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ANTIBACTERIAL AGENTS

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

: agents that generally kill


organisms. ( PCN,

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

C. General Principles of effective


antibacterial therapy
1. Use Selectively.
a. choice of antibacterial based on
susceptibility test.
(empirical use, increases prevalence of
bacterial
resistance epidemiological data in
the locality)
b. life threatening infection, collect
samples prior
for organism ID before start of empiric
treatment.
c. use of potent, broad spectrum
antibiotic vs. more
common antibacterials.
2. Institute promptly
a. early treatment targets growing
bacteria- low bact.
Population.
b. early treatment shorten therapyreduces possibility of
superinfection.
3. Special situations
a. infection of poorly vascularized
tissue, treat with
bactericidal agents.
b. abscess or foreign bodies obstruction
surgery
4. Follow through
* In immunocompromised Pxs, the choice,
dosages & route of admin. Need to be
chosen carefully to inc. tx success.

*All antiviral act intracellularly; while many


antibacterial are not effective intracellularly.
( Tc, Chloram & flouroquinolones)
*Watch out for presence of superinfection
( antibiotic asso with colitis )
Follow through.
inadequate use of antibacterials
( dosing, premature termination)--- Resistant strain.
a. In immunocompromised patients :
choice, dosages, & route of administration..
b. Infections with IC bacteria usually
requires prolonged administration of
antibiotics
all antiviral agents act intracellularly,
bec this is essential for interference with
viral replication.
in contrast many antibact. Agents are
not effective IC organisms. ( Tc,
chloramphenicol & flouroquinolones) in
infected macrophages
c. In all patients receiving broadspectrum antibacterial agents, watch out for
SSx .suggestive of superinfection. (antibioticassoc colitis)
CLASSIFICATION
I . Antibacterial agents that inhibit cell wall
synthesis
II. Antibacterial agents that inhibit nucleotide
synthesis
III. Antibacterial agents that inhibit nucleicacid synthesis
IV. Antibacterial agents that inhibits protein
synthesis
I. Antibacterial agents that inhibit cell
wall synthesis
-LACTAM ANTIBACTERIAL AGENTS : all
are bactericidal
a. Penicillins .
Discovered by Fleming in the
1920s
- True antibiotic-antibacterial
compounds from molds genus
Penicillium
(1). Chemistry : all PCNs are
derived from 6-

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.

(c). Extended-spectrum Penicillins :


effective vs. a variety of Gram(+) & Gram(-)
bacteria. -----

also be allergic to Cephalosporins.


Mildly nephrotoxic esp. later
generations.

Other -lactam antibacterial agents:


(1). Carbapenems ( imipenem) : very
broadspectrum activity

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

*Carbapenems : only Listeria; grp. D strep,


Pseudomonas, & pasteurella multicida.
Resistant
(2). Monobactams ( aztreonam) :
effective vs. some Gram(-), aerobic bacteria
*Monobactams : effective vs. pseudomonas
Other inhibitors of bacterial cell wall
synthesis:
a. Cycloserine : rarely used, 2nd line antimycobacterial
drug. Ototoxic (when adm
parenterally)
b. Vancomycin : antibiotic of choice for
infections
caused by methicillin R
staphylococci and penicillanseproducing enterococci.
: poorly absorbed by the
intestinal mucosa

(c). 3rd gen : mostly injectables.


Cefotaxime ,
Ceftriaxone

: can be adm orally for local


treatment of intestinal
infections (e.g.
pseudomembranous colitis due
to Clostridium difficile)

(3). Spectrum of activity : broad-spectrum


ntibacterials

: more toxic than PCN, main


target of toxicity is the kidney

(a). Most cephalosporins are R to


staphylococcal
penicillanases
(b). 2nd & 3rd gen. cephalosporins are R
to most Lactamases produced by gramnegative org

(4). Toxicity : 10 -15% of patients allergic to


PCN might

c. Bacitracin : mainly used in topical


ointments, due to
nephrotoxicity & Ototoxicity
when adm parenterally.
Antibacterial agents that inhibit
nucleotide synthesis
1. Sulfonamides
: sulfadiazine (s)
sulfamethoxazole &
sulfisoxazole (m)

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

*Aminoglycosides & -lactams are


synergistic when used in combination. ( both
are bactericidal)
Toxicity : Renal and Nervous system
toxicity
b. Tetracyclines;
- produced by STREPTOMYCES species
b.1. short-acting : Tetracycline ;
Oxytetracycline ;
chlortetracycline;
Demeclocycline,
Methacycline
b.2. long-acting : Doxycycline ;
Minocycline
- broad-spectrum
bacteriostatic agents.
- effective vs.
intracellular bacteria
- alternative to PCN in
syphilis &
gonorrhea
- metabolized by the
liver , not
excreted in the urine
TC toxicity :
1. GI upset . ( antibiotic-assoc colitis)
2. Superinfection (loss of normal flora )
3. Yellowish discoloration of teeth
(contraindicated in pregnant women
and children.)
4. Increased photosensitivity
2. Inhibitors of 50S ribosomal unit
a. Chloramphenicol
: 1st antimicrobial compound
synthesized in the laboratory:
: broad spectrum, effective vs
anaerobes
: penetrate blood-brain
barrier
*Chloramphenicol : DOC in Typhoid fever;
Rocky
Mountain spotted fever; H. influenza
meningitis
Chloramphenicol Toxicity :
(a). Gray baby syndrome
(b). Blood dyscrasias .

- anemia, leukopenia, &


thrombocytopenia,
which may progress to aplastic
anemia.
b. Macrolide antibiotics :
= binds to 50S unit, & cause
premature peptide
chain termination.
= narrow spectrum
a. Erythromycin :DOC for Legionella &
Mycoplasma
alternate to PCN
b. Clarithromycin : acid-stable, useful in
Helicobacter
pylori & Myco avium- IC
c. Azithromycin : antichlamydial agent
*Gray baby syndrome : Chloram is
metabolized in the liver , where it is
conjugated to glucuronide. In NB often do
not have normal levels of glucoronyl
transferase so the drug may accumulate in
the blood- reaching toxic levels. Babys
ashen gray color, seizures, heart failure,
edema hepatomegaly, die. In infants dosage
must be adjusted carefully.
Macrolide Toxicity : hepatotoxic
c. Lincosamides
Lincomycin : prototype drug of this
group
Clindamycin : effective vs anaerobes.
: associated with
profound
disturbance of the intestinal
flora
resulting to overgrowth
of
Clostridium difficile ---antibiotic assoc.
diarrhea and pseudomembranous colitis.

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

Strategies to combat drug resistance:


1. drugs given at a conc. high enough to
destroy susceptible bacteria & most
spontaneous mutants
= drug combinations ( anti-TB)
2. chemotherapeutic drugs should be used
only when
necessary, pathogen should be
identified, drug
sensitivity done.
3. search for new antimicrobials