Case 1Case 1

Tunyapon SasithornTunyapon Sasithorn

Pharmacology Pharmacology

Clinical caseClinical case

Problem 1Problem 1

A clinical study evaluating the efficiency A clinical study evaluating the efficiency of the of the antibiotic treatmentantibiotic treatment of the of the meningitismeningitis was carried out. One group was carried out. One group of patients with of patients with pneumococcal pneumococcal meningitismeningitis received parenteral received parenteral penicillinpenicillin. A second group received . A second group received penicillin plus tetracyclinepenicillin plus tetracycline therapy. therapy.

A.A.

How do penicillin and How do penicillin and tetracycline differ in tetracycline differ in their mechanism of their mechanism of action?action?

PenicillinPenicillin Mechanism of ActionMechanism of Action B- B- lactam antibiotics work by inhibiting the lactam antibiotics work by inhibiting the

formation of peptidoglycan cross links in the formation of peptidoglycan cross links in the bacterial cell wall. bacterial cell wall.

The The B- B- lactam moiety of penicillin binds to the lactam moiety of penicillin binds to the enzyme (transpeptidase) that links the enzyme (transpeptidase) that links the peptidoglycan molecules in bacteria, and this peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium when it weakens the cell wall of the bacterium when it multiplies multiplies

This causes cell cytolysis or death when the This causes cell cytolysis or death when the bacterium tries to divide.bacterium tries to divide.

The build-up of peptidoglycan precursors The build-up of peptidoglycan precursors triggers the activation of bacterial cell wall triggers the activation of bacterial cell wall hydrolases which further digest the bacteria's hydrolases which further digest the bacteria's existing peptidoglycan.existing peptidoglycan.

TetracyclineTetracycline Mechanism of ActionMechanism of Action

Tetracyclines inhibit bacterial protein Tetracyclines inhibit bacterial protein synthesis by blocking the attachment of synthesis by blocking the attachment of the transfer RNA-amino acid to the the transfer RNA-amino acid to the ribosome. ribosome.

They are inhibitors of the codon-They are inhibitors of the codon-anticodon interaction. anticodon interaction.

Mechanism of ActionMechanism of Action

PenicillinPenicillinBactericidalBactericidal

TetracyclineTetracyclineBacteriostaticBacteriostatic

22..

Which group had a Which group had a lower mortality ratelower mortality rate??

MortalityMortality was was significantly highersignificantly higher in the in the penicillin– tetracyclinepenicillin– tetracycline group compared group compared to the single drug penicillin group:to the single drug penicillin group:

Mortality rateMortality rate

Penicillin – Penicillin – tetracyclinetetracycline groupgroup 79%79%

∞∞one of seven patients survivedone of seven patients survived

Penicillin group Penicillin group

30%30%

∞∞ nine of 20 patients survivednine of 20 patients survived

3.3.

If there was a If there was a difference, what would difference, what would

account for the account for the observation?observation?

Penicillin Penicillin group experienced a group experienced a bactericidal bactericidal effecteffect which is very important in treating which is very important in treating patients with pneumococcal meningitispatients with pneumococcal meningitis..

Penicillin – tetracyclinePenicillin – tetracycline – a combination of a – a combination of a cell wall agent, the bactericidal activity of which cell wall agent, the bactericidal activity of which depends on cell growth (penicillin), with a depends on cell growth (penicillin), with a reversible protein synthesis inhibitor that reversible protein synthesis inhibitor that interferes with cell growth (tetracycline), is a interferes with cell growth (tetracycline), is a classical example of classical example of antibiotic antagonismantibiotic antagonism, , resulting in the lower mortality rate of resulting in the lower mortality rate of

penicillin – tetracycline group.penicillin – tetracycline group.

Antagonist reaction of Antagonist reaction of Penicillin Penicillin and tetracyclineand tetracycline renders these renders these drugs in combination ineffective.drugs in combination ineffective.

The mutual antagonist reaction The mutual antagonist reaction produces an overall bacteriostatic produces an overall bacteriostatic activity which proves ineffective in activity which proves ineffective in treating patients with treating patients with pneumococcal meningitispneumococcal meningitis..

4.4.

Any other drug Any other drug combination that you combination that you can recommend? On can recommend? On

what basis?what basis?

Other drug Other drug recommendationsrecommendationsdue to:due to: Meningitis with penicillin resistant Meningitis with penicillin resistant

pneumococcuspneumococcus

Other synergistic reactionOther synergistic reaction

Drug combinationsDrug combinations Drugs of first choiceDrugs of first choice

ChildrenChildren CeftriaxoneCeftriaxone Cefotaxime +/- Cefotaxime +/- VancomycinVancomycinAdultsAdults CeftriaxoneCeftriaxone CefotaximeCefotaxime

OthersOthers Rifampin Rifampin B B lactam antibioticlactam antibiotic

Ex: Penicillin, Ampicillin, Ex: Penicillin, Ampicillin, Piperacillin and CefuroximePiperacillin and Cefuroxime

+ Gentamicin+ Gentamicin

Alternative drugsAlternative drugsChildrenChildren ChloramphenicolChloramphenicol Systematic Systematic corticosteroids corticosteroids

AdultsAdults Vancomycin + Vancomycin +

CeftriaxoneCeftriaxone Vancomycin + Vancomycin +

Cefotaxime Cefotaxime

Thank YouThank Yousir, mam.sir, mam.

Come again!Come again!

:P:P