Microbial Resistance to Drugs

1 Role of the Outer Membrane of Gram-Negative Bacteria in Antimicrobial Resistance.- A. Introduction.- B. The Outer Membrane Barrier.- I. The Lipid Bilayer.- II. The Porin Pathway.- III. The Specific Pathways.- C. The Measurement of Outer Membrane Permeability.- I. Measurement in Intact Cells.- II. Measurement in Reconstituted Vesicles.- D. Permeability of Bacterial Outer Membranes to ?-Lactam Antibiotics.- I. Penetration Rates in E. coli.- II. Permeation Rate and Efficacy in E. coli.- III. Outer Membrane Permeability in Other Enteric Bacteria.- IV. Outer Membrane Permeability in P. aeruginosa and Other “Intrinsically Resistant” Organisms.- V. Gram-Negative Bacteria with Very High Sensitivity to ?-Lactams.- E. Permeation of Some Other Agents Through Porin Channels.- F. Contribution of Non-porin Pathways.- G. Outer Membrane Permeability to Polycationic Agents.- I. Polymyxin and Related Antibiotics.- II. Aminoglycosides.- H. Conclusions.- References.- 2 Cytoplasmic Membrane Transport and Antimicrobial Resistance.- A. Summary of Transport Systems.- I. Diffusional.- II. Active Transport.- III. Group Translocation.- B. Antimicrobial Resistance Associated with Antimicrobial Transport.- I. Introduction.- II. Use of Existing Transport Systems.- III. Use of Special Transport Systems.- IV. Diffusional Systems.- References.- 3 Susceptibility and Resistance of Plasmodium falciparum to Chloroquine.- A. Introduction.- I. Magnitude of Malaria as a Medical Problem and the Importance of Antimalarials.- II. Potential Interventions — Vaccines Vs. Drugs.- III. The Effect of Parasite Stage.- IV. Drugs Active Against Asexual Erythrocytic Parasites.- B. Mechanism of Chloroquine Action.- I. Previous Theories of Chloroquine Action.- II. Chloroquine and Acid Vesicles.- III. Chloroquine as a Weak Base.- IV. The Effect of Weak Bases on Lysosomal (Intravesicular) pH.- V. Concentration of Weak Bases Within Acid Vesicles.- VI. Effects of Mono- and Diprotic Weak Bases on Vesicle pH.- VII. The “Non-weak Base” Effect.- VIII. Chloroquine Accumulation by Plasmodium falciparum.- IX. Potential Biological Consequences of Raising Intravesicular pH.- C. Mechanism of Chloroquine Resistance.- D. Action of Mefloquine, Quinine, and Quinidine.- I. Mechanism of Mefloquine Action.- II. Quinine and Quinidine as Weak Bases.- III. Non-weak Base Activity and the Safety of Antimalarials.- E. Summary of Basic Concepts and Prospects for the Future.- I. The Acid Vesicle as a Pharmacologic Target Site.- II. Structure-Activity Relationships.- III. Prospects for the Future.- References.- 4 Resistance to ?-Lactam Antibiotics Mediated by Alterations of Penicillin-Binding Proteins.- A. Introduction.- B. Mechanisms of Resistance to ?-Lactam Antibiotics.- C. Classification of PBP Alterations in ?-Lactam-Resistant Strains.- I. Alterations in the Affinities of PBPs for ?-Lactam Antibiotics.- II. Alterations in the Amounts of PBPs.- III. Resistance by Illegitimate Acquisition of a Resistant PBP.- IV. Resistance by Homologous Acquisition of a Resistant PBP.- D. Laboratory Studies on the Development of ?-Lactam-Resistant PBPs in E. coli.- I Amino Acid Substitutions That Decrease the Affinity of PBP 3 for ?-Lactam Antibiotics.- II. Re-modelling of the Active Centre of PBP 3 to Obtain High Level Resistance to ?-Lactam Antibiotics.- E. PBP Alterations in Clinical Isolates.- I. Neisseria gonorrhoea.- II. Neisseria meningitidis.- III. Haemophilus influenzae.- IV. Streptococcus pneumoniae.- V. Staphylococcus aureus.- VI. Enterococci.- F. Concluding Remarks.- References.- 5 Plasmid-Determined Beta-Lactamases.- A. Introduction.- B. General Properties of Beta-Lactamases.- C. Classification of Beta-Lactamases.- D. Properties of Plasmid-Determined Beta-Lactamases.- I. Broad-Spectrum Beta-Lactamases.- II. Oxacillin-Hydrolyzing Beta-Lactamases.- III. Carbenicillin-Hydrolyzing Beta-Lactamases.- IV. Amp C Type Beta-Lactamases.- V. Staphylococcal Beta-Lactamases.- VI. Streptococcal Beta-Lactamases.- E. Relatedness of Plasmid-Determined Beta-Lactamases.- I. Immunological Cross-Reactivity.- II. DNA Hybridization.- III Amino Acid and Nucleotide Sequencing.- F. Spread of Plasmid-Deter mined Beta-Lactamases in Patient Flora.- I. Emergence of Variant Beta-Lactamases Active Against Newer Beta-Lactams.- G. Contribution of Plasmid-Determined Beta-Lactamases to Beta-Lactam Antibiotic Resistance.- References.- 6 The Chromosomal Beta-Lactamases.- A. Introduction.- B. General Characteristics.- I. The Reaction Catalyzed.- II. Classification Schemes.- C. Cephalosporinases.- I. Inducible Cephalosporinases.- II. Constitutive Cephalosporinases.- D. Oxyiminocephalosporinases.- I. Inducible Oxyiminocephalosporinases.- II. Constitutive Oxyiminocephalosporinases.- E. Penicillinases.- F. Broad-Spectrum Beta-Lactamases.- I. Metalloenzymes.- II. Enzymes from Klebsiella.- G. Subclassification Scheme for Chromosomal Beta-Lactamases.- References.- 7 Beta-Lactamases: Genetic Control.- A. Introduction.- B. Classification of Beta-Lactamases.- C. Regulation of Class A Enzymes.- I. Bacillus licheniformis.- II. Staphylococcus aureus.- D. Regulation of Class C Enzymes.- I. Constitutive: Escherichia coli.- II. Inducible.- E. Conclusion.- References.- 8 Resistance to Quinolones and Fluoroquinolones.- A. Introduction.- B. Mechanism of Action.- I. DNA Gyrase.- II. SOS Response.- III. Other Properties of Quinolones.- C. Mechanisms of Resistance.- I. Properties of DNA Gyrase Mutants.- II. Other Genetically Characterised Mutations Conferring Quinolone Resistance.- III. Properties of Mutants Defective in Components of the SOS Response.- IV. Properties of Strains of Gram-Negative Bacteria with Phenotypically Characterised Mechanisms of Resistance.- V. Mechanisms of Resistance in Bacteria Selected In Vivo.- VI. Inherent Resistance.- D. Clinical Implications of Resistance Mechanisms.- I. Pharmacokinetics.- II. Pathogenicity.- E. Summary and Conclusions.- References.- 9 Ribosomal Changes Resulting in Antimicrobial Resistance.- A. Introduction.- B. Changes in Ribosomal Proteins.- I. Protein Changes in the Eubacterial Small Ribosomal Subunit.- II. Protein Changes in the Small Subunit from Eukaryotic Ribosomes.- III. Protein Changes in the Eubacterial 50S Subunit.- IV. Protein Changes in the Eukaryotic 60S Subunit.- C. Changes in Ribosomal RNA Which Result in Antimicrobial Resistance.- I. RNA Changes in the Small Ribosomal Subunit.- II. RNA Changes in the Large Ribosomal Subunit.- D. Antibiotics and Phylogeny.- E. Ribosomal Antibiotic Resistance in Clinical Isolates.- F. Conclusions and Perspectives.- References.- 10 Methylation of RNA and Resistance to Antibiotics.- A. Introduction.- B. Resistance Due to Target Site Modification.- I. Resistance to Aminoglycosides.- II. Resistance to Thiostrepton.- III. Resistance to Macrolides, Lincosamides, and Antibiotics Related to Streptogramin B.- C. Concluding Remarks.- References.- 11 Resistance to Trimethoprim.- A. Introduction.- B. Mechanisms of Resistance.- I. Thymine-Requiring Strains.- II. Decreased Permeability.- III. Mutations in Dihydrofolate Reductase Structural Gene.- IV. Mutations Affecting Dihydrofolate Reductase Expression.- V. Trimethoprim Resistance in Staphylococcus aureus.- VI. Intrinsic Resistance.- VII. R-Plasmid Resistance in Gram-Negative Organisms.- C. Epidemiology of Trimethoprim Resistance.- I. Trimethoprim Resistance in Gram-Negative Organisms.- II. Trimethoprim Resistance in the Enteric Organisms Shigella and Salmonella.- III. Trimethoprim Resistance in the Non-enterobacteriaceae.- IV. Role of Transposition in the Dissemination of Plasmid Dihydrofolate Reductase Genes.- D. Mechanism and Epidemiology of Trimethoprim Resistance in Gram-Positive Organisms.- E. Conclusion.- References.- 12 Resistance to Sulfonamides.- A. Introduction.- B. Sulfonamide Usage Today.- I. Sulfonamides Alone and Combined with Antibiotics.- II. Sulfonamides in Combination with Dihydrofolate Reductase Inhibitors.- III. Sulfones and Other Agents.- IV. Sulfonamides in Veterinary Medicine.- C. Prevalence of Sulfonamide Resistance.- I. Bacteria.- II. Protoza.- D. Mode of Action of Sulfonamides.- E. Mechanisms of Sulfonamide Resistance.- I. Bacteria.- II. Plasmodia.- F. Genetics of Sulfonamide Resistance.- References.- 13 Chloramphenicol Acetyltransferases.- A. Chloramphenicol Resistance: General Aspects.- I. Introduction.- II. Chemistry and Properties of Chloramphenicol.- III. Emergence of Resistance to Chloramphenicol.- B. Enzymology of Chloramphenicol-Acetylation.- I. Acetylation and Inactivation.- II. Mechanism of the Reaction.- III. Structure of Chloramphenicol Acetyltransferase.- IV. Sequence Comparisons and Natural Variation.- C. Control of Expression of Chloramphenicol Acetyltransferases.- I. General Considerations.- II. Gram-Negative Bacteria.- III. Gram-Positive Bacteria.- References.- 14 General Properties of Resistance Plasmids.- A. Introduction.- B. Plasmid Classification.- I. Incompatibility Testing.- II. Extant and Religated Incompatibility Groups in Enterobacteriaceae.- III. Incompatibility Groups in Pseudomonas aeruginosa.- IV. Incompatibility Groups in Staphylococcus aureus.- V. Designation of Incompatibility Subgroups and Complexes.- C. Structure of Plasmids.- I. General Structure.- II. Molecular Sizes of Plasmids.- III. Plasmid Organization.- D. Plasmid Transfer.- I. Conjugative Pili.- II. Transfer Conditions.- III. Transfer Gene Organization.- IV. Surface Exclusion Systems.- E. Plasmid Maintenance and Replication.- I. Maintenance of IncH Plasmids.- II. Replication Functions of Mini-plasmids.- III. Incompatibility.- F. Antibiotic Resistance and Other Plasmid-Encoded Properties.- I. Chloramphenicol Resistance.- II. Tetracycline Resistance.- III. Trimethoprim Resistance.- IV. Tellurium Resistance.- V. Bacteriophage Inhibition.- VI. Citrate Utilization.- VII. Lactose Utilization.- VIII. Determinants of Pathogenicity.- G. Conclusions and Directions for Future Studies.- References.- 15 Clinical Laboratory Testing for Antimicrobial Resistance.- A. Introduction.- B. Standardization of Test Procedures.- I. Early Efforts.- II. Reports, Guidelines, and Standards by the National Committee for Clinical Laboratory Standards.- III. Culture Media for Antimicrobic Susceptibility Tests.- IV. Present State of Standardized AST.- V. Remaining Problems.- C. Relevance of Testing and Clinical Laboratory Correlation.- I. Influence of the Nature and Design of the Test System.- II. Influence of Host Factors.- III. Influence of Reporting Methods.- IV. Problems with Certain Organisms and Antibiotics.- D. DNA Probes for AST.- E. Conclusions.- References.- 16 The Molecular Epidemiology of Antimicrobial Resistance.- A. Introduction.- B. Plasmids as Strain Markers.- I. Brief Review of Methods.- II. Plasmids as Strain Markers.- III. Molecular Epidemiology in Gram-Positive Cocci.- C. Epidemic Plasmids.- D. Endemic Antibiotic Resistance.- I. The Spread of Resistant Strains.- II. Endemic Resistance Resulting from the Spread of R Plasmids Between Strains.- III. The Contribution of Stable R Plasmids to Endemic Resistance.- IV. The Role of Antibiotic Usage in the Selection and Dissemination of Antibiotic Resistance.- References.- 17 Microbial Persistence or Phenotypic Adaptation to Antimicrobial Agents: Cystic Fibrosis as an Illustrative Case.- A. Introduction.- B. Cystic Fibrosis and Microbial Persistence.- C. Factors Associated with Persistence of P. aeruginosa During Antimicrobial Therapy in Cystic Fibrosis.- I. Host-Related Factors.- II. Bacterially Related Factors.- References.- 18 Microbes Causing Problems of Antimicrobial Resistance.- A. Staphylococcus Species.- B. Streptococcus Species.- I. Streptococcus pneumoniae.- II. Streptococcus pyogenes.- III. Streptococcus faecalis.- IV. Haemophilus influenzae.- V. Neisseria gonorrhoeae.- C. Gram-Negative Aerobic Bacilli.- I. Gastrointestinal Pathogens.- II. Nosocomial Gram-Negative Bacteria.- III. Mycobacteria.- IV. Bacteroides Species.- V. Legionella pneumophila.- VI. Miscellaneous Bacteria.- References.