Antibiotics, lactam toxicity

C) The 3-lactam antibiotics prevent toxic effects of the aminoglycoside antibiotics. 

Peptide antibiotics are not often the drags of first choice for systemic therapy of important human disease. However, the World Health Organization, which chooses drags especially for Third World use based on efficacy, safety, quality, price, and availability, includes as essential such peptide antibiotics as bleomycin, dactinomycin, and bacitracin (as an ointment containing neomycin), plus several /8-lactams. See also Antibiotics, Antibiotics -Lactams. Systemic use of peptide antibiotics is many times limited by nephroloxicity and other toxicities. Semisynthesis or complete chemical synthesis of analogues of peptide antibiotics has most often not resulted in improved drags. 

P-lactam antibiotics, exert thek antibacterial effect by interfering with the synthesis of the bacterial cell wall. These antibiotics tend to be "kreversible" inhibitors of cell wall biosynthesis and they are usually bactericidal at concentrations close to thek bacteriostatic levels. Cephalospotins are widely used for treating bacterial infections. They are highly effective antibiotics and have low toxicity. 

The origin of the success of fl-lactam antibiotics mainly results from the extreme low toxicity of these compounds with regard to human beings. In other words, P-lactam antibiotics have a highly selective toxicity for bacteria since they do not interfere with human metabolism, but inhibit the formation of the cell wall of growing bacteria. 

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. 

As already noted, beta-lactam antibiotics interfere with biosynthesis of the primary component of cell membranes—pepfidoglycan. Because of the fact that this process does not take place in human and other mammalian cells, beta-lactam antibiotics are relatively non-toxic to humans. 

While ertapenem possesses toxicity similar to the beta-lactam group of antibiotics, periodic assessment of organ system function, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. 

Vancomycin and teicoplanin display excellent activity against staphylococci and streptococci, but because of the wide availability of equally effective and less toxic drugs, they are second-line drugs in the treatment of most infections. As antistaphylococcal agents they are less effective than 3-lactam cephalosporin antibiotics, such as nafciUin and cefazoUn. They have attained much wider use in recent years as a consequence of the emergence of methicUlin-resistant S. aureus (MRSA) infections, in particular the growing importance of Staphylococcus epidermidis infections associated with the use of intravascular catheters and in patients with peritonitis who are on continuous ambulatory peritoneal dialysis. 

Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to a B-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci. The dosage is 50-100 mg/kg/d in four divided doses. 

Parent molecules, metabolites, and transformation products may undergo further transformation (Figure 9.3). A few API compounds can be hydrolyzed, such as some of the (3-lactam antibiotics [44]. Stable degradation products may result from these processes. Often the toxicity and potential environmental hazards of such transformation products are not known. Even if APIs are eliminated to some extent, they may still persist in the aquatic environment if the rate of input is higher than the rate of removal. The resulting situation in such cases is reminiscent of persistent pollutants. 

Tune BM. The renal toxicity of beta-lactam antibiotics mechanisms and clinical implications. In DeBroe ME, Porter GE, Bennett WM, et al. eds. Clinical Nephrotoxins Renal Injury from Drugs and Chemicals. Dordrecht Kluwer Academic, 1998. 

ANTIBIOTICS CHLORAMPHENICOL AND ANALOGUES. Chloramphenicol (1. R = N02), CnH CLNjOs, is a commercially significant antibacterial agent and its status in clinical practice has been reviewed. Although widespread use of this antibiotic declined in the United States in the 1960s because of reports of serious toxic effects, this situation changed a decade later when ampicillin-resistant Hemophilus influenzae emerged on the clinical scene. The appearance of Bacteroides species and of Streptococcus pneumoniae resistant to /1-lactam antibiotics contributed further to... 

For example, l,2-dithioIo[4,3-6]pyrrole derivatives such as holomycin, thiolutin, aureo-thricin and isobutyropyrrothine are antibiotic substances produced by certain Streptomyces species. They are the first recognized examples of microbiologicafiy active unsaturated lactams. In the series of aflatoxins, the presence of the furo[2,3-6]furan ring portion is necessary for the toxicities to be effective. 

---