17. Penicillins and beta-lactamase inhibitors Flashcards
Structure of penicillins
Beta-lactam ring (that can be cleaved by beta-lactamase) and thiazolidine ring. Two chains that are responsible for pharmacokinetics and antimicrobial spectrum.
How does structure influence pharmacokinetic properties of penicillins?
- If Na/K -> water-soluble -> can be given IV. 2-3h
- if procaine -> bad water solubility, relatively long action. Is not usually given alone. Up to 24h
- Benzatine -> least water-soluble. Very long action. Up to 72 hours
What is the target of penicillins?
PBP - penicillin binding proteins: transpeptidase and carboxipeptidase - enzymes responsible for last step of bacterial cell wall synthesis - transpeptidation.
Beta-lactam drugs have similar structure to peptide chain -> PBP will bind beta-lactam drugs and not the bacterial peptide chain -> IRREVERSIBLE INACTIVATION of PBP -> cross-linking doesn’t happen -> weak cell wal -> collapsing of the cell wall and death
What is peptidoglycan? What is its structure?
= Murein. Layer of bacterial cell wall. Is important for cell wall integrity especially in Gram+ bacteria.
N-acetyl-muranic acid (NAM) and N-acetyl-glucose amine chain (NAG) make long chains that are connected to each other by transpeptide bonds. For formation of these bonds PBP (penicillin binding proteins) are responsible.
Mechanism of action of penicillins
Inhibition of synthesis of the peptidoglycan layer of bacterial cell wall. Irreversible inactivation if PBP (penicillin binding proteins) -> cross-linking (transpeptidation) does not happen -> collapse of cell wall and death of bacteria
Mode of action of penicillins
BACTERIACIDAL. Time-dependent. Also hav PAE (postantibiotic effect) 4-8h.
Why penicillins should NOT be used with bacteriostatic drugs?
Penicillins work against cell wall synthesis => against dividing bacteria.
Bacteriostatic drugs INHIBIT division of bacteria
Against what type of bacteria penicillins are most effective? Why?
Against Gram+ bacteria because
- huge part of their cell wall is peptidoglycan -> very sensitive to beta-lactam antibacterial drugs.
- PBPs are locate between cell wall and cell membrane an it’s much easier for drug to penetrate cell wall of Gram+ bacteria than Gram- (in gram- it can come only through PORINS)
Types of resistance against penicillins
- Ab ovo (primary). Never effective against pathogen: mycoplasma
- Beta-lactamase production
- PBP-gene mutation (e.g. MRSA, MRSP)
Examples of ab ovo resistance to penicilins
- Mycoplasma - absence of cell wall. (resp tract infection in poultry and swine)
- acid-fast bacteria - penicillin cannot penetrate and reach the target (Mycobacteria)
Against what bacteria were penicillinase stable penicillins created?
Against Staphylococcus. Gram+ bacteria that produces beta-lactamase
What bacteria produce beta-lactamase?
all gram– and Staphylococci
What are the ways to avoid beta-lactamase resistance?
- To use clavulonic acid
- To change structure of the drug
What happens if bacteria modifies its PBP? Can we apply penicillins?
If PBP is changed - NONE of beta-lactam antibacterial drugs will be efficient
MRSA - ?
Methicillin resistant Staphylococcus aureus.
Staphylococci produce beta lactamase -› penicilinase resistant penicillins were created with slightly different structure (methicillin, oxacillin, cloxacillin) -› PBPs mutated and changed structure -› none of beta-lactam antibacterial drugs is anymore resistant against MRSA
MRSP -?
Methicillin Resistant Staphylococcus pseudintermedius
What are the types of antibacterial spectrum of penicillins?
- Narrow spectrum bacteria
- Penicilinnase stable penicillins
- Extended spectrum penicillins
- Penicillins acting against Pseudonomas spp.
Narrow spectrum penicillins act against …
Most of gram+ bacteria, fastidious gram- + Leptospira, Borrelia, anaerobes
What are the drugs belonging to narrow spectrum penicillins?
- benzylpenicillin - Na/K (water-soluble)
- benzylpenicillin - procaine
- benzylpenicillin - benzathine
- phenoxymethyl-penicillin (acid-stable, can be given orally)
- penethamat (can cross blood-milk barrier)
What bacteria are fastidious gram- ?
- Pasteurella
- Haemophilus
- Actinobacillus
- Mannheima
mainly cause respiratory tract infections
Narrow spectrum penicilins are the first choice of trearment of: …
- swine erysipelas (diamond skin disease) Erysipelothrix rhusiopathiae
- anthrax - Bacillus anthracis
- tetanus - Clostridium tetani
- necrotic enteritis of poultry - Clostridium perfringens
- streptococcosis (mastitis, dermatitis, pharyngitis)
respiratory infections - not the first choice but can be treated
What narrow spectrum penicillin can be absorbed orally?
phenoxymethyl-penicillin
What is the distribution of narrow spectrum penicillins (PK)?
Distribution is poor. Hydrophilic. Can’t enter the cells -› not effective against intracellular organisms.
Most of penicillins can’t cross special biological barriers (exception: penethamat - can cross blood-milk barrier)
What is the metabolism and excretion of narrow spectrum penicillins (PK)?
Metabolism is minimal. Can be given to patience with liver failure.
Excretion mainly via kidney. In active form and also concentrated.
What are side effects of narrow spectrum penicillins?
- allergy, non-immunological anaphylactic reaction (because of histamine release from mast cells). If adminestered IV then even more severe
- dysbacteriosis (esp. in HORSES and RODENTS)
- the most toxic nar. sp. pen. - procaine-penicilin (because of procaine) - restlessness, tremor. PIGLETS and FOALS are esp. sensitive. Doping drug.
Can respiratory infections be treated by narrow spectrum penicillins?
Yes. But mostly not the first choice
What narrow spectrum penicillins are often used together?
benzylpenicillin-procaine and benzylpenicillin-benzathine to increase duration of action
Against what bacteria were penicillinase stable penicillins invented for?
Against Staphylococci and Streptococci mostly causing mastitis and dermatitis
Are penicillinase stable penicillins effective against gram- bacteria?
NO
What drugs belong to the penicilinase stable penicillins?
- methicillin (now only historical significance. first kind of this kind)
- Oxaciline
- Cloxacillin
- Dicloxacillin
- Flucloxacillin
usually used as intramammary infusion in case of mastitis.
Extended spectrum penicillins act against what type of bacteria?
Most of gram+ bacteria and several gram- bacteria
Extended spectrum penicillins are important because they can act against…
E. coli and Salmonella
Drugs belonging to broad spectrum penicillins
- amphicillin (outdated: bad oral absorption, feed reduces it even more)
- amoxicillin
Why amphicillin considered outdated drug
Relatively bad oral absorption and fee reduces it even more. Instead amoxicillin is used
Broad spectrum penicillins are used in case of:
- same as narrow spectrum penicilllins and in case of respiratory infections are more effective
- urinary tract infections - 1st choice
- GI infection
- Dermatitis, soft tissue infections
- Lyme-disease
- Osteomyelitis
- Oral cavity infection, bite wounds
- Septicaemia, bacteraemia
Penicillins acting against Pseudonoas spp. Drugs:
- Piperacillin (+tazobactam)
- Ticarcillin (+ clavulonic acid)
To what group of AMEG classification do penicillins acting against Pseudonomas spp. belong?
A. Avoid => only in small animals
