Transcript Cell Wall Inhibitor Penicillins

Principle of Antimicrobial &
Cell Wall inhibitors
General Pharmacology
M212
Dr. Laila M. Matalqah
Ph.D. Pharmacology
Mechanisms of Action of antimicrobials
 Inhibition of bacterial cell wall synthesis or activation of




enzymes that disrupt cell walls (Penicillin, Cephalosporins,
Vancomycin)
Inhibition of protein synthesis (tetracyclines, clindamycin,
aminoglycosides)
Inhibition of microbial cell membranes function (antifungals)
Inhibition of organism reproduction by interfering nucleic
acid synthesis (fluoroquinolones, -antivirals)
Inhibition of cell metabolism and growth (sulfonamides)
Sites Of Antimicrobial Actions
Drug Selection
 Best if based on culture and sensitivity (the organism’s





identity)
organism’s susceptibility to a particular agent, MIC:
minimum inhibitory concentration—lowest concentration of
a drug that prevents visible growth of microorganisms
site of the infection: Drug’s ability to penetrate infected
tissues (prostate, CNS)
Drug’s toxicity and the risk-to-benefit ratio
Drug costs
patient factors
Drug Selection: site of the infection
The lipid solubility of a drug:
 For example, lipid-soluble drugs, such as chloramphenicol and
metronidazole, have significant penetration into the CNS.
 β-lactam antibiotics, such as penicillin, are ionized at
physiologic pH and have low solubility in lipids
1.

However, In infections such as meningitis the barrier does not
function as effectively, and local permeability is increased.
Some β-lactam antibiotics can then enter the CSF in
therapeutic amounts
other factors: Molecular weight of the drug, Protein
binding of the drug
Drug Selection: patients factors
1.
2.
3.
4.
5.
6.
Immune system : Alcoholism, diabetes, AIDS,
malnutrition, autoimmune diseases, pregnancy
Renal dysfunction: (for example, aminoglycosides? C/I)
Hepatic dysfunction: Antibiotics that are concentrated
or eliminated by the liver (for example, erythromycin and
tetracycline
Age : Young children should not be treated with
tetracyclines or quinolones, which affect bone growth.
Pregnancy
Lactation:
Antibiotic Combination Therapy
 Used when infection is caused by multiple microorganisms
 Serious infections in which a combination is synergistic
(aminoglycoside and antipseudomonal penicillin)
 β-lactam antibiotics are synergistic with the aminoglycosides.??
How?
 Likely emergence of drug resistant organisms
 In those who are immunosuppressed
Chemotherapeutic Spectra
A. Narrow-spectrum antibiotics: acting only on a single or a
limited group of microorganisms e.g., Isoniazid is active only
against mycobacteria
B. Extended-spectrum antibiotics: antibiotics that are effective
against gram-positive organisms and also against a significant
number of gram-negative bacteria e.g. Ampicillin
C. Broad-spectrum antibiotics: affect a wide variety of microbial
species and can alter the nature of the normal bacterial flora and
precipitate a superinfection of an organism such as Clostridium
difficile ex., Tetracycline
Antimicrobial characteristics
 Bacteriostatic: Inhibit the growth and replication of bacteria
thus limiting the spread of infection until the body’s immune
system attacks, immobilizes, and eliminates the pathogen.
 Bactericidal: kill bacteria at drug serum levels achievable in the
patient
 Minimum inhibitory concentration (MIC):the lowest
concentration of antibiotic that inhibits bacterial growth
 Minimum bactericidal concentration (MBC) : the
minimum concentration of antibiotic that kills the bacteria
Determinants of Rational Dosing
 Concentration-dependent killing:
 antimicrobial show a significant increase in the rate of bacterial
killing as the concentration of antibiotic increases from 4 to 64
fold the MIC of the drug for the infecting organism, e.g.,
aminoglycosides,
 Time-dependent killing:
 The effect is directly proportional to the percentage of TIME the
concentration of the antibiotic at the site of infection is ABOVE the MIC. ,
e.g., β-lactams AND macrolides.
 Postantibiotic effect:
 is a persistent suppression of microbial growth that occurs after
levels of antibiotic have fallen below the MIC
“Time Dependant vs. Conc dependent”
Mechanisms of Resistance
 Enzymatic inactivation: Generating enzymes that
inactivate the antibiotic (beta lactamase) :
1) β-lactamases (“penicillinases”) that hydrolytically inactivate the β-lactam
ring of penicillins, cephalosporins, and related drugs;
2) acetyltransferases: inactivating chloramphenicol or aminoglycosides;
3) esterases that hydrolyze macrolides
 Changing structure of target site (beta lactams –
change in penicillin-binding protein)
 Preventing cellular accumulation of antibiotics by
altering outer membrane proteins or using efflux pumps
 Gram negatives possess an outer membrane and cytoplasmic membrane
preventing passage of abx through porins
 Changing the metabolic pathway that is being blocked
Cell Wall Inhibitors
 β-Lactam Antibiotics
 Penicillins
 Cephalosporins
 Carbapenems
 Monobactams
 Other Antibiotics
 Vancomycin
 Daptomycin
 β-Lactamase Inhibitors
Clavulanic acid, Sulbactam, Tazobactam
β-Lactam Antibiotics : Contain a beta-lactam
ring
β-lactam ring
β-Lactam Antibiotics: Penicillins
 Mechanism of action
 Inhibit the last step of bacterial cell wall synthesis
(transpeptidation or cross-linkage), THEN Cell lysis
 Most effective when bacterial cells are dividing
 Note: they are inactive against organisms lack cell wall
structure, such as mycobacteria, protozoa, fungi, and viruses.
1. Inactivate penicillin-binding proteins (PBPs) ( bacterial
enzymes involved in the synthesis of the cell wall)
2. Inhibition of transpeptidase: Some PBPs catalyze
formation of the cross-linkages between peptidoglycan chains
 Production of autolysins:degradative enzymes
Penicillins
 Range from very narrow spectrum to very broad spectrum
depend on their ability to cross the bacterial peptidoglycan cell
wall to reach the PBPs
 Factors : the size, charge, and hydrophobicity of the particular
β-lactam antibiotic.
 Gram-negative micro organisms have an outer lipopolysaccharide
membrane (envelope) acts s barrier to the water-soluble penicillins
but some have porins to permit transmembrane entry.
 The β-lactams are BACTERICIDAL
 The β-lactams are “time-dependent” killers
Penicillins Classification
1.
Natural penicillins
 Penicillin G (I.V) , Penicillin V (oral)
2.
3.
Extended-spectrum penicillins (Aminopenicillins)
 Ampicillin, Amoxicillin
Antistaphylococcal penicillins
 Oxacillin, Dicloxacillin, Nafcillin
4. Antipseudomonal penicillins:
 Ticarcillin, Piperacillin,
1. Natural penicillins
 obtained from fermentations of the mold Penicillium
chrysogenum.
 Spectrum: gram-positive and gram-negative cocci and grampositive bacilli
 Penicillins are susceptible to inactivation by β-lactamases
(penicillinases).
 Penicillin G: Available IM, IV
 Penicillin V: Orally
is more acid-stable
 Long-acting forms
 Procaine PenG (12 hrs)
 Benzathine Pen (4 weeks)
2. Extended-spectrum penicillins
(Aminopenicillins)
 Ampicillin and Amoxicillin: I.V and Orally
 Spectrum: same like Penicillin G but more against gram-
negative bacilli.
 Listeria monocytogenes
 Enterococcus
 Dental Prophylaxis .
 Integral in H. pylori
 Amoxicillin better tolerated orally
3. Antistaphylococcal penicillins
 Nafcillin, Oxacillin, And Dicloxacillin are
penicillinase-resistant penicillins.
 Their use is restricted to the treatment of infections caused
by penicillinase-producing staphylococci, including
methicillin sensitive S. aureus (MSSA)

Methicillin withdrawn from market because of
interstitial nephritis
4. Antipseudomonal penicillins
 Carbenicillin
 Ticarcillin
 Piperacillin
 activit against P. Aeruginosa and gram-negative bacilli
 Formulation of ticarcillin or piperacillin with clavulanic acid or
tazobactam, respectively, extends the antimicrobial spectrum of these
antibiotics to include penicillinase-producing organisms
PHARMACOKINETICS (penicillins)
 Absorption: decrease by food in the stomach, must be administered 30
min before meals or 2 to 3 hours postprandial
 Route of administration:
 Penicillin V, amoxicillin, and amoxicillin combined with clavulanic acid are
oral preparations
 Ticarcillin, piperacillin, and the combinations of ampicillin with sulbactam,
ticarcillin with clavulanic acid, and piperacillin with tazobactam, must be
administered intravenously (IV) or intramuscularly (IM).
 Depot forms: Procaine penicillin G and benzathine penicillin G are
administered IM and serve as depot forms
PHARMACOKINETICS (penicillins)
 Distribution:
 Cross Placenta (not teratogenic)
 Bone, CSF (inflammation)
 Prostate (insufficient)
 Clearance :
 Renal tubular secretion & G.F.
 Impaired renal function, dose adjustment?
 Probenecid inhibits the secretion of penicillins by competing for active tubular
secretion via the organic acid transporter and, thus, can increase blood levels
Adverse reactions: Penicillins
 Hypersensitivity; penicilloic acid (5%) varies from rash,
angioedema to anaphylactic shock.
 Diarrhea: for extended spectrum, pseudomembranous colitis
from clostridium difficiles
 Nephritis: methicillin \ Withdrawn from market
 Neurotoxicity: seizures if injected intrathecally
 Hematologic toxicities; ex. Piperillicin decreased
coagulation
β-Lactamase Inhibitors
 Hydrolysis of the β-lactam ring, by β-lactamase destroys the
antimicrobial activity of a β-lactam antibiotic
 β-Lactamase inhibitors, do not have significant antibacterial
activity, they inactivate β-lactamases, so, protecting
antibiotics
 Formulation with a β-lactamase inhibitor, such as
clavulanic acid or sulbactam, protects amoxicillin or ampicillin,
respectively, from enzymatic hydrolysis and extends their
antimicrobial spectrum.
 For example, without the β-lactamase inhibitor, MSSA is
resistant to ampicillin and amoxicillin
Beta lactamase inhibition combinations:
 Augmentin® (amoxicillin/clavulanate), Orall
 Unasyn® (ampicillin/sulbactam) , IV
 Timentin® (ticaricillin/clavulanate), IV
Resistant to penicillin
 Beta lactamase activity (G+ve and G-ve)
 Decreased permeability of drugs (efflux mechanism in
Kelbsiella pneumonia )
 Altered PBP (ex. MRSA)
THANK YOU