Midterm Antibacterials Flashcards
accidental discovery of the anti-
bacterial properties of penicillin in 1929
Sir Alexander Fleming
introduced penicillin into therapy
Florey and Chain, 1938
used in Chinese folk medicine to treat boils
and carbuncles.
molded curd of
soybean
had also been used for centuries by Chinese and Ukrainian peasants to treat infected
wounds.
Moldy cheese
The discovery in 1877
of anthrax bacilli
Pasteur and Joubert
antibiosis
“against life”
Vuillemin
a substance
produced by microorganisms, which has the capacity of inhibiting the growth and even of destroying other microorganisms.
an antibiotic or antibiotic substance:
1942, Waksman
- It is a product of metabolism (although it may be
duplicated or even have been anticipated by chemical synthesis). - It is a synthetic product produced as a structural analog of a naturally occurring antibiotic.
- It antagonizes the growth or survival of one or more
species of microorganisms. - It is effective in low concentrations.
a substance is classified as an antibiotic if the
following conditions are met:
The isolation of the antibacterial antibiotic tyrocidin
from the soil bacterium Bacillus brevis by Dubois
suggested
the probable existence of many antibiotic substances
in nature and provided the impetus for the search for them
streptomycin
from Streptomyces griseus: Waksman
The discovery that this antibiotic (Streptomyces griseus) possessed in vivo activity against
Mycobacterium tuberculosis
& numerous of species of Gram-negative bacilli
antibiotic must possess attributes
1- it must exhibit sufficient selective toxicity to be decisively effective against pathogenic microorganisms or neoplastic tissue, on the one hand, without causing significant toxic effects
2- antibiotic should be chemically stable enough to be isolated, processed, and stored for a reasonable length of time without deterioration of potency
3- the rates of biotransformation and elimination of the antibiotic should be slow enough to allow a convenient dosing schedule, yet rapid and complete enough to facilitate removal of the drug and its metabolites from the body soon after administration has been discontinued
commercial production of antibiotics for medicinal
use follows a general pattern
(a) preparation of a pure culture of the desired
organism for use in inoculation of the fermentation medium;
(b) fermentation, during which the antibiotic is formed;
(c) isolation of the antibiotic from the culture medium;
(d) purification;
(e) assays for potency, sterility, absence of pyrogens, and other necessary data; and
(f) formulation into acceptable and stable dosage forms.
The ability of some antibiotics, such as chloramphenicol and the tetracyclines, to antagonize the growth of numerous pathogens
broad-spectrum antibiotics
are active only in relatively high concentrations
against some of the species of microorganisms often
included in the “spectrum.
Many of the broad-spectrum antibiotics
the basis for the future develop-
ment of modern chemotherapeutic agents
understanding of those mechanisms that are peculiar to the metabolic systems of infectious organisms
are the most successful anti-infective agents
Antibiotics that interfere with the metabolic systems found in microorganisms and not in mammalian cells
have a high potential for selective toxicity
antibiotics that interfere
with the synthesis of bacterial cell walls
believed to be an antimetabolite for D-alanine, a constituent of bacterial cell walls.
cycloserine
antibiotics selectively interfere with microbial protein synthesis
aminoglycosides,
tetracyclines,
macrolides,
chloramphenicol, and
lincomycin
antibiotics selectively interfere
with nucleic acid synthesis
rifampin
believed to interfere with the integrity and function of microbial cell membranes
polymyxins and the polyenes
Site of Action: Cell wall
Process Interrupted:
* Mucopeptide synthesis
* Cell wall cross-linking
* Synthesis of cell wall peptides
* Membrane integrity
* Protein synthesis and fidelity
* mRNA synthesis
Bactericidal
Bactericidal Antibiotics
Bacitracin
Cephalosporin
Cycloserine
Penicillins
Vancomycin
Polymyxins
Aminoglycosides
Rifampin
Site of Action:
Ribosomes
50S subunit
30S subunit
Process Interrupted:
Protein synthesis
Bacteriostatic
Bacteriostatic Antibiotic
Chloramphenicol
Erythromycin
Lincomycins
Tetracyclines
determines in general, whether the agent exerts a bactericidal or a bacteriostatic action.
mechanism of action of an antibiotic
macrolide structure
a large lactone ring
conjugated polyene compounds
nystatin and the amphotericins
polypeptides that exhibit antibiotic action
bacitracins,
tyrothricin, and
polymyxin
Beta-lactam ring–containing antibiotics
derived from amino acids
(a four-membered cyclic amide)
penicillins and
cephalosporins
The first antibiotic to be used in therapy
penicillin (penicillin G or benzylpenicillin), and a close biosynthetic relative, phenoxymethyl penicillin
(penicillin V)
remain the agents of choice for the treatment of infections caused by most species of Gram-positive bacteria
penicillin (penicillin G or benzylpenicillin), and a close biosynthetic relative, phenoxymethyl penicillin
(penicillin V)
second major group of beta-lactam antibiotics
The cephalosporins
effective against bacterial species known to be
resistant to penicillin, in particular, penicillinase-producing staphylococci and Gram-negative bacilli
second major group of beta-lactam antibiotics, the cephalosporins, and chemical modifications of naturally occurring penicillins and cephalosporins
two properties contribute to the unequaled importance of beta-lactam antibiotics in chemotherapy
1- a potent and rapid bactericidal action against bacteria in the growth phase and
2- a very low frequency of toxic and other adverse reactions in the host
PBPs 1a and 1b
are transpeptidases involved in peptidoglycan synthesis associated with cell elongation
autolysins
bacterial enzymes that create nicks
in the cell wall
PBP 2
a transpeptidase involved in maintaining the rod
shape of bacilli
PBP 3
a transpeptidase required for septum formation
during cell division
PBPs 4 through 6
carboxypeptidases responsible for the hydrolysis of D-alanine–D-alanine terminal peptide bonds of the cross-linking peptides
Commercial production of biosynthetic penicillins today depends chiefly on various strains of
Penicillium notatum and
Penicillium chrysogenum
defined as the smallest amount of penicillin
that will inhibit, in vitro, the growth of a strain of
Staphylococcus in 50 mL of culture medium under specified conditions.
1 Oxford unit
the United States Pharmacopoeia (USP) defines unit as the antibiotic activity of
0.6 microgram of penicillin G sodium reference
standard
naturally resistant to the action of penicillins
Some bacteria, in particular most species of Gram-negative bacilli
Other normally sensitive species can develop penicillin resistance
either through natural selection of resistant individuals
or through mutation
enzymes that catalyze the hydrolytic
opening of the lactam ring of penicillins to produce
inactive penicilloic acids.
beta-lactamases.
The well-known resistance among strains of Staphylococcus aureus is apparently entirely because of the production of an inducible
beta-lactamase
enzymes that inactivate
penicillins
non-specific name penicillinases
penicillinases are of two general types:
beta-lactamases and acylases
Beta- Lactamases produced by Gram-negative bacilli appear to be
cytoplasmic enzymes that remain in the bacterial cell
Beta-lactamases elaborated by S. aureus are
synthesized in the cell wall and released extracellularly
(enzymes that can hydrolyze the acyl-
amino side chain of penicillins
acylases
less active and hydrolyzed more rapidly
(enzymatically and nonenzymatically) than penicillin
6-APA
The cell envelope in most Gram-negative bacteria is
more complex than in Gram-positive bacteria. It contains an outer membrane (linked by lipoprotein bridges to the peptidoglycan cell wall) not present in Gram-positive bacteria, which creates
a physical barrier to the penetration of
antibiotics, especially those that are hydrophobic
pores formed by proteins called
porins
ampicillin and amoxicillin
Extended-Spectrum Penicillins
ampicillin and amoxicillin,
are generally effective against such Gram-negative genera as
Escherichia,
Klebsiella,
Haemophilus,
Salmonella,
Shigella, and
non–indole-producing Proteus
active against both beta-lactamase
producing and non–beta-lactamase-producing strains of Gram-negative bacteria.
Carbenicillin
carbenicillin (and other penicillins), when com-
bined with aminoglycosides
exerts a synergistic bactericidal
action against bacteria
Allergy to Penicillins
a variety of skin and mucous membrane rashes to drug
fever and anaphylaxis
For years, the most popular penicillin.
Remains the agent of choice for the
treatment of more different kinds of bacterial infection than any other antibiotic
Penicillin G
The first widely used amine salt of penicillin G
Penicillin G Procaine
is the salt of a diamine, 2 moles of penicillin are available from each molecule.
It is very insoluble in water, requiring about 3,000 mL to dissolve 1 g.
Penicillin G Benzathine
In 1948, Behrens et al.46 reported it as a biosynthetic
product.
it has enjoyed wide use because of its resistance to
hydrolysis by gastric juice and its ability to produce uniform concentrations in blood (when administered orally).
*phenoxymethylpenicillin
Penicillin V
-(5-methyl3-phenyl-4-isoxazolyl)penicillin
sodium monohydrate (Prostaphlin), is the salt of a semisynthetic penicillin that is highly resistant to inactivation by penicillinase.
is available in capsule form, is
reasonably well absorbed from the gastrointestinal (GI)
tract, particularly in fasting patients.
Oxacillin Sodium
[3-(o-chlorophenyl)-5-methyl-4-isoxazolyl]
The chlorine atom ortho to the position of attachment of the phenyl ring to the isoxazole ring enhances the activity
Cloxacillin Sodium
Its antibacterial spectrum is nearly identical with that of
ampicillin, and like ampicillin, it is resistant to acid, susceptible to alkaline and beta-lactamase hydrolysis, and
weakly protein bound.
Amoxicillin
6-[D--aminophenylacetamido]penicillanic acid,
D--aminobenzylpenicillin (Penbritn, Polycillin, Omnipen,
Amcill, Principen), meets another goal of the research on
semisynthetic penicillins—an antibacterial spectrum broader than that of penicillin G.
Ampicillin
appears to be more active against
Providencia spp. and K. pneumoniae
Mezlocillin
is the most generally useful of the ex-
tended-spectrum acylureidopenicillins. It is more active than mezlocillin against susceptible strains of Gram-negative aerobic bacilli, such as Serratia marcescens, Proteus, Enterobacter, Citrobacter spp., and P. aeruginosa.
Piperacillin (Pipracil)
is destroyed rapidly by stomach acid; there-
fore, it is active only by intramuscular or intravenous
administration
Piperacillin
Beta lactamase inhibitors MOA
Mechanism-based inhibitors interact with -lactamases in a similar manner to natural substrates, forming an acyl-enzyme intermediate that is either slowly hydrolyzed or inactivated.
These inhibitors are also known as “suicide substrates” because they are eventually destroyed in the process of inhibiting the enzyme
Classes of beta-Lactamase Inhibitors:
Class I inhibitors (e.g., clavulanic acid, sulbactam) have a heteroatom leaving group at position 1 and cause prolonged inactivation of certain -lactamases.
Class II inhibitors (e.g., carbapenems) do not have a leaving group at position 1 and cause transient inhibition of -lactamases.
are useful in combination with extended-spectrum, beta-lactamase-sensitive penicillins to treat infections caused by -lactamase-producing bacteria
Beta-lactamase
Class I inhibitors
The carbapenem imipenem has potent antibacterial activity in addition to transient beta-lactamase inhibition.
Beta-lactamase
class II inhibitor
Beta-lactamase groups
*group A (serine enzymes) are generally susceptible to class I inhibitors
*group B (metallo- -lactamases) and group C (chromosomally encoded serine enzymes) are resistant to class I inhibitors.
*
