Penicillins Beta-lactam antibiotics

Penicillin (beta-lactam antibiotic) fermentation Penicillinium... 

Penicillin G 24 million units/24 h IV in four to six equally divided doses may be used in place of nafcillin or oxacillin if strain is penicillin susceptible (minimum inhibitory concentration 0,1 mcg/mL) and does not produce /5-lactamase vancomycin should be used in patients with immediate-type hypersensitivity reactions to beta-lactam antibiotics (see Table 37-3 for dosing guidelines) cefazolin may be substituted for nafcillin or oxacillin in patients with non-immediate-type hypersensitivity reactions to penicillins... 

Later in his career, Nagata s group made notable and useful synthetic contributions to the beta lactam field. This included developing an economically feasible synthetic method for the industrial manufacture of 1-oxacephems from penicillin G. These efforts led to the worldwide introduction in the 1980s of several clinically prominent and effective beta lactam antibiotics of the 1-oxacephem class including moxalactam. 

Beta-lactam antibiotics are a second great class of antibacterials penicillins, cephalosporins, carbapenems, and monobactams. They act by inhibiting bacterial cell wall synthesis. 

Cephalosporins. These beta-lactam antibiotics share many features with the penicillins including mechanism, spectrum of action, distribution ans toxicity potential. At the present time, the cephalosporins are classified into three groups, designated as generations. 

Beta-lactam antibiotics specifically bind with a number of proteins of cytoplasmic membranes known as penicillin-binding proteins (PBP). These proteins are enzymes involved in the reaction of transpeptidafion during the break up of cell membranes during growth and division. 

There are many beta-lactamases and they can be classified differently by type of substrate, replacement of genes (chromosomes or plasmids), and place of production. A few of these enzymes directly hydrolyze penicillins (penicillinases), others hydrolyze cephalosporins (cephalosporinases), and others extend to a broad spectrum of substrates. A few bacteria have the ability to induce synthesis of beta-lactamase. Synthesis of beta-lactamase, which in a normal condition is suppressed, is induced in the presence of some beta-lactam antibiotics. 

Oral beta-lactam antibiotics such as amoxycillin, cotrimoxazole or doxycycline for 7-10 days are suitable for the treatment of bacterial sinusitis. Furuncles of the nose should be treated with an anti-staphyloccal drug for 5 days. Standard treatment for streptococcal pharyngitis consists of 10 days of penicillin. Malignant otitis externa responds to high dose quinolone therapy (e.g. ciprofloxacin 750 mg 2 t.d.) administered orally. For parapharyngeal abscess, high dose penicillin plus beta-lactamase inhibitors such as amoxycillin-clavulanic acid can be used. Duration of treatment is guided by clinical and parameters of inflammation, and abscesses often need several weeks to resolve by conservative treatment. 

Beta lactam antibiotics having a (3-lactam ring, which includes penicillin, in which a thiazolidine ring is attached to a betalactam ring that carries a secondary amino group. Other similar compounds are cephalosporins, monobactams and carbapenems. 

Warnings If patient is penicillin-sensitive, caution should be used because there have been reports of cross-hypersensitivity among beta-lactam antibiotics Pseudomembranous colitis has been reported... 

The cephalosporin drugs, which are also classified as beta-lactam antibiotics, exert their bactericidal effects in a manner similar to that of the penicillins (inhibition of PBPs, resulting in inadequate peptidoglycan production).56 Generally, the cephalosporins serve as alternative agents to penicillins if the penicillin drugs are ineffective or poorly tolerated by the patient. Cephalosporins may also be the drugs of choice in certain types of urinary tract infections (see Tables 33-5). 

A primary problem in using penicillins, cephalosporins, and other beta-lactam antibiotics is that certain bacteria produce enzymes known as beta-lactamases.26,70 These beta-lactamase enzymes bind to the beta-lactam drug and destroy it before it can exert an antibacterial... 

Petri WA. Penicillins, cephalosporins, and other beta-lactam antibiotics. In Brunton LL, et al, eds. The Pharmacological Basis of Therapeutics. 11th ed. New York McGraw-Hill 2006. 

Waxman DJ, Strominger JL. Penicillin-binding proteins and the mechanism of action of beta-lactam antibiotics. Ann Rev Biochem 1983 52 825-869. 

The sulfur-free analogs of penicillins and cephalosporins have attracted much attention of both synthetic and medicinal chemists, since the successful development of new 1-oxacepham antibiotics by the Shionogi group17 . Namely, oxazoline-azeti-dinone derivatives 19 have been used as key intermediates in the synthetic chemistry of new beta-lactam antibiotics 18). The compounds 19 have usually been prepared by a two-step operation involving the reaction of 79 with chlorine or t-butylhypochlorite followed by treatment with a base. 

Thiazoline-azetidinone 36 is a versatile intermediate for the synthesis of varieties of beta-lactam antibiotics 24>. The most straightforward route to 36 must be the removal of the feta-lactam A-substituents of thiazoline-azetidinone 35, which is readily obtained from penicillins by Copper s method 4>. This has usually been done by the two-step operation, involving ozonolysis and subsequent methanolysis 25). Direct transformation of 35 to 36 also has been achieved by oxidation with potassium permanganate or osminum tetraoxide, but yields are unsatisfactory (—37%)25). An efficient method for the removal of A-substituents of 35 is the electrochemical acetoxylation procedure which may lead to the compound 36 along with 37 (Scheme 2-12)3). For example, the... 

As beta-lactam antibiotics continue to be a major contributor to human health preservation, research on the biosynthesis of penicillin, an almost ancient drug, continues to open up roads to new technologies and perspectives. The provision of precursor peptides to be transformed enzymatically with chemically unachieved efficiency into mono- or bicyclic antibiotics has been termed by Jack Baldwin and colleagues the irreversible commitment of metabolic carbon to the secondary metabolism [1]. The synthesis of such peptides is indeed performed by a remarkable class of synthetases which, in contrast to the protein-synthesizing machinery, have been termed a nonribosomal system or nonribosomal peptide synthetases (NRPS) [2]. These peptide synthetases have been shown to catalyze the irreversible synthesis of peptides differing both in sequence and stmctural variability, thus extending the scope of directly gene-encoded poly-... 

Penicillin or other beta-lactam antibiotics should not be used in production cell cultures. Minimum concentrations of other antibiotics or inductor agents in the culture may be acceptable however, the presence of any antibiotic or inductor agents in the final product is not acceptable. 

So-called atypical bacteria such as Chlamydia pneumoniae and Mycoplasma pneumoniae are the next most important group of community-acquired pneumonia pathogens, accounting for around one case in every eight in hospitalised patients. Atypical bacteria are not sensitive to beta-lactam antibiotics such as penicillins and cephalosporins and the treatment of choice is a macrolide such as erythromycin. 

The overwhelming majority of semisynthetic beta-lactam antibiotics, the penicillins and cephalosporin, currently available to physicians trace their origins to the intense research effort devoted to this field several decades ago. The emergence of pathogens resistant to those antibiotics has led some laboratories to revisit this field. The modified cephalosporin ceftobiprole (220), a compound with a rather complex extended side chain, has shown activity in the clinic against some strains of multidrug resistant bacteria. The synthesis starts with the well-precedented acylation of the of the cephalosporin (215), available in several steps from the commercially available 7-acetoxy cephalosporanic acid, with the activated... 

The crucial event that initiates the antimicrobial effects of beta-lactam antibiotics is binding to and inhibition of bacterial enzymes located in the cell membrane, the so-called penicillin-binding proteins (2). This happens by... 

Many reactions to beta-lactam antibiotics are clearly not immune mediated. These include bleeding disorders, neurotoxicity, and most cases of diarrhea. In addition, many reactions, the pathogenesis of which is still being discussed, clearly depend on the daily and the cumulative dose of beta-lactam antibiotics and hence the duration of treatment. Although the rare, but well-understood, immune hemolysis after penicillin is seen mostly with high-dose and long-term treatment, dose dependency and time dependency point to direct toxicity rather than to immunological mechanisms. Indeed, direct toxic effects of beta-lactam antibiotics on eukaryotic cells and specific interactions with receptor proteins and enzymes have been shown (4) and may underlie particular reactions. 

Altered platelet numbers and function Platelet dysfunction occurs dose-dependently with carbenicillin, ticarcillin, and, infrequently, other broad-spectrum penicillins (105), but the NMTT cephalosporin moxalactam has also been associated with altered platelet function in both healthy subjects and in patients treated with standard regimens (106-110). In contrast, clinical studies including cefotaxime, ceftizoxime, cefoperazone, and ceftracone did not show platelet dysfunction attributable to these compounds (109-111). There is evidence that beta-lactam-antibiotic-induced platelet dysfunction is at least partially irreversible (112). 

Gastrointestinal upsets, nausea, and vomiting have been observed with virtually all beta-lactam antibiotics, both oral and parenteral. Even when comparing analogous applications and doses, no particular risk can be clearly ascribed to a given compound. Acute hemorrhagic colitis without pseudomembrane formation has been described after treatment with various penicillins and cephalosporins (SEDA-21, 261). 

More severe liver disease, presenting as hepatitis and/ or intrahepatic cholestasis, has been seen with beta-lactam antibiotics of various classes, the isoxazolyl penicillins being most frequently involved. Co-amoxiclav has repeatedly been associated with cholestatic hepatitis. 

Non-IgE-antibody-mediated immunological reactions Modification of erythrocyte surface components due to binding of beta-lactams or their metabolic products is thought to be the cause of the formation of antierythrocyte antibodies and the development of a positive Coombs test implicated in the development of immune hemolytic anemia (211). About 3% of patients receiving large doses of intravenous penicillin (10-20 million units/ day) will develop a positive direct Coombs test (212). However, only a small fraction of Coombs positive patients will develop frank hemolytic anemia (213). Antibody-coated erythrocytes are probably eliminated by the reticuloendothelial system (extravascular hemolysis) (214), or less often by complement-mediated intravascular erythrocyte destruction (215). Another mechanism implicates circulating immune complexes (anti-beta-lactam antibody/beta-lactam complexes), resulting in erythrocyte elimination by an innocent bystander mechanism (82). Similar mechanisms have been implicated in thrombocytopenia associated with beta-lactam antibiotics (216,217). 

Modification of the targets of beta-lactam antibiotics, that is, the penicillin-binding proteins (286,287), resulting in a reduced affinity of the antibiotic. 

The unique feature of MRSA is based on the acquisition of a low-affinity penicillin-binding protein for beta-lactam antibiotic molecules (the penicillin-binding protein 2A), which allows the bacteria to carry on synthesis of its cell wall, whereas the other penicillin-binding proteins are already inactivated by the high concentration of methicillin or other beta-lactamase-resistant beta-lactam antibiotics. 

Burroughs SF, Johnson GJ. Beta-lactam antibiotic-induced platelet dysfunction evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin. Blood 1990 75(7) 1473-80. 

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