Midterm Antibacterials Flashcards by EDGAR JORDAN ESPINOLA

accidental discovery of the anti-
bacterial properties of penicillin in 1929

Sir Alexander Fleming

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introduced penicillin into therapy

Florey and Chain, 1938

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used in Chinese folk medicine to treat boils
and carbuncles.

molded curd of
soybean

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had also been used for centuries by Chinese and Ukrainian peasants to treat infected
wounds.

Moldy cheese

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The discovery in 1877
of anthrax bacilli

Pasteur and Joubert

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antibiosis

“against life”
Vuillemin

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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

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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:

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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

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streptomycin

from Streptomyces griseus: Waksman

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The discovery that this antibiotic (Streptomyces griseus) possessed in vivo activity against

Mycobacterium tuberculosis
& numerous of species of Gram-negative bacilli

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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

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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.

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The ability of some antibiotics, such as chloramphenicol and the tetracyclines, to antagonize the growth of numerous pathogens

broad-spectrum antibiotics

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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

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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

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are the most successful anti-infective agents

Antibiotics that interfere with the metabolic systems found in microorganisms and not in mammalian cells

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have a high potential for selective toxicity

antibiotics that interfere
with the synthesis of bacterial cell walls

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believed to be an antimetabolite for D-alanine, a constituent of bacterial cell walls.

cycloserine

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antibiotics selectively interfere with microbial protein synthesis

aminoglycosides,
tetracyclines,
macrolides,
chloramphenicol, and
lincomycin

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antibiotics selectively interfere
with nucleic acid synthesis

rifampin

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believed to interfere with the integrity and function of microbial cell membranes

polymyxins and the polyenes

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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

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Bactericidal Antibiotics

Bacitracin
Cephalosporin
Cycloserine
Penicillins
Vancomycin
Polymyxins
Aminoglycosides
Rifampin

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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. *