basicand 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 effectsand potential drug-drug interaction for quinolones

Antimycobacterial agents

Drugs to Treat Mycobacterial Infections

• Overview

○ 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:

1. Isoniazid (INH)

2. Rifampin (Rimactane)

3. Pyrazinamide

4. Ethambutol

5. spectinomycin (Trobicin)

Second Line Drugs

○ Amikacin (Amikin)

○ Aminosalicylic Acid

○ Capreomycin

○ Ciprofloxacin (Cipro)

○ Clofazimine

○ Cycloserine

○ Ethionamide

○ Ofloxacin (Floxin)

○ Rifabutin (Mycobutin)

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Mechanisms of Actions of Antimycobacterial Agents

• Isoniazid (INH)

○ Overview:

Isoniazid (INH) is the most active for treatment of tuberculosis.

INH inhibits mycolic acid synthesis, an essential part of mycobacterial cellwalls.

Given alone, INH administration selects out resistant mutants whichnecessitates 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 predispositionto fast- or slow acetylation. Dosage adjustments may be required INHmetabolites 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 preventativetreatment.

○ Single drug: INH treatment is also indicated as a preventative for individuals who

have been in close contact with individuals who have active pulmonarytuberculosis.

• 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 muchreduced 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, someenteric organisms, mycobacteria and Chlamydia.

Rifampin binds selectively to bacterial DNA-dependent RNA polymerasethus inhibiting RNA synthesis.

Rifampin is bacteriocidal for myobacteria.



○ Clinical Uses

Rifampin co-administered with isoniazid or ethambutol to treatmyobacterial 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 includingosteomyelitis and prosthetic valve endocarditis.

Rifampin in combination with ceftriaxone or vancomycin to treatmeningitis caused by highly penicillin-resistant pneumococcal isolates

○ Adverse Effects

Harmless orange coloration to urine, sweat, tears.

Occasional effects: rash, nephritis, thrombocytopenia, flu-like symptomsdepending on dosing intervals

Rifampin microsomal P450 induction increases the metabolism of manydrugs

• Antimycobacterial agents Membrane Structure

• Clinical Uses of Antibacterials (for management of gram positive organisms)

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