Title: CEPHALOSPORINS
1CEPHALOSPORINS
21. Introduction
- Antibacterial agents which inhibit bacterial cell
wall synthesis - Discovered from a fungal colony in Sardinian
sewer water (1948) - Cephalosporin C identified in 1961
36. Mechanism of Action
- The acetoxy group acts as a good leaving group
and aids the mechanism
4The Cephalosporins
Generation Parenteral Agents Oral Agents
First-generation Cefazolin Cefadroxil, cephalexin
Second-generation Cefotetan, cefoxitin, cefuroxime Cefaclor, cefprozil, cefuroxime axetil, loracarbef
Third-generation Cefotaxime, ceftazidime, ceftizoxime, ceftriaxone Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime
Fourth-generation Cefepime
58. First Generation Cephalosporins
Cephalothin
- First generation cephalosporin
- More active than penicillin G vs. some Gram -ve
bacteria - Less likely to cause allergic reactions
- Useful vs. penicillinase producing strains of S.
aureus - Not active vs. Pseudonomas aeruginosa
- Poorly absorbed from GIT
- Administered by injection
- Metabolised to give a free 3-hydroxymethyl group
(deacetylation) - Metabolite is less active
68. First Generation Cephalosporins
Cephalothin - drug metabolism
Less active OH is a poorer leaving group
- Strategy
- Replace the acetoxy group with a metabolically
stable leaving group
78. First Generation Cephalosporins
Cephaloridine
- The pyridine ring is stable to metabolism
- The pyridine ring is a good leaving group
(neutralisation of charge) - Exists as a zwitterion and is soluble in water
- Poorly absorbed through the gut wall
- Administered by injection
88. First Generation Cephalosporins
Cefalexin
- The methyl group at position 3 is not a good
leaving group - The methyl group is bad for activity but aids
oral absorption - mechanism unknown - Cefalexin can be administered orally
- A hydrophilic amino group at the a-carbon of the
side chain helps to compensate for the loss of
activity due to the methyl group
9First Generation Cephalosporins
Cefazolin
Cefadroxil
Cefalexin
10First Generation Cephalosporins include Cefazolin
(parenteral) as well as cefadroxil and cephalexin
(oral).
Gram-positive bacteria Streptococcus pyogenes, Some virdans streptococci, Some Staphylococcus aureus, Some Streptococcus pneumoniae
Gram-negative bacteria Some Eschericia coli, Some Klebsiella pneumoniae, Some Proteus mirabilis
119. Second Generation Cephalosporins
9.1 Cephamycins
Cephamycin C
- Isolated from a culture of Streptomyces
clavuligerus - First b-lactam to be isolated from a bacterial
source - Modifications carried out on the 7-acylamino side
chain
129. Second Generation Cephalosporins
9.1 Cephamycins
Cefoxitin
- Broader spectrum of activity than most first
generation cephalosporins - Greater resistance to b-lactamase enzymes
- The 7-methoxy group may act as a steric shield
- The urethane group is stable to metabolism
compared to the ester - Introducing a methoxy group to the equivalent
position of penicillins (position 6) eliminates
activity.
139. Second Generation Cephalosporins 9.2
Oximinocephalosporins
Cefuroxime
- Much greater stability against some b-lactamases
- Resistant to esterases due to the urethane group
- Wide spectrum of activity
- Useful against organisms that have gained
resistance to penicillin - Not active against P. aeruginosa
- Used clinically against respiratory infections
14- Second generation
- The second-generation cephalosporins have a
greater Gram-negative spectrum while retaining
some activity against Gram-positive cocci. They
are also more resistant to beta-lactamase. - Cefaclor (Ceclor, Distaclor, Keflor, Raniclor)
- Cefonicid (Monocid)
- Cefprozil (cefproxil Cefzil)
- Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym)
- Cefuzonam
15Forms of Cefuroxime (2nd generation
cephalosporin)
Cefuroxime (ZINACEF)
Cefuroxime axetil (CEFTIN)
16The Second-generation cephalosporins include
Cefotetan, cefoxitin, and cefuroxime (all
parenteral) as well as Cefaclor, cefprozil,
cefuroxime axetil, and loracarbef (all oral).
Gram-positive bacteria True cephalosporins have activity equivalent to first-generation agents. Cefoxitin and cefotetan have little activity
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Neisseria spp.
Anaerobic bacteria Cefoxitin and cefotetan have moderate anaerobic activity.
1710. Third Generation Cephalosporins
Oximinocephalosporins
- Aminothiazole ring enhances penetration of
cephalosporins across the outer membrane of Gram
-ve bacteria - May also increase affinity for the
transpeptidase enzyme - Good activity against Gram -ve bacteria
- Variable activity against Gram ve cocci
- Variable activity vs. P. aeruginosa
- Lack activity vs MRSA
- Generally reserved for troublesome infections
1810. Third Generation Cephalosporins
Oximinocephalosporins
Ceftazidime
- Injectable cephalosporin
- Excellent activity vs. P. aeruginosa and other
Gram -ve bacteria - Can cross the blood brain barrier
- Used to treat meningitis
19The Third-generation Cephalosporins include
Cefotaxime, ceftazidime, ceftizoxime, and
ceftriaxone (all parenteral) as well as Cefdinir,
cefditoren, cefpodoxime proxetil, ceftibuten, and
cefixime (all oral).
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae, Modest activity against Staphylococcus aureus
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Some Enterobacteriaceae.
Anaerobic bacteria
Atypical bacteria
Spirochetes Borrelia burgorferi
2011. Fourth Generation Cephalosporins
Oximinocephalosporins
- Zwitterionic compounds
- Enhanced ability to cross the outer membrane of
Gram negative bacteria - Good affinity for the transpeptidase enzyme
- Low affinity for some b-lactamases
- Active vs. Gram ve cocci and a broad array of
Gram -ve bacteria - Active vs. P. aeruginosa
21Fourth Generation Cephalosporins include cefepime
(parenteral).
Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptocossus pneumoniae. Modest activity against Staphylococcus aureus
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeruginosa.
Anaerobic bacteria
Atypical bacteria
22Newer b-Lactam Antibiotics
Thienamycin (Merck 1976)(from Streptomyces
cattleya)
- Potent and wide range of activity vs Gram ve and
Gram -ve bacteria - Active vs. Pseudomonas aeruginosa
- Low toxicity
- High resistance to b-lactamases
- Poor stability in solution (ten times less stable
than Pen G)
23Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
24The Carbapenems include Imipenem/cilstatin,
Meropenem, and Ertapenem (all parenteral)
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Modest activity against Staphylococcus aureus, Some enterococci, Listeria monocytogenes
Gram-negative bacteria Haemophilus influenzae, Neisseria spp., Enterobacteriaceae, Pseudomonas aeruginosa
Anaerobic bacteria Bacteroides fragilis, Most other anaerobes.
25Newer b-Lactam Antibiotics
Clinically useful monobactam
- Administered by intravenous injection
- Can be used for patients with allergies to
penicillins - and cephalosporins
- No activity vs. Gram ve or anaerobic bacteria
- Active vs. Gram -ve aerobic bacteria
26The Monobactams include only Aztreonam, which is
parenteral
Gram-positive bacteria
Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Most Enterobacteriaceae, Many Pseudomonas aeruginosa.
Anaerobic bacteria
Atypical bacteria
27Vancomycin
Vancomycin is called a glycopeptide, meaning
that it is a cyclic peptide, with sugar residues
attached to it.
28Vancomycin Mechanism of Action
- Bacterial Cell Wall Synthesis (review)
- http//student.ccbcmd.edu/courses/bio141/lecguide/
unit2/control/ppgsynanim.html
Penicillin Mechanism of Action (review) http//stu
dent.ccbcmd.edu/courses/bio141/lecguide/unit2/cont
rol/penres.html
- http//student.ccbcmd.edu/courses/bio141/lecguide/
unit2/control/vanres.html
29Mechanism of Action of Vancomycin
Vancomycin binds to the D-alanyl-D-alanine
dipeptide on the peptide side chain of newly
synthesized peptidoglycan subunits, preventing
them from being incorporated into the cell wall
by penicillin-binding proteins (PBPs). In many
vancomycin-resistant strains of enterococci, the
D-alanyl-D-alanine dipeptide is replaced with
D-alanyl-D-lactate, which is not recognized by
vancomycin. Thus, the peptidoglycan subunit is
appropriately incorporated into the cell wall.
30Vancomycin Uses
- Vancomycin is used to treat aerobic Gram
bacteria, including MRSA and strains of
penicillin-resistant Streptococcus pneumoniae - Vancomycin is administered intraveneously
- Vancomycin can also be used to treat anearobic
Gram bacteria, including Clostridium difficile
(in the case of a GI infection, Vancomycin can be
administered orally). - Vancomycin cannot be used to treat Gram
bacteria, since the large size of the vancomycin
molecule prohibits its passing of the outer
membrane.
31Vancomycin Resistance
- Some Enterococci have developed resistance to
vancomycin (Enterococcus faecium and Enterococcus
faecalis). - These bacteria are called Vancomycin Resistant
Enterococci (VRE) - The mechanism of resistance involves the
transformation of the D-Ala-D-Ala linkage in the
peptide side chain into D-Ala-D-Lac (i.e.
replacement of the NH2 group by an OH group) - This terminal linkage is still recognized by the
essential PBPs (so the cell wall can still be
constructed), but is not recognized by vancomycin
(thus resulting in resistance).
32Antimicrobial Activity of Vancomycin
Gram-positive bacteria Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Some enterococci.
Gram-negative bacteria
Anaerobic bacteria Clostridium spp. Other Gram-positive anaerobes.
Atypical bacteria
33Daptomycin
- Daptomycin is called a lipopeptide antibiotic
- Approved for use in 2003
- Lipid portion inserts into the bacterial
cytoplasmic membrane where it forms an
ion-conducting channel. - Marketed under the trade name Cubicin
34Uses of Daptomycin
- Daptomycin is active against many aerobic
Gram-positive bacteria - Includes activity against MRSA,
penicillin-resistant Streptococcus pneumoniae,
and some vancomycin-resistant Enterococci (VRE) - Daptomycin is not active against Gram negative
strains, since it cannot penetrate the outer
membrane. - Primarily been used to treat skin and soft tissue
infections - Poor activity in the lung.
35Antimicrobial Activity of Daptomycin
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.
Gram-negative bacteria
Anaerobic bacteria Some Clostridium spp.
Atypical
36Rifamycins
- Rifampin is the oldest and most widely used of
the rifamycins - Rifampin is also the most potent inducer of the
cytochrome P450 system - Therefore, Rifabutin is favored over rifampin in
individuals who are simultaneously being treated
for tuberculosis and HIV infection, since it will
not result in oxidation of the antiviral drugs
the patient is taking - Rifaximin is a poorly absorbed rifamycin that is
used for treatment of travelers diarrhea.
37Mechanism of Action of Rifampin
- Rifampin inhibits transcription by inactivating
bacterial RNA polymerase - Resistance develops relatively easily, and can
result from one of a number of single mutations
in the baqcterial gene that encodes RNA
polymerase. - Therefore, Rifampin is rarely used as monotherapy
(i.e. not used as a single agent) but usually
combined with other antibiotics
38Uses of Rifampin
- Used, in combination with other drugs, to treat
Mycobacterium tuberculosis - Used to treat some Staphylococcal infections.
39The Rifamycins include Rifampin, Rifabutin,
Rifapentine, and Rifaximin, all of which can be
administered orally. Rifampin can also be
administered parenterally.
Gram-positive bacteria Staphylococci
Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis
Anaerobic bacteria
Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacteriumleprae.
40Aminoglycosides
The structure of the aminoglycoside amikacin.
Features of aminoglycosides include amino sugars
bound by glycosidic linkages to a relatively
conserved six-membered ring that itself contains
amino group substituents.
41Aminoglycoside Mechanism of Action
- Aminoglycosides bind to the 30S subunit of the
bacterial ribosome, thereby inhibiting bacterial
protein synthesis (translation) - http//www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altribo_
antibiot.html - http//www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altribo_
antibiot.html
42Uses of Aminoglycoside Antibiotics
- Unlike vancomycin, the aminoglycosides have
excellent activity against Gram aerobic
bacteria - Their extensive positive charge enables them to
bind to and penetrate the negatively charged
outer membrane and get into the periplasm - They are further transported into the cytoplasm
by a bacterial transport system.
43Lipopolysaccharide is Part of the Outer Membrane
of Gram Negative Bacteria
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46- Bacterial lipopolysaccharides are toxic to
animals. When injected in small amounts LPS or
endotoxin activates several host responses that
lead to fever, inflammation and shock. Endotoxins
may play a role in infection by any Gram-negative
bacterium. The toxic component of endotoxin (LPS)
is Lipid A. The O-specific polysaccharide may
provide for adherence or resistance to
phagocytosis, in the same manner as fimbriae and
capsules. The O polysaccharide (also referred to
as the O antigen) also accounts for multiple
antigenic types (serotypes) among Gram-negative
bacterial pathogens. Thus, E. coli O157 (the
Jack-in-the-Box and Stock Pavillion E. coli) is
157 of the different antigenic types of E. coli
and may be identified on this basis.
47- Bacterial resistance to aminoglycosides occurs
via one of three mechanisms that prevent the
normal binding of the antibiotic to its ribosomal
target - Efflux pumps prevent accumulation of the
aminoglycoside in the cytosol of the bacterium. - Modification of the aminoglycoside prevents
binding to the ribosome. - Mutations within the ribosome prevent
aminoglycoside binding.
48The Aminoglycosides include Streptomycin,
Gentamicin, Tobramycin, and Amikacin (all
parenteral), as well as Neomycin (oral).
Gram-positive bacteria Used synergistically against some Staphylococci, Streptococci, Enterococci, and Listeria monocytogenes
Gram-negative bacteria Haemophilus influenzae, Enterobacteiaceae, Pseudomonas aeruginosa
Anaerobic bacteria
Atypical bacteria
Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex.
49Macrolides and Ketolides
The structures of erythromycin and telithromycin
Circled substituents and distinguish
telithromycin from the macrolides. Substituent
allows telithromycin to bind to a second site on
the bacterial ribosome.
50Mechanism of Action of Macrolide Antibiotics
- Macrolides bind tightly to the 50S subunit of the
bacterial ribosome, thus blocking the exit of the
newly synthesized peptide - Thus, they are interfering with bacterial
translation - http//www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altribo_
antibiot.html - http//www.microbelibrary.org/microbelibrary/files
/ccImages/Articleimages/kaiser/mechanisms/altribo_
antibiot.html
51Uses of Macrolide Antibiotics
- Active against a broad range of bacteria
- Effective against some stphylococci and
streptococci, but not usually used for MRSA or
penicillin-resistant streptococci - Most aerobic Gram- bacteria are resistant
- Active against many atypical bacteria and some
mycobacteria and spirochetes
52The macrolide group consists of Erythromycin,
Clarithromycin, and Azithromycin (all oral, with
erythromycin and azithromycin also being
available parenterally).
Gram-positive bacteria Some Streptococcus pyogenes. Some viridans streptococci, Some Streptococcus pneumoniae. Some Staphylococcus aureus.
Gram-negative bacteria Neiseria spp. Some Haemophilus influenzae. Bordetella pertussis
Anaerobic bacteria
Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila, Some Rickettsia spp.
Mycobacteria Mycobacterium avium complex, Mycobacterium leprae.
Spirochetes Treponema pallidum, Borrelia burgdorferi.
53Uses of Telithromycin (a ketolide)
- Telithromycin is approved for use against
bacterial respiratory infections - Active against most strains of Streptococcus
pneumoniae, including penicillin- and
macrolide-resistant strains - Also active against more strains of Staphylococci
- Only available in oral formulation
54The related ketolide class consists of
Telithromycin (oral).
Gram-positive bacteria Streptococcus pyogenes, Streptococcus pneumoniae, Some Staphylococcus aureus
Gram-negative bacteria Some Haemophilus influenzae, Bordetella pertussis
Anaerobic bacteria
Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila
55The Tetracycline Antibiotics
The structure of tetracycline
56Tetracycline Antibiotics
Tetracycline
Tigecycline
Doxycycline
57Mechanism of Action of the Tetracycline
Antibiotics
- The tetracyclines bind to the 30S subunit of the
bacterial ribosome and prevent binding by tRNA
molecules loaded with amino acids. - http//student.ccbcmd.edu/courses/bio141/lecguide/
unit2/control/tetres.html
58Uses of the Tetracycline Antibiotics
- Main use is against atypical bacteria, including
reckettsiae, chlamydiae, and mycoplasmas - Also active agains some aerobic Gram-positive
pathogens and some aerobic Gram-negative bacteria
59The Tetracycline Class of Antibiotics consists of
Doxycycline and Tigecycline (parenteral) as well
as Tetracycline, Doxycycline and Minocycline
(oral)
Gram-positive bacteria Some Streptococcus pneumoniae
Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis
Anaerobic bacteria Some Clostridia spp. Borrelia burgdorferi, Treponema pallidum
Atypical bacteria Rickettsia spp. Chlamydia spp.
60Tigecycline
61The antimicrobial activity of Tigecycline
(parenteral)
Gram-positive bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci, Listeria monocytogenes
Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Enterobacteriaceae
Anaerobic bacteria Bacteroides fragilis, Many other anaerobes
Atypical bacteria Mycoplasma spp.
62Chloramphenicol
63Mechanism of Action of Chloroamphenicol
- Binds to the 50S subunit of the bacterial
ribosome, where it blocks binding of tRNA
64Uses of Chloramphenicol
- Severe toxicity limits utility
- The most serious side effect of chloramphenicol
treatment is aplastic anaemia (a condition where
bone marrow does not produce sufficient new cells
to replenish blood cells) - This effect is rare and is generally fatal there
is no treatment and there is no way of predicting
who may or may not get this side effect. - The effect usually occurs weeks or months after
chloramphenicol treatment has been stopped.
65Uses of Chloramphenicol
- However, despite its toxicity, chloramphenicol
has a wide spectrum of activity, that includes
many aerobic Gram-positive, Gram-negative,
anaerobic, and atypical bacteria
66The Antimicrobial Activity of Chloramphenicol
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci. Some Streptococcus pneumoniae
Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Salmonella spp. Shigella spp.
Anaerobic bacteria Bacteroides fragilis. Some Clostridia spp. Other anaerobic Gram-positive and Gram negative bacteria
Atypical bacteria Rickettsia spp. Chlamydia trachomatis, Mycoplasma spp.
67Clindamycin
68Mechanism of Action of Clindamycin
- Clindamycin binds to the 50S subunit of the
ribosome to inhibit protein synthesis
69Uses of Clindamycin
- Clindamycin is a member of the lincosamide series
of antibiotics - Main utility is in treatment of Gram-positive
bacteria and anaerobic bacteria - Active against staphylococcus, including some
strains of MRSA - Not useful against Gram-negative bacteria
70Toxicity of Clindamycin
- Clindamycin kills many components of the
gastrointestinalo flora, leaving only Clostridium
difficile - This can result in overgrowth by C. difficile,
which is resistant
71The Antimicrobial Activity of Clindamycin (both
oral and parenteral)
Gram-positive bacteria Some Streptococcus pyogenes, Some viridans group streptococci. Some Streptococcus pneumoniae, Some Staphylococcus aureus
Gram-negative bacteria
Anaerobic bacteria Some Bacteroides fragilis, Some Clostridium spp. Most other anaerobes.
Atypical bacteria
72Streptogramins
73Mechanism of Action of Streptogramins
- Dalfopristin inhibits the early phase of protein
synthesis in the bacterial ribosome and
quinupristin inhibits the late phase of protein
synthesis. The combination of the two components
acts synergistically and is more effective in
vitro than each component alone.
74Uses of the Streptogramins
- Have activity against Gram positive aerobic
bacteria - Including MRSA, penicillin-resistant
Streptococcus pneumoniae and some VRE (active
against vancomycin resistant Enterococcus
faecelis, but not Enterococcus faecium) - The Quinupristin/Dalfopristin mixture is marketed
as Synercid
75The Antimicrobial Activity of Quinupristin/Dalfopr
istin (parenteral)
Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci.
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria
76The Oxazolidinones
The structure of Linezolide
77Mechanism of Action of the Oxazolidinones
- Binds to the 50S subunit and prevents association
of this unit with the 30S subunit. - http//student.ccbcmd.edu/courses/bio141/lecguide/
unit6/genetics/protsyn/translation/oxazolres_anim.
html
78Uses of the Oxazolidinones
- Has excellent activity against most aerobic
Gram-positive bacteria, including MRSA and VRE. - Only oxazolidonone on the market now is
Linezolid, which is both oral and intravenous.
79The Antimicrobial Activity of Linezolid (both
oral and parenteral)
Gram-positive bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.
Gram-negative bacteria
Anaerobic bacteria
Atypical bacteria
80The Sulfa Drugs
- Most commonly used sulfa drug is a mixture of the
sulfa drug Sulfamethoxazole and Trimethoprim - These two drugs work in synergy, with the
combination being superior to either drug alone. - This combination is known as co-trimoxazole,
TMP-sulfa, or TMP-SMX
Sulfamethoxazole
Trimethoprim
81Mechanism of Activity of Sulfa Drugs
- Trimethoprim-sulfamethoxazole works by preventing
the synthesis of tetrahydrofolate (THF), an
essential cofactor for the metabolic pathways
that generate deoxynucleotides, the building
blocks of DNA.
82Tetrahydrofolic Acid Biosynthetic Pathway
- In the first step of the pathway, the
sulfonamides are mistaken for the natural
substrate, p-aminobenzoic acid (PABA) and the
drug acts as a competitive inhibitor of this
enzyme - In a later step, the trimethoprim acts as a
structural analog of dihydrofolate and therefore
inhibits dihydrofolate reductase
83Structural Resemblance of Sulfamethoxazole and
p-Aminobenzoic Acid
Sulfamethoxazole
p-Aminobenzoic Acid
84Another sulfa drug is Dapsone, which is used to
treat Mycobacterium leprae
Dapsone
85Structural Comparison of Two Sulfa Drugs
86The Antimicrobial Activity of the Sulfa Drugs
Gram-positive bacteria Some Sreptococcus pneumoniae, Some Staphylococci, Listeria monocytogenes
Gram-negative bacteria Some Haemophilus influenzae, Some Enterobacteriaceae
Anaerobic bacteria
Atypical bacteria
Mycobacteria (Dapsone) Mycobacterium leprae
87The Fluoroquinolones
88Mechanism of Action Quinolones
- Quinolone antibiotics inhibit bacterial DNA
gyrase (Gram negative bacteria) or Topoisomerase
IV (Gram positive bacteria) - http//can-r.ca/images/Flash/fluoroquinolones.swf
89Uses of the Quinolone Antibiotics
- Urinary Tract Infections fluoroquinolones are
more effective than trimethoprim-sulfamethoxazole
- Prostatitis
- Respiratory tract infections
- Gastrointestinal and Abdominal Infections
90Antimicrobial Activity of the Quinolones (oral)
Gram-positive bacteria Some Staphylococcus aureus, Streptococcus pyogenes, Virdans group streptococci, Streptococcus pneumoniae
Gram-negative bacteria Neisseria spp. Haemophilus influenzae Many Enterobacteriaceae, Some Pseudomonas aeruginosa
Anaerobic bacteria Some clostridia spp, Some Bacteroides spp.
Atypical bacteria Chlamydia and Chlamydophilia, Mycoplasma pneumoniae, Legionella spp
Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacterium leprae
91Metronidazole (Flagyl)
Metronidazole is used in the treatment of
infections caused by anaerobic bacteria
92Metronidazole Mechanism of Action
Metronidazole is a prodrug. It is converted in
anaerobic organisms by the redox enzyme
pyruvate-ferredoxin oxidoreductase. The nitro
group of metronidazole is chemically reduced by
ferredoxin (or a ferredoxin-linked metabolic
process) and the products are responsible for
disrupting the DNA helical structure, thus
inhibiting nucleic acid synthesis.
93Mechanism of Action of Metronidazole
- Metronidazole is selectively taken up by
anaerobic bacteria and sensitive protozoal
organisms because of the ability of these
organisms to reduce metronidazole to its active
form intracellularly.
94- Systemic metronidazole is indicated for the
treatment of - Vaginitis due to Trichomonas vaginalis
(protozoal) infection in both symptomatic
patients as well as their asymptomatic sexual
contacts - Pelvic inflammatory disease in conjunction with
other antibiotics such as ofloxacin,
levofloxacin, or ceftriaxone - Protozoal infections due to Entamoeba histolytica
(Amoebic dysentery or Hepatic abscesses), and
Giardia lamblia (Giardiasis) should be treated
alone or in conjunction with iodoquinol or
diloxanide furoate - Anaerobic bacterial infections such as
Bacteroides fragilis, spp, Fusobacterium spp,
Clostridium spp, Peptostreptococcus spp,
Prevotella spp, or any other anaerobes in
intraabdominal abscess, peritonitis, empyema,
pneumonia, aspiration pneumonia, lung abscess,
diabetic foot ulcer, meningitis and brain
abscess, bone and joint infections, septicemia,
endometritis, tubo-ovarian abscess, or
endocarditis - Pseudomembranous colitis due to Clostridium
difficile - Helicobacter pylori eradication therapy, as part
of a multi-drug regimen in peptic ulcer disease - Prophylaxis for those undergoing potentially
contaminated colorectal surgery and may be
combined with neomycin
95Antimicrobial Activity of Metronidazole (both
oral and intravenous)
Gram-positive bacteria
Gram-negative bacteria
Anaerobic bacteria Bacteroides fragilis, Clostridium spp. Most other anaerobes
Atypical bacteria
96Antimicobacterial Agents
- Mycobacterial infections are very slow
progressing - Many antibiotics have poor activity against slow
growing infections - Mycobacteria must be treated for a long time, and
therefore, may readily develop resistance to a
single antibiotic - Typically, several antibiotic agents are used
simultaneously
97Antimycobacterial Agents
Pyrazinamide
Rifampin
Ethambutol
98Mycobacterial Infections
http//www.nature.com/nrmicro/animation/imp_animat
ion/index.html http//web.uct.ac.za/depts/mmi/lst
eyn/cellwall.html
99Mycolic Acids provide protection
- Mycolic acids are long fatty acids found in the
cell walls of the mycolata taxon, a group of
bacteria that includes Mycobacterium
tuberculosis, the causative agent of the disease
tuberculosis. They form the major component of
the cell wall of mycolata species. - The presence of mycolic acids gives M.
tuberculosis many characteristics that defy
medical treatment. They lend the organism
increased resistance to chemical damage and
dehydration, and prevent the effective activity
of hydrophobic antibiotics. In addition, the
mycolic acids allow the bacterium to grow readily
inside macrophages, effectively hiding it from
the host's immune system.
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101Mechanism of Action of Anti-Mycobacterial
Antibiotics
- Rifampin is an inhibitor of RNA polymerase
- Isoniazide inhibits the synthesis of mycolic acid
- Pyrazinoic acid inhibits the enzyme fatty acid
synthetase I, which is required by the bacterium
to synthesise fatty acids. - Ethambutol disrupts the formation of the cell wall
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