New Antimicrobials: For the Present and the Future

Description

This is a timely and essential companion to the recently published Antimicrobial Resistance in the 21st Century, Second Edition. Antimicrobial resistance is a major threat to global population health, with government reports projecting it could result in over 10 million deaths in the next 35 years. Development of new agents to combat this threat is one of the WHO's top priorities, but in 2017, it conceded that the current drug development pipeline was insufficient to mitigate the threat. This book discusses recent progress and bolster new agent discovery and development, by providing researchers and students who will soon enter the field with a thorough guide to the advancements made in the last decade.  Coverage includes new systemic antimicrobials approved since 2010, with detailed analysis of antibiotics, antivirals, antifungals, and antiparasitics, as well as agents in development for future use. Discussion of each drug will include its chemical nature, pharmacology/pharmacokinetics, antimicrobial spectrum, dosage, adverse reactions, drug interactions, microbial resistance, indications, clinical efficacy compared to older agents, and lists of similar agents with cost comparison. This volume is designed for researchers and students of infectious disease and medical microbiology, as well as clinicians in need of a comprehensive guide to newly developed agents.  Preface Contents Chapter 1: Antimicrobial Resistance: A Crisis in the Making 1.1 Introduction 1.2 Antimicrobial Resistance: An Evolutionary Process 1.3 Mechanisms of Microbial Resistance 1.4 Bacterial Resistance 1.4.1 Restriction of Access 1.4.2 Modification of Target 1.4.3 Degradation by Enzymes 1.4.3.1 Beta-lactamases 1.4.3.2 Aminoglycoside-Modifying Enzymes 1.4.3.3 Chloramphenicol Acetyltransferase 1.4.3.4 Efflux Pumps 1.4.4 Genetic Mechanisms of Bacterial Resistance 1.5 The Toll of Antimicrobial Resistance 1.5.1 Effect on Healthcare 1.5.2 Economic Effect 1.6 Global Response to Antimicrobial Resistance 1.6.1 Comments on Global Response References Part I: New Antibacterial Agents Chapter 2: New Cephalosporins: Fifth and Sixth Generations 2.1 Introduction 2.2 Ceftaroline 2.2.1 Mechanism of Action and Microbial Spectrum 2.2.2 Pharmacokinetics of Ceftaroline 2.2.3 Clinical Efficacy of Ceftaroline 2.2.4 Side Effects of Ceftaroline 2.3 Ceftobiprole 2.3.1 Mechanism of Action and Microbial Activity of Ceftobiprole 2.3.2 Pharmacology of Ceftobiprole 2.3.3 Phase 3 Clinical Studies of Ceftobiprole 2.3.4 Safety Profile of Ceftobiprole 2.3.5 Role of Ceftaroline and Ceftobiprole in Clinical Practice 2.4 Cefiderocol: A Novel Siderophore Cephalosporin 2.4.1 Chemistry and Mechanisms of Action of Cefiderocol 2.4.2 In Vitro Activity of Cefiderocol 2.4.3 Resistance to Cefiderocol 2.4.4 Pharmacokinetic/Pharmacodynamic Aspects of Cefiderocol 2.4.5 Efficacy and Tolerability of Cefiderocol 2.4.6 Role of Cefiderocol in Clinical Infectious Diseases References Chapter 3: New β-Lactam-β-Lactamase Inhibitor Combinations 3.1 Introduction 3.2 Ceftolozane-Tazobactam 3.2.1 Antimicrobial Activity of Ceftolozane/Tazobactam 3.2.2 Pharmacokinetics/Pharmacodynamics of Ceftolozane/Tazobactam 3.2.3 Resistance to Ceftolozane/Tazobactam 3.2.4 Clinical Efficacy and Safety of Ceftolozane/Tazobactam 3.2.5 Summary and Place in Therapy of Ceftolozane/Tazobactam 3.3 Ceftazidime/Avibactam 3.3.1 In Vitro Activity of Ceftazidime/Avibactam 3.3.2 Pharmacokinetic/Pharmacodynamics of Ceftazidime/Avibactam 3.3.3 Therapeutic Efficacy of Ceftazidime/Avibactam 3.3.4 Safety of Ceftazidime/Avibactam 3.3.5 Role of Ceftazidime/Avibactam in Gram-Negative Bacteria Infections 3.4 Carbapenem/β-Lactamase Inhibitor Combinations 3.4.1 Meropenem/Vaborbactam 3.4.2 Antibacterial Activity of Meropenem/Vaborbactam 3.4.3 Resistance to Meropenem/Vaborbactam 3.4.4 Pharmacologic/Pharmacodynamic Aspects of Meropenem/Vaborbactam 3.4.5 Clinical Efficacy of Meropenem/Vaborbactam 3.4.6 Imipenem-Cilastatin/Relebactam 3.4.7 In Vitro Activity of Imipenem/Relebactam 3.4.8 Pharmacokinetics/Pharmacodynamics of Imipenem/Relebactam 3.4.9 Clinical Efficacy and Side Effects of Imipenem/Relebactam 3.4.10 Place in Therapy of Meropenem/Vaborbactam and Imipenem/Relebactam References Chapter 4: New Glycopeptides: Telavancin, Dalbavancin, and Oritavancin 4.1 Introduction 4.2 Mechanism of Action and Resistance Mechanism 4.3 Second-Generation Glycopeptides 4.3.1 Telavancin 4.3.2 Pharmacology/Pharmacokinetics of Telavancin 4.3.3 In Vitro Activity of Telavancin 4.3.4 Clinical Efficacy and Side Effects of Telavancin 4.3.5 Dalbavancin 4.3.6 Pharmacokinetics and Pharmacodynamics of Dalbavancin 4.3.7 In Vitro Activity of Dalbavancin 4.3.8 Clinical Efficacy and Safety of Dalbavancin 4.3.9 Off-Label Use of Dalbavancin 4.3.10 Oritavancin 4.3.11 Pharmacokinetics and Pharmacodynamics of Oritavancin 4.3.12 In Vitro Activity of Oritavancin 4.3.13 Clinical Efficacy of Oritavancin 4.3.14 Off-Label Use of Oritavancin 4.3.15 Comments References Chapter 5: A New Fluoroquinolone: Delafloxacin 5.1 Introduction 5.2 Pharmacology and Pharmacokinetics 5.3 Pharmacodynamics 5.4 In Vitro Activity 5.4.1 Microbial Resistance 5.5 Clinical Efficacy 5.6 Adverse Events 5.7 Role in Therapy References Chapter 6: New Oxazolidinone: Tedizolid 6.1 Introduction 6.2 Antimicrobial Activity 6.3 Mechanisms of Resistance 6.4 Pharmacology and Pharmacokinetics 6.5 Clinical Activity 6.5.1 Safety 6.6 Place in Therapy References Chapter 7: New Tetracyclines: Eravacycline and Omadacycline 7.1 Introduction 7.2 Eravacycline 7.3 Pharmacokinetics and Pharmacodynamics of Eravacycline 7.4 Microbial Activity of Eravacycline 7.5 Resistance Mechanisms Affecting Eravacycline 7.6 Clinical Efficacy and Safety of Eravacycline 7.7 Omadacycline 7.7.1 Pharmacokinetics and Pharmacodynamics of Omadacycline 7.8 Microbiologic Activity of Omadacycline 7.8.1 Resistance to Omadacycline 7.9 Clinical Efficacy and Safety of Omadacycline 7.10 Place in Therapy with the Modern Tetracyclines References Chapter 8: Pleuromutilin: A New Class of Antibiotic: Lefamulin 8.1 Introduction 8.2 Chemical Structure and Mechanism of Action 8.3 Antimicrobial Activity 8.4 Microbial Resistance to Lefamulin 8.5 Pharmacokinetics 8.6 Clinical Efficacy 8.7 Adverse Effects 8.8 Place in Therapy References Chapter 9: New Anti-tuberculous Drugs: Bedaquiline, Delamanid, and Pretomanid 9.1 Introduction 9.2 Bedaquiline 9.2.1 Microbial Activity of Bedaquiline 9.2.2 Resistance to Bedaquiline 9.3 Pharmacokinetics of Bedaquiline 9.3.1 Drug-Drug Interactions of Bedaquiline 9.3.2 Adverse Effects of Bedaquiline 9.3.3 Efficacy of Bedaquiline 9.4 Delamanid 9.4.1 In Vitro Activity of Delamanid 9.4.2 Resistance to Delamanid 9.4.3 Pharmacokinetics of Delamanid 9.4.4 Efficacy and Safety of Delamanid 9.5 Pretomanid 9.5.1 In Vitro Activity of Pretomanid 9.5.2 Resistance to Pretomanid 9.5.3 Pharmacology of Pretomanid 9.5.4 Clinical Efficacy and Safety of Pretomanid 9.6 Conclusion and Discussion References Part II: New Systemic Antifungal Agents Chapter 10: New Systemic Antifungal: Isavuconazole 10.1 Introduction 10.2 Isavuconazole 10.3 In Vitro Activity 10.4 Resistance to Isavuconazole 10.5 Pharmacology 10.6 Drug-Drug Interactions 10.7 Clinical Efficacy 10.7.1 Aspergillosis 10.7.2 Mucormycosis 10.7.3 Candidiasis 10.7.4 Other Fungal Infections 10.8 Safety 10.9 Conclusion References Part III: Anti-Parasitic Agents Chapter 11: Newly Approved Anti-parasitic Drugs for Malaria, Fascioliasis, Onchocerciasis, Chagas Disease, and African Trypanosomiasis 11.1 Introduction 11.2 Benznidazole 11.2.1 Chagas Disease 11.2.2 Treatment of Chagas Disease 11.2.3 Efficacy of Benznidazole 11.2.4 Adverse Effects of Benznidazole 11.3 Fexinidazole 11.3.1 African Trypanosomiasis 11.3.2 Treatment of African Trypanosomiasis 11.3.3 Pharmacology of Fexinidazole 11.3.4 Clinical Efficacy of Fexinidazole 11.3.5 Side Effects of Fexinidazole 11.4 Moxidectin 11.4.1 Onchocerciasis 11.4.2 Treatment of Onchocerciasis 11.4.3 Pharmacology of Moxidectin 11.4.4 Mechanism of Action of Moxidectin 11.4.5 Clinical Efficacy of Moxidectin 11.4.6 Adverse Effects of Moxidectin 11.5 Tafenoquine 11.5.1 Plasmodium vivax Malaria 11.5.2 Pharmacology of Tafenoquine 11.5.3 Antimalarial Activity of Tafenoquine 11.5.4 Clinical Efficacy of Tafenoquine 11.5.5 Safety of Tafenoquine 11.6 Triclabendazole 11.6.1 Human Fascioliasis 11.6.2 Triclabendazole for Fascioliasis 11.6.3 Pharmacology of Triclabendazole 11.6.4 Clinical Efficacy of Triclabendazole 11.6.5 Treatment Failure and Resistance to Triclabendazole 11.6.6 Safety of Triclabendazole 11.7 Conclusion References Part IV: New Antiviral Agents Chapter 12: New Antiretroviral Agents for HIV Infection 12.1 Introduction 12.2 Bictegravir/Emtricitabine/Tenofovir Alafenamide (Biktarvy) 12.2.1 Pharmacokinetics of Biktarvy (BIC/FTC/TAF) 12.2.2 Drug Interactions with Biktarvy (BIC/FTC/TAF) 12.2.3 Clinical Efficacy of Biktarvy (BIC/FTC/TAF) 12.2.4 Safety of Biktarvy (BIC/FTC/TAF) 12.2.5 Biktarvy Place in Management of HIV-1 12.3 Dovato (Dolutegravir/Lamivudine) 12.4 Pharmacokinetics of Dolutegravir/Lamivudine (Dovato) 12.5 Drug-Drug Interaction of Dovato (DTG/3TC) 12.6 Clinical Efficacy of Dovato (DTG/3TC) 12.6.1 Safety Issues of Dovato (DTG/3TC) 12.7 Conclusions on Dovato 12.8 Delstrigo (Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate) 12.8.1 Pharmacokinetics of Doravirine/Lamivudine/Tenofovir DF 12.8.2 Clinical Efficacy and Safety of Delstrigo (DOR/3TC/TDF) 12.8.3 Conclusion on Delstrigo (DOR/3TC/TDF) 12.9 Cabotegravir and Cabenuva (Cabotegravir/Rilpivirine) 12.9.1 Pharmacokinetics of Cabotegravir/Rilpivirine 12.9.2 Clinical Efficacy of Cabenuva (CAB-LA/RPV-LA) 12.9.3 Safety and Drug Interactions of Cabenuva (CAB/RPV) 12.9.4 Indication and Dosing of Cabenuva (CAB/RPV) 12.9.5 Cabotegravir for Prevention of HIV 12.9.6 Conclusion on Cabotegravir and Cabenuva 12.10 Ibalizumab-uiyk (Trogarzo) 12.10.1 Pharmacodynamics and Antiviral Activity of Ibalizumab 12.10.2 Resistance to Ibalizumab 12.10.3 Pharmacokinetics of Ibalizumab 12.10.4 Efficacy of Ibalizumab 12.10.5 Safety of Ibalizumab 12.10.6 Conclusion on Ibalizumab 12.11 Fostemsavir 12.11.1 Pharmacokinetics of Fostemsavir 12.11.2 Clinical Data on Fostemsavir 12.11.3 Safety of Fostemsavir 12.11.4 Conclusion on Fostemsavir References Chapter 13: New Antiviral Agents for Cytomegalovirus Diseases 13.1 Introduction 13.2 Letermovir 13.2.1 Pharmacokinetics of Letermovir 13.2.2 Drug Interactions of Letermovir 13.2.3 Clinical Efficacy of Letermovir 13.2.4 Safety of Letermovir 13.2.5 Letermovir Resistance 13.2.6 Conclusion on Letermovir 13.2.7 Maribavir for the Treatment of Cytomegalovirus Infection 13.2.8 Pharmacokinetics of Maribavir 13.2.9 Clinical Efficacy of Maribavir 13.2.9.1 Prophylactic Trials 13.2.9.2 Preemptive Trials 13.2.9.3 Maribavir for Resistant or Refractory CMV Infections 13.2.9.4 Safety of Maribavir 13.2.10 Resistance to Maribavir 13.2.11 Conclusion on Maribavir References Chapter 14: New Antiviral Agent for Influenza: Baloxavir 14.1 Introduction 14.2 Established Antivirals for Influenza Therapy 14.3 Baloxavir a Novel Anti-Influenza Agent 14.4 Pharmacokinetics of Baloxavir 14.5 Drug-Drug Interactions of Baloxavir 14.6 Clinical Efficacy of Baloxavir 14.7 Viral Resistance to Baloxavir 14.8 Role of Baloxavir in Influenza Treatment References Chapter 15: Direct Antiviral Agents for Hepatitis C 15.1 Introduction 15.2 Treatment of Hepatitis C 15.3 Combinations of Direct Antiviral Agents for Hepatitis C 15.3.1 Ledipasvir/Sofosbuvir 15.3.2 Efficacy and Indication of Ledipasvir/Sofosbuvir 15.3.3 Side Effects and Drug-Drug Interaction of Ledipasvir/Sofosbuvir 15.3.4 Resistance to Ledipasvir/Sofosbuvir 15.3.5 Elbasvir/Grazoprevir 15.3.6 Drug Interactions of Elbasvir/Grazoprevir 15.3.7 Clinical Efficacy of Elbasvir/Grazoprevir 15.3.8 Adverse Effects of Elbasvir/Grazoprevir 15.3.9 Resistance to Elbasvir/Grazoprevir 15.3.10 Sofosbuvir/Velpatasvir 15.3.11 Drug Interactions of Sofosbuvir/Velpatasvir 15.3.12 Efficacy of Sofosbuvir/Velpatasvir 15.3.13 Safety of Sofosbuvir/Velpatasvir 15.3.14 Resistance to Sofosbuvir/Velpatasvir 15.3.15 Glecaprevir/Pibrentasvir 15.3.16 Drug Interactions of Glecaprevir/Pibrentasvir 15.3.17 Efficacy of Glecaprevir/Pibrentasvir 15.3.18 Adverse Effects of Glecaprevir/Pibrentasvir 15.3.19 Resistance to Glecaprevir/Pibrentasvir 15.3.20 Sofosbuvir/Velpatasvir/Voxilaprevir 15.3.21 Drug Interactions of Sofosbuvir/Velpatasvir/Voxilaprevir 15.3.22 Clinical Efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir 15.3.23 Safety of Sofosbuvir/Velpatasvir/Voxilaprevir 15.3.24 Resistance to Sofosbuvir/Velpatasvir/Voxilaprevir 15.3.25 Summary References Chapter 16: Antiviral Drugs for SARS-CoV-2 and COVID-19 16.1 Introduction 16.2 Coronaviruses 16.3 Antiviral Drugs for SARS-CoV 16.4 Remdesivir 16.4.1 Animal Studies 16.4.2 Clinical Data on Remdesivir 16.4.3 Side Effects and Drug Interactions of Remdesivir 16.4.4 SARS-CoV-2 Resistance to Remdesivir 16.4.5 Molnupiravir 16.4.6 Animal Studies with Molnupiravir 16.4.7 Clinical Efficacy of Molnupiravir 16.4.8 Safety of Molnupiravir 16.4.9 Resistance to Molnupiravir 16.4.10 Nirmatrelvir/Ritonavir 16.4.11 Drug-Drug Interactions of Nirmatrelvir/Ritonavir 16.4.12 Animal Models Treated with Nirmatrelvir/Ritonavir 16.4.13 Clinical Efficacy of Nirmatrelvir/Ritonavir 16.4.14 Side Effects of Nirmatrelvir/Ritonavir 16.4.15 Rebound of COVID-19 after Antiviral Treatment 16.4.16 Resistance to Nirmatrelvir 16.5 Summary and Comments of Antiviral Agents for COVID-19 References Part V: Future Antimicrobials Chapter 17: New Promising Antimicrobials in Development and Novel Approaches for Treatment of Infections 17.1 Introduction 17.2 New Antibiotics in Development 17.3 Traditional Antibiotics in Phase 3 Trials Against WHO Priority Pathogens 17.3.1 New Antibiotic Being Developed in Phase 1 and 2 Trials 17.3.2 New Traditional Antibacterial Agents in Phase 1/2 Trials for Mycobacteria Tuberculosis and Nontuberculous Mycobacteria 17.4 Nontraditional Antibacterial Agents in Phase 3 Trials 17.4.1 Nontraditional Antibacterial Agents in Phase 1 and 2 17.5 New Antifungal Agents in Development 17.5.1 Derivatives of Existing Class of Antifungals 17.5.2 Novel Antifungal Agents 17.6 New Anti-Parasitic Agents in Development 17.6.1 New Antimalarial Agents in Development 17.7 New Antivirals in Development 17.7.1 New Antivirals for HIV 17.7.2 New Antivirals for Chronic Hepatitis B 17.8 Summary of New Antimicrobial Agents in Development References Index