antibiotics outline

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Chapter 35 Antibacterial Drugs

Menu• Bacterial Cell Wall: Sites of

Antibacterial Action

• Inhibitors of Cell-Wall

Synthesis,e.g.

◦ Penicillins

◦ Cephalosporins

◦ Vancomycin (Vancocin)

• Membrane-Active Agents,e.g.

◦ polymixin

◦

gramicidin• Inhibitors of Protein Synthesis,

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,

Streptomycin

• Clinical Use of Antibacterial

Drugs• Drugs of Choice for treating:

◦ Pneumonia

◦ Meningitis

◦ Sepsis Syndrome

◦ Urinary Tract Infection

• Management of vancomycin

(Vancocin)-resistant

Enterococcus faecium (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 Sexually

Transmitted Infections

◦ Chlamydia

◦ Gonorrhea

◦ Epididymitis

◦ Pelvic Inflammatory

Disease

◦ Vaginal Infections

◦ Syphilis

◦ Chancroid

◦ Genital Herpes

◦ Pediculosis & Scabies

◦ Genital Warts &

human papillomavirus

(HPV) infection

• Linezolid (Zyvox): newantibiotic for treatment of

infection due to vancomycin

(Vancocin)-resistant

Enterococcus faecium

http://www.pharmacology2000.com/Antibacterial/ML1.htm

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http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Antimycobacterial%20agents

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#DNA%20gyrase

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#folate

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http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Membrane

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Cell-Wall


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http://www.pharmacology2000.com/Antibacterial/linezolid1.htm






http://www.pharmacology2000.com/Antibacterial/sex5.htm#Genital%20Warts%20&%20human%20papillomavirus%20%28HPV%29%20infection


http://www.pharmacology2000.com/Antibacterial/sex5.htm#Pediculosis%20&%20Scabies

http://www.pharmacology2000.com/Antibacterial/sex3.htm#Vaginal%20Infections

http://www.pharmacology2000.com/Antibacterial/sex2.htm#Pelvic%20Inflammatory%20Disease

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http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Thoracic%20%28noncardiac%29


http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Neurosurgery

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Head%20&%20Neck%20Surgery

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Genitourinary

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Gynecologic%20&%20Obstetric

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Gastrointestinal%20diseases


http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Cardiac%20Surgery

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Overview%20--Choice%20of%20agents%20%28principles%29

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http://www.pharmacology2000.com/Antibacterial/sex5.htm#Pediculosis%20&%20Scabies

http://www.pharmacology2000.com/Antibacterial/sex5.htm#Genital%20Herpes

http://www.pharmacology2000.com/Antibacterial/sex5.htm#Chancroid


http://www.pharmacology2000.com/Antibacterial/sex3.htm#Vaginal%20Infections





http://www.pharmacology2000.com/Antibacterial/sex1.htm#Gonorrhea:

http://www.pharmacology2000.com/Antibacterial/sex1.htm#Chlamydia



http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Vascular

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Thoracic%20%28noncardiac%29

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Orthopedic

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Ophthalmic

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Neurosurgery

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Head%20&%20Neck%20Surgery

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Genitourinary

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Gynecologic%20&%20Obstetric


http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Cardiac%20Surgery

http://www.pharmacology2000.com/Antibacterial/surg_pro1.htm#Overview%20--Choice%20of%20agents%20%28principles%29

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http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Antimycobacterial%20agents

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#DNA%20gyrase




http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Membrane







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

efficientpermeability

barrier

containing

lipopolysacchari

des (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

porouspeptidoglycan

layer

[graphic: © Linda M.

Stannard used with

permission]

Peptidoglycan Layers

Cytoplasmic

Membrane

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Chemotherapy:%20Antibacterial%20Drugs



Multiple sites of inhibition by antibacterial agents

Gram-negative CellMembrane Model

• Gram-negative

bacteria are

surrounded by

two membranes.

• The outer

membrane

functions as an

efficient

permeability

barriercontaining

lipopolysacchari

des (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

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Inhibitors of Cell-Wall Synthesis

Penicillin G

• Overview:

◦ Penicillin G is bacteriocidal for sensitive strains, that is the agentitself 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 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)

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).

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Penicillin Structural Features and Requirements for Antibacterial Activity

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Penicillin%20Basics



• Penicillins have similar

structures: a thiazolidine ring

(A) atached to a ß-lactam

ring (B).

• Substituents are attached tothe amino group (R).

Moieties A and B together

constitute the 6-

aminopennicillanic acid

nucleus required for

antibacterial activity.

• Cleaving the ß-lactam ring by

penicillinases (ß-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 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 PBP

genes (e.g. pneumococcal, gonococcal and meningococcal resistance).



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 (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));

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.

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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, can

lessen 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, 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 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 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 areangioedema 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 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)

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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.



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.



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 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

increased resistance to beta-lactamase-producing bacteria.

5.

Interlude: Microorganisms

1Bacteriodes fragilis

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Proteus

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Klebsiella

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#E%20.%20coli

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Moraxella%20catarrhalis

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Bacteriodes%20fragilis



• 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 andcolon 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

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-Organisms http://

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

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) arefrequently (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

Universit of Texas Medical Branch, htt :// sbs.utmb.edu/microbook/ch026.htm


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




3Moraxella catarrhalis

•3 Moraxella 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 tractinfection 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, GebhardtBM, 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

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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 (exceptfor 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 • First

Generation:

Cefazolin

(Ancef)

• Third-

generation:Cefotaxime

(Claforan);

Ceftriaxone

(Rocephin);

Ceftazidime

(Ceptaz)

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Staphylococcus%20aureus

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Staphylococcus%20aureus

http://www.pharmacology2000.com/Antibacterial/antibactobj.htm#Streptococci:



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

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 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 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. 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-negativeorganisms (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-lineantibiotics 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 menningitiscaused 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.



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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.


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. 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) 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. 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

◦ 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 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.


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

infectionsendocarditis

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


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 Basicand 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.


◦ Alone or in combination with polymyxin or neomycin: treatment of mixed skin,

wound or mucous membrane infections.

• Adverse Effects

◦ Significant nephrotoxicity with systemic administration


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


◦ Used almost exclusively for treating tuberculosis caused by M. tuberculosis

isolates resistant to primary drugs.

• Adverse Effects

◦ CNS toxicity at higher than clinical doses


and 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 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


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


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.

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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 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.!

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.


Tetracycline:

• Tetracycline binds to 40S ribosomal RNA, blocking association of amino acid-charged

tRNA with its acceptor site on the ribosomal mRNA complex.


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.

Aminoglycosides:

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



• Detailed analysis of streptomycin suggest three specific protein synthesis inhibition

mechanisms:

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. 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 withaminoglycoside-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.



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

• 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.


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

◦ 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.


▪ Nephrotoxicity

▪ Deafness


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.



• 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.



• 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



• 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 creatininelevels 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.



• 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.




Division), 1998, p. 859.



Tetracyclines, macrolides, chloramphenicol, clindamycin, spectinomycin


• Specific indications for use

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http://www.pharmacology2000.com/Antibacterial/ips_clin_use.htm


http://www.pharmacology2000.com/Antibacterial/tetra_spectrum1.htm



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




◦ Sulfonamides,chemical analogs of PABA, are competitive

inhibitors of dihydropteroate synthetase.



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)

http://www.pharmacology2000.com/Antibacterial/sulfa1.htm



◦ 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

• 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

http://www.pharmacology2000.com/Antibacterial/dnagyr1.htm



◦ Amikacin (Amikin)

◦ Aminosalicylic Acid

◦ Capreomycin

◦ Ciprofloxacin (Cipro)

◦ Clofazimine

◦ Cycloserine

◦ Ethionamide

◦ Ofloxacin (Floxin)

◦ Rifabutin (Mycobutin)

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

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 treatleprosy.

▪ 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 treatmeningitis 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

• Antimycobacterial agents Membrane Structure

• Clinical Uses of Antibacterials (for management of gram positive

organisms)

Pneumococcal Infections

•

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p

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s

•

P

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is

• Pneumococci (Streptococci pneumoniae): gram-positive cocci that grow in

chains.

• Streptococci pneumoniae colonize the nasopharynx

Infections caused by S. pneumoniae from most to least common in

adults

1. Acute sinusitis

◦ S. pneumoniae is the most common organism cultured

from middle ear fluid or from paranasal sinus from patients

with otitis media or sinusitis respectively.

◦ Almost equally common is nontypable Hemophilus

influenzae.

2. Pneumonia

◦ Pneumococcal pneumonia is most common in the very



.

◦ Symptoms include:

▪ Cough and sputum production

▪ fever

▪ plain film detection of an infiltrate

◦ Most adults with pneumococcal pneumonia have an

underlying disease the make them more vulnerable to

infection. Predisposing factors include:

▪ prior viral respiratory illness

▪ alcoholism

▪ malnutrition

▪ chronic pulmonary disease

▪ diabetes mellitus

▪ hepatic cirrhosis

▪ renal insufficiency

▪ congestive heart failure

▪ infection with human immunodeficiency virus(HIV)

3. Acute purulent tracheobronchitis

4. Otitis media

◦ S. pneumoniae is the most common organism cultured

from middle ear fluid or from paranasal sinus from patients

with otitis media or sinusitis respectively.

◦ Almost equally common is nontypable Hemophilus

influenzae.

5. Empyema

6. Meningitis

◦ S. pneumoniae is the most common cause of bacterial

meningitis in adults {except during meningococcal

infection}

◦ S. pneumoniae is also the most common cause of bacterial

meningitis in infants and toddlers (but not new borns) due

to the effectiveness of vaccination against H. influenzae.

◦ Meningitis usually results from extension of sinus or

middle ear infection, but may occur from bacteremia and

subsequent infection of the choroid plexus.

7. Primary bacteremia

8. Osteomyelitis9. Septic arthritis

10. Peritonitis

11. Pericarditis

12. Endometritis

13. Cellulitis

14. Brain abscess



Treatment Principles

• ß-Lactam antibiotics are the primary drugs used in treating pneumococcal

infections.• With the development of resistance, higher drug concentrations or different

agents have been used.

• By 1995 about 20% of streptococcal strains showed intermediate levels ;

between 2% to 5% of strains showing a high degree of resistance.

• Some intermediate level of resistant strains also showed resistance to

erythromycin, newer macrolides, tetracyclines, trimethoprim-

sulfamethoxazole (Bactrim) and clindamycin (Cleocin).

• Some highly penicillin-resistant strains are also resistant to second-

generation and some third-generation cephalosporins.

• Most strains remain sensitive to cefotaxime (Claforan), ceftriaxone

(Rocephin), and imipenem.• The vast majority of pneumococcal strains remain sensitive to vancomycin

(Vancocin), although acquisistion of resistance to this agent is of concern in

view of the emergence of vancomycin-resistant enterococci and other gram-

positive microbes.

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Specific Antibiotic Treatment:

Pneumonia:

• For penicillin-sensitive or intermediate resistant strains: penicillin is used.

• Clindamycin is also efficacious in treating these strains.

• For highly resistant strains, i.v. cefotaxime, ceftriaxone or imipenem is

usually effective (90%).

• For strains resistant to these agents, vancomycin must be used.

• If the infection is thought to be life-threatening and without susceptibility

information, initial treatment with cefotaxime or ceftriaxone would be

appropriate.

• For hospitalized patients with suspected pneumococcal pneumonia, a life-

threatening condition, this approach might be considered.• Patients with severe drug allergy to penicillins may be treated with an

advanced macrolide, clindamycin, or vancomycin pending susceptibility

testing results.

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http://www.pharmacology2000.com/Antibacterial/pneumo1.htm#Pneumococcal%20Infections



Meningitis:

• Meningitis: the most life-threatening of pneumococcal infections.

• Initial Treatment: cefotaxime plus vancomycin.

◦ Cefotaxime is highly efficacious against most strains and penetrates

the blood-brain barrier; vancomycin is very effective, but may not

reliably enter the CNS.

• If the strain is sensitive to penicillin, then treatment can be continued with

penicillin.

• Rifampin inhibits the activity of ß-lactam agents and should not be used in

this situation

Staphylococcal Intoxications, Infections, and DrugTherapy

• Introduction:

• Staphlococcal Intoxications:

• Staphylococcal• InfectionsDrug Treatment

Introduction

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http://www.pharmacology2000.com/Antibacterial/staphylo1.htm#Staphylococcal%20Infections:

http://www.pharmacology2000.com/Antibacterial/staphylo1.htm#Staphylococcal%20Infections:

http://www.pharmacology2000.com/Antibacterial/staphylo1.htm#Staphylococcal%20Intoxications:

http://www.pharmacology2000.com/Antibacterial/staphylo1.htm#Introduction



• Staphylococci are common bacteria that colonize human skin and mucous

membranes.

• Staphylococci are the leading cause of bacteremia, surgical wound infection

and the second leading cause of nosocomial infections.

• Staphylococci are responsible for the following syndromes:

◦ superficial and deep pyogenic infections◦ systemic intoxications

◦ urinary tract infection

• Within the genus, Staphylococcus aureus is the most important human

pathogen, in part because of increasing resistance to antimicrobial agents.

• Other important Staph pathogen include: Staphylococcus epidermidis

[prosthetic materials adherance and nosocomial infections] and

Staphylococcus saprophyticus [urinary tract infection]

Return to top menu

Deresiewicz, R.L., and Parsonnet, J., Staphylococcal 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. 875.

Staphylococcal Intoxications:

• Toxic Shock Syndrome (TSS): caused by toxic exoproteins produced by S.

aureus.

◦ Symptoms: hypotension, fever, rash, multiorgan dysfunction.

◦ Treatment: decontamination of the anatomical site producing toxin,fluid replacement and administration of anti-staphylococcal agents.

◦ Effective drugs : semisynthetic penicillins {nafcillin, oxacillin} and

the possibly more effective protein synthesis inhibitor clindamycin.

• Food poisoning: caused by the presence of staphylococcal enterotoxins

(SEs) which are resistant to cooking temperatures.

• Most cases are self-limiting with symptoms resolving between 8 to 24 h.

following onset of nausea, vomiting, abdominal pain and diarrhea.

• Staphylococcal Scalded Skin Syndrome: Cutaneous diseases of differing

severity caused by staphylococcal enterotoxins (SE)- producing strains of

Staph. aureus.

• Depending on the manifestation, mortality from dehydration and sepsis canrange from 3% in children to 50% in adult patients.

• Treatment: fluid/electrolyte management, care to denuded skin and

antistaphylococcal drugs.

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http://www.pharmacology2000.com/Antibacterial/staphylo1.htm#and




Deresiewicz, R.L., and Parsonnet, J., Staphylococcal 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. 877-879.

Staphylococcal Infections

Skin and Soft Tissue Infections

• Skin and Soft-tissue Infections: S. aureus is the most common cause and

may be manifest as boils and carbuncles.

• S. aureus causes bullous impetigo, a cutaneous infection seen primarily in

children.

• Cellulitis, an infection of subcutaneous tissue, may be caused by S. aureus

but more commonly by ß-hemolytic streptococci.• Post-surgical/traumatic wound secondary infection is most likely due to

Staph. aureus.

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Respiratory Tract Infection

• S. aureus may cause pneumonia, but this occurence is rare in the absence of

predisposing host factors or epidemiological factors that impair

immunological defense mechanisms.

• S. aureus is occasionally the cause of sore throat with exudative

pharyngitis.

• S. aureus is a significant cause of chronic sinusitis and sphenoid sinusitis

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Central Nervous System Infection

• S. aureus: important cause of brain abscess.

• S. aureus: common cause of space-filling suppurative intracranial infections

such as subduralempyema [osteomyelitis of the skull]• S. aureus: most common cause of spinal epidural abscess.

• S. aureus: most common cause of septic intracranial thrombophlebitis

[arising from facial soft tissue infection, sinusitis, or mastoiditis]

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Endovascular Infection

• S. aureus: most common cause of acute bacterial endocarditis of native and

prosthetic cardiac valves. [The microbe tends to adhere and infect damaged

tissue]

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Musculoskeletal Infection

• S. aureus: most common cause of acute osteomyelitis in adults and a

prominent cause in children.

• S. aureus: prominent cause of chronic osteomyelitis.

• S. aureus: significant cause of septic arthritis & septic bursitis

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Drug Treatment

• Although most pathogenic strains of S. aureus are resistant to penicillin,

efficacious semi-synthetic penicillinase-resistant drugs have been developed.

• Nafcillin and oxacillin (ß-lactamase resistant) are effective and drugs of

choice in treating staphylococcal infection.

• Combinations that include a penicillinase-inhibitor and penicillin are also

efficacious but may be best reserved for mixed-infections.

• On the basis of potency, cost and spectrum of coverage, first-generationcephalosporins (e.g. cefazolin) would be appropriate.

• Vancomycin (parenteral) is efficacious as are dicloxacillin and cephalexin

(oral, for minor infection or continuous treatment)

• An example of synergy in treating S. aureus bacteremia (endocarditis) is the

combinaton of an aminoglycoside/ß- lactam combination.

• Rifampin in combination with a ß- lactam antibiotic or vancomycin is

effective in otherwise refractory disease, but should not be employed as

monotherapy due to toxicity due to rapid resistance development.

• ifampin should be reserved for refractory infections in which the added risk

of rifampin toxicity is justified.

Streptococcal Infections





• General Classification

• Lancefield Group Classifications

• Group A Streptococci:

Pharyngitis

• Group A streptococci: Impetigo

• Group A streptococci: Cellulitis• Group A streptococci: Deep Soft

Tissue Infection

• Group A streptococci:

Pneumonia and Empyema

• Group C and G Streptococci

• Group B Streptococci

• Viridans

General Classifications:

• Streptococcal classifications: Lansfield Groups A, B, C, D, G, Variable:

• Lancesfield classification is based on differing serologic reactions to specific

antisera with cell-wall carbohydrate bacterial antigens.• Each group is characterized by a particular pattern of human infection.

Nearly all organisms belonging to groups A, B, C and G are beta-hemolytic

streptococci.

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Wessels, M.R., Streptococcal and Enterococcal 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. 885-892.

Classification of Streptococci

Lancefield Group ExampleHemolytic

PatternInfections

A S. pyogenes ß

pharyngitis, scarlet

fever, impetigo,

cellulitis

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http://www.pharmacology2000.com/Antibacterial/hemolytic2.htm

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http://www.pharmacology2000.com/Antibacterial/strept1.htm#Viridans

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http://www.pharmacology2000.com/Antibacterial/strept1.htm#Group%20C%20and%20G%20streptococci:

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Pneumonia%20and%20Empyema:

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Pneumonia%20and%20Empyema:

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Deep%20Soft%20Tissue%20Infection:

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Deep%20Soft%20Tissue%20Infection:

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Cellulitis

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Impetigo:

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Pharyngitis

http://www.pharmacology2000.com/Antibacterial/strept1.htm#Pharyngitis

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http://www.pharmacology2000.com/Antibacterial/strept1.htm#General%20Classifications:

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B S. agalactiae ß

Neonatal sepsis and

meningitis,

puerperal infection,

urinatry tract

infection (UTI),

diabetic ulcerinfection,

endocarditis

C S. equi ß

Cellulitis,

bacteremia,

endocarditis

DEnterococci: E.

faecalis, E. faecium

usually non-

hemolytic

UTI, wound

infections,

endocarditis

DNonenterococcal: s.

bovis

usually non-

hemolytic

Bacteremia,

endocarditis

G S. canis ß

Cellulitis,

bacteremia,

endocarditis

Variable/Non-

groupable

Viridans

streptococci: S.

mutans, S. sanguis

alpha

endocarditis, dental

abscess, brain

abscess

Variable/Non-

groupable

Intermedius or

milleri group: S.

intermedius

variableBrain abscess,

visceral abscess

Variable/Non-

groupable

Anaerobic

streptococci:

Peptostreptococcus

magnus

usually non-

hemolytic

Sinusitis,

pneumonia,

empyema, brain

abscess, liver

abscess

Table from: Wessels, M.R., Streptococcal and Enterococcal 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. 885.

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Group A streptococci:

Pharyngitis

• Group A streptococcal pharyngitis is one of the most common bacterial

infections of childhood (20% to 40%) of cases, although rare under the age

of three.

• Following an incubation period of 1 - 4 days, symptoms commonly include

sore throat, fever and chills and occasionally vomiting, especially in

children.

• Definitive diagnosis is by throat culture (gold standard) , but high

specificity (95%) using rapid diagnostic kits (using latex agglutination or

enzyme immunoassay of swab specimens) make these kits useful.

• A positive result from these kits can allow definitivie diagnosis andeliminate the need for throat culture; however, a negative result should be

confirmed with throat culture because the kits are relatively less sensitive

(55% to 90%).

• Follow-up culture may be warrented if there is concern for Rheumatic fever

development (cases reported in the community)

Drug Treatment: Benazthine Penicillin; penicillin V or erthyromycin in patients

allergic to penicillin

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Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci,


Division), 1998, p. 886.


Impetigo:




• Impetigo: superficial skin infection is caused by Group A streptococci,

although S. aureus may be present later in the course of infection.

• Drug Treatment: Dicloxacillin, cephalexin, topical mupirocin are most

reliable; penicillin (benzathine penicillin/penicillin V) or erythromycin is less

costly and equally effective.

Return to top menu


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. 887.


Cellulitis

• Cellulitis: Infection involving the skin and subcutaneous tissue.

• Steptococcal cellulitis is most often localized to sites of normal lymphatic

drainage.

• Localized cellulitis may be accompanied by lymphangitis (red streaking

along superificial lymphatics)

• Drug Treatment: Severe: penicillin G; mild to moderate: procaine penicillin

Return to top menu





Division), 1998, p. 888.


Deep Soft Tissue Infection:





• Necrotizing fasciitis or hemolytic streptococcal gangrene involves

superficial and/or deep fascia.

• If cases are associated with bowal flora, the infection is usually due to

Bacteriodes fragilis or anaerobic streptococci along with gram negative

bacilli).

• Cases not resulting from bowel contamination are ususally due to group Astreptococci (60% of the time)

• Drug Treatment: Penicillin G (surgical debridement essential)

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1998, p. 886.


Pneumonia and Empyema:

• Group A streptococci may cause pneumonia, occasionally, with pleural

effusions occurring about 50% of the time.

• Pleural effusions due to Group A streptococci are usually infected, by

contrast to that seen with pneumococcal penumonia.

• Drug Treatment: Penicillin GReturn to top menu





Division), 1998, p. 888.

Group C and G streptococci:





• Infections are similar to those caused by Group A.

• These infections occur most often in the elderly and chronically ill.

• Drug Treatment of Choice: Penicillin, with the addition of gentamicin if

patients respond poorly to penicillin alone for treatment of endocarditis or

septic arthritis.

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1998, p. 889.

Group B Streptococci

• Group B streptococci, S. agalactiae, is a significant cause of sepsis and

meningitis in the newborn and peripartum fever in women.

• Drug Treatment of Choice: Penicillin.

• Neonatal risk factors for Group B strept. infections: preterm deliver, eary

membrane rupture, prolonged labor, fever or chorioamnionitis.

• Emperical broad antibiotic coverage for suspected neonatal bacterial sepsis is

ampicillin and gentamicin.

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Division), 1998, p. 889-890.

Viridans





• Viridans streptococci consist of a variety of alpha-hemolytic streptococci,

including S. salivarius, mutans, sanguis, and mitis, all common oral flora.

Transient viridans endocarditis may be caused by eating, tooth-brushing,

etc.

• Viridans bacteremia is frequently observed in neutropenic patients,

especially after bone-marrow transplantation or high-dose cancerchemotherapy. Manifestation of infection may include high fever and shock

(sepsis syndrome).

• Risk factors include: antibiotic prophylaxis with trimethoprim-

sulfamethoxazole or a fluoroquinolone, mucositis, use of antacids or

histamine antagonists, and significant neutropenia.

• In the neutropenic patients, vancomycin is the initial drug of choice before

results of susceptibility testing are available, given that many viridans

steptococci strains isolated from the neutropenic patient are penicillin

resistant.

• Viridans streptococci strains isolated in other settings usually are sensitive

to penicillin.

Enterococci/Group D Streptococci• Significant human enterococcal infections are due to E. faecalis and E. faecium.

• Enterococcal urinary tract infections are common. Ampicillin is usually sufficient for

treatment of UTI.

• Enterococci cause about 10 to 20% of bacterial endocarditis localized on

natural and prosthetic valves.• Enterococci are not reliably killed by penicillin/ampicillin at typically achieved blood

and tissue levels.

• Accordingly, penicillin or ampicillin is combined with an aminoglycoside (gentamicin)

for serious infection.• In patients who have penicillin allergy, vancomycin may be used in combination with

gentamicin.

• Most enterococcal strains are steptomycin resistant and high-level resistance to

gentamicin has become common.

• In strains resistant to all aminoglycosides, high-dose/ long-duration treatment with

peinicillin or ampicillin is recommended.

• Enterococci may be resistant to penicillins (either by ß-lactamase production or due to

alteration of penicillin-binding proteins (PBPs).

• For enterococcal infections by isolates resistant to ß-lactam antibiotics, the combination

vancomycin + gentamicin is recommended.

• Vancomycin-resistant enterococci is also common.• No standard therapy infection by enterococcal isolates resistant to both ß-lactam

antibiotics and vancomycin

Group D Streptococcal Infections:

• Main nonenterococcal group D streptococcal infections are due to Streptococcus bovis.

S. bovis is sensitive to ß-lactam antibiotics.

• Penicillin, as a single agent, is the drug of choice in treating infections cause by S.



bovis.

•

• Diphtheria is caused by Corynebacterium diphtheriae, which is an aerobic, gram-

positive rod.

• C.diptheria infects mucous membranes, usually in the respiratory tract, and open

skin lesions.• Some strains elaborate diphtheria toxin which causes myocarditis polyneuritis

and other systemic toxicities.

• Primary respiratory tract infection is manifest as tonsillopharyneal but may

involve laryngeal, nasal and thraceobronchial structures.

• Complications of infection include obstruction of the respiratory tract (dyspnea,

tachypnea, cyanosis) resulting from extensive pseudomembrane formation and swelling early

in the disease and pseudomembrane sloughing later in disease progression. Pneumonia is

present in about 50% of diphtheria fatalities.

• Myocarditis and polyneuritits are the most significant toxic manifestions.

Myocarditis occurs in about 25% of patients. Polyneuritis, in mild disease, is seen about 10%

of the time; in severe disease: about 75% of the time.• Treatment involves the administration of horse-derived diptheria antitoxin.

Accordingly, a test for immediate hypersensitivity reaction is required.

• Antibody therapy allows rapid neutralization of diphtheria toxin.

• Elimination of C.diptheria accomplished by antibiotic treatment using

erythromycin, penicillin G, rifampin, or clindamycin. Vaccines are available for immunization

against diphtheria.

• Coryneform bacteria constitute a large, poorly classified family of gram-positive

staining bacilli or coccobacilli only superficially resembling C. diphtheriae.

• C. jeikeium is an example of a coryneform bacteria that causes infections in

immunocompromised patients and especially severe infections in neutropenic patientswith hematologic cancers.

• The antibiotic drug of choice for C. jeikeium is vancomycin (Vancocin)

• Strains of C. jeikeium are susceptible or only mildly resistant to ß-lactam antibiotics.

• For strains moderately resistant to ß-lactams, a ß-lactam in combination with an

aminoglycoside may be effective.

• Anthrax is a bacterial infection caused by Bacillus anthracis.

• Spores of Bacillus anthracis may be introduced by:

◦ animal contact

◦ contact with infected animal products

◦ inhalation◦ ingestion

◦ insect bites.

• B. anthracis is a chain-forming, aerobic gram-positive rod which can form oval spores.

• B. anthracis is an extracellular organism that:

◦ multiply rapidly

◦ release anthrax toxins and capsular polypeptides release



◦ prevent host phagocytosis.

• Anthrax toxin consists of three proteins:

◦ protective antigen (PA)

◦ edema factor (EF)

◦ lethal factor (LF). Entry of LF results in cell death by a yet to be elucidated

mechanism.• Main clinical manifestations:

◦ Cutaneous anthrax- 95% of anthrax is cutaneous.

◦ Most untreated cases resolve (80%-90%)

◦ In 10%-20% a progressive infection leads to bacteremia and death.

• Inhalation anthrax:

1. Cases present with symptoms similar to severe respiratory viral infection.

2. With three days, the disease progresses with increasing fever, dyspnea,

hypoxia, and hypotension and usually leads to death.

• Parentral penicillin G is highly effective in treating cutaneous anthrax. With penicillin

sensitivity, ciprofloxacin, erythromycin, tetracycline, or chloramphenicol may be used

instead.

• For inhalation or gastrointestinal anthrax, high-dose penicillin treatment is

recommended.

• With appropriate treatment the mortality rate for cutaneous anthrax is very

low.

• The mortality rate for gastrointestinal anthrax is about 50%, if treated.

• The mortality rate for inhalation anthrax may approach 100% if symptoms are

not promptly recognized and treated. The likelihood of an adverse outcome is

also probably dependent on the number of spores inhaled. There are recent

(2001) examples of individuals who recover from inhalation anthrax

ListeriaeIntroduction

• Listeria monocytogenes is a gram-positive rod found in soil, vegetation, and animals.

• Human infection by L. monocytogenes is most commonly seen in

immunocompromised patients or in pregancy.

• Most infections are due to eating contaminated foods, but invasive clinical syndromes

including meningitis, sepsis, chorioamnionitis, and still birth result.

• The increased risk of L. moncytogenes infection in pregnancy is thought to be due to

changes in both systemic and local immune system.◦ Immune suppression at the maternal-fetal placental interface may favor

intrauterine infection after transient maternal bacteremia.

Clinical presentations:

• Pregnancy-associated listeriosis:

◦ may occur at any stage of pregnancy, but usually detected during last trimester.



◦ Manifestations include chorioamnionitis, premature labor and intrauterine fetal

death.

◦ Clinical outcome is favorable following delivery or treatment with antibiotics.

• Neonatal listeriosis:

◦ Early onset disease is by second day

◦ Early-onset disease includes:▪ likelihood of obstetrical complications (chorioamnionitis;premature

delivery)

▪ sepsis

▪ respiratory distress

▪ skin lesions

▪ granulomatosis infantisepticum (abscesses involving liver, spleen,

adrenal glands, lungs, etc)

◦ Late-onset disease is more likely associated with normal delivery and later

development of meningitis.

• Non-pregnancy associated listeriosis:◦ Immunocompromised patients, especially the elderly

◦ Underlying conditions include: chronic glucocorticoid therapy, hematologic or

solid malignancies, diabetes mellitus, renal disease, liver disease, AIDS.

◦ Listeriosis is a relatively uncommon opportunistic infection in AIDS

• Sepsis: symptoms similar to bacteremia caused by other agents.

• CNS infection: meningitis

• Endocarditis: patients with prosthetic or previously damaged valves are at higher risk.

Treatment

• i.v. a mpicillin (Principen, Omnipen) or penicillin, often in combination with

synergistic-acting aminoglycoside.• In patients with penicillin allergy: the combination of trimethoprim-sulfamethoxazole

(Bactrim) is bactericidal and may be effective.

• Chloramphenicol (Chloromycetin) and rifampin (Rimactane) may antagonize

bactericidal effects of penicillins.

• Cephalosporins: not recommended.

Introduction

• Tetanus is manifest as increased muscle tone and spasms and is caused by a protein

toxin released by Clostridium tetani.

◦ Toxin enters axons and is transported to brainstem and spinal cord nerve cellbodies. The toxin then moves transynaptically from post- to presynaptic

terminals where release of inhibitory aminoacids GABA and glycine is blocked.

◦ As a result of decreased inhibitory input, alpha-motoneuron activity is increased

and regidity results. Disinhibition, in general, results in spasms and sympathetic

hyperactivity.

◦ Tetanospasmin and botulinum toxin may blocker acetylcholine release at

neuromuscular junctions. This blockade results in weakness or paralysis and



recovery requires de novo sprouting of nerve terminals.

◦ C. tetani is a ubiquitous, anaerobic, gram-positive rod found in soil and feces.

• In spore form, C. tetani is resistant to many disinfectants and boiling (20 min)

• In vegetative form, C. tetani is susceptible to antibiotic.

Clinical presentations

• Sequence of muscle effects

1. Increased muscle tone of the masseter (lockjaw)

2. Dysphagia, neck, shoulder, back pain.

3. Abdominal and proximal limb stiffness

4. Facial muscle contraction (risus sardonicus)

5. Spasms of the back--arched back (opistotonus)

6. Generalized spasms

• Autonomic dysfunction (severe cases):

◦ hypertension

◦ hyperpyrexia

◦ tachycardia/arrhythmias

◦ peripheral vasoconstriction (high circulating catecholamine levels)

Return to top Menu

Treatment

• remove

source of

toxin

• inactivate

unbound

toxin

• prevent

muscle

spasms

• respiratory

and general

patient

support

• Clean and debride the wound• Antibiotic treatment is of unproven value, but is used to eliminate vegetative cells that

are producing toxin. Metronidazole (Flagyl) (preferred) and penicillin may be

administered.

• Antitoxin: neutralizes circulating toxin: Antitoxin reduces mortality. Human tetanus

immune globulin (TIG) is preferred; alternatives: Equine tetanus antitoxin (TAT,shorter

half-life ) may be used, although serum sickness and hypersensitivity reactions are

common.

• Control of muscle spasm:

◦ Diazepam (Valium)--widely used;

◦ Other options: lorazepam (Ativan), midazolam (Versed)(both by i.v. infusion

such to short half-lives;

◦ Barbiturates/chlorpromazine (Thorazine): second-line agents.

• Autonomic dysfunction:

◦ hypertension : Labetalol (Trandate, Normodyne) (alpha + beta receptor

blockade);esmolol (Brevibloc); clonidine (Catapres);

◦ hypotension: volume expansion, vasopressors, chronotropic drugs, pacemaker

http://www.pharmacology2000.com/Antibacterial/tetanus1.htm#Listeriae%20Infections



Prevention: Active Immunization;

Prognosis: With respiratory support, mortality rates as low as 10% have been reported; Poorer

outcome is associated with neonates, the elderly, and in patients with a short incubation period.

Recovery is often complete, but may taken months.

BotulismIntroduction

• Botulism is caused by the most potent neurotoxins known.

◦ Neurotoxins are produced and liberated by Clostridium botulinum.

• C. botulinum, ubiquitously found in soil and marine environments, is a group of gram

positive anerobes that form spores.

• Eight distinct toxins have been characterized, all but one being neurotoxic.

• Botulinum neurotoxin affects cholinergic nerve terminals:

◦ postganglionic parasympatetic endings

◦ neuromuscular junctions◦ peripheral ganglia

• CNS is not involved.

• Botulinum neurotoxin prevents acetylcholine release:

1. binds presynaptically

2. internalized in vesicular form

3. released into the cytoplasm

4. the toxin(s), zinc endopeptidases) causes proteolysis of components of the

neuroexocytosis system.

Clinical presentations:

• Descending paralysis which can lead to respiratory failure• Onset of symptoms is referable to cranial nerve involvement:

◦ diplopia

◦ dysarthria/dysphagia

Treatment

• Supportive

• For food-borne illness, trivalent (types A,B and E) equine antitoxin

• Antibiotic treatment is of unproven value

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


• 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:


◦ 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


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 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


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


Inhibitors of Cell Wall Synthesis

• Penicillin-binding Proteins

(PBPs) catalyze an important

step in bacterial cell wall

synthesis [a transpeptidasereaction 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)

• 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 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.


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.




Tetracycline:

• Tetracycline binds to 40S ribosomal RNA, blocking association of amino acid-charged

tRNA with its acceptor site on the ribosomal mRNA complex.


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.

Aminoglycosides:

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

• Detailed analysis of streptomycin suggest three specific protein synthesis inhibition

mechanisms:

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. These

combined effects, occurring at the same time, are probably responsibile for

aminoglycoside bacteriocidal properties.


◦ 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 vestibulardamage: 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.

Most ototoxic-----------------------------Most toxic to the vestibular system

• neomycin

• kanamycin

• amikacin

• neomycin

• tobramycin

• gentamicin


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)


▪ 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.



• 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.


▪ Nephrotoxicity

▪ Deafness




• Tobramycin (Nebcin)

◦ Antibacterial spectrum of action similar to gentamicin.

◦ Some cross-resistance possible

◦ Nearly identical pharmacokinetic profile

◦ Similar antimicrobial spectum to gentamicin.


▪ Nephrotoxicity

▪ Deafness






• 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.



• 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 bowelflora.

◦ Ototoxicity (auditory) and nephrotoxicity.





• 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



• 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.



• 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.




Division), 1998, p. 859.



Tetracyclines, macrolides, chloramphenicol, clindamycin, spectinomycin


• Specific indications for use

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Inhibitors of folate-dependent pathways

• Production and use of folate derivatives in bacterial systems




◦ Sulfonamides,chemical analogs of PABA, are competitive inhibitors

of dihydropteroate synthetase.



Sulfonamides




http://www.pharmacology2000.com/Antibacterial/tetra_spectrum1.htm



• Introduction to sulfonamide pharmacology

• Mechanism of action of sulfonamides




◦ Sulfonamides,chemical analogs of PABA, are competitiveinhibitors of dihydropteroate synthetase.



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 thebiosynthetic 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.

http://www.pharmacology2000.com/Antibacterial/sulfa1.htm



• 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

• Overview

http://www.pharmacology2000.com/Antibacterial/dnagyr1.htm



◦ 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, forexample)

◦ 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


◦

Clofazimine

◦ Cycloserine

◦ Ethionamide




◦ Rifabutin (Mycobutin)

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

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

• Antimycobacterial agents Membrane Structure

• Clinical Uses of Antibacterials (for management of gram positiveorganisms)

DNA Gyrase Inhibitors

• Mechanism of Action

◦ Fluoroquinones represent an important class of antimicrobial which work

through inhibition of DNA gyrase.◦ Bacterial DNA gyrase (topoisomerase II) and topoisomerase IV are required for

DNA synthesis.

◦ Inhibition of DNA gyrase blocks relaxation of supercoiled DNA, relaxation

being a requirement for transcription and replication.

◦ Inhibition of topoisomerase IV is thought to interfere with sepation of replicated

chromosomal DNA

• .Fluoroquinones: Spectrum of Action

◦ Norfloxacin (Noroxin)-least active of the fluoroquinolones

◦ Enoxacin (Penetrex)

◦ Pefloxacin



◦ Lomefloxacin (Maxaquin)

◦ Sparfloxacin (Zagam) {new agent (1998) several times more potent than other

currently available fluoroquinolones}

*Ciprofloxacin (Cipro) & Ofloxacin (Floxin):inhibit gram negative cocci and bacilli:

Enterobacteriaceae, Pseudomonas, Neisseria, Haemophilus Campylobacter; Staphylococci and

streptococci are inhibited; Legionella, Chlamydia, M. tuberculosis, M avium are

inhibited;Anaerobes: generally resistant

• Pharmacokinetics◦ After oral administration, bioavailability is good, 80% - 95%.

◦ Half-lives range from 3 h (norfloxacin (Noroxin) and ciprofloxacin (Cipro)) to

10 (perfloxacin and fleroxacin)and 20 hours (sparfloxacin (Zagam)).

◦ Long half-lives of sparfloxacin (Zagam) and levofloxacin (Levaquin)

sparfloxacin and levofloxacin allow once daily dosing.

◦ Most flouroquinolones are excreted by the kidney (tubular secretion, may be

blocked by probenecid (Benemid)). Sparfloxacin (Zagam) is glucuronidated by



http://www.pharmacology2000.com/Antibacterial/mycomem1.htm



the liver then renally cleared

• Clinical Applications

◦ Effective in urinary tract infections (UTI) caused by multidrug resistant strains.

◦ Effective for diarrhea caused by Shigella, Salmonella, toxigenic E. coli or

Campylobacter infections.

◦ Most fluorquinolones that achieve adequate tissue concentrations are effective intreating soft-tissue, bone, and joint infections by multidrug resistant strains of

Pseudomonas and Enterobacter.

◦ Ciprofloxacin (Cipro): second-line agent for leginellosis.

◦ Ciprofloxacin (Cipro)/ofloxacin (Floxin): gonococcal infection.

• Adverse Effects

◦ Generally well tolerated

◦ Most common side effects are nausea vomiting diarrhea

◦ Concurrent administration of theophylline and ciprofloxacin may lead to

theophylline toxicity.

◦ Fluoroquinolones: damage to growing cartilage (not recommend for use in

patients under 18 years old); however, since such damage appears reversible,

these drugs may be used in children in some special cases--pseudomonal

infections in cystic fibrosis patients.

◦ Contraindicated in nursing mothers--drug excreted in breast milk.

Current Antibacterial Therapy

Menu

• Pneumonia

◦

Community-Acquired◦ Treatment: Hospitalized Patients

◦ Treatment: Ambulatory Patients

◦ Treatment: Hospital-Acquired Bacterial

Pneumonia

◦ Nosocomial pneumonia: intensive care unit

• Meningitis

• Sepsis

• Urinary Tract Infection

Pneumonia

• Community-acquired bacterial pneumonia: Streptococcus pneumoniae,

(Pneumococcus) Gram stain, sputum

◦ Most frequent cause: Streptococcus pneumoniae (pneumococci)

▪ Chest X-RAY

▪ > 30% of recent S. pneumoniae isolates:

• relatively or highly resistant to penicillin and

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sometimes cephalosporins.

◦ Other pathogens:

▪ Haemophilus influenzae

▪ Staphylococcus aureus

▪ Klebsiella pneumoniae

▪ occasionally: other gram-negative bacilli and anaerobicmouth organisms

▪ "Atypical" pathogens:

▪ Legionella

▪ Mycoplasma pneumoniae

▪ Chlamydia pneumoniae

▪ respiratory viruses

▪ tuberculosis

▪ Pneumocystis carinii

• Diagnosis

• Treatment: In Hospitalized Patients--◦ Pending culture results and susceptibility testing:

▪ Reasonable first-choice: cefotaxime or ceftriaxone

▪ Cefotaxime (Claforan), ceftriaxone (Rocephin), high-

doses of penicillin (IV) effective in treating

pneumococcal pneumonia (intermediate resistance)

▪ Vancomycin (Vancocin): high resistance

▪ Vancomycin (Vancocin) and cephalosporin: severe illness--

not responding to a beta-lactam.

▪ A macrolide (erythromycin, azithromycin (Zythromax), or

clarithromycin (Biaxin)) added to a fluoroquinone (good

activity against S. pneumoniae -- levofloxacin (Levaquin),grepafloxacin and trovafloxacin) can be used to cover

Legionella, Mycoplasma, chlamydia.

▪ If aspiration pneumonia is a concern: clindamycin

(Cleocin) or metronidazole (Flagyl) may be added.

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• Treatment for Ambulatory Patients:

◦ Treatment Recommended for otherwise healthy patients with

pneumonia due to Mycoplasma or Chlamydia:

▪ Oral macrolide ( erythromycin, azithromycin (Zythromax),

or clarithromycin (Biaxin)), doxycycline (Vibramycin,

Doryx), or fluoroquinones with good anti-pneumococcal

activity (levofloxacin (Levaquin), grepafloxacin,

trovafloxacin)

▪ Penicillin-resistant pneumococci: may be resistant to a

macrolide or doxycycline

▪ Older patients or patients with underlying disease:

recommendation --

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▪ levofloxacin (Levaquin)

▪ grepafloxacin

▪ trovafloxacin

• Treatment for hospital-acquired bacterial pneumonia:

◦ Most often cause by gram-negative bacilli:

▪ Klebsiella

▪ Enterobacter

▪ Serratia

▪ Acinetobacter AND


◦ Staphylococcus aureus

◦ The initial treatment: third-generation cephalosporin --

▪ cefotaxime (Claforan)

▪ ceftizoxime (Cefizox)

▪ ceftriaxone (Rocephin)

▪ ceftazidime (Fortax, Taxidime, Tazicef)◦ Or:

▪ cefepime (Maxipime)

▪ ticarcillin (Ticar)/ clavulanic acid

▪ piperacillin (Pipracil)/tazobactam

▪ meropenem (Merrem IV)

▪ imipenem

◦ with or without the aminoglycoside {tobramycin (Nebcin),

gentamicin (Garamycin), or amikacin (Amikin)}

◦ Considering third-generation cephalosporins:

▪ Cefotaxime (Claforan), ceftizoxime (Cefizox), andceftriaxone (Rocephin)} limited activity against

Pseudomonas

▪ Ceftazidime (Fortax, Taxidime, Tazicef)} more activity

against staphylococci and other gram-positive cocci

◦ In the intensive care unit -- nosocomial pneumonia due to highly

resistant gram-negative bacteria and Pseudomonas aeruginosa:

▪ Good first choices--

▪ imipenem


▪ plus aminoglycoside

▪ add vancomycin (Vancocin) in hospitals where

methicillin (Staphcillin)-resistant staphylococci are

common.

Meningitis

• Most common cause of bacterial meningitis1:



◦ Streptococcus pneumoniae

◦ Neisseria meningitidis

• Other causes:

◦ Enteric gram-negative bacteria:

▪ in the newborn

▪ in patients more than 60 years old▪ neurosurgical patients

▪ immunosuppressed patients

• Treatments in adults and in children > 2 months old (in the absence of culture

information):

◦ Cefotaxime (Claforan) or and ceftriaxone (Rocephin) and plus vancomycin

(Vancocin) (with or without rifampin (Rimactane) ) to cover resistant

pneumococci

▪ vancomycin may not reach sufficient levels in cerebral spinal fluid (in

certain patients

▪

if the causative organism is susceptible to cephalosporins, vancomycinand rifampin treatment should be discontinued.

• Treatment of Pseudomonas meningitis: ceftazidime (Fortax, Taxidime, Tazicef) plus

aminoglycoside (tobramycin (Nebcin), gentamicin (Garamycin), or amikacin (Amikin))

• Treatment of meningitis caused by Listeria: ampicillin (Principen, Omnipen) with or

without gentamicin (Garamycin)

Special Cases

• In penicillin-allergic patients:

◦ In the absence of allergic reactions to cephalosporins, cefotaxime (Claforan) or

ceftriaxone (Rocephin) may be used▪ vancomycin (Vancocin) with or without rifampin (Rimactane): added to

cover resistant pneumococci

◦ If cephalosporins may not be used: chloramphenicol (Chloromycetin) may serve

for initial treatment:

▪ may not be effective for infection due to enteric gram-negative bacilli or

in some patients with pneumococcal meningitis.

◦ Enteric gram-negative bacilli: aztreonam (Azactan)

◦ Listeria meningitis (penicillin-allergic patients): trimethoprim-sulfamethoxazole

(Bactrim)

• In Children:

◦ Administration of dexamethasone before or concurrent with the first antibiotic

dose has been recommended by some to reduce the incidence of hearing loss

and other neurological complications and children with meningitis.2

Most

pediatric infectious disease specialists recommended using dexamethasone at

least in meningitis due to Haemophilus influenzae.



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• In Newborns:

◦ Meningitis most often caused by:

▪ group B or other streptococci▪ gram-negative enteric bacteria

▪ Listeria

◦ Prior to definitive results from culture, treatment:

▪ ampicillin (Principen, Omnipen) plus cefotaxime (Claforan) (with or

without gentamicin (Garamycin))

SepsisIntroduction

• Factors in selecting appropriate drugs to manage sepsis syndrome:

◦ source of infection

◦ gram stain

◦ immune status

◦ bacterial resistance patterns in the community and hospital

• Treatment:

◦ gram-negative bacilli:

▪ Third or fourth generation cephalosporins



▪ cefoperazone (Cefobid)▪ ceftriaxone (Rocephin)


▪ ceftazidime (plus activity against gram-positive cocci)

▪ imipenem, meropenem (Merrem IV), aztreonam (Azactan)

◦ Cephalosporins (other than cefoperazone (Cefobid), cefepime (Maxipime), and

ceftazidime (Fortax, Taxidime, Tazicef)): limited efficacy against Pseudomonas

aeruginosa

◦ Pseudomonas aeruginosa: effectively treated with imipenem, meropenem

(Merrem IV), and aztreonam (Azactan).

◦ Aztreonam (Azactan): poor activity against gram-positive organisms andanaerobes

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• Initial treatment:

◦ Life-threatening sepsis and adults:

▪ Third or fourth generation cephalosporin







▪ ceftriaxone (Rocephin)


▪ ticarcillin (Ticar)/clavulanic acid


▪ imipenem or meropenem (Merrem IV) {each together withaminoglycoside [gentamicin (Garamycin), tobramycin (Nebcin), or

amikacin (Amikin)]}

◦ If methicillin-resistant staphylococci is a consideration:

▪ vancomycin (Vancocin) alone or

▪ vancomycin (Vancocin) with gentamicin (Garamycin) and/or rifampin

(Rimactane)

◦ If bacterial endocarditisis is a consideration (prior to pathogen identification):

▪ vancomycin (Vancocin) plus gentamicin (Garamycin)

◦ Treatment of intra-abdominal or pelvic infection (likely to involve anaerobes):

▪ticarcillin (Ticar)/clavulanic acid

▪ ampicillin (Principen, Omnipen)/sulbactam


▪ imipenem

▪ meropenem

▪ cefoxitin (Mefoxin) or cefotetan (Cefotan){each with or without an

aminoglycoside, metronidazole (Flagyl) OR clindamycin (Cleocin) with

an aminoglycoside}

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Special Cases

• Neutropenic patients with suspected bacteremia

◦ Treatment:

▪ ceftazidime (Fortax, Taxidime, Tazicef)

▪ imipenem


▪ cefepime (Maxipime) (in more seriously ill patients, add an

aminoglycoside

▪ amikacin (Amikin) and ceftriaxone (Rocephin) (single daily doses)

▪ piperacillin (Pipracil)/tazobactam plus amikacin

▪

Addition of vancomycin (Vancocin): in neutropenic cancer patients withbacteremia due to methicillin (Staphcillin)-resistant staphylococci were

some strains of viridans.

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• Resistant gram-negative bacilli

◦ Gram-negative bacilli resistant to:

▪ aminoglycosides

▪ third-generation cephalosporins

▪ aztreonam (Azactan)

◦ These bacilli susceptible to:▪ imipenem


▪ ciprofloxacin (Cipro)

◦ Pseudomonas aeruginosa strains resistant gentamicin (Garamycin):

▪ Susceptible to:

▪ amikacin (Amikin)

▪ ceftazidime (Fortax, Taxidime, Tazicef)


▪ imipenem

▪ meropenem (Merrem IV)▪ ciprofloxacin (Cipro)

▪ trovafloxacin

▪ aztreonam

▪ possibly tobramycin (Nebcin) or netilmicin (Netromycin)

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• Multiple antibiotic resistant enterococci◦ Many strains resistant to:

▪ penicillin

▪ ampicillin (Principen, Omnipen)

▪ gentamicin (Garamycin)

▪ streptomycin

▪ vancomycin (Vancocin)

◦ Susceptible (in vitro, but with variable clinical results) to:

▪ chloramphenicol (Chloromycetin)

▪ doxycycline (Vibramycin, Doryx)

▪

fluoroquinones◦ Urinary tract infection caused by resistant enterococci may respond to ampicillin

or amoxicillin, because very high drug concentrations are found in the urine.

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• Urinary tract infection (UTI)






◦ Diagnosis

◦ Acute, uncomplicated UTI: trimethoprim-sulfamethoxazole (Bactrim)(3-day

course of treatment)

▪ Alternative: fluoroquinone (three-day course of treatment)

▪ Alternative (longer treatment):

▪ oral cephalosporin▪ amoxicillin (Amoxil Polymox)(many urinary pathogens --

resistance to amoxicillin)

▪ fosfomycin (Monurol)(single dose)

◦ Repeated UTIs or UTI occurring in the hospital or nursing-home setting:

▪ may be due to antibiotic-resistant gram-negative bacilli

▪ Treatment:

▪ fluoroquinone

▪ oral amoxicillin (Amoxil Polymox)/clavulanic acid

▪ oral third-generation cephalosporin (cefixime (Suprax),

cefpodoxime (Vantin), ceftibuten) or idanyl ester of carbenicillin▪ in patients hospitalized with UTI:

▪ third-generation cephalosporin

▪ ticarcillin (Ticar)/clavulanic acid


▪ imipenem (occasionally in combination with aminoglycoside)

Quinuprisin/dalfopristin (Synercid)• Overview

◦ FDA-accelerated approval for:

▪ IV treatment of bacteremia & life-threatening infection due tovancomycin (Vancocin)-resistant Enterococcus faecium (VREF)

▪ Treatment of complicated skin & skin structure infections due to

Staphylococcus aureus and Streptococcus pyrogenes

• Quinuprisin/dalfopristin (Synercid): properties

◦ two streptogramin antibacterials (30:70 combination)

◦ Target: bacterial ribosomes

◦ Effect: disruption of protein synthesis

• Antibacterial Characteristics:

◦ Active: against E. faecium (not against Enterococcus faecalis)

◦ Active (in vitro): against methicillin (Staphcillin)-susceptible and-resistant S.

aureus and S. epidermidis◦ Active (in vitro): against penicillin-susceptible &-resistant Streptococcus

pneumoniae

◦ Active (in vitro): against

▪ Neisseria meningitidis, Moraxella cattarrhalis, Legionella

pneumophila, Mycoplasma pneumoniae, Clostridium perfringens

• Pharmacokinetics

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◦ IV administration

◦ hepatic metabolism

◦ biliary excretion

• Some clinical trial results:

◦ quinuprisin/dalfopristin (Synercid) --

▪ as effective as vancomycin (Vancocin) in treating catheter-relatedbacteremia due to S. aureus

▪ effective in treatingVREF in aortic graft

▪ effective in treating a prosthetic valve

▪ effective in treating pericarditis is associated with continuous peritoneal

dialysis

• Adverse Effects:

◦ Infusion site pain, inflammation, edema, thrombophlebitis -- frequency: 75%

◦ Arthralgias & myalgias: common, may be severe

◦ Drug-drug interactions

▪

quinuprisin/dalfopristin (Synercid) inhibitor of CYP3A4 (cytochromeP450 3A4) -- suggests cautious use in patients taking drugs metabolized

by this enzyme

• Increased serum nifedipine (Procardia, Adalat) concentration

• Increased midazolam (Versed) serum concentration

• Increased cyclosporine (Sandimmune, Neoral) serum

concentration

• Co-administration of quinuprisin/dalfopristin (Snercid) and

drugs metabolized by CYP3A4 which may prolong Q-T

intervals should be avoided (example: cisapride (Propulsid))

• Clinical Use-- conclusion

◦ Quinuprisin/dalfopristin (Synercid) -- modestly effective for treatment of vancomycin (Vancocin)-resistant Enterococcus faecium bacteremia-- this effect

may be life-saving

◦ High incidence of side effects and adverse drug-drug interactions suggest

quinuprisin/dalfopristin (Synercid) should only rarely be used to treat any other

type of infection

Linezolid (Zyvox)

• Overview

◦ Linezolid (Zyvox) should be used only for well-documented, serious

vancomycin (Vancocin) resistant enterococcal infections

◦ New antibiotic class: oxazolidinones◦ Management for infections caused by:

▪ Vancomycin (Vancocin)-resistant Enterococcus faecium

▪ Nosocomial & community-acquired Staphylococcus aureus pneumonia

▪ Nosocomial & community acquired danazol (Donocrine)-susceptible

Streptococcus pneumoniae

▪ Skin & skin-structure infections



• Two formulations FDA approved for treatment of vancomycin (Vancocin)-resistant

enterococci:

◦ linezolid (Zyvox)--oral & parenteral use

◦ quinupristin/dalfopristin (Synercid) -- parenteral use only

• Antibacterial characteristics

◦ Inhibits bacterial ribosomal-mediated protein synthesis◦ Bacteria static against streptococci

◦ Activity profile:

▪ Linezolid (Zyvox): effective against both E. faecium and Enterococcus

faecalis {quinupristin/dalfopristin (Synercid): active against vancomycin

(Vancocin)-resistant E. faecium but not Enterococcus faecalis}

▪ Linezolid (Zyvox):

▪ Active against staphylococci, including methicillin (Staphcillin)

resistance Staphylococcus aureus & methicillin (Staphcillin)

resistance Staphylococcus epidermidis

▪ Active against penicillin-resistant pneumococci &

Staphylococcus aureus with intermediate susceptibility

vancomycin (Vancocin)

▪ No clinical useful gram-negative activity

• Pharmacokinetics:

◦ Following oral administration: rapid/complete absorption from gastrointestinal

tract

◦ Partial hepatic metabolism

◦ Urinary excretion

• Side/Adverse Effects

◦ Well-tolerated

◦ Most-common adverse effects: gastrointestinal (nausea, diarrhea, vomiting)◦ With prolonged use: reversible thrombocytopenia

▪ For treatment > 2 weeks, platelet count monitoring is recommended

◦ Linezolid (Zyvox) oral suspension contains phenylalanine, contraindicated in

patients with phenylketonuria

• Drug-Drug Interactions

◦ Linezolid (Zyvox)-weak MAO inhibitor (nonselective)

◦ Patients should avoid tyramine-rich foods

◦ Cautious use with linezolid (Zyvox) in combination with:

antibiotics outline

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