This document provides an overview of antibiotics, including their sources, classifications, mechanisms of action, and principles of antimicrobial therapy and selection. It focuses on penicillins as a class of antibiotics that act by inhibiting bacterial cell wall synthesis. Penicillins were discovered from the mold Penicillium and their basic structure consists of a beta-lactam ring. They work by inhibiting the bacterial enzyme DD-transpeptidase and preventing cell wall synthesis, ultimately causing bacterial cell lysis. Factors such as acid stability, spectrum of activity, and resistance are considered in developing different penicillin derivatives.

1. ANTIBIOTICS
BY
W.C.SAKA

2. OVERVIEW
•Understanding drug therapy
•Principles of Antimicrobial Therapy
•Criteria for selection of Antimicrobials
•Antimicrobial Resistance
•Sources of Antibiotics
•Classification of Antibiotics

3. DRUG THERAPY
THERE ARE 5 MAIN DRUG ACTIONS:
•Stimulating or depressing cellular activity.
•Replacing deficient substances.
•Causing irritation.
•Killing invading foreign organisms (bactericidal)
•Weakening invading foreign organisms (bacteriostatic)

4. PRINCIPLES OF ANTIMICROBIAL THERAPY
•Antimicrobials are different from other classes of
pharmaceuticals because they exert their action on
bacteria infecting the host as opposed to acting directly
on the host.
•There are two guiding principles to consider when
treating patients with antimicrobials:
a) make the correct diagnosis and
b) do no harm (selective toxicity)
•Antimicrobial therapy takes advantage of the
biochemical differences that exist between
microorganisms and human beings.

5. •Selective toxicity; the ability to injure or kill an
invading microorganism without harming the cells
of the host.
•The selective toxicity is relative rather than
absolute, requiring that the concentration of the
drug be carefully controlled to attack the
microorganism, while still being tolerated by the
host.

6. SELECTION OF ANTIMICROBIAL AGENTS
•Selection of the most appropriate antimicrobial agent
requires knowing
• the organism’s identity
• the organism’s susceptibility to a particular agent
•the site of the infection,
•patient factors,
•the safety of the agent, and
•the cost of therapy.

7. A. Identification of the infecting organism
•Characterizing the organism is central to selection of the
proper drug. The following methods can be used;
• Gram Staining: a rapid assessment. Useful in identifying the
presence and morphologic features of organism.
• Other laboratory techniques: Definitive identification of the
infecting organism. Such as detection of microbial antigens,
DNA, or RNA, or an inflammatory or host immune response to
the microorganism.
•In body fluids that are normally sterile (blood, serum,
cerebrospinal fluid [CSF], pleural fluid, synovial fluid,
peritoneal fluid, and urine).

8. Empiric therapy prior to identification of the organism
•Ideally, the antimicrobial agent used to treat an infection
is selected after the organism has been identified and its
drug susceptibility established.
•However, in the critically ill patient, such a delay could
prove fatal, and immediate empiric therapy is indicated.
Two things must be considered;
1. Timing: Acutely ill patients with infections of unknown
origin,e.g. a patient with meningitis (characteristically
described by severe headache, neck rigidity, and
sensitivity to bright lights) require immediate treatment.

9. •Therapy should be initiated after specimens for
laboratory analysis have been obtained, but before the
results of the culture are available.
2. Selecting a drug: Drug choice in the absence of
susceptibility data is influenced by the site of infection
and the patient’s history (e.g. previous infections, age,
recent travel history, immune status,& whether the
infection was hospital- or community-acquired).
•Broad-spectrum therapy may be indicated initially when
the identity of an organism is unknown or poly-microbial
infection is likely.

10. •The choice of agent(s) may also be guided by known
association of particular organisms in a given clinical
setting.
•After a pathogen is cultured, its susceptibility to
specific antibiotics serves as a guide in choosing
antimicrobial therapy.
•Spectrum of Activity: is a term used to convey an
impression of the range of bacteria that a drug is
effective against.

11. •Narrow spectrum; if they are only effective against
one class of bacteria.
•Broad spectrum: if they are effective against a
range of bacteria.
•Extended spectrum; If a narrow-spectrum agent is
modified chemically (as in adding a new side chain),
and the new compound is effective against more
bacteria than the parent compound.

12. •Broad spectrum antimicrobials will increase the
likelihood that a patient will get better even without
knowing the bacteria causing infection.
•However, counter to this argument is the principle
of “Do no harm!” Broad antimicrobial coverage
does increase the likelihood of empirically killing a
causative pathogen; unfortunately, the
development of secondary infections can be caused
by selection of antimicrobial-resistant non-targeted
pathogens.

13. B. Determining antimicrobial susceptibility of
infective organisms
•After a pathogen is cultured, its susceptibility to specific
antibiotics serves as a guide in choosing antimicrobial
therapy
1. Bacteriostatic vs. bactericidal drugs:
•Antimicrobial drugs are classified as either bacteriostatic
or bactericidal.
•Bacteriostatic drugs: arrest the growth and replication at
serum or urine levels achievable in the patient, thus
limiting the spread of infection until the body’s immune
system attacks, immobilizes, and eliminates the pathogen.

14. •If the drug is removed before the immune system has
scavenged the organisms, enough viable organisms may
remain to begin a second cycle of infection.
•Bactericidal Drugs: kill bacteria at drug serum levels
achievable in the patient.
•Because of their more aggressive antimicrobial action,
bactericidal agents are often the drugs of choice in
seriously ill patients.

15. •An antibiotic can be bacteriostatic for one organism
and bactericidal for another. For example,
chloramphenicol is bacteriostatic against gram-
negative rods and is bactericidal against other
organisms, such as S. pneumoniae. replication of
bacteria at serum (or urine) level.

16. MIC vs MBC
•The minimum inhibitory and bactericidal concentrations
of a drug can be experimentally determined.
•Minimum Inhibitory Concentration (MIC): MIC is the
lowest concentration of antibiotic that inhibits bacterial
growth.
•Minimum Bactericidal Concentration (MBC): (MBC) is
the lowest concentration of antibiotic that kills 99.9
percent of bacteria (equals 32 in this example).

18. C. Effect of the site of infection on
therapy
•Adequate levels of an antibiotic must reach the site of
infection for the invading microorganisms to be
effectively eradicated.
• Capillaries with varying degrees of permeability carry
drugs to the body tissues.
•For example;the capillaries in the brain help to create
and maintain the blood-brain barrier.
•This barrier is formed by the single layer of tile-like
endothelial cells fused by tight junctions that impede
entry from the blood to the brain of virtually all
molecules, except those that are small and lipophilic.

19. •Drugs that pass through this barrier must be 1) Lipid
Soluble 2) Low Molecular Weight 3) Low or no
protein binding

20. D. Patient Factors
•In selecting an antibiotic, attention must be paid to
the condition of the patient.
•For example, the status of the patient’s immune
system, kidneys, liver, circulation, and age must be
considered. In women, pregnancy or breast-feeding
also affects selection of the antimicrobial agent.

21. E. Safety of the agent
•Many of the antibiotics, such as the penicillins, are
among the least toxic of all drugs because they
interfere with a site unique to the growth of
microorganisms.
•Other antimicrobial agents (for example,
chloramphenicol) are less microorganism specific
and are reserved for life-threatening infections
because of the drug’s potential for serious toxicity
to the patient.

22. F. Cost of therapy
•Often several drugs may show similar efficacy in
treating an infection, but vary widely in cost.
•Standard treatment of Helicobacter pylori includes
various combinations of two or three antimicrobial
agents along with a proton pump inhibitor.

23. •An inevitable consequence of exposing microbes to
antimicrobials is that some organisms will develop
resistance to the antimicrobial.

24. ANTIBIOTICS
•Are chemical substances produced by
microorganisms(Fungi, bacteria and
actinomycetes) that suppress growth of fellow
microorganisms and may eventually destroy them.
•They are applied in infection treatment.
•Non-infectious diseases too e.g Cancer

25. Classification
1. According to the source.
Antibiotics have been isolated from three types of
microorganisms.
a. Antibiotics from Fungi
Penicillin was isolated from a mould Penicillium notatum
and Penicillium chrysogenum. Griseofulvin was isolated
from Penicillium griseofulvum and others.
b. Antibiotics from actinomycetes
Are prokaryotic organisms under bacteria, but considered
as an individual group because they are unique.
5

26. •Streptomycin-Streptomyces griseus.
•Chlortetracycline-Streptomyces aureofaciens.
•Oxytetracycline-Streptomyces rimosus.
•Chloramphenicol-Streptomyces venezuelae.
•Erythromycin-Streptomyces erythreus.
c. Antibiotics from bacteria
•Bacitracin from Bacillus subtilis.
•Polymixins from Bacillus polymyxa and others.
6

27. 2. According to Mode of Action
a. Inhibitors of bacterial cell wall synthesis
• Penicillins
• Cephalosporins
• Bacitracin and others
b. Inhibitors of protein synthesis
• Aminoglycosides
• Tetracyclines
• Chloramphenicol
• Macrolides and others.
7

28. c. Inhibitors of cell membrane function
• Polymixins
• Nystatin
• Amphotericin B.
d. Inhibitors of nucleic acid synthesis and metabolism
• Griseofulvin
• Actinomycin
• Rifampicin
• Fluoroquinolones
8

29. 9
Cell membrane
THFA
PABA
Cell wall
DNA
MRA
Inhibitors of
Metabolism
-Sulphonamide
-Trimethoprim
Inhibitors of
cell wall synthesis
-beta lactams
-vancomycin
Inhibitors of
protein synthesis
-tetracycline
-aminoglycosides
-macrolides
-clindamycin
-chloramphenicol
Inhibitors of DNA
synthesis or function
-fluoroquinolones, griseofulvin
-rifampicin,
SITE OF ACTION OF ANTIBIOTICS
Inhibitors of cell
membrane function
-polymixins
-nystatin
-amphotericin -B

30. 3. According to the Antibacterial Spectrum
a. Narrow – Spectrum Antibiotics
Penicillins, Streptomycin,Erythromycin, Lincomycin,
Polymixin B, Vancomycin and others.
b. Broad – Spectrum Antibiotics
Chloramphenicol, Tetracyclines,
Kanamycin, Cephalosporins, Ampicillin, Amoxycillin
and others.
0

31. •The most important groups of antibiotics that act by
inhibiting bacterial cell wall synthesis are the Penicillins
and Cephalosporins.
•Also known as Beta-lactam antibiotics
1
INHIBITORS OF BACTERIAL CELL
WALL SYNTHESIS

32. 1. PENICILLINS
•Comprise substances some of which are natural
products while others are semi-synthetic compounds.
•They have a common chemical nucleus 6-
aminopenicillanic acid (6-APA) and a common mode of
antibacterial action, they inhibit cell wall muco-peptide
(peptidoglycans) synthesis.
2

33. HISTORY
•Penicillin was discovered by Sir Alexander Fleming in
1928 when he saw that “Colonies of staphylcocci were
lysed when contaminated by a mould.”
•The mould was later classified as Penicillium notatum.
•Crude penicillin G was available for limited therapeutic
trials in 1941.
•Up to 1959 biosynthesis of penicillins depended upon
growth of Penicillium notatum, Penicillium
chrysogenum.
3

34. Natural penicillin G has some limitations:
i. Acid labile so destroyed by HCl on oral administration.
ii. Destroyed by β-lactamase enzymes
iii. Has a narrow bacterial spectrum.
iv. Is rapidly excreted from the body.
v. Poor penetration into CSF.
vi. It is antigenic.
4

35. •These limitations of Penicillin G led to search for better
compounds.
•In 1958, the basic penicillin nucleus, 6-aminopenicillanic
acid was isolated.
•Now, It is possible to synthetically add side chains to 6-
APA to produce a range of penicillins that collectively
overcome the first four shortcomings of penicillin G.
•Isosterism-Bioisosteres
5

36. CHEMISTRY
•The basic structure is a sulphur containing Thiazolidine
ring fused to β-lactam ring, forming 6-aminopenicillanic
acid (6-APA), the so called penicillin nucleus, upon
which the antibacterial activity depends .
•The side chain determines the individual penicillin
characteristics.
6
6-AMINOPENICILLANIC ACID

37. 7
H H H S CH3
R N C C C
CH3
C N C
O H COOH
β–lactam ring
6 – aminopenicillanic acid
R – group determines the drug’s stability
to enzymatic or acidic hydrolysis
and affects its bacterial spectrum
Structure of beta-lactam antibiotics

38. •Bacterial β-lactamase (penicillinase) and acids such as
gastric acid hydrolyse penicillin to Penicilloic acid by
breaking the β-lactam ring.
•Penicilloic acid which is produced has no antibacterial
activity, but is very allergenic.
•Penicillin G has benzyl side chain, so substituting it with
Phenoxymethyl or Phenoxyethyl side chains produces
oral penicillins having increased acid stability.
•The addition of an alpha-NH3 group led to production of
broad spectrum penicillins -Ampicillin,Amoxycillin….
8

39. UNITS OF PENICILLIN
•IU of Penicillin is the specific penicillin activity contained
in 0.6µg of crystalline sodium salt of Penicillin G.
•1mg of pure sodium Penicillin G equals 1667 units for
Penicillins derived from 6-APA but for the synthetic
penicillins, dosage is in mg/body weight.
•1,000,000 units of Penicillin is one mega unit (MU)
9

40. •Beta-lactam antibiotics (Penicillins, cephalosporins)
selectively inhibit synthesis of Mucopeptides
(Peptidoglycans) in the bacterial cell wall of multiplying
bacteria hence preventing normal synthesis of cell wall.
•They inhibit DD-transpeptidase (penicillin-binding
protein),the enzyme which catalyzes cross-linking of
peptidoglycan chains.
•Since peptidoglycan cross-links cannot form but enzymes
that hydrolyze peptidoglycan cross-links continue to
function, an imbalance between cell wall production and
degradation develops.
0
Mode of Action

41. •This weakens bacterial cell wall and osmotic pressure
becomes increasingly uncompensated causing bacterial
cell death cytolysis).
1

42. •The bacteria cell wall construction and cell division
continues, but resulting cells have defective cell walls.
•The defective cells with defective walls easily lyse by
osmotic forces.
•β-lactamases split the beta-lactam ring of penicillins,
rendering penicillins inactive hence bacterial resistance
develops.
2

43. Pharmacokinetics of Penicillin G Preparations
Absorption
Three main types of penicillin G are available:
(i) Penicillin G for oral use.
(ii) Aqueous penicillin G for parenteral use.
(iii) Depot preparations as suspensions for parenteral use
•Penicillin G is erratically absorbed from GIT (15-20%)
•Most is destroyed by gastric acid b4 reaching duodenum,
where maximum absorption occurs.
•Should be taken on an empty stomach to minimise
destruction by acid and prevent delay in absorption.
3

44. •Parenteral administration is preferably by IM injection.
•Is rapidly absorbed from site of injection, peak plasma
levels attained within 20 mins.
•IV injection is used in life-threatening infections.
Distribution, Metabolism and Excretion
•Penicillin G is highly bound to plasma proteins.
•High concentration is achieved in kidney and urinary tract.
•90% of drug is excreted unchanged by the kidneys. Is also
excreted in milk.
4

45. Probenecid
•Delays rapid renal excretion of penicillin when
administered together.
•Probenecid competes with penicillin for the tubular
transport system that transports the antibiotic from
blood to tubular fluid.
5

46. Therapeutic Use of Penicillin G and
Phenoxymethylpenicillins (Penicillin V)
•Penicillin G 250,000U/5ml or procaine penicillin G
300,000U/ml are drugs of choice in Pneumonia, given
by IM 300,000 – 600,000 units 12 hourly for 7-10 days.
•Penicillin V 125/250/500mg tablets useful in Tonsillitis,
Pharyngitis & Endocarditis given orally,500mg qid for 10
days.
Penicillin V 125mg/5ml powder for suspension: 25-
50mg/kg/day in 3-6 divided doses in children.
Penicillin G given I.V is drug of choice in Pneumococcal
Meningitis 300,000IU – 8 MU per day.
6

47. •In Gas gangrene, Penicillin G is drug of choice 10 -20 MU
per day.
•In Gonorrhoea, Benzylpenicillin 600/1200mg/vial is
used 4.8 MU as single dose with 1g Probenecid orally.
•In Syphilis, Benzathine penicillin G (long acting Penicillin
G) 300,000/600,000U/ml: is used 2.4 MU I.M as single
dose or aqueous penicillin G 600,000U IM daily for 8
days
7

48. Toxicity
Penicillins are the least toxic of all antibiotics, just 10-
15 % incidence.
1. Hypersensitivity reactions
Fever, rash, erythema, urticaria, angioedema,
anaphylactic shock, asthma and hypotension occurs
due to exposure to penicillin dust, topical application,
oral and parenteral preparations of penicillin.
• Treatment of hypersensitivity reactions is by using Adrenaline,
antihistamines or Corticosteroids.
• It should be assumed that once hypersensitivity reaction occurs to a
patient, this patient will react to all other drugs in the class.
8

49. Broad-spectrum Penicillins
They are Ampicillin and Amoxycillin .
1. Ampicillin- Apart from those covered by Penicillin G,
Ampicillin is also active against E.coli, Proteus mirabilis,
H. Influenza, and Salmonella.
•Oral Ampicillin is poorly and slowly absorbed and
should be taken on empty stomach.
•After normal dose, peak blood levels attained after 2hrs.
9

50. •Preparations and dosage:
•Ampicillin caps 250/500mg: 250 mg q6h.
•Powder for suspension: 125/250mg/5ml: 50mg/kg/day
in divided doses q6h.
•Powder for Injection 1g,2g,10g/vial; I.V/I.M 25-
50mg/kg/day in divided doses.
•T1/2 is between 1-1.5hrs and distributes to 40% of body
weight.
•Within 6hrs 30% of dose is excreted mostly unchanged
in urine.
•Mostly indicated for Chronic bronchitis, Otitis media,
Urinary tract infections and Meningitis
0

51. 2. Amoxycillin - Derivative of Ampicillin with same
antibacterial spectrum but is more active against Strep.
faecalis and Salmonella species.
• Twice as well absorbed orally than ampicillin and twice peak
plasma levels
• Presence of food does not interfere with absorption.
• Peak blood levels reached within 2hrs and same T1/2 and
protein binding as Ampicillin.
1

52. Preparations and dosage:
•Caps/tabs 250/500mg: 250-500mg q8h.
•Powder for oral suspension 125/250mg/5ml: 25-
50mg/kg/day q8h.
•Powder for injection 500mg and 1g vials. I.M or I.V 500mg
tid.
2

53. Penicillinase-resistant Penicillins
•Most staphylococci is resistant to Penicillin G bcoz they
produce Penicillinases (β-lactamases), enzymes which
destroy beta-lactam ring.
• In Penicillinase-resistant penicillins, molecular
geometry of the drug hinders access of this enzyme to
beta-lactam ring.
These are Methicillin, Cloxacillin and Flucloxacillin.
Methicillin 1,4,6,10g/vial–IM/IV 4-6g/day in divided
doses q4-6h
3

54. Cloxacillin caps 250mg–p.o 250mg-1g q6h on empty
stomach.
Powder for oral suspension:125mg/ml: 50-100mg/kg/day
in divided doses q6h.
Powder for Injection 250/500mg/vial: 250-500mg q4-6h.
Flucloxacillin caps 250mg–p.o 250mg-500mg q6h, is
better absorbed than cloxacillin/
Powder for suspension 125mg/5ml: 25-50mg/kg/day
q6h.
Powder for Injection 250/500mg/vial: 250/500mg q6h
4

55. CEPHALOSPORINS
•Structurally & pharmacologically related to Penicillins.
•They are water soluble, broad spectrum, semi-synthetic
bactericidal antibiotics.
•Derived from 7-aminocephalosporanic acid (7-ACA)
having β–lactam ring and Dihydrothiazine ring fused
together.
5

56. 6
H H
S H
R1 C N C C H
O C N C CH2 R2
C
O
COOH
7- amino-cephalosporanic acid
Semi-synthetic cephalosporins are prepared by
attaching different chemical groups at R1 and R2
Structural features of cephalosporins

57. Antibacterial Spectrum
•Cephalosporins and related compounds are divided into
1st, 2nd & 3rd generation agents.
•They just differ is primarily in their pharmacokinetics &
antibacterial spectrum.
•From first to third generation exhibits:
•Broadening gram-ve spectrum.
•Loss of efficacy against gram +ve organisms.
•Greater efficacy against resistant organisms
7

58. Mode of action
•They inhibit mucopeptide synthesis in the bacterial cell
wall, making it defective and osmotically unstable.
•They are usually bactericidal based on dose, tissue
concentration & organism susceptibility.
Pharmacokinetics
•Cephalexin, Cephradine, Cefaclor Cefadroxil are well
absorbed orally.
•Absorption may be delayed by food but absolute amount
of the drug absorbed is not affected.
•Cephalosporins are widely distributed in most tissues and
fluids but highly concentrated in liver and kidney.
8

59. •1st & 2nd generation agents do not readily diffuse into
CSF except Cefuroxime.
•Most of them and their metabolites are excreted via the
kidneys.
β-lactam resistance
•First generation cephalosporins are inactivated by beta-
lactamase producing organisms.
•Cefuroxime, Ceftriaxone, Cefotaxime, Cefotetan etc
show high stability in presence of Penicillinases and
Cephalosporinases.
9

60. 0

61. •Preoperative, intraoperative & postoperative prophylaxis
to reduce incidence of infection in a surgery likely to be
contaminated e.g Gastrointestinal surgery, Cesarean
section, vaginal hysterectomy etc.
•Alternatives in patients who cannot tolerate penicillins.
•Drug of choice in Meningitis caused by gram –ve
bacteria because of their good penetration of the CSF.
1

62. FIRST GENERATION
Cephalexin caps 250mg:p.o 250-500mg q6h.
Oral suspension 125mg/5ml:25mg/kg/day q6h.
Cephradine, Cefadroxil, Cefazolin, Cefelixin, Cephalothin
SECOND GENERATION
Cefuroxime tabs 250/500mg:p.o 250-500mg bid.
Powder for injection 1.5g/vial:IM/IV 1-3g q8h.
Oral suspension 125mg/5ml: 125mg bid.
Cefaclor, Cefoxitin, Cefuroxime, Cefotetan.
2

63. THIRD GENERATION
Ceftriaxone 1,2g/vial : IM/IV 1-2g q12- 24h
Cefoperaxone, Ceftazidime, Ceftibuten, Cefotaxime
Adverse reactions
•GIT disturbances & hypersensitivity can occur.
•Cross sensitivity with Penicillins.
•Agranulocytosis, haemolytic anaemia, leucopenia,
thrombocytopenia have been reported.
•Nephrotoxic, coz acute tubular necrosis.
•Treatment alters normal flora in colon permitting
overgrowth of Clostridia.
3

64. Drug interactions
•Bacteriostatic agents interfere with the bactericidal
action of cephalosporins.
•Probenecid administered concurrently with
cephalosporins increases and prolongs plasma levels by
competitively inhibiting renal secretion.
•Concomitant administration with aminoglycosides
increases nephrotoxicity.
4

65. Other Inhibitors of Bacterial Wall Synthesis
•Apart from Penicillins & Cephalosporins: Bacitracin,
Cycloserine and Vancomycin also inhibit synthesis of
bacterial cell wall.
1. Bacitracin
•Bacitracin is a generic name for a group of at least four
bactericidal polypeptide antibiotics originally isolated
from Bacillus subtilis.
•Effective against gram +ve organisms, especially
common skin pathogens like Staphylcocci, Streptococci
and Neisseria.
•Inactive against most gram –ve bacteria.

66. • Bacitracin interferes with bacterial cell wall synthesis by preventing formation
of peptidoglycan chains that are crossed to form rigid bacterial cell wall.
• No longer used parenterally due to nephrotoxicity.
• Safe topically, hypersensitivity reaction like allergic dermatitis occurs.
• Topical combination of bacitracin with neomycin or polymyxin B increases
spectrum of activity.
• Such combinations are effective in the tx of topical ulcers, sycosis
(inflammation of hair follicles),otitis externa, pyodermas (any septic skin
lesions), infected traumatic and surgical wound and impetigo (acute infection
of the skin).
• Ophthalmic preparations are useful in treating superficial eye infections like
conjunctivitis, infected corneal ulcers.
6

67. 2. Cycloserine
• A broad spectrum bactericidal antibiotic from Streptomyces
archidaceous
• Restricted to treatment of Tuberculosis.
• Orally, it is rapidly absorbed and freely distributed to tissues and
CSF.
• Potential CNS toxicity limits its use,
• In prolonged therapy, plasma drug levels should be periodically
checked.
• Given in doses of 15mg/kg body weight, orally with 250mg
increments to reach serum levels of 15-35µg/ml
7

68. 3. Vancomycin
• Is a bactericidal glycopeptide antibiotic from Streptomyces
orientalis.
• Effective against gram +ve organisms.
• Most potent antibiotic against Staphylcocci in colitis.
• It is only used when less toxic antibiotics have failed because it is
toxic.
• Allergic skin rashes and anaphylactic reactions may occur.
• Administered in doses of 1g I.V bid.
8

69. β-lactamase Inhibitors
•They bind to β-lactamases and inactivate them so
preventing them from destroying beta-lactam ring
in antibiotics. This reduces resistance from bacteria.
1.Clavulanic acid
•From Streptomyces clavuligerus.
•Well absorbed orally.
•It can also be given parenterally.
O
N
COOH
CH-CH2OH
β-lactam ring
O
CLAVULANIC ACID

70. •It is combined with Amoxycillin forming (Augmentin,
Co-Amoxiclav, Clavulin, Spotclav…) for oral
administration and combined with Ticarcillin for
parenteral administration.
•Co-Amoxiclav 375mg tablets:
•Amoxycillin 250mg+clavulanic acid 125mg
•Co-Amoxiclav 625mg tablets:
•Amoxycillin 500mg+clavulanic acid 125mg
•Co-Amoxiclav 156mg/5ml Oral suspension:
•Amoxycillin 125mg+clavulanic acid 31mg
0

71. •Co-Amoxiclav 312mg
•Amoxycillin 250mg+Clavulanic acid 62mg
•Co-Amoxiclav 600mg for Injection
•Amoxycillin 500mg+Clavulanic acid 100mg
•Co-Amoxiclav 1200mg for Injection
•Amoxycillin 1000mg+Clavulanic acid 200mg
Doses: Expressed as Amoxycillin
By mouth: 250mg tid, doubled in severe infection.
Children: 125mg – 250mg tid.
Injection: IV or Infusion 1g tid: children 25mg/kg tid.
1

72. 2. Sulbactam
•Structurally resembling clavulanic acid.
•Used orally or parenterally along with β-lactams such as
ampicillin.
•Usual dose is 1-2g of Ampicillin with 0.5-1g sulbactam
q6h.
•Combination successfully used in mixed intra-abdominal
and pelvic infections.
2

73. SULBACTAM
3
β-lactam
ring

74. Inhibitors of Protein Synthesis
1. Aminoglycosides.
2. Tetracyclines.
3. Chloramphenicol.
4. Maclorides.
5. Lincosamides.

75. 1. AMINOGLYCOSIDES
• Made of amino sugars linked by glycosidic
bonds hence the name.
• Most are prepared by natural fermentation from
Streptomyces spp, except Gentamicin which is
fermented from Micromonospora purpurea.
• Aminoglycosides- Gentamicin, Streptomycin,
Kanamycin, Neomycin, Tobramycin, Framycetin

76. •All aminoglycosides are bactericidal against Gram-
negative aerobes and some anaerobic bacilli where
resistance has not yet arisen but generally not against
Gram-positive and anaerobic Gram-negative bacteria.
•Streptomycin and Kanamycin are also active against
Mycobacterium tuberculosis.
6
Antibacterial Spectrum

77. •Bacteria develop eternal resistance to Aminoglycosides
by any of the following:
• Resistance (R) factor passed on between bacteria.
• Development of ribosomes which do not bind
aminoglycosides.
• Acquisition of inactivating enzymes.
• Reduced permeability to the drug.
•Cross resistance is more common on prolonged therapy.
7
Bacterial Resistance

78. • They act on bacterial 30S ribosomal subunits distorting mRNA
translation of genetic code thereby preventing the formation of the
normal complex required to initiate protein synthesis.
• They don’t act on human ribosomes.
• They also have strong cationic charges which combine with anionic
membrane groups and damage the bacterial cell membranes
• So they inhibit bacterial protein synthesis and are bactericidal.
8
Mode of Action

79. • Poorly absorbed following oral administration because of
charges.
• Given by injection to treat systemic infections.
• Also poorly bound to plasma protein (20-30%) & are widely
distributed throughout the body except CNS & eye
• Potency is increased in alkaline pH, so in UTI treatment,
alkalinizing of urine is advisable.
• Excreted unchanged by glomerular filtration.
9
Pharmacokinetics

80. Adverse reactions to aminoglycosides are
• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade.
In Ototoxicity both auditory and vestibular divisions of the 8th
cranial nerve are affected.
Nephrotoxicity is based on dose and occurs first week of therapy.
Neomycin is the most nephrotoxic.
Neuromuscular blockade can lead to paralysis and respiratory
arrest.
• Contraindicated in renal and liver insufficiency.
0
Adverse Reactions

81. 1. Streptomycin – major indication is in the treatment of TB in
combination with Isoniazid, Ethambutol or Rifampicin.
Also used in combination with Penicillin G or Ampicillin in
treatment of enterococci, surgical infections and mixed UTIs.
Dosage: Available as 1g vial. In TB treatment is 0.5-2.0g I.M/day.
2. Kanamycin – Useful in treating urinary and biliary infections,
pre-operative bowel sterilization and TB.
Dosage: Mostly given by IM but orally for bowel sterilization. I.M
15mg/Kg body weight in two equally divided doses q12h.
Orally up to 8g daily in divided doses.
1
THERAPEUTIC USES

82. 3. Gentamicin
•The most vital member of the group and is used in
serious infections.
•Broad spectrum bactericidal antibiotic chemically like
streptomycin.
•Isolated from Micromonospora purpurae in 1963.
•Highly water soluble and stable in solution.
2

83. • Effective against Salmonella,shigella, H. Influenza, E.Coli,
Pseudomonas aeruginosa etc.
• Suitable for tx of UTIs. Alkaline urine increases efficacy of
gentamicin.
• Also used topically for skin infections and in eye infections.
• But main use is in Septicemia and Neonatal
Sepsis,Meningitis & other CNS infections.
• Main adverse reactions of Gentamicin are Vestibular damage
and Nephrotoxicity.
3

84. Gentamicin products and doses:
Injection: 40/80mg/ml:IM or IV 3-5mg/kg body daily in
divided doses.
Eye drops: 0.3% as sulphate single dose (minims) or multi-
dose: 1drop q2h, reduce frequency as infection subside.
Ear Drops: 0.3% as sulphate; 2-3 drops tid & nocte
Skin ointments/cream: Combined with antifungal &
corticosteroids for use in mixed skin infections.
4

85. 4. Neomycin Sulphate
• Because of toxicity, it is used orally or topically.
• Used for bowel sterilization prior to surgery or infections of eye,
ear, nose or skin.
Dosage: Oral: Neomycin Sulphate tabs 500mg: 1g hourly for 4hrs in
bowel sterilization
• Cream: Neomycin Sulphate 0.5% for bacterial skin infection; 2-4
times daily for not more than 7days.
• Eye drops/ointment: 0.5% Neomycin sulphate; 2-3 drops 2-4
times a day.
• Combined with antifungals and corticosteroids in ear and nose
drops and skin preparations.
5

86. •These are bacteriostatic antibiotics.
•The first drug in this group was Chlortetracycline from
soil organism Streptomyces aureofaciens followed by
Oxytetracycline produced from Streptomyces rimosus.
•Molecular modification of Chlortetracycline produced
Tetracycline.
6
2. TETRACYCLINES

87. •These three were the first broad spectrum bacteriostatic
antibiotics
•More studies of mutant strains of Streptomyces
aureofaciens led to discovery of demethyltetracyclines
such as Minocycline, Doxycycline known as ‘newer’
tetracyclines.
•They also have a broad antibacterial spectrum across
gram-ve and gram+ve bacteria.
7

88. •Tetracyclines enter bacterial cells by either passive
diffusion thru pores or active transport where they bind
specifically to 30S ribosomes thereby blocking binding
of tRNA to the mRNA-ribosome complex thus inhibiting
protein synthesis.
•They also chelate Mg, Mn and Ca. This chelation is also
responsible for their antibacterial action.
8
Mode of Action

89. •Bacterial Resistance
•An increasing number of pathogens like streptococci,
pneumococci and staphylococci has developed
resistance.
•Cross resistance develops within the group so they are
not very much useful
•Resistance is by efflux(main), enzymatic inactivation,
ribosomal protection, reduced permeability and
ribosome mutation.
9

90. • Tetracyclines usually given orally but IV or IM and local
application to eye & skin are also possible.
• Absorption from stomach and intestine is variable and
incomplete partially due to low solubility and partially due
to binding to Ca2+, Al3+,Fe3+ and Mg2+ in food or drugs in
the GIT.
• Thus absorption is depressed by food except Doxycycline.
• Plasma concentration shows a slow rise, a prolonged
plateau and a slow fall due to slow absorption, high
protein binding and enterohepatic circulation of the drugs.
0
PHARMACOKINETICS

91. •Doxycycline and Minocycline CSF levels are 20-25% of
plasma levels, other tetracyclines do not penetrate into
CSF.
•They are laid down in growing bones & teeth probably
because of their chelating with calcium.
•On IV administration, mostly excreted in urine by, less is
excreted in bile and enterohepatic circulation.
•Also excreted in milk during lactation period.
1

92. Therapeutic Uses
Clinical usefulness is due to their broad-spectrum activity.
The main indications are:
I. First-line choice for:
1. Acute chronic bronchitis
2. Non-specific urethritis
3. Primary atypical pneumonia.
4. Rickettsial infections (typhus).
5. Brucellosis-undulantfevercausedbybrucella
6. Pustular acne (pimples producing pus) (low dose but prolonged treatment).
7. Trachoma
8. Cholera
2

93. II. Second-line choice for:
1. Syphilis-priority in penicillin-allergic pts.
2. Anthrax
3. Meningococcal infections
• They are used in yellow fluorescence diagnostic tests for gastric and
colonic cancer due to their colour.
• Also used to determine rate of bone turnover due to their calcium
chelation.
• Orally, tetracyclines depress bacterial flora in colon.
• Vit B2 and folic acid deficiency can occur with prolonged use, so
multivitamins shd be given.
3

94. Contraindications
•Tetracyclines usually contraindicated during pregnancy,
lactation, in peptic ulcers and hepatic disease.
•Becuase of bacteriostaticity, they are not suitable for
patients with defective immunity.
Adverse Reactions
•Generally have low toxicity at normal dose levels so side
effects depends on dose and length of treatment.
4

95. • In about 10% of patients, anorexia, GIT upset, heartburn,
nausea and vomiting, flatulence, diarrhoea occurs.
• In 20-30% of patients-black hairy tongue, cheilosis (pain
sores in angles of mouth) anogenital pruritus, glossitis.
• Superinfections can occur especially if used at once with
immunosuppressive agents due to depression of normal
flora.
• Superinfection is a 2nd infection on top of an earlier one
caused by a different microbe of exogenous or endogenous
origin, that is resistant to tx being used against the 1st
infection
5

96. •Long continued I.V use may cause pulmonary
candidiasis.
•Hypersensitive reactions-skin rashes of all types,
dermatitis and anaphylactic shock may occur.
•Brown staining of teeth and nails and cause stunted
growth in children due to deposit in growing bones and
teeth.
•Nephrotoxicity and fatty degeneration of the liver.
6

97. •Dosage and preparations:
•Tetracycline, oxytet. and chlortet: 250mg tabs or caps:
250-500mg qid for 7days orally.
• Skin ointment:Tetracycline hydrochloride 3% for cuts and
bruises.
• Eye ointment:Tetracycline hydrochloride 1%.
•Doxycycline 100mg caps: 200mg first day, then 100mg
daily for 5-7 days p.o.
•Monocycline 50mg caps: 1caps daily for acne.
7

98. 3. CHLORAMPHENICOL
•Was isolated from a soil organism Streptomyces
venezuelae in 1947.
•It is a potent, potentially toxic and broad spectrum
bacteriostatic antibiotic
•Reserved for life-threatening infections caused by H.
Influenza or K. Pneumoniae and Typhoid fever.
Antibacterial spectrum
•Has a broad-spectrum of activity like tetracyclines.
•It is effective against many gram –ve and gram +ve
organisms and also exhibits activity against Rickettsiae
and Salmonelloses.
8

99. Mode of action
•Chloramphenicol binds to 50S subunit of the bacterial
70S ribosomes, inhibiting Peptidyltransferase enzyme, an
enzyme which catalyzes protein chain elongation hence
blocking protein synthesis.
•Also inhibits mammalian mitochondrial 70S ribosomes
that’s why it is toxic to man.
Pharmacokinetics
•Well absorbed from the intestines.
•Peak plasma levels reached after 2-5hrs and t1/2 is 1.5 –
3.0hrs.
9

100. •In neonates, peak plasma levels are reached after 6-12hrs
and T1/2 is 24-48hrs, because the immature low levels of
enzyme Glucuronyl transferase responsible for
chloramphenicol conjugation.
•Plasma levels through I.V and I.M administration are
same as from oral.
•Is 60% bound to plasma proteins and penetrates tissue
better than any other antibiotic.
•Enters eye, foetus, saliva, and sputum. CSF levels are 30-
50% of those of the plasma.
0
0

101. •Mostly metabolised in liver by either reduction or
conjugation to glucuronide
•Interacts with barbiturates which induce liver
microsomal enzymes and hence lower chloramphenicol
blood levels.
•Chloramphenicol itself depresses microsomal function
and may impair metabolism of Phenytoin and
Tolbutamide increasing their action.
•Chloramphenicol is mainly (90%) excreted in the urine
and 10% as unchanged.
•About 3% undergoes biliary excretion as conjugated
chloramphenicol and enters enterohepatic circulation.
0
1

102. THERAPEUTIC USES
•Due to serious bone marrow depression, chloramphenicol
is restricted to infections not treatable with other agents.
•Accepted indications are Enteric fever and H. influenzae
meningitis.
•Is also used topically for eye and infections on skin.
0
2

103. Adverse reactions
•Bone marrow depression due to inhibition of
mitochondrial protein synthesis and is dose related, it is
reversible on stoppage of therapy.
•Irreversible aplastic anaemia may occur and may be
fatal and unpredictable and is not dose related.
•Hypersensitivity reactions like skin rushes, fever,
angioedema, urticarial may occur.
•GIT disturbances such as nausea, vomiting, glossitis,
diarrhoea, etc.
•Neonates and prematures infants may develop ‘Grey
baby syndrome’ due to cyanosis leading to death within
4-5 days.
0
3

104. Dosage and preparations
•Caps 250mg for oral use 1.5-3.0g daily in divided doses
q6-8h.
•Chloramphenicol palmitate suspension 125mg/5ml
given as 50mg/kg/day in divided doses q6-8h.
•Chloramphenicol sodium succinate 1g vials for
parenteral use. 50mg/kg/day in divided doses.
•Chloramphenicol 3% skin ointment for cuts and bruises.
•Eye ointment: Chloramphenicol 1% for bacterial
conjuctivitis.
•Eye drops: Chloramphenicol 0.5% single dose or multi-
dose.
0
4

105. They include Erythromycin, Azithromycin Clarithromycin
etc.
Mode of Action
•Erythromycin is bound to the 50S subunit of bacterial
ribosome and blocks the execution of instructions coded
by mRNA.
•Macrolides don’t attach to human ribosomes.
•Erythromycin is bacteriostatic but in high concentrations
exerts bactericidal effect.
0
5
4. MACROLIDES

106. •Isolated from Streptomyces erythreus in 1952. Currently
its use diminished due to bacterial resistance.
•Mainly effective against gram+ve cocci, H. influenza,
rickettsiae, mycoplasma pneumonia etc.
Pharmacokinetics
•Erythromycin base is destroyed by gastric acid so it
exists as Erythromycin stearate or Erythromycin estolate
to resist gastric acid.
•These acid resistant salts are well absorbed and produce
good plasma levels.
0
6
1.Erythromycin

107. • The stearate has to be sugar coated to protect from gastric
acid.
• Peak plasma levels attained after 2-4hr
• Distributed to most of the tissues except the brain within
6hrs.
• The T1/2 is 1.5-3.0hrs.
• Only 20% is excreted by kidneys, the remainder is
metabolized by demethylation or appears in the bile.
0
7

108. THERAPEUTIC USES
•Alternative in penicillin-allergic patients or in penicillin
resistant gram +ve pathogens.
•Also useful in atypical pneumonia caused by
Mycoplasma pneumonia, syphilis or infections with
Haemophilus influenza.
•First line choice as alternative to penicillin in syphilis,
gonorrhea, pneumococcal infections.
•Second line choice in bronchitis, otitis media and
sinusitis and chronic prostatitis.
0
8

109. Adverse Reactions
One of the safer antibiotics.
•GIT disturbances and allergy are common adverse
reactions.
•With oral therapy-nausea, anorexia, diarrhoea, glossitis,
stomatitis.
•Superinfection with candida albicans over prolonged
therapy.
•Hypersensitivity reactions with fever, lymphocytosis,
headache, skin rashes are sometimes seen.
0
9

110. Resistance
•Resistance to Erythromycin is develops due to:
• The inability of the organism to take up Erythromycin.
• Decreased affinity of the 50S ribosomal subunit for
Erythromycin.
• Presence of a plasmid-associated erythromycin esterase.
•Clarithromycin and Azithromycin show cross-resistance
with Erythromycin.
1
0

111. Dosage
• Erythromycin stearate 250mg caps/tabs given orally,
250-500mg qid for 7days
• Erythromycin Ethyl Succinate 125mg/5ml suspension,
4-6mg/kg/4-6hourly.
• Erythromycin Lactobionate 1g/vial iv 300mg q6h.
1
1

112. 2. Clarithromycin
•Has a spectrum of antibacterial activity similar to that of
Erythromycin.
•It is also effective against Haemophilus influenza.
•It’s activity against intracellular pathogens such as
Chlamydia, Legionella is higher.
Dose
Oral: 250-500mg bid for 7–14 days.
Suspension: 125 – 250mg/5ml.I.V: 500mg bid.
Side effects: as for erythromycin.
1
2

113. 3. Azithromycin
•Is more effective against respiratory infections due to H
influenza and Mirabella catarrhalis.
•Is a preferred tx for urethritis caused by Chlamydia
trachomatis.
•Dose: 500mg o.d for 3 days orally.
•Side effects: same as for erythromycin.
1
3

114. •The bacterial cytoplasmic membrane serves as:
The site for cell wall synthesis.
An osmotic barrier.
An organ for selective intercellular
transport of essential cell nutrients.
•Members of this group are Polymyxins
1
4
INHIBITORS OF CELL MEMBRANE FUNCTION

115. •Is a generic name for six strongly basic cyclic
polypeptides (A, B, C, D, E and M) which differ in their
amino acid content.
•Obtained from various strains of Bacillus polymyxa.
•Only B and E are therapeutically useful.
Polymyxin B forms water soluble salts with mineral acids.
The usual preparation is Polymyxin B sulphate.
Antibacterial spectrum – Polymyxin B has a narrow
spectrum. it is active against gram –ve organisms.
Particularly active against Ps.Aeruginosa E.coli,
H.influenza, K.pneumonia, salmonella and shigella.
1
5
Polymyxins

116. Mode of action
• Polymyxin B is bactericidal.
• Binds to phospholipid of cytoplasmic membrane of
susceptible bacteria so impairing the bacterial cell membrane
function, causing leakage of small molecules (e.g phosphate,
nucleosides) from the bacteria.
THERAPEUTIC USES
• Second line choice agents in treatment of P. aerugenosa
infections particularly of UTI, external ear, conjuctiva,
Meninges and in septicaemia.
1
6

117. PHARMACOKINETICS
•Usually administered topically with no absorption from
site.
•In CSF infection given by intrathecal injection, can also
be given by IV.
•No absorption from GIT in adults, appreciable in
children.
•Primarily cleared by the kidneys.
1
7

118. Adverse reactions
•Minimal on topical application.
•Oral therapy may cause nausea, vomiting and diarrhoea.
•On IM administration-facial flushing, drug fever, skin
rushes, urticarial.
•The most serious adverse reaction after parenteral
administration is kidney damage.
1
8

119. Interactions
Interactswithcephalosporins,chloramphenicol,heparinand tetracyclinesso
shouldnotbeco-administered.
Preparations and dosage
• Polymyxin B sulphate is available for local, oral or systemic
administration.
• Frequently combined with other antibiotics like bacitracin and
neomycin and with hydrocortisone for topical use.
• Oral dose: 4.0mg/kg daily in 3-4 divided doses.
• IM/IV dose: 1.2-2.5mg/daily in 3-4 divided doses.
• Intrathecally: 5mg/day with a 0.5 mg/ml concentration.
• Topically: 0.25% cream or ointment.
1
9

120. Fluoroquinolones
Griseofulvin (covered under antibiotics)
Rifampicin etc (Covered under other topics)
2
0
(iv) INHIBITORS OF NUCLEIC ACID (DNA) SYNTHESIS AND
METABOLISM