Prepared by Shahidullah Kayser ,

2. Antibacterial agents
Antibiotics:
Antibiotics are chemical substances produced by various
species of microorganisms such as bacteria, fungi,
actinomycetes etc and are used for either killing or
inhibiting the growth of other pathogenic
microorganisms without affecting the host tissue.

3. Properties of an ideal antibiotic:
 It should have a broad spectrum of antimicrobial
activity.
 It should exert its action in low concentration
 It should have bactericidal activity rather than
bacteriostatic activity
 It should exhibit selective and effective antimicrobial
activity.
 It should be highly toxic for the parasite but
completely atoxic for the host.
 No bacterial resistance should be developed rapidly.
 It should not interfere with the host’s natural defense
mechanism such as phagocytosis and production of
antibodies.

4.  It should have sufficient solubility in aqueous fluid to
facilitate good distribution to all body tissues.
 It should be excreted in urine in bactericidal concentration
specially in urinary tract infection.
 It’s antimicrobial efficacy should not be reduced by body
fluids, exudates, plasma protein or tissue enzymes.
 Antibiotic should possess sufficient chemical stability that
it can be isolated, processed that stored for reasonable
length of time without deterioration of potency.
 The rates of biotransformation and elimination of the
antibiotic should be sufficiently slow to allow a convenient
dosing schedule.
Properties of an ideal antibiotic: cont…

5. Tetracycline
Example: Oxytetracycline, Demeclocycline, Methacycline.
M/A:
Tetracyclines inhibit bacterial protein synthesis by binding to
the 30S bacterial ribosome and preventing access of aminoacyl
tRNA to the acceptor (A) site on the mRNA-ribosome
complex. These drugs enter gram-negative bacteria by passive
diffusion through the hydrophilic channels formed by the
porin proteins of the outer cell membrane and by active
transport via an energy-dependent system that pumps all
tetracyclines across the cytoplasmic membrane. Entry of these
drugs into gram-positive bacteria requires metabolic energy,
but is not as well understood.

6. Mechanism of antibacterial action
There are five main mechanisms by which antibacterial agent act-
Inhibition of cell metabolism:
Antibacterial agents which inhibit cell metabolism are called
antimetabolites. These compounds inhibit the metabolism of
microorganism but not the metabolism of the host. They can do this
by inhibiting an enzyme catalyzed reaction which is present in the
bacterial cell, but not in animal cells. e. g. sulfonamides.
Inhibition of bacterial cell wall synthesis:
Inhibition of bacterial cell wall synthesis leads to bacterial cell lysis and
death.

7. Interaction with plasma membrane:
Some antibacterial agents interact with the plasma membrane of
bacterial cells to affect the membrane permeability. This has
fatal results for the cell. E. g. polymixins, tyrothricin.
Disruption of protein synthesis:
Disruption of protein synthesis means that essential proteins and
enzymes required for the cell’s survival can no longer be made.
E. g. rifamycins, aminoglycosides, tetracyclins and
chloramphenicol
Inhibition of nucleic acid transcription and replication
Inhibition of nucleic acid function prevents cell division and/or
the synthesis of essential proteins. e. g. –nalidixic acid,
proflavin, fluoroquinolone

8. Classification of Antibiotics:
Although there are several classification schemes for antibiotics,
based on bacterial spectrum (broad versus narrow) or type of
activity (bactericidal vs. bacteriostatic), the most useful is based
on chemical structure. Antibiotics within a structural class will
generally have similar patterns of effectiveness, toxicity, and
allergic potential.
The main classes of antibiotics are:
 Beta-Lactams
 Penicillins
 Cephalosporins
 Macrolides
 Fluoroquinolones
 Tetracyclines
 Aminoglycosides

10. β-Lactam Characteristics
 Same Mechanism of Action : Inhibit cell wall
synthesis
 Bactericidal (except against Enterococcus sp.);
time-dependent killers
 Short elimination half-life
 Primarily renal elimination
 Cross-allergenicity -except aztreonam

11. Mechanism of Action (ALL β-lactams)
 Interfere with cell wall synthesis by binding to
penicillin-binding proteins (PBPs) which are located
in bacterial cell walls
 Inhibition of PBPs leads to inhibition of peptidoglycan
synthesis→ Cell death

12. Mechanisms of Resistance
1. production of β-lactamase enzymes
 most important and most common
 hydrolyzes beta-lactamring causing inactivation
2. Trapping mechanism
 Some β –lactams tightly bind with β – lactamase and
stay outside the bacterial cell. Thus, these beta-
lactams can’t enter the bacterial cell wall to combine
with the PBPs.
3. Modification of target PBPs.
 responsible for methicillin resistance in staphylococci
and penicillin resistance in pneumococci.

13. Mechanisms of Resistance
4. Impaired penetration of drug to target PBPs.
 which occurs only in G-species, is due to
impermeability of the outer membrane that is present
in G- but not in G+ bacteria.
5. The shortage of autolytic enzyme.
 Under this circumstance, the beta-lactams have
normal inhibiting action, but their kill effects are very
poor.
6. The presence of an efflux pump.
 Some organisms also may transport beta- lactam
antibiotics from the periplasm back across the cell wall
via an efflux pump

14. Penicillins
 The structure of the penicillins consists of a
thiazolidine ring connected to a beta-lactamring,
which is attached to a side chain.
 All penicillins are derived from 6-Amino- penicillanic
acid.
 The various penicillins differ in their side chain
structure.

15. Classification of penicillin
 Penicillins are divided into natural and semisynthetic ones
 Natural penicillins: extracted from the cultural solution of
penicillia.
 penicillin G
 Is pH sensitive. Therefore not given orally.
 Effective against Gram-positive cells
 Susceptible to penicillinase
 Semisynthetic penicillins:
 Produce by growing Penicillium in culture so that only the
nucleus is synthesized. Attach R group in lab.
 Or, grow Penicillium, extract natural penicillin, remove R
group, and attach wanted R group.
 Have broader spectrum. Are effective against Gram-negative
cells, too.
 Are not resistant to penicillinases

16. Semisynthetic penicillins:
 Acid-stable penicillins(e.g. penicillin V);
 Penicillinase-resistant penicillins (e.g. oxacillin);
 Extended-spectrum penicillins (e.g. ampicillinand
antipseudomonal);
 Antistaphylococcal penicillins (e.g. nafcillin).

17. Mechanisms of Resistance - Penicillins
 Inactivation of antibiotic by β- lactamase enzymes
 Modification of target PBPs
 Impaired penetration of drug to target PBPs
 The presence of an efflux pump

18. Pharmacokinetics of Penicillins G
 It is relatively unstable in acid, thus the bioavailability
is low.
 There is poor penetration into the cerebrospinal (CSF),
unless inflammation is presetent.
 Active renal tubular secretion results in a short half-
life.
Spectrum of activity
 G+ cocci : Pneumococci , Staphylococci, Streptococci ,
(many Staphylococci are now resistant)
 G- cocci: Meningococci and gonococci
 G+ bacilli: Bacillus perfringens, Bacillus diphtheriae
 Spirochetes: Treponema pallidum, Leptospira and
Actinomyces

19. Therapeutic uses
 It is the drug of first choice for treating the infections
of the above mentioned pathogens.
 The simultaneous administration of the relevant
antitoxin is often necessary for the treatment of
diphtheria and tetanus.
 The combination of an aminoglycoside is also
necessary for bactericidal effects in enterococcal
endocarditis.

20. Acid-stable Penicillins- penicillin V
 The oral form of penicillins,
 Indicated only in minor infections because of their
relatively poor bioavailability, weaker antimicrobial
activity, the need for dosing many times
 Narrow antimicrobial spectrum.

21. Penicillins: Adverse effects
 Hypersensitivity –
 5 to 20 % skin rashes, fever, eosinophilia, angioedema,
serum sickness, and anaphylactic shock.
 Cross-reactivity exists among all penicillins and even
other b-lactams
 The most serious hypersensitivity reaction is
anaphylactic shock. (very rare, the ratio is about 0.5 to 1
of 10000 patients )
 As soon as anaphylactic shock occurs, instantly inject
adrenaline to deliver trachea edema and spasm.

22. Penicillins: Adverse effects
 Other adverse effects:
 Gastrointestinal upset, ( orally administered
preparations)
 Nephrotoxicity, is very rare.
 Superinfections.
 results from alterations in intestinal flora. A higher
incidence occurs with broad-spectrum penicillins.

23. Cephalosporins
 The cephalosporins are derivatives of 7- amino-
cephalosporanic acid and are closely related in
structure to penicillin.
 They have a beta- lactamring.
 They are relatively stable in dilute acid and are highly
resistant to penicillinase.
Mechanism of action
 Cephalosporins inhibit the peptido- glycansynthesis of
bacterial cell wall in a manner similar to that of
penicillin and are considered bactericidal.

24. Classification of cephalosporins
 First-generation cephalosporins
 Second-generation cephalosporins
 Third-generation cephalosporins
 Fouth-generation cephalosporins

25. First Generation Cephalosporins
EXAMPLES: cephalothin, cefazolin, and cephalexinet al
 They have a stronger antimicrobial action on G+ bacteria
than that of the other generations, but they action on G-
bacteria is relatively poor.
 These cephalosporinshave nephrotoxicity to a certain
degree.
 They are NOT effective against pseudomonas.
 Comparatively, they are stable for beta-
lactamase(penicillinase).
 They are chiefly used in treating infection of the
penicillinase-productive aurococcus (S.aureus)and
surgical prophylaxisction.
 Cefazolindo not penetrate the central nervous system
and can not be used to treat meningitis.

26. Second Generation Cephalosporins
Example: cefamandole, cefoxitin, cefaclor, cefonicid, cefuroxime,
cefotetan, cefprozil.
 Action of this generation on G+ bacteria is the same or a little bit
less than that of the first generation.
 Their antimicrobial action on G- bacteria is obviously increased
 Some of them are effective against anaerobes such as B. fragilis.
 Ineffective against P. aeruginosa.
 They are stable to many kinds of beta- lactamases and have less
nephrotoxicity than the first generation.
 Cefuroxime is the only second-generation drug that crosses the
blood-brain barrier well enough to be used for thetreatment of
meningitis, especially H.influenzae meningitis, and sepsis.

27. Third Generation Cephalosporins
Example: cefotaxime, ceftizoxime, ceftriaxone, cefoperazone,
ceftazidime, cefixime, cefpodoxime
 The broadest spectrums of all Cephalosporins
 The highest activities against G- bacteria.
 The lowest activities against G+ bacteria.
 The highest resistance to β-lactamase.
 The best penetration into the CSF; almost no nephrotoxicity.
 Ceftizoximehave good activity against B. fragilis.
 Some of them are effective against P. aeruginosa and enteric
bacilli.
 They are chiefly used in the infections of the urethral or biliary
tract with the drug-resistant strains and Pseudomonas.
 They are also used in some serious pneumonia, sepsis and
meningitis.

28. Macrolides antibiotics
Example: Erythromycin, Clarithromycin and Azithromycin
M/A:
Macrolide antibiotics are bacteriostatic agents that inhibit
protein synthesis by binding reversibly to 50S ribosomal
subunits of sensitive microorganisms. Erythromycin does not
inhibit peptide bond formation per se, but rather inhibits the
translocation step wherein a newly synthesized peptidyl
tRNA molecule moves from the acceptor site on the ribosome
to the peptidyl donor site. Gram-positive bacteria accumulate
about 100 times more erythromycin than do gram-negative
bacteria. Cells are considerably more permeable to the un-
ionized form of the drug, which probably explains the
increased antimicrobial activity at alkaline pH.

29. Resistance:
 Resistance to macrolides can result from:
 Drug efflux by an active pump mechanism;
 Ribosomal protection by inducible or constitutive
production of methylase enzymes that modify the
ribosomal target and decrease drug binding;
 macrolide hydrolysis by esterases produced by
Enterobacteriaceae; and
 Chromosomal mutations that alter a 50S ribosomal
protein.

30. Absorption, Distribution, and Excretion:
 Orally absorbed, erythromycin from enteric coated tablet
others oral absorption is good, metabolized in the liver,
excreted in the bile and some through urine.
 Distributed throughout the tissues except brain & CSF.
Therapeutic Uses:
 Mycoplasma pneumoniae, Legionnaire disease, Chlamydia
infections, Helicobacter pylori infection, Diphtheria,
Streptococcal infection, Campylobacter infections,
Tetanus, Syphilis, Mycobacterium infections, other
infections.
 Prophylactic use in recurrent rheumatic fever.
 The drug cannot be used in patients sensitive to macrolide
antibiotics.
 Cannot be used in chronic liver diseases.

31. Therapeutic use of tetracyclines:
 Rickettsial infections (Rocky Mountain spotted fever),
Mycoplasma infections (Mycoplasma pneumoniae),
Chlamydia (Pneumonia, bronchitis or sinusitis caused by
Chlamydia responds to tetracycline therapy), Doxycycline is
effective in reducing stool volume in Vibrio cholerae, not
effective in S. Typhosa and Shigellosis due drug resistance.
 Sexually transmitted diseases: Uncomplicated gonococal
infections
 Chlortetracycline is 30% absorbed in oral dose, but oxy and
tetracycline absorbed up to 60-80%, Doxy and minocycline,
95-100% Resistance plasmid mediated, decreased influx,
decreased entry to ribosome’s because of ribosome
protection enzymes.

32. Aminoglycosides
M/A: The aminoglycoside antibiotics are rapidly bactericidal.
Bacterial killing is concentration-dependent: The higher
the concentration, the greater is the rate at which bacteria
are killed. Aminoglycosides diffuse through aqueous
channels formed by porin proteins in the outer membrane
of gram-negative bacteria to enter the periplasmic space.
Drug is then actively transported across the cell membrane
into the cytoplasm by an oxygen-dependent process. The
transmembrane electrochemical gradient supplies the
energy for this process, and transport is coupled to a proton
pump. Low extracellular pH and anaerobic conditions
inhibit transport by reducing the gradient. Transport may
be enhanced by cell wall-active drugs such as penicillin or
vancomycin; this enhancement may be the basis of the
synergism of these antibiotics with aminoglycosides.

33. Therapeutic Uses:
STREPTOMYCIN:
 Tularemia: Streptomycin (or gentamicin) is the drug of
choice for the treatment of tularemia. Most cases
respond to the administration of 1 g (15 to 25 mg/kg)
streptomycin per day (in divided doses) for 7 to 10 days.
 Brucellosis: streptomycin, 1 g/d (15 mg/kg/d for
children), is given intramuscularly in combination with
an oral tetracycline.
 Bacterial Endocarditis
 Urinary Tract Infection
 Tuberculosis

34. Therapeutic Uses:
 GENTAMICIN:
 Skin & Soft Tissue Infections
 Wound, burn
 Bacterial Endocarditis
 Urinary Tract Infection
 Tuberculosis
 Tularemia
 Neomycin:
Ointments, often formulated as a neomycin-
polymyxin-bacitracin combination, can be applied to
infected skin lesions.