Antibacterial agents ANTIBIOTICS

Fadhel A Alomar, Ph.D.

Dept. of Pharmacology, College of medicine
Imam Abdulrahman Bin Faisal University
 1-Cell wall synthesis Inhibitor antibiotics
❑ Beta lactams antibiotics:
▪ Beta lactams antibiotics are classified to …

A. Penicillins
B. Cephalosporins
C. Carbapenems
D. Monobactam
B-Beta lactams-Cephalosporins
 B-Beta lactams-Cephalosporins FYI

❑ The first cephalosporin antibiotic was isolated from the fungus

cephalosporium found in a sewage outfall off the Sardinian coast in 1948
by Giuseppe Brotzu; italian pharmacologist)

❑ He noticed that this fungus produced three distinct antibiotic

cephalosporin (P, N & C)
❑ They are broad-spectrum antibiotics & have activity against a wide variety
of Gram+ve and Gram+ve bacteria e.g Salmonella typhi (typhoid fever)

❑ Chemical modifications of cephalosporin C (weak antibiotic activity) have

produced a variety of clinically useful antibiotic drugs
 B-Beta lactams-Cephalosporins
❑ Clinical indications

1. Used to treat upper respiratory tract infection (URTI) e.g. Cefaclor

2. Used to treat urinary tract infection (UTI) e.g. cefuroxime

3. Used to treat septicemia and meningitis e.g. ceftazidime

4. Thy are also used as alternative to penicillin allergic patients

❑ Adverse effects

1. Hypersensitivity reactions, but less compared to penicillins

2. Clostridium difficile-associated diarrhea (CDAD)

3. Nephrotoxicity BUT less than aminoglycoside

 B-Beta lactams-Cephalosporins
❑ Pharmacokinetics

❖ They can be given orally or parenterally

❖ Because of many of cephalosporins have poor absorption from GIT,
the majority of them must be given parenterally IV or I
o IM administration is painful

❖ Cephalosporins are widely distributed in the body, BUT

❖ The majority of cephalosporins reach poor in cerebrospinal fluid (CSF)
o Cefuroxime, cefotaxime and ceftriaxone easily cross BBB

❖ Almost all of them are execrated by the kidney, THUS

o Dose reduction is necessary in patients with renal impairment
 B-Beta lactams-Cephalosporins
❑ Mechanism of action (MOA)

❖ They are bactericidal & they have similar MOA to those of the β-lactam

penicillins , BUT

o Cephalosporins are less susceptible to β-lactamase compared to

β-lactam penicillin antibiotics (advantage)

❖ They irreversibly bind to & inhibit transpeptidase enzyme (PBP) that

crosslinks the peptide side chains of peptidoglycan strands (a polymer

NAM-NAG)

❖ Which in the end results in osmotic lysis and death of the bacteria
 B-Beta lactams-Cephalosporins
❑ Are classified into five generations based on their spectrum of activities

❑ 1st generation cephalosporins

❖ Cephalexin (orally) & Cefazolin (parenterally)

o Used as surgical prophylactic antibiotics
o Are active against Gram-positive (staphylococci & streptococci)
BUT not MRSA
o They have modest activity against Gram-negative bacteria
o They have limited activity against Moraxella catarrhalis

o M. catarrhalis are frequently present in the sputum of patients with

chronic obstructive pulmonary disease (COPD) and many of them
produce beta-lactamases

o M. catarrhalis are susceptible to fluoroquinolones, most second- &

third-generation cephalosporins & amoxicillin-clavulanate
 B-Beta lactams-Cephalosporins
❑ 2nd generation cephalosporins

❖ Cefaclor (orally) & Cefuroxime (orally; & parenterally)

o They are less active than 1st generation agents against
Gram-positive bacteria
o They have more activity against Gram-negative bacteria (H.
influenzae) than 1st generation
o Cefuroxime can cross BBB
o Medications that reduce stomach acid such as ranitidine &
PPI may decrease the absorption of cefurexime
 B-Beta lactams-Cephalosporins
❑ 3rd generation cephalosporins
❖ Cefixime (orally) & ceftriaxone, cefotazidime (parenterally)
o They have a higher activity against Gram -ve than 1st & 2nd
generation
• They are active against P. aeruginosa

o They are less active than 1st generation against G+ve

o Ceftriaxone & cefotazidime are DOC to treat meningitis due

to H. influenzae, Sterp. pneumonia or N. meningitidis

o Ceftriaxone is the DOC to treat uncomplicated gonorrhea

infection (250 mg intramuscularly; single dose)
 B-Beta lactams-Cephalosporins
❑ 4th generation cephalosporins
❖ Cefepime (parenterally)

o Has a greater resistance to β-lactamases than the 3rd

generation cephalosporins

o Has a similar activity against G +ve bacteria as 1st

generation cephalosporins & greater activity against G -ve

bacteria than the 2nd & 3rd generation cephalosporin

o It is useful in empirical treatment of hospitalized patient

 B-Beta lactams-Cephalosporins
❑ 5th generation cephalosporins
❖ Ceftaroline (parenterally) – FDA approved 2010

o It has an excellent active against a wide range of Gram-

positive and Gram-negative bacteria infection

o Has activity similar to 4th generation plus methicillin-

resistant-staphylococcus-aureus (MRSA)
➢ The only β-lactam antibiotics that are effective against
MRSA are 5th generation cephalosporins

➢ 1st, 2nd, 3rd and 4th are not effective against MRSA
 C-Beta lactams-Carbapenems
❑ Imipenem and Meropenem

❖ They were originally developed from the carbapenem thienamycin, a

naturally product of Streptomyces cattleya (Gram +ve cooci)

❖ Highly resistant to most β-lactamases

❖ Effective against G +ve & G -ve including Pseudomonas aeruginosa

❖ Imipenem
o Used in combination with cilastatin (a dipeptidase inhibitor) to
inhibit the degradation of imipenem by a renal tubular dipeptidase
(also known as dehydropeptidase) enzyme
❖ Meropenem
o Dose not required co-administration with cilastatin
 C-Beta lactams-Carbapenems
❑ Imipenem and Meropenem

❖ Therapeutic uses; they are used to treat…

o UTI, intra-abdominal infection & lower respiratory tract

infection (particularly, infection with multi-drug resistant)

o Mixed aerobic & anaerobic infections

❖ Adverse effects

o N/V (20%) & hypersensitivity

o Seizures (3 times more common with imipenem compared to

meropenem)
 D-Beta lactams-Monobactams
❑ Aztreonam (IM & IV)

❖ Aztreonam is resistant to β-lactamases elaborated by most

gram-negative bacteria

❖ It has narrow spectrum antibiotic & effective only against

aerobic G-ve bacteria such as P. aeruginosa & H. influenzae

❖ No activity against Gram-positive or anaerobic bacteria

❖ Hepatotoxicity, especially in infants and young children, may

occur.
 D-Beta lactams-Monobactams
❑ Aztreonam (IM & IV)

❖ Therapeutic uses
o It is used IM or IV to treat various of Gram -ve bacteria infection
o It is also used as alternative to treat infection in patients allergic to
penicillins (there is no cross allergenicity with penicillins &
cephalosporins)

❖ Adverse effects
o N/V and skin rash
o Hepatotoxicity, especially in infants and young children, may occur.
1-Cell wall synthesis Inhibitors-Miscellaneous
 1-Cell wall synthesis Inhibitors-Vancomycin FYI
❑ it is a large glycopeptide compound produced by Strep. orientalis
 1-Cell wall synthesis Inhibitors-Vancomycin
❑ Clinical indications

1. It is a bactericidal & very active against a broad spectrum of Gram

positive bacteria

2. Used parenterally to treat sepsis or endocarditis caused by MRSA

3. It is used orally (not absorbed ) as 2nd line to treat clostridium difficile-

associated diarrhea (CDAD)

4. Inhaled vancomycin has also been used (off-label), via nebulizer, to

treat a various infections of the upper & lower respiratory tract infection
 1-Cell wall synthesis Inhibitors-Vancomycin
❑ Pharmacokinetics
❖ It is not absorbed orally (used orally to treat CDAD)
❖ Eliminated primarily via kidneys (~90% unchanged in urine within 24 h)
❖ Distributed into all tissue EXCEPT brain

❑ M.O.A
❖ Inhibits polymerization of cell wall precursors (NAM-NAG) by binding
with high affinity to D-alanyl-D-alanine terminus of the cell wall precursor
units → inhibits the addition of NAM-NAG (peptidoglycan) to the NAM-
NAG-chain (inhibiting transglycosylation ) & thus inhibits the synthesis
of the cell wall in sensitive bacteria → bacteria death
o It dose not inhibits cross-linking b/c it does not inhibits
transpeptidase enzyme
 1-Cell wall synthesis Inhibitors

Transglycosylation
Cross-linking
Inhibit
transpeptidase

Inhibits polymerization

Murein
monomers

• NAM = N-acetylmuramic acid; NAG = N-acetylglucosamine ; BP = bactoprenol (Lipid)

• PEP = phosphoenolpyruvate ; BP-PP = bactoprenol pyrophosphate
 1-Cell wall synthesis Inhibitors-Vancomycin
❑ Adverse effects
1. Ototoxicity (dose-dependent, >30 μg/ml in plasma)
2. Nephrotoxicity (increased with aminoglycosides) D-D- interaction
❖ Monitoring of serum vancomycin level reduces side effects
3. Local pain, thrombophlebitis & vein inflammation (IV vancormycin)

❑ Problem
❖ Emergence of vancomycin-resistant Staphylococcus aureus (VRSA)
and vancomycin-resistant Enterococcus (VRE)
❖ Resistance to vancomycin is the result of alteration of the D-alanyl-D-
alanine target to D-alanyl-D-lactate or D-alanyl D-serine which
preventing binding of vancomicin
❖ Linezolid & Streptogramin is effective to treat VRE & VRSA respectively
 1-Cell wall synthesis Inhibitors-Fosfomycin
❑ Clinical indications
❖ It has a broad-spectrum activity against both G+ve & –ve bacteria
❖ It is available as an intravenous injection & as a powder that is
dissolved in water to be taken orally
❖ It is used to treat uncomplicated UTI- e.g E. coli (a single 3-g dose) &
complicated UTI (3 g every other day for three doses

❑ Mechanism of action (is a bactericidal antibiotic agent)

❖ It covalently binds to & inhibits the enzyme MurA → inhibition of the
first step of cell wall biosynthesis; the formation of the peptidoglycan
precursors → triggers cell wall break down & bacteria death

❑ Adverse effects
❖ Painful and difficult urination
 1-Cell wall synthesis Inhibitors-Bacitracin
❑ Clinical indications
❖ Has bactericidal activity against both Gram +ve and –ve organism
❖ Highly toxic if used internally (orally/IV), thus it is used topically only
❖ Ophthelmic & dermatological ointment

❑ Mechanism of action
❖ Inhibits bactoprenol dephosphorylation, a molecule that carries the
building-blocks of the peptidoglycan (NAM-ANG) bacterial cell wall
outside of the cytoplasm for construction causing the formation
of bacteria with weak cell wall which then undergoes lysis and death

❑ Adverse effects
❖ Hypersensitivity (topical application) & serious nephrotoxicity (IV)
1-Cell wall synthesis Inhibitors-Summary

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