Penicillin Sensitization mechanism

There are really two factors to be considered. First, the capability of a particular drug to cause the event which I just described, and secondly the capability of a drug administered to a person in which this process has taken place to be immediately recognized as antigenic and to elicit an anaphylactic reaction. A number of different chemical reactions have been associated with this phenomenon. One of them is simple acylation of protein by the / -lactam. Inasmuch as the mechanism of action of both the penicillins and cephalosporins is also thought to involve acylation by the -lactam, I think that it is very unlikely that there will ever be a -lactam antibiotic which is active and which will not in some patients form antigenic material by this same mechanism. It is my impression that cephalosporins have a lesser tendency to sensitize than some penicillins and that not all penicillin-sensitive people react to a given cephalosporin. The differences are probably quantitative and will never be qualitative. 

The distinction between penicillin-sensitive enzymes (PSEs) and PBPs appears arbitrary and is probably a reflection of the interests of the investigators. Three non-membrane bound water-soluble D-alanyl-D-alanine peptidases have been studied in detail (Frere and Joris, 1985) R39, R61 and alhus G enzymes. The R61 and alhus G enzymes have been crystallised and the crystal structure for R61 solved to 2.8 A resolution (Kelly et al., 1985). Although for both R61 and R39 it is very unlikely that these exocellular enzymes are the killing targets of (3-lactam antibiotics (Dusart et al., 1973), their study has provided useful models for the mechanism of inhibition of the enzymes anchored in the bacterial plasma membrane. The albus G enzyme contains zinc(II) and catalyses the hydrolysis of the C-terminal D-alanine of o-alanyl-o-alanine terminated peptides but it is only very weakly inactivated by penicillins and cephalosporins (Frere and Joris, 1985). 

In summary, the main mechanistic studies of P-lactam antibiotics with penicillin-sensitive enzymes have been performed with soluble exocellular enzymes which act as hydrolytic catalysts. Unfortunately, mechanistic studies with membrane-bound PBPs which act as penicillin-sensitive enzymes are far less advanced and so the molecular mechanism for the lethal action of P-Iactam antibiotics remains speculative. 

The mechanism of antibacterial activity is through inhibition of gram-positive bacterial cell-wall synthesis thus, the penicillins are most effective against actively multiplying organisms. Because mammalian cells do not have a definitive cell-wall stmcture as do bacteria, the mammalian toxicity of the penicillins is low. Allergic phenomena in patients following sensitization may occur. 

Much information on the mechanism of action and cross-resistance of purine analogues has been obtained in bacteria, some of which are quite sensitive to certain of these compounds in vitro. There is a great deal of variation in response of the various bacteria to a particular agent and of a particular bacterium to the various cytotoxic purine analogues. Some, if not most, of these differences are probably due to differences in the anabolism of the various compounds. Despite the fact that certain purine analogues have quite a spectrum of antibacterial activity in vitro, none has been useful in the treatment of bacterial infections in vivo because their toxicity is not selective—the metabolic events whose blockade is responsible for their antibacterial activity are also blocked in mammalian cells and thus inhibition of bacterial growth can only be attained at the cost of prohibitive host toxicity. In contrast, the sulpha drugs and antibiotics such as penicillin act on metabolic events peculiar to bacteria. 

Contact dermatitis was often observed when penicillin was used in topical formulations and still continues to be described in cases of occupational exposure to beta-lactams (218,219). The underlying mechanism is thought to involve chemical modification of antigen-presenting cells in the epidermis, leading to sensitization of drug-specific T cells (220,221). 

The P-lactam ring in the lactam-thiazolidine structure of penicillin (I) is much more sensitive to nucleophilic attack than simple P-lactams. The dibasic penicilloic acid (III) is the product formed under mild hydrolysis conditions in neutral and alkaline solutions. For penicillin G at constant temperature the reaction is first order with respect to penicillin and hydroxide ion concentrations. The mechanism in neutral... 

MECHANISMS OF BACTERIAL RESISTANCE TO PENICILLINS AND CEPHALOSPORINS A sensitive strain may acquire resistance by mutations that decrease the affinity of PBPs for the antibiotic. Because /5-lactam antibiotics inhibit many different PBPs, their affinity for several PBPs must decrease to confer resistance. Methidllin-resistant S. aureus are resistant via acquisition of an additional high-molecular-weight PBP (via a transposon) with a very low affinity for all /5-lactam antibiotics this mechanism is responsible for methicillin resistance in the coagu-lase-negative staphylococci. 

Salamon DJ, Nusbacher J, Stroupe T, Wilson JH, Hanrahan JB (2004) Red cell and platelet-hound IgG penicillin antibodies in a patient with thrombocytopenia. Semin Thromb Hemost 30 273—283 Shuhnan NR (1964) A mechanism of cell destruction in individuals sensitized to foreign antigens and its implications in autoimmunity. Ann Int Med 60 506-521 Shuhnan NR, Reid DM (1993) Mechanisms of drag-induced hnmunologically mediated cytope-nias. Transfus Med Rev 7 215-229... 

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