0-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). 

Mercaptopurine [6-MP] (Purinethol) [Antineoplastic/ Antimeta lite] Uses Acute leukemias, 2nd-line Rx of CML NHL, maint ALL in children, immunosuppressant w/ autoimmune Dzs (Crohn Dz) Action Antimetabolite, mimics hypoxanthine Dose Adults. 80-100 mg/mVd or 2.5-5 mg/kg/d maint 1.5-2.5 mg/kg/d Peds. Per protocol X w/ renal/hepatic insuff on empty stomach Caution [D, ] Contra Severe hepatic Dz, BM suppression, PRG Disp Tabs SE Mild hematotox, mucositis, stomatitis, D rash, fever, eosinophilia, jaundice. Hep Interactions T Effects W/ allopurinol T risk of BM suppression W/ trimethoprim-sulfamethoxazole X effects OF warfarin EMS May falsely T glucose OD May cause NA and liver necrosis symptomatic and supportive Meropenem (Merrem) [Antibiotic/Carbapenem] Uses lntra-abd Infxns, bacterial meningitis Action Carbapenem X cell wall synth, a [3-lactam Dose Adults. 1 to 2 g IV q8h Peds. >3 mo, <50 kg 10-40 mg/kg IV q 8h in renal insuff Caution [B, ] Contra [3-Lactam sensitivity Disp Inj 500 mg, 1 g SE Less Sz potential than imipenem D, thrombocytopenia Interactions T Effects W/ probenecid EMS Monitor for signs of electrolyte disturbances and... 

Piperacillin-Tazobactam (Zesyn) [Anribioric/Extended Spectrum Penicillin, Beta Lactamase Inhibitor] Uses Infxns of skin, bone, resp urinary tract, abd, sepsis Action PCN plus 3-lactamase inhibitor bactericidal i cell wall synth Dose Adults. 3.375-4.5 g IV q6h i in renal insuff Caution [B, M] Contra PCN or 3-lactam sensitivity Disp Powder for inj frozen, premix inj 3.25, 3.375, 4.5 g SE D, HA, insomnia, GI upset, serum sickness-like Rxn, pseudomembranous colitis Interactions T Effects W/ probenecid T effects OF anticoagulants, MTX i effects W/ macrolides, tetracyclines i effects OF OCPs EMS T Effects of anticoagulants monitor for signs of electrolyte disturbances and hypovolemia d/t D such as X- K+ may cause allergic Rxn in pts sensitive to PCN OD May cause N/V/D, resp difficulty, and Szs symptomatic and supportive... 

C. Clinical Uses Because of its toxicity, chloramphenicol has very few uses as a systemic drug. It is a backup drug for severe infections caused by salmonella and for the treatment of pneumococcal and meningococcal meningitis in beta-lactam-sensitive persons. Some H influenzae strains are... 

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

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

APA may be either obtained directly from special Penicillium strains or by hydrolysis of penicillin Q with the aid of amidase enzymes. A major problem in the synthesis of different amides from 6-APA is the acid- and base-sensitivity of its -lactam ring which is usually very unstable outside of the pH range from 3 to 6. One synthesis of ampidllin applies the condensation of 6-APA with a mixed anhydride of N-protected phenylglydne. Catalytic hydrogenation removes the N-protecting group. Yields are low (2 30%) (without scheme). 

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). 

TFA, phenol, 1 h, 45°, 73-93% yield. These conditions were developed for the mild cleavage of acid-sensitive esters of j3-lactam-related antibiotics, Diphenylmethyl and f-butyl esters were cleaved with similarly high efficiency. 

Some examples are given66,67. It appears that even the very sensitive / -lactam ring is oxidized to give an optically pure thienamycin precursor67. 

Staphylococcus aureus cells can acquire large DNA fragments containing the mecA gene which encodes a complete new penicillin binding protein 2A (PBP 2A), as part of a transposon. PBP2A can substitute the natural set of penicillin-sensitive PBPs thereby mediating a complete cross resistance to all (3-lactam antibiotics. 

Based on the properties of ionic hquids in high-temperature microwave-enhanced reactions, the authors chose l-butyl-3-methylimidazolium tetraflu-orophosphate ([bmimjPFe) as the suitable ionic liquid (Scheme 23). The addition of 0.15 mmol of [bmimjPFe to a reaction in 2.0 mL of DCF was found to increase the reaction rate dramatically and a set-temperature of 190 °C was reached in a mere 1 min, while the reactions programmed at 190 °C, in the absence of the ionic liquid, reached only 170 °C in 10 min. The reactions were finished in a mere 18-25 min of irradiation time, including the hydrolysis of the sensitive imidoyl chloride moiety with water. The formed bis-lactams were isolated in good yield and purity. 

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]. 

The estimated sensitivity of skin tests for muscle relaxants is approximately 94-97%. Sensitivity for other substances varies. It is good for synthetic gelatins, (3-lactams, but poor for barbiturates, opioids and benzodiazepines dyes, and chlorhexidine. 

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