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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
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Bacterial Cell Wall: Sites of Antibacterial Action
Bacterial cell wall structure
Gram-negative Bacterial Membrane Structure
Gram-negative Cell
Membrane Model
• Gram-negative
bacteria are
surrounded by
two membranes.
• The outer
membrane
functions as an
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
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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
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• 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)
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• 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).
Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall
Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p.
725.; Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In
Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E.,
Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (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
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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
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• 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
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rods.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall
Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p.
728.
• As noted earlier penicillins may be sensitive to beta-lactamase producing bacteria. Those penicillins resistant to beta-lactamase producing staphylococcal strains
include: methicillin (Staphcillin), nafcillin (Nafcil, Unipen) and certain isoxazolyl
penicillins such as oxacillin (generic), cloxacillin (Cloxapen), and dicloxacillin
(Dynapen)
◦ Clinical Indications for penicillins resistant to beta-lactamase producing
staphylococcal strains.
▪ The primary indication would of course the infection by beta-lactamase
producing staphylococcal organisms. However, other susceptible
bacteria include penicillins susceptible strains of streptococci and
pneumococci. These drugs however all are enacted against enterococci,
anaerobic bacteria, gram-negative cocci and rods.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Beta-Lactam & Other Inhibitors of Cell Wall
Synthesis,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p.
729.
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
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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
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• 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
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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/
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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
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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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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)
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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
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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.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 734.
Specific Second Generation Cephalosporin Drugs
• Review & Overview: Second Generation Cephalosporins
◦ Second generation agents are active against gram-positive cocci an exhibit an
extended gram-negative spectrum compared to first generation drugs.
◦ Second generation drugs are generally effective against beta-lactamase reducing
H.influenzae.
◦ They exhibit good activity against anaerobes and are effective in mixed-
infections, as an example, peritonitis. Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 734
Examples of second generation cephalosporins:
• Cefaclor (Ceclor), cefamandole (Mandol), cefaclor (Ceclor), and cefonicid
(Monocid).
• Cefuroxime (Zinacef, Ceftin) is effective in community-acquired pneumonia or take
your leave the causative organism may be beta-lactamase producing H.influenzae or
Klebsiella pneumoniae. Cefuroxime (Zinacef, Ceftin) is the only second-generation
drug across the blood-brain barrier, although third-generation agents such as
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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)
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• 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.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp.
732-736;Chambers, H.F., Beta-Lactam Antibiotics & Other Inhibitors of Cell Wall Synthesis
in Basic and Clinical Pharmacology, (Katzung, B. G., ed), Appleton-Lange, 2001, p. 766.
Other ß-lactam containing antibacterials
Aztreonam (Azactan) • Aztreonam (Azactan) is a synthetic monobactam antibiotic, having a moncyclic, rather
than a bicyclic nucleus.
• This agent inhibits synthesis of bacterial cell wall by high-affinity binding to penicillin-
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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
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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
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 737..;Shannon,
M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing
Implications Appleton & Lange, 1995, pp. 614-615.
Clavulanic acid, Sulbactam, Tazobactam
• Clavulanic acid, sulbactam and tazobactam are potent inhibitors of many bacterial ß-
lactamases.
• These agents are given together with hydrolyzable penicillins to protect them from
inactivation.
Most effective against plasmid-encoded beta-lactamases including those produced by:
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• 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
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◦ Endocarditis due to methicillin resistant staphylococci
◦ note:Methicillin-susceptible Staph isolates would be more effectively treated
with methicillin than vancomycin.
◦
Treatment alternative enterococcal endocarditis.: Vancomycin with gentamycin:for patient allergic to penicillin.
◦ Vancomycin incombination with cefotaxime, ceftriaxone or rifampim:
appropriate for treatment of mennigitis when the suspected infecting agent is
thought/known to be highly penicillin resistant.
• Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in
Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp.
737-739.
Bacitracin
• Bacitracin is a cyclic peptide mixture that is active against gram-positive microbes.
• Bacitracin inhibits cell wall formation by interfering with peptidoglycan transfer to the
developing cell wall and exhibits no cross-resistance between bacitracin and other
antimicrobials.
• Due to systemic toxicity, bacitracin is limited to topical use.
• Major Clinical Use
◦ Alone or in combination with polymyxin or neomycin: treatment of mixed skin,
wound or mucous membrane infections.
• Adverse Effects
◦ Significant nephrotoxicity with systemic administration
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 739.
Cycloserine
• Cycloserine, a structural analog of D-alanine, inhibits both Gram-positive and Gram-
negative bacteria.
• Mechanism of action is inhibition of D-alanine incorporation into peptidoglycan by
inhibiting alanine racemase (which converts L-alanine to D-alanine) and D-alanyl-D-
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analanine ligase
• Major Clinical Use
◦ Used almost exclusively for treating tuberculosis caused by M. tuberculosis
isolates resistant to primary drugs.
• Adverse Effects
◦ CNS toxicity at higher than clinical doses
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 739-740
Return to top Menu
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
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◦ 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
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◦ Most anaerobic cocci
◦ Neisseriae
◦ tetanus bacilli
◦ diphtheria bacilli
Robertson, D.B, and Maibach, H.I. Dermatologic Pharmacology , in Basic and Clinical
Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p 1000.
Mechanistic Comparisons: Membrane Active Agents vs. Inhibitors of Cell-Wall
Synthesis
Polymixin B
• Polymixins (polymixin E): basic
peptides which are amphipathic
(containing lipophilic and
lipophobic groups)
• Disrupt bacterial cell membranes
through strong interactions with
phospholipid components.
Inhibitors of Cell Wall Synthesis
• Penicillin-binding Proteins
(PBPs) catalyze an important
step in bacterial cell wall
synthesis [a transpeptidase
reaction which removes a
terminal alanine in a crosslinking
reaction with a nearby peptide].
• One mechanism of penicillin
antibacterial action is through
binding to these proteins, thereby
inhibiting their activity.
Return to top Menu
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
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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.
• Protein synthesis stops.!
Tetracycline:
• Tetracycline binds to 40S ribosomal RNA, blocking association of amino acid-charged
tRNA with its acceptor site on the ribosomal mRNA complex.
• Protein synthesis stops.!
Susceptibility Differences between bacterial and mammalian cells
• Mammalian 80S ribosomal RNA does not bind chloramphenicol.
• However, mammalian mitochondrial ribosomal RNA (70S) does bind chloramphenicol.
• Chloramphenicol (Chloromycetin) dose-related bone marrow suppression may be due
to drug's effect on mitochondrial ribosomes
• Tetracycline inhibits mammalian cell protein synthesis, but an active efflux system may
prevent intracellular drug concentrations from reaching toxic levels.
Aminoglycosides:
• Protein synthesis inhibition is probably due to binding to 30S ribosomal proteins.
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• 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.
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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.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 754.
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• 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.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
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and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 755.
• Tobramycin (Nebcin)
◦ Antibacterial spectrum of action similar to gentamicin.
◦ Some cross-resistance possible
◦ Nearly identical pharmacokinetic profile
◦ Similar antimicrobial spectum to gentamicin.
◦ Adverse Reactions
▪ Nephrotoxicity
▪ Deafness
▪ Vestibular toxicity which tends to be irreversible.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 756-758.
• Amikacin (Amikin)
◦ Amikacin: semisynthetic derivative of kanamycin, but less toxic.
◦ Amikacin may be used against microbes resistant to:
▪ gentamicin or tobramycin because it is resistant to enzymes which
inactivate those agents.
◦ Often effective in treating multi-drug resistant strains of Mycobacterium
tuberculosis.
◦ Kanamycin resistant isolates are likely to exhibit cross-resistance to amikacin.
◦ Amikacin (Amikin) is ototoxic (auditory component especially) and
nephrotoxic, as are all aminoglycosides.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 758.
• Kanamycin & Neomycin
◦ Kanamycin & Neomycin: Active against gram-positive, gram-negative and
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some mycobacteria.
◦ Pseudomonas and streptococci: resistant
◦ Mechanisms of action and resistance follow that of other aminoglycosides.
◦ Cross-resistance between these agents and kanamycin and neomycin
◦ Neomycin: topical and oral use only due to toxicity associated with parenteral
administration.
◦ Neomycin use: given prior to elective bowel surgery, reducing aerobic bowel
flora.
◦ Ototoxicity (auditory) and nephrotoxicity.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 758-759.
• Spectinomycin (Trobicin)
◦ Spectinomycin: structurally-related to aminoglycosides.
◦ Used almost exclusively to treat gonorrhea resistant to other drugs or if the
patient is allergic to penicillin.
◦ No cross-resistance between spectinomycin and other drugs used to treat
gonorrhea
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 759.
• The dependency of therapeutic and toxic effects on pharmacokinetics
◦ Aminoglycosides are poorly absorbed from the G.I. tract
◦ Most of the oral dose is excreted directly. Aminoglycosides are usually
administered intravenously (i.v).
◦ Highly polar molecules, aminoglycosides do not penetrate the CNS or eye.
◦ In menningitis with attendant inflammation, cerebral spinal fluid levels may
reach 20% of plasma concentration.
▪ Higher concentration requires directly intrathecal or intraventricular
administration.
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◦ 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.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 753.
• Development of resistance to aminoglycosides
◦ Most common mechanism of resistance is antibiotic inactivation by enzyme-
mediated covalent modification which results in phosphate, adenyl or acetyl
group transfer.
◦ Aminoglycoside-modifying enzymes are plasmid localized.
◦ The modified antibiotic is also less active because of decreased transport &
decreased binding to the ribosomal target site
◦ Aminoglycoside-modifying enzymes have been found in both gram-negative
and gram-positive bacteria.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's
Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D.,
Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions
Division), 1998, p. 859.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 752.
Tetracyclines, macrolides, chloramphenicol, clindamycin, spectinomycin
• Spectrum of activity and clinical uses
• Specific indications for use
Return to top Menu
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Inhibitors of folate-dependent pathways
• Production and use of folate derivatives in bacterial systems
◦ Certain microbes require p-aminobenzoic acid (PABA) in order to
synthesize dihydrofolic acid which is required to produce purines
and ultimately nucleic acids.
◦ Sulfonamides,chemical analogs of PABA, are competitive inhibitors
of dihydropteroate synthetase.
◦ Sulfonamides therefore are reversible inhibitors of folic acid
synthesis and bacterostatic not bacteriocidal.
Sulfonamides
• Introduction to sulfonamide pharmacology• Mechanism of action of sulfonamides
◦ Certain microbes require p-aminobenzoic acid (PABA) in order to
synthesize dihydrofolic acid which is required to produce purines
and ultimately nucleic acids.
◦ Sulfonamides,chemical analogs of PABA, are competitive
inhibitors of dihydropteroate synthetase.
◦ Sulfonamides therefore are reversible inhibitors of folic acid
synthesis and bacterostatic not bacteriocidal.
Trimethoprim
• Trimethoprim (generic) mechanism of action
◦ Trimethoprim is an inhibitor of bacterial dihydrofolic acid reductase.
◦ Pyrimethamine (Daraprim) is an excellent inhibitor of dihydrofolic
acid reductase in protozoa
◦ These reductases are required for the synthesis of purines and hence
DNA.
◦ Inhibition of these enzymes are responsible for bacteriostatic and
bacteriocidal activities.
◦ When trimethoprim or pyrimethamine is combined with
sulfonamides (sulfamethoxazole) there is sequential blocking of the
biosynthetic pathway leading to drug synergism and enhanced
antimicrobial activity. (see figure below)
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◦ 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.
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Chambers, H.F. and Jawetz, E.Sulfonamides,Trimethoprim, and Quinolones,in
Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p.
761-763.
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
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◦ 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
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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
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▪ 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
•
T
r
e
a
t
m
e
nt
P
r
i
n
c
i
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p
l
e
s
•
P
n
e
u
m
o
n
i
a
•
M
e
n
i
n
g
i
t
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
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.
◦ 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
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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.
Return to top menu
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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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• 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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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
Return to top menu
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]
Return to top menu
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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
Return to top menu
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
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• 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.
Return to top menu
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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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.
Return to top menu
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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
Return to top menu
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. 886.
Group A streptococci:
Impetigo:
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• 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
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. 887.
Group A streptococci:
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
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. 888.
Group A streptococci:
Deep Soft Tissue Infection:
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• 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)
Return to top menu
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. 886.
Group A streptococci:
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
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. 888.
Group C and G streptococci:
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• 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.
Return to top menu
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. 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.
Return to top menu
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. 889-890.
Viridans
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• 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.
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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
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◦ 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.
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◦ 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
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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
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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
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• 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.
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1143-1144.
Gramicidin
• Gramicidin: peptide antibiotic which alters membrane permeability-effective againstgram-positive organisms
• Gramicidin may be used in combination with neomycin, polymyxin B or both.
• Available only for topical usage
• Systemic toxicity
• Gramicidin Active Against:
◦ Streptococci
◦ Pneumococci
◦ Staphylococci
◦ Most anaerobic cocci
◦ Neisseriae
◦ tetanus bacilli
◦ diphtheria bacilli
Robertson, D.B, and Maibach, H.I. Dermatologic Pharmacology , in Basic and Clinical
Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p 1000.
Mechanistic Comparisons: Membrane Active Agents vs. Inhibitors of Cell-Wall
Synthesis
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Polymixin B
• Polymixins (polymixin E): basic
peptides which are amphipathic
(containing lipophilic and
lipophobic groups)
• Disrupt bacterial cell membranes
through strong interactions with
phospholipid components.
Inhibitors of Cell Wall Synthesis
• Penicillin-binding Proteins
(PBPs) catalyze an important
step in bacterial cell wall
synthesis [a 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.
• 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.
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• Protein synthesis stops.!
Tetracycline:
• Tetracycline binds to 40S ribosomal RNA, blocking association of amino acid-charged
tRNA with its acceptor site on the ribosomal mRNA complex.
• Protein synthesis stops.!
Susceptibility Differences between bacterial and mammalian cells
• Mammalian 80S ribosomal RNA does not bind chloramphenicol.
• However, mammalian mitochondrial ribosomal RNA (70S) does bind chloramphenicol.
• Chloramphenicol (Chloromycetin) dose-related bone marrow suppression may be due
to drug's effect on mitochondrial ribosomes
• Tetracycline inhibits mammalian cell protein synthesis, but an active efflux system may
prevent intracellular drug concentrations from reaching toxic levels.
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
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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
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:
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▪ plague
▪ tularemia,
▪ bucellosis.
◦ In combination with penicillin:
▪ treatment for enterococcal endocarditis
▪ viridans streptococcal endocarditis (two-week regimen)
◦ Adverse Reactions
▪ fever
▪ rash (hypersensitivity)
▪ Most serious toxic effect: vestibular toxicity which tends to be
irreversible.
▪ treptomycin administration during pregnancy may result in deafness in
the newborn.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 754.
• Gentamicin (Garamycin): ◦ Gentamicin (Garamycin): effective against gram-positive and gram-negative
microbes
◦ Active alone but shows synergism with ß-lactam antimicrobials in managing
◦ Pseudomonas
◦ Proteus
◦ Enterobacter
◦ Klebsiella
◦ Serratia
◦ Stenotrophomonas
◦ Other gram-negative rods
•
◦ No activity against anaerobes.
◦ Primary clinical use: Treatment of severe gram-negative bacterial infections
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(sepsis/pneumonia) when the bacteria is likely resistant to other antibiotics.
◦ The combination of gentamicin and a cephalosporin or penicillin may be life-
saving in the immunocompromised patient.
◦
Gentamicin + penicillin G: viridans streptococcal endocarditis
◦ Gentamicin + nafcillin (Nafcil, Unipen) in some cases of staphylococcal
endocarditis.
◦ Gentamicin should not be used as a single agent due to rapid development of
resistance.
◦ Aminoglycosides should not be used as single therapy in pneumonia due to
poor tissue penetration.
◦ Nephrotoxicity: requires serum gentamicin monitoring if administration
exceeds a few days.
◦ Adverse Reactions
▪ Nephrotoxicity
▪ Deafness
▪ Vestibular toxicity which tends to be irreversible.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 755.
• Tobramycin (Nebcin)
◦ Antibacterial spectrum of action similar to gentamicin.
◦ Some cross-resistance possible
◦ Nearly identical pharmacokinetic profile
◦ Similar antimicrobial spectum to gentamicin.
◦ Adverse Reactions
▪ Nephrotoxicity
▪ Deafness
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▪ Vestibular toxicity which tends to be irreversible.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 756-758.
• Amikacin (Amikin)
◦ Amikacin: semisynthetic derivative of kanamycin, but less toxic.
◦ Amikacin may be used against microbes resistant to:
▪ gentamicin or tobramycin because it is resistant to enzymes which
inactivate those agents.
◦ Often effective in treating multi-drug resistant strains of Mycobacterium
tuberculosis.
◦ Kanamycin resistant isolates are likely to exhibit cross-resistance to amikacin.
◦ Amikacin (Amikin) is ototoxic (auditory component especially) and
nephrotoxic, as are all aminoglycosides.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 758.
• Kanamycin & Neomycin
◦ Kanamycin & Neomycin: Active against gram-positive, gram-negative and
some mycobacteria.
◦ Pseudomonas and streptococci: resistant
◦ Mechanisms of action and resistance follow that of other aminoglycosides.
◦ Cross-resistance between these agents and kanamycin and neomycin
◦ Neomycin: topical and oral use only due to toxicity associated with parenteral
administration.
◦ Neomycin use: given prior to elective bowel surgery, reducing aerobic bowelflora.
◦ Ototoxicity (auditory) and nephrotoxicity.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 758-759.
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• Spectinomycin (Trobicin)
◦ Spectinomycin: structurally-related to aminoglycosides.
◦ Used almost exclusively to treat gonorrhea resistant to other drugs or if the
patient is allergic to penicillin.
◦ No cross-resistance between spectinomycin and other drugs used to treat
gonorrhea
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin, in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 759.
• The dependency of therapeutic and toxic effects on pharmacokinetics
◦ Aminoglycosides are poorly absorbed from the G.I. tract
◦ Most of the oral dose is excreted directly. Aminoglycosides are usually
administered intravenously (i.v).
◦ Highly polar molecules, aminoglycosides do not penetrate the CNS or eye.
◦ In menningitis with attendant inflammation, cerebral spinal fluid levels may
reach 20% of plasma concentration.
▪ Higher concentration requires directly intrathecal or intraventricular
administration.
◦ Tissue drug levels are generally low, except in the renal cortex.
◦ Renal aminoglycosides clearance rates are directly proportion to creatinine
clearance rates.
◦ Many factors (age, gender) influence the relationship between serum creatinine
levels and creatinine clearance. Reliance on estimated creatinine clearance is
appropriate in determining aminoglycoside dosage in a patient.
◦ In renal insufficiency, care must be used to avoid toxicity due to drug
accumulation.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 753.
• Development of resistance to aminoglycosides
◦ Most common mechanism of resistance is antibiotic inactivation by enzyme-
mediated covalent modification which results in phosphate, adenyl or acetyl
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group transfer.
◦ Aminoglycoside-modifying enzymes are plasmid localized.
◦ The modified antibiotic is also less active because of decreased transport &
decreased binding to the ribosomal target site
◦ Aminoglycoside-modifying enzymes have been found in both gram-negative
and gram-positive bacteria.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's
Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D.,
Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions
Division), 1998, p. 859.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Aminoglycosides and Spectinomycin,in Basic
and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 752.
Tetracyclines, macrolides, chloramphenicol, clindamycin, spectinomycin
• Spectrum of activity and clinical uses
• Specific indications for use
Return to top Menu
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
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• Introduction to sulfonamide pharmacology
• Mechanism of action of sulfonamides
◦ Certain microbes require p-aminobenzoic acid (PABA) in order to
synthesize dihydrofolic acid which is required to produce purines
and ultimately nucleic acids.
◦ Sulfonamides,chemical analogs of PABA, are competitiveinhibitors of dihydropteroate synthetase.
◦ Sulfonamides therefore are reversible inhibitors of folic acid
synthesis and bacterostatic not bacteriocidal.
Trimethoprim
• Trimethoprim (generic) mechanism of action
◦ Trimethoprim is an inhibitor of bacterial dihydrofolic acid reductase.
◦ Pyrimethamine (Daraprim) is an excellent inhibitor of dihydrofolic
acid reductase in protozoa
◦ These reductases are required for the synthesis of purines and hence
DNA.
◦ Inhibition of these enzymes are responsible for bacteriostatic and
bacteriocidal activities.
◦ When trimethoprim or pyrimethamine is combined with
sulfonamides (sulfamethoxazole) there is sequential blocking of 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.
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• 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
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◦ 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
◦ Ciprofloxacin (Cipro)
◦
Clofazimine
◦ Cycloserine
◦ Ethionamide
◦ Ofloxacin (Floxin)
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◦ 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).
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◦ 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
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▪ 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
◦ Ciprofloxacin (Cipro)
◦ Ofloxacin (Floxin)
◦ 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
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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.
return to main menu
• 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
◦ Pseudomonas aeruginosa
◦ 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
▪ meropenem (Merrem IV)
▪ plus aminoglycoside
▪ add vancomycin (Vancocin) in hospitals where
methicillin (Staphcillin)-resistant staphylococci are
common.
Meningitis
• Most common cause of bacterial meningitis1:
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◦ 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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return to main menu
• 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
▪ cefotaxime (Claforan)
▪ ceftizoxime (Cefizox)
▪ cefoperazone (Cefobid)▪ ceftriaxone (Rocephin)
▪ cefepime (Maxipime)
▪ 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
return to main menu
• Initial treatment:
◦ Life-threatening sepsis and adults:
▪ Third or fourth generation cephalosporin
▪ cefotaxime (Claforan)
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▪ ceftizoxime (Cefizox)
▪ ceftriaxone (Rocephin)
▪ cefepime (Maxipime)
▪ ticarcillin (Ticar)/clavulanic acid
▪ piperacillin (Pipracil)/tazobactam
▪ 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
▪ piperacillin (Pipracil)/tazobactam
▪ imipenem
▪ meropenem
▪ cefoxitin (Mefoxin) or cefotetan (Cefotan){each with or without an
aminoglycoside, metronidazole (Flagyl) OR clindamycin (Cleocin) with
an aminoglycoside}
return to main menu
Special Cases
• Neutropenic patients with suspected bacteremia
◦ Treatment:
▪ ceftazidime (Fortax, Taxidime, Tazicef)
▪ imipenem
▪ meropenem (Merrem IV)
▪ 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.
return to main menu
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• Resistant gram-negative bacilli
◦ Gram-negative bacilli resistant to:
▪ aminoglycosides
▪ third-generation cephalosporins
▪ aztreonam (Azactan)
◦ These bacilli susceptible to:▪ imipenem
▪ meropenem (Merrem IV)
▪ ciprofloxacin (Cipro)
◦ Pseudomonas aeruginosa strains resistant gentamicin (Garamycin):
▪ Susceptible to:
▪ amikacin (Amikin)
▪ ceftazidime (Fortax, Taxidime, Tazicef)
▪ cefepime (Maxipime)
▪ imipenem
▪ meropenem (Merrem IV)▪ ciprofloxacin (Cipro)
▪ trovafloxacin
▪ aztreonam
▪ possibly tobramycin (Nebcin) or netilmicin (Netromycin)
return to main menu
• 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.
return to main menu
• Urinary tract infection (UTI)
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◦ 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
▪ piperacillin (Pipracil)/tazobactam
▪ 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
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• 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: