Lactams Penicillins and Cephalosporins

PHARMACOKINETICS, DISTRIBUTION, BIOAVAILABILITY, AND RELATIONSHIP TO ANTIBIOTIC RESIDUES 

When fi-lactams are formulated as aqueous solutions for parenteral (intramuscular or subcutaneous) use, they are rapidly absorbed to achieve maximum concentrations in 0.25-1 h. In many cases, therefore, the plasma concentration-time profile is very similar for intravenous and intramuscular routes. 

It has been commonly assumed that, because of their lipophobic character and excretion in high concentrations in urine, f)-lactams are metabolized slightly or not at all. This assumption is contraindicated (for amoxicillin) by the identification of metabolites, amoxicilloic acid. 

The pharmacokinetic profiles of P-lactams dictate tissue depletion profiles. Concentrations are generally high in the kidney, very low in fat, and also low in muscle. For example, in pigs, Martinez-Larranaga et al. reported concentrations (mg/kg) of amoxicillin of 23.6 (muscle), 

7 (fat), 49.1 (liver), and 559.7 (kidney) 2 days after oral dosing of 20 mg/kg orally for 5 days. ° In broiler chickens administered amoxicillin in drinking water daily for 5 days, tissue concentrations (p,g/kg) 1 h or less after final doses were 138 (muscle), 108 (fat), 484 (skin and fat), 2178 (liver), and 4363 (kidney). For fat, the poor uptake is explained by both low bloodflow and the lipophobic character of the drugs. For muscle, the low concentration is related to poor intracellular penetration and hence restriction to the extracellular fraction of the tissue. 

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Among other oxidations mediated by (dichloroiodo)benzene, some unique transformations of /J-lactams, penicillins and cephalosporins are of interest [19]. 

Penicillin, the first natural antibiotic produced by genus Penicillium, discovered in 1928 by Fleming, as well as sulfonamides, the first chemotherapeutic agents discovered in the 1930s, lead a long list of currently known antibiotics. Besides 3-lactams (penicillins and cephalosporines) and sulfonamides, the list includes aminoglycosides, macrolides, tetracyclines, quinolones, peptides, polyether ionophores, ri-famycins, linkosamides, coumarins, nitrofurans, nitro heterocytes, chloramphenicol, and others. 

In previous papers/ we reported the effect of column temperature on resolution in RP-HPLC to separate various p-lactams (penicillins and cephalosporins) from a single sample. In this work we describe the effect of column temperature and volume fraction of an organic solvent on resolution in the isocratic elution conditions of some p-lactam antibiotics. 

Adverse reactions to -lactams (penicillins and cephalosporins) are not related to dose or blood concentrations. They are commonly administered in doses 10 to 100 times greater than necessary to inhibit organism growth, and appropriate dosing may be guided by susceptibility testing. Patient compliance and evaluation of patients with renal impairment are the most likely reasons to monitor the blood concentration. 

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

In the period up to 1970 most P-lactam research was concerned with the penicillin and cephalosporin group of antibiotics (1). Since that time, however, a wide variety of new mono- and bicychc P-lactam stmctures have been described. The carbapenems, characterized by the presence of the bicychc ting systems (1, X = CH2) originated from natural sources the penem ring (1, X = S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxyhc acid [78854-41-8] CyH NO, and 7-oxo-(R)-4-thia-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxylic a.cid [69126-94-9], C H NO S, respectively. 

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

Fermentation. The commercial P-lactam antibiotics which act as starting material for all of the cephalosporins ate produced by submerged fermentation. The organisms used for the commercial production of the penicillins and cephalosporins ate mutants of PenicU/in chTysogenum and Cephalosporium acremonium respectively (3,153,154). Both ate tme fungi (eucaryotes). In contrast, the cephamycins ate produced by certain species of procaryotic Streptomyces including Streptomyces clavuligerus and Streptomyces lipmanii (21,103). 

The P-lactam antibiotics ate produced by secondary metaboHc reactions that differ from those responsible for the growth and reproduction of the microorganism. In order to enhance antibiotic synthesis, nutrients must be diverted from the primary pathways to the antibiotic biosynthetic sequences. Although most media for the production of penicillins and cephalosporins are similar, they ate individually designed for the specific requkements of the high yielding strains and the fermentation equipment used. 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

One of the major differences between penicillins and cephalosporins is the possibility for a concerted elimination of the C-3 substituent in the case of cephalosporins (6->7). There is now considerable evidence to support the idea that an increase in the ability of the C-3 substituent to act as a leaving group results in an increased reactivity of the 8-lactam carbonyl (75JMC408). Thus, both the hydrolysis rate of the 8-lactam and antibacterial activity... 

Just as fflnides are more stable than esters, lactfflns are more stable than lactones. Thus, although p-lactones are rare (Section 19.15), p-lactfflns are fflnong the best known products of the phaiinaceutical industry. The penicillin and cephalosporin antibiotics, which are so useful in treating bacterial infections, are p-lactfflns and are customarily refeired to as (3-lactam antibiotics. 

The biological activity of penicillins and cephalosporins is due to the presence of the strained /3-lactam ring, which reacts with and deactivates the transpeptidase enzyme needed to synthesize and repair bacterial cell walls. With the wall either incomplete or weakened, the bacterial cell ruptures and dies. 

The antibiotic activity of certain (3-lactams depends largely on their interaction with two different groups of bacterial enzymes. (3-Lactams, like the penicillins and cephalosporins, inhibit the DD-peptidases/transpeptidases that are responsible for the final step of bacterial cell wall biosynthesis.63 Unfortunately, they are themselves destroyed by the [3-lactamases,64 which thereby provide much of the resistance to these antibiotics. Class A, C, and D [3-lactamases and DD-peptidases all have a conserved serine residue in the active site whose hydroxyl group is the primary nucleophile that attacks the substrate carbonyl. Catalysis in both cases involves a double-displacement reaction with the transient formation of an acyl-enzyme intermediate. The major distinction between [3-lactamases and their evolutionary parents the DD-peptidase residues is the lifetime of the acyl-enzyme it is short in (3-lactamases and long in the DD-peptidases.65-67... 

Penicillins and cephalosporins both have a [1-lactam ring joined to an S-containing ring structure (penicillins a thia-zolidine ring cephalosporins a dihydrothiazine ring). Because of their structural likeness, allerginicity between... 

Development of resistance to P -lactam antibiotics, including penicillins and cephalosporins, has significantly impacted the management of bacterial meningitis. Approximately 17% of United States pneumococcal CSF isolates are resistant to penicillin, and 3.5% of CSF isolates are resistant to cephalosporins.26 The Clinical and Laboratory Standards Institute (CLSI) has set a lower ceftriaxone susceptibility breakpoint for pneumococcal CSF isolates (1 mg/L) than for isolates from non-CNS sites (2 mg/L). Increasing pneumococcal resistance to penicillin G... 

Oxygen activation is a central theme in biochemistry and is performed by a wide range of different iron and copper enzymes. In addition to our studies of the dinuclear non-heme iron enzymes MMO and RNR, we also studied oxygen activation in the mononuclear non-heme iron enzyme isopenicillin N synthase (IPNS). This enzyme uses O2 to transform its substrate ACV to the penicillin precursor isopenicillin N [53], a key step in the synthesis of the important P-lactam antibiotics penicillins and cephalosporins [54, 55],... 

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. 

Penicillins and cephalosporins Probenecid, aspirin Blocked excretion of /3-lactams Use if prolonged high concentration of /J-lactam desirable... 

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