CHAPTER: 2

ANTIBACTERIAL
TOPICS:
1. CELL WALL SYNTHESIS INHIBITOR
2. PROTEIN SYNTHESIS INHIBITOR
3. NUCLEIC ACID SYNTHESIS INHIBITOR
4. FOLATE ANTAGONIST
5. URINARY TRACT ANTISEPTICS
6. ANTIMYCOBACTERIAL DRUGS
 TOPIC: 1
CELL WALL INHIBITORS
 Some antimicrobial drugs selectively interfere with synthesis of the
bacterial cell wall
 The cell wall is composed of a polymer called peptidoglycan that consists
of glycan units joined to each other by peptide cross-links
 To be effective, inhibitors of cell wall synthesis require actively
proliferating microorganisms. They have little or no effect on bacteria that
are not growing and dividing
 The most important members of this group of drugs are the β-lactam
antibiotics, vancomycin, and daptomycin
Cell Wall Inhibitors
 PENICILLINS
• The Penicillin's are among the most widely effective and
the least toxic drugs known, but increased resistance has
limited their use
• Members of this family differ from one another in the side
chain substituent attached to the 6-aminopenicillanic acid
residue
• The nature of this side chain affects the antimicrobial
spectrum, stability to stomach acid, cross hypersensitivity,
and susceptibility to bacterial degradative enzymes
 PENICILLINS INCLUDES

 Amoxicillin
 Ampicillin
 Penicillin G
 Penicillin V
 MECHANISM OF ACTION

 The Penicillin’s interfere with the last step of bacterial cell wall
synthesis, resulting in exposure of the osmotically less stable
membrane
 Cell lysis then occur, either through osmotic pressure or through the
activation of autolysins
 These drugs are bactericidal and work in a time-dependent fashion
 Penicillin’s are only effective against rapidly growing organisms that
synthesize a peptidoglycan cell wall
 They are inactive against organisms devoid of this structure, such as
mycobacteria, protozoa, fungi, and viruses.
 Antibacterial spectrum

• The antibacterial spectrum of the various penicillins is determined, by their ability to

cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic
space.
• Gram-positive microorganisms have cell walls that are easily traverse by penicillins,
and they are susceptible to these drugs.
• Gram-negative microorganisms have an outer lipopolysaccharide membrane
surrounding the cell wall that presents a barrier to the water-soluble penicillins.
However,gram-negative bacteria have proteins inserted in the lipopolysaccharide
layer that act as water-filled channels (called porins) to permit transmembrane
entry.
1. Natural penicillins: penicillin G and penicillinV are obtained from fermentations
of the fungus. Semisynthetic penicillins, such as amoxicillin and ampicillin are
created by chemically.
• Penicillin remains the drug of choice for the treatment of gas gangrene and
syphilis.
• Penicillin V is more acid stable than penicillin G and is often employed orally
in the treatment of infections.
• Penicillins are susceptible to inactivation by β-lactamases.
2. Antistaphylococcal penicillins: Methicillin , nafcillin, oxacillin and
dicloxacillin are β-lactamase-resistant penicillins.
• Their use is restricted to the treatment of infections causedby penicillinase-
producing staphylococci.
• MRSA is currently a source of serious community and nosocomial (hospital-
acquired) infections and is resistant to most commercially available β-lactam
antibiotics.
 3. Extended-spectrum penicillins:

• Ampicillin and amoxicillin are more effective against gram negative bacilli.
• Ampicillin is the drug of choice for the gram-positive bacillus Listeria
monocytogenes.
• These extended-spectrum agents are also widely used in the treatment of
respiratory infections.
• Inactivated by plasmid mediated-pencillinase.
• Formulation with a β-lactamase inhibitor, such as clavulanic acid protects
amoxicillin from enzymatic hydrolysis and extends their antimicrobial
spectra.
4. Antipseudomonal penicillins:

• Piperacillin and ticarcillin ,because of their activity against

Pseudomonas aeruginosa
• Piperacillin is the most potent of these antibiotics.
• These agents are available in parenteral formulations only.
They are effective against many gram-negative bacilli.
• Activity against respiratory infections.
• Formulation of piperacillin with tazobactam, extends its
antimicrobial spectrum

• Therapeutic Effects of Pencillins

• Use in Gonorrhea ,Syphillis, Pneumococcal pneumonia
 Resistance

• Natural resistance to the penicillins occurs in organisms that either lack

a peptidoglycan cell wall or have cell walls that are impermeable to the drugs.
• Acquired resistance to the penicillins occurs by plasmid-mediated
β-lactamases.

1. β-Lactamase activity: (major cause)

• This family of enzymes hydrolyzes the β-lactam ring, which results in loss of
bactericidal activity. β-Lactamases are constitutive, produced by the bacterial
chromosome.
2. Decreased permeability to the drug:
• Decreased penetration of the antibiotic through the outer cell membrane of
the bacteria prevents the drug from reaching the target PBPs.
3 . Altered PBPs:
• Modified PBPs have a lower affinity for β-lactam antibiotics, requiring
clinically unattainable concentrations of the drug to effect inhibition of
bacterial growth.
• Pharmacokinetics
• The route of administration is determined by the stability of the drug to
gastric acid and by the severity of the infection.
• Drugs should be taken on an empty stomach.
• All the penicillins cross the placental barrier, but none have been shown to
have teratogenic effects.
• The penicillins are also excreted in breast milk.

Adverse Effects
 Hypersensitivity
 Diarrhea
 Nephritis
 Neurotoxicity
 Hematologic toxicities
 CEPHALOSPORINS

• The cephalosporins are bactericidal β-lactam

antibiotics.
• They are derived from Acremonium (fungus).
• They are produced semisynthetically by the
chemical attachment of side chains to 7-
aminocephalosporanic acid.
• Cephalosporins have been classified as first, second,
third, fourth generation and advanced generation.
Classification
 Antibacterial Spectrum
• 1. First generation: The first-generation cephalosporins
act as penicillin G substitutes. They have high activity
against Gram +ve (Staphylococcus epidermidis)
compared to Gram –ve. They also have activity against
E. coli, and Klebsiella pneumoniae. Cefazolin is given
IM (can cause mild pain) and IV. It has longer duration
of action.
• 2. Second generation: These have greater activity
against Gram-negative organisms: H. influenzae,
Enterobacter aerogenes, and Neisseria species, whereas
activity against gram-positive organisms is weaker.
Cefuroxime has longer half life and is used for
community-acquired bronchitis and
immunocompromised patients. It has resistance against
B. fragilis (Colon).
• 3. Third generation: These have enhanced activity
against gram-negative bacilli including β-lactamase
producing strains of H. influenzae. Ceftriazone and
Cefotaxime are agents of choice in the treatment of
meningitis. (High levels in blood and CSF). Ceftazidime
has activity against P. aeruginosa. Third generation
cephalosporins must be used with caution, as they are
associated with the spread of antimicrobial resistance.

• 4. Fourth generation: Cefepime must be administered

parenterally. It is highly resistant against β-lactamase.
Cefepime is active against streptococci and staphylococci
(but only those that are methicillin susceptible). Cefepime
is also effective against aerobic gram-negative organisms,
such as Enterobacter species, E. coli, P. aeruginosa.

• 5. Fifth generation: Ceftaroline is active against MRSA

• B. Pharmacokinetics

• 1. Administration: Many of the cephalosporins must be

administered IV or IM because of their poor oral absorption.
Except Cephalexin, Cefdinir, Cefixime.

• 2. Elimination: Elimination occurs through tubular

secretion and glomerular filtration. An exception is
ceftriaxone which is excreted through the bile into the feces
and is employed in patients with renal insufficiency.
• C. Adverse effects
• 1. Allergic manifestations: Patients who have had an
anaphylactic response, Stevens-Johnson syndrome, or toxic
epidermal necrolysis to penicillins should not receive
cephalosporins. The cephalosporins should be avoided or
used with caution in individuals who are allergic to
penicillins. The rate of highest allergic cross sensitivity is
between penicillin and first generation cephalosporins.
 OTHER β-LACTAM
ANTIBIOTICS:

A. Carbapenems:
 CLASSIFICATION:
• Imipenem, meropenem , doripenem, and ertapenem are
the drugs of this group currently available.
 ANTIBACTERIAL SPECTRUM:
• Imipenem resists hydrolysis by most β-lactamases.
• This drug plays a role in empiric therapy because it is active
against β-lactamase–producing gram-positive and gram-
negative organisms, anaerobes, and P. aeruginosa.
• Meropenem and doripenem have antibacterial activity similar
to that of imipenem.
β-LACTAMASE INHIBITORS
Hydrolysis of the β-lactam ring, either by
enzymatic cleavage with a β-lactamase or
by acid, destroys the antimicrobial activity of
a β-lactam antibiotic.
β-Lactamase inhibitors, such as clavulanic
acid, sulbactam and tazobactam ,contain a
β-lactam ring but, by themselves, do not
have significant antibacterial activity or
cause any significant adverse effects.
Instead, they bind to and inactivate β-
lactamases, thereby protecting the
antibiotics that are normally substrates for
these enzymes.
 VANCOMYCIN DAPTOMYCIN TELAVANCIN
Mechanism of Inhibits synthesis of Causes rapid Inhibits bacterial
Action bacterial cell wall depolarization of cell wall synthesis;
phospholipids as the disrupts cell
well as cell membrane, membrane
peptidoglycan inhibits intracellular
polymerization synthesis of DNA,
RNA, and protein
Route IV IV IV
Pharmacokinetics Renal elimination Renal elimination Renal elimination
Normal half-life: 6– Normal half-life: 7– Normal half-life: 7–
10 hours 8 hours 9 hours

Adverse Effects: Fever, chills. Myalgias. Taste disturbances,

Phlebitis. elevated hepatic foamy urine, QTc
transaminases and Prolongation.
creatine
phosphokinases
nephrotoxicity not recommended
in pregnancy
Sulfonamides (bacteriostatic)
Mechanism of Action:
Sulfonamides are structural analogs of PABA that
competitively inhibit dihydropteroate synthase. They inhibit
growth by reversibly blocking folic acid synthesis.
Pharmacokinetics:
• Cross blood brain barrier and placenta.
• Therapeutic range lies between 40–100 mcg/mL of
blood.
• Blood levels generally peak 2–6 hours after oral
administration
Clinical Uses:
1. Oral Absorbable Agents:
Sulfisoxazole and sulfamethoxazole are short- to medium-
acting agents that are used to treat UTI, respiratory tract
infections, sinusitis, otitis media, and dysentery.
Sulfadiazine in combination with pyrimethamine is first-line
therapy for treatment of acute toxoplasmosis.
Oral Non-absorbable Agents:
Sulfasalazine is widely used in ulcerative colitis, enteritis, and
other inflammatory bowel disease.
Topical Agents:
Sodium sulfacetamide ophthalmic solution or ointment is effective
treatment for bacterial conjunctivitis.
Drug Interactions:
Sulfonamides taken near the end of pregnancy increase the risk of
kernicterus in newborns
Adverse Drug reactions:
fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria
Resistance:
(1) Cause overproduction of PABA,
(2) Cause production of a folic acid synthesizing enzyme that has
low affinity for sulfonamides
(3) Impair permeability to the sulfonamide.
Trimethoprim (bactericidal)
Mechanism of Action:
Dihydrofolic acid reductases convert dihydrofolic acid to
tetrahydrofolic acid, a stage leading to the synthesis of purines and
ultimately to DNA. Trimethoprim inhibits bacterial dihydrofolic
acid reductase.
Clinical Uses:
• Oral trimethoprim is used for UTI and many community
acquired organisms
• It is the agent of choice for moderately severe to severe
pneumocystis pneumonia.
• It has more antibacterial activity in prostatic and vaginal fluids.
Adverse Drug Reactions:
Megaloblastic anemia, leukopenia, and granulocytopenia. This can
be reversed by the simultaneous administration of folinic acid.
Resistance:
Altered dihydrofolate reductase that has a lower affinity for
trimethoprim
Cotrimoxazole
• The combination of trimethoprim with sulfamethoxazole, called
cotrimoxazole (synergistic activity)
Mechanism of Action:
• Sulfamethoxazole inhibits the incorporation of PABA into
dihydrofolic acid precursors, and trimethoprim prevents
reduction of dihydrofolate to tetrahydrofolate.
Clinical Uses:
Chronic UTIs and respiratory tract infections, as well as
toxoplasmosis, and ampicillin or chloramphenicol-resistant
salmonella infections. Cotrimoxazole has a broader spectrum of
antibacterial action. It also have activity against H. influenza,
MRSA, community-acquired skin and soft tissue infections.
Adverse Drug Reactions:
Dermatologic reactions, Glossitis, Megaloblastic anemia,
leukopenia, thrombocytopenia