Antimicrobial Agents: Antibacterials and Antifungals
Editor: André Bryskier, M.D.1Category: Bacterial Pathogenesis
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Antimicrobial Agents: Antibacterials and Antifungals is a significant revision of an original French reference published by Ellipses in 1999. Featuring more than 1,200 illustrations, over 1,500 tables, and more than 3,000 references, this major new volume comprehensively covers the history, chemistry, synthesis, mechanisms of action, pharmacology, and efficacy of all antimicrobial agents.
Written by experts, Antimicrobial Agents opens with foundational material covering the history of antibacterial chemotherapy, the system of classifying antimicrobial agents, the epidemiology of resistance, and the development of an antibiotic. The body of the text is divided into antimicrobial classes, including new chapters that extensively cover Helicobacter pylori and methicillin-resistant Staphylococcus aureus. Also examined are antimicrobial agents that are in advanced states of development, products that are used on animals, agents that are as yet unexplored, and those for which development has ceased. All existing chapters have been thoroughly updated to reflect advances in technology and research since the publication of the first edition.
Unmatched in depth and scope of coverage, the new edition of Antimicrobial Agents: Antibacterials and Antifungals is the reference source for physicians, microbiologists, chemists, pharmacologists, research scientists, and all others involved in antimicrobial research and development.
Hardcover, 1,426 pages, illustrations, index.
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Chapter 1 : Historical Review of Antibacterial Chemotherapy
- Author: A. Bryskier
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Apart from a few parasitic diseases, the antibacterial chemotherapy developed by Paul Ehrlich at the end of the 19th century was limited purely to the treatment of syphilis. From 1945, research in the field of antibacterial chemotherapy followed two directions: (i) synthetic antibacterial agents not found in nature and (ii) antibiotics extracted from the fermentation of molds, actinomycetes, and other bacterial genera. In 1929, Fleming published his studies on the potent antibacterial activity of a very active substance known as penicillin, which was capable of inhibiting the growth of Streptococcus aureus and S. pyogenes and that was also practically devoid of toxicity. In the mid-1970s, the bacterial ecology of hospitals changed and the focus of concerns in anti-infective therapy moved towards P. aeruginosa and certain species of Enterobacteriaceae, particularly Proteus spp. Research into β-lactams was conducted simultaneously in the fields of penicillins and cephems. The major characteristic of these molecules is their good activity against cephalosporinase-producing strains of enterobacteria. In 1907, Charles Nicolle noted that Bacillus subtilis was capable of lysing pneumococci. Later, E. Duclaux discovered the same property in other Bacillus species. Future research into antibacterial chemotherapy should consider not only the potential antibacterial activity of the new derivatives but also their immunological properties.
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Chapter 2 : Antibiotics and Antibacterial Agents: Classifications and Structure-Activity Relationship
- Author: A. Bryskier
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This chapter focuses on the classification and structural-activity relationship of antibiotics and antibacterial agents. The β-lactam family comprises four groups of molecules: penams, penems, cephems, and monocyclic β-lactams. To these should be added the β-lactamase inhibitors, some of the structures of which are featured in the four main groups. The azetidinone nucleus alone can be replaced, and monobactams, monocarbams, monophosphatams, and other heterocycles can be distinguished according to the substituents of the nitrogen atom. Based on studies by researchers, who demonstrated the transferability of resistance to certain antibiotics between Escherichia coli and Shigella spp., other researchers were able to demonstrate that shigellae inactivated chloramphenicol. The majority of aminoglycosides have similar basic structures and are divided into four groups: streptomycin derivatives, 2-deoxystreptamine derivatives, spectinomycin derivatives, and fortimicin derivatives. The macrolides are macrocyclic antibiotics characterized by a central lactone ring containing 12 to 16 members, few double bonds, and no nitrogen atom; one or two amino sugars and/or neutral sugars are attached to the lactone or aglycone ring. More than 400 compounds constitute the family of peptide antibiotics. Dihydrofolate reductase (DHFR) inhibitors used therapeutically are the result of studies relating to the specificity of this enzyme for bacterial, parasitic, or epithelial cells. The antibacterial compounds display good antibacterial activity and a lack of inhibitory activity against epithelial cell DHFR.
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Chapter 3 : Epidemiology of Resistance to Antibacterial Agents
- Author: A. Bryskier
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All bacterial species and phyla are involved in the phenomenon of resistance to antibacterial agents, sometimes posing genuine therapeutic problems. The strategy of Enterobacteriaceae faced with the aggression represented by the oxyimino cephalosporins was the production of conventional enzymes commonly known as extendedbroad-spectrum β-lactamases (ESBLs). The prevalence of nosocomial infections varied from 5 to 17% for patients admitted to ICUs in the hospital setting. In a survey conducted in central Europe, all of the strains of Staphylococcus aureus were susceptible to mupirocin, except in the case of Italy, where 1.5% of methicillin-resistant S. aureus (MRSA) strains were resistant. In S. aureus, the main mechanism of resistance of quinupristin-dalfopristin is methylation of the 23S rRNA with cross-resistance with macrolides, lincosamides, and streptogramin B. In the inducible type of resistance, quinupristin remains active because it is not an inducer of methylase; if constitutive, quinuprisitin is inactive and the combination become bacteriostatic due to alteration of quinupristin-dalfopristin activity in vitro and in vivo. S. pneumoniae is one of the major pathogenic agents of community-acquired or nosocomial parenchymatous respiratory tract infections (RTIs). The frequency of mutation of Mycobacterium tuberculosis varies according to the different antituberculosis agents. Antibiotic resistance in M. tuberculosis has long been known, particularly with streptomycin and isoniazid. Primary resistance of M. tuberculosis to isoniazid is greater than 10% in some countries.
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Chapter 4 : Development of an Antibiotic: Microbiology
- Author: A. Bryskier
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This chapter deals with the antibacterial agent that is only one molecule among a series of compounds prepared by chemists before becoming a drug. Preselection is a crucial stage in the life of a new drug. Once a molecule is synthesized, its in vitro activity against a panel of strains belonging to selected bacterial genera and species is determined. Activity against S. aureus producing penicillinase is added, as well as that against P. aeruginosa and Acinetobacter. Strains resistant to clindamycin and cephamycins must be included for gram-negative bacilli. Nondiscriminatory models are prepared during the preselection phase of a molecule. After determining the in vitro activity, it is essential to determine the in vivo activity parenterally and orally. In fact, the in vitro activity is not necessarily correlated with good in vivo activity. In these systemic infection models, activity is tested against gram-positive cocci, Enterobacteriaceae, and P. aeruginosa. The susceptibility of the bacterial strain considered responsible for the infection is determined in the clinical microbiology laboratory of the center in which the study is being conducted. However, semiautomatic devices related to the antibiotic sensitivity test are used by some microbiology laboratories. Determination of breakpoints is one of the major factors for an antibiotic. The mechanism of resistance is an important factor for determining breakpoints for given bacteria. The MIC at which these bacterial species are shown to be resistant is the cutoff and can be considered as the concentration under which the strain is considered susceptible.
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Chapter 5 : Penicillins
- Author: A. Bryskier
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The development of penicillins and cephalosporins occurred in parallel and with the same aim in mind. The preparation of semisynthetic penicillins yielded molecules that were more active against gram-negative bacilli, particularly Pseudomonas aeruginosa, such as the α-carboxypenicillins, the N-acylpenicillins, and the α-sulfopenicillins. The first factor essential to the action of penicillins, particularly in gram-negative bacilli, is their ability to penetrate the walls of these bacteria. Methicillin is less stable against acid hydrolysis than the isoxazole penicillins, whose stability is similar to that of the phenoxypenicillins. A phenomenon of tolerance has been described with penicillin G for Streptococcus pneumoniae, S. pyogenes, S. agalactiae, streptococci of the viridans group, group C streptococci, certain strains of enterococci, L. monocytogenes, and lactobacilli. The first strains of penicillin G-resistant S. aureus were isolated soon after the introduction of penicillin G into London, England, hospitals. Methicillin and nafcillin are both more stable than the isoxazole penicillins, which are, in descending order, dicloxacillin, oxacillin, cloxacillin, and floxacillin. Among the N-acylpenicillins, four subgroups may be distinguished: the carbamoyls and the ureido-, acylureido-, and carbamoylureidopenicillins. The pharmacokinetics of penicillins are summarized in this chapter. The breakpoints for the N-acylpenicillins recommended by the French Antibiotic Sensitivity Test Committee are reported in the chapter. The penam nucleus is inactive but is essential for the antibacterial activity. Penicillin N (6-D-aminoadipoyl penicillin G) is 100 times less active than penicillin G against grampositive bacilli but is considerably more active against gramnegative bacteria.
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Chapter 6 : Cephems for Parenteral Use
- Authors: A. Bryskier, J. Aszodi
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Due to the importance of the cephems, it is essential to classify them so as to allow their optimal use. The cephems are characterized by an azetidinone ring, to which is attached an unsaturated hexacycle. Five classes of cephems may be distinguished in terms of the nature of the moiety: cephalosporins, cephamycins and cephabacins, oxa-1-cephems, carba-1-cephems, and miscellaneous. The dosage and dosing frequency of a cephalosporin are the result of a balance between its antibacterial activity and its pharmacokinetic profile. The molecules all have the same antibacterial spectrum, which principally includes gram-negative bacilli and gram-negative and gram-positive cocci, except for S. aureus. The carbacephem-type molecules are asymmetrical, and the substituents on the β-lactam moiety are in the cis position; the cis stereochemistry of the carbacephems is less stable thermodynamically than the trans stereochemistry. The antibacterial activity RWJ-54428 was designed to overcome methicillin resistance in methicillin-resistant S. aureus (MRSA) strains and ampicillin resistance in E. faecium by penicillin-binding proteins (PBP) alterations. In all species, total clearance was slower and the apparent elimination half-life was longer than that of RWJ- 54428. The antistaphylococcal activities of RWJ-333442 in comparison with RWJ-54428, vancomycin, and quinupristindalfopristin against S. aureus Smith were investigated in a sepsis model (Swiss-Webster mice) and were also investigated for S. aureus 076, a methicillin-resistant strain. A synergistic activity was shown to be species dependent in combination with streptomycin against E. faecalis.
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Chapter 7 : Oral Cephalosporins
- Authors: A. Bryskier, M. Lebel
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This chapter discusses about the chemical structures of oral cephalosporins. The antibacterial spectrum includes gram-positive cocci such as Staphylococcus aureus and S. epidermidis, and S. pneumoniae and some gram-negative bacilli such as Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. These cephalosporins exhibit increased activity against gram-negative bacteria and are more stable against hydrolysis by several types of β-lactamases. The in vitro activity of oral cephalosporins is well documented. The natural antibacterial spectrum of oral cephalosporins covers gram-positive cocci, gram-negative cocci, and some gram-negative bacilli. In an epidemiological survey where 1,527 clinical isolates of S. pneumoniae were collected, about 12% of the isolates were resistant to cefuroxime. Among the new oral cephalosporins, the percentage of protein binding of cefpodoxime is the lowest (21 to 33%). Age-related alterations in renal function appear to have the greatest potential influence on the pharmacokinetics of oral cephalosporins. Very few studies have been undertaken to determine the impact of hepatic insufficiency on the pharmacokinetics of oral cephalosporins since these are principally eliminated renally. The adverse effects associated with administration of oral cephalosporins are generally benign and infrequent. Gastrointestinal disturbances are the most common adverse events reported with oral cephalosporins: nausea, vomiting, and diarrhea. The types of unfavorable reactions due to oral cephalosporins might arbitrarily be classified into three categories: gastrointestinal disorders, allergic reactions (cutaneous and systemic), and other adverse effects.
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Chapter 8 : Carbapenems
- Author: A. Bryskier
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Current research into carbapenems is directed towards the synthesis of molecules that are more stable against hydrolysis by dehydropeptidase I (DHP-I), the reduction of neurologic side effects, the improvement of pharmacokinetic characteristics, oral absorption, and the absence of cross-resistance with imipenem. The structure-activity relationships of the carbapenems are complex, as they derive from an equilibrium that is difficult to achieve between antibacterial activity, chemical stability, and stability against hydrolysis by renal DHP-I. The 1-β-aminoethyl derivatives are active in vitro but are unstable at high pH, as an intramolecular rearrangement is produced. The attachment of an amino acid or a small peptide prevents this rearrangement. In this series, the chloro-L-alanine derivative possesses good in vitro and in vivo activity against P. aeruginosa and Staphylococcus aureus. The carbapenems exhibit good activity against Neisseria gonorrhoeae and Neisseria meningitidis. The carbapenems possess remarkable activity against Enterobacteriaceae; in particular, they are active against strains producing plasmid-mediated broad-spectrum and extended-spectrum enzymes and chromosomally mediated enzymes. There are a number of mechanisms of resistance to carbapenems. These are based on single or multiple phenomena: crossing of the bacterial wall, modification of the target penicillin-binding proteins (PBPs), and hydrolysis by β-lactamases. The imipenemases are chromosomal metalloenzymes capable of hydrolyzing the carbapenems. The major problem with the carbapenems is their chemical instability in solution. The plasma pharmacokinetics of the carbapenems are complex because of their hydrolysis by renal DHP-I to various degrees, depending on the molecule, with major interindividual variability.
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Chapter 9 : Penems
- Author: A. Bryskier
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Penems are β-lactams with an unsaturated nucleus at position 2,3 and a sulfur atom at position 1 (thiazolidine nucleus). The pharmacokinetic properties, antibacterial activity, and toxicological properties are based on the C-2 side chain. The introduction of a 6-(1-hydroxyethyl) group increases the antibacterial activity and stability against hydrolysis by β-lactamases. However, these properties are dependent on the stereochemistry. Only the 5R,6S, 8R isomer is active, whereas the other three isomers, 5R,6S,8S, 5R,6R,8R, and 5R,6R,8S, are inactive. Among the isomers, the 5R isomers are responsible for the antibacterial activity of the penems. Several series have been prepared with the aim of extending the antibacterial spectrum so as to obtain good stability against hydrolysis by renal dehydropeptidase and reduce the lipophilicity of the molecules. The activity of the penems against Enterobacteriaceae is inferior to that of the parenteral cephems, particularly against Enterobacter cloacae and Serratia marcescens. After crossing the outer membrane, the penems penetrate the periplasmic space, in which the β-lactamases are found, and finally reach their target, the penicillin-binding proteins (PBP), which are enzymes responsible for the synthesis of peptidoglycan. The penems are stable against hydrolysis by β-lactamases and may also inhibit the activity of some of them. The currently available penems are administered parenterally, principally intravenously; in the case of ritipenem, the intramuscular route appears to be possible.
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Chapter 10 : Monocyclic β-Lactams
- Author: P. Le Noc
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This chapter focuses on a few models of monocyclic β-lactams in which the structural changes are accompanied by changes to their antibacterial properties. The spectrum of activity of the monocyclic β-lactams: activity of all molecules against gram-negative cocci, Haemophilus influenzae, and Enterobacteriaceae; variable activity against Pseudomonas spp. and Acinetobacter baumannii depending on the compound; and lack of activity against gram-positive cocci and anaerobic bacteria. All of the monocyclic β-lactams inhibit Neisseria spp., M. catarrhalis, and H. influenzae at concentrations equal to or less than 0.25 µg/ml. The monocyclic β-lactams that have been the subject of killing kinetics studies have killing kinetics similar to those of the other β-lactams. The monocyclic β-lactams represent very weak substrates for the standard β-lactamases of gram-negative bacilli and for this reason are very stable against the hydrolytic activity of these enzymes. At subinhibitory concentrations, aztreonam and carumonam significantly increase the phagocytic activity and bactericidal activity of murine macrophage lines against different species of Enterobacteriaceae and Pseudomonas aeruginosa. The monocyclic β-lactams exhibit the general pharmacokinetic behavior of β-lactams, with similar parameters for the two types of compounds. The behavior of aztreonam, however, must be interpreted for a few sites where antibiotics diffuse poorly, such as the bronchial mucus, cerebrospinal fluid, prostate, and aqueous humor.
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Chapter 11 : β-Lactam Prodrugs
- Author: A. Bryskier
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This chapter discusses about β-Lactam Prodrugs. Esters are the most common prodrugs, while amides have been tried but are chemically unstable. Morita et al. studied the absorption of cefazolin and cephradine in neonatal and 1-, 2-, and 3-week-old rats. There is a linear relationship between intestinal absorption of cefazolin and the intraluminal concentration in 1-week-old rats. This absorption is not modified by carnosine or glycylglycine. Conversely, with cephradine, absorption is a saturable phenomenon in rats of the same age, and absorption is inhibited by carnosine and glycylglycine. The β-lactams may be considered tripeptide analogs. It has been shown in rats that there are different transporters and that the β-aminopenicillins and β-aminocephems are absorbed differently according to the pH gradient. The chemical structure of β-lactams interferes with intestinal absorption. The presence of a hydroxyl group on the phenyl nucleus in the para position of ampicillin (amoxicillin) or cephalexin (cefadroxil) increases intestinal absorption. The surface of the intestine is a lipid barrier. As per “pH-partition” model for the absorption of drugs, the degree of absorption of bases and weak acids depends on their liposolubility and their degree of ionization. This hypothesis predicts that molecules with a pK of less than 3 will be weakly absorbed. Penicillins and cephalosporins are antibiotics in which the pK of the carboxyl group is between 2 and 3.
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Chapter 12 : Peptidoglycan Synthesis Inhibitors
- Authors: A. Bryskier, C. Dini
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Bacterial peptidoglycans were first identified in the 1940s. The nucleotide precursors were isolated and characterized in 1949. Peptidoglycan biosynthesis has been investigated in many bacterial species. The glycan chains of peptidoglycan are small and repeated units composed of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). The glmM gene was shown to be essential in Escherichia coli, but genetic data recently suggested that in Staphylococcus aureus there could be an alternative pathway for glucosamine-1-phosphate biosynthesis. The GlmU protein from E. coli is a bifunctional enzyme. Its C-terminal domain catalyzes acetylation of glucosamine-1-phosphate into GlcNAc-1-phosphate, whereas its N-terminal domain catalyzes uridylation to yield UDP-GlcNAc. Nucleoside antibiotics can be subdivided into different classes according to their chemical structures and/or their respective modes of action against MraY: the tunicamycin group, the ribosamino-uridine group, and finally the capuramycin group. Some of them possess activities against gram-positive bacteria, against Mycobacterium spp., and against Pseudomonas spp. This toxicity is explained by their high inhibitory activity upon glycoconjugate biosyntheses, such as of techoic acids, glycosaminoglycans, and glycoproteins. The major component, caprazamycin B, exhibits anti-M. tuberculosis activity and excellent activity against M. avium complex. The major chemical difference observed between liposidomycins and FR-900493 resides in the presence of an N-functionalized amino acid residue in the FR-900493 structure, instead of the diazepanone ring of liposidomycins. Lantibiotics such as mersacidin, are gene-encoded peptides that contain unusual thioether amino acids and/or 3-methyllanthionine.
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Chapter 13 : β-Lactamase Inhibitors
- Author: A. Kazmierczak
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The most widespread mechanism of bacterial resistance to β-lactams is the biosynthesis of chromosomal or plasmid-mediated β-lactamases. Generally, the term β-lactamase inhibitor is reserved for β-lactams whose spectrum of inhibition covers all the β-lactamases to various degrees. While proposed in a fixed combination with ampicillin, only sulbactam was also available for extemporaneous combination with the most appropriate β-lactam for the β-lactamase-producing bacterial species concerned. It can be seen that for three TEM-3-producing species, the combinations of sulbactam plus cefotaxime, ceftazidime, and aztreonam are more effective than the fixed combinations clavulanic acid-ticarcillin and tazobactam-piperacillin. With 70% bioavailability following oral administration, clavulanic acid has proved to be well absorbed by the intestinal mucosa; as the same applies to amoxicillin, the combination of the two products is suggested for oral administration. The inhibitor and the β-lactam present in the bacterium compete for binding to the active site of the β-lactamase. As the inhibitors generally have a better affinity for the enzyme, the β-lactam may escape the hydrolytic activity of the β-lactamase if the concentration of inhibitor combined with it is sufficient to inactivate all of the β-lactamase molecules. It can thus be seen that the ideal combination is that of the best inhibitor with the β-lactam most resistant to the hydrolytic activity of the β-lactamases. The results obtained therapeutically suggest that clavulanic acid and tazobactam might also be proposed. This would allow the prescription of the most suitable combination of inhibitor and β-lactam for the bacterial species responsible for the infection.
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Chapter 14 : β-Lactamase Inhibitors Under Research
- Authors: André Bryskier, Catherine Couturier, John Lowther
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The main modes of resistance to β-lactams are modification of cell targets (penicillin-binding proteins), impermeability of the cell wall, efflux, and production of inactivating enzymes, the β-lactamases. β-Lactamases are a complex family of enzymes, and currently more than 300 unique β-lactamases have been reported for gram-positive and gram-negative bacteria. Research on β-lactamases led to different classifications, one of which is the Ambler classification describing four classes: A, C, D (serine β-lactamases), and B (metalloprotease β-lactamases). β-Lactamase inhibitors can be divided globally into two groups: β-lactams and non-β-lactams. A number of compounds of clavulanic acid have been prepared to explore the structure-activity relationship. It was shown that (i) the lack of the C-4 carboxylic group does not eliminate the β-lactamase inhibitory activity and (ii) a catalytic group at position 2 enhances the inhibitory activity 4 to 10 times. Semisynthetic penicillanic derivatives such as halo penicillanic acid sulfones were designed to mimic the mechanism of enzyme inactivation observed with clavulanic acid. PS-5 is hydrolyzed by β-lactamases of B. cereus, Proteus vulgaris, C. freundii, and Streptomyces spp. Intensive research on β-lactamase inhibitors is needed: (i) enlarge the inhibitory spectrum to cover class C and class B enzymes, (ii) to overcome the rapid spread of ESBL, and (iii) to be prepared for an eventual reduction of activity of existing compounds, such as clavulanic acid.
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Chapter 15 : γ-Lactams and Derivatives
- Author: A. Bryskier
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The β-lactams represent the largest clinical class of antibiotics. Interest has since turned to the pentacycles, which possess certain affinities for penicillin-binding proteins (PBP), such as the γ-lactams, pyrazolidinones, and isoxazolidinones (lactivicin). The first γ-lactams molecules to exhibit antibacterial activity were described in 1986. The first derivative, derivative A, is active against Staphylococcus aureus. The opening of the γ-lactam ring is dependent on the substituent at C-3. The increase in lipophilicity of the substituent at C-3 or on the oxime residue enhanced the activity against gram-positive bacteria but decreased that against gram-negative bacteria. Lactivicin is an antibacterial agent isolated from the fermentation of Empedobacter lactamgenus YK-258 and Lysobacter albus YK-422. Lactivicin is an acidic antibiotic that is soluble in water. The physicochemical properties of lactivicin and the methylated esters of the carboxyl group are summarized. Lactivicin is active against gram-positive bacteria and inactive against gram-negative bacteria. The mechanism of action of lactivicin is similar to that of the β-lactams. Synthetic derivatives have been prepared to reduce the parenteral toxicity and to increase the activity and antibacterial spectrum. The acute toxicity is 400 mg/kg of body weight subcutaneously and more than 400 mg/kg orally. The lack of the γ-lactam nucleus suppresses the antibacterial activity. Derivatives with a D-phenylglycyl group are inactive because they are unstable in a neutral or basic medium.
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Chapter 16 : Aminocyclitol Aminoglycosides
- Authors: P. Veyssier, A. Bryskier
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This chapter gives an overview about aminocyclitol aminoglycosides. Aminoglycosides are rapidly bactericidal antibiotics, acting in particular on aerobic gram-negative bacilli, staphylococci, and gram-positive bacilli. The aminoglycosides are broad-spectrum antibiotics essentially active against gram-negative bacteria and staphylococci. A penicillin-aminoglycoside combination exerts synergistic and bactericidal activity on streptococci with low-level resistance to streptomycin. The antibiotics of the aminoglycoside family are bactericidal. Majority of studies relating to their mode of action have been undertaken with streptomycin. A number of studies have been conducted on the structure activity relationships of aminoglycosides. Certain bacteria may be naturally and consistently resistant to aminoglycosides. Resistance may be acquired by four different mechanisms: alteration of the target, interference with transport of the antibiotic, enzymatic inhibition of the antibiotic, and substitution of the target. The aminoglycosides can only be used parenterally, except for intestinal infections or indications for decontamination. Diffusion of the aminoglycosides is rapid. The apparent volume of distribution corresponds to 20 to 30% of body weight, a volume equivalent to that of the extracellular fluids. The pharmacokinetics of elimination of the aminoglycosides are dependent almost exclusively on renal function. The drug interactions observed with aminoglycosides are particularly detrimental when they are liable to exacerbate the specific toxic effects of aminoglycosides antibiotics: ototoxicity, nephrotoxicity, and curarizing effect. Aminoglycosides have both renal and cochleovestibular toxicity. Substantial progress has been made in terms of understanding the mechanisms of resistance and toxicity.
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Chapter 17 : Spectinomycin
- Author: A. Bryskier
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The spectinomycin is a disaccharide antibiotic with a neutral sugar fused to actinamine (N,N'dimethyl-2-epi-streptamine) by a β-glycoside bond and a hemiacetal type of bond (1,4-dioxane), producing a tricyclic structure. The 3'-(R)-isomer has good antibacterial activity, in contrast to the 3'-(S)-aminospectinomycin isomer. The difference in activity between the isomers is probably due to the poor binding of the molecule at the ribosomal receptor sites, which occurs through hydrogen bonds. The attachment of an α-hydroxyl group to this molecule reintroduces antibacterial activity weaker than that of spectinomycin, showing clearly the importance of the hydroxyl groups and their spatial positions. Spectinomycin and trospectomycin are inactive or weakly active against methicillin-susceptible and -resistant strains of Staphylococcus aureus and coagulase-negative staphylococci. Trospectomycin exhibits good activity against penicillin G-susceptible and -resistant strains of Streptococcus pneumoniae, whereas spectinomycin is inactive. Against gram-positive bacilli, trospectomycin is more active than spectinomycin. Spectinomycin is inactive against anaerobic bacteria, while trospectomycin possesses activity weaker than that of clindamycin. Trospectomycin and spectinomycin possess good activity against Haemophilus ducreyi. Trospectomycin is much more active than spectinomycin against spectinomycin-susceptible strains of Neisseria gonorrhoeae, including strains resistant to ampicillin through a plasmid-mediated (PPNG) or chromosomal (CMRNG) mechanism, with or without resistance to tetracyclines.
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Chapter 18 : Macrolides
- Authors: A. Bryskier, E. Bergogne-Bérézin
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The natural macrolides of importance in human pathology are the 14- and 16-membered-ring macrolides; the semisynthetic derivatives of importance in human pathology are the 15-membered-ring macrolides (azalides). A characteristic of new molecules is the increased acid stability of the macrolides. This can be fully achieved with roxithromycin and azithromycin. The principal physicochemical properties of the macrolides are listed in this chapter. The natural antibacterial spectrum of the macrolides, irrespective of their structure, includes gram-positive bacteria; gram-negative cocci; fastidious gram-negative bacilli, such as Haemophilus influenzae, Moraxella catarrhalis, Pasteurella spp., and Bordetella spp.; anaerobic bacteria; intracellular bacteria; mycoplasmas and related species; spirochetes; bacteria responsible for gastrointestinal infections (V. cholerae and other Vibrio spp. and Campylobacter spp.); and H. pylori. Roxithromycin and azithromycin are very effective in experimental infection in rabbits with Treponema pallidum strain Nichols, whereas these molecules have cross-resistance with erythromycin A, as has been demonstrated with an erythromycin A-resistant strain of T. pallidum. The macrolides inhibit protein synthesis by binding to the 50S subunit of the bacterial ribosomes. The absorption and bioavailability of macrolides vary according to the molecule, partly explaining the difference in unit and dosage rhythm of the different macrolides. Many publications have shown that macrolides have nonantibiotic pharmacological effects. Some of these effects have been studied for their therapeutic potential (motilide) or are the subject of important basic research: anti-inflammatory or cardiological effects.
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Chapter 19 : Ketolides
- Author: A. Bryskier
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The ketolides belong to group IIC of the classification of macrolides. All ketolides are characterized structurally by the absence of an α-L-cladinose at position 3 of the erythronolide A and the presence of a 3-keto group. The affinity for ribosomes is higher for ketolides than for erythromycin A. The dissociation constants are summarized. Cethromycin binds tightly to ribosomes in comparison to erythromycin A. Blockade of the exit tunnel by ketolides induces premature dissociation of peptidyl-tRNAs from the ribosome. The available ketolides inhibit the assembly of 50S sub-units of Staphylococcus aureus and Streptococcus pneumoniae. Various ketolides have been shown not to be capable of inducing resistance to other macrolides. This phenomenon has been explored with strains of S. aureus, S. pneumoniae, and Streptococcus pyogenes in the presence of ketolides and their counterpart with an L-cladinose and with clarithromycin, erythromycin A, and azithromycin. Erythromycin A accumulation dropped about 70 to 80% after erm induction. Ketolides could accumulate in the bacterial cell to preinduction level, and the concentration remains high enough to interfere with the ribosome. The efflux mechanism of resistance of S. pneumoniae involves a Mef protein, which binds to macrolides and ketolides and extrudes them from the bacterial cell, resulting in reduced intracellular drug concentrations. The ability of sequential subcultures in subinhibitory concentrations of telithromycin, azithromycin, roxithromycin, clindamycin, and pristinamycin to select for resistance was investigated. Introduction of halogen at the C-2 position of the erythronolide A ring leads to the synthesis of HMR 3562 and HMR 3787.
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Chapter 20 : Streptogramins
- Author: A. Bryskier
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The streptogramins form a complex group of unique antibacterial agents. The streptogramins are composed of a mixture of two types of molecules: group A streptogramins and group B streptogramins. Each molecular complex contains both structures, but several compounds of each of the two groups may belong to the complex. The combinations of streptogramins plus aminoglycosides, rifampin, or β-lactams are synergistic. Both streptogramins A and B penetrate the bacterial cell by passive diffusion. Group A streptogramins act on the early stage of the protein synthesis, especially on the elongation phase of translation. Group B streptogramins exert inhibitory activity at the end of the process during extension of the peptide chain, causing premature detachment of the incomplete chain. A new mechanism of resistance was described in 1984: isolated resistance to factor A (pristinamycin IIA) and lincosamides (LSA phenotype) conferring low-level resistance to streptogramins. In the Protek study conducted from 2000 to 2001, it was shown that less than 0.02% of Streptococcus pneumoniae strains are resistant to dalfopristin-quinupristin. Each isolate had a 5-aminoacid tandem duplication in the L22 ribosomal protein gene (rplV), preventing synergistic ribosomal binding of the streptogramin combination. Staphylococcus aureus possesses a hydrolase on the same plasmid that opens the macrolactone ring of pristinamycin IA and causes it to lose its antibacterial activity despite good ribosomal binding. The majority of these S. aureus strains have reduced susceptibility to lincosamides. This chapter also talks about dalfopristin-quinupristin (RP-59500), RPR 106972, and XRP 2868.
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Chapter 21 : Lincosamines
- Author: A. Bryskier
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This chapter talks about lincosamides that consist of three components: an amino acid, a sugar, and an amide bond connecting these two moieties to one another. Margerlein and Kajan synthesized derivatives from clindamycin with variable substituents at N-1 and C-4'of the proline. While the N-demethyllincomycin derivative possesses only 2% of the activity of lincomycin against Staphylococcus aureus, this is not the case with the derivatives of clindamycin. Against Campylobacter jejuni, clindamycin possesses good activity, whereas lincomycin is inactive. Lincomycin is active against Leptospira spp. Clindamycin has good activity against anaerobes. In 1967, Lewis et al. showed that clindamycin and its derivatives possessed good antiplasmodial activity, in contrast to lincomycin, which is devoid of it. They also showed that lincomycin possessed no activity against Plasmodium bergheiin murine infection. By contrast, its 7-chlorolincomycin derivative, or clindamycin, has antiplasmodial activity. Lincomycin is presented in several pharmaceutical forms: oral, intravenous, intramuscular, and rectal. Micrococcus luteus is used in the microbiological assay, and chromatographic methods have been described. The majority of results have been obtained with clindamycin hydrochloride, but the metabolism involves the free form of clindamycin. Apart from N-demethyl clindamycin, which has antibacterial activity similar to that of clindamycin, the derivatives are devoid of activity.
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Chapter 22 : Oxazolidinones
- Author: A. Bryskier
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The aryl-oxazolidinones constitute a huge family composed of different chemical entities: antibacterials, agriculture derivatives, monoamine oxidase inhibitors, and antihistaminics. The antibacterial spectrum of DuP 105 and DuP 721 includes gram-positive cocci, gram-positive bacilli, anaerobic bacteria, and Mycobacterium tuberculosis. They are inactive against gram negative bacilli. Against common pathogens, including methicillin-resistant S. aureus (MRSA), ranbezolid displays in vitro activity similar to that of linezolid. Ranbezolid is active against gram-negative anaerobes. The oxazolidinones cannot cross the outer membrane of gram-negative bacilli, which explains their lack of activity against Enterobacteriaceae. A mutation in the 23S rRNA gene has been detected in linezolid- or eperezolid-resistant S. aureus and E.faecalis strains. New series of oxazolidinones have been synthesized with the intention of increasing the solubility in water so as to be able to prepare a pharmaceutical formulation for intravenous use, enlarge the antibacterial spectrum or enhance the antibacterial activity, or overcome linezolid resistance. A series of oxazolidinones has been synthesized with the aim of enhancing the activity against H. influenzae and M. catarrhalis. One of the concerns of the available oxazolidinones is the inhibition of monoamineoxidase (MAO), especially type A due to a structural similarity to MAO inhibitors such as toloxatone.
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Chapter 23 : Fusidic acid
- Author: A. Bryskier
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The steroidal antibiotics are divided into four classes: fusidic acid and its derivatives, helvolic acid and its derivatives, cephalosporin P1 and its derivatives, and viridomic acids A, B, and C. In the various series produced, the most active derivative is 3a-azido-3-deoxyfusidic acid, which has activity equal to 30% of that of fusidic acid. The 7a-hydroxyfusidic derivative has weak antistaphylococcal activity (10% of that of fusidic acid) but is twice as active against streptococci. Fusidic acid inhibits protein synthesis at the translation stage. When fusidic acid is used in combination with other antibacterials, the time to appearance of mutant strains is longer. Researchers in 1986 showed that fusidic acid inhibits the growth of Giardia lamblia in vitro. In patients with hepatic impairment, administration of fusidic acid must be avoided because of the possibility of (reversible) jaundice. It has recently been shown that the pharmacokinetics of fusidic acid in certain patients with hepatic insufficiency are unchanged. Fusidic acid concentrations of 1.0 to 2.3 µg/ml were detected in peritoneal fluid from six of the seven CAPD patients. Fusidic acid is highly albumin bound, on the order of 97 to 98%. Fusidic acid acts on mononuclear cells by reversibly reducing the amounts of interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α) released by activated cells. Fusidic acid also prevents the inhibitory effect of IL-β and the stimulatory effect of IL-6 on glucose-induced insulin production in vitro. Fusidic acid is antistaphylococcal antibiotic that does not exhibit cross-resistance with the β-lactams or rifampin.
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Chapter 24 : Tetracyclines
- Author: André Bryskier
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The use of tetracyclines is less widespread now than in the past due to the emergence of antibacterial resistance to these antibiotics and the discovery of more effective and selective molecules. The physicochemical properties of the tetracyclines may be modified by minimal structural variations. The antibacterial spectrum and activity of the tetracyclines include numerous gram-positive and gram-negative bacteria, anaerobes, rickettsiae, mycoplasmas, chlamydiae, Helicobacter pylori, and spirochetes. In the case of gram-negative bacteria, the first obstacle to be overcome is the bacterial outer membrane. Tetracyclines probably penetrate the periplasmic space via transmembrane proteins forming hydrophilic channels. The therapeutic use of tetracyclines is increasingly undermined by the frequent emergence of resistance. Hypersensitivity reactions to tetracyclines are rare but may include anaphylactic shock, urticaria, periorbicular edema, rashes, and morbilliform rashes. The hepatotoxicity of the tetracyclines, first described with chlortetracycline, is now known for all tetracyclines. The results of experimental studies in animals are contradictory with respect to the teratogenicity of tetracyclines: some authors have reported inhibited growth and skeletal deformities in the rat and chicken, whereas according to other authors this risk is nonexistent. Several authors have reported yellow or brown discoloration of the milk teeth in children born to mothers treated with tetracyclines (tetracycline and oxytetracycline) during the second and particularly the third trimesters of pregnancy. Majority of tetracyclines can cause a cerebral pseudotumor syndrome, characterized by a benign increase in intracranial pressure in children and adults. Tetracyclines are used in cases of nonspecific urethritis and urethral syndrome.
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Chapter 25 : Tetracyclines Under Investigation
- Author: A. Bryskier
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Tetracycline appears to bind directly to the S7 protein and to the region of 16S RNA from bases 892 to 1054. The hydroxyl group of tetracycline binds to the A892 base. At physiological pH, the tetracyclines exist as a mixture of two forms: (i) a low-energy, nonionized, lipophilic form and (ii) a high-energy zwitterionic form. Resistance to the action of tetracyclines is due principally to the acquisition of the Tet determinant and not to a chromosomally mediated mutation. The mechanisms of resistance of Neisseria gonorrhoeae are an exception. The tet(A) and tet(R) gene repressor and the TetA export molecule recognize the tetracyclines in the form of the chelation complex. Tet(M) and Tet(O) are 70% homologous in terms of their amino acid sequence, and likewise Otr(A), Tet(B)(P), and Tet(Q) are 45% homologous and form a third group. They appear to prevent the binding of tetracyclines to the ribosomes. The pharmacokinetics of thiacycline were determined versus those of doxycycline by Dingeldein and Ungethüm in 17 volunteers. Single doses of 100 and 200 mg of thiacycline and 200 mg of doxycycline were administered orally. The aglycone, dactylocyclinone or Sch-34164, possesses cross-resistance with the tetracyclines and is active against gram-negative bacteria. The MICs of minocycline are lower and dependent on the nature of the tet determinant. Tigecycline exhibits good in vitro activity against Streptococcus mitis, Streptococcus anginosus, Streptococcus sanguinis, Streptococcus bovis, and Streptococcus salivarius, with MICs under 0.25 µg/ml.
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Chapter 26 : Fluoroquinolones
- Author: A. Bryskier
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The majority of new fluoroquinolones have two ionizable functions: the 3-carboxyl group and a protonizable site at position 7, such as a 7-piperazinyl heterocycle. The majority of fluoroquinolones have good antistaphylococcal activity. Sitafloxacin, moxifloxacin, gatifloxacin, trovafloxacin, and gemifloxacin have excellent activity, while for grepafloxacin and gatifloxacin, the MIC50s are, respectively, 0.125 and 0.25 µg/ml. DC-756 is as active as sitafloxacin (DU-6859a), one of the most active fluoroquinolones against gram-positive cocci, against Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. KRQ 10099 is an analog of ofloxacin bearing a bicyclic nucleus instead of a piperazinyl moiety. KRQ 10018 is an 8-methyl-2-pyridone derivative. Against reference strains, KRQ 10018 is extremely active against gram-positive cocci, including ciprofloxacin-resistant S. aureus isolates and ofloxacin-resistant Staphylococcus epidermidis. The majority of fluoroquinolones are eliminated principally renally and/or biliarly. The major system is CYP1A2, the activity of which may be inhibited by the fluoroquinolones. In addition to its antiviral activity, zidovudine possesses a certain antibacterial activity against Enterobacteriaceae through its action on bacterial DNA. As a result of its activity on DNA, zidovudine might modify the activity of the fluoroquinolones. The currently available fluoroquinolones are not treatments for acute forms of malaria, but they may abolish a pauciparasitic form if administered simultaneously for another disease.
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Chapter 27 : DNA Gyrase Inhibitors Other Than Fluoroquinolones
- Author: A. Bryskier
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Conventional DNA gyrase inhibitors belong to two major families of antibacterial agents, the fluoroquinolones and the coumarin derivatives. A number of other antibacterial agents possess DNA gyrase-inhibitory activity, directed against either the A subunit or the B subunit of DNA gyrase. These are principally cinodine, coumadin, the pyrimido [1,6-α] benzimidazoles, cyclothialidine, clerocidin, or 2-pyridinecarboxyl derivatives. The potential point of interest of these molecules is that they have a mode of action similar to that of the fluoroquinolones or coumarin derivatives, but the molecular target is different, suggesting partial cross-resistance. The cinodines differ from one another by the structure of the pentose attached to the terminal part of the trisaccharide. A number of derivatives of coumadins, including molecule A, possess in vitro activity against certain bacterial genera, and they possess activity similar to that of clindamycin against anaerobes. The β-keto group of the fluoroquinolones is attached by hydrogen bonds to the purine and pyrimidine bases of DNA, with the exception of the cytosine. Clerocidin was isolated from Oidiodendron truncatum and Fusidium viride. Clerocidin exhibits cross-resistance with the fluoroquinolones against gram-negative bacilli, but this is only partial against Staphylococcus aureus. If the culture medium contains 9 mM Mg2+, the MICs and minimum bactericidal concentrations increase 2 to 4-fold, whereas those of the fluoroquinolones increase 16-fold. The products of the mcbB to -D genes allow the conversion of the glycyl-cysteine and glycyl-serine residues to 2-aminomethylthiazolyl-4-carboxylic acid and 2-amino-methyloxazolyl-4-carboxylic acid, respectively, which are essential for the activity of microcin B17.
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Chapter 28 : Codrugs
- Author: A. Bryskier
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The majority of codrugs studied possess either a cephalosporin, a penem, or a carbapenem. Studies of the mechanisms of action of codrugs have been conducted principally with Ro-23-9424, Ro-24-4384 (carbamate), and Ro-24-8138 (tertiary amine). The activity of the fluoroquinolones is evaluated in vitro in terms of the inhibition of DNA gyrase activity and in vivo in the bacterium in terms of its action on the nucleoid (topoisomerase IV) using 4’,6’-diamidino-2-phenylindole. Studies have been conducted on E. coli TE-18, which is a strain derived from E. coli K-12. The selection of fleroxacin-resistant mutants from this strain is greater than that observed with fleroxacin alone or from another strain, such as E. coli JF 568. The 3’-esters are much less chemically stable than the other derivatives. The first molecule in which a cephalosporin and a quinolone were combined was Ro-23-5068. The most widely studied molecule has been Ro-23-9424, but Ro-24-6392 has also been widely studied in vitro and in terms of the mechanism of action. Ro-25-0534 is a combination of a catechol-type cephalosporin and ciprofloxacin, linked by a tertiary amine bond. This molecule is active against strains of Enterobacteriaceae which are cefotaxime resistant as a result of cephalosporinase production. Combinations of penems and fluoroquinolones have been synthesized with the various bonds described for the cephalosporins. The chapter also talks about carbapenems-fluoroquinolones, penicillins-Quinolones, monocyclic β-lactams/quinolones, and oxazolidinones-quinolones.
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Chapter 29 : Coumarin Antibiotics: Novobiocin, Coumermycin, and Clorobiocin
- Authors: A. Bryskier, M. Klich
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This chapter provides an overview about coumarin antibiotics such as novobiocin, coumermycin, and clorobiocin. Novobiocin was the first antibacterial agent of this chemical class to be described. Two other chemical entities have been described in this chapter: the coumermycin complex and clorobiocin. Clorobiocin is composed of an 8-amino chlorocoumarin nucleus, a sugar (L-noviose substituted with a 5-methyl-1H-pyrrole-2-carboxylic moiety), and a benzoic chain identical to that of novobiocin. Two products are identical to coumermycin A1 (sugordomycin D-1a and sugordomycin D-1d). BL-C43 is active against gram-positive cocci and bacilli and against certain fastidious gram-negative bacilli, such as Haemophilus influenzae, Moraxella catarrhalis, Pasteurella multocida, and gram-negative cocci such as Neisseria gonorrhoeae. It is inactive against Enterobacteriaceae and nonfermentative gram-negative bacilli. This molecule appears to be slightly less active in vitro than novobiocin, but it is more active than lincomycin or erythromycin A. The determination of susceptibility by the antibiotic sensitivity test method involves disks with a dose of 5 µg. Antibacterial activities of natural coumarinic acid derivatives are listed in this chapter. Novobiocin binds to the 24-kDa protein fragment and stabilizes the structure so as to prevent the binding of triphosphate nucleosides. This reduces the pool of available enzymes and inhibits the hydrolysis of ATP. Novobiocin is well absorbed by the gastrointestinal tract. Less than 3% of the administered dose is eliminated in the urine; the drug is mainly eliminated in the bile. Concentrations in the feces are high.
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Chapter 30 : Peptide Antibiotics
- Author: A. Bryskier
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Peptide antibiotics differ structurally from conventional peptides in that they are cyclic and contain ester bonds and D-configured or unusual amino acids, unusual nuclei (such as saturated or unsaturated fatty acids), and heterocycles or amino or nonamino sugars. The peptide antibiotics can be divided into seven groups: I, linear peptides; II, cyclic peptides; III, glycopeptides; IV, lipoglycopeptides; V, lipopeptides; VI, thiazolopeptides; and VII, thiopeptides and chromopeptides. Polypeptide antibiotics induced during an infection in insects, such as cecropins or attacins, have been described in this class. It is highly effective against gram-negative bacilli like Escherichia coli and Pseudomonas aeruginosa, whereas gram-positive cocci, such as Staphylococcus aureus, are poorly inhibited. The majority of peptides of natural or synthetic origin cannot be used as therapeutic agents, as they are unstable in biological liquids, they are toxic, their antibacterial spectrum is limited, and they manifest only weak activity. The cyclic peptides are among the best-studied peptide antibiotics. The majority of molecules have two chlorine atoms on the triphenyl ether nucleus. The teichomycins are lipoglycopeptide antibiotics obtained from fermentation of an actinomycete, Actinoplanes teichomyceticus. In order of inhibitory activity, the pneumocandins may be classified as follows: B0 > A0, A4 > A2, B2 > C0. The bacitracin group consists of hexapeptide antibiotics with a substituted thiazolidine nucleus.
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Chapter 31 : Glycopeptides and Lipoglycopeptides
- Authors: A. Bryskier, P. Veyssier
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The glycopeptide and lipoglycopeptide antibiotics are natural antibiotics obtained from cultures of certain microorganisms. These antibiotics inhibit bacterial cell wall peptidoglycan synthesis but cannot cross the cell wall of gram-negative bacteria. Their antibacterial spectrum includes aerobic and anaerobic gram-positive bacteria. The glycopeptides may be divided into at least five groups on the basis of their chemical structures. Due to their large mass, glycopeptides cannot cross the lipoprotein cell wall of gram-negative bacteria and are therefore totally inactive against them. The molecules belonging to group II (Avoparcin Type) are mainly actinodin, avoparcin, chloropolysporin, galacardin, helvecardin, and synmonicin. Resistance to vancomycin and teicoplanin is due to synthesis of modified precursors that display decreased affinity for both compounds. Six types of resistance have been reported to date: VanA, VanB, VanC, VanD, VanE, and VanG. The combination of a glycopeptide with an aminoglycoside is synergistic against the majority of strains of staphylococci and enterococci. The in vitro activity of dalbavancin was investigated by following NCCLS-recommended methods and comparatively with vancomycin, linezolid, and quinuprisitin-dalfoprisitin (Q-D).
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Chapter 32 : Ansamycins
- Author: A. Bryskier
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Rifampin was obtained by semisynthesis from the 3-formylrifamycin derivative. It is possible to separate two groups of molecules within the ansamycin family according to the aromatic nucleus: ansamycins of the naphthalene type and ansamycins of the benzene type. Chemical modifications of the ansa in general cause a reduction or even complete abolition of antibacterial activity. The chapter discusses the physiochemical properties and production of rifamycin. The activity of the ansamycins decreases in parallel over time in phosphate-buffered saline (PBS) medium or in 7 H10 medium with or without Tween 80. The majority of rifamycins inhibit the transcription of DNA to RNA. The use of rifampin as monotherapy is associated with the rapid appearance of resistant mutants among common pathogens, particularly Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Neisseria meningitidis. The ansamycins have weak activity against enteric gram-negative bacilli and non-fermenting gram-negative bacteria. Rifampin is one of the pivotal drugs in the treatment of tuberculosis. The ansamycins are extensively concentrated in phagocytic cells. Rifampin is one of the pivotal drugs in the treatment of tuberculosis. The ansamycins are extensively concentrated in phagocytic cells. Rifampin, rifabutin, and rifapentine are primarily antituberculosis and antileprosy agents. Staphylococcal infections are one of the indications of rifampin. The adverse effects of rifampin are dependent on treatment duration and dose.
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Chapter 33 : Phenicols
- Authors: A. Fisch, A. Bryskier
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Chloramphenicol was the first broad-spectrum antibiotic to be used both systemically and orally. All phenicols are derived from dichloroacetic acid, with two other parts: an aromatic nucleus with an alkyl group in the para position and an aminopropanediol chain. In bacteria, the phenicols inhibit protein synthesis, but not that of peptidoglycan, polysaccharides, or nucleic acids. Binding of phenicols to the 50S ribosomal subunit inhibits the peptidation reaction, as chloramphenicol reduces the catalytic activity of peptidyltransferase; the translation of bacterial mRNA is therefore inhibited. Resistance to chloramphenicol is usually crossed with resistance to thiamphenicol. Sometimes another, more contingent mechanism of resistance is involved: acquired reduction in permeability of the bacterial outer membrane to phenicols. Pharmacokinetic studies with malnourished subjects are rare, although the phenicols are widely used in the most disadvantaged countries. The distribution of chloramphenicol in body tissues and fluids is very extensive, partly as a result of its marked lipophilicity. Chloramphenicol may interfere with a number of drugs, chiefly because of its hepatic metabolism. Chloramphenicol may interfere with a number of drugs, chiefly because of its hepatic metabolism. This interference has not been described with thiamphenicol. The principal problem of tolerance relates to chloramphenicol and the possibility of induction of hematologic accidents that are often irreversible and fatal. Typhoid fever, a classic indication for phenicol, has now become rapidly curable with fluoroquinolones. On the basis of the tropical public health data, the indications for phenicols very definitely remain much more extensive than in the industrialized countries.
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Chapter 34 : 5-Nitroimidazoles
- Author: L. Dubreuil
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This chapter summarizes information related mainly to the antibacterial activity of the 5-nitroimidazoles. Three 5-nitroimidazoles have been selected: metronidazole, ornidazole, and tinidazole. Metronidazole is the prototype and is therefore used most often as the representative molecule of the class; tinidazole is principally used as an antiprotozoal agent. The 5-nitroimidazoles are very active against the majority of gram-negative anaerobic bacteria and Clostridium. Anaerobic gram-positive cocci are more often susceptible to 5-nitroimidazoles, even if in the majority of studies 2 to 10% resistant strains are observed. Ornidazole levels measured in the cerebrospinal fluid (CSF) and brain represent at least 80% of levels in plasma; the same applies to concentrations in appendiceal fluid. The apparent elimination half-life and plasma clearance of ornidazole in nondialyzed subjects with renal insufficiency are similar to those in subjects with normal renal function. In patients with hepatic insufficiency, the peak concentrations in plasma occur later and the apparent elimination half-lives are prolonged. It is on the neurologic level that the most serious adverse effects are observed during high-dose and/or prolonged treatments. The three 5-nitroimidazole derivatives have very similar antibacterial properties; the pharmacokinetics are very similar, with a longer apparent elimination half-life for ornidazole than for metronidazole, possibly allowing the number of doses of ornidazole to be reduced. These 5-nitroimidazoles derivatives have excellent in vitro activity and well-established clinical efficacy in the treatment of anaerobic infections or in mixed infections when combined with antibiotics effective against aerobes.
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Chapter 35 : Dihydrofolate Reductase Inhibitors, Nitroheterocycles (Furans), and 8-Hydroxyquinolines
- Authors: P. Veyssier, A. Bryskier
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This chapter talks about dihydrofolate reductase inhibitors (DHFR), nitroheterocycles (furans), and 8-hydroxyquinolines. Trimethoprim and brodimoprim contain two nitrogen atoms on the pyrimidine ring which are easily protonable according to the pH of environment. Co-trimoxazole is one of the main antibacterial agents for the treatment of uncomplicated cystitis. Pharmacology studies show that the combination of compounds does not modify their behavior and that if co-trimoxazole is compared with the other combinations an advantage may be found for trimethoprim-sulfadiazine in urinary tract infections and renal insufficiency. Many 6-6 fused rings have been prepared with the aim of increasing the selectivity for T. gondii and P. carinii DHFR. A series of hybrids was synthesized. Within this series one analog was 500-fold more potent than trimethoprim against P. carinii and T. gondii and displayed an excellent selectivity. The combination of epiroprim and dapsone is highly effective against P. carinii pneumonia in rats and T. gondii infection in mice. In vitro, the sulfones are active against T. gondii, particularly dapsone. In murine P. carinii pneumocystosis, dapsone is effective in treatment and prevention. In humans, the combination trimethoprim-dapsone in curative treatment and dapsone alone in preventive treatment are effective. Like the sulfonamides, the sulfones interfere with folate synthesis. They also have a potent antioxidant action. Lastly, dapsone inhibits the transport of adenosine through the erythrocyte wall and prevents its incorporation in the nucleic acid of plasmodia and probably toxoplasmas and P. carinii.
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Chapter 36 : Mupirocin
- Author: A. Bryskier
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Mupirocin is active against gram-positive cocci: it has moderate activity against gram-positive bacilli such as Listeria monocytogenes and Erysipelothrix rhusiopathiae; it is inactive against corynebacteria and Bacillus anthracis. It is inactive against Chlamydia spp. It is active against Staphylococcus aureus, whether the strains are susceptible or resistant to penicillin G, tetracyclines, erythromycin A, fusidic acid, lincomycin, chloramphenicol, or methicillin. Mupirocin has good activity against human and animal mycoplasmas. As mupirocin is highly serum protein bound, the in vitro activity is reduced in the presence of human serum. Mupirocin alters protein synthesis by blocking the incorporation of isoleucine into the peptide during synthesis. Since 1985, when mupirocin was introduced into clinical practice, two types of resistant strains have been described: those for which the MICs are between 8 and 256 µg/ml and those for which the MICs are 512 µg/ml. Extensive use of mupirocin has resulted in the emergence of resistant strains of S. aureus in the United Kingdom. Local application of mupirocin yields in situ concentrations of 20,000 mg/kg. Skin and skin structure infections are very common, but the use of topical antibiotics or other antibacterial agents is limited by a number of factors: the complexity of the anatomy of the skin, the bacterial ecology of the skin, and the nature of the microorganisms involved in these infections. Mupirocin eradicates methicillin-resistant strains of S. aureus colonizing the skin and produces an improvement in the healing of skin wounds.
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Chapter 37 : Fosfomycin and Derivatives
- Author: E. Bergogne-BéRézin
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This chapter provides an overview about fosfomycin and derivatives. Fosfomycin belongs to the class of phosphonic antibiotics possessing a broad spectrum and exhibiting bactericidal activity against bacteria that fall within that spectrum. Two studies are reported in the literature; in one a broth medium was used to determine the MICs, while in the other the MICs in Mueller-Hinton agar were investigated. The in vitro activity of fosfomycin trometamol was better than that of pipemidic acid against Staphylococcus aureus and Enterococcus faecalis and better than that of amoxicillin against Escherichia coli and Klebsiella pneumoniae. Fosfomycin inhibits bacterial cell wall biosynthesis by acting on the initial stage in the synthesis of peptidoglycan precursors. N-Acetylglucosamine-3-O-enolpyruvyl transferase is essential for any bacterium possessing muramic acid in its cell wall structure, which accounts for the broad spectrum of antibacterial activity of fosfomycin since numerous gram-positive or -negative species possess muramic acid that constitutes cell wall peptidoglycan. For fosmidomycin, the principal intracellular target has not been identified. It would appear that fosfomycin and fosmidomycin have different targets in E. coli and/or that, in the absence of the hexose phosphate transport route, these two products are transported into the bacterial cell by different mechanisms. The results of studies of combinations of fosfomycin with other antibiotics, particularly β-lactams, are described in this chapter. Due to its good diffusion into bone, fosfomycin has been recommended in the treatment of staphylococcal bone and joint infections or those due to Pseudomonas.
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Chapter 38 : Orthosomycins
- Author: A. Bryskier
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The family of orthosomycins includes the everninomicins, which are oligosaccharide antibiotics containing two orthodiester bonds and a dichloroeverninic acid residue. The everninomicins are original antibiotics that belong structurally to the oligosaccharide antibacterial agents. They are characterized by an oligosaccharide structure with the presence of one or more orthodiester-type bonds. This type of bond is unusual in nature but has been described for a series of molecules grouped together in a family known as orthosomycins. Avilamycin is an orthosomycin complex extracted from Streptomyces viridochromogenes Tü 57 in 1965. An approach to the structure and activity of everninomicins has been undertaken by means of chemical modifications, particularly of evernimicin. The configuration of the two orthoester bonds at C-49 and C-16 is important for the antibacterial activity. Mechanisms of resistance to evernimicin are complex phenomena which include mainly mutations, methylation, and efflux. Recently it was shown that avilamycin A and evernimicin share common mechanisms of resistance. The rplP gene mutations have been also reported for enterococcal isolates resistant to avilamycin A. The steady-state apparent volume of distribution is on the order of 22 liters, indicating that evernimicin is distributed in the extravascular media. Evernimicin was thought to be an alternative in severe pneumococcal infections for which no other treatment is possible because of a multiresistant strain.
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Chapter 39 : Peptidyl Deformylase Inhibitors
- Authors: André Bryskier, John Lowther
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The chapter mainly focuses on peptidyl deformylase (PDF) inhibitors. Bacterial peptidyl deformylase (PDF) belongs to subfamily 3, with at least two other members: thermolysin and matrix metalloproteases (MMPs), namely, matricins and/or metzincins. Two classes of aminopeptidases are described: MAP-1 and MAP-2. MAP-1 and MAP-2 have similar specificities, with methionine cleavage depending on the nature of the second amino acid. MAP-2 is inhibited by fumagillin and TNP-470. Bacterial PDFs are small monomers composed of about 160 to 200 amino acids with few variations in the lengths of their N- and C-terminal extremities. Deformylase inhibitors can be classified in three groups: natural compounds, hydroxamate derivatives, and miscellaneous compounds. The hydroxamic moiety is crucial for the antibacterial activity, but the pseudopeptide backbone can be altered, such as the methionine-like structure. In addition to the antibacterial activity, it has been shown that actinonin inhibits several aminopeptidases, such as human seminal alanyl aminopeptidase, as well as tumor growth. A series of β-sulfonyl and β-sulfinyl hydroxamic acid derivatives has been shown to be potent PDF inhibitors with in vitro antibacterial activity. A macrocyclic deformylase peptide inhibitor was reported. The improved affinity for PDF is probably due to the rigidity introduced by cyclization. Some compounds exhibited good activity against Bacillus subtilis, Haemophilus influenzae, and Moraxella catarrhalis but weak activity against Streptococcus pneumoniae; they were inactive against Staphylococcus aureus.
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Chapter 40 : Helicobacter pylori and Antibacterial Agents
- Authors: André. Bryskier, John Lowther, Catherine Couturier
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The recognition of Helicobacter pylori as an etiological agent of gastric peptic ulcer, gastric adenocarcinoma, and mucosaassociated lymphoid tissue lymphoma is one of the most important advances made in gastroenterology in the past 50 years. Eradication therapy is recommended for infected persons who develop peptic ulcer disease or gastric lymphoma or who are beginning long-term treatment with nonsteroidal anti-inflammatory drugs. Among the few conserved families of efflux systems associated with bacterial resistance to antibacterial agents, one is widespread among gram-negative bacilli: the RND family. In Tartu, Estonia, 56 patients suffering from H. pylori infections were enrolled for testing of the susceptibility of H. pylori clinical isolates to antibacterial agents. There are few data regarding the H. pyloriresistance rate in the United States. The frequency of primary clarithromycin and metronidazole resistance among patients enrolled in different geographical areas in the U.S.-based clinical trials between 1993 and 1999 was assessed by MIC determinations using E-test. The rate of resistance to amoxicillin and tetracycline in this study among H. pylori isolates was low. The marked decrease of metronidazole in gastric juice after repeated administration of omeprazole is explained by the elevation of gastric pH induced by omeprazole. Ciprofloxacin was administered as a single dose of 500mg in 15 patients undergoing biopsies. Ciprofloxacin levels ranged from 1.5 to 1,762 mg/kg. Optimal concentrations were obtained after 1 h of dosing and reached 500 mg/kg. The in vitro activities of various antibacterial agents against H. pylori were assessed, including linezolid, dalfopristin-quinupristin, mupirocin, aminoglycosides, and fosfomycin.
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Chapter 41 : Microbial Efflux of Antibiotics and Inhibitors of Efflux Pumps
- Author: André Bryskier
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Detergent-like bile salts kill bacterial cells by destroying bacterial multidrug resistance (MDR) efflux systems. These not only play an important role in antibacterial resistance but also contribute to bacterial pathogenesis. Reserpine and H+/K+ ATPase inhibitors can significantly reduce MICs, increase killing activity, and prolong the postantibiotic effect of fluoroquinolones. Two proteins, NorM and YdhE, are representative of MDR efflux pumps. Resistance nodulation cell division family (RND) transporters are a three-component system. The RND pumps utilize the energy of the proton motive force to extract dyes, detergents, disinfectants, solvents, and antibiotics from the cell. AcrAB appears to regulate primarily by global regulators such as MarA (which responds to the presence of antibiotics or inhibitors). Few antibiotics are effective for the treatment of Acinetobacterinfections due to the numerous mechanisms of resistance and the frequency of MDR strains. Two genes, floR and tetC, encode efflux pumps belonging to the major facilitator superfamily (MFS) family. ATP-binding cassette (ABC) transporters are composed of at least 28 families for sugars, amino acids, ions, drugs, antibiotics, vitamins, iron complexes, peptides, proteins, complex carbohydrates, etc. Efflux pump inhibitors may be novel molecules belonging to a given new chemical family. In addition to being involved in the reduced susceptibility of gram-positive bacteria to fluoroquinolones, efflux pumps contribute to the acquired resistance which is selected upon exposure to the antibacterials.
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Chapter 42 : Paldimycin
- Author: A. Bryskier
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Paldimycin belongs to the group of antibiotics containing an isothiocyanate group. Three groups of molecules have been isolated: the proceomycins, senfolomycins A and B and the paulomycins. Proceomycin can be isolated from the fermentation broth of Streptomyces albolongus sp. nov. The physicochemical properties of Senfolomycins A and B are summarized in this chapter. They have good activity against Staphylococcus aureus and Enterococcus faecalis, but they are inactive against gram-negative bacilli. It has been possible to isolate paulomycins A and B, paldimycins A and B, and products 273a1α [A] and 273a1β [B]). The paulomycins differ from one another in the group at R1, which is a 2-methylbutyryl for paulomycin A and an isobutyryl for paulomycin B. The paldimycins and the 273a2 compounds are produced by the addition of two and one N-acetyl-l-cysteine, respectively, to paulomycins A and B. Paldimycin exhibits optimal antibacterial activity when the pH of the culture medium is less than 7. Paldimycin has good activity against S. aureus and coagulase-negative staphylococci, irrespective of whether the strains are methicillin susceptible or resistant. Among the molecules that manifest good activity against methicillin-resistant strains of S. aureus, paldimycin is one of the most active. Paldimycin has moderate activity against Listeria monocytogenes, but it has good activity against Corynebacterium jeikeium. Paldimycin appears to be active against Chlamydia trachomatis.
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Chapter 43 : Antituberculosis Agents
- Authors: André Bryskier, Jacques Grosset
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This chapter provides an overview on antituberculosis agents that include streptomycin, ansamycin and rifapentine. The discovery of the anti-tuberculosis (TB) activity of p-aminosalicylic acid (PAS) and isoniazid led to the standard 18-month treatment of TB with the triple combination of streptomycin, isoniazid, and PAS. Depending on their antibacterial activities and their toxicities to humans, anti-TB antibiotics are classified as first-line antibiotics, administered as first-choice treatment in any new case of TB, and second-line antibiotics, reserved for the treatment of patients with Mycobacterium tuberculosisresistant to the first-line antibiotics. Rifapentine looks like a sustainedrelease rifampin that is as active administered once weekly as rifampin administered daily. D-Cycloserine possesses a broad antibacterial spectrum, being active against the majority of mycobacteria, including M. avium-M. intracellulare, gram-positive bacteria such as Staphylococcus aureus, and gram-negative bacteria such as E. coli. The different species of M. tuberculosis complex have natural or clinical resistance to most of the standard antibacterials, such as macrolides. Treatment of mycobacterial infections is often difficult because the bacteria are intrinsically resistant to most antibacterials due to the specific outer membrane of M. tuberculosis. To conclude, it is important to emphasize the fact that therapeutic success depends not only on the initial susceptibility of the bacilli and the quality of the antibiotic combination prescribed but also on good treatment compliance. The HpsX protein can help M. tuberculosis to establish latency. It is required for growth in macrophages. It could be a new target for anti- M. tuberculosis treatment.
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Chapter 44 : Fluoroquinolones and Tuberculosis: a Review
- Authors: André Bryskier, John Lowther
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Some fluoroquinolones have been demonstrated to be effective companions in standard regimens of tuberculosis (TB) therapy, but the emergence of M. tuberculosis isolates resistant to fluoroquinolones, all of them having a cross-resistance, has led to discontinuation of their use in monotherapy. In a study, Tosufloxacin, a 1,8-naphthyridone compound, was shown to be inactive against 98 isolates of M. tuberculosis in a nonspecified agar medium. In this study, it was shown that in vitro sparfloxacin was the most active compound against all M. tuberculosis isolates. The in vitro activities of balofloxacin, cadrofloxacin (CS-940), and other fluoroquinolones against 100 M. tuberculosis isolates were assessed using an egg-based Ogawa medium and 7H10 Middlebrook agar medium. Fluoroquinolones are widely distributed in tissue, including within cells, where M. tuberculosis resides. Moxifloxacin at 20 mg/kg daily allowed a 100% survival rate, in comparison with a 50% survival rate in control mice after challenge with a large inoculum of the virulent strain CSU 98. It has been shown in murine infection induced by M. tuberculosis H37RV that among the fluoroquinolones and aminoglycosides, sparfloxacin at 50 mg/kg and amikacin at 200 mg/kg are the most active compounds after isoniazid (25 mg/kg) in treating TB in mice. The most active compound is PD-161144-like gatifloxacin, which was reported to show good antimycobacterial activity.
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Chapter 45 : Antituberculosis Compounds Under Investigation
- Author: A. Bryskier
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New antituberculosis (anti-TB) drugs are needed due to the emerging and spreading resistance of Mycobacterium tuberculosis to standard treatment such as isoniazid (INH), rifampin, pyrazinamide, ethambutol, or streptomycin. The AIDS pandemic stimulated research into and development of novel anti-TB agents; such agents have also been used to treat the opportunistic infections associated with AIDS such as Mycobacterium avium complex (MAC) infections, pneumocystosis, toxoplasmosis, cryptosporidiosis, and fungal infections. Pyrazinamide is an important component of short-course chemotherapy against TB because of its activity against semidormant bacilli sequestered within macrophages. Some fluoroquinolones exhibit good activity against M. tuberculosis and are used in second-line therapy, because resistance mutations occur rapidly. Mycobacteria are relatively resistant to drying, alkali, and many chemical disinfectants, making it difficult to prevent the transmission of TB in institutions and in urban environments in general. The anatomical and the physiological structures of mycobacteria can be good targets for research of novel derivatives. N-Octanesulfonylacetamide (OSA) is an inhibitor of fatty acid and mycolic acid biosynthesis in mycobacteria. Ethambutol is an effective inhibitor of the arabinan component of arabinogalactan. Rhein is a dried root and is derived from the outer corky layer of R. rhizoma.
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Chapter 46 : Antibacterial Treatment of Leprosy
- Author: J. Grosset
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Acquired resistance of Mycobacterium lepraeto the thioamides has been demonstrated in patients suffering from lepromatous leprosy treated with thioamides alone. Only the antibacterial treatment of leprosy, the principles on which it is based, the combinations with recommended antibiotics, and the results obtained to date in the field are discussed in this chapter. The whole argument behind modern chemotherapy of leprosy is based on the treatment of lepromatous or multibacillary leprosy, in the same way that the rationale for the chemotherapy of tuberculosis is based on the treatment of patients suffering from cavitary pulmonary tuberculosis. Dapsone, rifampin, and clofazimine therefore are automatically part of the initial phase of the chemotherapy of leprosy. From 109 at the beginning of treatment, the total number of viable M. leprae bacilli in a patient suffering from multibacillary leprosy therefore fell to 104! The majority of susceptible bacilli and mutants resistant to dapsone and clofazimine, which by definition are susceptible to rifampin, were eliminated. The first reason for continuing treatment beyond the first doses of rifampin is to prevent the risk of selection of rifampin-resistant bacilli. The second reason is that after very short-term multidrug therapy in patients suffering from Bamako multibacillary leprosy, it was found that the shorter the duration of antibiotic administration, the earlier relapses occurred. It is difficult to reduce the duration of the multidrug therapy recommended by the WHO. It is based on the combination of the three best-tolerated antibiotics, rifampin, dapsone, and clofazimine, of which only rifampin is highly bactericidal.
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Chapter 47 : Primycin
- Author: A. Bryskier
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Primycin is a product obtained from fermentation of Thermomonospora galeriensis, and is a complex of macrocyclic antibiotics comprising 20 compounds. This molecular complex is stable, and the molecules are linked to one another by hydrogen bonds. Primycin is insoluble in water, moderately soluble in methanol and 1,2-propanediol, and freely soluble in warm N-methylpyrroli-done, and it forms a stable gel that can contain up to 30% primycin (Ebrimycin). This gel forms the basis of the various pharmaceutical preparations. The molecular mass is on the order of 1,000 Da for each of the components, and the pK is 11. The median lethal dose in the mouse is greater than 3,000 mg/kg of body weight orally and 56 mg/kg intraperitoneally. No skin lesions have been observed after chronic cutaneous applications (90 days) in rabbits. Primycin possesses good in vitro antibacterial activity against Staphylococcus aureus and coagulase-negative staphylococci, but its activity against Streptococcus pyogenes and enterococci is moderate. After oral administration of 10 mg of primycin per kg to rats, no antibacterial activity was measured in the plasma (microbiological method using Bacillus subtilis) between 30 and 360 min after administration. The results were the same when primycin was administered at a dosage of 5 mg/kg for 7 days. No antibiotic activity was detected in the serum after application of 250 mg/kg.
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Chapter 48 : Benzonaphthyridones
- Author: A. Bryskier
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The use of mupirocin and fusidic acid in topical applications is jeopardized by the emergence of resistant bacteria. New medicinal chemical entities are needed to overcome this threat. Benzonaphthyridone molecules are one of the potential alternatives. From a new series of benzonaphthyridones, RP-60556A was selected for further preclinical investigation focused on its potential use as a topical antibacterial agent. RP-60556A is active against Staphylococcus aureus isolates with GlrA or GyrA mutations as well as against strains harboring an efflux mechanism of resistance (NorA). RP-60556A displays activity similar to those of fusidic acid and mupirocin against S. aureus strains susceptible to those antibacterials but remains active against mupirocin-and/or fusidic acid-resistant isolates. RP-60556A exhibits good in vitro activity against gram-positive anaerobes and against Bacteroides fragilis. This slight bactericidal activity remains against mupirocin-resistant S. aureus isolates. In vivo in a guinea pig model of cutaneous infection with S. aureus, a significant reduction of staphylococcal load per wound was shown in 24 h. The in vivo activity of a 2% topical formulation of RP-60556A in comparison with that of a 2% mupirocin formulation was investigated in a model of staphylococcal wound infection in guinea pigs. Antibacterials were applied 18 h after local bacterial challenge. RPR 203246 is slightly less active against S. aureus irrespective of the mechanism of resistance to pefloxacin.
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Chapter 49 : Agents against Methicillin-Resistant Staphylococcus aureus
- Author: André Bryskier
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Infections due to methicillin-resistant Staphylococcus aureus (MRSA) are associated with a mortality rate of 15 to 60%. The first report of S. aureus resistant to penicillin occurred in 1942. A series of glycopeptides was prepared at Shionogi and displayed good in vitro anti-MRSA activity, with MICs ranging from 0.20 to 6.25 µg/ml. Daptomycin possesses an unusual amino acid, kynurenine. Modifications of this amino acid were attempted on the ketone and anilino groups. These modifications highlighted the importance of this amino acid for antibacterial activity. One of the most effective antibacterial strategies is to disrupt the integrity of bacterial cell wall formation. Peptidoglycan includes four steps in which amino acid residues are ligated to uridine-diphospho-N-acetylmuramic acid (UDP-MurNac). Benzylidene rhodamine is an inhibitor of MurC and is active against MRSA (MICs, 31 µM). A series of derivatives was synthesized, with the aim of improving logP and water solubility, as well as protein binding. Molecular iron is an essential factor for bacterial growth, iron being used during respiration, DNA replication, and other biological processes. One of the targets of a research was to improve water solubility, to obtain in vivo activity against MRSA, and to obtain both anti-MRSA activity and activity against gram-negative bacteria, including Pseudomonas aeruginosa. Deformylase is an essential bacterial metallo-enzyme responsible for the removal of the N-terminal formyl group from methionine following protein synthesis. Methionine aminopeptidases play a pivotal role in protein biosynthesis.
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Chapter 50 : Mutilins
- Author: A. Bryskier
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Some mutilins, such as tiamulin and valnemulin, were introduced into veterinary medicine for the treatment of swine infections with Brachyspira hyodysenteriae (diarrhea) and Mycoplasma hyopneumoniae (pneumonia). Mutilins are semisynthetic derivatives having a tricyclic diterpenoid structure. They differ in their side chains. It was shown that the C-14 side chain is essential for antibacterial activity. The tricyclic diol mutilin did not inhibit protein synthesis. Pleuromutilins are mainly active against gram-positive bacteria and display moderate activity against fastidious gram-negative bacilli. Tiamulin MICs of >32, 4.0, and 0.06 to 0.5 µg/ml are observed for Bordetella bronchiseptica, Leptospira spp., and Mycoplasma spp., respectively. Tiamulin and valnemulin interact with adenines 2058 and 2059 and uracils 2506, 2584, and 2585. A new series of semisynthetic pleuromutilins was presented and one compound was selected for a preclinical investigation, SB264128. In pneumococcal infections, the burden reduction obtained with SB 264128 was significant (2.7 ± 1.0 log10 CFU/lung [mean plus/minus standard deviation]). In Haemophilus influenzae H 128 infection, bacterial counts in untreated rats were 5.3 plus/minus 0.7 log10 CFU/lung. SB 264128 exhibited a higher clearing activity (1.8 ± 0.2 log10 CFU/lung) than co-amoxiclav (3.5 ± 1.2 log10 CFU/lung).
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Chapter 51 : In Pursuit of New Antibiotics
- Author: André Bryskier
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Antibacterial agents were required to eradicate Helicobacter pylori, Clostridium difficile, and Legionella pneumophila microorganisms, and the objective has been achieved satisfactorily in the case of some bacterial species but not others, or intensive research has not yet resulted in one or more medications that fulfill the requirements, as for H. pylori. From 1980s to the 1990s, about two families of antibiotics resulting from the fermentation products of microorganisms were developed, such as mupirocin and monocyclic β-lactams from sulfazecin, giving rise to two medications, aztreonam and carumonam. More complex research has shown that the mechanisms of expulsion may differ in the same family of antibiotics. Bacteria need the iron which is found in the external environment for their physiology, and they use siderophores to obtain it. Some antibiotics, such as cephalosporins of the catechol type, use this route as a second mechanism of action. The adherence of bacteria can occur through pili for gram-negative bacilli or sortases for gram-positive bacilli. To enlarge the potential of virulence factor inhibitors, the central regulatory pathway was focused to avoid the narrow spectrum obtained with antipili, antitoxins. Anti-infective agents are not limited to antibacterial agents, and intensive research has been conducted on antifungal agents. There is an urgent need to find agents against Plasmodium falciparum, but also to increase the number of agents active against Leishmania donovani and Trypanosoma gambiense, to find drugs active against Chagas’ disease, and to produce new molecules against Giardia lamblia.
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Chapter 52 : Systemic Antifungal Agents
- Authors: R. Grillot, B. Lebeau
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Schematically, the current systemic antifungal agents can be divided into two categories: that of the antifungal antibiotics, which include griseofulvin and amphotericin B (AMB), and that of the chemical agents, which comprise all of the other molecules, flucytosine (5FC), the extremely rich series of azoles and, more recently, the allylamines and echinocandins. Given their value in the treatment of systemic mycoses, the authors discuss the three systemic azoles currently commercially available in parallel with voriconazole, which is currently available under an authorization for compassionate use, and conclude with the most recent triazoles under development. The azole compounds possess a relatively broad spectrum against numerous pathogenic or opportunistic fungal species, a spectrum that is exceeded only by that of AMB. Although all of these derivatives share good activity against some of these fungi (such as Candida albicans, Candida neoformans, and dimorphic fungi), major differences have been found in vitro and subsequently confirmed in animals and in clinical trials. Despite the considerable advances in antifungal therapy over the last few years, we are still far from possessing the ideal antifungal and progress is still necessary. Fungal infections remain a matter of concern, particularly in severe neutropenia (frequent inefficacy in disseminated mycoses) and AIDS (frequency of relapses and/or resistance in oroesophageal candidosis and cryptococcosis).
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Chapter 53 : Antifungal Targets and Research into Antifungal Agents
- Author: A. Bryskier
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Systemic infections of fungal origin are an attendant feature in immunodepressed patients. A study conducted in the United States between 1980 and 1989 already showed that nosocomial infections of fungal origin had increased by 40%. The number of species responsible for these infections remains relatively limited: Candida albicans (80%), Aspergillus fumigatus (15%), Candida tropicalis, and Cryptococcus neoformans. The activity of antifungal agents against P. marquandii is weak. The polyenes are a complex chemical class of macrocyclic agents that include amphotericin B (AMB) (parenteral use), pimaricin, nystatin (NYT), and candicidin. The fungal wall is an important target for potential antifungal agents. Mannoproteins are 50% composed of carbohydrates and are a potential cell wall target of antifungal agents. Antifungal agents have other sites of action: protein synthesis, cell division, and topoisomerases. Other potential sites of action of antifungal agents are under evaluation. The majority of molecules penetrate the fungal wall readily, the first obstacle being the cytoplasmic membrane, where the molecules must use permeases to penetrate the cytoplasm. The efflux mechanism is similar to the multidrug resistance mechanism of the other mammalian eukaryotic cells and has been described to occur in C. albicans for fluconazole.
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Chapter 54 : Drug Interactions during Anti-Infective Treatments
- Authors: O. Petitjean, P. Nicolas, M. Tod, C. Padoin, A. Jacolot
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The chapter presents an overview of drug-drug interactions that occur during anti-infective treatments. The solubilization of antifungal azoles, indinavir, delavirdine, or even dapsone requires an acidic pH, so acid suppressants greatly reduce their bioavailability. Di- or trivalent cations lead to the formation of insoluble or weakly soluble chelates with FQ, tetracyclines, rifampin, and ethambutol. Any metabolizable drug that penetrates the enterocyte and gains access to its cytosol will be metabolized by enterocytic CYP, a new stage which may be the subject of an interaction either by competition between substrates or by modification of the metabolic capacities of the enterocyte following coprescription of an enzyme inducer or inhibitor. Pulmonary CYPs are induced by cigarette smoke, a means of eliminating more actively chemicals contained in the smoke. Nowadays, evaluation of potential drug-drug interactions is mandatory for the registration of new drugs by regulatory agencies. The participation of substrate metabolites in drug-drug interactions at both levels, drug transport proteins and CYP enzymes, could also lead to discrepancies. In the vast literature dedicated to metabolic drug interactions, CYP3A4 has received the greatest attention. In the vast literature dedicated to metabolic drug interactions, CYP3A4 has received the greatest attention. The question of a fixed margin versus a varying margin in noninferiority trials has been addressed statistically for anti-infective treatments, taking into account the variable underlying clinical success rate of the reference treatment.
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Chapter 55 : Antibiotic Treatments and the Intestinal Ecosystem
- Author: A. Andremont
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Antibacterial agents belong to the therapeutic class whose use over the last few decades has most transformed human health and the prognosis for numerous systemic or localized infectious diseases. It is from the bacteria in the digestive tract that a number of systemic, opportunistic, and nosocomial infections arise. It is also within the intestinal ecosystem that favorable conditions exist for genetic exchanges between bacteria, exchanges which when they are fruitful may be the source of dissemination of the trait of resistance. This chapter talks about two essential concepts that need to be understood when attention is devoted to the human colonic flora: first of all, the host specificity of the bacterial species that make up the flora and, second, the stability of the composition within the same species and over time in the same individual. It also focuses on dominant and subdominant flora. Diseases due to anaerobic bacteria in the intestinal flora are much less common, but these too involve opportunistic types of disease. Many bacterial species may also be found in the human colonic flora. In fact, this apparent diversity masks great stability within the resident flora under normal conditions. The deleterious effect of antibiotic treatments on colonization resistance has been observed on many occasions. The chapter discusses the effect of antibiotics on the resident flora and decontamination. The digestive tract is the preferential site of multiplication and dissemination of resistance traits during antibiotic treatment.
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Chapter 56 : Interaction between Antimicrobial Agents and the Oropharyngeal and Intestinal Normal Microflora
- Authors: Åsa Sullivan, Charlotta Edlund, Carl Erik Nord
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The present knowledge of the impact of antimicrobial agents on the oropharyngeal and intestinal microflora and the optimal performance of such studies are discussed in this chapter. Disturbances in the oropharyngeal microflora are caused by administration of antimicrobial agents that reach high concentrations in oral tissues. Studies on the impact of antimicrobial agents on the normal microflora should be performed as comparative double-blind studies. Data on the impact of penicillins, cephalosporin, macrolides, ketolides, lincosamides, tetracyclines, nitroimidazoles and quinolones on the oropharyngeal microflora are summarized, as also the influence of monobactams, carbapenems, glycopeptides and streptogramins on the intestinal microflora. Knowledge about the interaction between antimicrobial agents and the normal microflora gives the clinician the possibility to choose agents associated with lesser degrees of ecological disturbances. Consequently, the risk of development of resistant strains and transfer of resistance elements between microorganisms is reduced. Further, consideration of the ecological consequences is also an important step to prevent distribution of resistant strains between patients in hospital settings. Individual pharmacokinetic variations as well as the character of composition and susceptibility of the normal microflora are variables that further influence the interactions.
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Chapter 57 : Clinical Quality Assurance and the International Development of New Anti-Infective Agents
- Authors: J. M. Husson, C. Lim, A. Bryskier
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This chapter analyzes the specific features of the clinical development of anti-infective agents (AIA) (antibacterials, antivirals, and antifungals) and identifies the general or specific rules for obtaining optimal quality. It discusses quality assurance (QA) of clinical trials on medical products, and problems posed by clinical evaluation of AIA. The only means of evaluating and improving the quality of French clinical trials will be (i) the official institution of inspections (medical and pharmaceutical inspectors) by the French authorities and (ii) the possible inspection by the FDA, the ideal in the future being the mutual recognition by the United States, Europe, and Japan of clinical trials after inspection by local authorities; this would require the prior institution of a system of inspection within the framework of the European Union. Total quality is an aim to be achieved in clinical research for any pharmaceutical company. The absence of standards in clinical bacteriology makes the systematic introduction of good laboratory practice (GLP) and clinical QAS within a short period a matter of necessity. Only a stricter methodological approach will allow the efficacy of AIA to be correctly evaluated but will also allow an intercenter comparison in the main countries of the world.
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Doody Enterprises
15 August 2013
At A Glance
Antimicrobial Agents: Antibacterials and Antifungals is a significant revision of an original French reference published by Ellipses in 1999. Featuring more than 1,200 illustrations, over 1,500 tables, and more than 3,000 references, this major new volume comprehensively covers the history, chemistry, synthesis, mechanisms of action, pharmacology, and efficacy of all antimicrobial agents. Unmatched in depth and scope of coverage, the new edition of Antimicrobial Agents: Antibacterials and Antifungals is the reference source for physicians, microbiologists, chemists, pharmacologists, research scientists, and all others involved in antimicrobial research and development.
Description
This is a comprehensive reference on antibiotics and antifungal agents. The chapters are arranged in a systematic fashion and cover each class of antibiotics as well as the mechanism of antibiotic resistance.
Purpose
According to the author, the purpose is to "bring together as much information as possible on the subject of antimicrobial agents." He has accomplished this purpose and this is a remarkable reference book! I am not aware of another publication with so much information on antimicrobial agents.
Audience
This is a book that should be used by all individuals studying, testing, or prescribing antibiotics. The authors studiously explain each antibiotic by structure, function, metabolic activity, and antimicrobial mechanism of action. They also look at the antibiotic from the bacterial view, thus explaining how antibiotic resistance occurs. In addition, new drugs under development are evaluated by comparison with antibiotics currently in use. This is a treasure trove of useful information.
Features
This book will become the ultimate reference for understanding antibiotics. The first few chapters summarize the history of antibiotic development and the different antibiotic classes. The remaining chapters systematically detail the various classes of antibiotics. Numerous figures show the structure of the antimicrobial molecules and how the structure is modified as new agents are generated. As I read through the first chapters, I was reminded again of the great miracle that antibiotics provide to mankind and the great scientists that committed themselves to this endeavor. We must use the information in this book to go forward with the struggle to overcome bacterial resistance to antibiotics.
Assessment
This is a second edition of a book that was first published in French. I would highly recommend to the large audience of scientists who study antimicrobial agents. As we move from the era of antibiotic development to antibiotic resistance, a complete understanding of these agents and the history behind their development is needed. This book will become the "go-to" reference for researchers, pharmacists, pharmacologists, microbiologists, and infectious disease physicians as we struggle to fight antibiotic resistance.
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Reviewer: Rebecca Horvat, PhD, D(ABMM) (University of Kansas Medical Center)
Review Date: Unknown
©Doody’s Review Service