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.Outbreaks of measles and chickenpox therefore tend tooccur annually in the late summer amongst children attending school for the first time.This has the effect of concentrating all susceptible individuals in one, often confined,space at the same time.The proportion of susceptibles can be reduced through rigorousvaccination programmes (Chapter 16).Provided that the susceptible population doesnot exceed the threshold FIP value, then herd immunity against epidemic spread of thedisease will be maintained.Certain types of infectious agent (e.g.influenza virus) are able to combat herdimmunity such as this through undergoing major antigenic changes.These render themajority of the population susceptible, and their occurrence is often accompanied byspread of the disease across the entire globe (pandemics).Further readingBisno A.L.& Waidvogel F.A.(1994) Infections Associated with Indwelling Medical Devices, 2nd edn.Washington: American Society for Microbiology.Minis C.A.(1991) The Pathogenesis of Infectious Disease, 4th edn.London: Academic Press.Salyers A.A.& Drew D.D.(1994) Bacterial Pathogenesis; a Molecular Approach.Washington:American Society for Microbiology Press.Smith H.(1990) Pathogenicity and the microbe in vivo.J Gen Microbiol, 136, 377-393. Part 2Antimicrobial AgentsThe theme of this section is antimicrobial agents; these are considered in three categories:first, antibiotics and de novo chemically synthesized chemotherapeutic agents; second,non-antibiotic antimicrobial compounds (disinfectants, antiseptics and preservatives);and third, immunological products.The subjects covered comprise the manufacture,evaluation and properties of antibiotics; the evaluation and properties of disinfectants,antiseptics and preservatives; the fundamentals of immunology; and the manufacture,quality control and clinical uses of immunological products.The mechanisms of actionof antibiotics and non-antibiotic agents are also considered, together with an accountof the ever-present problem of natural and acquired resistance.The principles involvedin the clinical uses of antimicrobial drugs are discussed in Chapter 6.Problems of recent years involving listeriosis, salmonellosis, giardiasis andLegionnaire's disease have received attention, as have the re-emergence of tuberculosisand the importance of methicillin-resistant Staphylococcus aureus (MRSA) andvancomycin-resistant enterococci (VRE).Appropriate suggestions for additional reading are provided. Types of antibiotics and synthetic5antimicrobial agents1 Antibiotics 8.1 Vancomycin1.1 Definition 8.2 Teicoplanin1.2 Sources9 Miscellaneous antibacterial antibiotics2 /3-lactam antibiotics 9.1 Chloramphenicol2.1 Penicillins and mecillinams 9.2 Fusidic acid2.2 Cephalosporins 9.3 Lincomycins2.2.1 Structure-activity relationships 9.4 Mupirocin (pseudomonic acid A)2.2.2 Pharmacokinetic properties2.3 Clavams 10 Antifungal antibiotics2.4 1-oxacephems 10.1 Griseofulvin2.5 1-carbapenems 10.2 Polyenes2.5.1 Olivanic acids2.5.2 Thienamycin and imipenem 11 Synthetic antimicrobial agents2.6 1-carbacephems 11.1 Sulphonamides2.7 Nocardicins 11.2 Diaminopyrimidine derivatives2.8 Monobactams 11.3 Co-trimoxazole2.9 Penicillanic acid derivatives 11.4 Dapsone2.10 Hypersensitivity 11.5 Antitubercular drugs11.6 Nitrofuran compounds3 Tetracycline group 11.7 4-quinolone antibacterials3.1 Tetracyclines 11.8 Imidazole derivatives3.2 Glycylcyclines 11.9 Flucytosine11.10 Synthetic allylamines4 Rifamycins 11.11 Synthetic thiocarbamates5 Aminoglycoside-aminocyclitol 12 Antiviral drugsantibiotics 12.1 Amantadines12.2 Methisazone6 Macrolides 12.3 Nucleoside analogues6.1 Older members 12.4 Non-nucleoside compounds6.2 Newer members 12.5 Interferons7 Polypeptide antibiotics 13 Drug combinations8 Glycopeptide antibiotics 14 Further readingAntibioticsDefinitionAn antibiotic was originally defined as a substance, produced by one microorganism,which inhibited the growth of other microorganisms.The advent of synthetic methodshas, however, resulted in a modification of this definition and an antibiotic now refersto a substance produced by a microorganism, or to a similar substance (produced whollyor partly by chemical synthesis), which in low concentrations inhibits the growth ofother microorganisms.Chloramphenicol was an early example.Antimicrobial agentsTypes of antibiotics 91 such as sulphonamides (section 11.1) and the 4-quinolones (section 11.7), producedsolely by synthetic means, are often referred to as antibiotics.SourcesThere are three major sources from which antibiotics are obtained.1 Microorganisms.For example, bacitracin and polymyxin are obtained from someBacillus species; streptomycin, tetracyclines, etc.from Streptomyces species; gentamicinfrom Micromonospora purpurea; griseofulvin and some penicillins and cephalosporinsfrom certain genera (Penicillium, Acremonium) of the family Aspergillaceae; and mono-bactams from Pseudomonas acidophila and Gluconobacter species.Most antibioticsin current use have been produced from Streptomyces spp.2 Synthesis.Chloramphenicol is now usually produced by a synthetic process.3 Semisynthesis.This means that part of the molecule is produced by a fermentationprocess using the appropriate microorganism and the product is then further modifiedby a chemical process.Many penicillins and cephalosporins (section 2) are producedin this way./^-lactam antibioticsThere are several different types of /3-lactam antibiotics that are valuable, or potentiallyimportant, antibacterial compounds.These will be considered briefly.Penicillins and mecillinamsThe penicillins (general structure, Fig.5.1 A) may be considered as being of the followingtypes.1 Naturally occurring.For example, those produced by fermentation of moulds suchas Penicillium notatum and P.chrysogenum.The most important examples arebenzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V).2 Semisynthetic.In 1959, scientists at Beecham Research Laboratories succeeded inisolating the penicillin 'nucleus', 6-aminopenicillanic acid (6-APA; Fig.5.1A: Rrepresents H).During the commercial production of benzylpenicillin, phenylacetic(phenylethanoic) acid (C6H5.CH2.COOH) is added to the medium in which thePenicillium mould is growing (see Chapter 7).This substance is a precursor of the sideFig.5.1 A, General structure of penicillins; B, removal of side chain from benzylpenicillin; C, siteof action of /3-lactamases. chain (R; see Fig.5.2) in benzylpenicillin.Growth of the organism in the absence ofphenylacetic acid led to the isolation of 6-APA; this has a different RF value frombenzylpenicillin which allowed it to be detected chromatographically.A second method of producing 6-APA came with the discovery that certainmicroorganisms produce enzymes, penicillin amidases (acylases), which catalyse theremoval of the side chain from benzylpenicillin (Fig.5.IB).Acylation of 6-APA with appropriate substances results in new penicillins beingproduced which differ only in the nature of the side chain (Table 5.1; Fig.5.2).Some ofthese penicillins have considerable activity against Gram-negative as well as Gram-positive bacteria, and are thus broad-spectrum antibiotics.Pharmacokinetic propertiesmay also be altered.The sodium and potassium salts are very soluble in water but they are hydrolysedin solution, at a temperature-dependent rate, to the corresponding penicilloic acid (Fig.5.3A; see also Fig.9.3), which is not antibacterial.Penicilloic acid is produced at alkalinepH or (via penicillenic acid; Fig.5 [ Pobierz całość w formacie PDF ]
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.Outbreaks of measles and chickenpox therefore tend tooccur annually in the late summer amongst children attending school for the first time.This has the effect of concentrating all susceptible individuals in one, often confined,space at the same time.The proportion of susceptibles can be reduced through rigorousvaccination programmes (Chapter 16).Provided that the susceptible population doesnot exceed the threshold FIP value, then herd immunity against epidemic spread of thedisease will be maintained.Certain types of infectious agent (e.g.influenza virus) are able to combat herdimmunity such as this through undergoing major antigenic changes.These render themajority of the population susceptible, and their occurrence is often accompanied byspread of the disease across the entire globe (pandemics).Further readingBisno A.L.& Waidvogel F.A.(1994) Infections Associated with Indwelling Medical Devices, 2nd edn.Washington: American Society for Microbiology.Minis C.A.(1991) The Pathogenesis of Infectious Disease, 4th edn.London: Academic Press.Salyers A.A.& Drew D.D.(1994) Bacterial Pathogenesis; a Molecular Approach.Washington:American Society for Microbiology Press.Smith H.(1990) Pathogenicity and the microbe in vivo.J Gen Microbiol, 136, 377-393. Part 2Antimicrobial AgentsThe theme of this section is antimicrobial agents; these are considered in three categories:first, antibiotics and de novo chemically synthesized chemotherapeutic agents; second,non-antibiotic antimicrobial compounds (disinfectants, antiseptics and preservatives);and third, immunological products.The subjects covered comprise the manufacture,evaluation and properties of antibiotics; the evaluation and properties of disinfectants,antiseptics and preservatives; the fundamentals of immunology; and the manufacture,quality control and clinical uses of immunological products.The mechanisms of actionof antibiotics and non-antibiotic agents are also considered, together with an accountof the ever-present problem of natural and acquired resistance.The principles involvedin the clinical uses of antimicrobial drugs are discussed in Chapter 6.Problems of recent years involving listeriosis, salmonellosis, giardiasis andLegionnaire's disease have received attention, as have the re-emergence of tuberculosisand the importance of methicillin-resistant Staphylococcus aureus (MRSA) andvancomycin-resistant enterococci (VRE).Appropriate suggestions for additional reading are provided. Types of antibiotics and synthetic5antimicrobial agents1 Antibiotics 8.1 Vancomycin1.1 Definition 8.2 Teicoplanin1.2 Sources9 Miscellaneous antibacterial antibiotics2 /3-lactam antibiotics 9.1 Chloramphenicol2.1 Penicillins and mecillinams 9.2 Fusidic acid2.2 Cephalosporins 9.3 Lincomycins2.2.1 Structure-activity relationships 9.4 Mupirocin (pseudomonic acid A)2.2.2 Pharmacokinetic properties2.3 Clavams 10 Antifungal antibiotics2.4 1-oxacephems 10.1 Griseofulvin2.5 1-carbapenems 10.2 Polyenes2.5.1 Olivanic acids2.5.2 Thienamycin and imipenem 11 Synthetic antimicrobial agents2.6 1-carbacephems 11.1 Sulphonamides2.7 Nocardicins 11.2 Diaminopyrimidine derivatives2.8 Monobactams 11.3 Co-trimoxazole2.9 Penicillanic acid derivatives 11.4 Dapsone2.10 Hypersensitivity 11.5 Antitubercular drugs11.6 Nitrofuran compounds3 Tetracycline group 11.7 4-quinolone antibacterials3.1 Tetracyclines 11.8 Imidazole derivatives3.2 Glycylcyclines 11.9 Flucytosine11.10 Synthetic allylamines4 Rifamycins 11.11 Synthetic thiocarbamates5 Aminoglycoside-aminocyclitol 12 Antiviral drugsantibiotics 12.1 Amantadines12.2 Methisazone6 Macrolides 12.3 Nucleoside analogues6.1 Older members 12.4 Non-nucleoside compounds6.2 Newer members 12.5 Interferons7 Polypeptide antibiotics 13 Drug combinations8 Glycopeptide antibiotics 14 Further readingAntibioticsDefinitionAn antibiotic was originally defined as a substance, produced by one microorganism,which inhibited the growth of other microorganisms.The advent of synthetic methodshas, however, resulted in a modification of this definition and an antibiotic now refersto a substance produced by a microorganism, or to a similar substance (produced whollyor partly by chemical synthesis), which in low concentrations inhibits the growth ofother microorganisms.Chloramphenicol was an early example.Antimicrobial agentsTypes of antibiotics 91 such as sulphonamides (section 11.1) and the 4-quinolones (section 11.7), producedsolely by synthetic means, are often referred to as antibiotics.SourcesThere are three major sources from which antibiotics are obtained.1 Microorganisms.For example, bacitracin and polymyxin are obtained from someBacillus species; streptomycin, tetracyclines, etc.from Streptomyces species; gentamicinfrom Micromonospora purpurea; griseofulvin and some penicillins and cephalosporinsfrom certain genera (Penicillium, Acremonium) of the family Aspergillaceae; and mono-bactams from Pseudomonas acidophila and Gluconobacter species.Most antibioticsin current use have been produced from Streptomyces spp.2 Synthesis.Chloramphenicol is now usually produced by a synthetic process.3 Semisynthesis.This means that part of the molecule is produced by a fermentationprocess using the appropriate microorganism and the product is then further modifiedby a chemical process.Many penicillins and cephalosporins (section 2) are producedin this way./^-lactam antibioticsThere are several different types of /3-lactam antibiotics that are valuable, or potentiallyimportant, antibacterial compounds.These will be considered briefly.Penicillins and mecillinamsThe penicillins (general structure, Fig.5.1 A) may be considered as being of the followingtypes.1 Naturally occurring.For example, those produced by fermentation of moulds suchas Penicillium notatum and P.chrysogenum.The most important examples arebenzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V).2 Semisynthetic.In 1959, scientists at Beecham Research Laboratories succeeded inisolating the penicillin 'nucleus', 6-aminopenicillanic acid (6-APA; Fig.5.1A: Rrepresents H).During the commercial production of benzylpenicillin, phenylacetic(phenylethanoic) acid (C6H5.CH2.COOH) is added to the medium in which thePenicillium mould is growing (see Chapter 7).This substance is a precursor of the sideFig.5.1 A, General structure of penicillins; B, removal of side chain from benzylpenicillin; C, siteof action of /3-lactamases. chain (R; see Fig.5.2) in benzylpenicillin.Growth of the organism in the absence ofphenylacetic acid led to the isolation of 6-APA; this has a different RF value frombenzylpenicillin which allowed it to be detected chromatographically.A second method of producing 6-APA came with the discovery that certainmicroorganisms produce enzymes, penicillin amidases (acylases), which catalyse theremoval of the side chain from benzylpenicillin (Fig.5.IB).Acylation of 6-APA with appropriate substances results in new penicillins beingproduced which differ only in the nature of the side chain (Table 5.1; Fig.5.2).Some ofthese penicillins have considerable activity against Gram-negative as well as Gram-positive bacteria, and are thus broad-spectrum antibiotics.Pharmacokinetic propertiesmay also be altered.The sodium and potassium salts are very soluble in water but they are hydrolysedin solution, at a temperature-dependent rate, to the corresponding penicilloic acid (Fig.5.3A; see also Fig.9.3), which is not antibacterial.Penicilloic acid is produced at alkalinepH or (via penicillenic acid; Fig.5 [ Pobierz całość w formacie PDF ]