Professional Documents
Culture Documents
ANTIBIOTICS
Assoc. Prof. Ivan Lambev
e-mail: itlambev@mail.bg
www.medpharm-sofia.eu
Antimicrobial agents are among the most dramatic
examples of the advances of modern medicine.
Many infectious diseases once considered incurable
and lethal now can be treated. The remarkably powerful
and specific activity of antimicrobial drugs is due to their
selective toxicity for targets that are either unique
to microorganisms or much more important in them
than in humans.
Among these targets are bacterial and fungal
cell wall-synthesizing enzymes, the bacterial ribosome,
the enzymes required for nucleotide synthesis and
DNA replication, the mechanism of viral replication,
etc. The much older and less selective cytotoxic
drugs are the antiseptics and disinfectants.
Antiinfective agents may be classified
according to their antimicrobial activity:
1. Antibacterial drugs (antibiotics
and synthetic drugs)
2. Antiviral drugs
3. Antifungal drugs
4. Antiprotozoal drugs
5. Anthelmintic drugs
6. Insecticides for ectoparasites
7. Antiseptics and Disenfectant (Not are drugs)
8. Prepartaions for Disinsection (Not are drugs)
9. Prepartaions for Deratisation (Not are drugs)
10. Vaccines, Serums, and Immunoglobulins
Antibacterial drugs have been
classified broadly into:
-lactams, Glycopeptides
Polymyxins Rifampicin
30S: Aminoglycosides
30S: Tetracyclines
50S: Chloramphenicol
50S: Macrolides, Lincosamides
50S: Linezolide, Streptogramins
Adverse Drug Reactions (ADRs)
Antibacterial drugs may cause:
direct host toxicity (aminoglycosides, peptides)
toxic interactions with other drugs
interference with protective effects of normal host
microora (by suppressing obligate anaerobes, for
example selection or promotion of drug resistance
tissue lesions at injection sites (tetracyclines)
impairment of host immune or defense
mechanisms (chloramphenicol)
reduced phagocytosis, and chemotactic activity
of neutrophils (tetracyclines)
inhibition of phagocytosis (aminoglycosides)
hypersensitivity reactions (beta-lactams,
aminosides, sulfonamides)
hepatic microsomal enzyme induction
(e.g. rifampin) or inhibition (e.g. chloramphenicol)
that interferes with their own metabolism as well as
that of concurrent medications,
Selection or promotion of resistance
Antibacterial agents do not cause bacteria to
become resistant but their use preferentially
selects resistant populations of bacteria.
Some genes that code for resistance have been
identied in bacterial cultures. The most clinically
important for resistance are plasmids. They carry
genes that may benefit survival of the
organism (e.g. antibacterial resistance)
transmitted from one bacterium to another.
Plasmids are cytoplasmic
genetic elements which transfer drug
resistance to previously susceptible bacteria.
Acquired resistance is not a problem in all bacteria.
For example, Gram-positive bacteria (with
some exceptions, incl. Staphylococcus spp) are
often unable to acquire resistance plasmids
(and thus acquire resistance through mutation,
a slower process), whereas resistance is an
increasing problem in many Gram-negative
pathogens such as the Enterobacteriaceae.
BETA-LACTAM ANTIBIOTICS
(inhibitors of cell wall synthesis)
Their structure contains a beta-lactam ring.
The major subdivisions are:
(a) penicillins whose official names
usually include or end in cillin
(b) cephalosporins which are
recognized by the inclusion
of cef or ceph in their
official names.
(c) carbapenems (e.g. meropenem,
imipenem)
(d) monobactams (e.g. aztreonam)
(e) beta-lactamase inhibitors (e.g.
clavulanic acid, sulbactam).
A. FLEMING I. PENICILLINS
(18811955)
Penicillin G
- P. notatum
(1929)
Penicillium chrysogenum
The cell wall completely surrounds the cytoplasmic
membrane, maintains cell shape and integrity, and
prevents cell lysis from high osmotic pressure. The
cell wall is composed of a complex cross-linked
polymer of polysaccharides and polypeptides,
peptidoglycan (murein, mucopeptide). The
polysaccharide contains alternating amino sugars,
N-acetylglucosamine, and N-acetylmuramic acid.
A five-amino-acid peptide is linked to the
N-acetylmuramic acid sugar. This peptide
terminates in D-alanyl-D-alanine.
Penicillin-binding protein (PBP, an enzyme)
removes the terminal alanine in the process of
forming a cross-link with a nearby peptide.
Cross-links give the cell wall its structural rigidity.
Beta-lactam antibiotics covalently bind to
the active site of PBPs. This inhibits the
transpeptidation reaction, halting
peptidoglycan synthesis, and the cell dies.
Beta-lactams kill bacterial cells only
when they are actively growing and
synthesizing cell wall.
NARROW SPECTRUM PENICILLINS
Biosynthetic (natural) penicillins
Antistaphylococcal beta-lactamase
resistant penicillins
Phenoxymethylpenicillin
Potassium (Penicillin-VK)
Procaine penicillin G is rarely used nowadays
because many strains are penicillin-resistant.
b) Antistaphylococcal penicillins
Isoxazolyl penicillins
- Cloxacillin, Dicloxacillin
- Flucloxacillin, Oxacillin
Others
- Methicillin
- Nafcillin
500 mg
Flucloxacillin
These semisynthetic penicillins are indicated for
infection by beta-lactamase-producing staphylococci,
although penicillin-susceptible strains of streptococci
and pneumococci are also susceptible.
Listeria, enterococci, and methicillin-resistant strains
(MRS) of staphylococci are resistant.
a) Aminopenicillins
The aminopenicillins have identical spectrum and
activity, but amoxicillin is better absorbed orally
(7090%). They are effective against
streptococci, enterococci, and some
Gram-negative organisms (including H. pylori)
but have variable activity against staphylococci
and are ineffective against P. aeruginosa.
Amoxicillin and Ampicillin
Amoxicillin, 500 mg 3 times daily,
is equivalent to the same amount of ampicillin given
four times daily. These drugs are given orally to treat
urinary tract infections, sinusitis, otitis, and lower
respiratory tract infections. Aminopenicillins are
the most active of the oral beta-lactams against
penicillin-resistant pneumococci and are the
preferred beta-lactams for treating infections
suspected to be caused by these resistant strains.
Amoxicillin in VM
Ampicillin (but not amoxicillin) is effective for
shigellosis.
Ampicillin, at dosages of 412 g/d i.v., is useful for
treating serious infections caused by penicillin-
susceptible organisms, including anaerobes,
enterococci, L. monocytogenes, and beta-lactamase-
negative strains of Gram-negative cocci and bacilli
such as E. coli, and salmonella species. Non-beta-
lactamase-producing strains of H. influenzae are
generally susceptible. Many Gram-negative species
produce beta-lactamases and are resistant.
b) Antipseudomonal penicillins
These drugs retain activity against streptococci and
possess additional effects against Gram-negative
organisms, including various Enterobacteriaceae
and Pseudomonas.
Carboxypenicillins
- Carbenicillin
- Ticarcillin
Ureidopenicillins
- Azlocillin
- Mezlocillin
- Piperacillin
Carbenicillin, the very first antipseudomonal
carboxypenicillin, is obsolete.
Klebsiella pneumoniae
1. First-generation cephalosporins
cefadroxil, cefazolin, cefalexin,
cefalothin, cefapirin, cefradine
Doripenem
Ertapenem
Meropenem
Tienam (imipenem/cilastatin)
Imipenem has a wide spectrum with good activity
against many Gram-negative rods, including P. aeru-
ginosa, Gram-positive organisms, and anaerobes.
It is resistant to most -lactamases but not metallo-
beta-lactamases. E. faecium, MRS of staphylococci,
C. difficile and some others microorganisms are
resistant.
Imipenem is inactivated by dehydropeptidases
in renal tubules, resulting in low urinary concen-
trations. Consequently, it is administered together
with an inhibitor of renal dehydropeptidase,
Cilastatin, for clinical use.
Meropenem is similar to imipenem but has slightly
greater activity against Gram-negative aerobes and
slightly less activity against Gram-positives. It is not
significantly degraded by renal dehydropeptidase
and does not require an inhibitor.
Ertapenem is less active than meropenem or imipe-
nem against P. aeruginosa and Acinetobacter species.
It is not degraded by renal dehydropeptidase.
()
Clavulanic acid
Sulbactam
Tazobactam
Resistance to penicillins and other beta-lactams
is due to one of four general mechanisms:
(1) inactivation of the antibiotic by beta-lactamase;
(2) modification of the target PBPs;
(3) impaired penetration of the drug to the target PBPs;
(4) efflux of the drug from bacterial cells.
Beta-lactamase production is the most common
mechanism of resistance. Many hundreds of different
beta-lactamases have been identified. Some, such
as those produced by Staphylococcus aureus,
Haemophilus spp., and Escherichia coli, are relatively
narrow in substrate specificity, preferring penicillins
to cephalosporins. They are called penicillinases
and cephalosporinases.
Other -lactamases produced by P. aeruginosa
and Enterobacter spp., and extended-spectrum
beta-lactamases, hydrolyze both cephalosporins
and penicillins.
Clavulox
Clavulox
in
in VM
VM
(Veterinary
(Veterinary
Medicine!)
Medicine!)
Antibacterial spectrum for ticarcillin-clavulanate