Clavams

The question of tolerability of penicillins, monobactams, and carbapenems in patients with IgE hypersensitivity to cephalosporins was recently assessed in 98 subjects by serum IgE antibody assays, challenge tests, and skin testing with penicillin reagents, aztreonam, imipenem-cilastatin, and meropenem. Approximately 25 % of cephalosporin-allergic subjects were positive to penicillins, while 3.1,2, and 1 % showed positive results to aztreonam, imipenem, and meropenem, respectively. A reaction to a cephalosporin with a similar or identical side chain to penicillin was a sigifificant predictor of cross-reactivity. For skin testing, the following concentrations were used ampicillin and amoxicillin 1 and 20 mg/ml cephalosporins 2 mg/ml aztreonam 2 mg/ml imipenem-cilastatin 0.5 mg/ml and meropenem 1 mg/ml. 

From the relatively few investigations carried out on the carbapenems, it seems clear that poten- 

In an evaluation of 276 patients who had a reaction attributed to amoxicUlin-clavulanic acid, 55 patients (19.9 %) reacted positively to different penicillin determinants. Of the 221 with negative skin tests, 15 were positive to amoxicillin and seven were judged to be allergic to clavulanic acid on the basis of tolerance to benzylpenicillin and amoxicillin and an immediate reaction to clavulanic acid following challenges. In the skin test-positive group, skin and 

Hepatitis and jaundice caused by the combination of amoxicillin and clavulanic acid were first identified in 1988. The combination of the two drugs is associated with a higher incidence of liver injury than the administration of amoxicillin alone. The risk of this drug-induced liver injury, mostly cholestatic in nature, increases with age and by about a factor of 3 after 2 or more consecutive courses of drug. 

There are at least three reports of delayed reactions to clavulanic acid manifesting as generalized urticaria, generalized itchy erythema, and allergic contact dermatitis with pruritic erythematous patches. Diagnoses were confirmed by patch testing with amoxicUhn-clavulanic acid dried syrup at 10 and 1 mg/ml and clavulanic acid 10 mg/ml and for one patient, by skin prick and intradermal tests. 

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The clavams differ from penicillins (based on the penam structure) in two respects, namely the replacement of S in the penicillin thiazolidine ring (Fig. 5.1) with oxygen in the clavam oxazolidine ring (Fig. 5.5 A) and the absence of the side-chain at position... 

The 1-caibapenems (Fig. 5.5C) comprise a new family of fused /3-lactam antibiotics. They are analogues of penicillins or clavams, the snlphur (penicilhns) or o gen (calvams) atom being replaced by carbon. Examples are the olivanic acids (section 2.5.1) and thienamycin and imipenem (section 2.5.2). 

Lactams are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, carbapenems, and clavams (/8-lactamase inhibitors). The metabolic engineering of penicillin and cephalosporins production has been summarized by several good reviews [71,72], so the focus here is clavulanic acid, which has attracted interest in recent years. 

Tahlan, K., Park, H.U., Wong, A., Beatty, P.H. and Jensen, S.E. (2004) Two sets of paralogous genes encode the enzymes involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in streptomyces clavuligenis. 48, 930-939. 

Carbapenem basic structure Clavam basic structure... 

Scheme 102 Solid-phase synthesis of clavams and oxacephams trough P-lactam intermediate...

The first (3-lactams LE inhibitors were naturally occurring bicyclic compounds, such as clavams and cephalosporins [338], but more recently, synthetic monocyclic (3-lactams have been developed. Time-dependent inhibitors of enzyme HLE, based on the cephem nucleus, have been reported. A series of cephalosporin tert-butyl esters have been examined, and the activity of these compounds has been found to be very sensitive to the C-7 substituents, the greatest activity being showed by small, a-oriented, and electron-withdrawing groups. Additionally, the oxidation... 

An important group of four-membered heterocyclic compounds are the derivatives of the /i-lactam [azetidin-2-one (15)] system. Many of the compounds are biologically active, for example, the monocyclic nocardicins [e.g. (16)] and the bicyclic penicillin and cephalosporin antibiotics [e.g. (17) and (18) respectively], and the -lactamase inhibitors of the clavam group (19). 

Baggaley KH, Brown A and Schofield CJ (1997) Chemistry and biosynthesis of clavulanic acid and other clavams. Nat Prod Rep 14, 309-333. 

Intramolecular N-alkylation under phase-transfer conditions (PTCs) of 236 and 237 having the triisopropylbenze-nesulfonyl (TIBS) protecting groups give the corresponding clavams 238 where R = a-H and /3-H, respectively... 

The peneras were conceived by R.B. Woodward in 1976 as structural hybrids of penicillins and cephalosporins [84]. Unlike the carbapenems and clavams, they are not found in nature. They do however possess important biological properties and have therefore created considerable interest in both their total synthesis and their biological evaluation [85]. 

Edwards RG, Dewdney JM, Dobrzanski RJ, Lee D. Immunogenicity and allergenicity studies on two beta-lactam structures, a clavam, clavulanic acid, and a carbape-nem structure-activity relationships. Int Arch Allergy Appl Immunol 1988 85(2) 184-9. 

The clavams differ from penicillins (based on the penam structure) in two respects, namely the replacement of sulphur in the penicillin thiazolidine... 

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