Antibiotics clinical applications

Although host defense peptide resistance has remained rare within microbes, concerns have been raised regarding the potential for clinical applications of peptides to provoke peptide-resistant phenotypes. Indeed, the introduction of antibiotics as novel microbial eradicators was met almost instantaneously with bacteria that had manifested various forms of resistance. Thus, precautions should be taken with potential therapeutic application of host defense peptides to minimize similar resistance as seen with antibiotics. Many bacterial species rely on the use of two-component sensory systems to invoke phenotypes that increase virulence and recently one such system, the Salmonella PhoPQ system, has been demonstrated to respond directly to host defense peptides. ... 

An important issue that has been recognized recently concerns the potential adverse effect of absorption enhancers on the rectal mucosa, as shown in rats after a single application [61,62], Safety evaluation of the applicability of absorption enhancers is imperative. In clinical application, medium-chain fatty acids such as sodium caprate are used only for suppositories containing antibiotics [36],... 

Bergogne-Berezin, E., and A. Bryskier. 1999. The suppository form of antibiotic administration Pharmacokinetics and clinical application. J Antimicrob Chemother 43 177. 

Natural product with antibiotic 1976 activity, but no clinical application... 

Introduction of the first fluorinated quinolone, norfloxacin [nor FLOX a sin], has been rapidly followed by new members of this class. These agents are totally synthetic and are closely related structurally to an earlier quinolone, nalidixic acid [nal i DIX ik]. The principal member of this group is ciprofloxacin [sip ro FLOX a sin], which has the widest clinical application. Other antibiotics in this group available in the United States are primarily employed to treat urinary infections (Figure 32.1). It seems likely that the size of this class of antibiotics will increase due to its wide antibacterial spectrum, favorable pharmacokinetic properties and relative lack of adverse reactions. Unfortunately, their overuse has already led to the emergence of resistant strains resulting in limitations to their clinical usefulness. 

Nanoparticles were first developed in the mid-seventies by Birrenbach and Speiser. Later on, their application for the design of drug delivery systems was made available by the use of biodegradable polymers that were considered to be highly suitable for human applications. At that time, the research on colloidal carriers was mainly focusing on liposomes, but no one was able to produce stable lipid vesicles suitable for clinical applications. In some cases, nanoparticles have been shown to be more active than liposomes due to their better stability.This is the reason why in the last decades many drugs (e.g., antibiotics, antiviral and antiparasitic drugs, cytostatics, protein and peptides) were associated to nanoparticles. 

Montie T and Patamasucon P. Aminoglycosides the complex problem of antibiotic mechanisms and clinical applications. Eur J Clin Microbiol Infect Dis 14 85-87,1995. 

Some antibiotics that have been derived from peptides were mentioned in Chapter l. The biosynthesis of penicillins was discussed in Chapter 8. Many peptide antibiotics are known. Some find clinical applications but others such as gramicidin S (9.7), tyrocidine A (9.8) and polymyxins (9.9) are too toxic for use in humans. Cyclosporin A (Figure 1.4), however, has immunosuppressive properties and it has been used in transplant surgery for this reason rather than for its antibiotic properties. Peptide antibiotics have some non-standard structural features and these may explain in part their antibiotic properties. First, cyclic peptides are not found in animal cells. Secondly, peptide antibiotics usually contain some unusual amino acids they may have the d configuration, be A-methylated or have other non-standard structural features. Clearly, these features are not compatible with direct ribo-somal synthesis. 

Recent reports on a number of other antitumor antibiotics merit mention because of their pertinence to the study of normal cell metabolism although the drugs in question either have little clinical applicability or are yet to receive adequate trial. Cycloheximide and related glutarimide... 

The remarkably successful clinical application of aminoglycoside antibiotics attracted the attention of many organic chemists. With his continuous interest in this field for more than 20 years, Sumio Umezawa accomplished the first total synthesis of many aminoglycosides, including paromamine,- neamine," trehalosamine, kanamycins A, B, and C, 2 butirosin B, tobramycin, " streptomycin, dihydrostreptomycin, and neomycins B and C. ... 

The article by Miyake (Kawasaki), Maeda (Tokyo), and this writer details the long career of Sumio Umezawa devoted to the chemistry and medicinal applications of antibiotics, especially the aminocycUtols (aminoglycosides), afield dominated by Sumio and his microbiologist/biochemist brother Hamao from the earliest days of streptomycin through to practical semisynthetic analogues developed by Sumio that have enjoyed wide clinical application. The complementary articles by the two Umezawa brothers in Volume 30 of this series remain a definitive reference work on these antibiotics. 

Brevin, Brevolin and Edein, three peptide antibiotics with structures yet unknown, are not in clinical use Table 1.4). Tyrothricin consists of a whole group of chemically and biologically closely related individuals, a feature known for the polymyxins, the bacitracins and other peptide-type antibiotics. The tyrothricin group is interesting not only because of its clinical application, but also from a historical viewpoint. Tyrothricin was the second antibiotic found, 10 years after the discovery of penicillin, in a direct search for antibiotic substances. As the first antibiotic of strictly peptide nature, it... 

Several comprehensive reviews have appeared and the ones by Jawetz in 1956 and Schwartz in 1964 give valuable information about their clinical application. The main emphasis here will therefore be on the chemistry of these compounds. The recent structural elucidations and the syntheses have cleared much of the confusion existing in this group of antibiotics. 

Synergistic action of colistin and polymyxin in combination with other antibiotics in vitro and in vivo has been reported by several investigators " . In clinical application the effect of these combinations seems to be more a broadening of the antimicrobial spectrum than a synergistic interaction. Several salts and derivatives of both colistin and polymyxin have been reported. Commercially available are the sulphates and also recently the sodium sulphomethyl derivatives which are prepared by treatment of the free bases of polymyxin and colistin with formaldehyde and sodium bisulphite . These derivatives have a lower toxicity than the sulphates, however, and their in vitro antimicrobial activity is also reduced. 

Florey The Clinical Application of Antibiotics Penicillin Oxford University Press, London, 1952... 

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