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A. Definitions
I. Antibiotics
: Antibacterial
II. Bacteriostatic
: Bactericidal
III. Narrow-spectrum : Broadspectrum
Antibiotic : substance produced by a
microorganisms
that, in minute quantities is
able to inhibit
other microorganisms.
Antibacterial : any compound- natural,
synthetic, or
semi-synthetic, that is clinically
useful in
the treatment of
bacterial infection.
Bacteriostatic : agents that inhibit
bacterial growth
(ex. Sulfonamide,
chloramphenicol)
Bactericidal
only growing
streptomycin )
Narrow-spectrum : preferentially active
against either
Gram(-) or Gram (+)
bacteria.
Broad-spectrum : active against both
Gram(+) & (-)
bacteria.
B. General Criteria for effective
antibiotic action
1. Microorganisms: unique and vital target.
( specific
proteins or nucleic
acid)
2. Antibacterial agent :
a. must be able to penetrate bacterial
surface & reach
target in active form.
b. reach the infected tissue ( cross bloodbrain barrier)
c. intracellular organisms (Tc)
3. Host :
a. intact immune system
b. vascularization and drainage
*Bacterial infections are difficult to treat in
neutropenic patirnts & those with primary or
secondary immunodef.
Bacterial endocarditis, osteomyelitis &
abscesses are assoc. with minimal
vascularization of the infected tissue
Bronchiectasia, kidney stones & gall stones
impair drainage- can give origin to bact.
Infectn- surgical removal of obstruction
aminopenicillamic acid in
which
the - lactam group is
linked to
a thiazolidine ring. The
antibacterial and
pharmacologic properties
of the different PCNs
depend on the side
chains attached to the
basic nucleus.
(2). Mech. of action :
(a). The bacterial targets for PCNs
are
known as Penicillin-binding
proteins(PBPs);
- transpeptidase ;
carboxypeptidase ; autolytic
enzymes
*The major antibacterial agents can be
classified acc to their mechanisms of action.
( 1.) structurally , the most impy feature of
PCN, cephalosporins, carbapenems, &
monabactams is the -lactam ring.
PBPs several, as many as 7 in E. coli. Inhibit
PDG cross-linking bacterial lysis
(3.) Bacterial resistance.
_ some bacteria produce lactamase, an
enzyme that inactivates lactams
( 4.) Spectrum of activity :
(a). Natural PCNs are narrow
spectrum
antibiotics. ( vs. Gram + & most
anaerobes )
Exception: T. pallidum ,a grm(-)
Susceptible to PCN, ; Bacteroides fragilis ,
(anaerobe,beta-lactamase producer) is R to
PCN
(b). Semi-synthetic -lactamase resistant
PCNs (Methicillin, oxacillin, cloxacillin,
peninafcicillin and dicloxacillin ).
Penicillanase-resistant PCNs S. aureus
infection, penicillinase-resistant PCN are
preferred bec. Of high freq of -lactamase
isolates.
aminopenicillins (ampicillins,
amoxycillins)
carboxypenicillins ( carbenicillin,
ticarcillin)
ureidopenicillins ( azlocillin);
piperazine (piperacillin)
-lactamase inhibitors (clavulanic acid,
sulbactam
*Via manipulation of 6-aminopenicillamic
molecule.
5. Toxicity : allergic reactions
CEPHALOSPORINS:
(1). Chemistry :
semisynthetic -lactam antibacterial
agents from 6-aminopenicillamic acid,
however, the thiazolidine ring is
replaced by a dihydrothiazine ring.
(2). Classification : three(3) generations
chronological
Development
(a). 1st gen : oral & injectable forms
Cefazolin, Cephalexin ,
Cephalothin
(b). 2nd gen. : mostly injectables
Cefamandole, Cefaclor,
Cefoxitin , Cefuroxime
sulfamethoxydiazine (L)
Mech. : bacteriostatic / broad spectrum/
well
absorbed orally
-- blocks synthesis of
tetrahydrofolate & folate
-- weak inhibitors of dihydrofolate
reductase
Toxicity : HPS reaction ( 2nd to PCN)
-- high doses may cause
hematologic
dz & crystal formation in the
urinary tract.
*Sulfonamised are structurally similar to
PABA ( para amino benzoic acid)
2. Trimethoprim
: structurally similar to
dihydrofolic
acid, is bound by dihydro folate
reductase.
3. Sulfamethoxazole-trimethoprim:
strong synergistic
combi. ( bacteriostatic combi
=bactericidal)
: useful in GUT infections ,
bacterial gastroenteritis ; &
long-term prophylaxis of
bacterial infections in
immuno-compromised
patients. (HIV)
Antibiotic that inhibit nucleic acid
synthesis
1. DNA synthesis inhibitors
a. Novobiocin
:DNA gyrase inhibitors replaced by
quinolones
( same Mech action)
(2). Flouroquinolones
:derivatives of Nalidixic
acid eg ofloxacin ,
ciprofloxacin,
lomefloxacin )
c. Nitroimidazoles, Metronidazoles
: antiflagellates &
vs. obligate anaerobic bacteria.
2. RNA transcription inhibitors :
inactivate DNA-dependent RNA polymerase.
a. Rifampin
: 1st line anti TB drug. ; Leprosy
&
Legionella
: Chemoprophylaxis of
patients contact
during outbreaks due to
Neisseria meningitides & H.
influenzae
Antibacterial agents that inhibits
protein synthesis
1. Inhibitors of 30S ribosomal unit
a. Aminoglycosides ;
= binds irreversibly to 30S unit of
bacterial
chromosome, forming 30S- 50S ,
which
inactivates initiation sites & renders
the
bacteria unable synthesize a peptide
chain.
= distort the triplet coding of mRNA
and cause
mRNA misreading (streptomycin)
Mech. : Bactericidal/ broad spectrum
vs. Gram(-) organism.
Parenteral adm. Not absorbed in GIT
b. Quinolones
:DNA gyrase inhibitors
(1). Nalidixic acid
:1st quinolone, broadspectrum,
mainly used in GUT ;
relatively
toxic causing GIT &
neurologic
sx. (visual)
Aminoglycosides preparations;
1. Streptomycin :1st aminoglycoside.
Ototoxic.
2 nd- line anti TB
2. Neomycin : for local & topical admin
3. Kanamycin
4. Gentamicin , Tobramycin ,
Amikacin , Netilmicin
Drug Resistance
Mechanisms of Drug Resistance : (strategy)
1. Pathogen prevents entry of the drug
2. Presence of membrane translocases that
pumps drug
out of the cell.efflux pumps
3. Drug inactivation through chemical
modification.
ex. Hydrolysis of -lactam ring by
penicillanase
Origin and transmission of drug
resistance;
A. Genes for drug resistance are present
on both;
a. bacterial chromosome (spont.
mutation)
b. plasmids ( small extra chromosomal
DNA)
= R plasmids
B. Extensive drug treatment favors
development &
spread of antibiotic-resistant strains.
= superinfection
pseudomembranous enterocolitis
: C. difficile