Penicillin
Derivatives of 6-aminopenicillanic acid
Contains a beta-lactam ring structure
Alexander Fleming
first to suggest that a Penicillium mold (now known as Penicillium chrysogenum) must secrete an antibacterial substance
first to concentrate the active substance involved, which he named penicillin, in 1928
Beta-Lactam ring
site of hydrolysis by bacterial penicillinase or by acid
R group
determines drug’s stability to enzymatic or acidic hydrolysis and affects antibacterial spectrum
Thiazolidine ring
Beta-Lactam Compounds:
contains sulfur
gastric acid
Vary in resistance to ___
oral
Vary in their ___ bioavailability
Polar compounds
Not metabolized extensively
Glomerular filtration
Tubular excretion
Inhibited by Probenecid
Excreted unchanged in urine via ___
when meninges are inflamed
When does it cross the BBB?
Amoxicillin
Must be given on an empty stomach; except ___
Ampicillin and Nafcillin
Partly excreted in bile
30 min to 1 h
Plasma half-life
Procaine and Benzathine Penicillin G
Given intramuscularly
Long half-lives
released slowly
Cross blood-brain barrier when meninges are inflamed
Bactericidal drugs
Binding of the drug to specific receptors (penicillin-binding proteins [PBPs])
Inhibit cell wall synthesis by:
___ located in the bacterial cytoplasmic membrane
Inhibition of Transpeptidation
Inhibit cell wall synthesis by:
inhibition of reaction that cross-links the linear peptidoglycan chain constituents of the cell wall
Activation of autolytic enzymes
Inhibit cell wall synthesis by:
___ that cause lesions in the bacterial cell wall
Enzymatic hydrolysis of the beta-lactam ring
results in the lost of antibacterial activity
Beta-lactamases: Penicillinases
Hydrolysis of the β-lactam ring
Formed by most staphylococci and gram (-) organisms
Major mechanism for bacterial resistance
Clavulanic acid
Sulbactam
Tazobactam
Inhibitors of this enzymes are used in combination with penicillin to prevent their inactivation
Methicillin resistance in staphylococci
Penicillin G resistance in pneumococci
Structural changes in target PBPs
impeding access of penicillin to PBPs
Resistance in some gram (-) rods
Changes in the porin structure in the outer membrane
streptococci
cause sore throat
meningococci
cause meningitis
spirochetes
sexually transmitted
Penicillin G
Narrow-spectrum penicillinase-susceptible agents
limited spectrum; susceptible to β-lactamases
first line drug for syphilis (Benzathine)
streptococci, meningococci, gram-positive bacilli, spirochetes
Penicillin V
Narrow-spectrum penicillinase-susceptible agents
Oral; Oropharyngeal infections
Methicillin
Very Narrow-spectrum penicillinase-susceptible agents
Treatment of known or suspected staphylococcal infections
prototype drug
given 4x a day every 6 hrs
___ resistant S. aureus (MRSA)
Oxacillin
Cloxacillin (Dicloxacillin)
Nafcillin
Very Narrow-spectrum penicillinase-susceptible agents
currently available in the market
S. epidermidis (MRSE)
Very Narrow-spectrum penicillinase-susceptible agents
resistant to other members of this subgroup and often to multiple antimicrobial drugs
Ampicillin (IV) & Amoxicillin (Oral)
oral ampicillin - veterinary treatment/luminal
Wider-spectrum penicillinase-susceptible agents
Wider spectrum than Penicillin G
Susceptible to penicillinases
Enhanced when used with penicillinases (BLIC)
Synergistic (1+1=3) with aminoglycosides in enterococcal and listerial infections
Co-amoxiclav (amoxicillin + clavulanic acid)
Wider-spectrum penicillinase-susceptible agents: Ampicillin & Amoxicillin
Enhanced when used with penicillinases (BLIC)
Piperacillin & Ticarcillin (IV)
Wider-spectrum penicillinase-susceptible agents
Enhanced activity against gram negative
Pseudomonas, Enterobacter, Klebsiella
Susceptible to penicillinases
Enhanced activity in combination with inhibitors of penicillinases
Synergistic action with aminoglycloside
pip-tazo (piperacillin + tazo bactam) or ticarcillin + sulbactam inhibitor
Wider-spectrum penicillinase-susceptible agents: Piperacillin & Ticarcillin
Usually also combined with penicillinase inhibitors
Allergy
urticaria, pruritus, fever, joint swelling, anemia, anaphylaxis
Kissing disease
Nafcillin
neutropenia
Methicillin
interstitial nephritis
Ampicillin
maculopapular rashes
GI disturbances
Oral penicillins
nausea, diarrhea
Ampicillin
pseudomembranous colitis
caused by fungal or resistant bacteria overgrowth which can cause the formation of a layer of pseudomembrane
β-lactamase Inhibitors
Resemble β -lactam molecules, but have very weak antibacterial action
available only in fixed combinations with specific penicillins and cephalosporins