Microbial Resistance to Drugs

Most often when the subject of antimicrobial resistance is discussed, the organizational emphasis is on individual antimicrobial agents or groups of agents. Thus we tend to see discussion of resistance to f3-lactams, tetracyclines, amino­ glycosides etc. In this book many of the authors were asked to emphasize the mechanism of resistance in their discussion and from that to show how susceptibility to various agents was affected. In part this was done to help emphasize the enormous contribution that the study of antimicrobial resistance has made to our understanding of fundamental physiologic and genetic processes in bacteria. When one looks back over the study of antimicrobial resistance, it is clear that it has been the birthplace of many fundamental advances in molecular biology and of an appreciation of the role of many key functions in the life of a bacterium. In addition, and hopefully to an increasing extent in the future, such study has also contributed to advances in antimicrobial chemotherapy. Through­ out the book resistance mechanisms have been placed in perspective as to their significance as causes of resistance to key drugs or groups of drugs. Some are of much greater significance than others in terms of the prevalence or the degree of resistance produced. Whatever their numerical significance, however, each of the mechanisms, without question, throws light on fundamental cellular processes and the way in which they interact with antimicrobial agents.

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.