P-Lactams: sensitivity

Preliminary investigations involving a P-lactam-sensitive, bifimctional D-alanyl-carboxypeptidase—transpeptidase (C Pase—T Pase) from Streptomjces R61 have identified the three-dimensional stmcture and catalytic site of interaction with penicillins (63). 

The use of p-lactam-sensitive mutants, in combination with p-lacta-mases, allows a certain degree of characterization based on p-lactamase stability. 

Bacteria produce chromosomady and R-plasmid (resistance factor) mediated P-lactamases. The plasmid-mediated enzymes can cross interspecific and intergeneric boundaries. This transfer of resistance via plasmid transfer between strains and even species has enhanced the problems of P-lactam antibiotic resistance. Many species previously controded by P-lactam antibiotics are now resistant. The chromosomal P-lactamases are species specific, but can be broadly classified by substrate profile, sensitivity to inhibitors, analytical isoelectric focusing, immunological studies, and molecular weight deterrnination. Individual enzymes may inactivate primarily penicillins, cephalosporins, or both, and the substrate specificity predeterrnines the antibiotic resistance of the producing strain. Some P-lactamases are produced only in the presence of the P-lactam antibiotic (inducible) and others are produced continuously (constitutive). 

The p-lactams (penicillins and their derivatives) are the drugs which most frequently cause IgE-mediated anaphylactic reactions. Diagnosis is based on skin tests. To date, the best vaUdated in vitro diagnostic methods are specific IgE and BAT. As for the determination of specific IgE using ImmimoCap (Phadia AB, Uppsala, Sweden), the sensitivity of the technique in the diagnosis of immediate reaction to (3-lactams with positive skin test ranges, according to the study, from 37 to 54% with a specificity of between 83 and 100% [23,24]. 

Once the organism has been identified and sensitivities are known, drug selection should be adjusted to reflect the susceptibilities of the organism. Streptococcal, staphylococcal, and enterococcal species sensitive to P-lactam antibiotics should be treated with continuous IP dosing to increase efficacy and minimize resistance.49 Peritonitis caused by S. aureus or P. aeruginosa are often associated with catheter-related... 

Alkylation of P-lactams." Alkylation of the base- and acid-sensitive /5-lactam 1 can be effected efficiently hy carbenoid insertion into the N H bond using... 

A synthetic route to p-lactam-fused enediynes by intramolecular Kinugasa reaction has been successfully developed. The method has widened the scope of the Kinugasa reaction in the synthesis of sensitive systems like tricycle 193 (Scheme 69) [100]. 

Tl-triazene linker resulted in decomposition of the sensitive p-lactams. The relative configuration of p-lactams, was determined by NOE experiments to be the trans-configuration as observed in solution-phase synthesis [137]. 

It is known that p-lactamase catalyzes the rapid hydrolysis of the p-lactam ring of penicillins and cepharosporines. The hydrolytic activity of these enzymes eliminates the bacteriocidal action of many p-lactam antibiotics and makes the organism resistant to these molecules. For this reason, the p-lactamase inhibitors have long been regarded as promising targets from a medicinal viewpoint. A comparison between the kinetic characteristics of p-lactamase and penicillin-sensitive enzymes (carboxy-peptidase and transpeptidase) is of interest in this respect. p-Lactamases very efficiently hydrolyze p-lactam in contrast to penicillin-sensitive enzymes [high /e4 in Eq. (9)]. 

Figure 4 Hydrolytically sensitive antibiotics include the macrolides, oxirane, and p-lactams. The hydrolytically sensitive region is circled in each structural class.

The U-4CR products 49 of the isocyanides 48 with P-alanine and isobutyraldehyde, as shown in Scheme 15, can be converted into their cyclized derivatives 50, which are hydrolyzed by neutral water to yield the compounds 51 and 52.b l These P-lactam derivatives clearly show that even highly sensitive U-4CR products are not destroyed by this chemistry. ... 

Methicillin and oxacillin their use is now confined to laboratory sensitivity tests. Identification of methicillin-resistant Staphylococcus aureus (MRSA) in patients indicates the organisms are resistant to flucloxacillin and cloxacillin, all other P-lactam antibiotics and often to other antibacterial drugs, and demands special infection-control measures. 

The problems of P-lactam and quinolone resistance in Neisseria gonorrhoeae are increasing, and selection of a particular drug will depend on sensitivity testing and a knowledge of resistance patterns in different geographical locations. Effective treatment... 

Clavulanic acid was discovered in 1976 and is a P-lactam antibiotic with low antibiotic activity, but does protect p-lactamase-sensitive compounds of high intrinsic activity such as benzylpenicillin, ampicilhn, and amoxicillin from p-lactamase destruction. Subsequently other p-lactamase inhibitors such as sulbactam and tazobactam were developed [4]. 

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